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Zhang J, Chen X, Chai Y, Jin Y, Li F, Zhuo C, Xu Y, Wang H, Ju E, Lao YH, Xie X, Li M, Tao Y. Mesenchymal stromal/stem cell spheroid-derived extracellular vesicles advance the therapeutic efficacy of 3D-printed vascularized artificial liver lobules in liver failure treatment. Bioact Mater 2025; 49:121-139. [PMID: 40124595 PMCID: PMC11930233 DOI: 10.1016/j.bioactmat.2025.02.042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 02/25/2025] [Accepted: 02/25/2025] [Indexed: 03/25/2025] Open
Abstract
Acute liver failure (ALF) is a highly lethal condition characterized by massive tissue necrosis, excessive oxidative stress, and serious inflammatory storms, necessitating prompt medical intervention. Although hepatocyte-like cells (HLCs) derived from mesenchymal stromal/stem cells (MSCs) offer a promising alternative cell source for hepatocyte therapy, their low in-vivo integration and differentiation efficiency may compromise the eventual therapeutic efficacy. To this end, MSCs are bioengineered into multicellular spheroids in the present study. The proteomic analyses and experimental results reveal that extracellular vesicles (EVs) derived from these MSC spheroids (SpEV) contain abundant highly expressed bioactive proteins and can be efficiently endocytosed by recipient cells, resulting in enhanced pro-angiogenic and antioxidative effects. In addition, MSC spheroids exhibit superior hepatic cell differentiation compared to an equivalent number of dissociated single MSCs, particularly when being co-cultured with hexagonally patterned endothelial cells in a liver lobule-like arrangement. Following orthotopic implantation in the mouse model, the enhanced paracrine effects of SpEV, combined with an immunoregulatory decellularized extracellular matrix hydrogel carrier and functional artificial liver lobules (ALL), synergically contribute to the effective amelioration of ALF, highlighting the substantial potential for clinical translation.
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Affiliation(s)
- Jiabin Zhang
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Xiaodie Chen
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yurong Chai
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yuanyuan Jin
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Fenfang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Chenya Zhuo
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yanteng Xu
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Haixia Wang
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Enguo Ju
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
| | - Yeh-Hsing Lao
- Department of Pharmaceutical Sciences, University at Buffalo, The State University of New York, Buffalo, NY, 14214, USA
| | - Xi Xie
- State Key Laboratory of Optoelectronic Materials and Technologies, Guangdong Province Key Laboratory of Display Material and Technology, School of Electronics and Information Technology, Sun Yat-sen University, Guangzhou, 510006, China
| | - Mingqiang Li
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
- Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-Sen University, Guangzhou, 510275, China
| | - Yu Tao
- Laboratory of Biomaterials and Translational Medicine, Center for Nanomedicine, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510630, China
- Key Laboratory for Polymeric Composite and Functional Materials of Ministry of Education, Sun Yat-Sen University, Guangzhou, 510275, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, 510630, China
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Yuan M, Shi M, Yang H, Ashraf S, Iqbal S, Turkez H, Boren J, Zhang C, Uhlén M, Altay O, Mardinoglu A. Targeting PKLR in liver diseases. Trends Endocrinol Metab 2025:S1043-2760(25)00054-2. [PMID: 40221236 DOI: 10.1016/j.tem.2025.03.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2024] [Revised: 03/11/2025] [Accepted: 03/17/2025] [Indexed: 04/14/2025]
Abstract
Pyruvate kinase is a key regulator in hepatic glucose metabolism, encoded by the gene pyruvate kinase liver/red blood cells (PKLR). Systems biology-based approaches, including metabolic and gene co-expression networks analyses, as well as genome-wide association studies (GWAS), have led to the identification of PKLR as a pivotal gene influencing liver metabolism in patients with metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma (HCC). Here, we review the critical role of PKLR in MASLD and HCC progression and examine the effects of PKLR modulation both in vitro and in vivo. We also discuss the development of therapeutic strategies for patients with MASLD and HCC by modulating PKLR, highlighting its promising future in a broader range of liver diseases.
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Affiliation(s)
- Meng Yuan
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, SE-17165, Sweden
| | - Mengnan Shi
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, SE-17165, Sweden
| | - Hong Yang
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, SE-17165, Sweden
| | - Sajda Ashraf
- Trustlife Laboratories, Drug Research & Development Center, 34774, Istanbul, Turkey
| | - Shazia Iqbal
- Trustlife Laboratories, Drug Research & Development Center, 34774, Istanbul, Turkey
| | - Hasan Turkez
- Medical Biology Department, Faculty of Medicine, Atatürk University, Erzurum TR-25240, Turkey
| | - Jan Boren
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Cheng Zhang
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, SE-17165, Sweden; Institute of Liver Studies, King's College London, London, SE5 8AF, UK
| | - Mathias Uhlén
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, SE-17165, Sweden
| | - Ozlem Altay
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, SE-17165, Sweden.
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm, SE-17165, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK.
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3
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El Hafi M, Bouzian Y, Parvizi N, Kim W, Subaşioğlu M, Ozcan M, Turkez H, Mardinoglu A. Synthesis and biological assessment of BUB1B inhibitors for the treatment of clear cell renal cell carcinoma. Eur J Med Chem 2025; 285:117247. [PMID: 39818011 DOI: 10.1016/j.ejmech.2025.117247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Revised: 12/28/2024] [Accepted: 01/04/2025] [Indexed: 01/18/2025]
Abstract
Clear cell renal cell carcinoma (ccRCC) presents substantial therapeutic challenges due to its molecular heterogeneity, limited response to conventional therapies, and widespread drug resistance. Recent advancements in molecular research have identified novel targets, such as BUB1B, which has been identified through global transcriptomic profiling and gene co-expression network analysis as critical in ccRCC progression. In this study, we synthesized 40 novel derivatives of TG-101209 to modulate BUB1B expression and activity, leading to the induction of apoptosis in Caki-1 cells. The molecular structures of all compounds were confirmed via 1H and 13C NMR and mass spectrometry. Computational docking studies were conducted using Schrödinger Maestro software. The efficacy of the compounds on cell viability was screened using the MTT assay and further validated by the LDH assay. The expression of the target protein BUB1B and apoptosis-related proteins was analyzed via western blotting. BUB1B activity was assessed through an enzymatic assay, and compound binding efficacy was evaluated using a cellular thermal shift assay (CETSA). The results indicated that four compounds (7h, 8h, 8i, and 8j) demonstrate stronger molecular interactions and better conformational fit within the target cavity, leading to improved binding affinity. These compounds also exhibited more potency in reducing the viability of Caki-1 cells compared to TG-101209. In particular, compound 8h was identified as the most effective, exhibiting the strongest inhibitory effect on BUB1B and inducing apoptosis. Compound 8h demonstrated intracellular binding with BUB1B, similar to TG-101209, but through a different binding moiety that destabilizes the BUB1B protein structure, whereas TG-101209 stabilizes it. In conclusion, compound 8h, by destabilizing BUB1B and inducing apoptosis, shows promise as a potent therapeutic candidate for clear cell renal cell carcinoma (ccRCC) treatment.
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Affiliation(s)
- Mohamed El Hafi
- Trustlife Labs Drug Research & Development Center, 34774, Istanbul, Turkey; Faculty of Medicine and Pharmacy, Mohammed First University, Oujda, Morocco
| | - Younos Bouzian
- Trustlife Labs Drug Research & Development Center, 34774, Istanbul, Turkey
| | - Negar Parvizi
- Trustlife Labs Drug Research & Development Center, 34774, Istanbul, Turkey
| | - Woonghee Kim
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE, 17165, Sweden
| | - Mine Subaşioğlu
- Trustlife Labs Drug Research & Development Center, 34774, Istanbul, Turkey
| | - Mehmet Ozcan
- Department of Medical Biochemistry, Faculty of Medicine, Zonguldak Bulent Ecevit University, Zonguldak, Turkey
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, SE, 17165, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, UK.
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Yang H, Atak D, Yuan M, Li M, Altay O, Demirtas E, Peltek IB, Ulukan B, Yigit B, Sipahioglu T, Álvez MB, Meng L, Yüksel B, Turkez H, Kirimlioglu H, Saka B, Yurdaydin C, Akyildiz M, Dayangac M, Uhlen M, Boren J, Zhang C, Mardinoglu A, Zeybel M. Integrative proteo-transcriptomic characterization of advanced fibrosis in chronic liver disease across etiologies. Cell Rep Med 2025; 6:101935. [PMID: 39889710 PMCID: PMC11866494 DOI: 10.1016/j.xcrm.2025.101935] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 09/20/2024] [Accepted: 01/08/2025] [Indexed: 02/03/2025]
Abstract
Chronic hepatic injury and inflammation from various causes can lead to fibrosis and cirrhosis, potentially predisposing to hepatocellular carcinoma. The molecular mechanisms underlying fibrosis and its progression remain incompletely understood. Using a proteo-transcriptomics approach, we analyze liver and plasma samples from 330 individuals, including 40 healthy individuals and 290 patients with histologically characterized fibrosis due to chronic viral infection, alcohol consumption, or metabolic dysfunction-associated steatotic liver disease. Our findings reveal dysregulated pathways related to extracellular matrix, immune response, inflammation, and metabolism in advanced fibrosis. We also identify 132 circulating proteins associated with advanced fibrosis, with neurofascin and growth differentiation factor 15 demonstrating superior predictive performance for advanced fibrosis(area under the receiver operating characteristic curve [AUROC] 0.89 [95% confidence interval (CI) 0.81-0.97]) compared to the fibrosis-4 model (AUROC 0.85 [95% CI 0.78-0.93]). These findings provide insights into fibrosis pathogenesis and highlight the potential for more accurate non-invasive diagnosis.
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Affiliation(s)
- Hong Yang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Dila Atak
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, İstanbul 34010, Turkiye
| | - Meng Yuan
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Mengzhen Li
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Ozlem Altay
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Elif Demirtas
- School of Medicine, Koç University, Istanbul 34450, Turkiye
| | | | - Burge Ulukan
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, İstanbul 34010, Turkiye
| | - Buket Yigit
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, İstanbul 34010, Turkiye
| | - Tarik Sipahioglu
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, İstanbul 34010, Turkiye
| | - María Bueno Álvez
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Lingqi Meng
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | | | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkiye
| | - Hale Kirimlioglu
- Department of Pathology, School of Medicine, Acibadem Mehmet Ali Aydinlar University Istanbul 34752, Turkiye
| | - Burcu Saka
- Department of Pathology, School of Medicine, Koç University, Istanbul 34010, Turkiye
| | - Cihan Yurdaydin
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, İstanbul 34010, Turkiye
| | - Murat Akyildiz
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, İstanbul 34010, Turkiye
| | - Murat Dayangac
- Department of General Surgery, International School of Medicine, Medipol University, Istanbul 34010, Turkiye
| | - Mathias Uhlen
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Jan Boren
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Cheng Zhang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK.
| | - Mujdat Zeybel
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, İstanbul 34010, Turkiye; Clinical Trials Unit, Koç University Hospital, Istanbul 34010, Turkiye.
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Yang H, Zhang C, Kim W, Shi M, Kiliclioglu M, Bayram C, Bolar I, Tozlu ÖÖ, Baba C, Yuksel N, Yildirim S, Iqbal S, Sebhaoui J, Hacımuftuoglu A, Uhlen M, Boren J, Turkez H, Mardinoglu A. Multi-tissue network analysis reveals the effect of JNK inhibition on dietary sucrose-induced metabolic dysfunction in rats. eLife 2025; 13:RP98427. [PMID: 39932177 PMCID: PMC11813226 DOI: 10.7554/elife.98427] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/13/2025] Open
Abstract
Excessive consumption of sucrose, in the form of sugar-sweetened beverages, has been implicated in the pathogenesis of metabolic dysfunction-associated fatty liver disease (MAFLD) and other related metabolic syndromes. The c-Jun N-terminal kinase (JNK) pathway plays a crucial role in response to dietary stressors, and it was demonstrated that the inhibition of the JNK pathway could potentially be used in the treatment of MAFLD. However, the intricate mechanisms underlying these interventions remain incompletely understood given their multifaceted effects across multiple tissues. In this study, we challenged rats with sucrose-sweetened water and investigated the potential effects of JNK inhibition by employing network analysis based on the transcriptome profiling obtained from hepatic and extrahepatic tissues, including visceral white adipose tissue, skeletal muscle, and brain. Our data demonstrate that JNK inhibition by JNK-IN-5A effectively reduces the circulating triglyceride accumulation and inflammation in rats subjected to sucrose consumption. Coexpression analysis and genome-scale metabolic modeling reveal that sucrose overconsumption primarily induces transcriptional dysfunction related to fatty acid and oxidative metabolism in the liver and adipose tissues, which are largely rectified after JNK inhibition at a clinically relevant dose. Skeletal muscle exhibited minimal transcriptional changes to sucrose overconsumption but underwent substantial metabolic adaptation following the JNK inhibition. Overall, our data provides novel insights into the molecular basis by which JNK inhibition exerts its metabolic effect in the metabolically active tissues. Furthermore, our findings underpin the critical role of extrahepatic metabolism in the development of diet-induced steatosis, offering valuable guidance for future studies focused on JNK-targeting for effective treatment of MAFLD.
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Affiliation(s)
- Hong Yang
- Science for Life Laboratory, KTH Royal Institute of TechnologyStockholmSweden
| | - Cheng Zhang
- Science for Life Laboratory, KTH Royal Institute of TechnologyStockholmSweden
| | - Woonghee Kim
- Science for Life Laboratory, KTH Royal Institute of TechnologyStockholmSweden
| | - Mengnan Shi
- Science for Life Laboratory, KTH Royal Institute of TechnologyStockholmSweden
| | - Metin Kiliclioglu
- Department of Pathology, Veterinary Faculty, Atatürk UniversityErzurumTurkiye
| | - Cemil Bayram
- Department of Medical Pharmacology, Faculty of Medicine, Atatürk UniversityErzurumTurkiye
| | - Ismail Bolar
- Department of Pathology, Veterinary Faculty, Atatürk UniversityErzurumTurkiye
| | - Özlem Özdemir Tozlu
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical UniversityErzurumTurkiye
| | - Cem Baba
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical UniversityErzurumTurkiye
| | - Nursena Yuksel
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical UniversityErzurumTurkiye
| | - Serkan Yildirim
- Department of Pathology, Veterinary Faculty, Atatürk UniversityErzurumTurkiye
- Department of Pathology, Faculty of Veterinary Medicine, Kyrgyz-Türkish Manas ÜniversityBishkekKyrgyzstan
| | - Shazia Iqbal
- Trustlife Labs Drug Research and Development CenterIstanbulTurkiye
| | - Jihad Sebhaoui
- Trustlife Labs Drug Research and Development CenterIstanbulTurkiye
| | - Ahmet Hacımuftuoglu
- Department of Medical Pharmacology, Faculty of Medicine, Atatürk UniversityErzurumTurkiye
| | - Matthias Uhlen
- Science for Life Laboratory, KTH Royal Institute of TechnologyStockholmSweden
| | - Jan Boren
- Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University HospitalGothenburgSweden
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk UniversityErzurumTurkiye
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH Royal Institute of TechnologyStockholmSweden
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College LondonLondonUnited Kingdom
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Mardinoglu A, Palsson BØ. Genome-scale models in human metabologenomics. Nat Rev Genet 2025; 26:123-140. [PMID: 39300314 DOI: 10.1038/s41576-024-00768-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/29/2024] [Indexed: 09/22/2024]
Abstract
Metabologenomics integrates metabolomics with other omics data types to comprehensively study the genetic and environmental factors that influence metabolism. These multi-omics data can be incorporated into genome-scale metabolic models (GEMs), which are highly curated knowledge bases that explicitly account for genes, transcripts, proteins and metabolites. By including all known biochemical reactions catalysed by enzymes and transporters encoded in the human genome, GEMs analyse and predict the behaviour of complex metabolic networks. Continued advancements to the scale and scope of GEMs - from cells and tissues to microbiomes and the whole body - have helped to design effective treatments and develop better diagnostic tools for metabolic diseases. Furthermore, increasing amounts of multi-omics data are incorporated into GEMs to better identify the underlying mechanisms, biomarkers and potential drug targets of metabolic diseases.
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Affiliation(s)
- Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, UK.
| | - Bernhard Ø Palsson
- Bioinformatics and Systems Biology Program, University of California, San Diego, La Jolla, CA, USA.
- Department of Bioengineering, University of California, San Diego, La Jolla, CA, USA.
- Department of Paediatrics, University of California, San Diego, La Jolla, CA, USA.
- Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA, USA.
- Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, Kongens Lyngby, Denmark.
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Yulug B, Altay O, Li X, Hanoglu L, Cankaya S, Velioglu HA, Lam S, Yang H, Coskun E, Idil E, Bayraktaroglu Z, Nogaylar R, Ozsimsek A, Yildirim S, Bolat I, Kiliclioglu M, Bayram C, Yuksel N, Tozlu OO, Arif M, Shoaie S, Hacimuftuoglu A, Zhang C, Nielsen J, Turkez H, Borén J, Uhlén M, Mardinoglu A. Multi-omics characterization of improved cognitive functions in Parkinson's disease patients after the combined metabolic activator treatment: a randomized, double-blinded, placebo-controlled phase II trial. Brain Commun 2025; 7:fcae478. [PMID: 39816194 PMCID: PMC11733689 DOI: 10.1093/braincomms/fcae478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 11/07/2024] [Accepted: 01/03/2025] [Indexed: 01/18/2025] Open
Abstract
Parkinson's disease is primarily marked by mitochondrial dysfunction and metabolic abnormalities. We recently reported that the combined metabolic activators improved the immunohistochemical parameters and behavioural functions in Parkinson's disease and Alzheimer's disease animal models and the cognitive functions in Alzheimer's disease patients. These metabolic activators serve as the precursors of nicotinamide adenine dinucleotide and glutathione, and they can be used to activate mitochondrial metabolism and eventually treat mitochondrial dysfunction. Here, we designed a randomized, double-blinded, placebo-controlled phase II study in Parkinson's disease patients with 84 days combined metabolic activator administration. A single dose of combined metabolic activator contains L-serine (12.35 g), N-acetyl-L-cysteine (2.55 g), nicotinamide riboside (1 g) and L-carnitine tartrate (3.73 g). Patients were administered either one dose of combined metabolic activator or a placebo daily for the initial 28 days, followed by twice-daily dosing for the next 56 days. The main goal of the study was to evaluate the clinical impact on motor functions using the Unified Parkinson's Disease Rating Scale and to determine the safety and tolerability of combined metabolic activator. A secondary objective was to assess cognitive functions utilizing the Montreal Cognitive Assessment and to analyse brain activity through functional MRI. We also performed comprehensive plasma metabolomics and proteomics analysis for detailed characterization of Parkinson's disease patients who participated in the study. Although no improvement in motor functions was observed, cognitive function was shown to be significantly improved (P < 0.0000) in Parkinson's disease patients treated with the combined metabolic activator group over 84 days, whereas no such improvement was noted in the placebo group (P > 0.05). Moreover, a significant reduction (P = 0.001) in Montreal Cognitive Assessment scores was observed in the combined metabolic activator group, with no decline (P > 0.05) in the placebo group among severe Parkinson's disease patients with lower baseline Montreal Cognitive Assessment scores. We showed that improvement in cognition was associated with critical brain network alterations based on functional MRI analysis, especially relevant to areas with cognitive functions in the brain. Finally, through a comprehensive multi-omics analysis, we elucidated the molecular mechanisms underlying cognitive improvements observed in Parkinson's disease patients. Our results show that combined metabolic activator administration leads to enhanced cognitive function and improved metabolic health in Parkinson's disease patients as recently shown in Alzheimer's disease patients. The trial was registered in ClinicalTrials.gov NCT04044131 (17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131).
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Affiliation(s)
- Burak Yulug
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya 07070, Turkey
| | - Ozlem Altay
- Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden
| | - Xiangyu Li
- Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden
| | - Lutfu Hanoglu
- Department of Neurology, Faculty of Medicine, Istanbul Medipol University, Istanbul 34815, Turkey
| | - Seyda Cankaya
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya 07070, Turkey
| | - Halil A Velioglu
- Department of Women’s and Children’s Health, Karolinska Institute, Neuroimaging Lab, Stockholm 17177, Sweden
- Functional Imaging and Cognitive-Affective Neuroscience Lab, Istanbul Medipol University, Istanbul 34815, Turkey
| | - Simon Lam
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London WC2R 2LS, UK
| | - Hong Yang
- Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden
| | - Ebru Coskun
- Department of Neurology, Faculty of Medicine, Istanbul Medipol University, Istanbul 34815, Turkey
| | - Ezgi Idil
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya 07070, Turkey
| | - Zubeyir Bayraktaroglu
- Functional Imaging and Cognitive-Affective Neuroscience Lab, Istanbul Medipol University, Istanbul 34815, Turkey
| | - Rahim Nogaylar
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya 07070, Turkey
| | - Ahmet Ozsimsek
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya 07070, Turkey
| | - Serkan Yildirim
- Department of Pathology, Faculty of Veterinary, Atatürk University, Erzurum 25240, Turkey
| | - Ismail Bolat
- Department of Pathology, Faculty of Veterinary, Atatürk University, Erzurum 25240, Turkey
| | - Metin Kiliclioglu
- Department of Pathology, Faculty of Veterinary, Atatürk University, Erzurum 25240, Turkey
| | - Cemil Bayram
- Department of Medical Pharmacology, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey
| | - Nursena Yuksel
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum 25050, Turkey
| | - Ozlem O Tozlu
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum 25050, Turkey
| | - Muhammad Arif
- Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden
| | - Saeed Shoaie
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London WC2R 2LS, UK
| | - Ahmet Hacimuftuoglu
- Department of Pathology, Faculty of Veterinary, Atatürk University, Erzurum 25240, Turkey
| | - Cheng Zhang
- Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden
| | - Jens Nielsen
- BioInnovation Institute, Copenhagen DK-2200, Denmark
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey
| | - Jan Borén
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg 41345, Sweden
| | - Mathias Uhlén
- Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH—Royal Institute of Technology, Stockholm 17165, Sweden
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London WC2R 2LS, UK
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Kaynar A, Kim W, Ceyhan AB, Zhang C, Uhlén M, Turkez H, Shoaie S, Mardinoglu A. Unveiling the Molecular Mechanisms of Glioblastoma through an Integrated Network-Based Approach. Biomedicines 2024; 12:2237. [PMID: 39457550 PMCID: PMC11504402 DOI: 10.3390/biomedicines12102237] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 09/23/2024] [Accepted: 09/27/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: Despite current treatments extending the lifespan of Glioblastoma (GBM) patients, the average survival time is around 15-18 months, underscoring the fatality of GBM. This study aims to investigate the impact of sample heterogeneity on gene expression in GBM, identify key metabolic pathways and gene modules, and explore potential therapeutic targets. Methods: In this study, we analysed GBM transcriptome data derived from The Cancer Genome Atlas (TCGA) using genome-scale metabolic models (GEMs) and co-expression networks. We examine transcriptome data incorporating tumour purity scores (TPSs), allowing us to assess the impact of sample heterogeneity on gene expression profiles. We analysed the metabolic profile of GBM by generating condition-specific GEMs based on the TPS group. Results: Our findings revealed that over 90% of genes showing brain and glioma specificity in RNA expression demonstrate a high positive correlation, underscoring their expression is dominated by glioma cells. Conversely, negatively correlated genes are strongly associated with immune responses, indicating a complex interaction between glioma and immune pathways and non-tumorigenic cell dominance on gene expression. TPS-based metabolic profile analysis was supported by reporter metabolite analysis, highlighting several metabolic pathways, including arachidonic acid, kynurenine and NAD pathway. Through co-expression network analysis, we identified modules that significantly overlap with TPS-correlated genes. Notably, SOX11 and GSX1 are upregulated in High TPS, show a high correlation with TPS, and emerged as promising therapeutic targets. Additionally, NCAM1 exhibits a high centrality score within the co-expression module, which shows a positive correlation with TPS. Moreover, LILRB4, an immune-related gene expressed in the brain, showed a negative correlation and upregulated in Low TPS, highlighting the importance of modulating immune responses in the GBM mechanism. Conclusions: Our study uncovers sample heterogeneity's impact on gene expression and the molecular mechanisms driving GBM, and it identifies potential therapeutic targets for developing effective treatments for GBM patients.
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Affiliation(s)
- Ali Kaynar
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.K.); (A.B.C.); (S.S.)
| | - Woonghee Kim
- Science for Life Laboratory, KTH-Royal Institute of Technology, 171211 Stockholm, Sweden; (W.K.); (C.Z.); (M.U.)
| | - Atakan Burak Ceyhan
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.K.); (A.B.C.); (S.S.)
| | - Cheng Zhang
- Science for Life Laboratory, KTH-Royal Institute of Technology, 171211 Stockholm, Sweden; (W.K.); (C.Z.); (M.U.)
| | - Mathias Uhlén
- Science for Life Laboratory, KTH-Royal Institute of Technology, 171211 Stockholm, Sweden; (W.K.); (C.Z.); (M.U.)
| | - Hasan Turkez
- Medical Biology Department, Faculty of Medicine, Atatürk University, Erzurum 25240, Türkiye;
| | - Saeed Shoaie
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.K.); (A.B.C.); (S.S.)
- Science for Life Laboratory, KTH-Royal Institute of Technology, 171211 Stockholm, Sweden; (W.K.); (C.Z.); (M.U.)
| | - Adil Mardinoglu
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.K.); (A.B.C.); (S.S.)
- Science for Life Laboratory, KTH-Royal Institute of Technology, 171211 Stockholm, Sweden; (W.K.); (C.Z.); (M.U.)
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9
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Bouzian Y, El Hafi M, Parvizi N, Kim W, Subaşioğlu M, Ozcan M, Turkez H, Mardinoglu A. Design and evaluation of novel inhibitors for the treatment of clear cell renal cell carcinoma. Bioorg Chem 2024; 151:107597. [PMID: 39002511 DOI: 10.1016/j.bioorg.2024.107597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2024] [Revised: 06/23/2024] [Accepted: 06/25/2024] [Indexed: 07/15/2024]
Abstract
The efficacy of conventional chemotherapies in treating clear cell renal cell carcinoma (ccRCC) is often limited due to its high molecular diversity, generally low response rates to standard treatments, and prevalent drug resistance. Recent advancements in the molecular understanding of ccRCC, alongside the discovery of novel therapeutic agents targeting specific proteins, have significantly altered the treatment landscape for ccRCC. Here, we synthesized 27 new compounds that are derivatives of TG-101209 to modulate BUB1B (BUB1 mitotic checkpoint serine/threonine kinase B). BUB1B has been recently identified as a drug target for the development of effective ccRCC treatment based on global transcriptomics profiling of ccRCC tumours and gene co-expression network analysis. We characterized the molecular structures of these 27 compounds by 1H and 13C NMR and Mass spectrometry. We evaluated the effect of these 27 compounds by analysing the modulation of the BUB1B expression. Our primary objective was to design and assess the efficacy of these new compounds in reducing the viability of Caki-1 cells, a ccRCC cell line. We performed the computational docking studies by the Schrödinger Maestro software and demonstrated that three of these compounds (13a, 5i, and 5j) effectively downregulated BUB1B expression and eventually triggered necrosis and apoptosis in the Caki-1 cell line based on the structure-activity relationship (SAR) analysis. The IC50 values for compounds 13a, 5i, and 5j were calculated as 2.047 µM, 10.046 µM, and 6.985 µM, respectively, indicating their potent inhibitory effects on cell viability. Our study suggests that these compounds targeting BUB1B could offer a more effective and promising approach for ccRCC treatment compared to the conventionally used tyrosine kinase inhibitors. Our study underscores the potential of leveraging targeted therapies against specific molecular pathways in ccRCC may open new avenues for the development of effective treatment strategies against ccRCC.
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Affiliation(s)
- Younos Bouzian
- Trustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye
| | - Mohamed El Hafi
- Faculty of Medicine and Pharmacy, Mohammed First University, Oujda, Morocco
| | - Negar Parvizi
- Trustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye
| | - Woonghee Kim
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm SE-17165, Sweden
| | - Mine Subaşioğlu
- Trustlife Labs Drug Research & Development Center, 34774 Istanbul, Turkiye
| | - Mehmet Ozcan
- Department of Medical Biochemistry, Faculty of Medicine, Zonguldak Bulent Ecevit University, Zonguldak, Turkey
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm SE-17165, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK.
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10
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Ambikan A, Akusjärvi SS, Sperk M, Neogi U. System-level integrative omics analysis to identify the virus-host immunometabolic footprint during infection. Adv Immunol 2024; 164:73-100. [PMID: 39523029 DOI: 10.1016/bs.ai.2024.08.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2024]
Abstract
The emergence and re-emergence of infectious diseases present significant global health threats. Understanding their pathogenesis is crucial for developing diagnostics, therapeutics, and preventive strategies. System-level integrative omics analysis offers a comprehensive approach to deciphering virus-host immunometabolic interactions during infections. Multi-omics approaches, integrating genomics, transcriptomics, proteomics, and metabolomics, provide holistic insights into disease mechanisms, host-pathogen interactions, and immune responses. The interplay between the immune system and metabolic processes, termed immunometabolism, has gained attention, particularly in infectious diseases. Immunometabolic studies reveal how metabolic processes regulate immune cell function, shaping immune responses and influencing infection outcomes. Metabolic reprogramming is crucial for immune cell activation, differentiation, and function. Using systems biological algorithms to understand the immunometabolic alterations can provide a holistic view of immune and metabolic pathway interactions, identifying regulatory nodes and predicting responses to perturbations. Understanding these pathways enhances the knowledge of immune regulation and offers avenues for therapeutic interventions. This review highlights the contributions of multi-omics systems biology studies in understanding infectious disease pathogenesis, focusing on RNA viruses. The integrative approach enables personalized medicine strategies, considering individual metabolic and immune variations. Leveraging these interdisciplinary approaches promises advancements in combating RNA virus infections and improving health outcomes, highlighting the transformative impact of multi-omics technologies in infectious disease research.
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Affiliation(s)
- Anoop Ambikan
- The Systems Virology Laboratory, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, ANA Futura, Campus Flemingsberg, Stockholm, Sweden
| | - Sara Svensson Akusjärvi
- The Systems Virology Laboratory, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, ANA Futura, Campus Flemingsberg, Stockholm, Sweden; Harvard Medical School, Division of Immunology, Boston Children's Hospital, Boston, MA, United States
| | - Maike Sperk
- The Systems Virology Laboratory, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, ANA Futura, Campus Flemingsberg, Stockholm, Sweden; Public Health Agency of Sweden, Solna, Sweden
| | - Ujjwal Neogi
- The Systems Virology Laboratory, Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, ANA Futura, Campus Flemingsberg, Stockholm, Sweden.
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11
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Xu Z, Amakye WK, Ren Z, Xu Y, Liu W, Gong C, Wong C, Gao L, Zhao Z, Wang M, Yan T, Ye Z, Zhong J, Hou C, Zhao M, Qiu C, Tan J, Xu X, Liu G, Yao M, Ren J. Soy Peptide Supplementation Mitigates Undernutrition through Reprogramming Hepatic Metabolism in a Novel Undernourished Non-Human Primate Model. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2306890. [PMID: 38816931 PMCID: PMC11304262 DOI: 10.1002/advs.202306890] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/20/2023] [Revised: 04/23/2024] [Indexed: 06/01/2024]
Abstract
In spite of recent advances in the field of undernutrition, current dietary therapy relying on the supply of high protein high calorie formulas is still plagued with transient recovery of impaired organs resulting in significant relapse of cases. This is partly attributed to the inadequacy of current research models in recapitulating clinical undernutrition for mechanistic exploration. Using 1636 Macaca fascicularis monkeys, a human-relevant criterion for determining undernutrition weight-for-age z-score (WAZ), with a cutoff point of ≤ -1.83 is established as the benchmark for identifying undernourished nonhuman primates (U-NHPs). In U-NHPs, pathological anomalies in multi-organs are revealed. In particular, severe dysregulation of hepatic lipid metabolism characterized by impaired fatty acid oxidation due to mitochondria dysfunction, but unlikely peroxisome disorder, is identified as the anchor metabolic aberration in U-NHPs. Mitochondria dysfunction is typified by reduced mito-number, accumulated long-chain fatty acids, and disruption of OXPHOS complexes. Soy peptide-treated U-NHPs increase in WAZ scores, in addition to attenuated mitochondria dysfunction and restored OXPHOS complex levels. Herein, innovative criteria for identifying U-NHPs are developed, and unknown molecular mechanisms of undernutrition are revealed hitherto, and it is further proved that soypeptide supplementation reprogramed mitochondrial function to re-establish lipid metabolism balance and mitigated undernutrition.
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Affiliation(s)
- Zhenzhen Xu
- School of Food Science and EngineeringSouth China University of TechnologyGuangzhou510640China
| | - William Kwame Amakye
- School of Food Science and EngineeringSouth China University of TechnologyGuangzhou510640China
| | - Zhengyu Ren
- The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory DiseaseGuangzhou510182China
- State Key Laboratory of Quality Research in Chinese MedicineInstitute of Chinese Medical Sciences (ICMS)University of MacauMacau999078China
| | - Yongzhao Xu
- School of Food Science and EngineeringSouth China University of TechnologyGuangzhou510640China
| | - Wei Liu
- School of Food Science and EngineeringSouth China University of TechnologyGuangzhou510640China
- Huazhen Laboratory Animal Breeding CenterGuangzhou510900China
| | - Congcong Gong
- School of Food Science and EngineeringSouth China University of TechnologyGuangzhou510640China
| | - Chiwai Wong
- Huazhen Laboratory Animal Breeding CenterGuangzhou510900China
| | - Li Gao
- School of Food Science and EngineeringSouth China University of TechnologyGuangzhou510640China
| | - Zikuan Zhao
- School of Food Science and EngineeringSouth China University of TechnologyGuangzhou510640China
| | - Min Wang
- School of Food Science and EngineeringSouth China University of TechnologyGuangzhou510640China
| | - Tao Yan
- School of Food Science and EngineeringSouth China University of TechnologyGuangzhou510640China
| | - Zhiming Ye
- The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory DiseaseGuangzhou510182China
| | - Jun Zhong
- School of Food Science and EngineeringSouth China University of TechnologyGuangzhou510640China
| | - Chuanli Hou
- School of Food Science and EngineeringSouth China University of TechnologyGuangzhou510640China
| | - Miao Zhao
- Center for Medical Genetics and Hunan Key Laboratory of Medical GeneticsSchool of Life ScienceCentral South UniversityChangsha410013P. R. China
| | - Can Qiu
- Center for Medical Genetics and Hunan Key Laboratory of Medical GeneticsSchool of Life ScienceCentral South UniversityChangsha410013P. R. China
| | - Jieqiong Tan
- Center for Medical Genetics and Hunan Key Laboratory of Medical GeneticsSchool of Life ScienceCentral South UniversityChangsha410013P. R. China
| | - Xin Xu
- College of Food Science and EngineeringYangzhou UniversityYangzhou225127China
| | - Guoyan Liu
- College of Food Science and EngineeringYangzhou UniversityYangzhou225127China
| | - Maojin Yao
- The First Affiliated Hospital of Guangzhou Medical UniversityGuangzhou Institute of Respiratory Disease & China State Key Laboratory of Respiratory DiseaseGuangzhou510182China
| | - Jiaoyan Ren
- School of Food Science and EngineeringSouth China University of TechnologyGuangzhou510640China
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12
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Kaynar A, Ozcan M, Li X, Turkez H, Zhang C, Uhlén M, Shoaie S, Mardinoglu A. Discovery of a Therapeutic Agent for Glioblastoma Using a Systems Biology-Based Drug Repositioning Approach. Int J Mol Sci 2024; 25:7868. [PMID: 39063109 PMCID: PMC11277330 DOI: 10.3390/ijms25147868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Revised: 07/14/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Glioblastoma (GBM), a highly malignant tumour of the central nervous system, presents with a dire prognosis and low survival rates. The heterogeneous and recurrent nature of GBM renders current treatments relatively ineffective. In our study, we utilized an integrative systems biology approach to uncover the molecular mechanisms driving GBM progression and identify viable therapeutic drug targets for developing more effective GBM treatment strategies. Our integrative analysis revealed an elevated expression of CHST2 in GBM tumours, designating it as an unfavourable prognostic gene in GBM, as supported by data from two independent GBM cohorts. Further, we pinpointed WZ-4002 as a potential drug candidate to modulate CHST2 through computational drug repositioning. WZ-4002 directly targeted EGFR (ERBB1) and ERBB2, affecting their dimerization and influencing the activity of adjacent genes, including CHST2. We validated our findings by treating U-138 MG cells with WZ-4002, observing a decrease in CHST2 protein levels and a reduction in cell viability. In summary, our research suggests that the WZ-4002 drug candidate may effectively modulate CHST2 and adjacent genes, offering a promising avenue for developing efficient treatment strategies for GBM patients.
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Affiliation(s)
- Ali Kaynar
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.K.); (S.S.)
| | - Mehmet Ozcan
- Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden; (M.O.); (X.L.); (C.Z.); (M.U.)
- Department of Medical Biochemistry, Faculty of Medicine, Zonguldak Bülent Ecevit University, Zongudak TR-67100, Turkey
| | - Xiangyu Li
- Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden; (M.O.); (X.L.); (C.Z.); (M.U.)
| | - Hasan Turkez
- Medical Biology Department, Faculty of Medicine, Atatürk University, Erzurum TR-25240, Turkey;
| | - Cheng Zhang
- Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden; (M.O.); (X.L.); (C.Z.); (M.U.)
| | - Mathias Uhlén
- Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden; (M.O.); (X.L.); (C.Z.); (M.U.)
| | - Saeed Shoaie
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.K.); (S.S.)
| | - Adil Mardinoglu
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.K.); (S.S.)
- Science for Life Laboratory, KTH-Royal Institute of Technology, SE-17121 Stockholm, Sweden; (M.O.); (X.L.); (C.Z.); (M.U.)
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13
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Buriti BMADB, Figueiredo PLB, Passos MF, da Silva JKR. Polymer-Based Wound Dressings Loaded with Essential Oil for the Treatment of Wounds: A Review. Pharmaceuticals (Basel) 2024; 17:897. [PMID: 39065747 PMCID: PMC11279661 DOI: 10.3390/ph17070897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 07/03/2024] [Accepted: 07/03/2024] [Indexed: 07/28/2024] Open
Abstract
Wound healing can result in complex problems, and discovering an effective method to improve the healing process is essential. Polymeric biomaterials have structures similar to those identified in the extracellular matrix of the tissue to be regenerated and also avoid chronic inflammation, and immunological reactions. To obtain smart and effective dressings, bioactive agents, such as essential oils, are also used to promote a wide range of biological properties, which can accelerate the healing process. Therefore, we intend to explore advances in the potential for applying hybrid materials in wound healing. For this, fifty scientific articles dated from 2010 to 2023 were investigated using the Web of Science, Scopus, Science Direct, and PubMed databases. The principles of the healing process, use of polymers, type and properties of essential oils and processing techniques, and characteristics of dressings were identified. Thus, the plants Syzygium romanticum or Eugenia caryophyllata, Origanum vulgare, and Cinnamomum zeylanicum present prospects for application in clinical trials due to their proven effects on wound healing and reducing the incidence of inflammatory cells in the site of injury. The antimicrobial effect of essential oils is mainly due to polyphenols and terpenes such as eugenol, cinnamaldehyde, carvacrol, and thymol.
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Affiliation(s)
- Bruna Michele A. de B. Buriti
- Instituto de Ciências Exatas e Naturais, Programa de Pós-Graduação em Química, Universidade Federal do Pará, Belém 66075-110, PA, Brazil;
| | - Pablo Luis B. Figueiredo
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Pará, Belém 66079-420, PA, Brazil; (P.L.B.F.); (M.F.P.)
| | - Marcele Fonseca Passos
- Programa de Pós-Graduação em Ciências Farmacêuticas, Universidade Federal do Pará, Belém 66079-420, PA, Brazil; (P.L.B.F.); (M.F.P.)
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Pará, Belém 66075-110, PA, Brazil
| | - Joyce Kelly R. da Silva
- Instituto de Ciências Exatas e Naturais, Programa de Pós-Graduação em Química, Universidade Federal do Pará, Belém 66075-110, PA, Brazil;
- Programa de Pós-Graduação em Biotecnologia, Universidade Federal do Pará, Belém 66075-110, PA, Brazil
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14
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Israr J, Alam S, Kumar A. System biology approaches for drug repurposing. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2024; 205:221-245. [PMID: 38789180 DOI: 10.1016/bs.pmbts.2024.03.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/26/2024]
Abstract
Drug repurposing, or drug repositioning, refers to the identification of alternative therapeutic applications for established medications that go beyond their initial indications. This strategy has becoming increasingly popular since it has the potential to significantly reduce the overall costs of drug development by around $300 million. System biology methodologies have been employed to facilitate medication repurposing, encompassing computational techniques such as signature matching and network-based strategies. These techniques utilize pre-existing drug-related data types and databases to find prospective repurposed medications that have minimal or acceptable harmful effects on patients. The primary benefit of medication repurposing in comparison to drug development lies in the fact that approved pharmaceuticals have already undergone multiple phases of clinical studies, thereby possessing well-established safety and pharmacokinetic properties. Utilizing system biology methodologies in medication repurposing offers the capacity to expedite the discovery of viable candidates for drug repurposing and offer novel perspectives for structure-based drug design.
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Affiliation(s)
- Juveriya Israr
- Institute of Biosciences and Technology, Shri Ramswaroop Memorial University, Lucknow-Deva Road, Barabanki, Uttar Pradesh, India; Department of Biotechnology Era University, Lucknow, Uttar Pradesh, India
| | - Shabroz Alam
- Department of Biotechnology Era University, Lucknow, Uttar Pradesh, India
| | - Ajay Kumar
- Department of Biotechnology, Faculty of Engineering and Technology, Rama University, Mandhana, Kanpur, Uttar Pradesh, India.
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15
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da Silva Rosa SC, Barzegar Behrooz A, Guedes S, Vitorino R, Ghavami S. Prioritization of genes for translation: a computational approach. Expert Rev Proteomics 2024; 21:125-147. [PMID: 38563427 DOI: 10.1080/14789450.2024.2337004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Accepted: 02/21/2024] [Indexed: 04/04/2024]
Abstract
INTRODUCTION Gene identification for genetic diseases is critical for the development of new diagnostic approaches and personalized treatment options. Prioritization of gene translation is an important consideration in the molecular biology field, allowing researchers to focus on the most promising candidates for further investigation. AREAS COVERED In this paper, we discussed different approaches to prioritize genes for translation, including the use of computational tools and machine learning algorithms, as well as experimental techniques such as knockdown and overexpression studies. We also explored the potential biases and limitations of these approaches and proposed strategies to improve the accuracy and reliability of gene prioritization methods. Although numerous computational methods have been developed for this purpose, there is a need for computational methods that incorporate tissue-specific information to enable more accurate prioritization of candidate genes. Such methods should provide tissue-specific predictions, insights into underlying disease mechanisms, and more accurate prioritization of genes. EXPERT OPINION Using advanced computational tools and machine learning algorithms to prioritize genes, we can identify potential targets for therapeutic intervention of complex diseases. This represents an up-and-coming method for drug development and personalized medicine.
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Affiliation(s)
- Simone C da Silva Rosa
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
| | - Amir Barzegar Behrooz
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
- Electrophysiology Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
| | - Sofia Guedes
- LAQV/REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
| | - Rui Vitorino
- LAQV/REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
- Department of Medical Sciences, Institute of Biomedicine-iBiMED, University of Aveiro, Aveiro, Portugal
- UnIC@RISE, Department of Surgery and Physiology, Faculty of Medicine of the University of Porto, Porto, Portugal
| | - Saeid Ghavami
- Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Science, University of Manitoba, Winnipeg, Canada
- Faculty of Medicine in Zabrze, Academia of Silesia, Katowice, Poland
- Research Institute of Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, Canada
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16
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Li Y, Deng X, Xiong H, Hu Q, Chen Y, Zhang W, Ma X, Zhao Y. Deciphering the toxicity-effect relationship and action patterns of traditional Chinese medicines from a smart data perspective: a comprehensive review. Front Pharmacol 2023; 14:1278014. [PMID: 37915415 PMCID: PMC10617680 DOI: 10.3389/fphar.2023.1278014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Accepted: 10/05/2023] [Indexed: 11/03/2023] Open
Abstract
In Chinese medicine, the primary considerations revolve around toxicity and effect. The clinical goal is to achieve maximize effect while minimizing toxicity. Nevertheless, both clinical and experimental research has revealed a distinct relationship between these two patterns of action in toxic Traditional Chinese Medicines (TCM). These TCM often exhibit characteristic "double-sided" or "multi-faceted" features under varying pathological conditions, transitioning between effective and toxic roles. This complexity adds a layer of challenge to unraveling the ultimate objectives of Traditional Chinese medicine. To address this complexity, various hypotheses have been proposed to explain the toxicity and effect of Traditional Chinese Medicines. These hypotheses encompass the magic shrapnel theory for effect, the adverse outcome pathway framework, and the indirect toxic theory for toxicity. This review primarily focuses on high-, medium-, and low-toxicity Traditional Chinese Medicines as listed in Chinese Pharmacopoeia. It aims to elucidate the essential intrinsic mechanisms and elements contributing to their toxicity and effectiveness. The critical factors influencing the mechanisms of toxicity and effect are the optimal dosage and duration of TCM administration. However, unraveling the toxic-effect relationships in TCM presents a formidable challenge due to its multi-target and multi-pathway mechanisms of action. We propose the integration of multi-omics technology to comprehensively analyze the fundamental metabolites, mechanisms of action, and toxic effects of TCM. This comprehensive approach can provide valuable insights into the intricate relationship between the effect and toxicity of these TCM.
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Affiliation(s)
- Yubing Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xinyu Deng
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Huiling Xiong
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Qichao Hu
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuan Chen
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Wenwen Zhang
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yanling Zhao
- Department of Pharmacy, The Fifth Medical Center of the PLA General Hospital, Beijing, China
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17
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Uzhytchak M, Lunova M, Smolková B, Jirsa M, Dejneka A, Lunov O. Iron oxide nanoparticles trigger endoplasmic reticulum damage in steatotic hepatic cells. NANOSCALE ADVANCES 2023; 5:4250-4268. [PMID: 37560414 PMCID: PMC10408607 DOI: 10.1039/d3na00071k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Accepted: 07/13/2023] [Indexed: 08/11/2023]
Abstract
Iron oxide nanoparticles (IONPs) are being actively researched in various biomedical applications, particularly as magnetic resonance imaging (MRI) contrast agents for diagnosing various liver pathologies like nonalcoholic fatty liver diseases, nonalcoholic steatohepatitis, and cirrhosis. Emerging evidence suggests that IONPs may exacerbate hepatic steatosis and liver injury in susceptible livers such as those with nonalcoholic fatty liver disease. However, our understanding of how IONPs may affect steatotic cells at the sub-cellular level is still fragmented. Generally, there is a lack of studies identifying the molecular mechanisms of potential toxic and/or adverse effects of IONPs on "non-heathy" in vitro models. In this study, we demonstrate that IONPs, at a dose that does not cause general toxicity in hepatic cells (Alexander and HepG2), induce significant toxicity in steatotic cells (cells loaded with non-toxic doses of palmitic acid). Mechanistically, co-treatment with PA and IONPs resulted in endoplasmic reticulum (ER) stress, accompanied by the release of cathepsin B from lysosomes to the cytosol. The release of cathepsin B, along with ER stress, led to the activation of apoptotic cell death. Our results suggest that it is necessary to consider the interaction between IONPs and the liver, especially in susceptible livers. This study provides important basic knowledge for the future optimization of IONPs as MRI contrast agents for various biomedical applications.
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Affiliation(s)
- Mariia Uzhytchak
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences Prague 18221 Czech Republic
| | - Mariia Lunova
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences Prague 18221 Czech Republic
- Institute for Clinical & Experimental Medicine (IKEM) Prague 14021 Czech Republic
| | - Barbora Smolková
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences Prague 18221 Czech Republic
| | - Milan Jirsa
- Institute for Clinical & Experimental Medicine (IKEM) Prague 14021 Czech Republic
| | - Alexandr Dejneka
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences Prague 18221 Czech Republic
| | - Oleg Lunov
- Department of Optical and Biophysical Systems, Institute of Physics of the Czech Academy of Sciences Prague 18221 Czech Republic
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18
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Ding L, Teng R, Zhu Y, Liu F, Wu L, Qin L, Wu X, Liu T. Electroacupuncture treatment ameliorates metabolic disorders in obese ZDF rats by regulating liver energy metabolism and gut microbiota. Front Endocrinol (Lausanne) 2023; 14:1207574. [PMID: 37441502 PMCID: PMC10335763 DOI: 10.3389/fendo.2023.1207574] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Accepted: 06/09/2023] [Indexed: 07/15/2023] Open
Abstract
Metabolic disorders represent a major therapeutic challenge to public health worldwide due to their dramatically increasing prevalence. Acupuncture is widely used as adjuvant therapy for multiple metabolic diseases. However, detailed biological interpretation of the acupuncture stimulations is still limited. The gut and the liver are intrinsically connected and related to metabolic function. Microbial metabolites might affect the gut-liver axis through multiple mechanisms. Liver metabolomics and 16S rRNA sequencing were used to explore the specific mechanism of electroacupuncture in treating ZDF rats in this study. Electroacupuncture effectively improved glycolipid metabolism disorders of the ZDF rats. Histopathology confirmed that electroacupuncture improved diffuse hepatic steatosis and hepatocyte vacuolation, and promoted glycogen accumulation in the liver. The treatment significantly improved microbial diversity and richness and upregulated beneficial bacteria that maintain intestinal epithelial homeostasis and decreased bacteria with detrimental metabolic features on host metabolism. Liver metabolomics showed that the main effects of electroacupuncture include reducing the carbon flow and intermediate products in the TCA cycle, regulating the metabolism of various amino acids, and inhibiting hepatic glucose output and de novo lipogenesis. The gut-liver axis correlation analysis showed a strong correlation between the liver metabolites and the gut microbiota, especially allantoin and Adlercreutzia. Electroacupuncture treatment can improve abnormal energy metabolism by reducing oxidative stress, ectopic fat deposition, and altering metabolic fluxes. Our results will help us to further understand the specific mechanism of electroacupuncture in the treatment of metabolic diseases.
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Affiliation(s)
- Lei Ding
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Rufeng Teng
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Yifei Zhu
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Fengming Liu
- Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Lili Wu
- Key Laboratory of Health Cultivation of the Ministry of Education, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
| | - Lingling Qin
- Department of Science and Technology, Beijing University of Chinese Medicine, Beijing, China
| | - Xi Wu
- Department of Education, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing, China
| | - Tonghua Liu
- Key Laboratory of Health Cultivation of the Ministry of Education, School of Traditional Chinese Medicine, Beijing University of Chinese Medicine, Beijing, China
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19
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Grausa K, Siddiqui SA, Lameyer N, Wiesotzki K, Smetana S, Pentjuss A. Metabolic Modeling of Hermetia illucens Larvae Resource Allocation for High-Value Fatty Acid Production. Metabolites 2023; 13:724. [PMID: 37367882 DOI: 10.3390/metabo13060724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 05/31/2023] [Accepted: 06/01/2023] [Indexed: 06/28/2023] Open
Abstract
All plant and animal kingdom organisms use highly connected biochemical networks to facilitate sustaining, proliferation, and growth functions. While the biochemical network details are well known, the understanding of the intense regulation principles is still limited. We chose to investigate the Hermetia illucens fly at the larval stage because this stage is a crucial period for the successful accumulation and allocation of resources for the subsequent organism's developmental stages. We combined iterative wet lab experiments and innovative metabolic modeling design approaches to simulate and explain the H. illucens larval stage resource allocation processes and biotechnology potential. We performed time-based growth and high-value chemical compound accumulation wet lab chemical analysis experiments on larvae and the Gainesville diet composition. We built and validated the first H. illucens medium-size, stoichiometric metabolic model to predict the effects of diet-based alterations on fatty acid allocation potential. Using optimization methods such as flux balance and flux variability analysis on the novel insect metabolic model, we predicted that doubled essential amino acid consumption increased the growth rate by 32%, but pure glucose consumption had no positive impact on growth. In the case of doubled pure valine consumption, the model predicted a 2% higher growth rate. In this study, we describe a new framework for researching the impact of dietary alterations on the metabolism of multi-cellular organisms at different developmental stages for improved, sustainable, and directed high-value chemicals.
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Affiliation(s)
- Kristina Grausa
- Department of Computer Systems, Latvia University of Life Sciences and Technologies, LV-3001 Jelgava, Latvia
- Institute of Microbiology and Biotechnology, University of Latvia, LV-1050 Riga, Latvia
| | - Shahida A Siddiqui
- Campus Straubing for Biotechnology and Sustainability, Technical University of Munich, Essigberg 3, D-94315 Straubing, Germany
- German Institute of Food Technologies (DIL e.V.), 49610 Quakenbrück, Germany
| | - Norbert Lameyer
- German Institute of Food Technologies (DIL e.V.), 49610 Quakenbrück, Germany
| | - Karin Wiesotzki
- German Institute of Food Technologies (DIL e.V.), 49610 Quakenbrück, Germany
| | - Sergiy Smetana
- German Institute of Food Technologies (DIL e.V.), 49610 Quakenbrück, Germany
| | - Agris Pentjuss
- Department of Computer Systems, Latvia University of Life Sciences and Technologies, LV-3001 Jelgava, Latvia
- Institute of Microbiology and Biotechnology, University of Latvia, LV-1050 Riga, Latvia
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20
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Guo H, Wu H, Kong X, Zhang N, Li H, Dong X, Li Z. Oat β-glucan ameliorates diabetes in high fat diet and streptozotocin-induced mice by regulating metabolites. J Nutr Biochem 2023; 113:109251. [PMID: 36513312 DOI: 10.1016/j.jnutbio.2022.109251] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Revised: 12/05/2022] [Accepted: 12/07/2022] [Indexed: 12/14/2022]
Abstract
Oats are widely distributed worldwide and oat β-glucan has positive effects on human health. Particularly, oat β-glucan is reported to be beneficial in the management of type 2 diabetes. The aim of the present study is to investigate the effects of oat β-glucan and its possible underlying mechanisms on diabetes in type 2 diabetic mice that was induced by streptozotocin/high-fat diet (STZ/HFD). The data indicated that oat β-glucan significantly reduced the fasting blood glucose, improved glucose tolerance, and insulin sensitivity. The results further showed that oat β-glucan remarkably decreased the levels of total cholesterol (TCHO), total triglyceride (TG), low-density lipoprotein cholesterol (LDL-C) and free fatty acids. Moreover, oat β-glucan remarkably increased the hepatic glycogen content, but largely decreased the levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in STZ/HFD-induced diabetic mice. Histological analysis showed that oat β-glucan alleviated visceral lesions. Finally, the metabolomic analysis indicated that the metabolic profile was remarkably changed after oat β-glucan intervention in diabetic mice. There were 88 and 106 differential metabolites screened as biomarkers in negative ion mode (NEG) and positive ion mode (POS) after oat β-glucan treatment, respectively. In addition, oat β-glucan significantly affected the serum metabolites of amino acids, organic acids and bile acids. Collectively, the current study elucidates oat β-glucan displays an effective nutritional intervention in diabetes.
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Affiliation(s)
- Huiqin Guo
- The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan, China
| | - Haili Wu
- Shanxi Key Laboratory for Research and Development of Regional Plants, College of Life Science, Shanxi University, Taiyuan, China
| | - Xiangqun Kong
- Shanxi Key Laboratory for Research and Development of Regional Plants, College of Life Science, Shanxi University, Taiyuan, China
| | - Nuonuo Zhang
- Shanxi Key Laboratory for Research and Development of Regional Plants, College of Life Science, Shanxi University, Taiyuan, China
| | - Hanqing Li
- Shanxi Key Laboratory for Research and Development of Regional Plants, College of Life Science, Shanxi University, Taiyuan, China
| | - Xiushan Dong
- Department of General Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Taiyuan, China
| | - Zhuoyu Li
- The Key Laboratory of Chemical Biology and Molecular Engineering of Ministry of Education, Institute of Biotechnology, Shanxi University, Taiyuan, China.
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21
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Song Y, Song Q, Liu W, Li J, Tu P. High-confidence structural identification of metabolites relying on tandem mass spectrometry through isomeric identification: A tutorial. Trends Analyt Chem 2023. [DOI: 10.1016/j.trac.2023.116982] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/12/2023]
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22
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Turkez H, Altay O, Yildirim S, Li X, Yang H, Bayram C, Bolat I, Oner S, Tozlu OO, Arslan ME, Arif M, Yulug B, Hanoglu L, Cankaya S, Lam S, Velioglu HA, Coskun E, Idil E, Nogaylar R, Ozsimsek A, Hacimuftuoglu A, Shoaie S, Zhang C, Nielsen J, Borén J, Uhlén M, Mardinoglu A. Combined metabolic activators improve metabolic functions in the animal models of neurodegenerative diseases. Life Sci 2023; 314:121325. [PMID: 36581096 DOI: 10.1016/j.lfs.2022.121325] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Revised: 12/13/2022] [Accepted: 12/21/2022] [Indexed: 12/27/2022]
Abstract
BACKGROUND Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), are associated with metabolic abnormalities. Integrative analysis of human clinical data and animal studies have contributed to a better understanding of the molecular and cellular pathways involved in the progression of NDDs. Previously, we have reported that the combined metabolic activators (CMA), which include the precursors of nicotinamide adenine dinucleotide and glutathione can be utilized to alleviate metabolic disorders by activating mitochondrial metabolism. METHODS We first analysed the brain transcriptomics data from AD patients and controls using a brain-specific genome-scale metabolic model (GEM). Then, we investigated the effect of CMA administration in animal models of AD and PD. We evaluated pathological and immunohistochemical findings of brain and liver tissues. Moreover, PD rats were tested for locomotor activity and apomorphine-induced rotation. FINDINGS Analysis of transcriptomics data with GEM revealed that mitochondrial dysfunction is involved in the underlying molecular pathways of AD. In animal models of AD and PD, we showed significant damage in the high-fat diet groups' brain and liver tissues compared to the chow diet. The histological analyses revealed that hyperemia, degeneration and necrosis in neurons were improved by CMA administration in both AD and PD animal models. These findings were supported by immunohistochemical evidence of decreased immunoreactivity in neurons. In parallel to the improvement in the brain, we also observed dramatic metabolic improvement in the liver tissue. CMA administration also showed a beneficial effect on behavioural functions in PD rats. INTERPRETATION Overall, we showed that CMA administration significantly improved behavioural scores in parallel with the neurohistological outcomes in the AD and PD animal models and is a promising treatment for improving the metabolic parameters and brain functions in NDDs.
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Affiliation(s)
- Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Ozlem Altay
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
| | - Serkan Yildirim
- Department of Pathology, Veterinary Faculty, Ataturk University, Erzurum, Turkey.
| | - Xiangyu Li
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
| | - Hong Yang
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
| | - Cemil Bayram
- Department of Medical Pharmacology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Ismail Bolat
- Department of Pathology, Veterinary Faculty, Ataturk University, Erzurum, Turkey.
| | - Sena Oner
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey
| | - Ozlem Ozdemir Tozlu
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey.
| | - Mehmet Enes Arslan
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey
| | - Muhammad Arif
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
| | - Burak Yulug
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Lutfu Hanoglu
- Department of Neurology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey.
| | - Seyda Cankaya
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Simon Lam
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, United Kingdom.
| | - Halil Aziz Velioglu
- Functional Imaging and Cognitive-Affective Neuroscience Lab, Istanbul Medipol University, Istanbul, Turkey; Department of Women's and Children's Health, Karolinska Institute, Neuroimaging Lab, Stockholm, Sweden
| | - Ebru Coskun
- Department of Neurology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Ezgi Idil
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Rahim Nogaylar
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Ahmet Ozsimsek
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey.
| | - Ahmet Hacimuftuoglu
- Department of Medical Pharmacology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Saeed Shoaie
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, United Kingdom.
| | - Cheng Zhang
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, PR China.
| | - Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden.
| | - Jan Borén
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden.
| | - Mathias Uhlén
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden.
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH Royal Institute of Technology, Stockholm, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, United Kingdom.
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23
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Yulug B, Altay O, Li X, Hanoglu L, Cankaya S, Lam S, Velioglu HA, Yang H, Coskun E, Idil E, Nogaylar R, Ozsimsek A, Bayram C, Bolat I, Oner S, Tozlu OO, Arslan ME, Hacimuftuoglu A, Yildirim S, Arif M, Shoaie S, Zhang C, Nielsen J, Turkez H, Borén J, Uhlén M, Mardinoglu A. Combined metabolic activators improve cognitive functions in Alzheimer's disease patients: a randomised, double-blinded, placebo-controlled phase-II trial. Transl Neurodegener 2023; 12:4. [PMID: 36703196 PMCID: PMC9879258 DOI: 10.1186/s40035-023-00336-2] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2022] [Accepted: 01/09/2023] [Indexed: 01/28/2023] Open
Abstract
BACKGROUND Alzheimer's disease (AD) is associated with metabolic abnormalities linked to critical elements of neurodegeneration. We recently administered combined metabolic activators (CMA) to the AD rat model and observed that CMA improves the AD-associated histological parameters in the animals. CMA promotes mitochondrial fatty acid uptake from the cytosol, facilitates fatty acid oxidation in the mitochondria, and alleviates oxidative stress. METHODS Here, we designed a randomised, double-blinded, placebo-controlled phase-II clinical trial and studied the effect of CMA administration on the global metabolism of AD patients. One-dose CMA included 12.35 g L-serine (61.75%), 1 g nicotinamide riboside (5%), 2.55 g N-acetyl-L-cysteine (12.75%), and 3.73 g L-carnitine tartrate (18.65%). AD patients received one dose of CMA or placebo daily during the first 28 days and twice daily between day 28 and day 84. The primary endpoint was the difference in the cognitive function and daily living activity scores between the placebo and the treatment arms. The secondary aim of this study was to evaluate the safety and tolerability of CMA. A comprehensive plasma metabolome and proteome analysis was also performed to evaluate the efficacy of the CMA in AD patients. RESULTS We showed a significant decrease of AD Assessment Scale-cognitive subscale (ADAS-Cog) score on day 84 vs day 0 (P = 0.00001, 29% improvement) in the CMA group. Moreover, there was a significant decline (P = 0.0073) in ADAS-Cog scores (improvement of cognitive functions) in the CMA compared to the placebo group in patients with higher ADAS-Cog scores. Improved cognitive functions in AD patients were supported by the relevant alterations in the hippocampal volumes and cortical thickness based on imaging analysis. Moreover, the plasma levels of proteins and metabolites associated with NAD + and glutathione metabolism were significantly improved after CMA treatment. CONCLUSION Our results indicate that treatment of AD patients with CMA can lead to enhanced cognitive functions and improved clinical parameters associated with phenomics, metabolomics, proteomics and imaging analysis. Trial registration ClinicalTrials.gov NCT04044131 Registered 17 July 2019, https://clinicaltrials.gov/ct2/show/NCT04044131.
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Affiliation(s)
- Burak Yulug
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Ozlem Altay
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Xiangyu Li
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Lutfu Hanoglu
- Department of Neurology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Seyda Cankaya
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Simon Lam
- Centre for Host-Microbiome Interaction's, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, UK
| | - Halil Aziz Velioglu
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
- Functional Imaging and Cognitive-Affective Neuroscience Lab, Istanbul Medipol University, Istanbul, Turkey
| | - Hong Yang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Ebru Coskun
- Department of Neurology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey
| | - Ezgi Idil
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Rahim Nogaylar
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Ahmet Ozsimsek
- Department of Neurology and Neuroscience, Faculty of Medicine, Alanya Alaaddin Keykubat University, Antalya, Turkey
| | - Cemil Bayram
- Department of Medical Pharmacology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Ismail Bolat
- Department of Pathology, Veterinary Faculty, Ataturk University, Erzurum, Turkey
| | - Sena Oner
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey
| | - Ozlem Ozdemir Tozlu
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey
| | - Mehmet Enes Arslan
- Department of Molecular Biology and Genetics, Faculty of Science, Erzurum Technical University, Erzurum, Turkey
| | - Ahmet Hacimuftuoglu
- Department of Medical Pharmacology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Serkan Yildirim
- Department of Pathology, Veterinary Faculty, Ataturk University, Erzurum, Turkey
| | - Muhammad Arif
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Saeed Shoaie
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
- Centre for Host-Microbiome Interaction's, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, UK
| | - Cheng Zhang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
- School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, People's Republic of China
| | - Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Jan Borén
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Mathias Uhlén
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.
- Centre for Host-Microbiome Interaction's, Faculty of Dentistry, Oral and Craniofacial Sciences, King's College London, London, UK.
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24
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Ezzamouri B, Rosario D, Bidkhori G, Lee S, Uhlen M, Shoaie S. Metabolic modelling of the human gut microbiome in type 2 diabetes patients in response to metformin treatment. NPJ Syst Biol Appl 2023; 9:2. [PMID: 36681701 PMCID: PMC9867701 DOI: 10.1038/s41540-022-00261-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 11/08/2022] [Indexed: 01/22/2023] Open
Abstract
The human gut microbiome has been associated with several metabolic disorders including type 2 diabetes mellitus. Understanding metabolic changes in the gut microbiome is important to elucidate the role of gut bacteria in regulating host metabolism. Here, we used available metagenomics data from a metformin study, together with genome-scale metabolic modelling of the key bacteria in individual and community-level to investigate the mechanistic role of the gut microbiome in response to metformin. Individual modelling predicted that species that are increased after metformin treatment have higher growth rates in comparison to species that are decreased after metformin treatment. Gut microbial enrichment analysis showed prior to metformin treatment pathways related to the hypoglycemic effect were enriched. Our observations highlight how the key bacterial species after metformin treatment have commensal and competing behavior, and how their cellular metabolism changes due to different nutritional environment. Integrating different diets showed there were specific microbial alterations between different diets. These results show the importance of the nutritional environment and how dietary guidelines may improve drug efficiency through the gut microbiota.
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Affiliation(s)
- Bouchra Ezzamouri
- grid.13097.3c0000 0001 2322 6764Centre for Host–Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, SE1 9RT London, UK ,grid.420545.20000 0004 0489 3985Unit for Population-Based Dermatology, St John’s Institute of Dermatology, King’s College London and Guy’s and St Thomas’ NHS Foundation Trust, London, UK
| | - Dorines Rosario
- grid.13097.3c0000 0001 2322 6764Centre for Host–Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, SE1 9RT London, UK
| | - Gholamreza Bidkhori
- grid.13097.3c0000 0001 2322 6764Centre for Host–Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, SE1 9RT London, UK ,Present Address: AIVIVO Ltd. Unit 25, Bio-innovation centre, Cambridge Science Park, Cambridge, UK
| | - Sunjae Lee
- grid.13097.3c0000 0001 2322 6764Centre for Host–Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, SE1 9RT London, UK
| | - Mathias Uhlen
- grid.5037.10000000121581746Science for Life Laboratory, KTH - Royal Institute of Technology, 171 21 Stockholm, Sweden
| | - Saeed Shoaie
- grid.13097.3c0000 0001 2322 6764Centre for Host–Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, SE1 9RT London, UK ,grid.5037.10000000121581746Science for Life Laboratory, KTH - Royal Institute of Technology, 171 21 Stockholm, Sweden
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25
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Lv W, Zhou H, Aazmi A, Yu M, Xu X, Yang H, Huang YYS, Ma L. Constructing biomimetic liver models through biomaterials and vasculature engineering. Regen Biomater 2022; 9:rbac079. [PMID: 36338176 PMCID: PMC9629974 DOI: 10.1093/rb/rbac079] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/19/2022] [Accepted: 10/08/2022] [Indexed: 04/04/2024] Open
Abstract
The occurrence of various liver diseases can lead to organ failure of the liver, which is one of the leading causes of mortality worldwide. Liver tissue engineering see the potential for replacing liver transplantation and drug toxicity studies facing donor shortages. The basic elements in liver tissue engineering are cells and biomaterials. Both mature hepatocytes and differentiated stem cells can be used as the main source of cells to construct spheroids and organoids, achieving improved cell function. To mimic the extracellular matrix (ECM) environment, biomaterials need to be biocompatible and bioactive, which also help support cell proliferation and differentiation and allow ECM deposition and vascularized structures formation. In addition, advanced manufacturing approaches are required to construct the extracellular microenvironment, and it has been proved that the structured three-dimensional culture system can help to improve the activity of hepatocytes and the characterization of specific proteins. In summary, we review biomaterials for liver tissue engineering, including natural hydrogels and synthetic polymers, and advanced processing techniques for building vascularized microenvironments, including bioassembly, bioprinting and microfluidic methods. We then summarize the application fields including transplant and regeneration, disease models and drug cytotoxicity analysis. In the end, we put the challenges and prospects of vascularized liver tissue engineering.
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Affiliation(s)
- Weikang Lv
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Hongzhao Zhou
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Abdellah Aazmi
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | - Mengfei Yu
- The Affiliated Stomatologic Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China
| | - Xiaobin Xu
- School of Materials Science and Engineering, Tongji University, Shanghai 201804, China
| | - Huayong Yang
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
| | | | - Liang Ma
- State Key Laboratory of Fluid Power and Mechatronic Systems, Zhejiang University, Hangzhou 310058, China
- School of Mechanical Engineering, Zhejiang University, Hangzhou 310058, China
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26
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Tebani A, Bekri S. [The promise of omics in the precision medicine era]. Rev Med Interne 2022; 43:649-660. [PMID: 36041909 DOI: 10.1016/j.revmed.2022.07.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 07/12/2022] [Indexed: 10/15/2022]
Abstract
The rise of omics technologies that simultaneously measure thousands of molecules in a complex biological sample represents the core of systems biology. These technologies have profoundly impacted biomarkers and therapeutic targets discovery in the precision medicine era. Systems biology aims to perform a systematic probing of complex interactions in biological systems. Powered by high-throughput omics technologies and high-performance computing, systems biology provides relevant, resolving, and multi-scale overviews from cells to populations. Precision medicine takes advantage of these conceptual and technological developments and is based on two main pillars: the generation of multimodal data and their subsequent modeling. High-throughput omics technologies enable the comprehensive and holistic extraction of biological information, while computational capabilities enable multidimensional modeling and, as a result, offer an intuitive and intelligible visualization. Despite their promise, translating these technologies into clinically actionable tools has been slow. In this contribution, we present the most recent multi-omics data generation and analysis strategies and their clinical deployment in the post-genomic era. Furthermore, medical application challenges of omics-based biomarkers are discussed.
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Affiliation(s)
- A Tebani
- UNIROUEN, Inserm U1245, Department of Metabolic Biochemistry, Normandie University, CHU Rouen, 76000 Rouen, France.
| | - S Bekri
- UNIROUEN, Inserm U1245, Department of Metabolic Biochemistry, Normandie University, CHU Rouen, 76000 Rouen, France
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Lefever DE, Miedel MT, Pei F, DiStefano JK, Debiasio R, Shun TY, Saydmohammed M, Chikina M, Vernetti LA, Soto-Gutierrez A, Monga SP, Bataller R, Behari J, Yechoor VK, Bahar I, Gough A, Stern AM, Taylor DL. A Quantitative Systems Pharmacology Platform Reveals NAFLD Pathophysiological States and Targeting Strategies. Metabolites 2022; 12:528. [PMID: 35736460 PMCID: PMC9227696 DOI: 10.3390/metabo12060528] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/28/2022] [Accepted: 06/03/2022] [Indexed: 11/17/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has a high global prevalence with a heterogeneous and complex pathophysiology that presents barriers to traditional targeted therapeutic approaches. We describe an integrated quantitative systems pharmacology (QSP) platform that comprehensively and unbiasedly defines disease states, in contrast to just individual genes or pathways, that promote NAFLD progression. The QSP platform can be used to predict drugs that normalize these disease states and experimentally test predictions in a human liver acinus microphysiology system (LAMPS) that recapitulates key aspects of NAFLD. Analysis of a 182 patient-derived hepatic RNA-sequencing dataset generated 12 gene signatures mirroring these states. Screening against the LINCS L1000 database led to the identification of drugs predicted to revert these signatures and corresponding disease states. A proof-of-concept study in LAMPS demonstrated mitigation of steatosis, inflammation, and fibrosis, especially with drug combinations. Mechanistically, several structurally diverse drugs were predicted to interact with a subnetwork of nuclear receptors, including pregnane X receptor (PXR; NR1I2), that has evolved to respond to both xenobiotic and endogenous ligands and is intrinsic to NAFLD-associated transcription dysregulation. In conjunction with iPSC-derived cells, this platform has the potential for developing personalized NAFLD therapeutic strategies, informing disease mechanisms, and defining optimal cohorts of patients for clinical trials.
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Affiliation(s)
- Daniel E. Lefever
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
| | - Mark T. Miedel
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; (F.P.); (M.C.)
| | - Fen Pei
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; (F.P.); (M.C.)
| | - Johanna K. DiStefano
- Diabetes and Fibrotic Disease Unit, Translational Genomics Research Institute TGen, Phoenix, AZ 85004, USA;
| | - Richard Debiasio
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
| | - Tong Ying Shun
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
| | - Manush Saydmohammed
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
| | - Maria Chikina
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; (F.P.); (M.C.)
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Lawrence A. Vernetti
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; (F.P.); (M.C.)
| | - Alejandro Soto-Gutierrez
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
- McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15203, USA
| | - Satdarshan P. Monga
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Ramon Bataller
- Division of Gastroenterology Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (R.B.); (J.B.)
| | - Jaideep Behari
- Division of Gastroenterology Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA; (R.B.); (J.B.)
- UPMC Liver Clinic, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA
| | - Vijay K. Yechoor
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
- Division of Endocrinology and Metabolism, Department of Medicine, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15203, USA
| | - Ivet Bahar
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; (F.P.); (M.C.)
| | - Albert Gough
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; (F.P.); (M.C.)
| | - Andrew M. Stern
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; (F.P.); (M.C.)
| | - D. Lansing Taylor
- Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA; (D.E.L.); (M.T.M.); (R.D.); (T.Y.S.); (M.S.); (L.A.V.); (A.S.-G.); (S.P.M.); (V.K.Y.); (I.B.); (A.G.)
- Department of Computational and Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15260, USA; (F.P.); (M.C.)
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Grausa K, Mozga I, Pleiko K, Pentjuss A. Integrative Gene Expression and Metabolic Analysis Tool IgemRNA. Biomolecules 2022; 12:biom12040586. [PMID: 35454176 PMCID: PMC9029533 DOI: 10.3390/biom12040586] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/11/2022] [Accepted: 04/14/2022] [Indexed: 01/27/2023] Open
Abstract
Genome-scale metabolic modeling is widely used to study the impact of metabolism on the phenotype of different organisms. While substrate modeling reflects the potential distribution of carbon and other chemical elements within the model, the additional use of omics data, e.g., transcriptome, has implications when researching the genotype–phenotype responses to environmental changes. Several algorithms for transcriptome analysis using genome-scale metabolic modeling have been proposed. Still, they are restricted to specific objectives and conditions and lack flexibility, have software compatibility issues, and require advanced user skills. We classified previously published algorithms, summarized transcriptome pre-processing, integration, and analysis methods, and implemented them in the newly developed transcriptome analysis tool IgemRNA, which (1) has a user-friendly graphical interface, (2) tackles compatibility issues by combining previous data input and pre-processing algorithms in MATLAB, and (3) introduces novel algorithms for the automatic comparison of different transcriptome datasets with or without Cobra Toolbox 3.0 optimization algorithms. We used publicly available transcriptome datasets from Saccharomyces cerevisiae BY4741 and H4-S47D strains for validation. We found that IgemRNA provides a means for transcriptome and environmental data validation on biochemical network topology since the biomass function varies for different phenotypes. Our tool can detect problematic reaction constraints.
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Affiliation(s)
- Kristina Grausa
- Department of Computer Systems, Latvia University of Life Sciences and Technologies, Liela Street 2, LV-3001 Jelgava, Latvia; (K.G.); (I.M.)
| | - Ivars Mozga
- Department of Computer Systems, Latvia University of Life Sciences and Technologies, Liela Street 2, LV-3001 Jelgava, Latvia; (K.G.); (I.M.)
| | - Karlis Pleiko
- Laboratory of Precision and Nanomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, 50411 Tartu, Estonia;
- Faculty of Medicine, University of Latvia, LV-1586 Riga, Latvia
| | - Agris Pentjuss
- Institute of Microbiology and Biotechnology, University of Latvia, Jelgavas Street 1, LV-1004 Riga, Latvia
- Correspondence:
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Li G, Han F, Xiao F, Gu K, Shen Q, Xu W, Li W, Wang Y, Liang B, Huang J, Xiao W, Kong Q. System-level metabolic modeling facilitates unveiling metabolic signature in exceptional longevity. Aging Cell 2022; 21:e13595. [PMID: 35343058 PMCID: PMC9009231 DOI: 10.1111/acel.13595] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/17/2022] [Accepted: 03/10/2022] [Indexed: 12/29/2022] Open
Abstract
Although it is well known that metabolic control plays a crucial role in regulating the health span and life span of various organisms, little is known for the systems metabolic profile of centenarians, the paradigm of human healthy aging and longevity. Meanwhile, how to well characterize the system‐level metabolic states in an organism of interest remains to be a major challenge in systems metabolism research. To address this challenge and better understand the metabolic mechanisms of healthy aging, we developed a method of genome‐wide precision metabolic modeling (GPMM) which is able to quantitatively integrate transcriptome, proteome and kinetome data in predictive modeling of metabolic networks. Benchmarking analysis showed that GPMM successfully characterized metabolic reprogramming in the NCI‐60 cancer cell lines; it dramatically improved the performance of the modeling with an R2 of 0.86 between the predicted and experimental measurements over the performance of existing methods. Using this approach, we examined the metabolic networks of a Chinese centenarian cohort and identified the elevated fatty acid oxidation (FAO) as the most significant metabolic feature in these long‐lived individuals. Evidence from serum metabolomics supports this observation. Given that FAO declines with normal aging and is impaired in many age‐related diseases, our study suggests that the elevated FAO has potential to be a novel signature of healthy aging of humans.
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Affiliation(s)
- Gong‐Hua Li
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
- Kunming Key Laboratory of Healthy Aging Study Kunming Yunnan China
| | - Feifei Han
- Harvard Medical School Immune and Metabolic Computational Center Massachusetts General Hospital Boston Massachusetts USA
| | - Fu‐Hui Xiao
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
- Kunming Key Laboratory of Healthy Aging Study Kunming Yunnan China
| | - Kang‐Su‐Yun Gu
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
- Kunming Key Laboratory of Healthy Aging Study Kunming Yunnan China
| | - Qiu Shen
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
| | - Weihong Xu
- Harvard Medical School Immune and Metabolic Computational Center Massachusetts General Hospital Boston Massachusetts USA
| | - Wen‐Xing Li
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
| | - Yan‐Li Wang
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
- School of Life Sciences Center for Life Sciences Yunnan University Kunming Yunnan China
| | - Bin Liang
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
- School of Life Sciences Center for Life Sciences Yunnan University Kunming Yunnan China
| | - Jing‐Fei Huang
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
| | - Wenzhong Xiao
- Harvard Medical School Immune and Metabolic Computational Center Massachusetts General Hospital Boston Massachusetts USA
| | - Qing‐Peng Kong
- State Key Laboratory of Genetic Resources and Evolution/Key Laboratory of Healthy Aging Research of Yunnan Province Kunming Institute of Zoology Chinese Academy of Sciences Kunming Yunnan China
- Kunming Key Laboratory of Healthy Aging Study Kunming Yunnan China
- CAS Center for Excellence in Animal Evolution and Genetics Chinese Academy of Sciences Kunming Yunnan China
- KIZ/CUHK Joint Laboratory of Bioresources and Molecular Research in Common Diseases Kunming Yunnan China
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Li X, Shong K, Kim W, Yuan M, Yang H, Sato Y, Kume H, Ogawa S, Turkez H, Shoaie S, Boren J, Nielsen J, Uhlen M, Zhang C, Mardinoglu A. Prediction of drug candidates for clear cell renal cell carcinoma using a systems biology-based drug repositioning approach. EBioMedicine 2022; 78:103963. [PMID: 35339898 PMCID: PMC8960981 DOI: 10.1016/j.ebiom.2022.103963] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2021] [Revised: 03/09/2022] [Accepted: 03/09/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The response rates of the clinical chemotherapies are still low in clear cell renal cell carcinoma (ccRCC). Computational drug repositioning is a promising strategy to discover new uses for existing drugs to treat patients who cannot get benefits from clinical drugs. METHODS We proposed a systematic approach which included the target prediction based on the co-expression network analysis of transcriptomics profiles of ccRCC patients and drug repositioning for cancer treatment based on the analysis of shRNA- and drug-perturbed signature profiles of human kidney cell line. FINDINGS First, based on the gene co-expression network analysis, we identified two types of gene modules in ccRCC, which significantly enriched with unfavorable and favorable signatures indicating poor and good survival outcomes of patients, respectively. Then, we selected four genes, BUB1B, RRM2, ASF1B and CCNB2, as the potential drug targets based on the topology analysis of modules. Further, we repurposed three most effective drugs for each target by applying the proposed drug repositioning approach. Finally, we evaluated the effects of repurposed drugs using an in vitro model and observed that these drugs inhibited the protein levels of their corresponding target genes and cell viability. INTERPRETATION These findings proved the usefulness and efficiency of our approach to improve the drug repositioning researches for cancer treatment and precision medicine. FUNDING This study was funded by Knut and Alice Wallenberg Foundation and Bash Biotech Inc., San Diego, CA, USA.
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Affiliation(s)
- Xiangyu Li
- Bash Biotech Inc, 600 est Broadway, Suite 700, San Diego, CA 92101, USA; Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden
| | - Koeun Shong
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden
| | - Woonghee Kim
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden
| | - Meng Yuan
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden
| | - Hong Yang
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden
| | - Yusuke Sato
- Department of Pathology and Tumor Biology, Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan; Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
| | - Haruki Kume
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan; Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm SE-17177, Sweden
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey
| | - Saeed Shoaie
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK
| | - Jan Boren
- Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg SE-41345, Sweden
| | - Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg SE-41296, Sweden; BioInnovation Institute, Copenhagen N DK-2200, Denmark
| | - Mathias Uhlen
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden
| | - Cheng Zhang
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden; Key Laboratory of Advanced Drug Preparation Technologies, School of Pharmaceutical Sciences, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China.
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm SE-17165, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK.
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Zeybel M, Arif M, Li X, Altay O, Yang H, Shi M, Akyildiz M, Saglam B, Gonenli MG, Yigit B, Ulukan B, Ural D, Shoaie S, Turkez H, Nielsen J, Zhang C, Uhlén M, Borén J, Mardinoglu A. Multiomics Analysis Reveals the Impact of Microbiota on Host Metabolism in Hepatic Steatosis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2104373. [PMID: 35128832 PMCID: PMC9008426 DOI: 10.1002/advs.202104373] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 12/22/2021] [Indexed: 05/03/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a complex disease involving alterations in multiple biological processes regulated by the interactions between obesity, genetic background, and environmental factors including the microbiome. To decipher hepatic steatosis (HS) pathogenesis by excluding critical confounding factors including genetic variants and diabetes, 56 heterogenous MAFLD patients are characterized by generating multiomics data including oral and gut metagenomics as well as plasma metabolomics and inflammatory proteomics data. The dysbiosis in the oral and gut microbiome is explored and the host-microbiome interactions based on global metabolic and inflammatory processes are revealed. These multiomics data are integrated using the biological network and HS's key features are identified using multiomics data. HS is finally predicted using these key features and findings are validated in a follow-up cohort, where 22 subjects with varying degree of HS are characterized.
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Affiliation(s)
- Mujdat Zeybel
- Department of Gastroenterology and HepatologySchool of MedicineKoç UniversityIstanbul34010Turkey
- NIHR Nottingham Biomedical Research CentreNottingham University Hospitals NHS Trust & University of NottinghamNottinghamNG5 1PBUK
- Nottingham Digestive Diseases CentreSchool of MedicineUniversity of NottinghamNottinghamNG7 2UHUK
| | - Muhammad Arif
- Science for Life LaboratoryKTH – Royal Institute of TechnologyStockholmSE‐17121Sweden
- Present address:
Laboratory of Cardiovascular Physiology and Tissue Injury and Section on Fibrotic DisordersNational Institute on Alcohol Abuse and Alcoholism, National Institutes of HealthRockvilleMD20852USA
| | - Xiangyu Li
- Science for Life LaboratoryKTH – Royal Institute of TechnologyStockholmSE‐17121Sweden
| | - Ozlem Altay
- Science for Life LaboratoryKTH – Royal Institute of TechnologyStockholmSE‐17121Sweden
| | - Hong Yang
- Science for Life LaboratoryKTH – Royal Institute of TechnologyStockholmSE‐17121Sweden
| | - Mengnan Shi
- Science for Life LaboratoryKTH – Royal Institute of TechnologyStockholmSE‐17121Sweden
| | - Murat Akyildiz
- Department of Gastroenterology and HepatologySchool of MedicineKoç UniversityIstanbul34010Turkey
| | - Burcin Saglam
- Department of Gastroenterology and HepatologySchool of MedicineKoç UniversityIstanbul34010Turkey
| | - Mehmet Gokhan Gonenli
- Department of Gastroenterology and HepatologySchool of MedicineKoç UniversityIstanbul34010Turkey
| | - Buket Yigit
- Department of Gastroenterology and HepatologySchool of MedicineKoç UniversityIstanbul34010Turkey
| | - Burge Ulukan
- Department of Gastroenterology and HepatologySchool of MedicineKoç UniversityIstanbul34010Turkey
| | - Dilek Ural
- School of MedicineKoç UniversityIstanbul34010Turkey
| | - Saeed Shoaie
- Science for Life LaboratoryKTH – Royal Institute of TechnologyStockholmSE‐17121Sweden
- Centre for Host‐Microbiome InteractionsFaculty of Dentistry, Oral & Craniofacial SciencesKing's College LondonLondonSE1 9RTUK
| | - Hasan Turkez
- Department of Medical BiologyFaculty of MedicineAtatürk UniversityErzurum25240Turkey
| | - Jens Nielsen
- Department of Biology and Biological EngineeringChalmers University of TechnologyGothenburgSE‐41296Sweden
| | - Cheng Zhang
- Science for Life LaboratoryKTH – Royal Institute of TechnologyStockholmSE‐17121Sweden
- Key Laboratory of Advanced Drug Preparation TechnologiesMinistry of EducationSchool of Pharmaceutical SciencesZhengzhou UniversityZhengzhouHenan Province450001China
| | - Mathias Uhlén
- Science for Life LaboratoryKTH – Royal Institute of TechnologyStockholmSE‐17121Sweden
| | - Jan Borén
- Department of Molecular and Clinical MedicineUniversity of Gothenburg and Sahlgrenska University Hospital GothenburgGothenburgSE‐41345Sweden
| | - Adil Mardinoglu
- Science for Life LaboratoryKTH – Royal Institute of TechnologyStockholmSE‐17121Sweden
- Centre for Host‐Microbiome InteractionsFaculty of Dentistry, Oral & Craniofacial SciencesKing's College LondonLondonSE1 9RTUK
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Giraudi PJ, Salvoza N, Bonazza D, Saitta C, Lombardo D, Casagranda B, de Manzini N, Pollicino T, Raimondo G, Tiribelli C, Palmisano S, Rosso N. Ficolin-2 Plasma Level Assesses Liver Fibrosis in Non-Alcoholic Fatty Liver Disease. Int J Mol Sci 2022; 23:2813. [PMID: 35269955 PMCID: PMC8911336 DOI: 10.3390/ijms23052813] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 02/25/2022] [Accepted: 03/02/2022] [Indexed: 01/27/2023] Open
Abstract
Fibrosis is the strongest predictor for disease-specific mortality in non-alcoholic fatty liver diseases (NAFLD), but the need for liver biopsy limits its diagnosis. We assessed the performance of plasma ficolin-2 (FCN-2) as a biomarker of fibrosis identified by an in silico discovery strategy. Two hundred and thirty-five morbidly obese (MO) subjects with biopsy-proven NAFLD stratified by fibrosis stage (F0, n = 44; F1, n = 134; F2, n = 46; F3/F4, n = 11) and 40 cirrhotic patients were enrolled. The cohort was subdivided into discovery (n = 76) and validation groups (n = 159). The plasma level of FCN-2 and other candidate markers was determined. FCN-2 was inversely correlated with the stage of liver fibrosis (ρ = −0.49, p < 0.001) independently of steatosis (p = 0.90), inflammation (p = 0.57), and ballooning (p = 0.59). In the global cohort, FCN-2 level decreased significantly in a stepwise fashion from F0/F1 (median 4753 ng/mL) to F2−F3−F4 (2760 ng/mL) and in cirrhotic subjects (1418 ng/mL). The diagnostic performance of FCN-2 in detecting F ≥ 2 was higher than other indexes (APRI, FIB-4) (AUROC 0.82, 0.68, and 0.6, respectively). The accuracy improved when combined with APRI score and HDL values (FCNscore, AUROC 0.85). Overall, the FCN-2 plasma level can accurately discriminate liver fibrosis status (minimal vs. moderate/advanced) significantly improving the fibrosis diagnostic algorithms.
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Affiliation(s)
- Pablo J. Giraudi
- Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg.Q SS14 Km, 163.5, 34149 Trieste, Italy; (N.S.); (C.T.); (S.P.); (N.R.)
| | - Noel Salvoza
- Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg.Q SS14 Km, 163.5, 34149 Trieste, Italy; (N.S.); (C.T.); (S.P.); (N.R.)
- Philippine Council for Health Research and Development, DOST Compound, Bicutan Taguig City 1631, Philippines
| | - Deborah Bonazza
- Surgical Pathology Unit, Cattinara Hospital, ASUGI, 34149 Trieste, Italy;
| | - Carlo Saitta
- Department of Clinical and Experimental Medicine, Unit of Medicine and Hepatology, Laboratory of Molecular Hepatology, University Hospital of Messina, 98121 Messina, Italy; (C.S.); (D.L.); (G.R.)
| | - Daniele Lombardo
- Department of Clinical and Experimental Medicine, Unit of Medicine and Hepatology, Laboratory of Molecular Hepatology, University Hospital of Messina, 98121 Messina, Italy; (C.S.); (D.L.); (G.R.)
| | - Biagio Casagranda
- Surgical Clinic Division, Cattinara Hospital, ASUGI, 34149 Trieste, Italy; (B.C.); (N.d.M.)
| | - Nicolò de Manzini
- Surgical Clinic Division, Cattinara Hospital, ASUGI, 34149 Trieste, Italy; (B.C.); (N.d.M.)
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy
| | - Teresa Pollicino
- Department of Human Pathology, Laboratory of Molecular Hepatology, University Hospital of Messina, 98121 Messina, Italy;
| | - Giovanni Raimondo
- Department of Clinical and Experimental Medicine, Unit of Medicine and Hepatology, Laboratory of Molecular Hepatology, University Hospital of Messina, 98121 Messina, Italy; (C.S.); (D.L.); (G.R.)
| | - Claudio Tiribelli
- Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg.Q SS14 Km, 163.5, 34149 Trieste, Italy; (N.S.); (C.T.); (S.P.); (N.R.)
| | - Silvia Palmisano
- Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg.Q SS14 Km, 163.5, 34149 Trieste, Italy; (N.S.); (C.T.); (S.P.); (N.R.)
- Surgical Clinic Division, Cattinara Hospital, ASUGI, 34149 Trieste, Italy; (B.C.); (N.d.M.)
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy
| | - Natalia Rosso
- Fondazione Italiana Fegato, Centro Studi Fegato, Area Science Park Basovizza Bldg.Q SS14 Km, 163.5, 34149 Trieste, Italy; (N.S.); (C.T.); (S.P.); (N.R.)
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Wang J, Huang D, Yu H, Cheng Y, Ren H, Zhao Y. Developing tissue engineering strategies for liver regeneration. ENGINEERED REGENERATION 2022; 3:80-91. [DOI: 10.1016/j.engreg.2022.02.003] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
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Li J, Chen C, Xia T. Understanding Nanomaterial-Liver Interactions to Facilitate the Development of Safer Nanoapplications. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2022; 34:e2106456. [PMID: 35029313 PMCID: PMC9040585 DOI: 10.1002/adma.202106456] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Revised: 12/23/2021] [Indexed: 05/02/2023]
Abstract
Nanomaterials (NMs) are widely used in commercial and medical products, such as cosmetics, vaccines, and drug carriers. Exposure to NMs via various routes such as dermal, inhalation, and ingestion has been shown to gain access to the systemic circulation, resulting in the accumulation of NMs in the liver. The unique organ structures and blood flow features facilitate the liver sequestration of NMs, which may cause adverse effects in the liver. Currently, most in vivo studies are focused on NMs accumulation at the organ level and evaluation of the gross changes in liver structure and functions, however, cell-type-specific uptake and responses, as well as the molecular mechanisms at cellular levels leading to effects at organ levels are lagging. Herein, the authors systematically review diverse interactions of NMs with the liver, specifically on major liver cell types including Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs), hepatic stellate cells (HSCs), and hepatocytes as well as the detailed molecular mechanisms involved. In addition, the knowledge gained on nano-liver interactions that can facilitate the development of safer nanoproducts and nanomedicine is also reviewed.
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Affiliation(s)
- Jiulong Li
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P. R. China
| | - Chunying Chen
- CAS Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience, National Center for Nanoscience and Technology, Beijing, 100190, P. R. China
| | - Tian Xia
- Center of Environmental Implications of Nanotechnology (UC CEIN), California NanoSystems Institute, Division of NanoMedicine, Department of Medicine, University of California Los Angeles, Los Angeles, CA, 90095, USA
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System and network biology-based computational approaches for drug repositioning. COMPUTATIONAL APPROACHES FOR NOVEL THERAPEUTIC AND DIAGNOSTIC DESIGNING TO MITIGATE SARS-COV-2 INFECTION 2022. [PMCID: PMC9300680 DOI: 10.1016/b978-0-323-91172-6.00003-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Recent advances in computational biology have not only fastened the drug discovery process but have also proven to be a powerful tool for the search of existing molecules of therapeutic value for drug repurposing. The system biology-based drug repurposing approaches shorten the time and reduced the cost of the whole process when compared to de novo drug discovery. In the present pandemic situation, these computational approaches have emerged as a boon to tackle the COVID-19 associated morbidities and mortalities. In this chapter, we present the overview of system biology-based network system approaches which can be exploited for the drug repurposing of disease. Besides, we have included information on relevant repurposed drugs which are currently used for the treatment of COVID-19.
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Vandermeulen MD, Cullen PJ. Gene by Environment Interactions reveal new regulatory aspects of signaling network plasticity. PLoS Genet 2022; 18:e1009988. [PMID: 34982769 PMCID: PMC8759647 DOI: 10.1371/journal.pgen.1009988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Revised: 01/14/2022] [Accepted: 12/09/2021] [Indexed: 11/18/2022] Open
Abstract
Phenotypes can change during exposure to different environments through the regulation of signaling pathways that operate in integrated networks. How signaling networks produce different phenotypes in different settings is not fully understood. Here, Gene by Environment Interactions (GEIs) were used to explore the regulatory network that controls filamentous/invasive growth in the yeast Saccharomyces cerevisiae. GEI analysis revealed that the regulation of invasive growth is decentralized and varies extensively across environments. Different regulatory pathways were critical or dispensable depending on the environment, microenvironment, or time point tested, and the pathway that made the strongest contribution changed depending on the environment. Some regulators even showed conditional role reversals. Ranking pathways' roles across environments revealed an under-appreciated pathway (OPI1) as the single strongest regulator among the major pathways tested (RAS, RIM101, and MAPK). One mechanism that may explain the high degree of regulatory plasticity observed was conditional pathway interactions, such as conditional redundancy and conditional cross-pathway regulation. Another mechanism was that different pathways conditionally and differentially regulated gene expression, such as target genes that control separate cell adhesion mechanisms (FLO11 and SFG1). An exception to decentralized regulation of invasive growth was that morphogenetic changes (cell elongation and budding pattern) were primarily regulated by one pathway (MAPK). GEI analysis also uncovered a round-cell invasion phenotype. Our work suggests that GEI analysis is a simple and powerful approach to define the regulatory basis of complex phenotypes and may be applicable to many systems.
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Affiliation(s)
- Matthew D. Vandermeulen
- Department of Biological Sciences, University at Buffalo, Buffalo, New York, United States of America
| | - Paul J. Cullen
- Department of Biological Sciences, University at Buffalo, Buffalo, New York, United States of America
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Yang H, Arif M, Yuan M, Li X, Shong K, Türkez H, Nielsen J, Uhlén M, Borén J, Zhang C, Mardinoglu A. A network-based approach reveals the dysregulated transcriptional regulation in non-alcoholic fatty liver disease. iScience 2021; 24:103222. [PMID: 34712920 PMCID: PMC8529555 DOI: 10.1016/j.isci.2021.103222] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Revised: 09/16/2021] [Accepted: 09/30/2021] [Indexed: 12/22/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease worldwide. We performed network analysis to investigate the dysregulated biological processes in the disease progression and revealed the molecular mechanism underlying NAFLD. Based on network analysis, we identified a highly conserved disease-associated gene module across three different NAFLD cohorts and highlighted the predominant role of key transcriptional regulators associated with lipid and cholesterol metabolism. In addition, we revealed the detailed metabolic differences between heterogeneous NAFLD patients through integrative systems analysis of transcriptomic data and liver-specific genome-scale metabolic model. Furthermore, we identified transcription factors (TFs), including SREBF2, HNF4A, SREBF1, YY1, and KLF13, showing regulation of hepatic expression of genes in the NAFLD-associated modules and validated the TFs using data generated from a mouse NAFLD model. In conclusion, our integrative analysis facilitates the understanding of the regulatory mechanism of these perturbed TFs and their associated biological processes.
Disease-associated gene modules are conserved across multiple NAFLD cohorts The central genes in disease-associated modules are key enzymes in cholesterol synthesis YY1 and KLF13 are potential key transcriptional regulators of NAFLD development
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Affiliation(s)
- Hong Yang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Muhammad Arif
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Meng Yuan
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Xiangyu Li
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Koeun Shong
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Hasan Türkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology, 41296 Gothenburg, Sweden.,BioInnovation Institute, 2200 Copenhagen, Denmark
| | - Mathias Uhlén
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Jan Borén
- Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Cheng Zhang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.,School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, PR China
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.,Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, UK
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38
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Shi K, Lin W, Zhao XM. Identifying Molecular Biomarkers for Diseases With Machine Learning Based on Integrative Omics. IEEE/ACM TRANSACTIONS ON COMPUTATIONAL BIOLOGY AND BIOINFORMATICS 2021; 18:2514-2525. [PMID: 32305934 DOI: 10.1109/tcbb.2020.2986387] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2023]
Abstract
Molecular biomarkers are certain molecules or set of molecules that can be of help for diagnosis or prognosis of diseases or disorders. In the past decades, thanks to the advances in high-throughput technologies, a huge amount of molecular 'omics' data, e.g., transcriptomics and proteomics, have been accumulated. The availability of these omics data makes it possible to screen biomarkers for diseases or disorders. Accordingly, a number of computational approaches have been developed to identify biomarkers by exploring the omics data. In this review, we present a comprehensive survey on the recent progress of identification of molecular biomarkers with machine learning approaches. Specifically, we categorize the machine learning approaches into supervised, un-supervised and recommendation approaches, where the biomarkers including single genes, gene sets and small gene networks. In addition, we further discuss potential problems underlying bio-medical data that may pose challenges for machine learning, and provide possible directions for future biomarker identification.
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Saydmohammed M, Jha A, Mahajan V, Gavlock D, Shun TY, DeBiasio R, Lefever D, Li X, Reese C, Kershaw EE, Yechoor V, Behari J, Soto-Gutierrez A, Vernetti L, Stern A, Gough A, Miedel MT, Lansing Taylor D. Quantifying the progression of non-alcoholic fatty liver disease in human biomimetic liver microphysiology systems with fluorescent protein biosensors. Exp Biol Med (Maywood) 2021; 246:2420-2441. [PMID: 33957803 PMCID: PMC8606957 DOI: 10.1177/15353702211009228] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2020] [Accepted: 03/23/2021] [Indexed: 12/12/2022] Open
Abstract
Metabolic syndrome is a complex disease that involves multiple organ systems including a critical role for the liver. Non-alcoholic fatty liver disease (NAFLD) is a key component of the metabolic syndrome and fatty liver is linked to a range of metabolic dysfunctions that occur in approximately 25% of the population. A panel of experts recently agreed that the acronym, NAFLD, did not properly characterize this heterogeneous disease given the associated metabolic abnormalities such as type 2 diabetes mellitus (T2D), obesity, and hypertension. Therefore, metabolic dysfunction-associated fatty liver disease (MAFLD) has been proposed as the new term to cover the heterogeneity identified in the NAFLD patient population. Although many rodent models of NAFLD/NASH have been developed, they do not recapitulate the full disease spectrum in patients. Therefore, a platform has evolved initially focused on human biomimetic liver microphysiology systems that integrates fluorescent protein biosensors along with other key metrics, the microphysiology systems database, and quantitative systems pharmacology. Quantitative systems pharmacology is being applied to investigate the mechanisms of NAFLD/MAFLD progression to select molecular targets for fluorescent protein biosensors, to integrate computational and experimental methods to predict drugs for repurposing, and to facilitate novel drug development. Fluorescent protein biosensors are critical components of the platform since they enable monitoring of the pathophysiology of disease progression by defining and quantifying the temporal and spatial dynamics of protein functions in the biosensor cells, and serve as minimally invasive biomarkers of the physiological state of the microphysiology system experimental disease models. Here, we summarize the progress in developing human microphysiology system disease models of NAFLD/MAFLD from several laboratories, developing fluorescent protein biosensors to monitor and to measure NAFLD/MAFLD disease progression and implementation of quantitative systems pharmacology with the goal of repurposing drugs and guiding the creation of novel therapeutics.
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Affiliation(s)
- Manush Saydmohammed
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Anupma Jha
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Vineet Mahajan
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Dillon Gavlock
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Tong Ying Shun
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Richard DeBiasio
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Daniel Lefever
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Xiang Li
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Celeste Reese
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Erin E Kershaw
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Vijay Yechoor
- Department of Medicine, Division of Endocrinology and Metabolism, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Jaideep Behari
- Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition, Pittsburgh, PA 15261, USA
- UPMC Liver Clinic, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Alejandro Soto-Gutierrez
- Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Larry Vernetti
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Andrew Stern
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Albert Gough
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - Mark T Miedel
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
| | - D Lansing Taylor
- University of Pittsburgh Drug Discovery Institute, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Pittsburgh Liver Research Center, University of Pittsburgh, Pittsburgh, PA 15261, USA
- Department of Computational and Systems Biology, University of Pittsburgh, Pittsburgh, PA 15261, USA
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Bayraktar A, Lam S, Altay O, Li X, Yuan M, Zhang C, Arif M, Turkez H, Uhlén M, Shoaie S, Mardinoglu A. Revealing the Molecular Mechanisms of Alzheimer's Disease Based on Network Analysis. Int J Mol Sci 2021; 22:11556. [PMID: 34768988 PMCID: PMC8584243 DOI: 10.3390/ijms222111556] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/19/2021] [Accepted: 10/21/2021] [Indexed: 12/11/2022] Open
Abstract
The complex pathology of Alzheimer's disease (AD) emphasises the need for comprehensive modelling of the disease, which may lead to the development of efficient treatment strategies. To address this challenge, we analysed transcriptome data of post-mortem human brain samples of healthy elders and individuals with late-onset AD from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP) and Mayo Clinic (MayoRNAseq) studies in the AMP-AD consortium. In this context, we conducted several bioinformatics and systems medicine analyses including the construction of AD-specific co-expression networks and genome-scale metabolic modelling of the brain in AD patients to identify key genes, metabolites and pathways involved in the progression of AD. We identified AMIGO1 and GRPRASP2 as examples of commonly altered marker genes in AD patients. Moreover, we found alterations in energy metabolism, represented by reduced oxidative phosphorylation and ATPase activity, as well as the depletion of hexanoyl-CoA, pentanoyl-CoA, (2E)-hexenoyl-CoA and numerous other unsaturated fatty acids in the brain. We also observed that neuroprotective metabolites (e.g., vitamins, retinoids and unsaturated fatty acids) tend to be depleted in the AD brain, while neurotoxic metabolites (e.g., β-alanine, bilirubin) were more abundant. In summary, we systematically revealed the key genes and pathways related to the progression of AD, gained insight into the crucial mechanisms of AD and identified some possible targets that could be used in the treatment of AD.
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Affiliation(s)
- Abdulahad Bayraktar
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.B.); (S.L.); (S.S.)
| | - Simon Lam
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.B.); (S.L.); (S.S.)
| | - Ozlem Altay
- Science for Life Laboratory, KTH–Royal Institute of Technology, SE-17121 Stockholm, Sweden; (O.A.); (X.L.); (M.Y.); (C.Z.); (M.A.); (M.U.)
| | - Xiangyu Li
- Science for Life Laboratory, KTH–Royal Institute of Technology, SE-17121 Stockholm, Sweden; (O.A.); (X.L.); (M.Y.); (C.Z.); (M.A.); (M.U.)
| | - Meng Yuan
- Science for Life Laboratory, KTH–Royal Institute of Technology, SE-17121 Stockholm, Sweden; (O.A.); (X.L.); (M.Y.); (C.Z.); (M.A.); (M.U.)
| | - Cheng Zhang
- Science for Life Laboratory, KTH–Royal Institute of Technology, SE-17121 Stockholm, Sweden; (O.A.); (X.L.); (M.Y.); (C.Z.); (M.A.); (M.U.)
| | - Muhammad Arif
- Science for Life Laboratory, KTH–Royal Institute of Technology, SE-17121 Stockholm, Sweden; (O.A.); (X.L.); (M.Y.); (C.Z.); (M.A.); (M.U.)
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Ataturk University, Erzurum 25240, Turkey;
| | - Mathias Uhlén
- Science for Life Laboratory, KTH–Royal Institute of Technology, SE-17121 Stockholm, Sweden; (O.A.); (X.L.); (M.Y.); (C.Z.); (M.A.); (M.U.)
| | - Saeed Shoaie
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.B.); (S.L.); (S.S.)
- Science for Life Laboratory, KTH–Royal Institute of Technology, SE-17121 Stockholm, Sweden; (O.A.); (X.L.); (M.Y.); (C.Z.); (M.A.); (M.U.)
| | - Adil Mardinoglu
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King’s College London, London SE1 9RT, UK; (A.B.); (S.L.); (S.S.)
- Science for Life Laboratory, KTH–Royal Institute of Technology, SE-17121 Stockholm, Sweden; (O.A.); (X.L.); (M.Y.); (C.Z.); (M.A.); (M.U.)
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41
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Zeybel M, Altay O, Arif M, Li X, Yang H, Fredolini C, Akyildiz M, Saglam B, Gonenli MG, Ural D, Kim W, Schwenk JM, Zhang C, Shoaie S, Nielsen J, Uhlén M, Borén J, Mardinoglu A. Combined metabolic activators therapy ameliorates liver fat in nonalcoholic fatty liver disease patients. Mol Syst Biol 2021; 17:e10459. [PMID: 34694070 PMCID: PMC8724764 DOI: 10.15252/msb.202110459] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 09/16/2021] [Accepted: 09/29/2021] [Indexed: 12/29/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) refers to excess fat accumulation in the liver. In animal experiments and human kinetic study, we found that administration of combined metabolic activators (CMAs) promotes the oxidation of fat, attenuates the resulting oxidative stress, activates mitochondria, and eventually removes excess fat from the liver. Here, we tested the safety and efficacy of CMA in NAFLD patients in a placebo-controlled 10-week study. We found that CMA significantly decreased hepatic steatosis and levels of aspartate aminotransferase, alanine aminotransferase, uric acid, and creatinine, whereas found no differences on these variables in the placebo group after adjustment for weight loss. By integrating clinical data with plasma metabolomics and inflammatory proteomics as well as oral and gut metagenomic data, we revealed the underlying molecular mechanisms associated with the reduced hepatic fat and inflammation in NAFLD patients and identified the key players involved in the host-microbiome interactions. In conclusion, we showed that CMA can be used to develop a pharmacological treatment strategy in NAFLD patients.
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Affiliation(s)
- Mujdat Zeybel
- NIHR Nottingham Biomedical Research CentreNottingham University Hospitals NHS Trust & University of NottinghamNottinghamUK
- Nottingham Digestive Diseases Centre, School of MedicineUniversity of NottinghamNottinghamUK
- Department of Gastroenterology and Hepatology, School of MedicineKoç UniversityIstanbulTurkey
| | - Ozlem Altay
- Science for Life LaboratoryKTH ‐ Royal Institute of TechnologyStockholmSweden
| | - Muhammad Arif
- Science for Life LaboratoryKTH ‐ Royal Institute of TechnologyStockholmSweden
| | - Xiangyu Li
- Science for Life LaboratoryKTH ‐ Royal Institute of TechnologyStockholmSweden
| | - Hong Yang
- Science for Life LaboratoryKTH ‐ Royal Institute of TechnologyStockholmSweden
| | - Claudia Fredolini
- Science for Life LaboratoryKTH ‐ Royal Institute of TechnologyStockholmSweden
| | - Murat Akyildiz
- Department of Gastroenterology and Hepatology, School of MedicineKoç UniversityIstanbulTurkey
| | - Burcin Saglam
- Department of Gastroenterology and Hepatology, School of MedicineKoç UniversityIstanbulTurkey
| | - Mehmet Gokhan Gonenli
- Department of Gastroenterology and Hepatology, School of MedicineKoç UniversityIstanbulTurkey
| | - Dilek Ural
- Department of Cardiology, School of MedicineKoç UniversityIstanbulTurkey
| | - Woonghee Kim
- Science for Life LaboratoryKTH ‐ Royal Institute of TechnologyStockholmSweden
| | - Jochen M Schwenk
- Science for Life LaboratoryKTH ‐ Royal Institute of TechnologyStockholmSweden
| | - Cheng Zhang
- Science for Life LaboratoryKTH ‐ Royal Institute of TechnologyStockholmSweden
- School of Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina
| | - Saeed Shoaie
- Science for Life LaboratoryKTH ‐ Royal Institute of TechnologyStockholmSweden
- Centre for Host‐Microbiome Interactions, Faculty of DentistryOral & Craniofacial Sciences, King’s College LondonLondonUK
| | - Jens Nielsen
- Department of Biology and Biological EngineeringChalmers University of TechnologyGothenburgSweden
| | - Mathias Uhlén
- Science for Life LaboratoryKTH ‐ Royal Institute of TechnologyStockholmSweden
| | - Jan Borén
- Department of Molecular and Clinical MedicineUniversity of Gothenburg and Sahlgrenska University HospitalGothenburgSweden
| | - Adil Mardinoglu
- Science for Life LaboratoryKTH ‐ Royal Institute of TechnologyStockholmSweden
- Centre for Host‐Microbiome Interactions, Faculty of DentistryOral & Craniofacial Sciences, King’s College LondonLondonUK
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42
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Lam S, Hartmann N, Benfeitas R, Zhang C, Arif M, Turkez H, Uhlén M, Englert C, Knight R, Mardinoglu A. Systems Analysis Reveals Ageing-Related Perturbations in Retinoids and Sex Hormones in Alzheimer's and Parkinson's Diseases. Biomedicines 2021; 9:1310. [PMID: 34680427 PMCID: PMC8533098 DOI: 10.3390/biomedicines9101310] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/22/2021] [Accepted: 09/22/2021] [Indexed: 01/13/2023] Open
Abstract
Neurodegenerative diseases, including Alzheimer's (AD) and Parkinson's diseases (PD), are complex heterogeneous diseases with highly variable patient responses to treatment. Due to the growing evidence for ageing-related clinical and pathological commonalities between AD and PD, these diseases have recently been studied in tandem. In this study, we analysed transcriptomic data from AD and PD patients, and stratified these patients into three subclasses with distinct gene expression and metabolic profiles. Through integrating transcriptomic data with a genome-scale metabolic model and validating our findings by network exploration and co-analysis using a zebrafish ageing model, we identified retinoids as a key ageing-related feature in all subclasses of AD and PD. We also demonstrated that the dysregulation of androgen metabolism by three different independent mechanisms is a source of heterogeneity in AD and PD. Taken together, our work highlights the need for stratification of AD/PD patients and development of personalised and precision medicine approaches based on the detailed characterisation of these subclasses.
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Affiliation(s)
- Simon Lam
- Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK;
| | - Nils Hartmann
- Leibniz Institute on Aging-Fritz Lipmann Institute, 07745 Jena, Germany; (N.H.); (C.E.)
| | - Rui Benfeitas
- National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, SE-17121 Stockholm, Sweden;
| | - Cheng Zhang
- Science for Life Laboratory, KTH—Royal Institute of Technology, SE-17121 Stockholm, Sweden; (C.Z.); (M.A.); (M.U.)
| | - Muhammad Arif
- Science for Life Laboratory, KTH—Royal Institute of Technology, SE-17121 Stockholm, Sweden; (C.Z.); (M.A.); (M.U.)
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, 25240 Erzurum, Turkey;
| | - Mathias Uhlén
- Science for Life Laboratory, KTH—Royal Institute of Technology, SE-17121 Stockholm, Sweden; (C.Z.); (M.A.); (M.U.)
| | - Christoph Englert
- Leibniz Institute on Aging-Fritz Lipmann Institute, 07745 Jena, Germany; (N.H.); (C.E.)
- Institute of Biochemistry and Biophysics, Freidrich-Schiller-University Jena, 07745 Jena, Germany
| | - Robert Knight
- Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK;
| | - Adil Mardinoglu
- Faculty of Dentistry, Oral and Craniofacial Sciences, King’s College London, London SE1 9RT, UK;
- Science for Life Laboratory, KTH—Royal Institute of Technology, SE-17121 Stockholm, Sweden; (C.Z.); (M.A.); (M.U.)
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43
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Doran S, Arif M, Lam S, Bayraktar A, Turkez H, Uhlen M, Boren J, Mardinoglu A. Multi-omics approaches for revealing the complexity of cardiovascular disease. Brief Bioinform 2021; 22:bbab061. [PMID: 33725119 PMCID: PMC8425417 DOI: 10.1093/bib/bbab061] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 01/20/2021] [Accepted: 02/05/2021] [Indexed: 02/06/2023] Open
Abstract
The development and progression of cardiovascular disease (CVD) can mainly be attributed to the narrowing of blood vessels caused by atherosclerosis and thrombosis, which induces organ damage that will result in end-organ dysfunction characterized by events such as myocardial infarction or stroke. It is also essential to consider other contributory factors to CVD, including cardiac remodelling caused by cardiomyopathies and co-morbidities with other diseases such as chronic kidney disease. Besides, there is a growing amount of evidence linking the gut microbiota to CVD through several metabolic pathways. Hence, it is of utmost importance to decipher the underlying molecular mechanisms associated with these disease states to elucidate the development and progression of CVD. A wide array of systems biology approaches incorporating multi-omics data have emerged as an invaluable tool in establishing alterations in specific cell types and identifying modifications in signalling events that promote disease development. Here, we review recent studies that apply multi-omics approaches to further understand the underlying causes of CVD and provide possible treatment strategies by identifying novel drug targets and biomarkers. We also discuss very recent advances in gut microbiota research with an emphasis on how diet and microbial composition can impact the development of CVD. Finally, we present various biological network analyses and other independent studies that have been employed for providing mechanistic explanation and developing treatment strategies for end-stage CVD, namely myocardial infarction and stroke.
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Affiliation(s)
- Stephen Doran
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, United Kingdom
| | - Muhammad Arif
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Simon Lam
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, United Kingdom
| | - Abdulahad Bayraktar
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, United Kingdom
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Mathias Uhlen
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Jan Boren
- Institute of Medicine, Department of Molecular and Clinical Medicine, University of Gothenburg and Sahlgrenska University Hospital Gothenburg, Sweden
| | - Adil Mardinoglu
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, SE1 9RT, United Kingdom
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
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44
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Altay O, Arif M, Li X, Yang H, Aydın M, Alkurt G, Kim W, Akyol D, Zhang C, Dinler‐Doganay G, Turkez H, Shoaie S, Nielsen J, Borén J, Olmuscelik O, Doganay L, Uhlén M, Mardinoglu A. Combined Metabolic Activators Accelerates Recovery in Mild-to-Moderate COVID-19. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:e2101222. [PMID: 34180141 PMCID: PMC8420376 DOI: 10.1002/advs.202101222] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/25/2021] [Revised: 05/19/2021] [Indexed: 05/02/2023]
Abstract
COVID-19 is associated with mitochondrial dysfunction and metabolic abnormalities, including the deficiencies in nicotinamide adenine dinucleotide (NAD+ ) and glutathione metabolism. Here it is investigated if administration of a mixture of combined metabolic activators (CMAs) consisting of glutathione and NAD+ precursors can restore metabolic function and thus aid the recovery of COVID-19 patients. CMAs include l-serine, N-acetyl-l-cysteine, nicotinamide riboside, and l-carnitine tartrate, salt form of l-carnitine. Placebo-controlled, open-label phase 2 study and double-blinded phase 3 clinical trials are conducted to investigate the time of symptom-free recovery on ambulatory patients using CMAs. The results of both studies show that the time to complete recovery is significantly shorter in the CMA group (6.6 vs 9.3 d) in phase 2 and (5.7 vs 9.2 d) in phase 3 trials compared to placebo group. A comprehensive analysis of the plasma metabolome and proteome reveals major metabolic changes. Plasma levels of proteins and metabolites associated with inflammation and antioxidant metabolism are significantly improved in patients treated with CMAs as compared to placebo. The results show that treating patients infected with COVID-19 with CMAs lead to a more rapid symptom-free recovery, suggesting a role for such a therapeutic regime in the treatment of infections leading to respiratory problems.
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Affiliation(s)
- Ozlem Altay
- Science for Life LaboratoryKTH—Royal Institute of TechnologyStockholmSE‐100 44Sweden
- Department of Clinical MicrobiologyDr Sami Ulus Training and Research HospitalUniversity of Health SciencesAnkara06080Turkey
| | - Muhammad Arif
- Science for Life LaboratoryKTH—Royal Institute of TechnologyStockholmSE‐100 44Sweden
| | - Xiangyu Li
- Science for Life LaboratoryKTH—Royal Institute of TechnologyStockholmSE‐100 44Sweden
| | - Hong Yang
- Science for Life LaboratoryKTH—Royal Institute of TechnologyStockholmSE‐100 44Sweden
| | - Mehtap Aydın
- Department of Infectious DiseasesUmraniye Training and Research HospitalUniversity of Health SciencesIstanbul34766Turkey
| | - Gizem Alkurt
- Genomic Laboratory (GLAB)Umraniye Training and Research HospitalUniversity of Health SciencesIstanbul34766Turkey
| | - Woonghee Kim
- Science for Life LaboratoryKTH—Royal Institute of TechnologyStockholmSE‐100 44Sweden
| | - Dogukan Akyol
- Genomic Laboratory (GLAB)Umraniye Training and Research HospitalUniversity of Health SciencesIstanbul34766Turkey
| | - Cheng Zhang
- Science for Life LaboratoryKTH—Royal Institute of TechnologyStockholmSE‐100 44Sweden
- School of Pharmaceutical Sciences & Key Laboratory of Advanced Drug Preparation TechnologiesMinistry of EducationZhengzhou UniversityZhengzhouHenan450001P. R. China
| | - Gizem Dinler‐Doganay
- Department of Molecular Biology and GeneticsIstanbul Technical UniversityIstanbul34469Turkey
| | - Hasan Turkez
- Department of Medical BiologyFaculty of MedicineAtatürk UniversityErzurum25240Turkey
| | - Saeed Shoaie
- Science for Life LaboratoryKTH—Royal Institute of TechnologyStockholmSE‐100 44Sweden
- Centre for Host‐Microbiome InteractionsFaculty of Dentistry, Oral & Craniofacial SciencesKing's College LondonLondonSE1 1ULUK
| | - Jens Nielsen
- Department of Biology and Biological EngineeringChalmers University of TechnologyGothenburgSE‐41296Sweden
| | - Jan Borén
- Department of Molecular and Clinical MedicineUniversity of Gothenburg and Sahlgrenska University Hospital GothenburgGothenburgSE‐41345Sweden
| | - Oktay Olmuscelik
- Department of Internal MedicineIstanbul Medipol UniversityBagcılarIstanbul34214Turkey
| | - Levent Doganay
- Department of GastroenterologyUmraniye Training and Research HospitalUniversity of Health SciencesIstanbul34766Turkey
| | - Mathias Uhlén
- Science for Life LaboratoryKTH—Royal Institute of TechnologyStockholmSE‐100 44Sweden
| | - Adil Mardinoglu
- Science for Life LaboratoryKTH—Royal Institute of TechnologyStockholmSE‐100 44Sweden
- Centre for Host‐Microbiome InteractionsFaculty of Dentistry, Oral & Craniofacial SciencesKing's College LondonLondonSE1 1ULUK
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45
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Li X, Kim W, Juszczak K, Arif M, Sato Y, Kume H, Ogawa S, Turkez H, Boren J, Nielsen J, Uhlen M, Zhang C, Mardinoglu A. Stratification of patients with clear cell renal cell carcinoma to facilitate drug repositioning. iScience 2021; 24:102722. [PMID: 34258555 PMCID: PMC8253978 DOI: 10.1016/j.isci.2021.102722] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Revised: 05/14/2021] [Accepted: 06/10/2021] [Indexed: 12/24/2022] Open
Abstract
Clear cell renal cell carcinoma (ccRCC) is the most common histological type of kidney cancer and has high heterogeneity. Stratification of ccRCC is important since distinct subtypes differ in prognosis and treatment. Here, we applied a systems biology approach to stratify ccRCC into three molecular subtypes with different mRNA expression patterns and prognosis of patients. Further, we developed a set of biomarkers that could robustly classify the patients into each of the three subtypes and predict the prognosis of patients. Then, we reconstructed subtype-specific metabolic models and performed essential gene analysis to identify the potential drug targets. We identified four drug targets, including SOAT1, CRLS1, and ACACB, essential in all the three subtypes and GPD2, exclusively essential to subtype 1. Finally, we repositioned mitotane, an FDA-approved SOAT1 inhibitor, to treat ccRCC and showed that it decreased tumor cell viability and inhibited tumor cell growth based on in vitro experiments.
Three consistent molecular ccRCC subtypes were found to guide patients' prognoses REOs-based biomarker was developed to robustly classify patients at individual level SOAT1 is identified as a common drug target for all ccRCC subtypes Mitotane was repositioned treatment of ccRCC via inhibiting SOAT1
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Affiliation(s)
- Xiangyu Li
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm 17165, Sweden.,Bash Biotech Inc, 600 West Broadway, Suite 700, San Diego, CA 92101, USA
| | - Woonghee Kim
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm 17165, Sweden
| | - Kajetan Juszczak
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm 17165, Sweden
| | - Muhammad Arif
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm 17165, Sweden
| | - Yusuke Sato
- Department of Pathology and Tumor Biology, Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan.,Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
| | - Haruki Kume
- Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8654, Japan
| | - Seishi Ogawa
- Department of Pathology and Tumor Biology, Institute for the Advanced Study of Human Biology (WPI-ASHBi), Kyoto University, Kyoto 606-8501, Japan.,Centre for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institute, Stockholm 17177, Sweden
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum 25240, Turkey
| | - Jan Boren
- Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg 41345, Sweden
| | - Jens Nielsen
- Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg 41296, Sweden.,BioInnovation Institute, Copenhagen N 2200, Denmark
| | - Mathias Uhlen
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm 17165, Sweden
| | - Cheng Zhang
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm 17165, Sweden.,Key Laboratory of Advanced Drug Preparation Technologies, School of Pharmaceutical Sciences, Ministry of Education, Zhengzhou University, Zhengzhou 450001, China
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH-Royal Institute of Technology, Stockholm 17165, Sweden.,Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK
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46
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Arif M, Klevstig M, Benfeitas R, Doran S, Turkez H, Uhlén M, Clausen M, Wikström J, Etal D, Zhang C, Levin M, Mardinoglu A, Boren J. Integrative transcriptomic analysis of tissue-specific metabolic crosstalk after myocardial infarction. eLife 2021; 10:66921. [PMID: 33972017 PMCID: PMC8186902 DOI: 10.7554/elife.66921] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Accepted: 04/25/2021] [Indexed: 12/14/2022] Open
Abstract
Myocardial infarction (MI) promotes a range of systemic effects, many of which are unknown. Here, we investigated the alterations associated with MI progression in heart and other metabolically active tissues (liver, skeletal muscle, and adipose) in a mouse model of MI (induced by ligating the left ascending coronary artery) and sham-operated mice. We performed a genome-wide transcriptomic analysis on tissue samples obtained 6- and 24 hr post MI or sham operation. By generating tissue-specific biological networks, we observed: (1) dysregulation in multiple biological processes (including immune system, mitochondrial dysfunction, fatty-acid beta-oxidation, and RNA and protein processing) across multiple tissues post MI and (2) tissue-specific dysregulation in biological processes in liver and heart post MI. Finally, we validated our findings in two independent MI cohorts. Overall, our integrative analysis highlighted both common and specific biological responses to MI across a range of metabolically active tissues. The human body is like a state-of-the-art car, where each part must work together with all the others. When a car breaks down, most of the time the problem is not isolated to only one part, as it is an interconnected system. Diseases in the human body can also have systemic effects, so it is important to study their implications throughout the body. Most studies of heart attacks focus on the direct impact on the heart and the cardiovascular system. Learning more about how heart attacks affect rest of the body may help scientists identify heart attacks early or create improved treatments. Arif and Klevstig et al. show that heart attacks affect the metabolism throughout the body. In the experiments, mice underwent a procedure that mimics either a heart attack or a fake procedure. Then, Arif and Klevstig et al. compared the activity of genes in the heart, muscle, liver and fat tissue of the two groups of mice 6- and 24-hours after the operations. This revealed disruptions in the immune system, metabolism and the production of proteins. The experiments also showed that changes in the activity of four important genes are key to these changes. This suggests that this pattern of changes could be used as a way to identify heart attacks. The experiments show that heart attacks have important effects throughout the body, especially on metabolism. These discoveries may help scientists learn more about the underlying biological processes and develop new treatments that prevent the harmful systemic effects of heart attacks and boost recovery.
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Affiliation(s)
- Muhammad Arif
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Martina Klevstig
- Department of Molecular and Clinical Medicine, University of Gothenburg, The Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Rui Benfeitas
- National Bioinformatics Infrastructure Sweden (NBIS), Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
| | - Stephen Doran
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, United Kingdom
| | - Hasan Turkez
- Department of Medical Biology, Faculty of Medicine, Atatürk University, Erzurum, Turkey
| | - Mathias Uhlén
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Maryam Clausen
- Translational Genomics, BioPharmaceuticals R&D, Discovery Sciences, AstraZeneca, Gothenburg, Sweden
| | - Johannes Wikström
- Bioscience Cardiovascular, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden
| | - Damla Etal
- Translational Genomics, BioPharmaceuticals R&D, Discovery Sciences, AstraZeneca, Gothenburg, Sweden
| | - Cheng Zhang
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden
| | - Malin Levin
- Department of Molecular and Clinical Medicine, University of Gothenburg, The Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH - Royal Institute of Technology, Stockholm, Sweden.,Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London, United Kingdom
| | - Jan Boren
- Department of Molecular and Clinical Medicine, University of Gothenburg, The Wallenberg Laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden
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47
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Chapman MA, Arif M, Emanuelsson EB, Reitzner SM, Lindholm ME, Mardinoglu A, Sundberg CJ. Skeletal Muscle Transcriptomic Comparison between Long-Term Trained and Untrained Men and Women. Cell Rep 2021; 31:107808. [PMID: 32579934 DOI: 10.1016/j.celrep.2020.107808] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Revised: 04/23/2020] [Accepted: 06/02/2020] [Indexed: 12/23/2022] Open
Abstract
To better understand the health benefits of lifelong exercise in humans, we conduct global skeletal muscle transcriptomic analyses of long-term endurance- (9 men, 9 women) and strength-trained (7 men) humans compared with age-matched untrained controls (7 men, 8 women). Transcriptomic analysis, Gene Ontology, and genome-scale metabolic modeling demonstrate changes in pathways related to the prevention of metabolic diseases, particularly with endurance training. Our data also show prominent sex differences between controls and that these differences are reduced with endurance training. Additionally, we compare our data with studies examining muscle gene expression before and after a months-long training period in individuals with metabolic diseases. This analysis reveals that training shifts gene expression in individuals with impaired metabolism to become more similar to our endurance-trained group. Overall, our data provide an extensive examination of the accumulated transcriptional changes that occur with decades-long training and identify important "exercise-responsive" genes that could attenuate metabolic disease.
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Affiliation(s)
- Mark A Chapman
- Department of Integrated Engineering, University of San Diego, San Diego, CA 92110, USA; Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden.
| | - Muhammad Arif
- Science for Life Laboratory, KTH-Royal Institute of Technology, 171 65 Solna, Sweden
| | - Eric B Emanuelsson
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Stefan M Reitzner
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Maléne E Lindholm
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Medicine, School of Medicine, Stanford University, Stanford CA 94305, USA
| | - Adil Mardinoglu
- Science for Life Laboratory, KTH-Royal Institute of Technology, 171 65 Solna, Sweden; Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, London SE1 9RT, UK
| | - Carl Johan Sundberg
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Learning, Informatics, Management and Ethics, Karolinska Institutet, 171 77 Stockholm, Sweden; Department of Laboratory Medicine, Karolinska Institutet, 141 52 Huddinge, Sweden
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48
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Gao Y, Zhang J, Xiao X, Ren Y, Yan X, Yue J, Wang T, Wu Z, Lv Y, Wu R. The Role of Gut Microbiota in Duodenal-Jejunal Bypass Surgery-Induced Improvement of Hepatic Steatosis in HFD-Fed Rats. Front Cell Infect Microbiol 2021; 11:640448. [PMID: 33869077 PMCID: PMC8050338 DOI: 10.3389/fcimb.2021.640448] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/16/2021] [Indexed: 12/12/2022] Open
Abstract
Bariatric surgery including duodenal-jejunal bypass surgery (DJB) improves insulin sensitivity and reduces obesity-associated inflammation. However, the underlying mechanism for such an improvement is still incompletely understood. Our objective was to investigate the role of the gut microbiota in DJB-associated improvement of hepatic steatosis in high fat diet (HFD)-fed rats. To study this, hepatic steatosis was induced in male adult Sprague-Dawley rats by feeding them with a 60% HFD. At 8 weeks after HFD feeding, the rats were subjected to either DJB or sham operation. HFD was resumed 1 week after the surgery for 3 more weeks. In additional groups of animals, feces were collected from HFD-DJB rats at 2 weeks after DJB. These feces were then transplanted to HFD-fed rats without DJB at 8 weeks after HFD feeding. Hepatic steatosis and fecal microbiota were analyzed at 4 weeks after surgery or fecal transplantation. Our results showed that DJB alleviated hepatic steatosis in HFD-fed rats. Fecal microbiota analysis showed that HFD-fed and standard diet-fed rats clustered differently. DJB induced substantial compositional changes in the gut microbiota. The fecal microbiota of HFD-fed rats received fecal transplant from DJB rats overlapped with that of HFD-DJB rats. Treatment of rats with HFD-induced liver lesions by fecal transplant from DJB-operated HFD-fed rats also attenuated hepatic steatosis. Thus, alterations in the gut microbiota after DJB surgery are sufficient to attenuate hepatic steatosis in HFD-fed rats. Targeting the gut microbiota could be a promising approach for preventing or treating human NAFLD.
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Affiliation(s)
- Yi Gao
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Gastrointestinal Surgery Department, Affiliated Hospital of Guilin Medical University, Guilin, China
| | - Jia Zhang
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xiao Xiao
- School of Basic Medicine, Hubei University of Medicine, Shiyan, China
| | - Yifan Ren
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xiaopeng Yan
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Jing Yue
- Gastrointestinal Surgery Department, Affiliated Hospital of Guilin Medical University, Guilin, China
- School of Basic Medicine, Hubei University of Medicine, Shiyan, China
| | - Tieyan Wang
- Department of Pathology, Shiyan Taihe Hospital, Hubei University of Medicine, Shiyan, China
| | - Zheng Wu
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yi Lv
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Rongqian Wu
- National Local Joint Engineering Research Center for Precision Surgery and Regenerative Medicine, Shaanxi Provincial Center for Regenerative Medicine and Surgical Engineering, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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49
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Rosario D, Bidkhori G, Lee S, Bedarf J, Hildebrand F, Le Chatelier E, Uhlen M, Ehrlich SD, Proctor G, Wüllner U, Mardinoglu A, Shoaie S. Systematic analysis of gut microbiome reveals the role of bacterial folate and homocysteine metabolism in Parkinson's disease. Cell Rep 2021; 34:108807. [PMID: 33657381 DOI: 10.1016/j.celrep.2021.108807] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 12/22/2020] [Accepted: 02/09/2021] [Indexed: 01/06/2023] Open
Abstract
Parkinson's disease (PD) is the most common progressive neurological disorder compromising motor functions. However, nonmotor symptoms, such as gastrointestinal (GI) dysfunction, precede those affecting movement. Evidence of an early involvement of the GI tract and enteric nervous system highlights the need for better understanding of the role of gut microbiota in GI complications in PD. Here, we investigate the gut microbiome of patients with PD using metagenomics and serum metabolomics. We integrate these data using metabolic modeling and construct an integrative correlation network giving insight into key microbial species linked with disease severity, GI dysfunction, and age of patients with PD. Functional analysis reveals an increased microbial capability to degrade mucin and host glycans in PD. Personalized community-level metabolic modeling reveals the microbial contribution to folate deficiency and hyperhomocysteinemia observed in patients with PD. The metabolic modeling approach could be applied to uncover gut microbial metabolic contributions to PD pathophysiology.
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Affiliation(s)
- Dorines Rosario
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, SE1 9RT London, UK
| | - Gholamreza Bidkhori
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, SE1 9RT London, UK
| | - Sunjae Lee
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, SE1 9RT London, UK
| | - Janis Bedarf
- Department of Neurology, University Hospital Bonn, Venusberg Campus 1, 53127 Bonn, Germany; Gut Microbes & Health, Quadram Institute Bioscience, Norwich Research Park, Norwich, Norfolk NR4 7UA, UK
| | - Falk Hildebrand
- Gut Microbes & Health, Quadram Institute Bioscience, Norwich Research Park, Norwich, Norfolk NR4 7UA, UK; European Molecular Biology Laboratory, Structural and Computational Biology Unit, 69117 Heidelberg, Germany; Digital Biology, Earlham Institute, Norwich, Norwich Research Park, Norwich NR4 7UZ, Norfolk, UK
| | | | - Mathias Uhlen
- Science for Life Laboratory (SciLifeLab), KTH - Royal Institute of Technology, Tomtebodavägen 23, 171 65 Solna, Stockholm, Sweden
| | | | - Gordon Proctor
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, SE1 9RT London, UK
| | - Ullrich Wüllner
- Department of Neurology, University Hospital Bonn, Venusberg Campus 1, 53127 Bonn, Germany; German Centre for Neurodegenerative Disease Research (DZNE), 53127 Bonn, Germany
| | - Adil Mardinoglu
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, SE1 9RT London, UK; Science for Life Laboratory (SciLifeLab), KTH - Royal Institute of Technology, Tomtebodavägen 23, 171 65 Solna, Stockholm, Sweden.
| | - Saeed Shoaie
- Centre for Host-Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, SE1 9RT London, UK; Science for Life Laboratory (SciLifeLab), KTH - Royal Institute of Technology, Tomtebodavägen 23, 171 65 Solna, Stockholm, Sweden.
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Harzandi A, Lee S, Bidkhori G, Saha S, Hendry BM, Mardinoglu A, Shoaie S, Sharpe CC. Acute kidney injury leading to CKD is associated with a persistence of metabolic dysfunction and hypertriglyceridemia. iScience 2021; 24:102046. [PMID: 33554059 PMCID: PMC7843454 DOI: 10.1016/j.isci.2021.102046] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/12/2020] [Accepted: 01/06/2021] [Indexed: 12/14/2022] Open
Abstract
Fibrosis is the pathophysiological hallmark of progressive chronic kidney disease (CKD). The kidney is a highly metabolically active organ, and it has been suggested that disruption in its metabolism leads to renal fibrosis. We developed a longitudinal mouse model of acute kidney injury leading to CKD and an in vitro model of epithelial to mesenchymal transition to study changes in metabolism, inflammation, and fibrosis. Using transcriptomics, metabolic modeling, and serum metabolomics, we observed sustained fatty acid metabolic dysfunction in the mouse model from early to late stages of CKD. Increased fatty acid biosynthesis and downregulation of catabolic pathways for triglycerides and diacylglycerides were associated with a marked increase in these lipids in the serum. We therefore suggest that the kidney may be the source of the abnormal lipid profile seen in patients with CKD, which may provide insights into the association between CKD and cardiovascular disease.
Following AKI, markers of fibrosis and inflammation go up simultaneously AKI is associated with reduced fatty acid oxidation and oxidative phosphorylation Changes in metabolism persist as chronic kidney disease develops Changes in metabolism are associated with increased serum levels of triglycerides
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Affiliation(s)
- Azadeh Harzandi
- Renal Sciences, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, SE5 9NU London, UK
| | - Sunjae Lee
- School of Life Sciences, Gwangju Institute of Science and Technology, Gwangju, Republic of Korea, 61005
- Centre for Host–Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, SE1 9RT London, UK
| | - Gholamreza Bidkhori
- Centre for Host–Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, SE1 9RT London, UK
| | - Sujit Saha
- Renal Sciences, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, SE5 9NU London, UK
| | - Bruce M. Hendry
- Renal Sciences, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, SE5 9NU London, UK
| | - Adil Mardinoglu
- Centre for Host–Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, SE1 9RT London, UK
- Science for Life Laboratory (SciLifeLab), KTH - Royal Institute of Technology, Tomtebodavägen 23, Solna, Stockholm 171 65, Sweden
- Corresponding author
| | - Saeed Shoaie
- Centre for Host–Microbiome Interactions, Faculty of Dentistry, Oral & Craniofacial Sciences, King's College London, SE1 9RT London, UK
- Science for Life Laboratory (SciLifeLab), KTH - Royal Institute of Technology, Tomtebodavägen 23, Solna, Stockholm 171 65, Sweden
- Corresponding author
| | - Claire C. Sharpe
- Renal Sciences, Department of Inflammation Biology, School of Immunology & Microbial Sciences, Faculty of Life Sciences and Medicine, King's College London, SE5 9NU London, UK
- Corresponding author
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