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1
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Zhang X, Guo Z, Li Y, Xu Y. Splicing to orchestrate cell fate. MOLECULAR THERAPY. NUCLEIC ACIDS 2025; 36:102416. [PMID: 39811494 PMCID: PMC11729663 DOI: 10.1016/j.omtn.2024.102416] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/16/2025]
Abstract
Alternative splicing (AS) plays a critical role in gene expression by generating protein diversity from single genes. This review provides an overview of the role of AS in regulating cell fate, focusing on its involvement in processes such as cell proliferation, differentiation, apoptosis, and tumorigenesis. We explore how AS influences the cell cycle, particularly its impact on key stages like G1, S, and G2/M. The review also examines AS in cell differentiation, highlighting its effects on mesenchymal stem cells and neurogenesis, and how it regulates differentiation into adipocytes, osteoblasts, and chondrocytes. Additionally, we discuss the role of AS in programmed cell death, including apoptosis and pyroptosis, and its contribution to cancer progression. Importantly, targeting aberrant splicing mechanisms presents promising therapeutic opportunities for restoring normal cellular function. By synthesizing recent findings, this review provides insights into how AS governs cellular fate and offers directions for future research into splicing regulatory networks.
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Affiliation(s)
- Xurui Zhang
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, P.R. China
| | - Zhonghao Guo
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, P.R. China
| | - Yachen Li
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, P.R. China
| | - Yungang Xu
- Department of Cell Biology and Genetics, School of Basic Medical Sciences, Xi’an Jiaotong University Health Science Center, Xi’an 710061, P.R. China
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2
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Yamazaki T, Cable EE, Schnabl B. Peroxisome proliferator-activated receptor delta and liver diseases. Hepatol Commun 2025; 9:e0646. [PMID: 39899669 DOI: 10.1097/hc9.0000000000000646] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 12/16/2024] [Indexed: 02/05/2025] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in transcriptional regulation and play an important role in many physiological and metabolic processes. Unlike PPAR-alpha and PPAR-gamma, PPAR-delta is ubiquitously expressed, and its activity is key to maintaining proper metabolic homeostasis within the liver. PPAR-delta not only regulates physiologic processes of lipid, glucose, and bile acid metabolism but also attenuates pathologic responses to alcohol metabolism, inflammation, fibrosis, and carcinogenesis, and is considered an important therapeutic target in liver diseases. Promising results have been reported in clinical trials for PPAR-delta agonists in liver disease, and the selective agonist seladelpar was recently conditionally approved in the United States as a new treatment option for primary biliary cholangitis. This review provides an overview of PPAR-delta's function and biology in the liver, examines its kinetics and therapeutic potential across different liver diseases, and discusses the current status of clinical trials involving its agonists.
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Affiliation(s)
- Tomoo Yamazaki
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan
| | | | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, California, USA
- Department of Medicine, VA San Diego Healthcare System, San Diego, California, USA
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3
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Raina S, Samuel E, Fuchs H. DT-13 Mediates Ligand-Dependent Activation of PPARγ Response Elements In Vitro. BIOLOGY 2024; 13:1015. [PMID: 39765682 PMCID: PMC11673078 DOI: 10.3390/biology13121015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 11/28/2024] [Accepted: 11/29/2024] [Indexed: 01/11/2025]
Abstract
Activation of inflammatory pathways releases a storm of cytokines. Moreover, unregulated cytokines contribute to chronic inflammatory disorders. However, ligand-activated peroxisome proliferator-activated receptor gamma (PPARγ) is involved in suppressing inflammatory cytokines via transrepression of nuclear factor kappa B (NFκB). Therefore, in this study, the anti-inflammatory saponin DT-13 is explored as a ligand of PPARγ. DT-13 upregulated the expression of PPARγ in lipopolysaccharide (LPS)-stimulated RAW264.7 cells in comparison to treatment with LPS alone. Applying a HEK transfection model, we observed a DT-13 dose-dependent increase in ligand-dependent activation of PPARγ, which was compared with troglitazone and rosiglitazone. DT-13 was not able to compete with the synthetic fluoromone tracer for binding to PPARγ as observed in a fluorescence polarization binding assay, whereas molecular docking showed a possible binding interaction of DT-13 with the PPARγ nuclear receptor. We proved the expression of PPARγ protein in the presence of DT-13 using a robust cell-based HEK293FT transfection model. More in-depth analysis needs to be performed to evaluate the efficiency of the binding of DT-13 to PPARγ. A possible binding interaction of DT-13 to PPARγ was observed, similar to that of rosiglitazone. This study revealed a novel mechanism for anti-inflammatory effects by DT-13 through PPARγ-dependent transrepression of NFκB.
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Affiliation(s)
| | | | - Hendrik Fuchs
- Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Institute of Diagnostic Laboratory Medicine, Clinical Chemistry and Pathobiochemistry, Augustenburger Platz 1, D-13353 Berlin, Germany
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Sharma S, Choudhary M, Sharma O, Injeti E, Mittal A. Mechanistic insights into antidiabetic potential of Ficus viren against multi organ specific diabetic targets: molecular docking, MDS, MM-GBSA analysis. Comput Biol Chem 2024; 113:108185. [PMID: 39217892 DOI: 10.1016/j.compbiolchem.2024.108185] [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: 05/15/2024] [Revised: 06/19/2024] [Accepted: 08/22/2024] [Indexed: 09/04/2024]
Abstract
Ficus viren has been traditionally used to treat diabetes, and its extract inhibits carbohydrate/lipid metabolism and possesses anti-hyperglycemic potential. However, there is conflicting investigation related to F. viren extract effect on carbohydrate metabolism. Thus, bioactive and mechanism behind its antidiabetic potential is still scanty. This study explored F. viren's anti-diabetic property by identifying potential phytoconstituents and mechanism. A sequential in-silico approach was used i.e., druglikeness, molecular docking, post-docking MM-GBSA, ADMET studies, molecular dynamic simulation (MDS), and post-MDS MM-GBSA. We screened ∼32 phytoconstituents and twelve potential organ-specific diabetic targets (O.S.D.Ts i.e., IR, DPP-4, ppar-γ, ppar-α, ppar-δ, GLP-1R, SIRT-1, AMPK, GSK-3β, RAGE, and AR). Drug likeness study identified 18 druggable candidates among 32 phytoconstituents. K3A, quercetin, scutellarein, sorbifolin, and vogeline J identified as potential ligands from druggable ligands, using IR as the standard target. Subsequently, potential ligands docked with remaining O.S.D.Ts. and data showed that K3A binds strongly with AMPK, ppar-δ, DPP-4, and GSK-3β, while scutellarein binds with AR and ppar-α. Sorbifolin, quercetin, and vogeline J binds with ppar-α, ppar-γ, and RAGE, respectively. Post-docking MM-GBSA data (∆GBind) also depicted potential ligand's strong binding affinities with their corresponding targets. Thereafter, simulation data revealed that only scutellarein and sorbifolin showed dynamic stability with their respective targets, i.e., AR/ppar-α and ppar-α, respectively. Interestingly, post-MDS MM-GBSA revealed that only scutellarein exhibited strong ∆GBind of -55.08 kcal/mol and -75.48 kcal/mol with AR and ppar-α, respectively. Though, collective computational analysis supports antidiabetic potential of F. viren through AR and ppar-α modulation by scutellarein.
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Affiliation(s)
- Sachin Sharma
- Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra 136119, India
| | - Manjusha Choudhary
- Institute of Pharmaceutical Sciences, Kurukshetra University, Kurukshetra 136119, India
| | - Onkar Sharma
- Skeletal Muscle Lab, IIHS, Kurukshetra University, Kurukshetra, Haryana 136119, India
| | - Elisha Injeti
- Department of Pharmaceutical Sciences, Cedarville University, Cedarville, OH 45314, USA
| | - Ashwani Mittal
- Skeletal Muscle Lab, IIHS, Kurukshetra University, Kurukshetra, Haryana 136119, India.
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Al Harake SN, Abedin Y, Hatoum F, Nassar NZ, Ali A, Nassar A, Kanaan A, Bazzi S, Azar S, Harb F, Ghadieh HE. Involvement of a battery of investigated genes in lipid droplet pathophysiology and associated comorbidities. Adipocyte 2024; 13:2403380. [PMID: 39329369 PMCID: PMC11445895 DOI: 10.1080/21623945.2024.2403380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Revised: 08/29/2024] [Accepted: 09/05/2024] [Indexed: 09/28/2024] Open
Abstract
Lipid droplets (LDs) are highly specialized energy storage organelles involved in the maintenance of lipid homoeostasis by regulating lipid flux within white adipose tissue (WAT). The physiological function of adipocytes and LDs can be compromised by mutations in several genes, leading to NEFA-induced lipotoxicity, which ultimately manifests as metabolic complications, predominantly in the form of dyslipidemia, ectopic fat accumulation, and insulin resistance. In this review, we delineate the effects of mutations and deficiencies in genes - CIDEC, PPARG, BSCL2, AGPAT2, PLIN1, LIPE, LMNA, CAV1, CEACAM1, and INSR - involved in lipid droplet metabolism and their associated pathophysiological impairments, highlighting their roles in the development of lipodystrophies and metabolic dysfunction.
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Affiliation(s)
- Sami N. Al Harake
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Yasamin Abedin
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Fatema Hatoum
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Nour Zahraa Nassar
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Ali Ali
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Aline Nassar
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Amjad Kanaan
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Samer Bazzi
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Sami Azar
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Frederic Harb
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
| | - Hilda E. Ghadieh
- Department of Biomedical Sciences, Faculty of Medicine and Medical Sciences, University of Balamand, Kalhat, Lebanon
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6
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Clayton SA, Mizener AD, Whetsell MA, Rentz LE, Meadows EM, Geldenhuys WJ, Pistilli EE. Preclinical Multi-Omic Assessment of Pioglitazone in Skeletal Muscles of Mice Implanted with Human HER2/neu Overexpressing Breast Cancer Xenografts. Cancers (Basel) 2024; 16:3640. [PMID: 39518077 PMCID: PMC11544806 DOI: 10.3390/cancers16213640] [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: 08/28/2024] [Revised: 10/10/2024] [Accepted: 10/26/2024] [Indexed: 11/16/2024] Open
Abstract
Background/Objectives: Breast cancer (BC) is the second most commonly diagnosed cancer worldwide and is accompanied by fatigue during both active disease and remission in the majority of cases. Our lab has measured fatigue in isolated muscles from treatment-naive BC patient-derived orthotopic xenograft (BC-PDOX) mice. Here, we conducted a preclinical trial of pioglitazone in BC-PDOX mice to determine its efficacy in ameliorating BC-induced muscle fatigue, as well as its effects on transcriptomic, metabolomic, and lipidomic profiles in skeletal muscle. Methods: The pioglitazone and vehicle groups were treated orally for 4 weeks upon reaching a tumor volume of 600 mm3. Whole-animal indirect calorimetry was used to evaluate systemic metabolic states. The transcriptome was profiled using short-read bulk RNA sequencing (RNA-seq). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to profile the metabolome and lipidome. Fast and slow skeletal muscle function were evaluated using isolated ex vivo testing. Results: Pioglitazone was associated with a 16.634% lower average O2 consumption (mL∙h-1, p = 0.035), 16.309% lower average CO2 production (mL∙h-1, p = 0.022), and 16.4% lower cumulative energy expenditure (EE) (kcal∙h-1, p = 0.035), with no changes in substrate utilization. RNA-seq supported the downstream effects of pioglitazone on target genes and displayed considerable upregulation of mitochondrial bioenergetic pathways. K-means cluster 5 showed enrichment of the PPAR signaling pathway (adj. p < 0.05, Log2FC = 2.58). Skeletal muscle metabolomic and lipidomic profiles exhibited dysregulation in response to BC, which was partially restored in pioglitazone-treated mice compared to vehicle-treated BC-PDOX mice. In particular, the overall abundance of total ceramide levels was significantly lower in the PioTx group (-46.327%, p = 0.048). Despite molecular support for pioglitazone's efficacy, isolated muscle function was not affected by pioglitazone treatment. No significant difference in the area under the fatigue curve (AUC) was found between the pioglitazone and vehicle groups (p = 0.596). Conclusions: BC induces multi-omic dysregulation in skeletal muscle, which pioglitazone partially ameliorates. Future research should focus on profiling systemic metabolic dysfunction, identifying molecular biomarkers of fatigue, and testing alternative pioglitazone treatment regimens.
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Affiliation(s)
- Stuart A. Clayton
- Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV 26505, USA; (S.A.C.); (M.A.W.); (L.E.R.); (E.M.M.)
| | - Alan D. Mizener
- Cancer Institute, West Virginia University School of Medicine, Morgantown, WV 26506, USA;
| | - Marcella A. Whetsell
- Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV 26505, USA; (S.A.C.); (M.A.W.); (L.E.R.); (E.M.M.)
| | - Lauren E. Rentz
- Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV 26505, USA; (S.A.C.); (M.A.W.); (L.E.R.); (E.M.M.)
| | - Ethan M. Meadows
- Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV 26505, USA; (S.A.C.); (M.A.W.); (L.E.R.); (E.M.M.)
| | - Werner J. Geldenhuys
- Department of Pharmaceutical Science, West Virginia University School of Pharmacy, Morgantown, WV 26506, USA;
| | - Emidio E. Pistilli
- Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV 26505, USA; (S.A.C.); (M.A.W.); (L.E.R.); (E.M.M.)
- Cancer Institute, West Virginia University School of Medicine, Morgantown, WV 26506, USA;
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506, USA
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7
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Szkopek D, Mendel M, Kinsner M, Fotschki B, Juśkiewicz J, Kozłowski K, Matusevičius P, Konieczka P. Interaction Between Peroxisome Proliferator-Activated Receptors and Cannabidiol in the Gut of Chickens Applied to Different Challenge Conditions. Int J Mol Sci 2024; 25:11398. [PMID: 39518951 PMCID: PMC11547005 DOI: 10.3390/ijms252111398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Revised: 10/16/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are important targets for cannabidiol (CBD), which mediate many of its biological actions. The hypothesis of the present research assumed that PPARs affect the gut response to different challenge factors in chickens (C. perfringens vs. lipopolysaccharides (LPS) from E. coli), and that CBD can mediate the pathways of this response. The study proved that CBD and the challenge factors significantly affect the expression level of PPARα (p = 0.001) and selected genes determining gut barrier function. A positive correlation was demonstrated between PPARs and genes involved in the formation of tight junctions, immune, and oxidative stress responses in chickens. Dietary supplementation with CBD actively mediated the expression rate of PPARs, but the mechanism of interaction between CBD and PPARs was different depending on the stress factor used. The addition of CBD to the birds' diets did not contribute to reducing intestinal permeability under induced stress conditions nor cause stress, as indicated by the absence of elevated blood cortisol and endotoxin levels. CBD also supported the mechanisms of protecting intestinal cells from the cytotoxic effects in a C. perfringens challenge through the levels of genes involved in oxidative stress. This study indicates the importance of research toward understanding the mechanisms of PPARs as a target for enhancing intestinal barrier function, provides new results on the biological action of CBD in chickens, and shows a constant PPAR association with the jejunum mucosa of birds.
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Affiliation(s)
- Dominika Szkopek
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland;
| | - Marta Mendel
- Division of Pharmacology and Toxicology, Institute of Veterinary Medicine, Warsaw University of Life Sciences, Ciszewskiego 8, 02-786 Warsaw, Poland;
| | - Misza Kinsner
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland;
| | - Bartosz Fotschki
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748 Olsztyn, Poland; (B.F.); (J.J.)
| | - Jerzy Juśkiewicz
- Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Tuwima 10, 10-748 Olsztyn, Poland; (B.F.); (J.J.)
| | - Krzysztof Kozłowski
- Department of Poultry Science and Apiculture, University of Warmia and Mazury in Olsztyn, Oczapowskiego 5, 10-719 Olsztyn, Poland;
| | - Paulius Matusevičius
- Department of Animal Nutrition, Lithuanian University of Health Sciences, Tilzes 18, LT-47181 Kaunas, Lithuania;
| | - Paweł Konieczka
- Department of Animal Nutrition, The Kielanowski Institute of Animal Physiology and Nutrition, Polish Academy of Sciences, Instytucka 3, 05-110 Jabłonna, Poland;
- Department of Poultry Science and Apiculture, University of Warmia and Mazury in Olsztyn, Oczapowskiego 5, 10-719 Olsztyn, Poland;
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8
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Shen X, Génard-Walton M, Williams PL, James-Todd T, Ford JB, Rexrode KM, Calafat AM, Zhang D, Chavarro JE, Hauser R, Mínguez-Alarcón L, the EARTH Study Team. Mixtures of Urinary Phenol and Phthalate Metabolite Concentrations in Relation to Serum Lipid Levels among Pregnant Women: Results from the EARTH Study. TOXICS 2024; 12:574. [PMID: 39195676 PMCID: PMC11359712 DOI: 10.3390/toxics12080574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 07/22/2024] [Accepted: 08/01/2024] [Indexed: 08/29/2024]
Abstract
We examined whether mixtures of urinary concentrations of bisphenol A (BPA), parabens and phthalate metabolites were associated with serum lipid levels among 175 pregnant women who enrolled in the Environment and Reproductive Health (EARTH) Study (2005-2017), including triglycerides, total cholesterol, high-density lipoprotein (HDL), non-HDL, and low-density lipoprotein (LDL). We applied Bayesian Kernel Machine Regression (BKMR) and quantile g-computation while adjusting for confounders. In the BKMR models, we found no associations between chemical mixture and lipid levels, e.g., total cholesterol [mean difference (95% CRI, credible interval) = 0.02 (-0.31, 0.34)] and LDL [mean difference (95% CRI) = 0.10 (-0.22, 0.43)], when comparing concentrations at the 75th to the 25th percentile. When stratified by BMI, we found suggestive positive relationships between urinary propylparaben and total cholesterol and LDL among women with high BMI [mean difference (95% CRI) = 0.25 (-0.26, 0.75) and 0.35 (-0.25, 0.95)], but not with low BMI [mean difference (95% CRI) = 0.00 (-0.06, 0.07) and 0.00 (-0.07, 0.07)]. No association was found by quantile g-computation. This exploratory study suggests mixtures of phenol and phthalate metabolites were not associated with serum lipid levels during pregnancy, while there were some suggestive associations for certain BMI subgroups. Larger longitudinal studies with multiple assessments of both exposure and outcome are needed to corroborate these novel findings.
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Affiliation(s)
- Xilin Shen
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; (X.S.); (D.Z.)
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA
| | - Maximilien Génard-Walton
- Université Rennes, Inserm, EHESP, Irset (Institut de Recherche en Santé, Environnement et Travail)—UMR_S 1085, F-35000 Rennes, France;
| | - Paige L. Williams
- Department of Biostatistics and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
| | - Tamarra James-Todd
- Department of Epidemiology and Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; (T.J.-T.); (R.H.)
| | - Jennifer B. Ford
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
| | - Kathryn M. Rexrode
- Division of Women’s Health, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
| | - Antonia M. Calafat
- National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA 30329, USA;
| | - Dan Zhang
- Key Laboratory of Reproductive Genetics (Ministry of Education) and Department of Reproductive Endocrinology, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China; (X.S.); (D.Z.)
- Clinical Research Center on Children’s Health of Zhejiang Province, Hangzhou 310006, China
| | - Jorge E. Chavarro
- Departments of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
- Channing Division of Network Medicine, Harvard Medical School & Brigham and Women’s Hospital, Boston, MA 02115, USA
| | - Russ Hauser
- Department of Epidemiology and Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; (T.J.-T.); (R.H.)
- Department of Obstetrics, Gynaecology and Reproductive Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Lidia Mínguez-Alarcón
- Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
- Departments of Nutrition and Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA;
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Zhang N, An B, Zhao L, Zhao D, Lv B, Liu S. Investigation of the mechanism of nephrotoxicity of nux-vomica by PTGS2/CYP2C9-mediated arachidonic acid pathway and Jian Pi Tong Luo compound's protective effect. Biomed Chromatogr 2024; 38:e5859. [PMID: 38618996 DOI: 10.1002/bmc.5859] [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: 12/19/2023] [Revised: 02/03/2024] [Accepted: 02/16/2024] [Indexed: 04/16/2024]
Abstract
The clinical effectiveness of nux-vomica in treating rheumatism and arthralgia is noteworthy; however, its nephrotoxicity has sparked global concerns. Hence, there is value in conducting studies on detoxification methods based on traditional Chinese medicine compatibility theory. Blood biochemistry, enzyme-linked immunosorbent assay, and pathological sections were used to evaluate both the nephrotoxicity of nux-vomica and the efficacy of the Jian Pi Tong Luo (JPTL) compound in mitigating this toxicity. Kidney metabolomics, using ultra-high-performance liquid chromatography-quadrupole-time-of-flight-MS (UPLC-Q-TOF-MS), was applied to elucidate the alterations in small-molecule metabolites in vivo. In addition, network pharmacology analysis was used to verify the mechanism and pathways underlying the nephrotoxicity associated with nux-vomica. Finally, essential targets were validated through molecular docking and western blotting. The findings indicated significant nephrotoxicity associated with nux-vomica, while the JPTL compound demonstrated the ability to alleviate this toxicity. The mechanism potentially involves nux-vomica activating the "PTGS2/CYP2C9-phosphatidylcholine-arachidonic acid metabolic pathway." This study establishes a scientific foundation for the clinical use of nux-vomica and lays groundwork for further research and safety assessment of toxic Chinese herbal medicines.
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Affiliation(s)
- Na Zhang
- Drug Safety Evaluation Centre, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Baisong An
- Drug Safety Evaluation Centre, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Liangyou Zhao
- Drug Safety Evaluation Centre, Heilongjiang University of Chinese Medicine, Harbin, China
| | - Dapeng Zhao
- The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Bochuan Lv
- The First Affiliated Hospital of Heilongjiang University of Chinese Medicine, Harbin, China
| | - Shumin Liu
- Institute of Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, China
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10
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Cooreman MP, Vonghia L, Francque SM. MASLD/MASH and type 2 diabetes: Two sides of the same coin? From single PPAR to pan-PPAR agonists. Diabetes Res Clin Pract 2024; 212:111688. [PMID: 38697298 DOI: 10.1016/j.diabres.2024.111688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/24/2024] [Indexed: 05/04/2024]
Abstract
Type 2 diabetes (T2D) and metabolic dysfunction-associated steatotic liver disease (MASLD), mainly related to nutrition and lack of physical activity, are both very common conditions, share several disease pathways and clinical manifestations, and increasingly co-occur with disease progression. Insulin resistance is an upstream node in the biology of both conditions and triggers liver parenchymal injury, inflammation and fibrosis. Peroxisome proliferator-activated receptor (PPAR) nuclear transcription factors are master regulators of energy homeostasis - insulin signaling in liver, adipose and skeletal muscle tissue - and affect immune and fibrogenesis pathways. Among distinct yet overlapping effects, PPARα regulates lipid metabolism and energy expenditure, PPARβ/δ has anti-inflammatory effects and increases glucose uptake by skeletal muscle, while PPARγ improves insulin sensitivity and exerts direct antifibrotic effects on hepatic stellate cells. Together PPARs thus represent pharmacological targets across the entire biology of MASH. Single PPAR agonists are approved for hypertriglyceridemia (PPARα) and T2D (PPARγ), but these, as well as dual PPAR agonists, have shown mixed results as anti-MASH treatments in clinical trials. Agonists of all three PPAR isoforms have the potential to improve the full disease spectrum from insulin resistance to fibrosis, and correspondingly to improve cardiometabolic and hepatic health, as has been shown (phase II data) with the pan-PPAR agonist lanifibranor.
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Affiliation(s)
- Michael P Cooreman
- Research and Development, Inventiva, Daix, France; Research and Development, Inventiva, New York, NY, USA.
| | - Luisa Vonghia
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Sven M Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Edegem, Belgium; InflaMed Centre of Excellence, Laboratory for Experimental Medicine and Paediatrics, Translational Sciences in Inflammation and Immunology, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.
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11
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Clayton SA, Mizener AD, Whetsell M, Rentz LE, Meadows E, Geldenhuys W, Pistilli EE. Preclinical Multi-Omic Assessment of Pioglitazone in Skeletal Muscles of Mice Implanted with Human HER2/neu Overexpressing Breast Cancer Xenografts. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.15.589557. [PMID: 38659807 PMCID: PMC11042380 DOI: 10.1101/2024.04.15.589557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/26/2024]
Abstract
Breast cancer (BC) is the most prevalent cancer worldwide and is accompanied by fatigue during both active disease and remission in the majority of cases. Our lab has measured fatigue in isolated muscles from treatment-naive BC patient-derived orthotopic xenograft (BC-PDOX) mice. Here, we conducted a preclinical trial of pioglitazone in BC-PDOX mice to determine its efficacy in ameliorating BC-induced muscle fatigue, as well as its effects on transcriptomic, metabolomic, and lipidomic profiles in skeletal muscle. Methods The pioglitazone and vehicle groups were treated orally for 4 weeks upon reaching a tumor volume of 600 mm3. Whole-animal indirect calorimetry was used to evaluate systemic metabolic states. The transcriptome was profiled using short-read bulk RNA sequencing (RNA-seq). Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to profile the metabolome and lipidome. Fast and slow skeletal muscle function were evaluated using isolated ex vivo testing. Results Pioglitazone was associated with a significant overall decrease in metabolic rate, with no changes in substrate utilization. RNA-seq supported the downstream effects of pioglitazone on target genes and displayed considerable upregulation of mitochondrial bioenergetic pathways. Skeletal muscle metabolomic and lipidomic profiles exhibited dysregulation in response to BC, which was partially restored in pioglitazone-treated mice compared to vehicle-treated BC-PDOX mice. Despite molecular support for pioglitazone's efficacy, isolated muscle function was not affected by pioglitazone treatment. Conclusions BC induces multi-omic dysregulation in skeletal muscle, which pioglitazone partially ameliorates. Future research should focus on profiling systemic metabolic dysfunction, identifying molecular biomarkers of fatigue, and testing alternative pioglitazone treatment regimens.
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Affiliation(s)
- Stuart A. Clayton
- Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV, 26505
| | - Alan D. Mizener
- Cancer Institute, West Virginia University School of Medicine, Morgantown, WV, 26506
| | - Marcella Whetsell
- Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV, 26505
| | - Lauren E. Rentz
- Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV, 26505
| | - Ethan Meadows
- Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV, 26505
| | - Werner Geldenhuys
- Department of Pharmaceutical Science, West Virginia University School of Pharmacy, Morgantown, WV, 26506
| | - Emidio E. Pistilli
- Division of Exercise Physiology, Department of Human Performance, West Virginia University School of Medicine, Morgantown, WV, 26505
- Cancer Institute, West Virginia University School of Medicine, Morgantown, WV, 26506
- Department of Microbiology, Immunology, and Cell Biology, West Virginia University School of Medicine, Morgantown, WV 26506
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12
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He L, Feng X, Hu C, Liu S, Sheng H, Cai B, Ma Y. HOXA9 gene inhibits proliferation and differentiation and promotes apoptosis of bovine preadipocytes. BMC Genomics 2024; 25:358. [PMID: 38605318 PMCID: PMC11007997 DOI: 10.1186/s12864-024-10231-3] [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: 09/24/2023] [Accepted: 03/15/2024] [Indexed: 04/13/2024] Open
Abstract
BACKGROUND Hox gene family is an important transcription factor that regulates cell process, and plays a role in the process of adipocytes differentiation and fat deposition. Previous transcriptome sequencing studies have indicated that the Homeobox A9 gene (HOXA9) is a candidate gene for regulating the process of bovine lipid metabolism, but the function and specific mechanism of action remain unclear. Therefore, this study aims to explore the role of HOXA9 in the proliferation, differentiation and apoptosis of bovine preadipocytes through gain-of-function and lose-of-function. RESULT It found HOXA9 highly expressed in bovine adipose tissue, and its expression level changed significantly during adipocytes differentiation process. It gave a hint that HOXA9 may be involved in the process of bovine lipid metabolism. The results of HOXA9 gain-of-function experiments indicated that HOXA9 appeared to act as a negative regulator not only in the differentiation but also in the proliferation of bovine preadipocytes, which is mainly reflected that overexpression of HOXA9 down-regulate the mRNA and protein expression level of PPARγ, CEBPα and FABP4 (P < 0.05). The mRNA expression level of CDK1, CDK2, PCNA, CCNA2, CCNB1, CCND1 and CCNE2, as well as the protein expression of CDK2 also significantly decreased. The decrease of lipid droplets content was the main characteristic of the phenotype (P < 0.01), which further supported the evidence that HOXA9 was a negative regulator of preadipocytes differentiation. The decrease of cell proliferation rate and EdU positive rate, as well as the limitation of transition of preadipocytes from G0/G1 phase to S phase also provided evidence for the inhibition of proliferation. Apart from this above, we noted an interesting phenomenon that overexpression of HOXA9 showed in a significant upregulation of both mRNA and protein level of apoptosis markers, accompanied by a significant increase in cell apoptosis rate. These data led us not to refute the fact that HOXA9 played an active regulatory role in apoptosis. HOXA9 loss-of-function experiments, however, yielded the opposite results. Considering that HOXA9 acts as a transcription factor, we predicted its target genes. Dual luciferase reporter assay system indicated that overexpression of HOXA9 inhibits activity of PCNA promoter. CONCLUSION Taken together, we demonstrated for the first time that HOXA9 played a role as a negative regulatory factor in the differentiation and proliferation of preadipocytes, but played a positive regulatory role in apoptosis, and it may play a regulatory role by targeting PCNA. This study provides basic data for further exploring the regulatory network of intramuscular fat deposition in bovine.
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Affiliation(s)
- Lixia He
- College of Animal Science and Technology, Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, Ningxia University, 750021, Yinchuan, China
| | - Xue Feng
- College of Animal Science and Technology, Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, Ningxia University, 750021, Yinchuan, China
| | - Chunli Hu
- College of Animal Science and Technology, Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, Ningxia University, 750021, Yinchuan, China
| | - Shuang Liu
- College of Animal Science and Technology, Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, Ningxia University, 750021, Yinchuan, China
| | - Hui Sheng
- College of Animal Science and Technology, Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, Ningxia University, 750021, Yinchuan, China
| | - Bei Cai
- College of Animal Science and Technology, Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, Ningxia University, 750021, Yinchuan, China
| | - Yun Ma
- College of Animal Science and Technology, Key Laboratory of Ruminant Molecular and Cellular Breeding of Ningxia Hui Autonomous Region, Ningxia University, 750021, Yinchuan, China.
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13
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Zhang J, Tang M, Shang J. PPARγ Modulators in Lung Cancer: Molecular Mechanisms, Clinical Prospects, and Challenges. Biomolecules 2024; 14:190. [PMID: 38397426 PMCID: PMC10886696 DOI: 10.3390/biom14020190] [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: 12/30/2023] [Revised: 01/22/2024] [Accepted: 02/02/2024] [Indexed: 02/25/2024] Open
Abstract
Lung cancer is one of the most lethal malignancies worldwide. Peroxisome proliferator-activated receptor gamma (PPARγ, NR1C3) is a ligand-activated transcriptional factor that governs the expression of genes involved in glucolipid metabolism, energy homeostasis, cell differentiation, and inflammation. Multiple studies have demonstrated that PPARγ activation exerts anti-tumor effects in lung cancer through regulation of lipid metabolism, induction of apoptosis, and cell cycle arrest, as well as inhibition of invasion and migration. Interestingly, PPARγ activation may have pro-tumor effects on cells of the tumor microenvironment, especially myeloid cells. Recent clinical data has substantiated the potential of PPARγ agonists as therapeutic agents for lung cancer. Additionally, PPARγ agonists also show synergistic effects with traditional chemotherapy and radiotherapy. However, the clinical application of PPARγ agonists remains limited due to the presence of adverse side effects. Thus, further research and clinical trials are necessary to comprehensively explore the actions of PPARγ in both tumor and stromal cells and to evaluate the in vivo toxicity. This review aims to consolidate the molecular mechanism of PPARγ modulators and to discuss their clinical prospects and challenges in tackling lung cancer.
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Affiliation(s)
- Jiyun Zhang
- School of Basic Medical Sciences, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou 511436, China;
- Guangzhou National Laboratory, Guangzhou 510005, China
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China
| | - Miru Tang
- Guangzhou National Laboratory, Guangzhou 510005, China
| | - Jinsai Shang
- School of Basic Medical Sciences, Guangzhou Laboratory, Guangzhou Medical University, Guangzhou 511436, China;
- Guangzhou National Laboratory, Guangzhou 510005, China
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14
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Zhu R, Feng Y, Yang X, Li R, Song Z, Liu Q, Shi D, Huang J. Functionally conserved PPARG exonic circRNAs enhance intramuscular fat deposition by regulating PPARG and HSL. Int J Biol Macromol 2024; 257:128613. [PMID: 38070814 DOI: 10.1016/j.ijbiomac.2023.128613] [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: 06/25/2023] [Revised: 11/19/2023] [Accepted: 11/26/2023] [Indexed: 12/17/2023]
Abstract
Circular RNAs (circRNA) are a kind of endogenous biological macromolecules that play significant roles in many biological processes, including adipogenesis, a precisely orchestrated process that is mediated by a large number of factors. Among them, peroxisome proliferator-activated receptor gamma (PPARG), is undoubtedly the most important regulator of adipocyte development in all types of adipose tissue. The formation of intramuscular fat (IMF), is a key factor that influences the meat quality in livestock animals. PPARG has been demonstrated to show a positive correlation with IMF deposition although the regulatory mechanism involved is not known. This study demonstrates that PPARG mediates IMF deposition by producing multiple exonic circRNAs (circPPARGs). Three circPPARGs promote adipogenic differentiation and inhibit the proliferation of intramuscular preadipocytes and these effects are conserved across several species including buffaloes, cattle and mice. Notably, circPPARG1 interacts with PPARG protein to inhibit the transcription of hormone sensitive lipase (HSL) involved in lipolysis. In addition, the positive effects of circPPARG1 on IMF deposition were identified in mice in vivo. Thus, PPARG drives IMF deposition, not only through the common transcription factor pathway, but also by producing circRNAs. This study provides new insights into our understanding of the regulatory mechanisms of PPARG in IMF deposition.
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Affiliation(s)
- Ruirui Zhu
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, Guangxi University, Nanning, Guangxi 530005, China
| | - Ye Feng
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, Guangxi University, Nanning, Guangxi 530005, China
| | - Xintong Yang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, Guangxi University, Nanning, Guangxi 530005, China
| | - Ruirui Li
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, Guangxi University, Nanning, Guangxi 530005, China
| | - Ziyi Song
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, Guangxi University, Nanning, Guangxi 530005, China
| | - Qingyou Liu
- Guangdong Provincial Key Laboratory of Animal Molecular Design and Precise Breeding, School of Life Science and Engineering, Foshan University, Foshan, Guangdong 528225, China
| | - Deshun Shi
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, Guangxi University, Nanning, Guangxi 530005, China.
| | - Jieping Huang
- State Key Laboratory for Conservation and Utilization of Subtropical Agro-Bioresources, Guangxi Key Laboratory of Animal Breeding, Disease Control and Prevention, Guangxi University, Nanning, Guangxi 530005, China.
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15
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Ludzki AC, Hansen M, Zareifi D, Jalkanen J, Huang Z, Omar-Hmeadi M, Renzi G, Klingelhuber F, Boland S, Ambaw YA, Wang N, Damdimopoulos A, Liu J, Jernberg T, Petrus P, Arner P, Krahmer N, Fan R, Treuter E, Gao H, Rydén M, Mejhert N. Transcriptional determinants of lipid mobilization in human adipocytes. SCIENCE ADVANCES 2024; 10:eadi2689. [PMID: 38170777 PMCID: PMC10776019 DOI: 10.1126/sciadv.adi2689] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Accepted: 12/01/2023] [Indexed: 01/05/2024]
Abstract
Defects in adipocyte lipolysis drive multiple aspects of cardiometabolic disease, but the transcriptional framework controlling this process has not been established. To address this, we performed a targeted perturbation screen in primary human adipocytes. Our analyses identified 37 transcriptional regulators of lipid mobilization, which we classified as (i) transcription factors, (ii) histone chaperones, and (iii) mRNA processing proteins. On the basis of its strong relationship with multiple readouts of lipolysis in patient samples, we performed mechanistic studies on one hit, ZNF189, which encodes the zinc finger protein 189. Using mass spectrometry and chromatin profiling techniques, we show that ZNF189 interacts with the tripartite motif family member TRIM28 and represses the transcription of an adipocyte-specific isoform of phosphodiesterase 1B (PDE1B2). The regulation of lipid mobilization by ZNF189 requires PDE1B2, and the overexpression of PDE1B2 is sufficient to attenuate hormone-stimulated lipolysis. Thus, our work identifies the ZNF189-PDE1B2 axis as a determinant of human adipocyte lipolysis and highlights a link between chromatin architecture and lipid mobilization.
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Affiliation(s)
- Alison C. Ludzki
- Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
| | - Mattias Hansen
- Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
| | - Danae Zareifi
- Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
| | - Jutta Jalkanen
- Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
| | - Zhiqiang Huang
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, SE-141 83 Stockholm, Sweden
| | - Muhmmad Omar-Hmeadi
- Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
| | - Gianluca Renzi
- Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
| | - Felix Klingelhuber
- Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany
- Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Sebastian Boland
- Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA
| | - Yohannes A. Ambaw
- Department of Molecular Metabolism, Harvard T. H. Chan School of Public Health, Boston, MA, USA
- Department of Cell Biology, Memorial Sloan Kettering Cancer Center (MSKCC), New York, NY, USA
| | - Na Wang
- Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
| | - Anastasios Damdimopoulos
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, SE-141 83 Stockholm, Sweden
| | - Jianping Liu
- Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
| | - Tomas Jernberg
- Department of Clinical Sciences, Karolinska Institutet, Danderyd Hospital, SE-182 88 Stockholm, Sweden
| | - Paul Petrus
- Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
| | - Peter Arner
- Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
| | - Natalie Krahmer
- Institute for Diabetes and Obesity, Helmholtz Center Munich, Neuherberg, Germany
- Center for Diabetes Research (DZD), Neuherberg, Germany
| | - Rongrong Fan
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, SE-141 83 Stockholm, Sweden
| | - Eckardt Treuter
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, SE-141 83 Stockholm, Sweden
| | - Hui Gao
- Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, SE-141 83 Stockholm, Sweden
| | - Mikael Rydén
- Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
| | - Niklas Mejhert
- Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital Huddinge, SE-141 86 Stockholm, Sweden
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16
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Sose PM, Kale PP, Doshi GM. Deciphering the Role of Peroxisome Proliferator-activated Receptor α and Phosphodiesterase Type 5 Targets in Alzheimer's Disease. CNS & NEUROLOGICAL DISORDERS DRUG TARGETS 2024; 23:956-970. [PMID: 37670711 DOI: 10.2174/1871527323666230904150841] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 07/05/2023] [Accepted: 07/20/2023] [Indexed: 09/07/2023]
Abstract
The most prevalent cause of dementia is Alzheimer's disease (AD). Although the global AD rate is on a constant rise, medical research is yet to find a cure for this neurological condition. Current available therapeutic drugs for AD treatment only provide symptomatic alleviation. Therefore, it is essential to establish effective AD treatment strategies in addressing clinical needs. The development of disease-modifying treatments for use in the disease's early stages and the advancement of symptomatic drugs principally used in the disease's later stages are priorities in AD research. Given that the etiology of AD is difficult to comprehend, using a multimodal therapy intervention that targets molecular targets of AD-related degenerative processes is a practical strategy to change the course of AD progression. The current review article discussed PPAR-α (Peroxisome proliferator-activated receptor-α) and PDE5 (Phosphodiesterase type 5) targets with evidence for their preclinical and clinical importance. Furthermore, we support the targets with AD-related processes, functions, and remedial measures. A unique synergistic method for treating AD may involve the beneficial combinatorial targeting of these two receptors. Furthermore, we reviewed different PDE chemical families in this research and identified PDE5 inhibitors as one of the promising AD-related experimental and clinical disease-modifying medications. Lastly, we suggest jointly targeting these two pathways would be more beneficial than monotherapy in AD treatments.
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Affiliation(s)
- Parnika M Sose
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V.M. Road, Vile Parle West, Mumbai-400056, India
| | - Pravin P Kale
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V.M. Road, Vile Parle West, Mumbai-400056, India
| | - Gaurav M Doshi
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V.M. Road, Vile Parle West, Mumbai-400056, India
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17
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Adeva-Andany MM, Domínguez-Montero A, Adeva-Contreras L, Fernández-Fernández C, Carneiro-Freire N, González-Lucán M. Body Fat Distribution Contributes to Defining the Relationship between Insulin Resistance and Obesity in Human Diseases. Curr Diabetes Rev 2024; 20:e160823219824. [PMID: 37587805 DOI: 10.2174/1573399820666230816111624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2023] [Revised: 04/28/2023] [Accepted: 05/31/2023] [Indexed: 08/18/2023]
Abstract
The risk for metabolic and cardiovascular complications of obesity is defined by body fat distribution rather than global adiposity. Unlike subcutaneous fat, visceral fat (including hepatic steatosis) reflects insulin resistance and predicts type 2 diabetes and cardiovascular disease. In humans, available evidence indicates that the ability to store triglycerides in the subcutaneous adipose tissue reflects enhanced insulin sensitivity. Prospective studies document an association between larger subcutaneous fat mass at baseline and reduced incidence of impaired glucose tolerance. Case-control studies reveal an association between genetic predisposition to insulin resistance and a lower amount of subcutaneous adipose tissue. Human peroxisome proliferator-activated receptorgamma (PPAR-γ) promotes subcutaneous adipocyte differentiation and subcutaneous fat deposition, improving insulin resistance and reducing visceral fat. Thiazolidinediones reproduce the effects of PPAR-γ activation and therefore increase the amount of subcutaneous fat while enhancing insulin sensitivity and reducing visceral fat. Partial or virtually complete lack of adipose tissue (lipodystrophy) is associated with insulin resistance and its clinical manifestations, including essential hypertension, hypertriglyceridemia, reduced HDL-c, type 2 diabetes, cardiovascular disease, and kidney disease. Patients with Prader Willi syndrome manifest severe subcutaneous obesity without insulin resistance. The impaired ability to accumulate fat in the subcutaneous adipose tissue may be due to deficient triglyceride synthesis, inadequate formation of lipid droplets, or defective adipocyte differentiation. Lean and obese humans develop insulin resistance when the capacity to store fat in the subcutaneous adipose tissue is exhausted and deposition of triglycerides is no longer attainable at that location. Existing adipocytes become large and reflect the presence of insulin resistance.
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Affiliation(s)
- María M Adeva-Andany
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Alberto Domínguez-Montero
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | | | - Carlos Fernández-Fernández
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Natalia Carneiro-Freire
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
| | - Manuel González-Lucán
- Nephrology Division, Department of Internal Medicine, Hospital General Juan Cardona, c/ Pardo Bazán s/n, 15406 Ferrol, Spain
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18
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Alami M, Boumezough K, Khalil A, Ramchoun M, Boulbaroud S, Fulop T, Morvaridzadeh M, Berrougui H. The Modulatory Bioeffects of Pomegranate ( Punica granatum L.) Polyphenols on Metabolic Disorders: Understanding Their Preventive Role against Metabolic Syndrome. Nutrients 2023; 15:4879. [PMID: 38068738 PMCID: PMC10707905 DOI: 10.3390/nu15234879] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2023] [Revised: 10/26/2023] [Accepted: 10/30/2023] [Indexed: 12/18/2023] Open
Abstract
Modern research achievements support the health-promoting effects of natural products and diets rich in polyphenols. Pomegranate (PG) (Punica granatum L.) contains a considerable number of bioactive compounds that exert a broad spectrum of beneficial biological activities, including antimicrobial, antidiabetic, antiobesity, and atheroprotective properties. In this context, the reviewed literature shows that PG intake might reduce insulin resistance, cytokine levels, redox gene expression, blood pressure elevation, vascular injuries, and lipoprotein oxidative modifications. The lipid parameter corrective capabilities of PG-ellagitannins have also been extensively reported to be significantly effective in reducing hyperlipidemia (TC, LDL-C, VLDL-C, and TAGs), while increasing plasma HDL-C concentrations and improving the TC/HDL-C and LDL-C/HDL-C ratios. The health benefits of pomegranate consumption seem to be acheived through the amelioration of adipose tissue endocrine function, fatty acid utilization, GLUT receptor expression, paraoxonase activity enhancement, and the modulation of PPAR and NF-κB. While the results from animal experiments are promising, human findings published in this field are inconsistent and are still limited in several aspects. The present review aims to discuss and provide a critical analysis of PG's bioeffects on the components of metabolic syndrome, type-2 diabetes, obesity, and dyslipidemia, as well as on certain cardiovascular-related diseases. Additionally, a brief overview of the pharmacokinetic properties, safety, and bioavailability of PG-ellagitannins is included.
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Affiliation(s)
- Mehdi Alami
- Department of Biology, Polydisciplinary Faculty, University Sultan Moulay Slimane, Beni Mellal 23020, Morocco; (M.A.); (K.B.); (M.R.); (S.B.)
- Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, QC J1H 4N4, Canada; (A.K.); (T.F.); (M.M.)
| | - Kaoutar Boumezough
- Department of Biology, Polydisciplinary Faculty, University Sultan Moulay Slimane, Beni Mellal 23020, Morocco; (M.A.); (K.B.); (M.R.); (S.B.)
| | - Abdelouahed Khalil
- Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, QC J1H 4N4, Canada; (A.K.); (T.F.); (M.M.)
| | - Mhamed Ramchoun
- Department of Biology, Polydisciplinary Faculty, University Sultan Moulay Slimane, Beni Mellal 23020, Morocco; (M.A.); (K.B.); (M.R.); (S.B.)
| | - Samira Boulbaroud
- Department of Biology, Polydisciplinary Faculty, University Sultan Moulay Slimane, Beni Mellal 23020, Morocco; (M.A.); (K.B.); (M.R.); (S.B.)
| | - Tamas Fulop
- Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, QC J1H 4N4, Canada; (A.K.); (T.F.); (M.M.)
| | - Mojgan Morvaridzadeh
- Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, QC J1H 4N4, Canada; (A.K.); (T.F.); (M.M.)
| | - Hicham Berrougui
- Department of Biology, Polydisciplinary Faculty, University Sultan Moulay Slimane, Beni Mellal 23020, Morocco; (M.A.); (K.B.); (M.R.); (S.B.)
- Department of Medicine, Geriatrics Service, Faculty of Medicine and Biological Sciences, University of Sherbrooke, Sherbrooke, QC J1H 4N4, Canada; (A.K.); (T.F.); (M.M.)
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19
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Wong AR, Yang AWH, Gill H, Lenon GB, Hung A. Mechanisms of Nelumbinis folium targeting PPARγ for weight management: A molecular docking and molecular dynamics simulations study. Comput Biol Med 2023; 166:107495. [PMID: 37742414 DOI: 10.1016/j.compbiomed.2023.107495] [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: 05/07/2023] [Revised: 09/08/2023] [Accepted: 09/15/2023] [Indexed: 09/26/2023]
Abstract
The lotus leaf, Nelumbinis folium (NF), has frequently appeared in obesity clinical trials as an intervention to promote weight loss and improve metabolic profiles. However, the molecular mechanisms by which it interacts with important obesity targets and pathways, such as the peroxisome proliferator-activated receptor gamma (PPARγ) within the PPAR signalling pathway, were not well understood. This study aims to screen for candidate compounds from NF with desirable pharmacokinetic properties and examine their binding feasibility at the PPARγ ligand-binding domain (LBD). Ligand- and structure-based screening of NF compounds were performed, and a consensus approach has been applied to identify druggable candidates. By examining the pharmacokinetic profiles, a large proportion of NF compounds exhibited favourable drug-likeness and oral bioavailability properties. Furthermore, the binding affinity scores and poses provided new insights on the distinctive binding behaviours of NF compounds at the LBD of PPARγ in its inactive form. Several NF compounds could bind strongly to PPARγ at sub-pockets where partial agonists and antagonists were found to bind and may induce conformational changes that influence co-repressor binding, trans-repression, and gene expression inhibition. Subsequent molecular dynamics simulations of a candidate compound (NF129 narcissin) bound to PPARγ revealed conformational stability, residue fluctuation, and binding behaviours comparable to that of the known inhibitor, SR1664. Therefore, it can be proposed that narcissin exhibits characteristics of a PPARγ antagonist. Further experimental validation to support the development of NF129 as a future anti-obesity agent is warranted.
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Affiliation(s)
- Ann Rann Wong
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Angela Wei Hong Yang
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Harsharn Gill
- School of Science, RMIT University, Melbourne, Victoria, Australia
| | - George Binh Lenon
- School of Health and Biomedical Sciences, RMIT University, Bundoora, Victoria, Australia
| | - Andrew Hung
- School of Science, RMIT University, Melbourne, Victoria, Australia.
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20
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Grander C, Meyer M, Steinacher D, Claudel T, Hausmann B, Pjevac P, Grabherr F, Oberhuber G, Grander M, Brigo N, Jukic A, Schwärzler J, Weiss G, Adolph TE, Trauner M, Tilg H. 24-Norursodeoxycholic acid ameliorates experimental alcohol-related liver disease and activates hepatic PPARγ. JHEP Rep 2023; 5:100872. [PMID: 37818230 PMCID: PMC10561126 DOI: 10.1016/j.jhepr.2023.100872] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2022] [Revised: 05/23/2023] [Accepted: 07/12/2023] [Indexed: 10/12/2023] Open
Abstract
Background & Aims Alcohol-related liver disease (ALD) is a global healthcare challenge with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a synthetic bile acid with anti-inflammatory properties in experimental and human cholestatic liver diseases. In the present study, we explored the efficacy of norUDCA in experimental ALD. Methods NorUDCA was tested in a preventive and therapeutic setting in an experimental ALD model (Lieber-DeCarli diet enriched with ethanol). Liver disease was phenotypically evaluated using histology and biochemical methods, and anti-inflammatory properties and peroxisome proliferator-activated receptor gamma activation by norUDCA were evaluated in cellular model systems. Results NorUDCA administration ameliorated ethanol-induced liver injury, reduced hepatocyte death, and reduced the expression of hepatic pro-inflammatory cytokines including tumour necrosis factor (Tnf), Il-1β, Il-6, and Il-10. NorUDCA shifted hepatic macrophages towards an anti-inflammatory M2 phenotype. Further, norUDCA administration altered the composition of the intestinal microbiota, specifically increasing the abundance of Roseburia, Enterobacteriaceae, and Clostridum spp. In a therapeutic model, norUDCA also ameliorated ethanol-induced liver injury. Moreover, norUDCA suppressed lipopolysaccharide-induced IL-6 expression in human peripheral blood mononuclear cells and evoked peroxisome proliferator-activated receptor gamma activation. Conclusions NorUDCA ameliorated experimental ALD, protected against hepatic inflammation, and affected gut microbial commensalism. NorUDCA could serve as a novel therapeutic agent in the future management of patients with ALD. Impact and implications Alcohol-related liver disease is a global healthcare concern with limited treatment options. 24-Norursodeoxycholic acid (NorUDCA) is a modified bile acid, which was proven to be effective in human cholestatic liver diseases. In the present study, we found a protective effect of norUDCA in experimental alcoholic liver disease. For patients with ALD, norUDCA could be a potential new treatment option.
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Affiliation(s)
- Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Moritz Meyer
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Daniel Steinacher
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Bela Hausmann
- Joint Microbiome Facility of the Medical University of Vienna, The University of Vienna, Vienna, Austria
- Department of Laboratory Medicine, Medical University of Vienna, Vienna, Austria
| | - Petra Pjevac
- Joint Microbiome Facility of the Medical University of Vienna, The University of Vienna, Vienna, Austria
- Division of Microbial Ecology, Department of Microbiology and Ecosystem Science, Centre for Microbiology and Environmental Systems Science, University of Vienna, Vienna, Austria
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Georg Oberhuber
- INNPATH, Tirol-Kliniken University Hospital Innsbruck, Innsbruck, Austria
| | - Manuel Grander
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria
| | - Natascha Brigo
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria
| | - Almina Jukic
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Günter Weiss
- Department of Internal Medicine II, Infectious Diseases, Immunology, Rheumatology, Pneumology, Medical University Innsbruck, Innsbruck, Austria
| | - Timon E. Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Medical University of Vienna, Vienna, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology and Metabolism, Medical University Innsbruck, Innsbruck, Austria
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21
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Riaz F, Wei P, Pan F. PPARs at the crossroads of T cell differentiation and type 1 diabetes. Front Immunol 2023; 14:1292238. [PMID: 37928539 PMCID: PMC10623333 DOI: 10.3389/fimmu.2023.1292238] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2023] [Accepted: 10/11/2023] [Indexed: 11/07/2023] Open
Abstract
T-cell-mediated autoimmune type 1 diabetes (T1D) is characterized by the immune-mediated destruction of pancreatic beta cells (β-cells). The increasing prevalence of T1D poses significant challenges to the healthcare system, particularly in countries with struggling economies. This review paper highlights the multifaceted roles of Peroxisome Proliferator-Activated Receptors (PPARs) in the context of T1D, shedding light on their potential as regulators of immune responses and β-cell biology. Recent research has elucidated the intricate interplay between CD4+ T cell subsets, such as Tregs and Th17, in developing autoimmune diseases like T1D. Th17 cells drive inflammation, while Tregs exert immunosuppressive functions, highlighting the delicate balance crucial for immune homeostasis. Immunotherapy has shown promise in reinstating self-tolerance and restricting the destruction of autoimmune responses, but further investigations are required to refine these therapeutic strategies. Intriguingly, PPARs, initially recognized for their role in lipid metabolism, have emerged as potent modulators of inflammation in autoimmune diseases, particularly in T1D. Although evidence suggests that PPARs affect the β-cell function, their influence on T-cell responses and their potential impact on T1D remains largely unexplored. It was noted that PPARα is involved in restricting the transcription of IL17A and enhancing the expression of Foxp3 by minimizing its proteasomal degradation. Thus, antagonizing PPARs may exert beneficial effects in regulating the differentiation of CD4+ T cells and preventing T1D. Therefore, this review advocates for comprehensive investigations to delineate the precise roles of PPARs in T1D pathogenesis, offering innovative therapeutic avenues that target both the immune system and pancreatic function. This review paper seeks to bridge the knowledge gap between PPARs, immune responses, and T1D, providing insights that may revolutionize the treatment landscape for this autoimmune disorder. Moreover, further studies involving PPAR agonists in non-obese diabetic (NOD) mice hold promise for developing novel T1D therapies.
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Affiliation(s)
- Farooq Riaz
- Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
| | - Ping Wei
- Department of Otolaryngology, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders (Chongqing), China International Science and Technology Cooperation base of Child Development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China
| | - Fan Pan
- Shenzhen Institute of Advanced Technology (SIAT), Chinese Academy of Sciences (CAS), Shenzhen, China
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22
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Kadasah SF, Radwan MO. Overview of Ursolic Acid Potential for the Treatment of Metabolic Disorders, Autoimmune Diseases, and Cancers via Nuclear Receptor Pathways. Biomedicines 2023; 11:2845. [PMID: 37893218 PMCID: PMC10604592 DOI: 10.3390/biomedicines11102845] [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: 10/06/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 10/29/2023] Open
Abstract
Nuclear receptors (NRs) form a family of druggable transcription factors that are regulated by ligand binding to orchestrate multifaceted physiological functions, including reproduction, immunity, metabolism, and growth. NRs represent attractive and valid targets for the management and treatment of a vast array of ailments. Pentacyclic triterpenes (PTs) are ubiquitously distributed natural products in medicinal and aromatic plants, of which ursolic acid (UA) is an extensively studied member, due to its diverse bio-pertinent activities against different cancers, inflammation, aging, obesity, diabetes, dyslipidemia, and liver injury. In fact, PTs share a common lipophilic structure that resembles NRs' endogenous ligands. Herein, we present a review of the literature on UA's effect on NRs, showcasing the resulting health benefits and potential therapeutic outcomes. De facto, UA exhibited numerous pharmacodynamic effects on PPAR, LXR, FXR, and PXR, resulting in remarkable anti-inflammatory, anti-hyperlipidemic, and hepatoprotective properties, by lowering lipid accumulation in hepatocytes and mitigating non-alcoholic steatohepatitis (NASH) and its subsequent liver fibrosis. Furthermore, UA reversed valproate and rifampicin-induced hepatic lipid accumulation. Additionally, UA showed great promise for the treatment of autoimmune inflammatory diseases such as multiple sclerosis and autoimmune arthritis by antagonizing RORγ. UA exhibited antiproliferative effects against skin, prostate, and breast cancers, partially via PPARα and RORγ pathways. Herein, for the first time, we explore and provide insights into UA bioactivity with respect to NR modulation.
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Affiliation(s)
- Sultan F. Kadasah
- Department of Biology, Faculty of Science, University of Bisha, P.O. Box 551, Bisha 61922, Saudi Arabia
| | - Mohamed O. Radwan
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan
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23
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Radwan MO, Kadasah SF, Aljubiri SM, Alrefaei AF, El-Maghrabey MH, El Hamd MA, Tateishi H, Otsuka M, Fujita M. Harnessing Oleanolic Acid and Its Derivatives as Modulators of Metabolic Nuclear Receptors. Biomolecules 2023; 13:1465. [PMID: 37892147 PMCID: PMC10604226 DOI: 10.3390/biom13101465] [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: 09/06/2023] [Revised: 09/25/2023] [Accepted: 09/27/2023] [Indexed: 10/29/2023] Open
Abstract
Nuclear receptors (NRs) constitute a superfamily of ligand-activated transcription factors with a paramount role in ubiquitous physiological functions such as metabolism, growth, and reproduction. Owing to their physiological role and druggability, NRs are deemed attractive and valid targets for medicinal chemists. Pentacyclic triterpenes (PTs) represent one of the most important phytochemical classes present in higher plants, where oleanolic acid (OA) is the most studied PTs representative owing to its multitude of biological activities against cancer, inflammation, diabetes, and liver injury. PTs possess a lipophilic skeleton that imitates the NRs endogenous ligands. Herein, we report a literature overview on the modulation of metabolic NRs by OA and its semi-synthetic derivatives, highlighting their health benefits and potential therapeutic applications. Indeed, OA exhibited varying pharmacological effects on FXR, PPAR, LXR, RXR, PXR, and ROR in a tissue-specific manner. Owing to these NRs modulation, OA showed prominent hepatoprotective properties comparable to ursodeoxycholic acid (UDCA) in a bile duct ligation mice model and antiatherosclerosis effect as simvastatin in a model of New Zealand white (NZW) rabbits. It also demonstrated a great promise in alleviating non-alcoholic steatohepatitis (NASH) and liver fibrosis, attenuated alpha-naphthol isothiocyanate (ANIT)-induced cholestatic liver injury, and controlled blood glucose levels, making it a key player in the therapy of metabolic diseases. We also compiled OA semi-synthetic derivatives and explored their synthetic pathways and pharmacological effects on NRs, showcasing their structure-activity relationship (SAR). To the best of our knowledge, this is the first review article to highlight OA activity in terms of NRs modulation.
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Affiliation(s)
- Mohamed O. Radwan
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan; (H.T.); (M.O.); (M.F.)
| | - Sultan F. Kadasah
- Department of Biology, Faculty of Science, University of Bisha, Bisha 61922, Saudi Arabia;
| | - Salha M. Aljubiri
- Department of Chemistry, College of Science, University of Bisha, Bisha 61922, Saudi Arabia;
| | | | - Mahmoud H. El-Maghrabey
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;
| | - Mohamed A. El Hamd
- Department of Pharmaceutical Sciences, College of Pharmacy, Shaqra University, Shaqra 11961, Saudi Arabia
- Department of Pharmaceutical Analytical Chemistry, Faculty of Pharmacy, South Valley University, Qena 83523, Egypt
| | - Hiroshi Tateishi
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan; (H.T.); (M.O.); (M.F.)
| | - Masami Otsuka
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan; (H.T.); (M.O.); (M.F.)
- Department of Drug Discovery, Science Farm Ltd., Kumamoto 862-0976, Japan
| | - Mikako Fujita
- Medicinal and Biological Chemistry Science Farm Joint Research Laboratory, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, Japan; (H.T.); (M.O.); (M.F.)
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24
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Knaack DA, Chang J, Thomas MJ, Sorci-Thomas MG, Chen Y, Sahoo D. Scavenger receptor class B type I is required for efficient glucose uptake and metabolic homeostasis in adipocytes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.21.554190. [PMID: 37662321 PMCID: PMC10473602 DOI: 10.1101/2023.08.21.554190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Obesity is a worldwide epidemic and places individuals at a higher risk for developing comorbidities that include cardiovascular disease and type 2 diabetes. Adipose tissue contains adipocytes that are responsible for lipid metabolism and reducing misdirected lipid storage. Adipocytes facilitate this process through insulin-mediated uptake of glucose and its subsequent metabolism into triglycerides for storage. During obesity, adipocytes become insulin resistant and have a reduced ability to mediate glucose import, thus resulting in whole-body metabolic dysfunction. Scavenger receptor class B type I (SR-BI) has been implicated in glucose uptake in skeletal muscle and adipocytes via its native ligands, apolipoprotein A-1 and high-density lipoproteins. Further, SR-BI translocation to the cell surface in adipocytes is sensitive to insulin stimulation. Using adipocytes differentiated from ear mesenchymal stem cells isolated from wild-type and SR-BI knockout (SR-BI -/- ) mice as our model system, we tested the hypothesis that SR-BI is required for insulin-mediated glucose uptake and regulation of energy balance in adipocytes. We demonstrated that loss of SR-BI in adipocytes resulted in inefficient glucose uptake regardless of cell surface expression levels of glucose transporter 4 compared to WT adipocytes. We also observed reduced glycolytic capacity, increased lipid biosynthesis, and dysregulated expression of lipid metabolism genes in SR-BI -/- adipocytes compared to WT adipocytes. These results partially support our hypothesis and suggest a novel role for SR-BI in glucose uptake and metabolic homeostasis in adipocytes.
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25
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Qin Y, Bily D, Aguirre M, Zhang K, Xie L. Understanding PPARγ and Its Agonists on Trophoblast Differentiation and Invasion: Potential Therapeutic Targets for Gestational Diabetes Mellitus and Preeclampsia. Nutrients 2023; 15:2459. [PMID: 37299422 PMCID: PMC10255128 DOI: 10.3390/nu15112459] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 05/16/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
The increasing incidence of pregnancy complications, particularly gestational diabetes mellitus (GDM) and preeclampsia (PE), is a cause for concern, as they can result in serious health consequences for both mothers and infants. The pathogenesis of these complications is still not fully understood, although it is known that the pathologic placenta plays a crucial role. Studies have shown that PPARγ, a transcription factor involved in glucose and lipid metabolism, may have a critical role in the etiology of these complications. While PPARγ agonists are FDA-approved drugs for Type 2 Diabetes Mellitus, their safety during pregnancy is not yet established. Nevertheless, there is growing evidence for the therapeutic potential of PPARγ in the treatment of PE using mouse models and in cell cultures. This review aims to summarize the current understanding of the mechanism of PPARγ in placental pathophysiology and to explore the possibility of using PPARγ ligands as a treatment option for pregnancy complications. Overall, this topic is of great significance for improving maternal and fetal health outcomes and warrants further investigation.
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Affiliation(s)
- Yushu Qin
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (Y.Q.); (D.B.); (M.A.); (K.Z.)
| | - Donalyn Bily
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (Y.Q.); (D.B.); (M.A.); (K.Z.)
- Department of Biology, Texas A&M University, College Station, TX 77843, USA
| | - Makayla Aguirre
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (Y.Q.); (D.B.); (M.A.); (K.Z.)
| | - Ke Zhang
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (Y.Q.); (D.B.); (M.A.); (K.Z.)
- Institute of Biosciences and Technology, Texas A&M University, Houston, TX 77030, USA
| | - Linglin Xie
- Department of Nutrition, Texas A&M University, College Station, TX 77843, USA; (Y.Q.); (D.B.); (M.A.); (K.Z.)
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26
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Francque S, Ratziu V. Future Treatment Options and Regimens for Nonalcoholic Fatty Liver Disease. Clin Liver Dis 2023; 27:429-449. [PMID: 37024217 DOI: 10.1016/j.cld.2023.01.010] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/08/2023]
Abstract
Recent progress in our understanding of the pathogenic mechanisms that drive progression of nonalcoholic steatohepatitis as well as lessons learned from several clinical trials that have been conducted over the past 15 years guide our current regulatory framework and trial design. Targeting the metabolic drivers should probably be the backbone of therapy in most of the patients, with some requiring more specific intrahepatic antiinflammatory and antifibrotic actions to achieve success. New and innovative targets and approaches as well as combination therapies are currently explored, while awaiting a better understanding of disease heterogeneity that should allow for future individualized medicine.
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Affiliation(s)
- Sven Francque
- Department of Gastroenterology and Hepatology, Antwerp University Hospital, Antwerp, Belgium; Laboratory of Experimental Medicine and Paediatrics (LEMP), Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; InflaMed Centre of Excellence, University of Antwerp, Antwerp, Belgium; Translational Sciences in Inflammation and Immunology, University of Antwerp, Antwerp, Belgium; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Antwerp University Hospital, Drie Eikenstraat 665, Edegem B-2650, Belgium.
| | - Vlad Ratziu
- Sorbonne Université, Paris, France; Institute of Cardiometabolism and Nutrition, Assistance Publique-Hôpitaux De Paris, Hôpital Pitié-Salpêtrière, 47-83 Boulevard de l'Hôpital, Paris Cedex 13 75651, France; INSERM UMRS 1138 CRC, Paris, France.
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27
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Zaiou M. Peroxisome Proliferator-Activated Receptor-γ as a Target and Regulator of Epigenetic Mechanisms in Nonalcoholic Fatty Liver Disease. Cells 2023; 12:1205. [PMID: 37190114 PMCID: PMC10136748 DOI: 10.3390/cells12081205] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2023] [Revised: 04/17/2023] [Accepted: 04/19/2023] [Indexed: 05/17/2023] Open
Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) belongs to the superfamily of nuclear receptors that control the transcription of multiple genes. Although it is found in many cells and tissues, PPARγ is mostly expressed in the liver and adipose tissue. Preclinical and clinical studies show that PPARγ targets several genes implicated in various forms of chronic liver disease, including nonalcoholic fatty liver disease (NAFLD). Clinical trials are currently underway to investigate the beneficial effects of PPARγ agonists on NAFLD/nonalcoholic steatohepatitis. Understanding PPARγ regulators may therefore aid in unraveling the mechanisms governing the development and progression of NAFLD. Recent advances in high-throughput biology and genome sequencing have greatly facilitated the identification of epigenetic modifiers, including DNA methylation, histone modifiers, and non-coding RNAs as key factors that regulate PPARγ in NAFLD. In contrast, little is still known about the particular molecular mechanisms underlying the intricate relationships between these events. The paper that follows outlines our current understanding of the crosstalk between PPARγ and epigenetic regulators in NAFLD. Advances in this field are likely to aid in the development of early noninvasive diagnostics and future NAFLD treatment strategies based on PPARγ epigenetic circuit modification.
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Affiliation(s)
- Mohamed Zaiou
- Institut Jean-Lamour, Université de Lorraine, UMR 7198 CNRS, 54505 Vandoeuvre-les-Nancy, France
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28
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Fang L, Fang C, Di S, Yu Y, Wang C, Wang X, Jin Y. Oral exposure to tire rubber-derived contaminant 6PPD and 6PPD-quinone induce hepatotoxicity in mice. THE SCIENCE OF THE TOTAL ENVIRONMENT 2023; 869:161836. [PMID: 36716866 DOI: 10.1016/j.scitotenv.2023.161836] [Citation(s) in RCA: 96] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 01/16/2023] [Accepted: 01/22/2023] [Indexed: 06/18/2023]
Abstract
N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) is a widely used additive for protecting various rubber products, and its product of oxidation N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPDQ) has attracted extensive attention in aquatic toxicity. However, the toxicity of 6PPD and 6PPDQ in mammals has not been reported yet. In this study, the effects of 6PPD and 6PPDQ on the liver of C57BL/6 mice were assessed by orally administering different doses of 6PPD and 6PPDQ (10, 30, and 100 mg/kg) in mice for 6 weeks. 6PPD and 6PPDQ were found to bioaccumulate in the liver in a dose-dependent manner. Moreover, a high dose of 6PPD and 6PPDQ exposure increased not only the liver weights but also liver triglyceride levels, indicating that 6PPD and 6PPDQ exposure induced hepatotoxicity in mice. Furthermore, transcriptomic analysis revealed that 6PPD and 6PPDQ induced differential expression of genes mainly enriched in glycolipid metabolism, immune-related, and glutathione metabolism pathways. Therefore, 6PPD and 6PPDQ altered hepatic metabolism in mice. Furthermore, 6PPDQ could induce an immune response by upregulating the transcription of immune-related genes and promoting macrophage infiltration in the liver. In conclusion, our study revealed the toxic effects of 6PPD and 6PPDQ exposure on multi-endpoints in the liver of mice and improve our understanding of the health risks of 6PPD and 6PPDQ to mammals. The findings of our study may help formulate better safety regulations for the use and disposal of rubber products.
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Affiliation(s)
- Liya Fang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Chanlin Fang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Shanshan Di
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products/Key Laboratory of Detection for Pesticide Residues and Control of Zhejiang, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
| | - Yundong Yu
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China; State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products/Key Laboratory of Detection for Pesticide Residues and Control of Zhejiang, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China
| | - Caihong Wang
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Xinquan Wang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products/Key Laboratory of Detection for Pesticide Residues and Control of Zhejiang, Institute of Agro-product Safety and Nutrition, Zhejiang Academy of Agricultural Sciences, Hangzhou 310021, China.
| | - Yuanxiang Jin
- College of Biotechnology and Bioengineering, Zhejiang University of Technology, Hangzhou 310032, China.
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Hartley A, Ahmad I. The role of PPARγ in prostate cancer development and progression. Br J Cancer 2023; 128:940-945. [PMID: 36510001 PMCID: PMC10006070 DOI: 10.1038/s41416-022-02096-8] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Revised: 11/16/2022] [Accepted: 11/28/2022] [Indexed: 12/14/2022] Open
Abstract
Advanced and metastatic prostate cancer is often incurable, but its dependency on certain molecular alterations may provide the basis for targeted therapies. A growing body of research has demonstrated that peroxisome proliferator-activated receptor gamma (PPARγ) is amplified as prostate cancer progresses. PPARγ has been shown to support prostate cancer growth through its roles in fatty acid synthesis, mitochondrial biogenesis, and co-operating with androgen receptor signalling. Interestingly, splice variants of PPARγ may have differing and contrasting roles. PPARγ itself is a highly druggable target, with agonists having been used for the past two decades in treating diabetes. However, side effects associated with these compounds have currently limited clinical use of these drugs in prostate cancer. Further understanding of PPARγ and novel techniques to target it, may provide therapies for advanced prostate cancer.
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Affiliation(s)
- Andrew Hartley
- School of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G61 1QH, UK
- CRUK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK
| | - Imran Ahmad
- School of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, G61 1QH, UK.
- CRUK Beatson Institute, Garscube Estate, Switchback Road, Bearsden, Glasgow, G61 1BD, UK.
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Li E, Li C, Horn N, Ajuwon KM. PPARγ activation inhibits endocytosis of claudin-4 and protects against deoxynivalenol-induced intestinal barrier dysfunction in IPEC-J2 cells and weaned piglets. Toxicol Lett 2023; 375:8-20. [PMID: 36596350 DOI: 10.1016/j.toxlet.2022.12.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 12/29/2022] [Accepted: 12/30/2022] [Indexed: 01/01/2023]
Abstract
The role of peroxisome proliferator activated receptor gamma (PPARγ) in the regulation of adipocyte differentiation has been well characterized. Besides adipose tissue, PPARγ is also highly expressed in the intestine. However, the functional role of PPARγ in the regulation of intestinal function still remains poorly understood. In the present study, we sought to understand the role of PPARγ activation on regulation of intestinal barrier function in intestinal porcine epithelial cells (IPEC-J2) and weaned piglets exposed to the mycotoxin, deoxynivalenol (DON). PPARγ activation by rosiglitazone and troglitazone, two pharmacological PPARγ ligands, increased the protein expression of tight junction proteins (TJP), claudin-3 and 4. PPARγ inhibition increased endocytosis of claudin-4 which was reversed by its activation with troglitazone. DON exposure decreased the protein expression of TJP, and also significantly suppressed PPARγ transcriptional activity. Interestingly, PPARγ activation reversed the reduction of claudin-3 and 4 caused by DON in vitro and in vivo. PPARγ activation also partially restored the transepithelial electrical resistance (TEER) and reduced the permeability of fluorescein isothiocyanate-dextran (FITC-dextran) that have been negatively impacted by DON. These effects were lost in the presence of a specific PPARγ antagonist or in PPARγ knockout cells, confirming the importance of PPARγ in the regulation of intestinal barrier function and integrity. Likewise, in weaned pigs exposed to DON, the PPARγ agonist pioglitazone mitigated the impaired villus-crypt morphology caused by DON. Therefore, pharmacological and natural bioactive compounds with PPARγ stimulatory activities could be effective in preventing DON-induced gut barrier dysfunction.
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Affiliation(s)
- Enkai Li
- Department of Animal Sciences, Purdue University, 270 S. Russell St., West Lafayette, IN 47907, United States
| | - Chuang Li
- Department of Biological Sciences, Purdue University, West Lafayette, IN 47907, United States
| | - Nathan Horn
- United Animal Health, 322S Main St #1113, Sheridan, IN 46069, United States
| | - Kolapo M Ajuwon
- Department of Animal Sciences, Purdue University, 270 S. Russell St., West Lafayette, IN 47907, United States.
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PPARs and the Kynurenine Pathway in Melanoma-Potential Biological Interactions. Int J Mol Sci 2023; 24:ijms24043114. [PMID: 36834531 PMCID: PMC9960262 DOI: 10.3390/ijms24043114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/28/2023] [Accepted: 02/01/2023] [Indexed: 02/08/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors involved in various physiological and pathological processes within the skin. PPARs regulate several processes in one of the most aggressive skin cancers, melanoma, including proliferation, cell cycle, metabolic homeostasis, cell death, and metastasis. In this review, we focused not only on the biological activity of PPAR isoforms in melanoma initiation, progression, and metastasis but also on potential biological interactions between the PPAR signaling and the kynurenine pathways. The kynurenine pathway is a major pathway of tryptophan metabolism leading to nicotinamide adenine dinucleotide (NAD+) production. Importantly, various tryptophan metabolites exert biological activity toward cancer cells, including melanoma. Previous studies confirmed the functional relationship between PPAR and the kynurenine pathway in skeletal muscles. Despite the fact this interaction has not been reported in melanoma to date, some bioinformatics data and biological activity of PPAR ligands and tryptophan metabolites may suggest a potential involvement of these metabolic and signaling pathways in melanoma initiation, progression, and metastasis. Importantly, the possible relationship between the PPAR signaling pathway and the kynurenine pathway may relate not only to the direct biological effect on melanoma cells but also to the tumor microenvironment and the immune system.
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Krapf SA, Lund J, Bakke HG, Nyman TA, Bartesaghi S, Peng XR, Rustan AC, Thoresen GH, Kase ET. SENP2 knockdown in human adipocytes reduces glucose metabolism and lipid accumulation, while increases lipid oxidation. Metabol Open 2023; 18:100234. [PMID: 37013149 PMCID: PMC10066554 DOI: 10.1016/j.metop.2023.100234] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 02/07/2023] [Accepted: 02/08/2023] [Indexed: 02/11/2023] Open
Abstract
Adipose tissue is one of the main regulative sites for energy metabolism. Excess lipid storage and expansion of white adipose tissue (WAT) is the primary contributor to obesity, a strong predisposing factor for development of insulin resistance. Sentrin-specific protease (SENP) 2 has been shown to play a role in metabolism in murine fat and skeletal muscle cells, and we have previously demonstrated its role in energy metabolism of human skeletal muscle cells. In the present work, we have investigated the impact of SENP2 on fatty acid and glucose metabolism in primary human fat cells by using cultured primary human adipocytes to knock down the SENP2 gene. Glucose uptake and oxidation, as well as accumulation and distribution of oleic acid into complex lipids were decreased, while oleic acid oxidation was increased in SENP2-knockdown cells compared to control adipocytes. Furthermore, lipogenesis was reduced by SENP2-knockdown in adipocytes. Although TAG accumulation relative to total uptake was unchanged, there was increased mRNA expression of metabolically relevant genes such as UCP1 and PPARGC1A and mRNA and proteomic data revealed increased levels of mRNA and proteins related to mitochondrial function by SENP2-knockdown. In conclusion, SENP2 is an important regulator of energy metabolism in primary human adipocytes and its knockdown reduce glucose metabolism and lipid accumulation, while increasing lipid oxidation in human adipocytes.
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Nartey MNN, Jisaka M, Syeda PK, Nishimura K, Shimizu H, Yokota K. Prostaglandin D 2 Added during the Differentiation of 3T3-L1 Cells Suppresses Adipogenesis via Dysfunction of D-Prostanoid Receptor P1 and P2. Life (Basel) 2023; 13:life13020370. [PMID: 36836727 PMCID: PMC9963520 DOI: 10.3390/life13020370] [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: 12/11/2022] [Revised: 01/20/2023] [Accepted: 01/27/2023] [Indexed: 01/31/2023] Open
Abstract
We previously reported that the addition of prostaglandin, (PG)D2, and its chemically stable analog, 11-deoxy-11-methylene-PGD2 (11d-11m-PGD2), during the maturation phase of 3T3-L1 cells promotes adipogenesis. In the present study, we aimed to elucidate the effects of the addition of PGD2 or 11d-11m-PGD2 to 3T3-L1 cells during the differentiation phase on adipogenesis. We found that both PGD2 and 11d-11m-PGD2 suppressed adipogenesis through the downregulation of peroxisome proliferator-activated receptor gamma (PPARγ) expression. However, the latter suppressed adipogenesis more potently than PGD2, most likely because of its higher resistance to spontaneous transformation into PGJ2 derivatives. In addition, this anti-adipogenic effect was attenuated by the coexistence of an IP receptor agonist, suggesting that the effect depends on the intensity of the signaling from the IP receptor. The D-prostanoid receptors 1 (DP1) and 2 (DP2, also known as a chemoattractant receptor-homologous molecule expressed on Th2 cells) are receptors for PGD2. The inhibitory effects of PGD2 and 11d-11m-PGD2 on adipogenesis were slightly attenuated by a DP2 agonist. Furthermore, the addition of PGD2 and 11d-11m-PGD2 during the differentiation phase reduced the DP1 and DP2 expression during the maturation phase. Overall, these results indicated that the addition of PGD2 or 11d-11m-PGD2 during the differentiation phase suppresses adipogenesis via the dysfunction of DP1 and DP2. Therefore, unidentified receptor(s) for both molecules may be involved in the suppression of adipogenesis.
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Affiliation(s)
- Michael N. N. Nartey
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan
- Council for Scientific and Industrial Research-Animal Research Institute, Achimota, Accra P.O. Box AH20, Ghana
| | - Mitsuo Jisaka
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Correspondence:
| | - Pinky Karim Syeda
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
| | - Kohji Nishimura
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Interdisciplinary Center for Science Research, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
| | - Hidehisa Shimizu
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Interdisciplinary Center for Science Research, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
| | - Kazushige Yokota
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Japan
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Japan
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De Nunzio V, Carrieri L, Scavo MP, Lippolis T, Cofano M, Caponio GR, Tutino V, Rizzi F, Depalo N, Osella AR, Notarnicola M. Plasma-Derived Exosomes from NAFLD Patients Modulate the Cannabinoid Receptors' Expression in Cultured HepaRG Cells. Int J Mol Sci 2023; 24:ijms24021739. [PMID: 36675254 PMCID: PMC9862025 DOI: 10.3390/ijms24021739] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 01/05/2023] [Accepted: 01/10/2023] [Indexed: 01/18/2023] Open
Abstract
Exosomes produced by hepatocytes upon lipotoxic insult play a relevant role in pathogenesis of nonalcoholic fatty liver disease (NAFLD), suggesting an inflammatory response by the activation of monocytes and macrophages and accelerating the disease progression. In the pathogenesis of NAFLD and liver fibrosis, the endogenous cannabinoids and their major receptors CB1 and CB2 appear to be highly involved. This study aimed at evaluating the expression of cannabinoids receptors (CB1R and CB2R) in plasma-derived exosomes extracted from patients with NAFLD, as well as investigating the in vitro effects of the circulating exosomes in cultured human HepaRG cells following their introduction into the culture medium. The results demonstrated that plasma-derived exosomes from NAFLD patients are vehicles for the transport of CB1R and are able to modulate CB receptors' expression in HepaRG cells. In particular, circulating exosomes from NAFLD patients are inflammatory drivers for HepaRG cells, acting through CB1R activation and the downregulation of CB2R. Moreover, CB1R upregulation was associated with increased expression levels of PPAR-γ, a well-known mediator of liver tissue injury. In conclusion, this study provides evidence for CB1R transport by exosomes and suggests that the in vitro effects of circulating exosomes from NAFLD patients are mediated by the expression of cannabinoid receptors.
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Affiliation(s)
- Valentina De Nunzio
- Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Livianna Carrieri
- Laboratory of Personalized Medicine, National Institute of Gastroenterology IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Maria Principia Scavo
- Laboratory of Personalized Medicine, National Institute of Gastroenterology IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Tamara Lippolis
- Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Miriam Cofano
- Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Giusy Rita Caponio
- Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Valeria Tutino
- Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Federica Rizzi
- Dipartimento di Chimica, Università degli Studi di Bari Aldo Moro, Via Orabona 4, 70125 Bari, Italy
- Institute for Chemical-Physical Processes (IPCF), Council National Research (CNR) Bari, Via Orabona 4, 70125 Bari, Italy
| | - Nicoletta Depalo
- Institute for Chemical-Physical Processes (IPCF), Council National Research (CNR) Bari, Via Orabona 4, 70125 Bari, Italy
| | - Alberto Ruben Osella
- Laboratory of Epidemiolgy and Biostatistics, National Institute of Gastroenterology IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
| | - Maria Notarnicola
- Laboratory of Nutritional Biochemistry, National Institute of Gastroenterology IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy
- Correspondence: ; Tel.: +39-080-4994342
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Senn L, Costa AM, Avallone R, Socała K, Wlaź P, Biagini G. Is the peroxisome proliferator-activated receptor gamma a putative target for epilepsy treatment? Current evidence and future perspectives. Pharmacol Ther 2023; 241:108316. [PMID: 36436690 DOI: 10.1016/j.pharmthera.2022.108316] [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: 09/14/2022] [Revised: 11/20/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022]
Abstract
The peroxisome proliferator-activated receptor gamma (PPARγ), which belongs to the family of nuclear receptors, has been mainly studied as an important factor in metabolic disorders. However, in recent years the potential role of PPARγ in different neurological diseases has been increasingly investigated. Especially, in the search of therapeutic targets for patients with epilepsy the question of the involvement of PPARγ in seizure control has been raised. Epilepsy is a chronic neurological disorder causing a major impact on the psychological, social, and economic conditions of patients and their families, besides the problems of the disease itself. Considering that the world prevalence of epilepsy ranges between 0.5% - 1.0%, this condition is the fourth for importance among the other neurological disorders, following migraine, stroke, and dementia. Among others, temporal lobe epilepsy (TLE) is the most common form of epilepsy in adult patients. About 65% of individuals who receive antiseizure medications (ASMs) experience seizure independence. For those in whom seizures still recur, investigating PPARγ could lead to the development of novel ASMs. This review focuses on the most important findings from recent investigations about the potential intracellular PPARγ-dependent processes behind different compounds that exhibited anti-seizure effects. Additionally, recent clinical investigations are discussed along with the promising results found for PPARγ agonists and the ketogenic diet (KD) in various rodent models of epilepsy.
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Affiliation(s)
- Lara Senn
- Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; PhD School of Clinical and Experimental Medicine (CEM), University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Anna-Maria Costa
- Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Rossella Avallone
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Katarzyna Socała
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, PL 20-033 Lublin, Poland
| | - Piotr Wlaź
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, PL 20-033 Lublin, Poland
| | - Giuseppe Biagini
- Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
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The Role of PPARs in Breast Cancer. Cells 2022; 12:cells12010130. [PMID: 36611922 PMCID: PMC9818187 DOI: 10.3390/cells12010130] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 12/07/2022] [Accepted: 12/26/2022] [Indexed: 12/31/2022] Open
Abstract
Breast cancer is a malignant tumor with high morbidity and lethality. Its pathogenesis is related to the abnormal expression of many genes. The peroxisome proliferator-activated receptors (PPARs) are a class of ligand-dependent transcription factors in the nuclear receptor superfamily. They can regulate the transcription of a large number of target genes, which are involved in life activities such as cell proliferation, differentiation, metabolism, and apoptosis, and regulate physiological processes such as glucose metabolism, lipid metabolism, inflammation, and wound healing. Further, the changes in its expression are associated with various diseases, including breast cancer. The experimental reports related to "PPAR" and "breast cancer" were retrieved from PubMed since the discovery of PPARs and summarized in this paper. This review (1) analyzed the roles and potential molecular mechanisms of non-coordinated and ligand-activated subtypes of PPARs in breast cancer progression; (2) discussed the correlations between PPARs and estrogen receptors (ERs) as the nuclear receptor superfamily; and (3) investigated the interaction between PPARs and key regulators in several signaling pathways. As a result, this paper identifies PPARs as targets for breast cancer prevention and treatment in order to provide more evidence for the synthesis of new drugs targeting PPARs or the search for new drug combination treatments.
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Bryant C, Webb A, Banks AS, Chandler D, Govindarajan R, Agrawal S. Alternatively Spliced Landscape of PPARγ mRNA in Podocytes Is Distinct from Adipose Tissue. Cells 2022; 11:cells11213455. [PMID: 36359851 PMCID: PMC9653906 DOI: 10.3390/cells11213455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Revised: 10/13/2022] [Accepted: 10/21/2022] [Indexed: 11/06/2022] Open
Abstract
Podocytes are highly differentiated epithelial cells, and their structural and functional integrity is compromised in a majority of glomerular and renal diseases, leading to proteinuria, chronic kidney disease, and kidney failure. Traditional agonists (e.g., pioglitazone) and selective modulators (e.g., GQ-16) of peroxisome-proliferator-activated-receptor-γ (PPARγ) reduce proteinuria in animal models of glomerular disease and protect podocytes from injury via PPARγ activation. This indicates a pivotal role for PPARγ in maintaining glomerular function through preservation of podocytes distinct from its well-understood role in driving insulin sensitivity and adipogenesis. While its transcriptional role in activating adipokines and adipogenic genes is well-established in adipose tissue, liver and muscle, understanding of podocyte PPARγ signaling remains limited. We performed a comprehensive analysis of PPARγ mRNA variants due to alternative splicing, in human podocytes and compared with adipose tissue. We found that podocytes express the ubiquitous PPARγ Var 1 (encoding γ1) and not Var2 (encoding γ2), which is mostly restricted to adipose tissue and liver. Additionally, we detected expression at very low level of Var4, and barely detectable levels of other variants, Var3, Var11, VartORF4 and Var9, in podocytes. Furthermore, a distinct podocyte vs. adipocyte PPAR-promoter-response-element containing gene expression, enrichment and pathway signature was observed, suggesting differential regulation by podocyte specific PPARγ1 variant, distinct from the adipocyte-specific γ2 variant. In summary, podocytes and glomeruli express several PPARγ variants, including Var1 (γ1) and excluding adipocyte-specific Var2 (γ2), which may have implications in podocyte specific signaling and pathophysiology. This suggests that that new selective PPARγ modulators can be potentially developed that will be able to distinguish between the two forms, γ1 and γ2, thus forming a basis of novel targeted therapeutic avenues.
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Affiliation(s)
- Claire Bryant
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
| | - Amy Webb
- Department of Bioinformatics, The Ohio State University, Columbus, OH 43210, USA
| | - Alexander S. Banks
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Dawn Chandler
- Center for Childhood Cancer and Blood Disease, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
| | - Rajgopal Govindarajan
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA
- Translational Therapeutics, The Ohio State University Comprehensive Cancer Center, Columbus, OH 43210, USA
| | - Shipra Agrawal
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH 43210, USA
- Division of Nephrology and Hypertension, Department of Medicine, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
- Correspondence:
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Wang Y, Lin ZJ, Huang J, Chu MZ, Ding XL, Li WJ, Mao QY, Zhang B. An integrated study of Shenling Baizhu San against hyperuricemia: Efficacy evaluation, core target identification and active component discovery. JOURNAL OF ETHNOPHARMACOLOGY 2022; 295:115450. [PMID: 35688256 DOI: 10.1016/j.jep.2022.115450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 05/20/2022] [Accepted: 06/06/2022] [Indexed: 06/15/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Shenling Baizhu San (SLBZ) is a famous Traditional Chinese Medicine (TCM) formula that strengthens the spleen for replenishing qi, removing dampness, and inducing diuresis to relieve diarrhea. Combining the TCM interpretation that dampness is a vital pathogenesis factor in hyperuricemia occurrence and development, SLBZ has excellent potential against hyperuricemia from the perspective of TCM theories. AIM OF THE STUDY This study aimed to investigate the efficacy of SLBZ against hyperuricemia and its possible mechanism with emphasis on the active components and the core targets. MATERIALS AND METHODS In the present study, we employed meta-analysis and a hyperuricemia quail model to evaluate the uric acid-lowering effect of SLBZ. Bodyweight, serum uric acid, and excreta uric acid levels in quails were assessed. Subsequently, we analyzed the potential active components and core targets of SLBZ against hyperuricemia by network pharmacology and calculated their interaction using molecular docking. Furthermore, the hyperuricemia rats treated with interfering agents of core targets were established to determine the central role of selected targets in hyperuricemia progression. Besides, we isolated and characterized the primary renal tubular epithelial cells of quails to verify the active components and core targets of SLBZ against hyperuricemia. Western blotting was used to observe the expression of core targets treated with active components under the stimulation of interfering agents. RESULTS Data from meta-analysis and animal experiments showed that SLBZ could work effectively against hyperuricemia. Hyperuricemia quails treated with SLBZ displayed significantly reduced serum uric acid levels accompanied by increased excretion of uric acid. According to network pharmacology and molecular docking results, 34 potential active components and the core target peroxisome proliferator-activated receptor gamma (PPARγ) for SLBZ against hyperuricemia were identified. The decreased serum uric acid levels in hyperuricemia rats treated with rosiglitazone, an agonist of PPARγ, confirms the essential role of PPARγ in the pathological process of hyperuricemia. Moreover, we first successfully isolated and characterized the primary renal tubular epithelial cells of quails and observed enhanced phosphorylation of PPARγ at Ser273 in cells handled with high-level uric acid. Whereas, the enhanced expression of p-PPARγ Ser273 could be down-regulated by luteolin and naringenin, two active components of SLBZ against hyperuricemia. CONCLUSION In summary, SLBZ is a promising anti-hyperuricemia agent, and luteolin and naringenin are the active components for SLBZ against hyperuricemia by down-regulating phosphorylation of PPARγ at Ser273.
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Affiliation(s)
- Yu Wang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Zhi-Jian Lin
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Jing Huang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Meng-Zhen Chu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Xue-Li Ding
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Wen-Jing Li
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Qiu-Yue Mao
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China
| | - Bing Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, 100029, China.
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Przybycień P, Gąsior-Perczak D, Placha W. Cannabinoids and PPAR Ligands: The Future in Treatment of Polycystic Ovary Syndrome Women with Obesity and Reduced Fertility. Cells 2022; 11:cells11162569. [PMID: 36010645 PMCID: PMC9406585 DOI: 10.3390/cells11162569] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2022] [Revised: 08/13/2022] [Accepted: 08/17/2022] [Indexed: 11/21/2022] Open
Abstract
Cannabinoids (CBs) are used to treat chronic pain, chemotherapy-induced nausea and vomiting, and multiple sclerosis spasticity. Recently, the medicinal use of CBs has attracted increasing interest as a new therapeutic in many diseases. Data indicate a correlation between CBs and PPARs via diverse mechanisms. Both the endocannabinoid system (ECS) and peroxisome proliferator-activated receptors (PPARs) may play a significant role in PCOS and PCOS related disorders, especially in disturbances of glucose-lipid metabolism as well as in obesity and fertility. Taking into consideration the ubiquity of PCOS in the human population, it seems indispensable to search for new potential therapeutic targets for this condition. The aim of this review is to examine the relationship between metabolic disturbances and obesity in PCOS pathology. We discuss current and future therapeutic interventions for PCOS and related disorders, with emphasis on the metabolic pathways related to PCOS pathophysiology. The link between the ECS and PPARs is a promising new target for PCOS, and we examine this relationship in depth.
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Affiliation(s)
- Piotr Przybycień
- Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, 31-034 Krakow, Poland
- Endocrinology Clinic, Holycross Cancer Centre, 25-734 Kielce, Poland
| | - Danuta Gąsior-Perczak
- Endocrinology Clinic, Holycross Cancer Centre, 25-734 Kielce, Poland
- Collegium Medicum, Jan Kochanowski University, 25-317 Kielce, Poland
| | - Wojciech Placha
- Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, 31-034 Krakow, Poland
- Correspondence: ; Tel.: +48-12-422-74-00
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Kant R, Chandra L, Verma V, Nain P, Bello D, Patel S, Ala S, Chandra R, Antony MA. Gut microbiota interactions with anti-diabetic medications and pathogenesis of type 2 diabetes mellitus. World J Methodol 2022; 12:246-257. [PMID: 36159100 PMCID: PMC9350729 DOI: 10.5662/wjm.v12.i4.246] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 05/03/2022] [Accepted: 06/18/2022] [Indexed: 02/06/2023] Open
Abstract
Microorganisms including bacteria, viruses, protozoa, and fungi living in the gastrointestinal tract are collectively known as the gut microbiota. Dysbiosis is the imbalance in microbial composition on or inside the body relative to healthy state. Altered Firmicutes to Bacteroidetes ratio and decreased abundance of Akkermansia muciniphila are the predominant gut dysbiosis associated with the pathogenesis of type 2 diabetes mellitus (T2DM) and metabolic syndrome. Pathophysiological mechanisms linking gut dysbiosis, and metabolic diseases and their complications include altered metabolism of short-chain fatty acids and bile acids, interaction with gut hormones, increased gut microbial metabolite trimethylamine-N-oxide, bacterial translocation/Leaky gut syndrome, and endotoxin production such as lipopolysaccharides. The association between the gut microbiota and glycemic agents, however, is much less understood and is the growing focus of research and conversation. Recent studies suggest that the gut microbiota and anti-diabetic medications are interdependent on each other, meaning that while anti-diabetic medications alter the gut microbiota, the gut microbiota also alters the efficacy of anti-diabetic medications. With increasing evidence regarding the significance of gut microbiota, it is imperative to review the role of gut microbiota in the pathogenesis of T2DM. This review also discusses the interaction between gut microbiota and the various medications used in the treatment of T2DM.
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Affiliation(s)
- Ravi Kant
- Department of Endocrinology, Diabetes and Metabolism, Medical University of South Carolina, Anderson, SC 29621, United States
- Department of Endocrinology, Diabetes and Metabolism, AnMed Health, Anderson, SC 29621, United States
| | - Lakshya Chandra
- Department of Internal Medicine, St Francis Hospital, Greenville, SC 29601, United States
| | - Vipin Verma
- Department of Internal Medicine, Medical University of South Carolina, Anderson, SC 29621, United States
- Department of Internal Medicine, AnMed Health, Anderson, SC 29621, United States
| | - Priyanshu Nain
- Department of Graduate Medical Education, Maulana Azad Medical College, Delhi 110002, India
| | - Diego Bello
- Department of Surgery, AnMed Health, Anderson, SC 29621, United States
| | - Siddharth Patel
- Department of Internal Medicine, Decatur Morgan Hospital, Decatur, AL 35601, United States
| | - Subash Ala
- Department of Internal Medicine, St Francis Hospital, Greenville, SC 29601, United States
| | - Rashmi Chandra
- Department of Internal Medicine, Medical University of South Carolina, Anderson, SC 29621, United States
| | - Mc Anto Antony
- Department of Endocrinology, Diabetes and Metabolism, Medical University of South Carolina, Anderson, SC 29621, United States
- Department of Endocrinology, Diabetes and Metabolism, AnMed Health, Anderson, SC 29621, United States
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Kant R, Chandra L, Verma V, Nain P, Bello D, Patel S, Ala S, Chandra R, Antony MA. Gut microbiota interactions with anti-diabetic medications and pathogenesis of type 2 diabetes mellitus. World J Methodol 2022; 12:246-257. [DOI: https:/doi.org/10.5662/wjm.v12.i4.246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/11/2025] Open
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Rieger TR, Allen RJ, Musante CJ. A Quantitative Systems Pharmacology Model of Liver Lipid Metabolism for Investigation of Non-Alcoholic Fatty Liver Disease. Front Pharmacol 2022; 13:910789. [PMID: 35928268 PMCID: PMC9343875 DOI: 10.3389/fphar.2022.910789] [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: 04/01/2022] [Accepted: 06/21/2022] [Indexed: 12/05/2022] Open
Abstract
Non-alcoholic fatty liver disease is a metabolic and inflammatory disease that afflicts many people worldwide and presently has few treatment options. To enhance the preclinical to clinical translation and the design of early clinical trials for novel therapeutics, we developed a Quantitative Systems Pharmacology model of human hepatocyte lipid metabolism. The intended application of the model is for simulating anti-steatotic therapies for reversing fatty liver. We parameterized the model using literature data from humans with both normal and elevated liver fat. We assessed that the model construct was sufficient to generate a virtual population of NAFLD patients that matched relevant statistics of a published clinical cohort, and then validated the model response to treatment by simulating pioglitazone and diet intervention in the virtual population. Finally, a sensitivity analysis was performed to determine the best points of intervention for reducing hepatic steatosis. Analysis of the model suggests the most potent method for reducing hepatic steatosis is by limiting non-esterified fatty acid flux from the adipose to the liver.
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Affiliation(s)
- Theodore R. Rieger
- Quantitative Systems Pharmacology, Early Clinical Development, Pfizer Inc, Cambridge, MA, United States
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WNT/β-catenin Pathway: a Possible Link Between Hypertension and Alzheimer's Disease. Curr Hypertens Rep 2022; 24:465-475. [PMID: 35788966 DOI: 10.1007/s11906-022-01209-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/14/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW Recent research has shown that older people with high blood pressure (BP), or hypertension, are more likely to have biomarkers of Alzheimer's disease (AD). Essential hypertension represents the most common cardiovascular disease worldwide and is thought to be responsible for about 13% of all deaths. People with essential hypertension who regularly take prescribed BP medications are half as likely to develop AD as those who do not take them. What then is the connection? RECENT FINDINGS We know that high BP can damage small blood vessels in the brain, affecting those parts that are responsible for memory and thinking. However, the link between AD and hypertension remains unclear. Recent advances in the field of molecular and cellular biology have revealed a downregulation of the canonical WNT/β-catenin pathway in both hypertension and AD. In AD, the glutamate transport function is decreased, a decrease that is associated with a loss of synapse and neuronal death. β-catenin signaling appears to act as a major regulator of glutamate transporters (EAAT and GS) expression and can be harnessed to remove excess glutamate in AD. This review focuses on the possible link between hypertension and AD through the decreased WNT/β-catenin which interacts with the glutamatergic pathway.
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Zorrilla Veloz RI, McKenzie T, Palacios BE, Hu J. Nuclear hormone receptors in demyelinating diseases. J Neuroendocrinol 2022; 34:e13171. [PMID: 35734821 PMCID: PMC9339486 DOI: 10.1111/jne.13171] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 04/20/2022] [Accepted: 05/27/2022] [Indexed: 11/28/2022]
Abstract
Demyelination results from the pathological loss of myelin and is a hallmark of many neurodegenerative diseases. Despite the prevalence of demyelinating diseases, there are no disease modifying therapies that prevent the loss of myelin or promote remyelination. This review aims to summarize studies in the field that highlight the importance of nuclear hormone receptors in the promotion and maintenance of myelination and the relevance of nuclear hormone receptors as potential therapeutic targets for demyelinating diseases. These nuclear hormone receptors include the estrogen receptor, progesterone receptor, androgen receptor, vitamin D receptor, thyroid hormone receptor, peroxisome proliferator-activated receptor, liver X receptor, and retinoid X receptor. Pre-clinical studies in well-established animal models of demyelination have shown a prominent role of these nuclear hormone receptors in myelination through their promotion of oligodendrocyte maturation and development. The activation of the nuclear hormone receptors by their ligands also promotes the synthesis of myelin proteins and lipids in mouse models of demyelination. There are limited clinical studies that focus on how the activation of these nuclear hormone receptors could alleviate demyelination in patients with diseases such as multiple sclerosis (MS). However, the completed clinical trials have reported improved clinical outcome in MS patients treated with the ligands of some of these nuclear hormone receptors. Together, the positive results from both clinical and pre-clinical studies point to nuclear hormone receptors as promising therapeutic targets to counter demyelination.
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Affiliation(s)
- Rocío I Zorrilla Veloz
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Cancer Biology Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Takese McKenzie
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Neuroscience Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Bridgitte E Palacios
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Cancer Biology Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
- Neuroscience Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
| | - Jian Hu
- Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
- Cancer Biology Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
- Neuroscience Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA
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Wang YF, Li JW, Wang DP, Jin K, Hui JJ, Xu HY. Anti-Hyperglycemic Agents in the Adjuvant Treatment of Sepsis: Improving Intestinal Barrier Function. Drug Des Devel Ther 2022; 16:1697-1711. [PMID: 35693534 PMCID: PMC9176233 DOI: 10.2147/dddt.s360348] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 05/28/2022] [Indexed: 12/19/2022] Open
Abstract
Intestinal barrier injury and hyperglycemia are common in patients with sepsis. Bacteria translocation and systemic inflammatory response caused by intestinal barrier injury play a significant role in sepsis occurrence and deterioration, while hyperglycemia is linked to adverse outcomes in sepsis. Previous studies have shown that hyperglycemia is an independent risk factor for intestinal barrier injury. Concurrently, increasing evidence has indicated that some anti-hyperglycemic agents not only improve intestinal barrier function but are also beneficial in managing sepsis-induced organ dysfunction. Therefore, we assume that these agents can block or reduce the severity of sepsis by improving intestinal barrier function. Accordingly, we explicated the connection between sepsis, intestinal barrier, and hyperglycemia, overviewed the evidence on improving intestinal barrier function and alleviating sepsis-induced organ dysfunction by anti-hyperglycemic agents (eg, metformin, peroxisome proliferators activated receptor-γ agonists, berberine, and curcumin), and summarized some common characteristics of these agents to provide a new perspective in the adjuvant treatment of sepsis.
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Affiliation(s)
- Yi-Feng Wang
- Department of Critical Care Medicine, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China
| | - Jia-Wei Li
- Department of Critical Care Medicine, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China
| | - Da-Peng Wang
- Department of Critical Care Medicine, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China
| | - Ke Jin
- Department of Critical Care Medicine, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China
| | - Jiao-Jie Hui
- Department of Critical Care Medicine, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China
| | - Hong-Yang Xu
- Department of Critical Care Medicine, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, Jiangsu, People's Republic of China
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Yuan Q, Tang B, Zhang C. Signaling pathways of chronic kidney diseases, implications for therapeutics. Signal Transduct Target Ther 2022; 7:182. [PMID: 35680856 PMCID: PMC9184651 DOI: 10.1038/s41392-022-01036-5] [Citation(s) in RCA: 186] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 05/20/2022] [Accepted: 05/24/2022] [Indexed: 12/11/2022] Open
Abstract
Chronic kidney disease (CKD) is a chronic renal dysfunction syndrome that is characterized by nephron loss, inflammation, myofibroblasts activation, and extracellular matrix (ECM) deposition. Lipotoxicity and oxidative stress are the driving force for the loss of nephron including tubules, glomerulus, and endothelium. NLRP3 inflammasome signaling, MAPK signaling, PI3K/Akt signaling, and RAAS signaling involves in lipotoxicity. The upregulated Nox expression and the decreased Nrf2 expression result in oxidative stress directly. The injured renal resident cells release proinflammatory cytokines and chemokines to recruit immune cells such as macrophages from bone marrow. NF-κB signaling, NLRP3 inflammasome signaling, JAK-STAT signaling, Toll-like receptor signaling, and cGAS-STING signaling are major signaling pathways that mediate inflammation in inflammatory cells including immune cells and injured renal resident cells. The inflammatory cells produce and secret a great number of profibrotic cytokines such as TGF-β1, Wnt ligands, and angiotensin II. TGF-β signaling, Wnt signaling, RAAS signaling, and Notch signaling evoke the activation of myofibroblasts and promote the generation of ECM. The potential therapies targeted to these signaling pathways are also introduced here. In this review, we update the key signaling pathways of lipotoxicity, oxidative stress, inflammation, and myofibroblasts activation in kidneys with chronic injury, and the targeted drugs based on the latest studies. Unifying these pathways and the targeted therapies will be instrumental to advance further basic and clinical investigation in CKD.
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Affiliation(s)
- Qian Yuan
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Ben Tang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China
| | - Chun Zhang
- Department of Nephrology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Dopkins N, Miranda K, Wilson K, Holloman BL, Nagarkatti P, Nagarkatti M. Effects of Orally Administered Cannabidiol on Neuroinflammation and Intestinal Inflammation in the Attenuation of Experimental Autoimmune Encephalomyelitis. J Neuroimmune Pharmacol 2022; 17:15-32. [PMID: 34757526 DOI: 10.1007/s11481-021-10023-6] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2021] [Accepted: 09/18/2021] [Indexed: 02/06/2023]
Abstract
Cannabidiol (CBD) is a bioactive compound isolated from Cannabis plants that has garnered attention within the medical community due to its potent anti-inflammatory properties. To better understand how CBD limits excessive neuroinflammation we administered CBD via oral gavage (20 mg/kg) in a murine model of multiple sclerosis (MS) known as experimental autoimmune encephalomyelitis (EAE). Using single cell RNA sequencing (scRNA Seq) and array-based transcriptomics we were able to delineate how CBD limits excessive inflammation within the central nervous system (CNS) as well as within the intestinal lining in EAE. In-depth scRNA Seq analysis of CNS tissue demonstrated that CBD treatment resulted in a significant reduction in CXCL9, CXCL10 and IL-1β expression within the CNS, leading to inhibited infiltration of inflammatory macrophages. CBD inhibited IL-1β production independent of the classical cannabinoid receptors, CB1 and CB2. CBD treatment also led to induction of Myeloid-derived Suppressor Cells (MDSCs) both in the CNS and periphery. Interestingly, CBD treatment of EAE mice revealed significant suppression of inflammation in the gastrointestinal (GI) tract. The intestinal epithelial cells (IECs) of CBD treated mice demonstrated a transcriptional inhibition of a family of pyroptosis initiators that drive localized inflammation known as gasdermins (GSDMs). Further investigation into the GI tract via 16s sequencing of cecal and fecal contents demonstrated that oral administration of CBD resulted in no significant changes in the intestinal microbiota composition. These findings demonstrate the beneficial effect of CBD treatment on autoimmune neuroinflammation by ablating expression of pro-inflammatory chemoattractants, regulating inflammatory macrophage activity, promoting MDSC expansion, and limiting the systemic low-grade inflammation in the GI tract, culminating in the attenuation of EAE.
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Affiliation(s)
- Nicholas Dopkins
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia SC, 29208, USA
| | - Kathryn Miranda
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia SC, 29208, USA
| | - Kiesha Wilson
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia SC, 29208, USA
| | - Bryan L Holloman
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia SC, 29208, USA
| | - Prakash Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia SC, 29208, USA
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, Columbia SC, 29208, USA.
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Bryant C, Rask G, Waller AP, Webb A, Galdino-Pitta MR, Amato AA, Cianciolo R, Govindarajan R, Becknell B, Kerlin BA, Neves FA, Fornoni A, Agrawal S. Selective modulator of nuclear receptor PPARγ with reduced adipogenic potential ameliorates experimental nephrotic syndrome. iScience 2022; 25:104001. [PMID: 35310946 PMCID: PMC8927998 DOI: 10.1016/j.isci.2022.104001] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 01/02/2022] [Accepted: 02/23/2022] [Indexed: 12/22/2022] Open
Abstract
Glomerular disease manifests as nephrotic syndrome (NS) with high proteinuria and comorbidities, and is frequently refractory to standard treatments. We hypothesized that a selective modulator of PPARγ, GQ-16, will provide therapeutic advantage over traditional PPARγ agonists for NS treatment. We demonstrate in a pre-clinical NS model that proteinuria is reduced with pioglitazone to 64%, and robustly with GQ-16 to 81% of nephrosis, comparable to controls. Although both GQ-16 and pioglitazone restore glomerular-Nphs1, hepatic-Pcsk9 and serum-cholesterol, only GQ-16 restores glomerular-Nrf2, and reduces hypoalbuminemia and hypercoagulopathy. GQ-16 and pioglitazone restore common and distinct glomerular gene expression analyzed by RNA-seq and induce insulin sensitizing adipokines to various degrees. Pioglitazone but not GQ-16 induces more lipid accumulation and aP2 in adipocytes and white adipose tissue. We conclude that selective modulation of PPARγ by a partial agonist, GQ-16, is more advantageous than pioglitazone in reducing proteinuria, NS associated comorbidities, and adipogenic side effects of full PPARγ agonists.
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Affiliation(s)
- Claire Bryant
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Galen Rask
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Amanda P. Waller
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
| | - Amy Webb
- The Ohio State University, Department of Biomedical Informatics, Columbus, OH, USA
| | - Marina R. Galdino-Pitta
- Laboratory of Design and Drug Synthesis, Bioscience Center, Federal University of Pernambuco, Recife, Brazil
| | - Angelica A. Amato
- Laboratório de Farmacologia Molecular, Departamento de Ciências Farmacêuticas, Faculdade de Ciências da Saúde, Universidade de Brasília, Brasilia, Brazil
| | - Rachel Cianciolo
- Deptartment of Veterinary Biosciences, The Ohio State University, Columbus, OH, USA
| | - Rajgopal Govindarajan
- Division of Pharmaceutics and Pharmacology, College of Pharmacy, The Ohio State University, Columbus, OH, USA
| | - Brian Becknell
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Bryce A. Kerlin
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
| | - Francisco A.R. Neves
- Laboratório de Farmacologia Molecular, Departamento de Ciências Farmacêuticas, Faculdade de Ciências da Saúde, Universidade de Brasília, Brasilia, Brazil
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Peggy and Harold Katz Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Shipra Agrawal
- Center for Clinical and Translational Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA
- Department of Pediatrics, College of Medicine, The Ohio State University, Columbus, OH, USA
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Lange NF, Graf V, Caussy C, Dufour JF. PPAR-Targeted Therapies in the Treatment of Non-Alcoholic Fatty Liver Disease in Diabetic Patients. Int J Mol Sci 2022; 23:ijms23084305. [PMID: 35457120 PMCID: PMC9028563 DOI: 10.3390/ijms23084305] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/06/2022] [Accepted: 04/08/2022] [Indexed: 02/06/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors of the nuclear hormone receptor superfamily, have been identified as key metabolic regulators in the liver, skeletal muscle, and adipose tissue, among others. As a leading cause of liver disease worldwide, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) cause a significant burden worldwide and therapeutic strategies are needed. This review provides an overview of the evidence on PPAR-targeted treatment of NAFLD and NASH in individuals with type 2 diabetes mellitus. We considered current evidence from clinical trials and observational studies as well as the impact of treatment on comorbid metabolic conditions such as obesity, dyslipidemia, and cardiovascular disease. Future areas of research, such as possible sexually dimorphic effects of PPAR-targeted therapies, are briefly reviewed.
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Affiliation(s)
- Naomi F. Lange
- Department of Visceral Surgery and Medicine, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland
- Graduate School for Health Sciences, University of Bern, 3012 Bern, Switzerland
- Correspondence: (N.F.L.); (J.-F.D.)
| | - Vanessa Graf
- Department of Diabetes, Endocrinology, Clinical Nutrition, and Metabolism, Inselspital, Bern University Hospital, University of Bern, 3010 Bern, Switzerland;
| | - Cyrielle Caussy
- Univ Lyon, CarMen Laboratory, INSERM, INRA, INSA Lyon, Université Claude Bernard Lyon 1, 69495 Pierre-Bénite, France;
- Département Endocrinologie, Diabète et Nutrition, Hôpital Lyon Sud, Hospices Civils de Lyon, 69495 Pierre-Bénite, France
| | - Jean-François Dufour
- Centre des Maladies Digestives, 1003 Lausanne, Switzerland
- Swiss NASH Foundation, 3011 Bern, Switzerland
- Correspondence: (N.F.L.); (J.-F.D.)
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50
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Yin L, Wang L, Shi Z, Ji X, Liu L. The Role of Peroxisome Proliferator-Activated Receptor Gamma and Atherosclerosis: Post-translational Modification and Selective Modulators. Front Physiol 2022; 13:826811. [PMID: 35309069 PMCID: PMC8924581 DOI: 10.3389/fphys.2022.826811] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 02/11/2022] [Indexed: 11/13/2022] Open
Abstract
Atherosclerosis is the hallmark of cardiovascular disease (CVD) which is a leading cause of death in type 2 diabetes patients, and glycemic control is not beneficial in reducing the potential risk of CVD. Clinically, it was shown that Thiazolidinediones (TZDs), a class of peroxisome proliferator-activated receptor gamma (PPARγ) agonists, are insulin sensitizers with reducing risk of CVD, while the potential adverse effects, such as weight gain, fluid retention, bone loss, and cardiovascular risk, restricts its use in diabetic treatment. PPARγ, a ligand-activated nuclear receptor, has shown to play a crucial role in anti-atherosclerosis by promoting cholesterol efflux, repressing monocytes infiltrating into the vascular intima under endothelial layer, their transformation into macrophages, and inhibiting vascular smooth muscle cells proliferation as well as migration. The selective activation of subsets of PPARγ targets, such as through PPARγ post-translational modification, is thought to improve the safety profile of PPARγ agonists. Here, this review focuses on the significance of PPARγ activity regulation (selective activation and post-translational modification) in the occurrence, development and treatment of atherosclerosis, and further clarifies the value of PPARγ as a safe therapeutic target for anti-atherosclerosis especially in diabetic treatment.
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Affiliation(s)
- Liqin Yin
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Lihui Wang
- Department of Medical Imaging, Shanghai East Hospital (East Hospital Affiliated to Tongji University), Tongji University, Shanghai, China
| | - Zunhan Shi
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Xiaohui Ji
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Longhua Liu
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
- *Correspondence: Longhua Liu,
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