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Chen C, Qin S, Song X, Wen J, Huang W, Sheng Z, Li X, Cao Y. PI3K p85α/HIF-1α accelerates the development of pulmonary arterial hypertension by regulating fatty acid uptake and mitophagy. Mol Med 2024; 30:208. [PMID: 39528930 PMCID: PMC11552344 DOI: 10.1186/s10020-024-00975-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2024] [Accepted: 10/24/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Pulmonary arterial hypertension (PAH) is characterized by lipid accumulation and mitochondrial dysfunction. This study was designed to investigate the effects of hypoxia-inducible factor-1α (HIF-1α) on fatty acid uptake and mitophagy in PAH. METHODS Peripheral blood samples were obtained from PAH patients. Human pulmonary arterial smooth muscle cells and rat cardiac myoblasts H9c2 were subjected to hypoxia treatment. Male Sprague-Dawley rats were treated with monocrotaline (MCT). Right ventricular systolic pressure (RVSP), right ventricular hypertrophy index (RVHI), pulmonary artery remodeling, and lipid accumulation were measured. Cell proliferation and ROS accumulation were assessed. Mitochondrial damage and autophagosome formation were observed. Co-immunoprecipitation was performed to verify the interaction between HIF-1α and CD36/PI3K p85α. RESULTS HIF-1α, CD36, Parkin, and PINK1 were upregulated in PAH samples. HIF-1α knockdown or PI3K p85α knockdown restricted the expression of HIF-1α, PI3K p85α, Parkin, PINK1, and CD36, inhibited hPASMC proliferation, promoted H9c2 cell proliferation, reduced ROS accumulation, and suppressed mitophagy. CD36 knockdown showed opposite effects to HIF-1α knockdown, which were reversed by palmitic acid. The HIF-1α activator dimethyloxalylglycine reversed the inhibitory effect of Parkin knockdown on mitophagy. In MCT-induced rats, the HIF-1α antagonist 2-methoxyestradiol (2ME) reduced RVSP, RVHI, pulmonary artery remodeling, lipid accumulation, and mitophagy. Recombinant CD36 abolished the therapeutic effect of 2ME but inhibited mitophagy. Activation of Parkin/PINK1 by salidroside (Sal) promoted mitophagy to ameliorate the pathological features of PAH-like rats, and 2ME further enhanced the therapeutic outcome of Sal. CONCLUSION PI3K p85α/HIF-1α induced CD36-mediated fatty acid uptake and Parkin/PINK1-dependent mitophagy to accelerate the progression of experimental PAH.
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Affiliation(s)
- Chenyang Chen
- Cardiovascular Department, The Third Xiangya Hospital of Central South University, Changsha, 410013, China.
| | - Sirun Qin
- Cardiovascular Department, The Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Xiaohua Song
- Department of Pediatrics, The 921, Hospital of Joint Logistics Support Force of Chinese People's Liberation Army, Changsha, 410011, China
| | - Juan Wen
- Cardiovascular Department, The Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Wei Huang
- Cardiovascular Department, The Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Zhe Sheng
- Cardiovascular Department, The Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Xiaogang Li
- Cardiovascular Department, The Third Xiangya Hospital of Central South University, Changsha, 410013, China
| | - Yu Cao
- Cardiovascular Department, The Third Xiangya Hospital of Central South University, Changsha, 410013, China
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Li A, Qin Y, Gong G. The Changes of Mitochondria during Aging and Regeneration. Adv Biol (Weinh) 2024; 8:e2300445. [PMID: 38979843 DOI: 10.1002/adbi.202300445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2023] [Revised: 05/30/2024] [Indexed: 07/10/2024]
Abstract
Aging and regeneration are opposite cellular processes. Aging refers to progressive dysfunction in most cells and tissues, and regeneration refers to the replacement of damaged or dysfunctional cells or tissues with existing adult or somatic stem cells. Various studies have shown that aging is accompanied by decreased regenerative abilities, indicating a link between them. The performance of any cellular process needs to be supported by the energy that is majorly produced by mitochondria. Thus, mitochondria may be a link between aging and regeneration. It should be interesting to discuss how mitochondria behave during aging and regeneration. The changes of mitochondria in aging and regeneration discussed in this review can provide a timely and necessary study of the causal roles of mitochondrial homeostasis in longevity and health.
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Affiliation(s)
- Anqi Li
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
| | - Yuan Qin
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
| | - Guohua Gong
- Key Laboratory of Laboratory Medicine, Ministry of Education, School of Laboratory Medicine and Life Sciences, Wenzhou Medical University, Wenzhou, 325035, China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China
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Su Z, Efremov L, Mikolajczyk R. Differences in the levels of inflammatory markers between metabolically healthy obese and other obesity phenotypes in adults: A systematic review and meta-analysis. Nutr Metab Cardiovasc Dis 2024; 34:251-269. [PMID: 37968171 DOI: 10.1016/j.numecd.2023.09.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 07/28/2023] [Accepted: 09/04/2023] [Indexed: 11/17/2023]
Abstract
AIMS The aim of this study was to systematically review and analyze differences in the levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) comparing metabolically healthy but obese (MHO) with metabolically healthy non-obese (MHNO), metabolically unhealthy non-obese (MUNO), and metabolically unhealthy obese (MUO) subjects. DATA SYNTHESIS We searched PubMed, Embase, Web of Science, and Scopus for studies that matched the relevant search terms. Differences in inflammatory marker levels between MHO and the other three phenotypes were pooled as standardized mean differences (SMD) or differences of medians (DM) using a random-effects model. We included 91 studies reporting data on 435,007 individuals. The CRP levels were higher in MHO than in MHNO subjects (SMD = 0.63, 95% CI: 0.49, 0.76; DM = 0.83 mg/L, 95% CI: 0.56, 1.11). The CRP levels were higher in MHO than in MUNO subjects (SMD = 0.16, 95% CI: 0.05, 0.28; DM = 0.39 mg/L, 95% CI: 0.09, 0.69). The CRP levels were lower in MHO than in MUO individuals (SMD = -0.43, 95% CI: -0.54, -0.31; DM = -0.82 mg/L, 95% CI: -1.16, -0.48). The IL-6 levels in MHO were higher than in MHNO while lower than in MUO subjects. The TNF-α levels in MHO were higher than in MHNO individuals. CONCLUSIONS This review provides evidence that CRP levels in MHO are higher than in MHNO and MUNO subjects but lower than in MUO individuals. Additionally, IL-6 levels in MHO are higher than in MHNO but lower than in MUO subjects, and TNF-α levels in MHO are higher than in MHNO individuals. SYSTEMATIC REVIEW REGISTRATION PROSPERO number: CRD42021234948.
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Affiliation(s)
- Zhouli Su
- Institute for Medical Epidemiology, Biometrics and Informatics (IMEBI), Interdisciplinary Center for Health Sciences, Martin-Luther-University Halle-Wittenberg, D-06112 Halle (Saale), Germany
| | - Ljupcho Efremov
- Institute for Medical Epidemiology, Biometrics and Informatics (IMEBI), Interdisciplinary Center for Health Sciences, Martin-Luther-University Halle-Wittenberg, D-06112 Halle (Saale), Germany; Department of Radiation Oncology, Martin-Luther-University Halle-Wittenberg, D-06120 Halle (Saale), Germany
| | - Rafael Mikolajczyk
- Institute for Medical Epidemiology, Biometrics and Informatics (IMEBI), Interdisciplinary Center for Health Sciences, Martin-Luther-University Halle-Wittenberg, D-06112 Halle (Saale), Germany.
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Yu B, Pan JB, Yu FY. The combination of nuclear receptor NR1D1 and ULK1 promotes mitophagy in adipocytes to ameliorate obesity. Adipocyte 2022; 11:202-212. [PMID: 35410572 PMCID: PMC9009922 DOI: 10.1080/21623945.2022.2060719] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Obesity is a severe disease worldwide. Mitochondrial autophagy (mitophagy) may be related to metabolic abnormalities in obese individuals, but the mechanism is still unclear. We aimed to investigate whether nuclear receptors NR1D1 and ULK1 influence obesity by affecting mitophagy. In vitro model was established by inducing 3T3-L1 cells differentiation. MTT was detected cell viability. ELISA was tested triglyceride (TG). Oil red O staining was performed to detect lipid droplets. Flow cytometry was measured mtROS. ChIP and Dual-luciferase reporter assay were verified NR1D1 bind to ULK1. LC3 level was detected by IF. After differentiation medium treatment, cell viability was decreased, TG content and lipid droplets were increased Moreover, NR1D1 expression was reduced in Model group. NR1D1 overexpression was increased cell viability, reduced TG content and lipid droplets. Subsequently, NR1D1 inhibited TOM20 and mtROS, whereas, Parkin and PINK1 were accelerated. NR1D1 overexpression facilitated LC3 expression, whereas ULK1 knockdown was reversed the effect of NR1D1 overexpression. Liensinine also reversed the effect of NR1D1 overexpression, that is, cell viability was reduced, mtROS, TG content and lipid droplets were increased. The combination of nuclear receptor NR1D1 and ULK1 promoted mitophagy in adipocytes to alleviate obesity, which provided new target and strategy for obesity treatment.Abbreviations: Mitochondrial autophagy (mitophagy), triglyceride (TG), Uncoordinated-51 like autophagy activating kinase 1 (ULK1), Nuclear receptor subfamily 1 group D member 1 (NR1D1), American Type Culture Collection (ATCC), fetal bovine serum (FBS), 3-isobutyl-1-methylxanthine (IBMX), dexamethasone (DEX), short hairpin RNA ULK1 (sh-ULK1), wild-type (WT), mutant (MUT), Enzyme-linked immunosorbent assay (ELISA), mitochondrial reactive oxygen species (mtROS), Chromatin immunoprecipitation (ChIP), Quantitative real-time PCR (qRT-PCR), Immunofluorescence (IF), standard deviation (SD).
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Affiliation(s)
- Bo Yu
- Department of General Medicine, Yueyang People’s Hospital, Yueyang Hospital Affiliated to Hunan Normal University, Yueyang, Hunan Province, P.R. China
| | - Jin-Bao Pan
- Department of General Medicine, Yueyang People’s Hospital, Yueyang Hospital Affiliated to Hunan Normal University, Yueyang, Hunan Province, P.R. China
| | - Fei-Yue Yu
- Department of Gastroenterology, Yueyang People’s Hospital, Yueyang Hospital Affiliated to Hunan Normal University, Yueyang, Hunan Province, P.R. China
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Bharath LP, Hart SN, Nikolajczyk BS. T-cell Metabolism as Interpreted in Obesity-associated Inflammation. Endocrinology 2022; 163:6657752. [PMID: 35932471 PMCID: PMC9756079 DOI: 10.1210/endocr/bqac124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Indexed: 11/19/2022]
Abstract
The appreciation of metabolic regulation of T-cell function has exploded over the past decade, as has our understanding of how inflammation fuels comorbidities of obesity, including type 2 diabetes. The likelihood that obesity fundamentally alters T-cell metabolism and thus chronic obesity-associated inflammation is high, but studies testing causal relationships remain underrepresented. We searched PubMed for key words including mitochondria, obesity, T cell, type 2 diabetes, cristae, fission, fusion, redox, and reactive oxygen species to identify foundational and more recent studies that address these topics or cite foundational work. We investigated primary papers cited by reviews found in these searches and highlighted recent work with >100 citations to illustrate the state of the art in understanding mechanisms that control metabolism and thus function of various T-cell subsets in obesity. However, "popularity" of a paper over the first 5 years after publication cannot assess long-term impact; thus, some likely important work with fewer citations is also highlighted. We feature studies of human cells, supplementing with studies from animal models that suggest future directions for human cell research. This approach identified gaps in the literature that will need to be filled before we can estimate efficacy of mitochondria-targeted drugs in clinical trials to alleviate pathogenesis of obesity-associated inflammation.
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Affiliation(s)
- Leena P Bharath
- Department of Nutrition and Public Health, Merrimack College, North Andover, MA 01845, USA
| | - Samantha N Hart
- Departments of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536, USA
| | - Barbara S Nikolajczyk
- Correspondence: Barbara S. Nikolajczyk, PhD, Healthy Kentucky Research Bldg. Rm. 217, 760 Press Ave, Lexington, KY 40536, USA.
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6
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Su L, Pan Y, Chen H. The Harm of Metabolically Healthy Obese and the Effect of Exercise on Their Health Promotion. Front Physiol 2022; 13:924649. [PMID: 35910571 PMCID: PMC9329531 DOI: 10.3389/fphys.2022.924649] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 06/24/2022] [Indexed: 11/13/2022] Open
Abstract
Obesity and obesity-related diseases [type 2 diabetes, cardiovascular disease (CVD), and cancer] are becoming more common, which is a major public health concern. Metabolically healthy obesity (MHO) has become a type of obesity, accounting for a large proportion of obese people. MHO is still harmful to health. It was discovered that MHO screening criteria could not well reflect health hazards, whereas visceral fat, adiponectin pathway, oxidative stress, chronic inflammation, and histological indicators at the microlevel could clearly distinguish MHO from health control, and the biological pathways involved in these micro indicators were related to MHO pathogenesis. This review reveals that MHO’s micro metabolic abnormality is the initial cause of the increase of disease risk in the future. Exploring the biological pathway of MHO is important in order to develop an effective mechanism-based preventive and treatment intervention strategy. Exercise can correct the abnormal micro metabolic pathway of MHO, regulate metabolic homeostasis, and enhance metabolic flexibility. It is a supplementary or possible alternative to the traditional healthcare prevention/treatment strategy as well as an important strategy for reducing MHO-related health hazards.
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Affiliation(s)
- Liqiang Su
- Physical Education of College, Jiangxi Normal University, Nanchang, China
| | - Yihe Pan
- Physical Education of College, Jiangxi Normal University, Nanchang, China
| | - Haichun Chen
- School of Physical Education and Sport Science, Fujian Normal University, Fuzhou, China
- *Correspondence: Haichun Chen,
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You S, Zheng J, Chen Y, Huang H. Research progress on the mechanism of beta-cell apoptosis in type 2 diabetes mellitus. Front Endocrinol (Lausanne) 2022; 13:976465. [PMID: 36060972 PMCID: PMC9434279 DOI: 10.3389/fendo.2022.976465] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Accepted: 08/01/2022] [Indexed: 11/23/2022] Open
Abstract
Type 2 diabetes mellitus(T2DM) is regarded as one of the most severe chronic metabolic diseases worldwide, which poses a great threat to human safety and health. The main feature of T2DM is the deterioration of pancreatic beta-cell function. More and more studies have shown that the decline of pancreatic beta-cell function in T2DM can be attributable to beta-cell apoptosis, but the exact mechanisms of beta-cell apoptosis in T2DM are not yet fully clarified. Therefore, in this review, we will focus on the current status and progress of research on the mechanism of pancreatic beta-cell apoptosis in T2DM, to provide new ideas for T2DM treatment strategies.
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Affiliation(s)
- SuFang You
- The Second Clinical Medical College of Fujian Medical University, Quanzhou, China
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - JingYi Zheng
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - YuPing Chen
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
| | - HuiBin Huang
- Department of Endocrinology, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, China
- *Correspondence: HuiBin Huang,
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8
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Wang J, Deng W, Zou T, Bai B, Chang AK, Ying X. Cadmium-induced oxidative stress in Meretrix meretrix gills leads to mitochondria-mediated apoptosis. ECOTOXICOLOGY (LONDON, ENGLAND) 2021; 30:2011-2023. [PMID: 34529205 DOI: 10.1007/s10646-021-02465-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 08/02/2021] [Indexed: 06/13/2023]
Abstract
Cadmium (Cd) is one of the most important marine environmental pollutants that can cause oxidative damage and apoptosis in living organisms, and mitochondria are the key cell organelles affected by Cd toxicity. In this study, we investigated the effect of Cd on the mitochondria in the gill cells of the clam Meretrix meretrix and the underlying mechanism of mitochondria-mediated apoptosis following exposure to the metal. Exposure of the clams to artificial seawater containing 1.5, 3, 6 and 12 mg L-1 Cd2+ led to swollen mitochondria compared with the untreated clams. The mitochondria also became vacuolated at the higher Cd2+ concentrations. Biochemical assays showed that monoamine oxidase (MAO) activity and mitochondrial membrane potential (Δψm) increased at 1.5 mg L-1 Cd2+, but decreased at higher Cd2+ concentrations, while the activities of malate dehydrogenase (MDH) and cytochrome oxidase (CCO) and the scavenging capacities of anti-superoxide anion (ASA) and anti-hydroxy radical (AHR) all decreased with increasing Cd2+ concentrations. Significant increases in the levels of malondialdehyde (MDA) and H2O2 as well as in the activity levels of caspase-3, -8, and -9 were also observed in the Cd2+-treated clams. The results implied that Cd might induce apoptosis in M. meretrix via the mitochondrial caspase-dependent pathway.
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Affiliation(s)
- Jinhua Wang
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, Zhejiang, People's Republic of China
| | - Wanfei Deng
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, Zhejiang, People's Republic of China
| | - Ting Zou
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, Zhejiang, People's Republic of China
| | - Binbin Bai
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, Zhejiang, People's Republic of China
| | - Alan K Chang
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, Zhejiang, People's Republic of China
| | - Xueping Ying
- College of Life and Environmental Sciences, Wenzhou University, Wenzhou, Zhejiang, People's Republic of China.
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9
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Capriello T, Félix LM, Monteiro SM, Santos D, Cofone R, Ferrandino I. Exposure to aluminium causes behavioural alterations and oxidative stress in the brain of adult zebrafish. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2021; 85:103636. [PMID: 33741517 DOI: 10.1016/j.etap.2021.103636] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 03/08/2021] [Accepted: 03/10/2021] [Indexed: 06/12/2023]
Abstract
Aluminium (Al) water pollution is an increasing environmental problem. Accordingly, this study aimed to find out more about its toxic effects on aquatic organisms. Adult zebrafish were exposed to 11 mg/L of Al and the behavioural responses and its correlation with brain oxidative stress, antioxidant-defences, changes in metabolism and neurotransmission were assessed at 10, 15 and 20 days of exposure. The behavioural and locomotory responses, suggest an increase in the anxiety state, especially observed in animals exposed to Al for 15 days. The reactive oxygen species increased in a time-dependent trend, while the oxidative damage varied over exposure time. The activity of antioxidant enzymes, as superoxide dismutase, glutathione peroxidase and glutathione S-transferases, and the metallothioneins levels increased after short-term exposures and tended to decrease or stabilize at longer times. The results contribute to understand the toxic mechanisms activated by Al highlighting correlations like behavioural disorders and oxidative state.
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Affiliation(s)
- Teresa Capriello
- Department of Biology, University of Naples "Federico II", Naples, Italy
| | - Luis M Félix
- Laboratory Animal Science (LAS), Institute for Research and Innovation in Health (i3S), University of Porto (UP), Porto, Portugal; Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Sandra M Monteiro
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Dércia Santos
- Centre for the Research and Technology of Agro-Environmental and Biological Sciences (CITAB), University of Trás-os-Montes and Alto Douro (UTAD), Vila Real, Portugal
| | - Rita Cofone
- Department of Biology, University of Naples "Federico II", Naples, Italy
| | - Ida Ferrandino
- Department of Biology, University of Naples "Federico II", Naples, Italy; BAT Center - Interuniversity Center for Studies on Bioinspired Agro-Environmental Technology, Portici, NA, Italy.
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Paczkowska-Abdulsalam M, Kretowski A. Obesity, metabolic health and omics: Current status and future directions. World J Diabetes 2021; 12:420-436. [PMID: 33889288 PMCID: PMC8040086 DOI: 10.4239/wjd.v12.i4.420] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 02/22/2021] [Accepted: 03/30/2021] [Indexed: 02/06/2023] Open
Abstract
The growing obesity epidemic is becoming a major public health concern, and the associated costs represent a considerable burden on societies. Among the most common complications of severe obesity are the development of hypertension, dyslipidemia, type 2 diabetes, cardiovascular disease, and various types of cancer. Interestingly, some obese individuals have a favorable metabolic profile and appear to be somehow protected from the detrimental effects of excessive adipose tissue accumulation. These individuals remain normoglycemic, insulin sensitive, and hypotensive with proper blood lipid levels, despite their high body mass index and/or waist circumference. Multiple independent observations have led to the concept of the metabolically healthy obese (MHO) phenotype, yet no consensus has been reached to date regarding a universal definition or the main mechanism behind this phenomenon. Recent technological advances and the use of high-throughput analysis techniques have revolutionized different areas of biomedical research. A multi-omics approach, which is used to investigate changes at different molecular levels in an organism or tissue, may provide valuable insights into the interplay between the molecules or pathways and the roles of different factors involved in the mechanisms underlying metabolic health deterioration. The aim of this review is to present the current status regarding the use of omics technologies to investigate the MHO phenotype, as well as the results of targeted analyses conducted in MHO individuals.
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Affiliation(s)
| | - Adam Kretowski
- Clinical Research Centre, Medical University of Bialystok, Bialystok 15-276, Poland
- Department of Endocrinology, Diabetology and Internal Medicine, Medical University of Bialystok, Bialystok 15-276, Poland
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11
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Yang J, Suo H, Song J. Protective role of mitoquinone against impaired mitochondrial homeostasis in metabolic syndrome. Crit Rev Food Sci Nutr 2020; 61:3857-3875. [PMID: 32815398 DOI: 10.1080/10408398.2020.1809344] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Mitochondria control various processes in cellular metabolic homeostasis, such as adenosine triphosphate production, generation and clearance of reactive oxygen species, control of intracellular Ca2+ and apoptosis, and are thus a critical therapeutic target for metabolic syndrome (MetS). The mitochondrial targeted antioxidant mitoquinone (MitoQ) reduces mitochondrial oxidative stress, prevents impaired mitochondrial dynamics, and increases mitochondrial turnover by promoting autophagy (mitophagy) and mitochondrial biogenesis, which ultimately contribute to the attenuation of MetS conditions, including obesity, insulin resistance, hypertension and cardiovascular disease. The regulatory effect of MitoQ on mitochondrial homeostasis is mediated through AMPK and its downstream signaling pathways, including MTOR, SIRT1, Nrf2 and NF-κB. However, there are few reviews focusing on the critical role of MitoQ as a therapeutic agent in the treatment of MetS. The purpose of this review is to summarize the mitochondrial role in the pathogenesis of MetS, especially in obesity and type 2 diabetes, and discuss the effect and underlying mechanism of MitoQ on mitochondrial homeostasis in MetS.
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Affiliation(s)
- Jing Yang
- Chongqing Engineering Research Center for Processing & Storage of Distinct Agricultural Products, Chongqing Technology and Business University, Chongqing, China.,Graduate School, Chongqing Technology and Business University, Chongqing, China
| | - Huayi Suo
- College of Food Science, Southwest University, Chongqing, China
| | - Jiajia Song
- College of Food Science, Southwest University, Chongqing, China
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12
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Pan Y, Ai CX, Zeng L, Liu C, Li WC. Modulation of copper-induced antioxidant defense, Cu transport, and mitophagy by hypoxia in the large yellow croaker (Larimichthys crocea). FISH PHYSIOLOGY AND BIOCHEMISTRY 2020; 46:997-1010. [PMID: 31925663 DOI: 10.1007/s10695-020-00765-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 01/06/2020] [Indexed: 06/10/2023]
Abstract
This study aimed to investigate the effects of hypoxia on Cu-induced antioxidant defense, Cu transport, and mitophagy in the liver of the large yellow croaker. Fish were exposed to hypoxia (3.0 mg L-1), Cu (120 μg L-1), and hypoxia (3.0 mg L-1) plus Cu (120 μg L-1) for 48 h. Hypoxia exposure increased antioxidant abilities to maintain cellular redox balance. Although Cu exposure alone improved antioxidant defense, Cu transport, and mitophagy, these stress responses could not completely neutralize Cu toxicity, as reflected by the elevated reactive oxygen species (ROS) and lipid peroxidation (LPO) and hepatic vacuoles. When compared with Cu stress alone, hypoxia increased Cu toxicity by inhibiting antioxidant defense, Cu transport, and mitophagy, leading to the increment of mortality, ROS, and LPO, and the deterioration of histological structure. The adverse effects of hypoxia on Cu-induced metal transport and mitophagy might be involved in metal-responsive element-binding transcription factor-1 (MTF-1) and Forkhead box O-3 (FoxO3) signaling pathways, respectively. Overall, hypoxia reduced antioxidant response, Cu transport, and mitophagy in fish exposed to Cu, which contributes to understanding the molecular mechanisms underlying negative effects of hypoxia on Cu toxicity in fish.
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Affiliation(s)
- Yun Pan
- National Engineering Research Center for Marine Aquaculture, Zhejiang Ocean University, Zhoushan, 316000, China
| | - Chun-Xiang Ai
- College of Ocean and Earth Sciences, Xiamen University, Xiamen, 361005, China
| | - Lin Zeng
- National Engineering Research Center for Marine Aquaculture, Zhejiang Ocean University, Zhoushan, 316000, China.
| | - Can Liu
- National Engineering Research Center for Marine Aquaculture, Zhejiang Ocean University, Zhoushan, 316000, China
| | - Wen-Cheng Li
- National Engineering Research Center for Marine Aquaculture, Zhejiang Ocean University, Zhoushan, 316000, China
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Zeng L, Ai CX, Zhang JS, Li WC. Pre-hypoxia exposure inhibited copper toxicity by improving energy metabolism, antioxidant defence and mitophagy in the liver of the large yellow croaker Larimichthys crocea. THE SCIENCE OF THE TOTAL ENVIRONMENT 2020; 708:134961. [PMID: 31787300 DOI: 10.1016/j.scitotenv.2019.134961] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 09/26/2019] [Accepted: 10/11/2019] [Indexed: 05/14/2023]
Abstract
This study investigated the effects of moderate hypoxia pre-exposure on energy metabolism, antioxidant defence and mitophagy in the liver of the large yellow croaker Larimichthys crocea exposed to Cu. Fish were pre-exposed to either normoxia or hypoxia (~3.0 mg L-1, 42% O2 saturation) for 48 h, and subsequently were subjected to either control (without Cu addition) or Cu (168 μg L-1) under normoxic conditions for another 48 h. Copper exposure under normoxia induced Cu toxicity that increased mortality, the production of reactive oxygen species (ROS) and malondialdehyde, and aberrant hepatic mitochondrial ultrastructure. Interestingly, hypoxia pre-exposure improved energy metabolism, antioxidant ability and mitophagy response, and reduced the Cu content to inhibit Cu toxicity, reflecting the enhanced survival rate and reduced oxidative damage. In these processes, hypoxia-inducible factor-1α (HIF-1α), transcription factors NFE2-related nuclear factor 2 (Nrf2), and forkhead box O-3 (FoxO3) mRNA levels were correlated with expression of genes related to energy metabolism, antioxidant defence and mitophagy, respectively, indicating HIF-1α, Nrf2, and FoxO3 are required for the induction of their respective target genes. Overall, moderate hypoxia pre-exposure was able to generate adaptive responses to mitigate Cu-induced toxicological effects, underlining a central role of hormesis.
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Affiliation(s)
- Lin Zeng
- National Engineering Research Center of Marine Facilities Aquaculture, Zhejiang Ocean University, Zhoushan 316022, PR China
| | - Chun-Xiang Ai
- College of Ocean and Earth Sciences, Xiamen University, Xiamen 361005, PR China
| | - Jian-She Zhang
- National Engineering Research Center of Marine Facilities Aquaculture, Zhejiang Ocean University, Zhoushan 316022, PR China.
| | - Wen-Cheng Li
- National Engineering Research Center of Marine Facilities Aquaculture, Zhejiang Ocean University, Zhoushan 316022, PR China
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14
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Metabolic Health-The Role of Adipo-Myokines. Int J Mol Sci 2019; 20:ijms20246159. [PMID: 31817641 PMCID: PMC6941068 DOI: 10.3390/ijms20246159] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2019] [Revised: 12/02/2019] [Accepted: 12/04/2019] [Indexed: 02/07/2023] Open
Abstract
Obesity is now a worldwide epidemic. In recent years, different phenotypes of obesity, ranging from metabolically healthy normal weight to metabolically unhealthy obese, were described. Although there is no standardized definition for these phenotypes or for metabolic health, the influence of lifestyle and early-life factors is undisputed. In this context, the ratio of muscle-to-fat tissue seems to play a crucial role. Both adipose tissue and skeletal muscle are highly heterogeneous endocrine organs secreting several hormones, with myokines and adipokines being involved in local autocrine/paracrine interactions and crosstalk with other tissues. Some of these endocrine factors are secreted by both tissues and are, therefore, termed adipo-myokines. High (cardiorespiratory) fitness as a surrogate parameter for an active lifestyle is epidemiologically linked to “better” metabolic health, even in the obese; this may be partly due to the role of adipo-myokines and the crosstalk between adipose and muscle tissue. Therefore, it is essential to consider (cardiovascular) fitness in the definition of metabolically healthy obese/metabolic health and to perform longitudinal studies in this regard. A better understanding of both the (early-life) lifestyle factors and the underlying mechanisms that mediate different phenotypes is necessary for the tailored prevention and personalized treatment of obesity.
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15
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Guo T, Liu T, Sun Y, Liu X, Xiong R, Li H, Li Z, Zhang Z, Tian Z, Tian Y. Sonodynamic therapy inhibits palmitate-induced beta cell dysfunction via PINK1/Parkin-dependent mitophagy. Cell Death Dis 2019; 10:457. [PMID: 31186419 PMCID: PMC6560035 DOI: 10.1038/s41419-019-1695-x] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 05/27/2019] [Accepted: 05/28/2019] [Indexed: 12/20/2022]
Abstract
In type 2 diabetes mellitus (T2DM), the overload of glucose and lipids can promote oxidative stress and inflammatory responses and contribute to the failure of beta cells. However, therapies that can modulate the function of beta cells and thus prevent their failure have not been well explored. In this study, beta cell injury model was established with palmitic acid (PA) to simulate the lipotoxicity (high-fat diet) found in T2DM. Sonodynamic therapy (SDT), a novel physicochemical treatment, was applied to treat injured beta cells. We found that SDT had specific effects on mitochondria and induced transient large amount of mitochondrial reactive oxygen species (ROS) production in beta cells. SDT also improved the morphology and function of abnormal mitochondria, inhibited inflammatory response and reduced beta cell dysfunction. The improvement of mitochondria was mediated by PINK1/Parkin-dependent mitophagy. Additionally, SDT rescued the transcription of PINK1 mRNA which was blocked by PA treatment, thus providing abundant PINK1 for mitophagy. Moreover, SDT also increased insulin secretion from beta cells. The protective effects of SDT were abrogated when mitophagy was inhibited by cyclosporin A (CsA). In summary, SDT potently inhibits lipotoxicity-induced beta cell failure via PINK1/Parkin-dependent mitophagy, providing theoretical guidance for T2DM treatment in aspects of islet protection.
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Affiliation(s)
- Tian Guo
- Department of Pathophysiology, Harbin Medical University, Harbin, 150081, China
| | - Tianyang Liu
- Department of Pathophysiology, Harbin Medical University, Harbin, 150081, China
| | - Yun Sun
- Department of Pathophysiology, Harbin Medical University, Harbin, 150081, China
| | - Xianna Liu
- Department of Pathophysiology, Harbin Medical University, Harbin, 150081, China
| | - Rongguo Xiong
- Department of Pathophysiology, Harbin Medical University, Harbin, 150081, China
| | - He Li
- Department of Pathophysiology, Harbin Medical University, Harbin, 150081, China
| | - Zhitao Li
- Department of Pathophysiology, Harbin Medical University, Harbin, 150081, China
| | - Zhiguo Zhang
- Laboratory of Photo- and Sono-theranostic Technologies and Condensed Matter Science and Technology Institute, Harbin Institute of Technology, Harbin, 150001, China
| | - Zhen Tian
- Department of Pathophysiology, Harbin Medical University, Harbin, 150081, China. .,Key Laboratory of Acoustic Photoelectric Magnetic Diagnosis and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, 150081, China.
| | - Ye Tian
- Department of Pathophysiology, Harbin Medical University, Harbin, 150081, China. .,Key Laboratory of Acoustic Photoelectric Magnetic Diagnosis and Treatment of Cardiovascular Diseases in Heilongjiang Province, Harbin, 150081, China. .,Department of Cardiology, The First Affiliated Hospital, Cardiovascular Institute, Harbin Medical University, Harbin, 150001, China.
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16
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Pan YX, Luo Z, Zhuo MQ, Wei CC, Chen GH, Song YF. Oxidative stress and mitochondrial dysfunction mediated Cd-induced hepatic lipid accumulation in zebrafish Danio rerio. AQUATIC TOXICOLOGY (AMSTERDAM, NETHERLANDS) 2018; 199:12-20. [PMID: 29604498 DOI: 10.1016/j.aquatox.2018.03.017] [Citation(s) in RCA: 108] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 03/15/2018] [Accepted: 03/16/2018] [Indexed: 06/08/2023]
Abstract
The present study was performed to determine the effect of waterborne CdCl2 exposure influencing lipid deposition and metabolism, oxidative stress and mitochondrial dysfunction, and explore the underlying molecular mechanism of cadmium (Cd)-induced disorder of hepatic lipid metabolism in fish. To this end, adult zebrafish were exposed to three waterborne CdCl2 concentrations (0(control), 5 and 25 μg Cd/l, respectively) for 30 days. Lipid accumulation, the activities of enzymes related to lipid metabolism and oxidative stress, as well as the expression level of genes involved in lipid metabolism and mitophagy were determined in the liver of zebrafish. Waterborne CdCl2 exposure increased hepatic triglyceride (TG) and Cd accumulation, the activities of fatty acid synthase (FAS), 6-phosphogluconate dehydrogenase (6PGD), glucose 6-phosphate dehydrogenase (G6PD) and malic enzyme (ME), and the mRNA level of fatty acid synthase (fas), acetyl-CoA carboxylase alpha (acaca), glucose 6-phosphate dehydrogenase (g6pd) and malic enzyme (me), but reduced the mRNA level of carnitine palmitoyl transferase 1 (cpt1), hormone-sensitive lipase alpha (hsla), and adipose triacylglyceride lipase (atgl). The activities of superoxide dismutase (SOD), glutathoinine peroxidase (GPx) and cytochrome c oxidase (COX) and the ATP level were significantly reduced after CdCl2 exposure. CdCl2 exposure significantly increased the mRNA level of genes (microtubule-associated protein light chain 3 alpha (lc3a), PTEN-induced putative kinase 1 (pink1), NIP3-like protein X (nix) and PARKIN (parkin)) related to mitophagy. To elucidate the mechanism, reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the mitochondrial permeability transition (MPT) inhibitor cyclosporine A (CsA) were used to verify the role of ROS and mitochondrial dysfunction in Cd-induced disorder of lipid metabolism. NAC pretreatment reversed the Cd-induced up-regulation of TG accumulation and activities of lipogenic enzymes, and the Cd-induced down-regulation of mRNA levels of lipolytic genes. Meanwhile, NAC pretreatment also blocked the mitochondrial membrane potential (MMP) collapse and decreased the ATP level, suggesting that ROS played a crucial role in regulating the Cd-induced mitochondrial dysfunction. Taken together, our findings, for the first time, highlight the importance of the oxidative stress and mitochondrial dysfunction in Cd-induced disorder of hepatic lipid metabolism, which proposed a novel mechanism for elucidating metal element exposure inducing the disorder of lipid metabolism in vertebrates.
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Affiliation(s)
- Ya-Xiong Pan
- Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Zhi Luo
- Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Fishery College, Huazhong Agricultural University, Wuhan 430070, China; Collaborative Innovation Center for Efficient and Health Production of Fisheries, Hunan University of Arts and Science, Changde 415000, China.
| | - Mei-Qing Zhuo
- Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Chuan-Chuan Wei
- Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Guang-Hui Chen
- Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
| | - Yu-Feng Song
- Freshwater Aquaculture Collaborative Innovative Centre of Hubei Province, Fishery College, Huazhong Agricultural University, Wuhan 430070, China
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