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Seneviratne AN, Majumdar A, Surendranath K, Miller MR. Environmental modulators of vascular physiology and inflammation. Exp Physiol 2025. [PMID: 40349311 DOI: 10.1113/ep092309] [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: 12/20/2024] [Accepted: 04/22/2025] [Indexed: 05/14/2025]
Abstract
Environmental factors play a crucial role in modulating vascular inflammation, contributing significantly to the development of atherosclerosis and cardiovascular disease. This review synthesizes current evidence on how various environmental exposures influence vascular function and inflammation, with a focus on pollutants such as particulate matter and chemical toxins like bisphenols and per- and polyfluoroalkyl substances. These environmental stressors can trigger oxidative stress, chronic inflammation and vascular dysfunction, potentially accelerating the progression of atherosclerosis. We also explore the protective effects of natural compounds and exposure to green spaces in dampening inflammation and reducing cardiovascular risk. By examining the complex interplay between traditional risk factors and environmental exposures, this work highlights the need for comprehensive public health strategies that address both individual lifestyle factors and broader environmental determinants of cardiovascular health. We underscore the importance of further research to elucidate the precise cellular and molecular mechanisms by which environmental factors influence vascular function, with the aim of developing targeted interventions to mitigate their harmful effects and promote cardiovascular well-being.
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Affiliation(s)
- Anusha N Seneviratne
- Department of Health Studies, Royal Holloway University of London, Egham, Surrey, UK
| | - Anne Majumdar
- Department of Health Studies, Royal Holloway University of London, Egham, Surrey, UK
| | - Kalpana Surendranath
- Genome Engineering Laboratory, School of Life Sciences, University of Westminster, London, UK
| | - Mark R Miller
- Centre for Cardiovascular Science, University of Edinburgh, Edinburgh, UK
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Zotta A, Toller-Kawahisa J, Palsson-McDermott EM, O’Carroll SM, Henry ÓC, Day EA, McGettrick AF, Ward RW, Ryan DG, Watson MA, Brand MD, Runtsch MC, Maitz K, Lueger A, Kargl J, Miljkovic JL, Lavelle EC, O’Neill LAJ. Mitochondrial respiratory complex III sustains IL-10 production in activated macrophages and promotes tumor-mediated immune evasion. SCIENCE ADVANCES 2025; 11:eadq7307. [PMID: 39841829 PMCID: PMC11789823 DOI: 10.1126/sciadv.adq7307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 12/19/2024] [Indexed: 01/24/2025]
Abstract
The cytokine interleukin-10 (IL-10) limits the immune response and promotes resolution of acute inflammation. Because of its immunosuppressive effects, IL-10 up-regulation is a common feature of tumor progression and metastasis. Recently, IL-10 regulation has been shown to depend on mitochondria and redox-sensitive signals. We have found that Suppressor of site IIIQo Electron Leak 1.2 (S3QEL 1.2), a specific inhibitor of reactive oxygen species (ROS) production from mitochondrial complex III, and myxothiazol, a complex III inhibitor, decrease IL-10 in lipopolysaccharide (LPS)-activated macrophages. IL-10 down-regulation is likely to be mediated by suppression of c-Fos, which is a subunit of activator protein 1 (AP1), a transcription factor required for IL-10 gene expression. S3QEL 1.2 impairs IL-10 production in vivo after LPS challenge and promotes the survival of mice bearing B16F10 melanoma by lowering tumor growth. Our data identify a link between complex III-dependent ROS generation and IL-10 production in macrophages, the targeting of which could have potential in boosting antitumor immunity.
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Affiliation(s)
- Alessia Zotta
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Juliana Toller-Kawahisa
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Eva M. Palsson-McDermott
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Shane M. O’Carroll
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Órlaith C. Henry
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Emily A. Day
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
- Department of Physiology and Pharmacology, Schulich School of Medicine & Dentistry, University of Western Ontario, London, ON, Canada
| | - Anne F. McGettrick
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Ross W. Ward
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Dylan G. Ryan
- Mitochondria Biology Unit, University of Cambridge, Cambridge, UK
| | | | | | - Marah C. Runtsch
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Kathrin Maitz
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Anna Lueger
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Julia Kargl
- Division of Pharmacology, Otto Loewi Research Center, Medical University of Graz, Graz, Austria
| | - Jan L. Miljkovic
- Mitochondria Biology Unit, University of Cambridge, Cambridge, UK
| | - Ed C. Lavelle
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
| | - Luke A. J. O’Neill
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland
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Chen L, Chang L, Wu W, Jing M, Li H, Niu C, Wei S, Zhu S, Zhao Y. Multi-omics analysis combined with network pharmacology revealed the mechanisms of rutaecarpine in chronic atrophic gastritis. JOURNAL OF ETHNOPHARMACOLOGY 2025; 339:119151. [PMID: 39581285 DOI: 10.1016/j.jep.2024.119151] [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: 09/19/2024] [Revised: 11/20/2024] [Accepted: 11/21/2024] [Indexed: 11/26/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Tetradium ruticarpum (A.Juss.) T.G.Hartley is a traditional Chinese medicine with a history of thousands of years, which plays an important role in the relief of gastric pain, indigestion, vomiting and diarrhea. Rutaecarpine (RUT) is one of the major active constituents of Tetradium ruticarpum (A.Juss.) T.G.Hartley with potential therapeutic activity in chronic atrophic gastritis (CAG). However, the mechanism of RUT to improve CAG is not well understood. AIM OF THIS STUDY This study aimed to evaluate the efficacy of RUT in treating CAG and its underlying mechanism. MATERIALS AND METHODS The CAG model of SD rats was established by induction with 0.1% ammonia and 20 mmol/L sodium deoxycholate solution, accompanied with irregular fasting cycle. The efficacy of RUT in treating CAG was assessed through pathological examination and serum biochemical indices including PP, IL-6, MTL, TNF-α, PG I, SS, PG II, IL-10 and GAS-17. Following this, network pharmacology, 16s rRNA sequencing, transcriptomics, and broadly targeted metabolomics were conducted to unravel the underlying mechanisms of RUT's action in CAG treatment. Ultimately, molecular docking, western blotting, and immunohistochemistry were employed to validate the critical targets and pathways involved in RUT's therapeutic approach for CAG. RESULTS RUT significantly improved body weight, gastric juice pH and gastric histologic injury in CAG rats. The results of serum biochemical indices showed that RUT significantly inhibited the expression levels of SS, GAS-17, IL-6 and TNF-α, and increased the levels of MTL, PP, PGI, PGII and IL-10. In addition, RUT apparently increased the expression of mucosal barrier proteins such as ZO-1, E-cadherin and claudin-4 and occludin. Network pharmacology in combination with transcriptomics revealed that the MAPK signaling pathway was the most important pathway for RUT treatment of CAG. Further analysis suggested that by regulating linoleic acid metabolism, metabolic pathways, etc. mainly related to energy metabolism, RUT intervention effectively ameliorated gastric tissue metabolic disorders in CAG rats. The 16S rRNA gene-based microbiota analysis revealed that RUT altered the composition of the intestinal microbiota and decreased the relative abundance of unclassified_Muribaculaceae. PICRUST analysis suggested that the differential bacteria may be involved in energy metabolism pathway regulation for the improvement of CAG. A comprehensive analysis of the transcriptome and metabolome showed that the RUT improved the differential metabolites through the regulation of TGER2, CBR1 and CTPS1 targets. CONCLUSION These findings indicated that RUT's mechanism of action in treating CAG was related to modulating the gut microbiota, influencing energy metabolism, and inhibiting the MAPK signaling pathway. This provided new insights into how RUT exerts its therapeutic effects on CAG.
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Affiliation(s)
- Lisheng Chen
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Lei Chang
- Department of Pharmacy, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Wenbin Wu
- Health Care Office of the Service Bureau of Agency for Offices Administration of the Central Military Commission, Beijing, China
| | - Manyi Jing
- Department of Pharmacy, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Haotian Li
- Department of Pharmacy, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Cong Niu
- Medical Supplies Center of PLA General Hospital, Beijing, China
| | - Shizhang Wei
- National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
| | - Shishu Zhu
- Department of Health Medicine, The Fifth Medical Center of PLA General Hospital, Beijing, China.
| | - Yanling Zhao
- College of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China; Department of Pharmacy, The Fifth Medical Center of Chinese PLA General Hospital, Beijing, China.
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Yan M, Wang Z, Qiu Z, Cui Y, Xiang Q. Platelet signaling in immune landscape: comprehensive mechanism and clinical therapy. Biomark Res 2024; 12:164. [PMID: 39736771 DOI: 10.1186/s40364-024-00700-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Accepted: 11/28/2024] [Indexed: 01/01/2025] Open
Abstract
Platelets are essential for blood clotting and maintaining normal hemostasis. In pathological conditions, platelets are increasingly recognized as crucial regulatory factors in various immune-mediated inflammatory diseases. Resting platelets are induced by various factors such as immune complexes through Fc receptors, platelet-targeting autoantibodies and other platelet-activating stimuli. Platelet activation in immunological processes involves the release of immune activation stimuli, antigen presentation and interaction with immune cells. Platelets participate in both the innate immune system (neutrophils, monocytes/macrophages, dendritic cells (DCs) and Natural Killer (NK) cells and the adaptive immune system (T and B cells). Clinical therapeutic strategies include targeting platelet activation, platelet-immune cell interaction and platelet-endothelial cell interaction, which display positive development prospects. Understanding the mechanisms of platelets in immunity is important, and developing targeted modulations of these mechanisms will pave the way for promising therapeutic strategies.
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Affiliation(s)
- Mengyao Yan
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China
| | - Zhe Wang
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China
| | - Zhiwei Qiu
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China
| | - Yimin Cui
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China.
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
| | - Qian Xiang
- Institute of Clinical Pharmacology, Peking University First Hospital, Beijing, China.
- Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
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Reczek CR, Chakrabarty RP, D'Alessandro KB, Sebo ZL, Grant RA, Gao P, Budinger GR, Chandel NS. Metformin targets mitochondrial complex I to lower blood glucose levels. SCIENCE ADVANCES 2024; 10:eads5466. [PMID: 39693440 DOI: 10.1126/sciadv.ads5466] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/19/2024] [Indexed: 12/20/2024]
Abstract
Metformin is among the most prescribed antidiabetic drugs, but the primary molecular mechanism by which metformin lowers blood glucose levels is unknown. Previous studies have proposed numerous mechanisms by which acute metformin lowers blood glucose, including the inhibition of mitochondrial complex I of the electron transport chain (ETC). Here, we used transgenic mice that globally express the Saccharomyces cerevisiae internal alternative NADH dehydrogenase (NDI1) protein to determine whether the glucose-lowering effect of acute oral administration of metformin requires inhibition of mitochondrial complex I of the ETC in vivo. NDI1 is a yeast NADH dehydrogenase enzyme that complements the loss of mammalian mitochondrial complex I electron transport function and is insensitive to pharmacologic mitochondrial complex I inhibitors including metformin. We demonstrate that NDI1 expression attenuates metformin's ability to lower blood glucose levels under standard chow and high-fat diet conditions. Our results indicate that acute oral administration of metformin targets mitochondrial complex I to lower blood glucose.
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Affiliation(s)
- Colleen R Reczek
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ram P Chakrabarty
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Karis B D'Alessandro
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Zachary L Sebo
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Rogan A Grant
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Peng Gao
- Robert H. Lurie Cancer Center Metabolomics Core, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - G R Budinger
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Navdeep S Chandel
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
- Chan Zuckerberg Biohub, Chicago, IL, USA
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Chen Y, Zhang J, Zhang T, Wu Y, Xi Y, Wu T, Li M, Li Y, Zhou S, Wu M, Wang S. Circulating Interleukin-6 Mediates PM 2.5-Induced Ovarian Injury by Suppressing the PPARγ Pathway. RESEARCH (WASHINGTON, D.C.) 2024; 7:0538. [PMID: 39639885 PMCID: PMC11617621 DOI: 10.34133/research.0538] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 10/30/2024] [Accepted: 11/05/2024] [Indexed: 12/07/2024]
Abstract
Exposure to airborne fine particulate matter (PM2.5) is strongly associated with poor fertility and ovarian damage. However, the mechanism underlying this remains largely unclear. Here, we found that PM2.5 markedly impaired murine ovarian reserve, decreased hormone levels, and aggravated ovarian inflammation. Circulating interleukin-6 (IL-6) was elevated in PM2.5-exposed mice and was further confirmed to mediate this damage by IL-6 recombinant protein intervention. PM2.5 exposure led to increased alveolar macrophage infiltration in the lungs. However, alveolar macrophage clearance with clodronate liposomes could not fully reverse the elevated IL-6 levels and ovarian injury, suggesting that alveolar macrophages were probably not the only source of circulating IL-6. Further experiments indicated that IL-6 mainly targeted ovarian theca-interstitial cells and impaired testosterone synthesis via suppressing the peroxisome proliferator-activated receptor γ (PPARγ) pathway. In addition, apoptosis of granulosa cells and restriction of follicular growth were observed in co-cultures with IL-6-treated theca-interstitial cells, which could be further reversed by the PPARγ agonist. Moreover, IL-6-neutralizing antibodies ameliorated PM2.5-induced ovarian damage. Notably, increased levels of circulating IL-6 were observed in premature ovarian aging patients and were inversely associated with their ovarian function. In summary, our findings offer a mechanistic explanation for PM2.5-induced ovarian dysfunction and verify IL-6 as a biomarker and potential therapeutic target.
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Affiliation(s)
- Yingying Chen
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
- Department of Gynecology, The First Affiliated Hospital of Zhengzhou University,
Zhengzhou University, Zhengzhou, China
| | - Jinjin Zhang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
| | - Tianyu Zhang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
| | - Yaling Wu
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
| | - Yueyue Xi
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
| | - Tong Wu
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
| | - Mo Li
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
| | - Yan Li
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
| | - Su Zhou
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
| | - Mingfu Wu
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
| | - Shixuan Wang
- Department of Obstetrics and Gynecology, National Clinical Research Center for Obstetrics and Gynecology, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
- Key Laboratory of Cancer Invasion and Metastasis (Ministry of Education), Hubei Key Laboratory of Tumor Invasion and Metastasis, Tongji Hospital, Tongji Medical College,
Huazhong University of Science and Technology, Wuhan, China
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Chavda VP, Feehan J, Apostolopoulos V. Inflammation: The Cause of All Diseases. Cells 2024; 13:1906. [PMID: 39594654 PMCID: PMC11592557 DOI: 10.3390/cells13221906] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 11/11/2024] [Indexed: 11/28/2024] Open
Abstract
Inflammation is an essential biological process that serves as the body's first line of defence against harmful stimuli, including pathogens, damaged cells, and irritants [...].
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Affiliation(s)
- Vivek P. Chavda
- Department of Pharmaceutics and Pharmaceutical Technology, L.M. College of Pharmacy, Ahmedabad 380009, Gujarat, India;
| | - Jack Feehan
- School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC 3083, Australia;
| | - Vasso Apostolopoulos
- School of Health and Biomedical Sciences, RMIT University, Melbourne, VIC 3083, Australia;
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Cui J, Chen W, Zhang D, Lu M, Huang Z, Yi B. Metformin attenuates PM 2.5-induced oxidative stress by inhibiting the AhR/CYP1A1 pathway in proximal renal tubular epithelial cells. Toxicol Mech Methods 2024; 34:1022-1034. [PMID: 39034811 DOI: 10.1080/15376516.2024.2378296] [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: 01/21/2024] [Revised: 06/30/2024] [Accepted: 07/01/2024] [Indexed: 07/23/2024]
Abstract
The harmful effects of PM2.5 on human health, including an increased risk of chronic kidney disease (CKD), have raised a lot of attention, but the underlying mechanisms are unclear. We used the Shanghai Meteorological and Environmental Animal Exposure System (Shanghai-METAS) to simulate the inhalation of PM2.5 in the real environment and established an animal model by exposing C57BL/6 mice to filtered air (FA) and Particulate Matter (PM2.5) for 8 weeks. PM2.5 impaired the renal function of the mice, and the renal tubules underwent destructive changes. Analysis of NHANES data showed a correlation between reduced kidney function and higher blood levels of PM2.5 components, polychlorinated biphenyls (PCBs) and dioxins, which are Aryl hydrocarbon Receptor (AhR) ligands. PM2.5 exposure induced higher levels of AhR and CYP1A1 and oxidative stress as evidenced by the higher levels of ROS, MDA, and GSSG in kidneys of mice. PM2.5 exposure led to AhR overexpression and nuclear translocation in proximal renal tubular epithelial cells. Inhibition of AhR reduced CYP1A1 expression and PM2.5-increased levels of ROS, MDA and GSSG. Our study suggested metformin can mitigate PM2.5-induced oxidative stress by inhibiting the AhR/CYP1A1 pathway. These findings illuminated the role of AhR/CYP1A1 pathway in PM2.5-induced kidney injury and the protective effect of metformin on PM2.5-induced cellular damage, offering new insights for air pollution-related renal diseases.
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Affiliation(s)
- Jing Cui
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center for Critical Kidney Disease in Hunan Province, Changsha, Hunan, China
| | - Weilin Chen
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center for Critical Kidney Disease in Hunan Province, Changsha, Hunan, China
| | - Dongdong Zhang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center for Critical Kidney Disease in Hunan Province, Changsha, Hunan, China
| | - Mengqiu Lu
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center for Critical Kidney Disease in Hunan Province, Changsha, Hunan, China
| | - Zhijun Huang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center for Critical Kidney Disease in Hunan Province, Changsha, Hunan, China
- Center for Clinical Pharmacology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
| | - Bin Yi
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China
- Clinical Research Center for Critical Kidney Disease in Hunan Province, Changsha, Hunan, China
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9
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Sirtori CR, Castiglione S, Pavanello C. METFORMIN: FROM DIABETES TO CANCER TO PROLONGATION OF LIFE. Pharmacol Res 2024; 208:107367. [PMID: 39191336 DOI: 10.1016/j.phrs.2024.107367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 08/12/2024] [Accepted: 08/21/2024] [Indexed: 08/29/2024]
Abstract
The metformin molecule dates back to over a century, but its clinical use started in the '50s. Since then, its use in diabetics has grown constantly, with over 150 million users today. The therapeutic profile also expanded, with improved understanding of novel mechanisms. Metformin has a major activity on insulin resistance, by acting on the insulin receptors and mitochondria, most likely by activation of the adenosine monophosphate-activated kinase. These and associated mechanisms lead to significant lipid lowering and body weight loss. An anti-cancer action has come up in recent years, with mechanisms partly dependent on the mitochondrial activity and also on phosphatidylinositol 3-kinase resistance occurring in some malignant tumors. The potential of metformin to raise life-length is the object of large ongoing studies and of several basic and clinical investigations. The present review article will attempt to investigate the basic mechanisms behind these diverse activities and the potential clinical benefits. Metformin may act on transcriptional activity by histone modification, DNA methylation and miRNAs. An activity on age-associated inflammation (inflammaging) may occur via activation of the nuclear factor erythroid 2 related factor and changes in gut microbiota. A senolytic activity, leading to reduction of cells with the senescent associated secretory phenotype, may be crucial in lifespan prolongation as well as in ancillary properties in age-associated diseases, such as Parkinson's disease. Telomere prolongation may be related to the activity on mitochondrial respiratory factor 1 and on peroxisome gamma proliferator coactivator 1-alpha. Very recent observations on the potential to act on the most severe neurological disorders, such as amyotrophic lateral sclerosis and frontotemporal dementia, have raised considerable hope.
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Affiliation(s)
- Cesare R Sirtori
- Center of Dyslipidemias, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Centro E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
| | - Sofia Castiglione
- Center of Dyslipidemias, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Centro E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Chiara Pavanello
- Center of Dyslipidemias, ASST Grande Ospedale Metropolitano Niguarda, Milan, Italy; Centro E. Grossi Paoletti, Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
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10
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Chang-Chien J, Huang JL, Tsai HJ, Wang SL, Kuo ML, Yao TC. Vitamin D ameliorates particulate matter induced mitochondrial damages and calcium dyshomeostasis in BEAS-2B human bronchial epithelial cells. Respir Res 2024; 25:321. [PMID: 39174953 PMCID: PMC11342659 DOI: 10.1186/s12931-024-02951-7] [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: 10/05/2023] [Accepted: 08/12/2024] [Indexed: 08/24/2024] Open
Abstract
BACKGROUND Mitochondria is prone to oxidative damage by endogenous and exogenous sources of free radicals, including particulate matter (PM). Given the role of mitochondria in inflammatory disorders, such as asthma and chronic obstructive pulmonary disease, we hypothesized that supplementation of vitamin D may play a protective role in PM-induced mitochondrial oxidative damages of human bronchial epithelial BEAS-2B cells. METHODS BEAS-2B cells were pretreated with 1,25(OH)2D3, an active form of vitamin D, for 1 h prior to 24-hour exposure to PM (SRM-1648a). Oxidative stress was measured by flow cytometry. Mitochondrial functions including mitochondrial membrane potential, ATP levels, and mitochondrial DNA copy number were analyzed. Additionally, mitochondrial ultrastructure was examined using transmission electron microscopy. Intracellular and mitochondrial calcium concentration changes were assessed using flow cytometry based on the expression of Fluo-4 AM and Rhod-2 AM, respectively. Pro-inflammatory cytokines, including IL-6 and MCP-1, were quantified using ELISA. The expression levels of antioxidants, including SOD1, SOD2, CAT, GSH, and NADPH, were determined. RESULTS Our findings first showed that 24-hour exposure to PM led to the overproduction of reactive oxygen species (ROS) derived from mitochondria. PM-induced mitochondrial oxidation resulted in intracellular calcium accumulation, particularly within mitochondria, and alterations in mitochondrial morphology and functions. These changes included loss of mitochondrial membrane integrity, disarrayed cristae, mitochondrial membrane depolarization, reduced ATP production, and increased mitochondrial DNA copy number. Consequently, PM-induced mitochondrial damage triggered the release of certain inflammatory cytokines, such as IL-6 and MCP-1. Similar to the actions of mitochondrial ROS inhibitor MitoTEMPO, 1,25(OH)2D3 conferred protective effects on mtDNA alterations, mitochondrial damages, calcium dyshomeostasis, thereby decreasing the release of certain inflammatory cytokines. We found that greater cellular level of 1,25(OH)2D3 upregulated the expression of enzymatic (SOD1, SOD2, and CAT) and non-enzymatic (GSH and NADPH) antioxidants to modulate cellular redox homeostasis. CONCLUSION Our study provides new evidence that 1,25(OH)2D3 acts as an antioxidant, enhancing BEAS-2B antioxidant responses to regulate mitochondrial ROS homeostasis and mitochondrial function, thereby enhancing epithelial defense against air pollution exposure.
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Affiliation(s)
- Ju Chang-Chien
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Hsin Street, Kweishan, Taoyuan, 33305, Taiwan
- School of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Jing-Long Huang
- School of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan
- Department of Pediatrics, New Taipei Municipal TuCheng Hospital, New Taipei, Taiwan
- Community Medicine Research Center, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan
| | - Hui-Ju Tsai
- Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
- College of Life Science, National Tsing-Hua University, Hsinchu, Taiwan
| | - Shih-Ling Wang
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Hsin Street, Kweishan, Taoyuan, 33305, Taiwan
| | - Ming-Ling Kuo
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Hsin Street, Kweishan, Taoyuan, 33305, Taiwan.
- Department of Pediatrics, New Taipei Municipal TuCheng Hospital, New Taipei, Taiwan.
- Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, 259 Wenhua 1st Road, Kweishan, Taoyuan, 33302, Taiwan.
| | - Tsung-Chieh Yao
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, 5 Fu-Hsin Street, Kweishan, Taoyuan, 33305, Taiwan.
- School of Medicine, Chang Gung University College of Medicine, Taoyuan, Taiwan.
- Community Medicine Research Center, Chang Gung Memorial Hospital at Keelung, Keelung, Taiwan.
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11
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Barnett D, Zimmer TS, Booraem C, Palaguachi F, Meadows SM, Xiao H, Chouchani ET, Orr AG, Orr AL. Mitochondrial complex III-derived ROS amplify immunometabolic changes in astrocytes and promote dementia pathology. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.08.19.608708. [PMID: 39229090 PMCID: PMC11370371 DOI: 10.1101/2024.08.19.608708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
Neurodegenerative disorders alter mitochondrial functions, including the production of reactive oxygen species (ROS). Mitochondrial complex III (CIII) generates ROS implicated in redox signaling, but its triggers, targets, and disease relevance are not clear. Using site-selective suppressors and genetic manipulations together with mitochondrial ROS imaging and multiomic profiling, we found that CIII is the dominant source of ROS production in astrocytes exposed to neuropathology-related stimuli. Astrocytic CIII-ROS production was dependent on nuclear factor-κB (NF-κB) and the mitochondrial sodium-calcium exchanger (NCLX) and caused oxidation of select cysteines within immune and metabolism-associated proteins linked to neurological disease. CIII-ROS amplified metabolomic and pathology-associated transcriptional changes in astrocytes, with STAT3 activity as a major mediator, and facilitated neuronal toxicity in a non-cell-autonomous manner. As proof-of-concept, suppression of CIII-ROS in mice decreased dementia-linked tauopathy and neuroimmune cascades and extended lifespan. Our findings establish CIII-ROS as an important immunometabolic signal transducer and tractable therapeutic target in neurodegenerative disease.
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Affiliation(s)
- Daniel Barnett
- Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY
- Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY
| | - Till S. Zimmer
- Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY
| | - Caroline Booraem
- Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY
- Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY
| | - Fernando Palaguachi
- Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY
| | - Samantha M. Meadows
- Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY
- Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY
| | - Haopeng Xiao
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA
- Department of Cell Biology, Harvard Medical School, Boston, MA
| | - Edward T. Chouchani
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA
- Department of Cell Biology, Harvard Medical School, Boston, MA
| | - Anna G. Orr
- Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY
- Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY
| | - Adam L. Orr
- Helen and Robert Appel Alzheimer’s Disease Research Institute, Weill Cornell Medicine, New York, NY
- Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY
- Neuroscience Graduate Program, Weill Cornell Medicine, New York, NY
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12
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Kim JH, Hwang KH, Kim SH, Kim HJ, Kim JM, Lee MY, Cha SK, Lee J. Particulate Matter-Induced Neurotoxicity: Unveiling the Role of NOX4-Mediated ROS Production and Mitochondrial Dysfunction in Neuronal Apoptosis. Int J Mol Sci 2024; 25:6116. [PMID: 38892302 PMCID: PMC11172693 DOI: 10.3390/ijms25116116] [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: 04/26/2024] [Revised: 05/27/2024] [Accepted: 05/30/2024] [Indexed: 06/21/2024] Open
Abstract
Urban air pollution, a significant environmental hazard, is linked to adverse health outcomes and increased mortality across various diseases. This study investigates the neurotoxic effects of particulate matter (PM), specifically PM2.5 and PM10, by examining their role in inducing oxidative stress and subsequent neuronal cell death. We highlight the novel finding that PM increases mitochondrial ROS production via stimulating NOX4 activity, not through its expression level in Neuro-2A cells. Additionally, PMs provoke ROS production via increasing the expression and activity of NOX2 in SH-SY5Y human neuroblastoma cells, implying differential regulation of NOX proteins. This increase in mitochondrial ROS triggers the opening of the mitochondrial permeability transition pore (mPTP), leading to apoptosis through key mediators, including caspase3, BAX, and Bcl2. Notably, the voltage-dependent anion-selective channel 1 (VDAC1) increases at 1 µg/mL of PM2.5, while PM10 triggers an increase from 10 µg/mL. At the same concentration (100 µg/mL), PM2.5 causes 1.4 times higher ROS production and 2.4 times higher NOX4 activity than PM10. The cytotoxic effects induced by PMs were alleviated by NOX inhibitors GKT137831 and Apocynin. In SH-SY5Y cells, both PM types increase ROS and NOX2 levels, leading to cell death, which Apocynin rescues. Variability in NADPH oxidase sources underscores the complexity of PM-induced neurotoxicity. Our findings highlight NOX4-driven ROS and mitochondrial dysfunction, suggesting a potential therapeutic approach for mitigating PM-induced neurotoxicity.
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Affiliation(s)
- Ji-Hee Kim
- Department of Occupational Therapy, Soonchunhyang University, Asan-si 31538, Republic of Korea;
| | - Kyu-Hee Hwang
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
- Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
- Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
| | - Seong-Heon Kim
- Department of Environmental and Energy Engineering, Yonsei University, Wonju 26493, Republic of Korea;
| | - Hi-Ju Kim
- Department of Psychiatry, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
| | - Jung-Min Kim
- Department of Medical Science, Soonchunhyang University, Asan-si 31538, Republic of Korea; (J.-M.K.); (M.-Y.L.)
| | - Mi-Young Lee
- Department of Medical Science, Soonchunhyang University, Asan-si 31538, Republic of Korea; (J.-M.K.); (M.-Y.L.)
- Department of Medical Biotechnology, Soonchunhyang University, Asan-si 31538, Republic of Korea
| | - Seung-Kuy Cha
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
- Department of Global Medical Science, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
- Mitohormesis Research Center, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea
| | - Jinhee Lee
- Department of Psychiatry, Yonsei University Wonju College of Medicine, Wonju 26426, Republic of Korea;
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Plowman TJ, Christensen H, Aiges M, Fernandez E, Shah MH, Ramana KV. Anti-Inflammatory Potential of the Anti-Diabetic Drug Metformin in the Prevention of Inflammatory Complications and Infectious Diseases Including COVID-19: A Narrative Review. Int J Mol Sci 2024; 25:5190. [PMID: 38791227 PMCID: PMC11121530 DOI: 10.3390/ijms25105190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 05/03/2024] [Accepted: 05/07/2024] [Indexed: 05/26/2024] Open
Abstract
Metformin, a widely used first-line anti-diabetic therapy for the treatment of type-2 diabetes, has been shown to lower hyperglycemia levels in the blood by enhancing insulin actions. For several decades this drug has been used globally to successfully control hyperglycemia. Lactic acidosis has been shown to be a major adverse effect of metformin in some type-2 diabetic patients, but several studies suggest that it is a typically well-tolerated and safe drug in most patients. Further, recent studies also indicate its potential to reduce the symptoms associated with various inflammatory complications and infectious diseases including coronavirus disease 2019 (COVID-19). These studies suggest that besides diabetes, metformin could be used as an adjuvant drug to control inflammatory and infectious diseases. In this article, we discuss the current understanding of the role of the anti-diabetic drug metformin in the prevention of various inflammatory complications and infectious diseases in both diabetics and non-diabetics.
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Affiliation(s)
| | | | | | | | | | - Kota V. Ramana
- Department of Biomedical Sciences, Noorda College of Osteopathic Medicine, Provo, UT 84606, USA
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14
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Li J, Wang Y, Shen W, Zhang Z, Su Z, Guo X, Pei P, Hu L, Liu T, Yang K, Guo L. Mitochondria-Modulating Liposomes Reverse Radio-Resistance for Colorectal Cancer. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2400845. [PMID: 38520732 PMCID: PMC11095197 DOI: 10.1002/advs.202400845] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/28/2024] [Indexed: 03/25/2024]
Abstract
Complete remission of colorectal cancer (CRC) is still unachievable in the majority of patients by common fractionated radiotherapy, leaving risks of tumor metastasis and recurrence. Herein, clinical CRC samples demonstrated a difference in the phosphorylation of translation initiation factor eIF2α (p-eIF2α) and the activating transcription factor 4 (ATF4), whose increased expression by initial X-ray irradiation led to the resistance to subsequent radiotherapy. The underlying mechanism is studied in radio-resistant CT26 cells, revealing that the incomplete mitochondrial outer membrane permeabilization (iMOMP) triggered by X-ray irradiation is key for the elevated expression of p-eIF2α and ATF4, and therefore radio-resistance. This finding guided to discover that metformin and 2-DG are synergistic in reversing radio resistance by inhibiting p-eIF2α and ATF4. Liposomes loaded with metformin and 2-DG (M/D-Lipo) are thus prepared for enhancing fractionated radiotherapy of CRC, which achieved satisfactory therapeutic efficacy in both local and metastatic CRC tumors by reversing radio-resistance and preventing T lymphocyte exhaustion.
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Affiliation(s)
- Junmei Li
- Department of Pathologythe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123China
| | - Yuhong Wang
- Department of Pathologythe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123China
| | - Wenhao Shen
- Department of OncologyTaizhou People's Hospital Affiliated to Nanjing Medical UniversityTaizhou225300China
| | - Ziyu Zhang
- State Key Laboratory of Radiation Medicine and ProtectionSchool of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD‐X)Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215123China
| | - Zhiyue Su
- Department of Pathologythe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123China
| | - Xia Guo
- Department of Pathologythe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123China
| | - Pei Pei
- State Key Laboratory of Radiation Medicine and ProtectionSchool of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD‐X)Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215123China
| | - Lin Hu
- State Key Laboratory of Radiation Medicine and ProtectionSchool of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD‐X)Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215123China
| | - Teng Liu
- State Key Laboratory of Radiation Medicine and ProtectionSchool of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD‐X)Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215123China
| | - Kai Yang
- Department of Pathologythe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123China
- State Key Laboratory of Radiation Medicine and ProtectionSchool of Radiation Medicine and Protection & School for Radiological and Interdisciplinary Sciences (RAD‐X)Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education InstitutionsSuzhou Medical CollegeSoochow UniversitySuzhouJiangsu215123China
| | - Lingchuan Guo
- Department of Pathologythe First Affiliated Hospital of Soochow UniversitySoochow UniversitySuzhouJiangsu215123China
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15
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Pervizaj-Oruqaj L, Ferrero MR, Matt U, Herold S. The guardians of pulmonary harmony: alveolar macrophages orchestrating the symphony of lung inflammation and tissue homeostasis. Eur Respir Rev 2024; 33:230263. [PMID: 38811033 PMCID: PMC11134199 DOI: 10.1183/16000617.0263-2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2023] [Accepted: 03/20/2024] [Indexed: 05/31/2024] Open
Abstract
Recent breakthroughs in single-cell sequencing, advancements in cellular and tissue imaging techniques, innovations in cell lineage tracing, and insights into the epigenome collectively illuminate the enigmatic landscape of alveolar macrophages in the lung under homeostasis and disease conditions. Our current knowledge reveals the cellular and functional diversity of alveolar macrophages within the respiratory system, emphasising their remarkable adaptability. By synthesising insights from classical cell and developmental biology studies, we provide a comprehensive perspective on alveolar macrophage functional plasticity. This includes an examination of their ontology-related features, their role in maintaining tissue homeostasis under steady-state conditions and the distinct contribution of bone marrow-derived macrophages (BMDMs) in promoting tissue regeneration and restoring respiratory system homeostasis in response to injuries. Elucidating the signalling pathways within inflammatory conditions, the impact of various triggers on tissue-resident alveolar macrophages (TR-AMs), as well as the recruitment and polarisation of macrophages originating from the bone marrow, presents an opportunity to propose innovative therapeutic approaches aimed at modulating the equilibrium between phenotypes to induce programmes associated with a pro-regenerative or homeostasis phenotype of BMDMs or TR-AMs. This, in turn, can lead to the amelioration of disease outcomes and the attenuation of detrimental inflammation. This review comprehensively addresses the pivotal role of macrophages in the orchestration of inflammation and resolution phases after lung injury, as well as ageing-related shifts and the influence of clonal haematopoiesis of indeterminate potential mutations on alveolar macrophages, exploring altered signalling pathways and transcriptional profiles, with implications for respiratory homeostasis.
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Affiliation(s)
- Learta Pervizaj-Oruqaj
- Department of Internal Medicine V, Universities of Giessen and Marburg Lung Center, University Hospital Giessen, Justus Liebig University, Member of the German Center for Lung Research (DZL), Giessen, Germany
- Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany
- Excellence Cluster Cardio-Pulmonary Institute (CPI), Giessen, Germany
| | - Maximiliano Ruben Ferrero
- Department of Internal Medicine V, Universities of Giessen and Marburg Lung Center, University Hospital Giessen, Justus Liebig University, Member of the German Center for Lung Research (DZL), Giessen, Germany
- Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany
- Excellence Cluster Cardio-Pulmonary Institute (CPI), Giessen, Germany
- Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
- Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA), Buenos Aires, Argentina
| | - Ulrich Matt
- Department of Internal Medicine V, Universities of Giessen and Marburg Lung Center, University Hospital Giessen, Justus Liebig University, Member of the German Center for Lung Research (DZL), Giessen, Germany
- Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany
- Excellence Cluster Cardio-Pulmonary Institute (CPI), Giessen, Germany
| | - Susanne Herold
- Department of Internal Medicine V, Universities of Giessen and Marburg Lung Center, University Hospital Giessen, Justus Liebig University, Member of the German Center for Lung Research (DZL), Giessen, Germany
- Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany
- Excellence Cluster Cardio-Pulmonary Institute (CPI), Giessen, Germany
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16
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Ribarič S. The Contribution of Type 2 Diabetes to Parkinson's Disease Aetiology. Int J Mol Sci 2024; 25:4358. [PMID: 38673943 PMCID: PMC11050090 DOI: 10.3390/ijms25084358] [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: 02/29/2024] [Revised: 03/29/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Type 2 diabetes (T2D) and Parkinson's disease (PD) are chronic disorders that have a significant health impact on a global scale. Epidemiological, preclinical, and clinical research underpins the assumption that insulin resistance and chronic inflammation contribute to the overlapping aetiologies of T2D and PD. This narrative review summarises the recent evidence on the contribution of T2D to the initiation and progression of PD brain pathology. It also briefly discusses the rationale and potential of alternative pharmacological interventions for PD treatment.
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Affiliation(s)
- Samo Ribarič
- Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloška 4, 1000 Ljubljana, Slovenia
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17
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Hou CY, Hsieh CC, Hung YC, Hsu CC, Hsieh CW, Yu SH, Cheng KC. Evaluation of the amelioration effect of Ganoderma formosanum extract on delaying PM2.5 damage to lung macrophages. Mol Nutr Food Res 2024; 68:e2300667. [PMID: 38282089 DOI: 10.1002/mnfr.202300667] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 11/26/2023] [Indexed: 01/30/2024]
Abstract
SCOPE Particulate matter (PM) contains toxic organic matter and heavy metals that enter the entire body through blood flow and may cause mortality. Ganoderma formosanum mycelium, a valuable traditional Chinese medicine that has been used since ancient times, contains various active ingredients that can effectively impede inflammatory responses on murine alveolar macrophages induced by PM particles. METHODS AND RESULTS An experimental study assessing the effect of G. formosanum mycelium extract's water fraction (WA) on PM-exposed murine alveolar macrophages using ROS measurement shows that WA reduces intracellular ROS by 12% and increases cell viability by 16% when induced by PM particles. According to RNA-Sequencing, western blotting, and real-time qPCR are conducted to analyze the metabolic pathway. The WA reduces the protein ratio in p-NF-κB/NF-κB by 18% and decreases the expression of inflammatory genes, including IL-1β by 38%, IL-6 by 29%, and TNF-α by 19%. Finally, the identification of seven types of anti-inflammatory compounds in the WA fraction is achieved through UHPLC-ESI-Orbitrap-Elite-MS/MS analysis. These compounds include anti-inflammatory compounds, namely thiamine, adenosine 5'-monophosphate, pipecolic acid, L-pyroglutamic acid, acetyl-L-carnitine, D-mannitol, and L-malic acid. CONCLUSIONS The study suggests that the WA has the potential to alleviate the PM -induced damage in alveolar macrophages, demonstrating its anti-inflammatory properties.
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Affiliation(s)
- Chih-Yao Hou
- Department of Seafood Science, College of Hydrosphere, National Kaohsiung University of Science and Technology, Kaohsiung, 81157, Taiwan
| | - Chen-Che Hsieh
- Institute of Biotechnology, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei, Taiwan
| | - Yin-Ci Hung
- Institute of Food Science Technology, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei, Taiwan
| | - Cheng-Chih Hsu
- Department of Chemistry, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei, 10617, Taiwan
| | - Chang-Wei Hsieh
- Department of Food Science and Biotechnology, National Chung Hsing University, 145 Xingda Rd., South Dist., Taichung, 40227, Taiwan
| | - Shu-Han Yu
- Institute of Biotechnology, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei, Taiwan
| | - Kuan-Chen Cheng
- Institute of Biotechnology, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei, Taiwan
- Institute of Food Science Technology, National Taiwan University, No. 1, Sec. 4, Roosevelt Rd., Taipei, Taiwan
- Department of Optometry, Asia University, 500, Lioufeng Rd., Wufeng, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, 91, Hsueh-Shih Road, Taichung, Taiwan
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18
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Sakata N. The anti-inflammatory effect of metformin: The molecular targets. Genes Cells 2024; 29:183-191. [PMID: 38311861 PMCID: PMC11448366 DOI: 10.1111/gtc.13098] [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: 09/28/2023] [Revised: 12/24/2023] [Accepted: 01/11/2024] [Indexed: 02/06/2024]
Abstract
Metformin is an anti-diabetic drug. Metformin mainly inhibits gluconeogenesis in the liver and reduces blood sugar. In addition to the anti-diabetic effects, many studies have revealed that metformin has anti-inflammatory effects. Various molecules were suggested to be the target of the metformin's anti-inflammatory effects. However, the conclusion is not clear. Metformin is related to a number of molecules and the identification of the main target in anti-inflammatory effects leads to the understanding of inflammation and metformin. In this article, I discuss each suggested molecule, involved mechanisms, and their relationship with various diseases.
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Caceres L, Abogunloko T, Malchow S, Ehret F, Merz J, Li X, Sol Mitre L, Magnani N, Tasat D, Mwinyella T, Spiga L, Suchanek D, Fischer L, Gorka O, Colin Gissler M, Hilgendorf I, Stachon P, Rog-Zielinska E, Groß O, Westermann D, Evelson P, Wolf D, Marchini T. Molecular mechanisms underlying NLRP3 inflammasome activation and IL-1β production in air pollution fine particulate matter (PM 2.5)-primed macrophages. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 341:122997. [PMID: 38000727 PMCID: PMC10804998 DOI: 10.1016/j.envpol.2023.122997] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/10/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023]
Abstract
Exposure to air pollution fine particulate matter (PM2.5) aggravates respiratory and cardiovascular diseases. It has been proposed that PM2.5 uptake by alveolar macrophages promotes local inflammation that ignites a systemic response, but precise underlying mechanisms remain unclear. Here, we demonstrate that PM2.5 phagocytosis leads to NLRP3 inflammasome activation and subsequent release of the pro-inflammatory master cytokine IL-1β. Inflammasome priming and assembly was time- and dose-dependent in inflammasome-reporter THP-1-ASC-GFP cells, and consistent across PM2.5 samples of variable chemical composition. While inflammasome activation was promoted by different PM2.5 surrogates, significant IL-1β release could only be observed after stimulation with transition-metal rich Residual Oil Fly Ash (ROFA) particles. This effect was confirmed in primary human monocyte-derived macrophages and murine bone marrow-derived macrophages (BMDMs), and by confocal imaging of inflammasome-reporter ASC-Citrine BMDMs. IL-1β release by ROFA was dependent on the NLRP3 inflammasome, as indicated by lack of IL-1β production in ROFA-exposed NLRP3-deficient (Nlrp3-/-) BMDMs, and by specific NLRP3 inhibition with the pharmacological compound MCC950. In addition, while ROFA promoted the upregulation of pro-inflammatory gene expression and cytokines release, MCC950 reduced TNF-α, IL-6, and CCL2 production. Furthermore, inhibition of TNF-α with a neutralizing antibody decreased IL-1β release in ROFA-exposed BMDMs. Using electron tomography, ROFA particles were observed inside intracellular vesicles and mitochondria, which showed signs of ultrastructural damage. Mechanistically, we identified lysosomal rupture, K+ efflux, and impaired mitochondrial function as important prerequisites for ROFA-mediated IL-1β release. Interestingly, specific inhibition of superoxide anion production (O2•-) from mitochondrial respiratory Complex I, but not III, blunted IL-1β release in ROFA-exposed BMDMs. Our findings unravel the mechanism by which PM2.5 promotes IL-1β release in macrophages and provide a novel link between innate immune response and exposure to air pollution PM2.5.
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Affiliation(s)
- Lourdes Caceres
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Químicas, C1113AAD, Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, Instituto de Bioquímica y Medicina Molecular Prof. Alberto Boveris (IBIMOL), C1113AAD, Buenos Aires, Argentina
| | - Tijani Abogunloko
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104, Freiburg, Germany
| | - Sara Malchow
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany
| | - Fabienne Ehret
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany; Faculty of Biology, University of Freiburg, 79104, Freiburg im Breisgau, Germany
| | - Julian Merz
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany
| | - Xiaowei Li
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany
| | - Lucia Sol Mitre
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany; Spemann Graduate School of Biology and Medicine (SGBM), University of Freiburg, 79104, Freiburg, Germany
| | - Natalia Magnani
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Químicas, C1113AAD, Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, Instituto de Bioquímica y Medicina Molecular Prof. Alberto Boveris (IBIMOL), C1113AAD, Buenos Aires, Argentina
| | - Deborah Tasat
- Universidad Nacional de General San Martín, Escuela de Ciencia y Tecnología, B1650, General San Martín, Argentina
| | - Timothy Mwinyella
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany
| | - Lisa Spiga
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany
| | - Dymphie Suchanek
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany
| | - Larissa Fischer
- Faculty of Biology, University of Freiburg, 79104, Freiburg im Breisgau, Germany; Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany
| | - Oliver Gorka
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany
| | - Mark Colin Gissler
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany
| | - Ingo Hilgendorf
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany
| | - Peter Stachon
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany
| | - Eva Rog-Zielinska
- Institute for Experimental Cardiovascular Medicine, University Heart Center, Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany
| | - Olaf Groß
- Institute of Neuropathology, Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany
| | - Dirk Westermann
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany
| | - Pablo Evelson
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Químicas, C1113AAD, Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, Instituto de Bioquímica y Medicina Molecular Prof. Alberto Boveris (IBIMOL), C1113AAD, Buenos Aires, Argentina
| | - Dennis Wolf
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany.
| | - Timoteo Marchini
- Department of Cardiology and Angiology, University Heart Center, University of Freiburg, 79106, Freiburg im Breisgau, Germany; Faculty of Medicine, University of Freiburg, 79110, Freiburg im Breisgau, Germany; Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Ciencias Químicas, C1113AAD, Buenos Aires, Argentina; CONICET - Universidad de Buenos Aires, Instituto de Bioquímica y Medicina Molecular Prof. Alberto Boveris (IBIMOL), C1113AAD, Buenos Aires, Argentina
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20
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Mertens RT, Kim JH, Ofori S, Olelewe C, Kamitsuka PJ, Kwakye GF, Awuah SG. A gold-based inhibitor of oxidative phosphorylation is effective against triple negative breast cancer. Biomed Pharmacother 2024; 170:116010. [PMID: 38128183 PMCID: PMC11254167 DOI: 10.1016/j.biopha.2023.116010] [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: 09/06/2023] [Revised: 11/28/2023] [Accepted: 12/13/2023] [Indexed: 12/23/2023] Open
Abstract
Triple-negative breast cancer (TNBC) is associated with metabolic heterogeneity and poor prognosis with limited treatment options. New treatment paradigms for TNBC remains an unmet need. Thus, therapeutics that target metabolism are particularly attractive approaches. We previously designed organometallic Au(III) compounds capable of modulating mitochondrial respiration by ligand tuning with high anticancer potency in vitro and in vivo. Here, we show that an efficacious Au(III) dithiocarbamate (AuDTC) compound induce mitochondrial dysfunction and oxidative damage in cancer cells. Efficacy of AuDTC in TNBC mouse models harboring mitochondrial oxidative phosphorylation (OXPHOS) dependence and metabolic heterogeneity establishes its therapeutic potential following systemic delivery. This provides evidence that AuDTC is an effective modulator of mitochondrial respiration worthy of clinical development in the context of TNBC. ONE SENTENCE SUMMARY: Metabolic-targeting of triple-negative breast cancer by gold anticancer agent may provide efficacious therapy.
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Affiliation(s)
- R Tyler Mertens
- Department of Chemistry, University of Kentucky; Lexington, KY 40506, United States
| | - Jong Hyun Kim
- Department of Chemistry, University of Kentucky; Lexington, KY 40506, United States
| | - Samuel Ofori
- Department of Chemistry, University of Kentucky; Lexington, KY 40506, United States; Department of Neuroscience, Oberlin College, Oberlin, OH 44074, United States; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, United States; University of Kentucky Markey Cancer Center, USA
| | - Chibuzor Olelewe
- Department of Chemistry, University of Kentucky; Lexington, KY 40506, United States; Department of Neuroscience, Oberlin College, Oberlin, OH 44074, United States; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, United States; University of Kentucky Markey Cancer Center, USA
| | - Paul J Kamitsuka
- Department of Neuroscience, Oberlin College, Oberlin, OH 44074, United States
| | - Gunnar F Kwakye
- Department of Neuroscience, Oberlin College, Oberlin, OH 44074, United States
| | - Samuel G Awuah
- Department of Chemistry, University of Kentucky; Lexington, KY 40506, United States; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, United States; University of Kentucky Markey Cancer Center, USA.
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21
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Marchini T. Redox and inflammatory mechanisms linking air pollution particulate matter with cardiometabolic derangements. Free Radic Biol Med 2023; 209:320-341. [PMID: 37852544 DOI: 10.1016/j.freeradbiomed.2023.10.396] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Revised: 09/27/2023] [Accepted: 10/15/2023] [Indexed: 10/20/2023]
Abstract
Air pollution is the largest environmental risk factor for disease and premature death. Among the different components that are present in polluted air, fine particulate matter below 2.5 μm in diameter (PM2.5) has been identified as the main hazardous constituent. PM2.5 mainly arises from fossil fuel combustion during power generation, industrial processes, and transportation. Exposure to PM2.5 correlates with enhanced mortality risk from cardiovascular diseases (CVD), such as myocardial infarction and stroke. Over the last decade, it has been increasingly suggested that PM2.5 affects CVD already at the stage of risk factor development. Among the multiple biological mechanisms that have been described, the interplay between oxidative stress and inflammation has been consistently highlighted as one of the main drivers of pulmonary, systemic, and cardiovascular effects of PM2.5 exposure. In this context, PM2.5 uptake by tissue-resident immune cells in the lung promotes oxidative and inflammatory mediators release that alter tissue homeostasis at remote locations. This pathway is central for PM2.5 pathogenesis and might account for the accelerated development of risk factors for CVD, including obesity and diabetes. However, transmission and end-organ mechanisms that explain PM2.5-induced impaired function in metabolic active organs are not completely understood. In this review, the main features of PM2.5 physicochemical characteristics related to PM2.5 ability to induce oxidative stress and inflammation will be presented. Hallmark and recent epidemiological and interventional studies will be summarized and discussed in the context of current air quality guidelines and legislation, knowledge gaps, and inequities. Lastly, mechanistic studies at the intersection between redox metabolism, inflammation, and function will be discussed, with focus on heart and adipose tissue alterations. By offering an integrated analysis of PM2.5-induced effects on cardiometabolic derangements, this review aims to contribute to a better understanding of the pathogenesis and potential interventions of air pollution-related CVD.
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Affiliation(s)
- Timoteo Marchini
- Vascular Immunology Laboratory, Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, 79106, Freiburg, Germany; Universidad de Buenos Aires, CONICET, Instituto de Bioquímica y Medicina Molecular Prof. Alberto Boveris (IBIMOL), Facultad de Farmacia y Bioquímica, C1113AAD, Buenos Aires, Argentina.
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22
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Cortés M, Brischetto A, Martinez-Campanario MC, Ninfali C, Domínguez V, Fernández S, Celis R, Esteve-Codina A, Lozano JJ, Sidorova J, Garrabou G, Siegert AM, Enrich C, Pintado B, Morales-Ruiz M, Castro P, Cañete JD, Postigo A. Inflammatory macrophages reprogram to immunosuppression by reducing mitochondrial translation. Nat Commun 2023; 14:7471. [PMID: 37978290 PMCID: PMC10656499 DOI: 10.1038/s41467-023-42277-4] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 10/05/2023] [Indexed: 11/19/2023] Open
Abstract
Acute inflammation can either resolve through immunosuppression or persist, leading to chronic inflammation. These transitions are driven by distinct molecular and metabolic reprogramming of immune cells. The anti-diabetic drug Metformin inhibits acute and chronic inflammation through mechanisms still not fully understood. Here, we report that the anti-inflammatory and reactive-oxygen-species-inhibiting effects of Metformin depend on the expression of the plasticity factor ZEB1 in macrophages. Using mice lacking Zeb1 in their myeloid cells and human patient samples, we show that ZEB1 plays a dual role, being essential in both initiating and resolving inflammation by inducing macrophages to transition into an immunosuppressed state. ZEB1 mediates these diverging effects in inflammation and immunosuppression by modulating mitochondrial content through activation of autophagy and inhibition of mitochondrial protein translation. During the transition from inflammation to immunosuppression, Metformin mimics the metabolic reprogramming of myeloid cells induced by ZEB1. Mechanistically, in immunosuppression, ZEB1 inhibits amino acid uptake, leading to downregulation of mTORC1 signalling and a decrease in mitochondrial translation in macrophages. These results identify ZEB1 as a driver of myeloid cell metabolic plasticity, suggesting that targeting its expression and function could serve as a strategy to modulate dysregulated inflammation and immunosuppression.
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Affiliation(s)
- Marlies Cortés
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain.
| | - Agnese Brischetto
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain
| | - M C Martinez-Campanario
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain
| | - Chiara Ninfali
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain
| | - Verónica Domínguez
- National Center of Biotechnology (CSIC-CNB) and Center for Molecular Biology Severo Ochoa (CSIC/UAM-CBMSO) Transgenesis Facility, Higher Research Council (CSIC) and Autonomous University of Madrid (UAM), Cantoblanco, 28049, Madrid, Spain
| | - Sara Fernández
- Medical Intensive Care Unit and Department of Internal Medicine, Hospital Clínic of Barcelona, Group of Muscle Research and Mitochondrial Function, IDIBAPS, and CIBERER, 08036, Barcelona, Spain
| | - Raquel Celis
- Arthritis Unit, Dept. of Rheumathology, Hospital Clínic and IDIBAPS, 08036, Barcelona, Spain
| | | | - Juan J Lozano
- Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute, 08036, Barcelona, Spain
| | - Julia Sidorova
- Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute, 08036, Barcelona, Spain
| | - Gloria Garrabou
- Medical Intensive Care Unit and Department of Internal Medicine, Hospital Clínic of Barcelona, Group of Muscle Research and Mitochondrial Function, IDIBAPS, and CIBERER, 08036, Barcelona, Spain
| | - Anna-Maria Siegert
- MRC Metabolic Diseases Unit, University of Cambridge Metabolic Research Laboratories, Wellcome Trust-MRC Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, CB1 0QQ, UK
| | - Carlos Enrich
- Department of Biomedicine, University of Barcelona School of Medicine and Health Sciences, 08036, Barcelona, Spain
| | - Belén Pintado
- National Center of Biotechnology (CSIC-CNB) and Center for Molecular Biology Severo Ochoa (CSIC/UAM-CBMSO) Transgenesis Facility, Higher Research Council (CSIC) and Autonomous University of Madrid (UAM), Cantoblanco, 28049, Madrid, Spain
| | - Manuel Morales-Ruiz
- Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute, 08036, Barcelona, Spain
- Department of Biomedicine, University of Barcelona School of Medicine and Health Sciences, 08036, Barcelona, Spain
- Department of Biochemistry and Molecular Genetics, Hospital Clínic of Barcelona and IDIBAPS, 08036, Barcelona, Spain
| | - Pedro Castro
- Medical Intensive Care Unit and Department of Internal Medicine, Hospital Clínic of Barcelona, Group of Muscle Research and Mitochondrial Function, IDIBAPS, and CIBERER, 08036, Barcelona, Spain
| | - Juan D Cañete
- Arthritis Unit, Dept. of Rheumathology, Hospital Clínic and IDIBAPS, 08036, Barcelona, Spain
| | - Antonio Postigo
- Group of Gene Regulation in Stem Cells, Cell Plasticity, Differentiation, and Cancer, IDIBAPS, 08036, Barcelona, Spain.
- Biomedical Research Networking Centers in Digestive and Hepatic Diseases (CIBERehd), Carlos III Health Institute, 08036, Barcelona, Spain.
- Molecular Targets Program, Division of Oncology, Department of Medicine, J.G. Brown Cancer Center, Louisville, KY, 40202, USA.
- ICREA, 08010, Barcelona, Spain.
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23
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Zhu H, Jia Z, Li YR, Danelisen I. Molecular mechanisms of action of metformin: latest advances and therapeutic implications. Clin Exp Med 2023; 23:2941-2951. [PMID: 37016064 PMCID: PMC10072049 DOI: 10.1007/s10238-023-01051-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 03/17/2023] [Indexed: 04/06/2023]
Abstract
Metformin is among the most widely used antidiabetic drugs. Studies over the past few years have identified multiple novel molecular targets and pathways that metformin acts on to exert its beneficial effects in treating type 2 diabetes as well as other disorders involving dysregulated inflammation and redox homeostasis. In this mini-review, we discuss the latest cutting-edge research discoveries on novel molecular targets of metformin in glycemic control, cardiovascular protection, cancer intervention, anti-inflammation, antiaging, and weight control. Identification of these novel targets and pathways not only deepens our understanding of the molecular mechanisms by which metformin exerts diverse beneficial biological effects, but also provides opportunities for developing new mechanistically based drugs for human diseases.
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Affiliation(s)
- Hong Zhu
- Department of Physiology and Pathophysiology, Jerry M. Wallace School of Osteopathic Medicine, Campbell University SOM, Buies Creek, NC, USA.
| | - Zhenquan Jia
- Department of Biology, College of Arts and Sciences, University of North Carolina, Greensboro, NC, USA
| | - Yunbo Robert Li
- Department of Pharmacology, Jerry M. Wallace School of Osteopathic Medicine, Campbell University, Buies Creek, NC, USA
| | - Igor Danelisen
- Geisinger Commonwealth School of Medicine, Scranton, PA, USA
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24
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Pang Y, Zhu S, Xu J, Su C, Wu B, Zhang C, Gao J. Myeloid Cells As a Promising Target for Brain-Bone Degenerative Diseases from a Metabolic Point of View. Adv Biol (Weinh) 2023; 7:e2200321. [PMID: 36750967 DOI: 10.1002/adbi.202200321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/11/2023] [Indexed: 02/09/2023]
Abstract
Brain and bone degenerative diseases such as Alzheimer's disease and osteoporosis are common in the aging population and lack efficient pharmacotherapies. Myeloid cells are a diverse group of mononuclear cells that plays important roles in development, immune defense, and tissue homeostasis. Aging drastically alters the expansion and function of myeloid cells, which might be a common pathogenesis of the brain-bone degenerative diseases. From this perspective, the role of myeloid cells in brain-bone degenerative diseases is discussed, with a particular focus on metabolic alterations in myeloid cells. Furthermore, targeting myeloid cells through metabolic regulation via drugs such as metformin and melatonin is proposed as a potential therapy for the clinical treatment of brain-bone diseases.
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Affiliation(s)
- Yidan Pang
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.600, Yishan Road, Shanghai, Shanghai, 200233, China
| | - Siyuan Zhu
- Department of General Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.600, Yishan Road, Shanghai, Shanghai, 200233, China
| | - Jun Xu
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.600, Yishan Road, Shanghai, Shanghai, 200233, China
| | - Cuimin Su
- Jinjiang Municipal Hospital (Shanghai Sixth People's Hospital Fujian), No. 16, Luoshan Section, Jinguang Road, Luoshan Street, Jinjiang City, Quanzhou, Fujian, 362200, China
| | - Bo Wu
- Department of General Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.600, Yishan Road, Shanghai, Shanghai, 200233, China
| | - Changqing Zhang
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.600, Yishan Road, Shanghai, Shanghai, 200233, China
| | - Junjie Gao
- Department of Orthopaedic Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, No.600, Yishan Road, Shanghai, Shanghai, 200233, China
- Jinjiang Municipal Hospital (Shanghai Sixth People's Hospital Fujian), No. 16, Luoshan Section, Jinguang Road, Luoshan Street, Jinjiang City, Quanzhou, Fujian, 362200, China
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25
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Ponce-Lopez T, González Álvarez Tostado JA, Dias F, Montiel Maltez KH. Metformin Prevents NDEA-Induced Memory Impairments Associated with Attenuating Beta-Amyloid, Tumor Necrosis Factor-Alpha, and Interleukin-6 Levels in the Hippocampus of Rats. Biomolecules 2023; 13:1289. [PMID: 37759689 PMCID: PMC10526195 DOI: 10.3390/biom13091289] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Revised: 08/11/2023] [Accepted: 08/16/2023] [Indexed: 09/29/2023] Open
Abstract
N-nitrosodiethylamine (NDEA) is a potential carcinogen known to cause liver tumors and chronic inflammation, diabetes, cognitive problems, and signs like Alzheimer's disease (AD) in animals. This compound is classified as probably carcinogenic to humans. Usual sources of exposure include food, beer, tobacco, personal care products, water, and medications. AD is characterized by cognitive decline, amyloid-β (Aβ) deposit, tau hyperphosphorylation, and cell loss. This is accompanied by neuroinflammation, which involves release of microglial cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin 1β (IL-1β), by nuclear factor kappa B (NF-κB) upregulation; each are linked to AD progression. Weak PI3K/Akt insulin-signaling inhibits IRS-1 phosphorylation, activates GSK3β and promotes tau hyperphosphorylation. Metformin, an antihyperglycemic agent, has potent anti-inflammatory efficacy. It reduces proinflammatory cytokines such as IL-6, IL-1β, and TNF-α via NF-κB inhibition. Metformin also reduces reactive oxidative species (ROS) and modulates cognitive disorders reported due to brain insulin resistance links. Our study examined how NDEA affects spatial memory in Wistar rats. We found that all NDEA doses tested impaired memory. The 80 µg/kg dose of NDEA increased levels of Aβ1-42, TNF-α, and IL-6 in the hippocampus, which correlated with memory loss. Nonetheless, treatment with 100 mg/kg of metformin attenuated the levels of pro-inflammatory cytokines and Aβ1-42, and enhanced memory. It suggests that metformin may protect against NDEA-triggered memory issues and brain inflammation.
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Affiliation(s)
- Teresa Ponce-Lopez
- Centro de Investigación en Ciencias de la Salud (CICSA), Facultad de Ciencias de la Salud, Universidad Anáhuac México Norte, Avenida Universidad Anáhuac 46, Lomas Anáhuac, Huixquilucan C.P. 52786, Estado de México, Mexico
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26
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Abstract
Currently, metformin is the first-line medication to treat type 2 diabetes mellitus (T2DM) in most guidelines and is used daily by >200 million patients. Surprisingly, the mechanisms underlying its therapeutic action are complex and are still not fully understood. Early evidence highlighted the liver as the major organ involved in the effect of metformin on reducing blood levels of glucose. However, increasing evidence points towards other sites of action that might also have an important role, including the gastrointestinal tract, the gut microbial communities and the tissue-resident immune cells. At the molecular level, it seems that the mechanisms of action vary depending on the dose of metformin used and duration of treatment. Initial studies have shown that metformin targets hepatic mitochondria; however, the identification of a novel target at low concentrations of metformin at the lysosome surface might reveal a new mechanism of action. Based on the efficacy and safety records in T2DM, attention has been given to the repurposing of metformin as part of adjunct therapy for the treatment of cancer, age-related diseases, inflammatory diseases and COVID-19. In this Review, we highlight the latest advances in our understanding of the mechanisms of action of metformin and discuss potential emerging novel therapeutic uses.
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Affiliation(s)
- Marc Foretz
- Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France
| | - Bruno Guigas
- Department of Parasitology, Leiden University Medical Center, Leiden, Netherlands
| | - Benoit Viollet
- Université Paris Cité, CNRS, Inserm, Institut Cochin, Paris, France.
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27
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Tong W, Hannou SA, Sargsyan A, Zhang GF, Grimsrud PA, Astapova I, Herman MA. "Metformin Impairs Intestinal Fructose Metabolism". BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.17.537251. [PMID: 37131695 PMCID: PMC10153158 DOI: 10.1101/2023.04.17.537251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/04/2023]
Abstract
Objective To investigate the effects of metformin on intestinal carbohydrate metabolism in vivo. Method Male mice preconditioned with a high-fat, high-sucrose diet were treated orally with metformin or a control solution for two weeks. Fructose metabolism, glucose production from fructose, and production of other fructose-derived metabolites were assessed using stably labeled fructose as a tracer. Results Metformin treatment decreased intestinal glucose levels and reduced incorporation of fructose-derived metabolites into glucose. This was associated with decreased intestinal fructose metabolism as indicated by decreased enterocyte F1P levels and diminished labeling of fructose-derived metabolites. Metformin also reduced fructose delivery to the liver. Proteomic analysis revealed that metformin coordinately down-regulated proteins involved carbohydrate metabolism including those involved in fructolysis and glucose production within intestinal tissue. Conclusion Metformin reduces intestinal fructose metabolism, and this is associated with broad-based changes in intestinal enzyme and protein levels involved in sugar metabolism indicating that metformin's effects on sugar metabolism are pleiotropic.
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Affiliation(s)
- Wenxin Tong
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
| | - Sarah A. Hannou
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
- Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, Houston, Texas, USA
| | - Ashot Sargsyan
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
| | - Guo-Fang Zhang
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
- Division of Endocrinology, Metabolism, and Nutrition, Duke University, Durham, North Carolina, USA
| | - Paul A. Grimsrud
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
- Division of Endocrinology, Metabolism, and Nutrition, Duke University, Durham, North Carolina, USA
| | - Inna Astapova
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
- Division of Endocrinology, Metabolism, and Nutrition, Duke University, Durham, North Carolina, USA
- Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, Houston, Texas, USA
| | - Mark A. Herman
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina, USA
- Division of Endocrinology, Metabolism, and Nutrition, Duke University, Durham, North Carolina, USA
- Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, Houston, Texas, USA
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28
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Castejon-Vega B, Cordero MD, Sanz A. How the Disruption of Mitochondrial Redox Signalling Contributes to Ageing. Antioxidants (Basel) 2023; 12:831. [PMID: 37107206 PMCID: PMC10135186 DOI: 10.3390/antiox12040831] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/16/2023] [Accepted: 03/25/2023] [Indexed: 03/31/2023] Open
Abstract
In the past, mitochondrial reactive oxygen species (mtROS) were considered a byproduct of cellular metabolism. Due to the capacity of mtROS to cause oxidative damage, they were proposed as the main drivers of ageing and age-related diseases. Today, we know that mtROS are cellular messengers instrumental in maintaining cellular homeostasis. As cellular messengers, they are produced in specific places at specific times, and the intensity and duration of the ROS signal determine the downstream effects of mitochondrial redox signalling. We do not know yet all the processes for which mtROS are important, but we have learnt that they are essential in decisions that affect cellular differentiation, proliferation and survival. On top of causing damage due to their capacity to oxidize cellular components, mtROS contribute to the onset of degenerative diseases when redox signalling becomes dysregulated. Here, we review the best-characterized signalling pathways in which mtROS participate and those pathological processes in which they are involved. We focus on how mtROS signalling is altered during ageing and discuss whether the accumulation of damaged mitochondria without signalling capacity is a cause or a consequence of ageing.
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Affiliation(s)
- Beatriz Castejon-Vega
- School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
| | - Mario D. Cordero
- School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
- Department of Molecular Biology and Biochemical Engineering, Universidad Pablo de Olavide, 41013 Seville, Spain
| | - Alberto Sanz
- School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow G12 8QQ, UK
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Liu J, Zhang M, Deng D, Zhu X. The function, mechanisms, and clinical applications of metformin: potential drug, unlimited potentials. Arch Pharm Res 2023; 46:389-407. [PMID: 36964307 DOI: 10.1007/s12272-023-01445-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 03/08/2023] [Indexed: 03/26/2023]
Abstract
Metformin has been used clinically for more than 60 years. As time goes by, more and more miraculous effects of metformin beyond the clinic have been discovered and discussed. In addition to the clinically approved hypoglycemic effect, it also has a positive metabolic regulation effect on the human body that cannot be ignored. Such as anti-cancer, anti-aging, brain repair, cardiovascular protection, gastrointestinal regulation, hair growth and inhibition of thyroid nodules, and other nonclinical effects. Metformin affects almost the entire body in the situation taking it over a long period, and the preventive effects of metformin in addition to treating diabetes are also beginning to be recommended in some guidelines. This review is mainly composed of four parts: the development history of metformin, the progress of clinical efficacy, the nonclinical efficacy of metformin, and the consideration and prospect of its application.
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Affiliation(s)
- Jianhong Liu
- Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou Medical College, Hangzhou, China
- Department of Cardiology, The Second Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China
| | - Ming Zhang
- Department of Physical Medicine and Rehabilitation, Zibo Central Hospital, Zibo, China
| | - Dan Deng
- Department of Cardiology, The Second Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China
| | - Xiao Zhu
- Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou Medical College, Hangzhou, China.
- Department of Cardiology, The Second Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang, China.
- Guangdong Provincial Key Laboratory of Systems Biology and Synthetic Biology for Urogenital Tumors, Shenzhen Key Laboratory of Genitourinary Tumor, Department of Urology, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital (Shenzhen Institute of Translational Medicine), Shenzhen, China.
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Wculek SK, Heras-Murillo I, Mastrangelo A, Mañanes D, Galán M, Miguel V, Curtabbi A, Barbas C, Chandel NS, Enríquez JA, Lamas S, Sancho D. Oxidative phosphorylation selectively orchestrates tissue macrophage homeostasis. Immunity 2023; 56:516-530.e9. [PMID: 36738738 DOI: 10.1016/j.immuni.2023.01.011] [Citation(s) in RCA: 107] [Impact Index Per Article: 53.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 09/02/2022] [Accepted: 01/12/2023] [Indexed: 02/05/2023]
Abstract
In vitro studies have associated oxidative phosphorylation (OXPHOS) with anti-inflammatory macrophages, whereas pro-inflammatory macrophages rely on glycolysis. However, the metabolic needs of macrophages in tissues (TMFs) to fulfill their homeostatic activities are incompletely understood. Here, we identified OXPHOS as the highest discriminating process among TMFs from different organs in homeostasis by analysis of RNA-seq data in both humans and mice. Impairing OXPHOS in TMFs via Tfam deletion differentially affected TMF populations. Tfam deletion resulted in reduction of alveolar macrophages (AMs) due to impaired lipid-handling capacity, leading to increased cholesterol content and cellular stress, causing cell-cycle arrest in vivo. In obesity, Tfam depletion selectively ablated pro-inflammatory lipid-handling white adipose tissue macrophages (WAT-MFs), thus preventing insulin resistance and hepatosteatosis. Hence, OXPHOS, rather than glycolysis, distinguishes TMF populations and is critical for the maintenance of TMFs with a high lipid-handling activity, including pro-inflammatory WAT-MFs. This could provide a selective therapeutic targeting tool.
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Affiliation(s)
- Stefanie K Wculek
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.
| | - Ignacio Heras-Murillo
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain
| | - Annalaura Mastrangelo
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain
| | - Diego Mañanes
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain
| | - Miguel Galán
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain
| | - Verónica Miguel
- Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa" (CBMSO, CSIC-UAM), 28049 Madrid, Spain
| | - Andrea Curtabbi
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain; Centro de Investigaciónes Biomédicas en Red en Fragilidad y Envejecimiento Saludabe (CIBERFES), 28029 Madrid, Spain
| | - Coral Barbas
- Centro de Metabolómica y Bioanálisis (CEMBIO), School of Pharmacy, Universidad San Pablo-CEU, CEU Universities, Urbanización Montepríncipe, Boadilla del Monte, 28660 Madrid, Spain
| | - Navdeep S Chandel
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
| | - José Antonio Enríquez
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain; Centro de Investigaciónes Biomédicas en Red en Fragilidad y Envejecimiento Saludabe (CIBERFES), 28029 Madrid, Spain
| | - Santiago Lamas
- Program of Physiological and Pathological Processes, Centro de Biología Molecular "Severo Ochoa" (CBMSO, CSIC-UAM), 28049 Madrid, Spain
| | - David Sancho
- Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), 28029 Madrid, Spain.
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Chang X, Ismail NI, Rahman A, Xu D, Chan RWY, Ong SG, Ong SB. Long COVID-19 and the Heart: Is Cardiac Mitochondria the Missing Link? Antioxid Redox Signal 2023; 38:599-618. [PMID: 36053670 PMCID: PMC10025846 DOI: 10.1089/ars.2022.0126] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 08/27/2022] [Indexed: 12/30/2022]
Abstract
Significance: Although corona virus disease 2019 (COVID-19) has now gradually been categorized as an endemic, the long-term effect of COVID-19 in causing multiorgan disorders, including a perturbed cardiovascular system, is beginning to gain attention. Nonetheless, the underlying mechanism triggering post-COVID-19 cardiovascular dysfunction remains enigmatic. Are cardiac mitochondria the key to mediating cardiac dysfunction post-severe acute respiratory syndrome coronavirus 2 (post-SARS-CoV-2) infection? Recent Advances: Cardiovascular complications post-SARS-CoV-2 infection include myocarditis, myocardial injury, microvascular injury, pericarditis, acute coronary syndrome, and arrhythmias (fast or slow). Different types of myocardial damage or reduced heart function can occur after a lung infection or lung injury. Myocardial/coronary injury or decreased cardiac function is directly associated with increased mortality after hospital discharge in patients with COVID-19. The incidence of adverse cardiovascular events increases even in recovered COVID-19 patients. Disrupted cardiac mitochondria postinfection have been postulated to lead to cardiovascular dysfunction in the COVID-19 patients. Further studies are crucial to unravel the association between SARS-CoV-2 infection, mitochondrial dysfunction, and ensuing cardiovascular disorders (CVD). Critical Issues: The relationship between COVID-19 and myocardial injury or cardiovascular dysfunction has not been elucidated. In particular, the role of the cardiac mitochondria in this association remains to be determined. Future Directions: Elucidating the cause of cardiac mitochondrial dysfunction post-SARS-CoV-2 infection may allow a deeper understanding of long COVID-19 and resulting CVD, thus providing a potential therapeutic target. Antioxid. Redox Signal. 38, 599-618.
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Affiliation(s)
- Xing Chang
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Nur Izzah Ismail
- Department of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
- Centre for Cardiovascular Genomics and Medicine (CCGM), Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
| | - Attaur Rahman
- Department of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
- Centre for Cardiovascular Genomics and Medicine (CCGM), Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
| | - Dachun Xu
- Department of Cardiology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
- Department of Cardiology, Qidong People's Hospital, Qidong, China
| | - Renee Wan Yi Chan
- Department of Paediatrics, Faculty of Medicine, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
- Laboratory for Paediatric Respiratory Research, Li Ka Shing Institute of Health Sciences, Faculty of Medicine, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
- Hong Kong Hub of Paediatric Excellence (HK HOPE), Hong Kong Children's Hospital (HKCH), Hong Kong SAR, China
- Department of Paediatrics, Chinese University of Hong Kong-University Medical Center Utrecht Joint Research Laboratory of Respiratory Virus and Immunobiology, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
| | - Sang-Ging Ong
- Department of Pharmacology & Regenerative Medicine, The University of Illinois College of Medicine, Chicago, Illinois, USA
- Division of Cardiology, Department of Medicine, The University of Illinois College of Medicine, Chicago, Illinois, USA
| | - Sang-Bing Ong
- Department of Medicine & Therapeutics, Faculty of Medicine, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
- Centre for Cardiovascular Genomics and Medicine (CCGM), Lui Che Woo Institute of Innovative Medicine, The Chinese University of Hong Kong (CUHK), Hong Kong SAR, China
- Hong Kong Hub of Paediatric Excellence (HK HOPE), Hong Kong Children's Hospital (HKCH), Hong Kong SAR, China
- Kunming Institute of Zoology—The Chinese University of Hong Kong (KIZ-CUHK) Joint Laboratory of Bioresources and Molecular Research of Common Diseases, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
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Remodeling articular immune homeostasis with an efferocytosis-informed nanoimitator mitigates rheumatoid arthritis in mice. Nat Commun 2023; 14:817. [PMID: 36781864 PMCID: PMC9925448 DOI: 10.1038/s41467-023-36468-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Accepted: 02/02/2023] [Indexed: 02/15/2023] Open
Abstract
Massive intra-articular infiltration of proinflammatory macrophages is a prominent feature of rheumatoid arthritis (RA) lesions, which are thought to underlie articular immune dysfunction, severe synovitis and ultimately joint erosion. Here we report an efferocytosis-informed nanoimitator (EINI) for in situ targeted reprogramming of synovial inflammatory macrophages (SIMs) that thwarts their autoimmune attack and reestablishes articular immune homeostasis, which mitigates RA. The EINI consists of a drug-based core with an oxidative stress-responsive phosphatidylserine (PtdSer) corona and a shell composed of a P-selectin-blocking motif, low molecular weight heparin (LMWH). When systemically administered, the LMWH on the EINI first binds to P-selectin overexpressed on the endothelium in subsynovial capillaries, which functions as an antagonist, disrupting neutrophil synovial trafficking. Due to the strong dysregulation of the synovial microvasculature, the EINI is subsequently enriched in the joint synovium where the shell is disassembled upon the reactive oxygen species stimulation, and PtdSer corona is then exposed. In an efferocytosis-like manner, the PtdSer-coroneted core is in turn phagocytosed by SIMs, which synergistically terminate SIM-initiated pathological cascades and serially reestablish intra-articular immune homeostasis, conferring a chondroprotective effect. These findings demonstrate that SIMs can be precisely remodeled via the efferocytosis-mimetic strategy, which holds potential for RA treatment.
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Metformin Alleviates Epirubicin-Induced Endothelial Impairment by Restoring Mitochondrial Homeostasis. Int J Mol Sci 2022; 24:ijms24010343. [PMID: 36613786 PMCID: PMC9820471 DOI: 10.3390/ijms24010343] [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: 10/18/2022] [Revised: 12/13/2022] [Accepted: 12/20/2022] [Indexed: 12/28/2022] Open
Abstract
Vascular endothelial injury is important in anthracycline-induced cardiotoxicity. Anthracyclines seriously damage the mitochondrial function and mitochondrial homeostasis. In this study, we investigated the damage of epirubicin to vascular endothelial cells and the protective role of metformin from the perspective of mitochondrial homeostasis. We found that epirubicin treatment resulted in DNA double-strand breaks (DSB), elevated reactive oxygen species (ROS) production, and excessive Angiotensin II release in HUVEC cells. Pretreatment with metformin significantly mitigated the injuries caused by epirubicin. In addition, inhibited expression of Mitochondrial transcription factor A (TFAM) and increased mitochondria fragmentation were observed in epirubicin-treated cells, which were partially resumed by metformin pretreatment. In epirubicin-treated cells, knockdown of TFAM counteracted the attenuated DSB formation due to metformin pretreatment, and inhibition of mitochondrial fragmentation with Mdivi-1 decreased DSB formation but increased TFAM expression. Furthermore, epirubicin treatment promoted mitochondrial fragmentation by stimulating the expression of Dynamin-1-like protein (DRP1) and inhibiting the expression of Optic atrophy-1(OPA1) and Mitofusin 1(MFN1), which could be partially prevented by metformin. Finally, we found metformin could increase TFAM expression and decrease DRP1 expression in epirubicin-treated HUVEC cells by upregulating the expression of calcineurin/Transcription factor EB (TFEB). Taken together, this study provided evidence that metformin treatment was an effective way to mitigate epirubicin-induced endothelial impairment by maintaining mitochondrial homeostasis.
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Duan J, Sun Q, Liu S, Lin L, Ren X, Li T, Xu Q, Sun Z. Co-exposure of PM 2.5 and high-fat diet induce lipid metabolism reprogramming and vascular remodeling. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2022; 315:120437. [PMID: 36272612 DOI: 10.1016/j.envpol.2022.120437] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/26/2022] [Revised: 10/11/2022] [Accepted: 10/12/2022] [Indexed: 06/16/2023]
Abstract
Fine particulate matter (PM2.5) exposure has been proved to increase the cardiovascular disease risk. However, there is a lack of comprehensive knowledge on whether a high-fat diet (HFD) affects PM2.5-induced cardiovascular disease. The purpose of this study was to investigate the impairment of lipid metabolism and vascular function by PM2.5 and HFD exposure in ApoE-/- mice. Oil red O staining indicated that co-treatment of PM2.5 and HFD resulted in markedly lipid deposition in the mice aorta. Blood biochemical analysis demonstrated that co-exposure of PM2.5 and HFD could cause dyslipidemia in vivo. Vascular Doppler ultrasound and histopathological analysis found that the functional and structural alterations with fibrosis and calcified remodeling of the vessels were detected after PM2.5 and HFD exposure. For in-depth study, the genome-wide transcriptional analysis performed in macrophages was further revealed that the endoplasmic reticulum stress, immune system process, regulation of cell proliferation etc. were response to PM2.5 exposure; while Lipid and atherosclerosis signaling pathways had a critical role in PM2.5-induced vascular injury. Results from validation experiments manifested that the release of supernatant in PM2.5- or ox-LDL-treated macrophages could decrease the cell viability and increase the lipid ROS in vascular smooth muscle cells (VSMCs). Moreover, the up-regulations of CCL2, IL-6 and IL-1β in aortic arch of mice were observed after co-exposure with PM2.5 and HFD. Our data hinted that PM2.5 could affect the lipid metabolism reprogramming and induce vascular remodeling, accompanied with synergistic effects of HFD.
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Affiliation(s)
- Junchao Duan
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China.
| | - Qinglin Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Shiqian Liu
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Lisen Lin
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Xiaoke Ren
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Tianyu Li
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
| | - Qing Xu
- Core Facilities for Electrophysiology, Core Facilities Center, Capital Medical University, Beijing, 100069, PR China
| | - Zhiwei Sun
- Department of Toxicology and Sanitary Chemistry, School of Public Health, Capital Medical University, Beijing, 100069, PR China; Beijing Key Laboratory of Environmental Toxicology, Capital Medical University, Beijing, 100069, PR China
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Targeting autophagy regulation in NLRP3 inflammasome-mediated lung inflammation in COVID-19. Clin Immunol 2022; 244:109093. [PMID: 35944881 PMCID: PMC9356669 DOI: 10.1016/j.clim.2022.109093] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 07/22/2022] [Accepted: 07/25/2022] [Indexed: 12/15/2022]
Abstract
Coronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Emerging evidence indicates that the NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome is activated, which results in a cytokine storm at the late stage of COVID-19. Autophagy regulation is involved in the infection and replication of SARS-CoV-2 at the early stage and the inhibition of NLRP3 inflammasome-mediated lung inflammation at the late stage of COVID-19. Here, we discuss the autophagy regulation at different stages of COVID-19. Specifically, we highlight the therapeutic potential of autophagy activators in COVID-19 by inhibiting the NLRP3 inflammasome, thereby avoiding the cytokine storm. We hope this review provides enlightenment for the use of autophagy activators targeting the inhibition of the NLRP3 inflammasome, specifically the combinational therapy of autophagy modulators with the inhibitors of the NLRP3 inflammasome, antiviral drugs, or anti-inflammatory drugs in the fight against COVID-19.
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Gonçalves CA, Sesterheim P, Wartchow KM, Bobermin LD, Leipnitz G, Quincozes-Santos A. Why antidiabetic drugs are potentially neuroprotective during the Sars-CoV-2 pandemic: The focus on astroglial UPR and calcium-binding proteins. Front Cell Neurosci 2022; 16:905218. [PMID: 35966209 PMCID: PMC9374064 DOI: 10.3389/fncel.2022.905218] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2022] [Accepted: 06/30/2022] [Indexed: 11/30/2022] Open
Abstract
We are living in a terrifying pandemic caused by Sars-CoV-2, in which patients with diabetes mellitus have, from the beginning, been identified as having a high risk of hospitalization and mortality. This viral disease is not limited to the respiratory system, but also affects, among other organs, the central nervous system. Furthermore, we already know that individuals with diabetes mellitus exhibit signs of astrocyte dysfunction and are more likely to develop cognitive deficits and even dementia. It is now being realized that COVID-19 incurs long-term effects and that those infected can develop several neurological and psychiatric manifestations. As this virus seriously compromises cell metabolism by triggering several mechanisms leading to the unfolded protein response (UPR), which involves endoplasmic reticulum Ca2+ depletion, we review here the basis involved in this response that are intimately associated with the development of neurodegenerative diseases. The discussion aims to highlight two aspects-the role of calcium-binding proteins and the role of astrocytes, glial cells that integrate energy metabolism with neurotransmission and with neuroinflammation. Among the proteins discussed are calpain, calcineurin, and sorcin. These proteins are emphasized as markers of the UPR and are potential therapeutic targets. Finally, we discuss the role of drugs widely prescribed to patients with diabetes mellitus, such as statins, metformin, and calcium channel blockers. The review assesses potential neuroprotection mechanisms, focusing on the UPR and the restoration of reticular Ca2+ homeostasis, based on both clinical and experimental data.
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Affiliation(s)
- Carlos-Alberto Gonçalves
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Patrícia Sesterheim
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Krista M. Wartchow
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Larissa Daniele Bobermin
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - Guilhian Leipnitz
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - André Quincozes-Santos
- Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
- Programa de Pós-Graduação em Neurociências, Instituto de Ciências Básicas da Saúde, Universidade Federal do Rio Grande do Sul, Porto Alegre, RS, Brazil
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Gao L, Li L, Hu J, Li G, Zhang Y, Dai X, De Z, Xu F. Metformin inhibits multiple myeloma serum-induced endothelial cell thrombosis by down-regulating miR-532. Ann Vasc Surg 2022; 85:347-357.e2. [PMID: 35561893 DOI: 10.1016/j.avsg.2022.04.035] [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: 11/01/2021] [Revised: 03/16/2022] [Accepted: 04/20/2022] [Indexed: 11/01/2022]
Abstract
OBJECTIVES Thrombotic complications in multiple myeloma (MM) impairs the quality of life of patients. Metformin has a certain effect on anti-thrombosis, but its role and mechanism in MM-induced thrombosis are still uncovered. Therefore, this study evaluated the effect of metformin on MM-induced thrombosis. METHODS Human umbilical vein endothelial cells (HUVECs) were exposed to normal serum (15%), MM serum (15%), metformin (0.01 mmol/L), or MM serum and metformin simultaneously. The expression of tissue factor (TF) in HUVECs was detected by flow cytometry and quantitative real-time PCR (qRT-PCR). QRT-PCR was also used to determine the expressions of endothelial protein C receptor (EPCR) and miR-532. The generation of thrombin and activated protein C was measured by thrombin generation and protein C activation assays. And EPCR, extracellular signal-regulated kinase (ERK) 1/2, p38 mitogen activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) pathway related protein expressions were detected by western blot. RESULT MM serum increased the expressions of TF, EPCR and miR-532, and induced thrombin generation and protein C activation in HUVECs. Based on the MM serum treatment, metformin decreased these expressions and inhibited the thrombin generation and protein C activation in HUVECs. However, miR-532 mimic reversed the effect of metformin and promoted the levels of thrombosis related indicators in HUVECs. Moreover, metformin activated the EPCR, ERK 1/2, p38 MAPK and NF-κB pathways but miR-532 mimic suppressed the activation of pathways. CONCLUSION Metformin played an inhibitory effect on MM serum-induced HUVEC thrombosis, suggesting that metformin could serve as a novel antithrombotic approach for MM patients.
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Affiliation(s)
- Lixia Gao
- Department of Hematology, Karamay Central Hospital
| | - Li Li
- Department of Hematology, Karamay Central Hospital
| | - Jun Hu
- Department of Hematology, Karamay Central Hospital
| | - Guiyuan Li
- Oncology Department, Tongji Hospital Affiliated to Shanghai, Tongji University
| | - Yizhi Zhang
- Department of Hematology, Karamay Central Hospital
| | - Xiangjun Dai
- Science Education Department, Karamay Central Hospital
| | - Zhenyi De
- Department of Pathology, Karamay Central Hospital
| | - Fenglei Xu
- Department of Neurology, Karamay Central Hospital.
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Billingham LK, Stoolman JS, Vasan K, Rodriguez AE, Poor TA, Szibor M, Jacobs HT, Reczek CR, Rashidi A, Zhang P, Miska J, Chandel NS. Mitochondrial electron transport chain is necessary for NLRP3 inflammasome activation. Nat Immunol 2022; 23:692-704. [PMID: 35484407 PMCID: PMC9098388 DOI: 10.1038/s41590-022-01185-3] [Citation(s) in RCA: 186] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 03/11/2022] [Indexed: 12/24/2022]
Abstract
The NLRP3 inflammasome is linked to sterile and pathogen-dependent inflammation, and its dysregulation underlies many chronic diseases. Mitochondria have been implicated as regulators of the NLRP3 inflammasome through several mechanisms including generation of mitochondrial reactive oxygen species (ROS). Here, we report that mitochondrial electron transport chain (ETC) complex I, II, III and V inhibitors all prevent NLRP3 inflammasome activation. Ectopic expression of Saccharomyces cerevisiae NADH dehydrogenase (NDI1) or Ciona intestinalis alternative oxidase, which can complement the functional loss of mitochondrial complex I or III, respectively, without generation of ROS, rescued NLRP3 inflammasome activation in the absence of endogenous mitochondrial complex I or complex III function. Metabolomics revealed phosphocreatine (PCr), which can sustain ATP levels, as a common metabolite that is diminished by mitochondrial ETC inhibitors. PCr depletion decreased ATP levels and NLRP3 inflammasome activation. Thus, the mitochondrial ETC sustains NLRP3 inflammasome activation through PCr-dependent generation of ATP, but via a ROS-independent mechanism.
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Affiliation(s)
- Leah K Billingham
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Joshua S Stoolman
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Karthik Vasan
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Arianne E Rodriguez
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Taylor A Poor
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Marten Szibor
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Cardiothoracic Surgery, Center for Sepsis Control and Care (CSCC), Jena University Hospital, Jena, Germany
- Department of Environment and Genetics, La Trobe University, Melbourne, Victoria, Australia
| | - Howard T Jacobs
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
- Department of Environment and Genetics, La Trobe University, Melbourne, Victoria, Australia
| | - Colleen R Reczek
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Aida Rashidi
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Peng Zhang
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jason Miska
- Department of Neurological Surgery, Lou and Jean Malnati Brain Tumor Institute, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Navdeep S Chandel
- Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
- Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
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Strength training alters the tissue fatty acids profile and slightly improves the thermogenic pathway in the adipose tissue of obese mice. Sci Rep 2022; 12:6913. [PMID: 35484170 PMCID: PMC9050661 DOI: 10.1038/s41598-022-10688-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Accepted: 02/14/2022] [Indexed: 12/18/2022] Open
Abstract
Obesity is a disease characterized by the exacerbated increase of adipose tissue. A possible way to decrease the harmful effects of excessive adipose tissue is to increase the thermogenesis process, to the greater energy expenditure generated by the increase in heat in the body. In adipose tissue, the thermogenesis process is the result of an increase in mitochondrial work, having as substrate H+ ions, and which is related to the increased activity of UCP1. Evidence shows that stress is responsible for increasing the greater induction of UCP1 expression via β-adrenergic receptors. It is known that physical exercise is an important implement for sympathetic stimulation promoting communication between norepinephrine/epinephrine with membrane receptors. Thus, the present study investigates the influence of short-term strength training (STST) on fatty acid composition, lipolysis, lipogenesis, and browning processes in the subcutaneous adipose tissue (sWAT) of obese mice. For this, Swiss mice were divided into three groups: lean control, obesity sedentary, and obese strength training (OBexT). Obese animals were fed a high-fat diet for 14 weeks. Trained obese animals were submitted to 7 days of strength exercise. It was demonstrated that STST sessions were able to reduce fasting glycemia. In the sWAT, the STST was able to decrease the levels of the long-chain fatty acids profile, saturated fatty acid, and palmitic fatty acid (C16:0). Moreover, it was showed that STST did not increase protein levels responsible for lipolysis, the ATGL, ABHD5, pPLIN1, and pHSL. On the other hand, the exercise protocol decreased the expression of the lipogenic enzyme SCD1. Finally, our study demonstrated that the STST increased browning process-related genes such as PGC-1α, PRDM16, and UCP1 in the sWAT. Interestingly, all these biomolecular mechanisms have been observed independently of changes in body weight. Therefore, it is concluded that short-term strength exercise can be an effective strategy to initiate morphological changes in sWAT.
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40
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McElroy GS, Chakrabarty RP, D'Alessandro KB, Hu YS, Vasan K, Tan J, Stoolman JS, Weinberg SE, Steinert EM, Reyfman PA, Singer BD, Ladiges WC, Gao L, Lopéz-Barneo J, Ridge K, Budinger GRS, Chandel NS. Reduced expression of mitochondrial complex I subunit Ndufs2 does not impact healthspan in mice. Sci Rep 2022; 12:5196. [PMID: 35338200 PMCID: PMC8956724 DOI: 10.1038/s41598-022-09074-3] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Accepted: 03/16/2022] [Indexed: 01/01/2023] Open
Abstract
Aging in mammals leads to reduction in genes encoding the 45-subunit mitochondrial electron transport chain complex I. It has been hypothesized that normal aging and age-related diseases such as Parkinson’s disease are in part due to modest decrease in expression of mitochondrial complex I subunits. By contrast, diminishing expression of mitochondrial complex I genes in lower organisms increases lifespan. Furthermore, metformin, a putative complex I inhibitor, increases healthspan in mice and humans. In the present study, we investigated whether loss of one allele of Ndufs2, the catalytic subunit of mitochondrial complex I, impacts healthspan and lifespan in mice. Our results indicate that Ndufs2 hemizygous mice (Ndufs2+/−) show no overt impairment in aging-related motor function, learning, tissue histology, organismal metabolism, or sensitivity to metformin in a C57BL6/J background. Despite a significant reduction of Ndufs2 mRNA, the mice do not demonstrate a significant decrease in complex I function. However, there are detectable transcriptomic changes in individual cell types and tissues due to loss of one allele of Ndufs2. Our data indicate that a 50% decline in mRNA of the core mitochondrial complex I subunit Ndufs2 is neither beneficial nor detrimental to healthspan.
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Affiliation(s)
- Gregory S McElroy
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ram P Chakrabarty
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Karis B D'Alessandro
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Yuan-Shih Hu
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Karthik Vasan
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jerica Tan
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Joshua S Stoolman
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Samuel E Weinberg
- Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Elizabeth M Steinert
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Paul A Reyfman
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Benjamin D Singer
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Warren C Ladiges
- Department of Comparative Medicine, University of Washington School of Medicine, Seattle, WA, USA
| | - Lin Gao
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.,Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Seville, Spain.,Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - José Lopéz-Barneo
- Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío, CSIC, Universidad de Sevilla, Seville, Spain.,Departamento de Fisiología Médica y Biofísica, Facultad de Medicina, Universidad de Sevilla, Seville, Spain.,Centro de Investigación Biomédica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Madrid, Spain
| | - Karen Ridge
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - G R Scott Budinger
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Navdeep S Chandel
- Department of Medicine Division of Pulmonary and Critical Care Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA. .,Department of Biochemistry and Molecular Genetics, Northwestern University Feinberg School of Medicine, Chicago, IL, 60611, USA.
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Tao F, Zhou Y, Wang M, Wang C, Zhu W, Han Z, Sun N, Wang D. Metformin alleviates chronic obstructive pulmonary disease and cigarette smoke extract-induced glucocorticoid resistance by activating the nuclear factor E2-related factor 2/heme oxygenase-1 signaling pathway. THE KOREAN JOURNAL OF PHYSIOLOGY & PHARMACOLOGY 2022; 26:95-111. [PMID: 35203060 PMCID: PMC8890943 DOI: 10.4196/kjpp.2022.26.2.95] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 11/08/2021] [Accepted: 11/29/2021] [Indexed: 11/15/2022]
Abstract
Chronic obstructive pulmonary disease (COPD) is an important healthcare problem worldwide. Often, glucocorticoid (GC) resistance develops during COPD treatment. As a classic hypoglycemic drug, metformin (MET) can be used as a treatment strategy for COPD due to its anti-inflammatory and antioxidant effects, but its specific mechanism of action is not known. We aimed to clarify the role of MET on COPD and cigarette smoke extract (CSE)-induced GC resistance. Through establishment of a COPD model in rats, we found that MET could improve lung function, reduce pathological injury, as well as reduce the level of inflammation and oxidative stress in COPD, and upregulate expression of nuclear factor E2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1), multidrug resistance protein 1 (MRP1), and histone deacetylase 2 (HDAC2). By establishing a model of GC resistance in human bronchial epithelial cells stimulated by CSE, we found that MET reduced secretion of interleukin-8, and could upregulate expression of Nrf2, HO-1, MRP1, and HDAC2. MET could also increase the inhibition of MRP1 efflux by MK571 significantly, and increase expression of HDAC2 mRNA and protein. In conclusion, MET may upregulate MRP1 expression by activating the Nrf2/HO-1 signaling pathway, and then regulate expression of HDAC2 protein to reduce GC resistance.
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Affiliation(s)
- Fulin Tao
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Yuanyuan Zhou
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Mengwen Wang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Chongyang Wang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Wentao Zhu
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Zhili Han
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Nianxia Sun
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
| | - Dianlei Wang
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, Anhui 230012, China
- Anhui Province Key Laboratory of Research & Development of Chinese Medicine, Hefei, Anhui 230012, China
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42
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Baindara P, Agrawal S, Franco OL. Host-directed therapies for malaria and tuberculosis: common infection strategies and repurposed drugs. Expert Rev Anti Infect Ther 2022; 20:849-869. [DOI: 10.1080/14787210.2022.2044794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Affiliation(s)
- Piyush Baindara
- Department of Molecular Microbiology & Immunology, School of Medicine, University of Missouri, Missouri, Columbia, MO, USA
| | - Sonali Agrawal
- Immunology Division, ICMR-National JALMA Institute for Leprosy and Other Mycobacterial Diseases, Agra, Uttar Pradesh, India
| | - O. L. Franco
- Proteomics Analysis and Biochemical Center, Catholic University of Brasilia, Brasilia, Brazil; S-Inova Biotech, Catholic University Dom Bosco, Campo Grande, MS, Brazil
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43
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Li Y, Li YC, Liu XT, Zhang L, Chen YH, Zhao Q, Gao W, Liu B, Yang H, Li P. Blockage of citrate export prevents TCA cycle fragmentation via Irg1 inactivation. Cell Rep 2022; 38:110391. [PMID: 35172156 DOI: 10.1016/j.celrep.2022.110391] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2021] [Revised: 12/12/2021] [Accepted: 01/24/2022] [Indexed: 12/21/2022] Open
Abstract
The metabolism of activated macrophages relies on aerobic glycolysis, while mitochondrial oxidation is disrupted. In lipopolysaccharide-activated macrophages, the citrate carrier (CIC) exports citrate from mitochondria to enhance glycolytic genes through histone acetylation. CIC inhibition or Slc25a1 knockdown reduces the occupancy of H3K9ac to hypoxia-inducible factor-1α (HIF-1α) binding sites in promoters of glycolytic genes to restrain glycolysis. HIF-1α also transcriptionally upregulates immune-responsive gene 1 for itaconate production, which is inhibited by CIC blocking. Isotopic tracing of [U-13C6] glucose shows that CIC blockage prevents citrate accumulation and itaconate production by reducing glycolytic flux and facilitating metabolic flux in the TCA cycle. Isotopic tracing of [U-13C5] glutamine reveals that CIC inhibition reduces succinate accumulation from glutaminolysis and the gamma-aminobutyric acid shunt by enhancing mitochondrial oxidation. By restraining glycolysis, CIC inhibition increases NAD+ content to ensure mitochondrial biogenesis for oxidative phosphorylation. Furthermore, blockage of citrate export reduces cerebral thrombosis by inactivation of peripheral macrophages.
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Affiliation(s)
- Yi Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Yu-Chen Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Xiao-Tian Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Lu Zhang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Yi-Hua Chen
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Qiong Zhao
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Wen Gao
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Baolin Liu
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China
| | - Hua Yang
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China.
| | - Ping Li
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, No. 24 Tongjia Lane, Nanjing 210009, China.
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44
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Pence BD. Growth Differentiation Factor-15 in Immunity and Aging. FRONTIERS IN AGING 2022; 3:837575. [PMID: 35821815 PMCID: PMC9261309 DOI: 10.3389/fragi.2022.837575] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Accepted: 01/24/2022] [Indexed: 11/21/2022]
Abstract
Aging increases susceptibility to and severity of a variety of chronic and infectious diseases. Underlying this is dysfunction of the immune system, including chronic increases in low-grade inflammation (inflammaging) and age-related immunosuppression (immunosenescence). Growth differentiation factor-15 (GDF-15) is a stress-, infection-, and inflammation-induced cytokine which is increased in aging and suppresses immune responses. This mini review briefly covers existing knowledge on the immunoregulatory and anti-inflammatory roles of GDF-15, as well as its potential importance in aging and immune function.
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45
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Arbo BD, Schimith LE, Goulart dos Santos M, Hort MA. Repositioning and development of new treatments for neurodegenerative diseases: Focus on neuroinflammation. Eur J Pharmacol 2022; 919:174800. [DOI: 10.1016/j.ejphar.2022.174800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 01/18/2022] [Accepted: 02/02/2022] [Indexed: 11/03/2022]
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Abstract
Autophagy, as the key nutrient recycling pathway, enables eukaryotic cells to adapt to surging cellular stress during aging and, thereby, delays age-associated deterioration. Autophagic flux declines with age and, in turn, decreases in autophagy contribute to the aging process itself and promote senescence. Here, we outline how autophagy regulates immune aging and discuss autophagy-inducing interventions that target senescent immune cells, which are major drivers of systemic aging. We examine how cutting-edge technologies, such as single-cell omics methods hold the promise to capture the complexity of molecular and cellular phenotypes associated with aging, driving the development of suitable putative biomarkers and clinical bioassays. Finally, we debate the urgency to initiate large-scale human clinical trials. We give special preference to small molecule probes and to dietary interventions that can extend healthy lifespan and are affordable for most of the world's population.
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Affiliation(s)
- Heidi Zinecker
- Turkish-German University, Department of Molecular Biotechnology, 34820, Beykoz/Istanbul, Turkey
| | - Anna Katharina Simon
- NDORMS, The Kennedy Institute of Rheumatology, University of Oxford, Oxford OX3 7FY, UK
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47
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Postler TS, Peng V, Bhatt DM, Ghosh S. Metformin selectively dampens the acute inflammatory response through an AMPK-dependent mechanism. Sci Rep 2021; 11:18721. [PMID: 34548527 PMCID: PMC8455559 DOI: 10.1038/s41598-021-97441-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Accepted: 08/25/2021] [Indexed: 12/30/2022] Open
Abstract
Metformin is a first-line drug in the treatment of type-2 diabetes mellitus (T2DM). In addition to its antigluconeogenic and insulin-sensitizing properties, metformin has emerged as a potent inhibitor of the chronic inflammatory response of macrophages. In particular, metformin treatment has been shown to reduce expression of interleukin (IL-) 1β during long-term exposure to the pro-inflammatory stimulus lipopolysaccharide (LPS) through a reduction in reactive oxygen species (ROS), which decreases the levels of the hypoxia-inducible factor (HIF) 1-α, and through enhanced expression of IL-10. However, the effect of metformin on the acute inflammatory response, before significant levels of ROS accumulate in the cell, has not been explored. Here, we show that metformin alters the acute inflammatory response through its activation of AMP-activated protein kinase (AMPK), but independently of HIF1-α and IL-10, in primary macrophages and two macrophage-like cell lines. Thus, metformin changes the acute and the chronic inflammatory response through fundamentally distinct mechanisms. Furthermore, RNA-seq analysis reveals that metformin pretreatment affects the levels of a large yet selective subset of inflammatory genes, dampening the response to short-term LPS exposure and affecting a wide range of pathways and biological functions. Taken together, these findings reveal an unexpected complexity in the anti-inflammatory properties of this widely used drug.
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Affiliation(s)
- Thomas S Postler
- Department of Microbiology & Immunology, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA
| | - Vincent Peng
- Department of Microbiology & Immunology, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Dev M Bhatt
- Department of Microbiology & Immunology, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA
- Amgen Research Oncology and Inflammation, South San Francisco, CA, 94080, USA
| | - Sankar Ghosh
- Department of Microbiology & Immunology, Vagelos College of Physicians & Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA.
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Kan C, Zhang Y, Han F, Xu Q, Ye T, Hou N, Sun X. Mortality Risk of Antidiabetic Agents for Type 2 Diabetes With COVID-19: A Systematic Review and Meta-Analysis. Front Endocrinol (Lausanne) 2021; 12:708494. [PMID: 34603199 PMCID: PMC8481667 DOI: 10.3389/fendo.2021.708494] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2021] [Accepted: 08/30/2021] [Indexed: 02/05/2023] Open
Abstract
AIMS We conducted a systematic review and meta-analysis to assess various antidiabetic agents' association with mortality in patients with type 2 diabetes (T2DM) who have coronavirus disease 2019 (COVID-19). METHODS We performed comprehensive literature retrieval from the date of inception until February 2, 2021, in medical databases (PubMed, Web of Science, Embase, and Cochrane Library), regarding mortality outcomes in patients with T2DM who have COVID-19. Pooled OR and 95% CI data were used to assess relationships between antidiabetic agents and mortality. RESULTS Eighteen studies with 17,338 patients were included in the meta-analysis. Metformin (pooled OR, 0.69; P=0.001) and sulfonylurea (pooled OR, 0.80; P=0.016) were associated with lower mortality risk in patients with T2DM who had COVID-19. However, patients with T2DM who had COVID-19 and received insulin exhibited greater mortality (pooled OR, 2.20; P=0.002). Mortality did not significantly differ (pooled OR, 0.72; P=0.057) between DPP-4 inhibitor users and non-users. CONCLUSIONS Metformin and sulfonylurea could be associated with reduced mortality risk in patients with T2DM who have COVID-19. Furthermore, insulin use could be associated with greater mortality, while DPP-4 inhibitor use could not be. The effects of antidiabetic agents in patients with T2DM who have COVID-19 require further exploration. SYSTEMATIC REVIEW REGISTRATION PROSPERO (identifier, CRD42021242898).
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Affiliation(s)
- Chengxia Kan
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Yang Zhang
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Fang Han
- Department of Pathology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Qian Xu
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Tongtong Ye
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Ningning Hou
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
| | - Xiaodong Sun
- Department of Endocrinology, Affiliated Hospital of Weifang Medical University, Weifang, China
- Clinical Research Center, Affiliated Hospital of Weifang Medical University, Weifang, China
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Xian H, Liu Y, Rundberg Nilsson A, Gatchalian R, Crother TR, Tourtellotte WG, Zhang Y, Aleman-Muench GR, Lewis G, Chen W, Kang S, Luevanos M, Trudler D, Lipton SA, Soroosh P, Teijaro J, de la Torre JC, Arditi M, Karin M, Sanchez-Lopez E. Metformin inhibition of mitochondrial ATP and DNA synthesis abrogates NLRP3 inflammasome activation and pulmonary inflammation. Immunity 2021; 54:1463-1477.e11. [PMID: 34115964 PMCID: PMC8189765 DOI: 10.1016/j.immuni.2021.05.004] [Citation(s) in RCA: 251] [Impact Index Per Article: 62.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 03/30/2021] [Accepted: 05/05/2021] [Indexed: 12/15/2022]
Abstract
Acute respiratory distress syndrome (ARDS), an inflammatory condition with high mortality rates, is common in severe COVID-19, whose risk is reduced by metformin rather than other anti-diabetic medications. Detecting of inflammasome assembly in post-mortem COVID-19 lungs, we asked whether and how metformin inhibits inflammasome activation while exerting its anti-inflammatory effect. We show that metformin inhibited NLRP3 inflammasome activation and interleukin (IL)-1β production in cultured and alveolar macrophages along with inflammasome-independent IL-6 secretion, thus attenuating lipopolysaccharide (LPS)- and SARS-CoV-2-induced ARDS. By targeting electron transport chain complex 1 and independently of AMP-activated protein kinase (AMPK) or NF-κB, metformin blocked LPS-induced and ATP-dependent mitochondrial (mt) DNA synthesis and generation of oxidized mtDNA, an NLRP3 ligand. Myeloid-specific ablation of LPS-induced cytidine monophosphate kinase 2 (CMPK2), which is rate limiting for mtDNA synthesis, reduced ARDS severity without a direct effect on IL-6. Thus, inhibition of ATP and mtDNA synthesis is sufficient for ARDS amelioration.
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Affiliation(s)
- Hongxu Xian
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA
| | - Yuan Liu
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA
| | - Alexandra Rundberg Nilsson
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA
| | - Raphaella Gatchalian
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA
| | - Timothy R Crother
- Departments of Biomedical Sciences and Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Warren G Tourtellotte
- Departments of Pathology, Neurology, Neurological Surgery and Biomedical Sciences, Cedars-Sinai Medical Center. Los Angeles, CA 90048, USA; Samuel Oschin Cancer Center, Cedars-Sinai Medical Center. Los Angeles, CA 90048, USA
| | - Yi Zhang
- Departments of Pathology, Neurology, Neurological Surgery and Biomedical Sciences, Cedars-Sinai Medical Center. Los Angeles, CA 90048, USA
| | - German R Aleman-Muench
- CVM discovery, Immunometabolism, Janssen Research & Development, San Diego CA 92121, USA
| | - Gavin Lewis
- CVM discovery, Immunometabolism, Janssen Research & Development, San Diego CA 92121, USA
| | - Weixuan Chen
- Janssen Research & Development, LLC, San Diego, CA, USA
| | - Sarah Kang
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA
| | - Melissa Luevanos
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Dorit Trudler
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Stuart A Lipton
- Neurodegeneration New Medicines Center and Department of Molecular Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA; Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA
| | - Pejman Soroosh
- CVM discovery, Immunometabolism, Janssen Research & Development, San Diego CA 92121, USA
| | - John Teijaro
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Juan Carlos de la Torre
- Department of Immunology and Microbiology, The Scripps Research Institute, La Jolla, CA 92037, USA
| | - Moshe Arditi
- Departments of Biomedical Sciences and Pediatrics, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA; Infectious and Immunologic Diseases Research Center, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA.
| | - Elsa Sanchez-Lopez
- Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, School of Medicine, UCSD, La Jolla, CA 92093, USA
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Aryal A, Harmon AC, Dugas TR. Particulate matter air pollutants and cardiovascular disease: Strategies for intervention. Pharmacol Ther 2021; 223:107890. [PMID: 33992684 PMCID: PMC8216045 DOI: 10.1016/j.pharmthera.2021.107890] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 04/21/2021] [Accepted: 04/27/2021] [Indexed: 02/07/2023]
Abstract
Air pollution is consistently linked with elevations in cardiovascular disease (CVD) and CVD-related mortality. Particulate matter (PM) is a critical factor in air pollution-associated CVD. PM forms in the air during the combustion of fuels as solid particles and liquid droplets and the sources of airborne PM range from dust and dirt to soot and smoke. The health impacts of PM inhalation are well documented. In the US, where CVD is already the leading cause of death, it is estimated that PM2.5 (PM < 2.5 μm in size) is responsible for nearly 200,000 premature deaths annually. Despite the public health data, definitive mechanisms underlying PM-associated CVD are elusive. However, evidence to-date implicates mechanisms involving oxidative stress, inflammation, metabolic dysfunction and dyslipidemia, contributing to vascular dysfunction and atherosclerosis, along with autonomic dysfunction and hypertension. For the benefit of susceptible individuals and individuals who live in areas where PM levels exceed the National Ambient Air Quality Standard, interventional strategies for mitigating PM-associated CVD are necessary. This review will highlight current state of knowledge with respect to mechanisms for PM-dependent CVD. Based upon these mechanisms, strategies for intervention will be outlined. Citing data from animal models and human subjects, these highlighted strategies include: 1) antioxidants, such as vitamins E and C, carnosine, sulforaphane and resveratrol, to reduce oxidative stress and systemic inflammation; 2) omega-3 fatty acids, to inhibit inflammation and autonomic dysfunction; 3) statins, to decrease cholesterol accumulation and inflammation; 4) melatonin, to regulate the immune-pineal axis and 5) metformin, to address PM-associated metabolic dysfunction. Each of these will be discussed with respect to its potential role in limiting PM-associated CVD.
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Affiliation(s)
- Ankit Aryal
- Louisiana State University School of Veterinary Medicine, Department of Comparative Biomedical Sciences, Skip Bertman Drive, Baton Rouge, Louisiana 70803, United States of America
| | - Ashlyn C Harmon
- Louisiana State University School of Veterinary Medicine, Department of Comparative Biomedical Sciences, Skip Bertman Drive, Baton Rouge, Louisiana 70803, United States of America
| | - Tammy R Dugas
- Louisiana State University School of Veterinary Medicine, Department of Comparative Biomedical Sciences, Skip Bertman Drive, Baton Rouge, Louisiana 70803, United States of America.
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