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Atlasbaf A, Kodehei AH, Bahadoran E, Zare I, Yousefzadeh S, Kesharwani P, Naderi Y, Sahebkar A. Bavachinin attenuates cerebral ischemia/reperfusion injury in rats via its anti-inflammatory and antioxidant effects. Tissue Cell 2025; 95:102886. [PMID: 40164017 DOI: 10.1016/j.tice.2025.102886] [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: 12/01/2024] [Revised: 03/20/2025] [Accepted: 03/21/2025] [Indexed: 04/02/2025]
Abstract
Cerebral ischemia is associated with memory deficits. Bavachinin, a natural flavonoid derived from Psoralea Corylifolia seeds, exhibits various pharmacological properties, including anti-inflammatory, antioxidant, anticancer, and anti-allergic activities. We looked into the neuroprotective effects of bavachinin on rats' memory impairments brought on by transient cerebral ischemia/reperfusion. Blocked carotid arteries caused transient cerebral ischemia/reperfusion injury. Wistar male rats were randomized to bavachinin, ischemia/reperfusion, and sham groups. After surgery, bavachinin (100 mg/kg) was injected intraperitoneally once a day for seven days. Spatial memory was evaluated using the Morris water maze test. The vitality of the hippocampal pyramidal neurons was assessed by Nissl staining. The production of pro-inflammatory cytokines (TNF-α and IL-1β) has been detected using ELISA. Oxidative stress was evaluated by determining the hippocampal levels of malondialdehyde (MDA). In rats with transient cerebral ischemia/reperfusion, bevacichinin markedly improved the performance of learning. The bavachinin-treated group had a higher number of surviving pyramidal neurons, as demonstrated by the Nissl staining. In the hippocampus, bevacichinin lowered MDA, TNF-α, and IL-1β levels. The antioxidant and anti-inflammatory properties of bavachinin likely protect against memory impairment caused by transient cerebral ischemia. These findings suggest that bavachinin could be a potent therapeutic agent for the prevention of cognitive deficits and neuronal damage associated with cerebral ischemia/reperfusion. More studies are needed to explore its clinical applications and mechanisms of action.
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Affiliation(s)
| | | | - Ensiyeh Bahadoran
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Isareza Zare
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Salar Yousefzadeh
- Student Research Committee, Qazvin University of Medical Sciences, Qazvin, Iran
| | - Prashant Kesharwani
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour Vishwavidyalaya, Sagar, Madhya Pradesh, India; University Institute of Pharma Sciences, Chandigarh University, Mohali, Punjab, India.
| | - Yazdan Naderi
- Cellular and Molecular Research Center, Research Institute for Prevention of Noncommunicable Disease, Qazvin University of Medical Sciences, Qazvin, Iran.
| | - Amirhossein Sahebkar
- Center for Global Health Research, Saveetha Medical College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India; Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran; Applied Biomedical Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
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Bazzazzadehgan S, Shariat-Madar Z, Mahdi F. Distinct Roles of Common Genetic Variants and Their Contributions to Diabetes: MODY and Uncontrolled T2DM. Biomolecules 2025; 15:414. [PMID: 40149950 PMCID: PMC11940602 DOI: 10.3390/biom15030414] [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: 12/30/2024] [Revised: 01/26/2025] [Accepted: 03/10/2025] [Indexed: 03/29/2025] Open
Abstract
Type 2 diabetes mellitus (T2DM) encompasses a range of clinical manifestations, with uncontrolled diabetes leading to progressive or irreversible damage to various organs. Numerous genes associated with monogenic diabetes, exhibiting classical patterns of inheritance (autosomal dominant or recessive), have been identified. Additionally, genes involved in complex diabetes, which interact with environmental factors to trigger the disease, have also been discovered. These genetic findings have raised hopes that genetic testing could enhance diagnostics, disease surveillance, treatment selection, and family counseling. However, the accurate interpretation of genetic data remains a significant challenge, as variants may not always be definitively classified as either benign or pathogenic. Research to date, however, indicates that periodic reevaluation of genetic variants in diabetes has led to more consistent findings, with biases being steadily eliminated. This has improved the interpretation of variants across diverse ethnicities. Clinical studies suggest that genetic risk information may motivate patients to adopt behaviors that promote the prevention or management of T2DM. Given that the clinical features of certain monogenic diabetes types overlap with T2DM, and considering the significant role of genetic variants in diabetes, healthcare providers caring for prediabetic patients should consider genetic testing as part of the diagnostic process. This review summarizes current knowledge of the most common genetic variants associated with T2DM, explores novel therapeutic targets, and discusses recent advancements in the pharmaceutical management of uncontrolled T2DM.
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Affiliation(s)
- Shadi Bazzazzadehgan
- Department of Pharmacy Administration, School of Pharmacy, University of Mississippi, University, MS 38677, USA;
| | - Zia Shariat-Madar
- Division of Pharmacology, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA;
| | - Fakhri Mahdi
- Division of Pharmacology, School of Pharmacy, University of Mississippi, Oxford, MS 38677, USA;
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Yang YM, Ma HB, Xiong Y, Wu Q, Gao XK. PEX11B palmitoylation couples peroxisomal dysfunction with Schwann cells fail in diabetic neuropathy. J Biomed Sci 2025; 32:20. [PMID: 39934809 DOI: 10.1186/s12929-024-01115-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Accepted: 11/22/2024] [Indexed: 02/13/2025] Open
Abstract
BACKGROUND Diabetic neuropathy (DN) is a prevalent and painful complication of diabetes; however, the mechanisms underlying its pathogenesis remain unclear, and effective clinical treatments are lacking. This study aims to explore the role of peroxisomes in Schwann cells in DN. METHODS The abundance of peroxisomes in the sciatic nerves of mice or Schwann cells was analyzed using laser confocal super-resolution imaging and western blotting. The RFP-GFP-SKL (Ser-Lys-Leu) probe was utilized to assess pexophagy (peroxisomes autophagy) levels. To evaluate the palmitoylation of PEX11B, the acyl-resin assisted capture (acyl-RAC) assay and the Acyl-Biotin Exchange (ABE) assay were employed. Additionally, MR (Mendelian randomization) analysis was conducted to investigate the potential causal relationship between DN and MS (Multiple sclerosis). RESULTS There was a decrease in peroxisomal abundance in the sciatic nerves of diabetic mice, and palmitic acid (PA) induced a reduction in peroxisomal abundance by inhibiting peroxisomal biogenesis in Schwann cells. Mechanistically, PA induced the palmitoylation of PEX11B at C25 site, disrupting its self-interaction and impeding peroxisome elongation. Fenofibrate, a PPARα agonist, effectively rescued peroxisomal dysfunction caused by PA and restored the peroxisomal abundance in diabetic mice. Lastly, MR analysis indicates a notable causal influence of DN on MS, with its onset and progression intricately linked to peroxisomal dysfunction. CONCLUSIONS Targeting the peroxisomal biogenesis pathway may be an effective strategy for preventing and treating DN, underscoring the importance of addressing MS risk at the onset of DN.
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Affiliation(s)
- Yu Mei Yang
- Department of Endocrinology, Center for Metabolism Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Hang Bin Ma
- Department of Radiology, Center of Regenerative and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Yue Xiong
- Department of Endocrinology, Center for Metabolism Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China
| | - Qian Wu
- Department of Radiology, Center of Regenerative and Aging Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
| | - Xiu Kui Gao
- Department of Endocrinology, Center for Metabolism Medicine, the Fourth Affiliated Hospital of School of Medicine, and International School of Medicine, International Institutes of Medicine, Zhejiang University, Yiwu, 322000, China.
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Miyata R, Suzuki M, Okazaki Y, Abe D, Nakajima Y. Peroxisome Proliferator-Activated Receptor-Gamma Activation by an Active Compound in Lythrum anceps (Koehne) Makino. J Cell Biochem 2025; 126:e70009. [PMID: 39980354 DOI: 10.1002/jcb.70009] [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: 12/06/2024] [Revised: 02/04/2025] [Accepted: 02/07/2025] [Indexed: 02/22/2025]
Abstract
Lythrum anceps (Koehne) Makino (Japanese common name: "Misohagi") is an edible plant belonging to the Lythraceae family. It is mainly distributed in Asia, Northern Africa, and Europe. Plants of the genus Lythrum exhibit a broad range of biological activities including anti-inflammatory and antimicrobial activities. Because of this, the plants are used in traditional medicine to treat hemorrhage, infected wounds, and dysentery. The activation of peroxisome proliferator-activated receptor-gamma (PPARγ) is an effective target for improving insulin resistance and anti-inflammatory activity. However, PPARγ activation by the genus Lythrum remains unclear. Aiming to evaluate PPARγ activation by L. anceps, we generated a reporter cell line using an artificial chromosome vector that stably expresses dual-color beetle luciferases. Dual-color real-time bioluminescence monitoring revealed marked PPARγ activation in L. anceps extracts. Moreover, ellagic acid was identified as a PPARγ activator present in L. anceps by a bioassay-guided fractionation approach.
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Affiliation(s)
- Ryo Miyata
- Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Takamatsu, Kagawa, Japan
| | - Masanobu Suzuki
- Resources and Environment Division, Kochi Prefectural Industrial Technology Center, Kochi, Kochi, Japan
| | - Yuka Okazaki
- Resources and Environment Division, Kochi Prefectural Industrial Technology Center, Kochi, Kochi, Japan
| | - Daigo Abe
- Western Region Agricultural Research Center, National Agricultural and Food Research Organization (NARO), Zentsuji, Kagawa, Japan
| | - Yoshihiro Nakajima
- Health and Medical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST), Takamatsu, Kagawa, Japan
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Choi H, An S, Hyun YE, Noh M, Jeong LS. Design, synthesis and biological evaluation of truncated 1'-homologated 4'-selenonucleosides as PPARγ/δ dual modulators. Bioorg Chem 2025; 154:108042. [PMID: 39705933 DOI: 10.1016/j.bioorg.2024.108042] [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: 09/23/2024] [Revised: 11/22/2024] [Accepted: 12/04/2024] [Indexed: 12/23/2024]
Abstract
This study explores the synthesis and evaluation of truncated 1'-homologated 4'-selenonucleosides as dual modulators of PPARγ and PPARδ. Starting with d-lyxose, a 4'-selenosugar was synthesized and condensed with a nucleobase via an SN2 reaction, followed by modifications at the C2- and N6-positions, yielding compounds 3a-l. Structure-activity trend analysis identified compound 3h, featuring 2-chloro and N6-3-iodobenzylamine substituents, as a potent PPARγ partial agonist and PPARδ antagonist (PPARγ Ki = 2.8 μM, PPARδ Ki = 43 nM). This compound significantly enhanced adiponectin production and promoted adipogenic differentiation in hBM-MSCs. The 4'-seleno substitution preserved ligand functionality while enhancing binding affinity and pharmacological efficacy. In silico docking studies supported these binding affinities, demonstrating optimal binding poses for 3h at both PPARγ and PPARδ. These findings underscore the potential of 4'-selenonucleosides as therapeutic agents for metabolic disorders associated with hypoadiponectinemia, meriting further investigation and clinical development.
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Affiliation(s)
- Hongseok Choi
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Seungchan An
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Young Eum Hyun
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Minsoo Noh
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Lak Shin Jeong
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea; Future Medicine Co., Ltd, 54 Changup-ro, Sujeong-gu, Seongnam, Gyeonggi-do 13449, Republic of Korea.
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Diab F, Zbeeb H, Zeaiter L, Baldini F, Pagano A, Minicozzi V, Vergani L. Unraveling the metabolic activities of bioactive compounds on cellular models of hepatosteatosis and adipogenesis through docking analysis with PPARs. Sci Rep 2024; 14:28196. [PMID: 39548141 PMCID: PMC11568224 DOI: 10.1038/s41598-024-78374-7] [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: 07/07/2024] [Accepted: 10/30/2024] [Indexed: 11/17/2024] Open
Abstract
Obesity is associated with fatty liver disease. Available therapies show modest efficacy, and nutraceuticals with good effectiveness and safety are largely investigated. We focused on five natural compounds, three plant phenolic compounds (carvacrol, rosmarinic acid, silybin), and two thyroid hormones (T2: 3,5-diiodo-l-thyronine; T3: 3,5,3'-triiodo-L-thyronine) as comparison, to assess their beneficial effects on two cellular models of hepatosteatosis and adipogenesis. All compounds ameliorated the lipid accumulation and oxidative stress in both models, but with different potencies. The peroxisome proliferator-activated receptors (PPARs) are pivotal controllers of adipogenesis and lipid metabolism. For the main isoforms, PPARγ and PPARa, we assessed their possible binding to the compounds by molecular docking calculations, and their expression pattern by real-time PCR. All compounds bind both PPARs with different affinity, while not all compounds affect their expression. The results may clarify the distinctive molecular mechanisms underlying the action of the five compounds in the different cell models with possible applications to treat obesity.
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Affiliation(s)
- Farah Diab
- DISTAV, Department for the Earth, Environment and Life Sciences, University of Genova, Corso Europa 26, 16132, Genova, Italy
- DIMES, Department of Experimental Medicine, University of Genoa, Genova, Italy
| | - Hawraa Zbeeb
- DISTAV, Department for the Earth, Environment and Life Sciences, University of Genova, Corso Europa 26, 16132, Genova, Italy
| | - Lama Zeaiter
- DISTAV, Department for the Earth, Environment and Life Sciences, University of Genova, Corso Europa 26, 16132, Genova, Italy
- Istituto Italiano Tecnologia, Genova, Italy
| | | | - Aldo Pagano
- DIMES, Department of Experimental Medicine, University of Genoa, Genova, Italy
| | - Velia Minicozzi
- Department of Physics, University of Rome Tor Vergata and INFN - Section of Rome Tor Vergata, Rome, Italy
| | - Laura Vergani
- DISTAV, Department for the Earth, Environment and Life Sciences, University of Genova, Corso Europa 26, 16132, Genova, Italy.
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Masenga SK, Desta S, Hatcher M, Kirabo A, Lee DL. How PPAR-alpha mediated inflammation may affect the pathophysiology of chronic kidney disease. Curr Res Physiol 2024; 8:100133. [PMID: 39665027 PMCID: PMC11629568 DOI: 10.1016/j.crphys.2024.100133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 10/03/2024] [Accepted: 11/12/2024] [Indexed: 12/13/2024] Open
Abstract
Chronic kidney disease (CKD) is a major risk factor for death in adults. Inflammation plays a role in the pathogenesis of CKD, but the mechanisms are poorly understood. Peroxisome proliferator-activated receptor alpha (PPAR-α) is a nuclear receptor and one of the three members (PPARα, PPARβ/δ, and PPARγ) of the PPARs that plays an important role in ameliorating pathological processes that accelerate acute and chronic kidney disease. Although other PPARs members are well studied, the role of PPAR-α is not well described and its role in inflammation-mediated chronic disease is not clear. Herein, we review the role of PPAR-α in chronic kidney disease with implications for the immune system.
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Affiliation(s)
- Sepiso K. Masenga
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone Campus, Zambia
- Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Selam Desta
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, USA
| | - Mark Hatcher
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, USA
| | - Annet Kirabo
- Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Infection, Immunology, and Inflammation, Vanderbilt University Medical Center, Nashville, TN, USA
- Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Dexter L. Lee
- Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC, USA
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Lin HY, Lin CH, Kuo YH, Shih CC. Antidiabetic and Antihyperlipidemic Activities and Molecular Mechanisms of Phyllanthus emblica L. Extract in Mice on a High-Fat Diet. Curr Issues Mol Biol 2024; 46:10492-10529. [PMID: 39329975 PMCID: PMC11430370 DOI: 10.3390/cimb46090623] [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: 08/05/2024] [Revised: 09/09/2024] [Accepted: 09/11/2024] [Indexed: 09/28/2024] Open
Abstract
We planned to explore the protective activities of extract of Phyllanthus emblica L. (EPE) on insulin resistance and metabolic disorders including hyperlipidemia, visceral obesity, and renal dysfunction in high-fat diet (HFD)-progressed T2DM mice. Mice treatments included 7 weeks of HFD induction followed by EPE, fenofibrate (Feno), or metformin (Metf) treatment daily for another 4-week HFD in HFD-fed mice. Finally, we harvested blood to analyze some tests on circulating glycemia and blood lipid levels. Western blotting analysis was performed on target gene expressions in peripheral tissues. The present findings indicated that EPE treatment reversed the HFD-induced increases in blood glucose, glycosylated HbA1C, and insulin levels. Our findings proved that treatment with EPE in HFD mice effectively controls hyperglycemia and hyperinsulinemia. Our results showed that EPE reduced blood lipid levels, including a reduction in blood triglyceride (TG), total cholesterol (TC), and free fatty acid (FFA); moreover, EPE reduced blood leptin levels and enhanced adiponectin concentrations. EPE treatment in HFD mice reduced BUN and creatinine in both blood and urine and lowered albumin levels in urine; moreover, EPE decreased circulating concentrations of inflammatory NLR family pyrin domain containing 3 (NLRP3) and kidney injury molecule-1 (KIM-1). These results indicated that EPE displayed antihyperglycemic and antihyperlipidemic activities but alleviated renal dysfunction in HFD mice. The histology examinations indicated that EPE treatment decreased adipose hypertrophy and hepatic ballooning, thus contributing to amelioration of lipid accumulation. EPE treatment decreased visceral fat amounts and led to improved systemic insulin resistance. For target gene expression levels, EPE enhanced AMP-activated protein kinase (AMPK) phosphorylation expressions both in livers and skeletal muscles and elevated the muscular membrane glucose transporter 4 (GLUT4) expressions. Treatment with EPE reduced hepatic glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) expressions to suppress glucose production in the livers and decreased phosphorylation of glycogen synthase kinase 3β (GSK3β) expressions to affect hepatic glycogen synthesis, thus convergently contributing to an antidiabetic effect and improving insulin resistance. The mechanism of the antihyperlipidemic activity of EPE involved a decrease in the hepatic phosphorylation of mammalian target of rapamycin complex C1 (mTORC1) and p70 S6 kinase 1 (S6K1) expressions to improve insulin resistance but also a reduction in hepatic sterol regulatory element binding protein (SREBP)-1c expressions, and suppression of ACC activity, thus resulting in the decreased fatty acid synthesis but elevated hepatic peroxisome proliferator-activated receptor (PPAR) α and SREBP-2 expressions, resulting in lowering TG and TC concentrations. Our results demonstrated that EPE improves insulin resistance and ameliorates hyperlipidemia in HFD mice.
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Affiliation(s)
- Hsing-Yi Lin
- Department of Internal Medicine, Cheng Ching Hospital, No. 139, Pingdeng St., Central District, Taichung City 40045, Taiwan
| | - Cheng-Hsiu Lin
- Department of Internal Medicine, Fengyuan Hospital, Ministry of Health and Welfare, Fengyuan District, Taichung City 42055, Taiwan
| | - Yueh-Hsiung Kuo
- Department of Chinese Pharmaceutical Sciences and Chinese Medicine Resources, China Medical University, Taichung City 40402, Taiwan
| | - Chun-Ching Shih
- Department of Nursing, College of Nursing, Central Taiwan University of Science and Technology, No. 666 Buzih Road, Beitun District, Taichung City 40601, Taiwan
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Skoczyńska A, Ołdakowska M, Dobosz A, Adamiec R, Gritskevich S, Jonkisz A, Lebioda A, Adamiec-Mroczek J, Małodobra-Mazur M, Dobosz T. PPARs in Clinical Experimental Medicine after 35 Years of Worldwide Scientific Investigations and Medical Experiments. Biomolecules 2024; 14:786. [PMID: 39062500 PMCID: PMC11275227 DOI: 10.3390/biom14070786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2024] [Revised: 06/27/2024] [Accepted: 06/28/2024] [Indexed: 07/28/2024] Open
Abstract
This year marks the 35th anniversary of Professor Walter Wahli's discovery of the PPARs (Peroxisome Proliferator-Activated Receptors) family of nuclear hormone receptors. To mark the occasion, the editors of the scientific periodical Biomolecules decided to publish a special issue in his honor. This paper summarizes what is known about PPARs and shows how trends have changed and how research on PPARs has evolved. The article also highlights the importance of PPARs and what role they play in various diseases and ailments. The paper is in a mixed form; essentially it is a review article, but it has been enriched with the results of our experiments. The selection of works was subjective, as there are more than 200,000 publications in the PubMed database alone. First, all papers done on an animal model were discarded at the outset. What remained was still far too large to describe directly. Therefore, only papers that were outstanding, groundbreaking, or simply interesting were described and briefly commented on.
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Affiliation(s)
- Anna Skoczyńska
- Department of Internal and Occupational Medicine and Hypertension, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Monika Ołdakowska
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Agnieszka Dobosz
- Department of Basic Medical Sciences and Immunology, Division of Basic Medical Sciences, Wroclaw Medical University, Borowska 211, 50-556 Wrocław, Poland
| | - Rajmund Adamiec
- Department of Diabetology and Internal Medicine, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
- Department of Internal Medicine, Faculty of Medical and Technical Sciences, Karkonosze University of Applied Sciences, Lwówiecka 18, 58-506 Jelenia Góra, Poland
| | - Sofya Gritskevich
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Anna Jonkisz
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Arleta Lebioda
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Joanna Adamiec-Mroczek
- Department of Ophthalmology, Wroclaw Medical University, Borowska 213, 50-556 Wroclaw, Poland;
| | - Małgorzata Małodobra-Mazur
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
| | - Tadeusz Dobosz
- Department of Forensic Medicine, Division of Molecular Techniques, Wroclaw Medical University, M. Sklodowskiej-Curie 52, 50-369 Wroclaw, Poland; (M.O.); (A.J.); (A.L.); (M.M.-M.); (T.D.)
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Pasha R, Bashir B, Omed D, Adam S, Kamath A, Elhofy A, Ferdousi M, Azmi S, Soran H. Impact of Lipid-lowering Therapy on Cancer Risk: A Narrative Review. Clin Ther 2024; 46:411-419. [PMID: 38744540 DOI: 10.1016/j.clinthera.2024.03.004] [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: 11/13/2023] [Revised: 02/27/2024] [Accepted: 03/13/2024] [Indexed: 05/16/2024]
Abstract
PURPOSE There are inconsistent reports of an association between low cholesterol, use of lipid-lowering agents, and carcinogenesis. The purpose of this paper was to examine the relationship between cancer, lipids, statin use, and use of other lipid-lowering therapies. METHODS This comprehensive literature review incorporated article searches in electronic databases (Embase, PubMed, OVID) and reference lists of relevant articles, with the authors' expertise in lipidology. This review considered seminal and novel research looking at the relationship between cholesterol, lipid-lowering therapies, and cancer. FINDINGS Statin use has been reported to reduce the risk for incident cancer or progression of cancer; however, it is unknown whether this reduced risk of carcinogenesis is due to the pleotropic properties of statins or the effects of low cholesterol. The effect of ezetimibe on carcinogenesis has been regarded as neutral, despite earlier concerns of increased cancer risk with its use. Proprotein convertase subtilisin/kexin (PCSK)-9 monoclonal antibodies have been shown to have a neutral effect on carcinogenesis. Despite anti-cancer effects of fibrates in vitro, studies in humans have yielded inconsistent outcomes leaning toward protection against the development and progression of cancer. IMPLICATIONS Statins, fibrates, PCSK9 monoclonal antibodies, and ezetimibe have a neutral effect on cancer risk, and the first three may provide some protection. PSCK9 monoclonal antibodies have the potential to enhance the response to checkpoint inhibitor therapy for cancer. Further research is needed to determine which drugs can be issued in adjuvant therapy to improve outcomes in patients undergoing cancer treatment.
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Affiliation(s)
- Raabya Pasha
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; Manchester University NHS Foundation Trust, Manchester, United Kingdom; NIHR/Wellcome Trust Clinical Research Facility, Manchester, United Kingdom
| | - Bilal Bashir
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; Manchester University NHS Foundation Trust, Manchester, United Kingdom; NIHR/Wellcome Trust Clinical Research Facility, Manchester, United Kingdom
| | - Diya Omed
- Faculty of Medicine, University of Kurdistan, Erbil, Iraq
| | - Safwaan Adam
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; Department of Endocrinology, The Christie NHS Foundation Trust, Manchester, United Kingdom
| | - Anoushka Kamath
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom
| | - Ahmed Elhofy
- Manchester University NHS Foundation Trust, Manchester, United Kingdom
| | - Maryam Ferdousi
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; NIHR/Wellcome Trust Clinical Research Facility, Manchester, United Kingdom
| | - Shazli Azmi
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; Diabetes, Endocrinology and Metabolism Centre, Manchester University NHS Trust, Manchester, United Kingdom
| | - Handrean Soran
- Division of Cardiovascular Sciences, University of Manchester, Manchester, United Kingdom; NIHR/Wellcome Trust Clinical Research Facility, Manchester, United Kingdom; Diabetes, Endocrinology and Metabolism Centre, Manchester University NHS Trust, Manchester, United Kingdom.
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11
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Sinnathamby ES, Urban BT, Clark RA, Roberts LT, De Witt AJ, Wenger DM, Mouhaffel A, Willett O, Ahmadzadeh S, Shekoohi S, Kaye AD, Varrassi G. Etiology of Drug-Induced Edema: A Review of Dihydropyridine, Thiazolidinedione, and Other Medications Causing Edema. Cureus 2024; 16:e53400. [PMID: 38435190 PMCID: PMC10908346 DOI: 10.7759/cureus.53400] [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: 12/21/2023] [Accepted: 01/31/2024] [Indexed: 03/05/2024] Open
Abstract
Edema is an accumulation of fluid in the body's tissues that affects millions of Americans yearly. It can affect multiple body parts, for example, the brain or eyes, but often occurs in the periphery, including the feet and legs. Medications, such as dihydropyridine and thiazolidinediones (TZDs), can be the etiology of edema. Edema can develop in association with problems in the vasculature or lymphatic flow. In recent years, a better understanding of these drug-induced mechanisms has been appreciated. Specifically, dihydropyridines can increase hydrostatic pressure and cause selective pre-capillary vessel vasodilation. TZDs can cause edema through increased vascular permeability and increased hydrostatic pressure. Specifically, peroxisome proliferator-activated receptor gamma (PPARγ) stimulation increases vascular endothelial permeability, vascular endothelial growth factor (VEGF) secretion, renal sodium, and fluid retention. Other drugs that can cause edema include neuropathic pain agents, dopamine agonists, antipsychotics, nitrates, nonsteroidal anti-inflammatory (NSAIDS), steroids, angiotensin-converting enzyme (ACE) inhibitors, and insulin. There are various clinical presentations of edema. Since multiple mechanisms can induce edema, it is important to understand the basic mechanisms and pathophysiology of drug-induced edema. Edema can even become fatal. For example, angioedema can occur from ACE inhibitor therapy. In this regard, it is considered a medical emergency when there is laryngeal involvement. This review aims to thoroughly appreciate the multiple causes of drug-induced edema and the ways it can be treated or prevented.
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Affiliation(s)
- Evan S Sinnathamby
- School of Medicine, Louisiana State University Health Sciences Center (LSUHSC) New Orleans, New Orleans, USA
| | - Bretton T Urban
- School of Medicine, Louisiana State University Health Sciences Center (LSUHSC) New Orleans, New Orleans, USA
| | - Robert A Clark
- School of Medicine, Louisiana State University Health Sciences Center (LSUHSC) New Orleans, New Orleans, USA
| | - Logan T Roberts
- School of Medicine, Louisiana State University Health Sciences Center (LSUHSC) New Orleans, New Orleans, USA
| | - Audrey J De Witt
- School of Medicine, Louisiana State University (LSU) Health, Shreveport, USA
| | - Danielle M Wenger
- School of Medicine, The University of Arizona College of Medicine - Phoenix, Phoenix, USA
| | - Aya Mouhaffel
- Department of Anesthesiology, Louisiana State University (LSU) Health, Shreveport, USA
| | - Olga Willett
- Department of Anesthesiology, Louisiana State University (LSU) Health, Shreveport, USA
| | - Shahab Ahmadzadeh
- Department of Anesthesiology, Louisiana State University (LSU) Health, Shreveport, USA
| | - Sahar Shekoohi
- Department of Anesthesiology, Louisiana State University (LSU) Health, Shreveport, USA
| | - Alan D Kaye
- Department of Anesthesiology, Louisiana State University (LSU) Health, Shreveport, USA
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12
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Soileau LG, Nguyen A, Senthil A, Boullion JA, Talbot NC, Ahmadzadeh S, Shekoohi S, Kaye AD, Varrassi G. Bromocriptine and Colesevelam Hydrochloride: Novel Therapies for Type II Diabetes Mellitus. Cureus 2023; 15:e50138. [PMID: 38192911 PMCID: PMC10771968 DOI: 10.7759/cureus.50138] [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: 11/01/2023] [Accepted: 12/07/2023] [Indexed: 01/10/2024] Open
Abstract
The increasing prevalence of type II diabetes mellitus (T2DM) is a worldwide healthcare concern. Over the years, our understanding of T2DM has grown considerably in uncovering the pathophysiology of the disease and, in turn, understanding how improved treatment methods can be used to slow disease progression. Some long-term complications that are responsible for most T2DM mortalities include cardiovascular disease, neurological decline, and renal failure. In treating T2DM, it is important that not only glycemic control be obtained but also control of associated complications. Bromocriptine and colesevelam hydrochloride have both been approved by the Food and Drug Administration (FDA) to treat T2DM but are not readily used in practice. These medications are known to treat glycemic dysregulation via unconventional mechanisms, which might contribute to their potential to provide protection against common diabetic complications such as cardiovascular disease. In order to ensure that these overlooked medications become more readily used, it is vital that more research be performed to further elucidate their efficacy in a clinical setting. Future studies should continue to provide clinicians a better understanding of the role these medications have on the treatment of T2DM such as their ability to be used in combination with other commonly used T2DM medications or as monotherapies.
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Affiliation(s)
- Lenise G Soileau
- School of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Angela Nguyen
- School of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Aarthi Senthil
- School of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Jolie A Boullion
- School of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Norris C Talbot
- School of Medicine, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Shahab Ahmadzadeh
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Sahar Shekoohi
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Alan D Kaye
- Department of Anesthesiology, Louisiana State University Health Sciences Center, Shreveport, USA
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13
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Huang SM, Lin CH, Chang WF, Shih CC. Antidiabetic and antihyperlipidemic activities of Phyllanthus emblica L. extract in vitro and the regulation of Akt phosphorylation, gluconeogenesis, and peroxisome proliferator-activated receptor α in streptozotocin-induced diabetic mice. Food Nutr Res 2023; 67:9854. [PMID: 37850072 PMCID: PMC10578056 DOI: 10.29219/fnr.v67.9854] [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: 07/25/2023] [Revised: 09/05/2023] [Accepted: 09/15/2023] [Indexed: 10/19/2023] Open
Abstract
Background The fruits of Phyllanthus emblica L. are high in nutrients and have excellent health care function and developmental value. There are many management strategies available for diabetes and hyperlipidemia. Nevertheless, there is a lack of an effective and nontoxic drug. Objective The present study was designed to first screen four extracts of P. emblica L. on insulin signaling target gene expression levels, including glucose transporter 4 (GLUT4) and p-Akt/t-Akt. The ethyl acetate extract of P. emblica L. (EPE) exhibited the most efficient activity among the four extracts and was thus chosen to explore the antidiabetic and antihyperlipidemic activities in streptozotocin (STZ)-induced type 1 diabetic mice. Design All mice (in addition to one control (CON) group) were administered STZ injections (intraperitoneal) for 5 consecutive days, and then STZ-induced mice were administered EPE (at 100, 200, or 400 mg/kg body weight), fenofibrate (Feno) (at 250 mg/kg body weight), glibenclamide (Glib) (at 10 mg/kg body weight), or vehicle by oral gavage once daily for 4 weeks. Finally, histological examination, blood biochemical parameters, and target gene mRNA expression levels were measured, and liver tissue was analyzed for the levels of malondialdehyde (MDA), a maker of lipid peroxidation. Results EPE treatment resulted in decreased levels of blood glucose, HbA1C, triglycerides (TGs), and total cholesterol and increased levels of insulin compared with the vehicle-treated STZ group. EPE treatment decreased blood levels of HbA1C and MDA but increased glutathione levels in liver tissue, implying that EPE exerts antioxidant activity and could prevent oxidative stress and diabetes. The EPE-treated STZ mice displayed an improvement in the sizes and numbers of insulin-expressing β cells. EPE treatment increased the membrane expression levels of skeletal muscular GLUT4, and also reduced hepatic mRNA levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase thereby inhibiting hepatic gluconeogenesis. This resulted in a net glucose lowering effect in EPE-treated STZ mice. Furthermore, EPE increased the expression levels of p-AMPK/t-AMPK in both the skeletal muscle and liver tissue compared with vehicle-treated STZ mice. EPE-treated STZ mice showed enhanced expression levels of fatty acid oxidation enzymes, including peroxisome proliferator-activated receptor α (PPARα), but reduced expression levels of lipogenic genes including fatty acid synthase, as well as decreased mRNA levels of sterol regulatory element binding protein 1c (SREBP1c), apolipoprotein-CIII (apo-CIII), and diacylglycerol acyltransferase-2 (DGAT2). This resulted in a reduction in plasma TG levels. EPE-treated STZ mice also showed reduced expression levels of PPAR γ. This resulted in decreased adipogenesis, fatty acid synthesis, and lipid accumulation within liver tissue, and consequently, lower TG levels in liver tissue and blood. Furthermore, EPE treatment not only displayed an increase in the Akt activation in liver tissue, but also in C2C12 myotube in the absence of insulin. These results implied that EPE acts as an activator of AMPK and /or as a regulator of the insulin (Akt) pathway. Conclusions Taken together, EPE treatment exhibited amelioration of the diabetic and hyperlipidemic state in STZ-induced diabetic mice.
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Affiliation(s)
- Shin-Ming Huang
- Department of Gastroenterology, Jen-Ai Hospital, Dali Branch, Taichung City, Taiwan
| | - Cheng-Hsiu Lin
- Department of Internal Medicine, Fengyuan Hospital, Ministry of Health and Welfare, Taichung City, Taiwan
| | - Wen-Fang Chang
- Department of Cardiology, Jen-Ai Hospital, Taichung City, Taiwan
| | - Chun-Ching Shih
- Department of Nursing, College of Nursing, Central Taiwan University of Science and Technology, Taichung City, Taiwan
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Hong JH, Moon JS, Seong K, Lim S. Comparison of therapeutic efficacy and safety of sitagliptin, dapagliflozin, or lobeglitazone adjunct therapy in patients with type 2 diabetes mellitus inadequately controlled on sulfonylurea and metformin: Third agent study. Diabetes Res Clin Pract 2023; 203:110872. [PMID: 37574137 DOI: 10.1016/j.diabres.2023.110872] [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: 06/03/2023] [Revised: 08/07/2023] [Accepted: 08/10/2023] [Indexed: 08/15/2023]
Abstract
AIMS Compare the efficacy and safety of sitagliptin, dapagliflozin, and lobeglitazone in patients with uncontrolled type 2 diabetes, despite metformin and sulfonylurea therapy. METHODS The study randomized patients into three groups, receiving sitagliptin 100 mg, dapagliflozin 10 mg, or lobeglitazone 0.5 mg daily (n = 26 each) and monitored changes in biochemical parameters and body composition for 24 months. The primary efficacy endpoint was changes in HbA1c at 24 months. RESULTS The mean change in HbA1c in the sitagliptin, dapagliflozin, and lobeglitazone groups was -0.81 ± 0.21%, -1.05 ± 0.70%, and -1.08 ± 0.98%, after 24 months. Dapagliflozin treatment significantly lowered systolic blood pressure by 5.5 mmHg and alanine aminotransferase levels. Dapagliflozin and lobeglitazone treatment significantly reduced proteinuria and insulin resistance. Dapagliflozin decreased whole body fat percentage by 1.2%, whereas sitagliptin and lobeglitazone increased it by 1.1% and 1.8%, respectively. Whole body muscle percentage increased in the dapagliflozin group and decreased in the lobeglitazone group. The safety profiles of the three treatments were comparable. CONCLUSIONS All three drugs displayed good glucose-lowering efficacy and comparable safety profiles. However, dapagliflozin therapy produced favorable changes in body composition. Dapagliflozin may be a suitable adjunct therapy for patients with type 2 diabetes seeking to improve their body composition.
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Affiliation(s)
- Jun Hwa Hong
- Department of Internal Medicine, Daejeon Eulji Medical Center, Eulji University, Daejeon, Republic of Korea.
| | - Jun Sung Moon
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Republic of Korea.
| | - Kayeon Seong
- Department of Internal Medicine, Daejeon Eulji Medical Center, Eulji University, Daejeon, Republic of Korea.
| | - Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam, Republic of Korea.
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Menezes Junior ADS, Oliveira VMR, Oliveira IC, de Sousa AM, Santana AJP, Carvalho DPC, Paro Piai RF, Matos FH, de Paiva AM, Reis GBB. Dual PPRαϒ Agonists for the Management of Dyslipidemia: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Clin Med 2023; 12:5674. [PMID: 37685742 PMCID: PMC10488550 DOI: 10.3390/jcm12175674] [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: 08/14/2023] [Revised: 08/21/2023] [Accepted: 08/25/2023] [Indexed: 09/10/2023] Open
Abstract
Saroglitazar is a novel medication for dyslipidemia, but its specific effects remain unclear. Therefore, we performed a systematic review and meta-analysis to assess the efficacy and safety of saroglitazar for managing dyslipidemia. The PubMed, Scopus, and EMBASE databases were systematically searched for randomized controlled trials (RCTs) comparing 2 and 4 mg of saroglitazar with placebos for treating dyslipidemia. A random-effects model calculated the pooled mean differences for continuous outcomes with 95% confidence intervals. The study included seven RCTs involving 1975 patients. Overall, 340 (31.0%) and 513 (46.8%) participants received 2 and 4 mg of saroglitazar, respectively; 242 (22.11%) received the placebo. The mean ages ranged from 40.2 to 62.6 years, and 436 (39.8%) were women. Compared to the control group, 4 mg of saroglitazar significantly decreased the triglyceride and low-density lipoprotein (LDL) cholesterol levels but did not affect the high-density lipoprotein cholesterol level. Furthermore, the alanine aminotransferase level significantly decreased, the creatine level significantly increased, and body weight did not differ between the groups. Finally, 4 mg of saroglitazar, compared to 2 mg, significantly lowered the triglyceride level. Saroglitazar (4 mg) may be an effective treatment, but safety concerns remain.
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Affiliation(s)
- Antonio da Silva Menezes Junior
- Faculty of Medicine, Federal University of Goiás, Goiânia 74605020, Brazil; (V.M.R.O.); (I.C.O.); (A.M.d.S.); (A.J.P.S.); (D.P.C.C.); (R.F.P.P.); (F.H.M.); (A.M.d.P.); (G.B.B.R.)
- School of Medical and Life Sciences, Pontifical Catholic University of Goiás, Goiânia 74605050, Brazil
| | - Vinícius Martins Rodrigues Oliveira
- Faculty of Medicine, Federal University of Goiás, Goiânia 74605020, Brazil; (V.M.R.O.); (I.C.O.); (A.M.d.S.); (A.J.P.S.); (D.P.C.C.); (R.F.P.P.); (F.H.M.); (A.M.d.P.); (G.B.B.R.)
| | - Izadora Caiado Oliveira
- Faculty of Medicine, Federal University of Goiás, Goiânia 74605020, Brazil; (V.M.R.O.); (I.C.O.); (A.M.d.S.); (A.J.P.S.); (D.P.C.C.); (R.F.P.P.); (F.H.M.); (A.M.d.P.); (G.B.B.R.)
| | - André Maroccolo de Sousa
- Faculty of Medicine, Federal University of Goiás, Goiânia 74605020, Brazil; (V.M.R.O.); (I.C.O.); (A.M.d.S.); (A.J.P.S.); (D.P.C.C.); (R.F.P.P.); (F.H.M.); (A.M.d.P.); (G.B.B.R.)
| | - Ana Júlia Prego Santana
- Faculty of Medicine, Federal University of Goiás, Goiânia 74605020, Brazil; (V.M.R.O.); (I.C.O.); (A.M.d.S.); (A.J.P.S.); (D.P.C.C.); (R.F.P.P.); (F.H.M.); (A.M.d.P.); (G.B.B.R.)
| | - Davi Peixoto Craveiro Carvalho
- Faculty of Medicine, Federal University of Goiás, Goiânia 74605020, Brazil; (V.M.R.O.); (I.C.O.); (A.M.d.S.); (A.J.P.S.); (D.P.C.C.); (R.F.P.P.); (F.H.M.); (A.M.d.P.); (G.B.B.R.)
| | - Ricardo Figueiredo Paro Piai
- Faculty of Medicine, Federal University of Goiás, Goiânia 74605020, Brazil; (V.M.R.O.); (I.C.O.); (A.M.d.S.); (A.J.P.S.); (D.P.C.C.); (R.F.P.P.); (F.H.M.); (A.M.d.P.); (G.B.B.R.)
| | - Fernando Henrique Matos
- Faculty of Medicine, Federal University of Goiás, Goiânia 74605020, Brazil; (V.M.R.O.); (I.C.O.); (A.M.d.S.); (A.J.P.S.); (D.P.C.C.); (R.F.P.P.); (F.H.M.); (A.M.d.P.); (G.B.B.R.)
| | - Arthur Marot de Paiva
- Faculty of Medicine, Federal University of Goiás, Goiânia 74605020, Brazil; (V.M.R.O.); (I.C.O.); (A.M.d.S.); (A.J.P.S.); (D.P.C.C.); (R.F.P.P.); (F.H.M.); (A.M.d.P.); (G.B.B.R.)
| | - Gabriel Baêta Branquinho Reis
- Faculty of Medicine, Federal University of Goiás, Goiânia 74605020, Brazil; (V.M.R.O.); (I.C.O.); (A.M.d.S.); (A.J.P.S.); (D.P.C.C.); (R.F.P.P.); (F.H.M.); (A.M.d.P.); (G.B.B.R.)
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16
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Sheng W, Wang Q, Qin H, Cao S, Wei Y, Weng J, Yu F, Zeng H. Osteoarthritis: Role of Peroxisome Proliferator-Activated Receptors. Int J Mol Sci 2023; 24:13137. [PMID: 37685944 PMCID: PMC10487662 DOI: 10.3390/ijms241713137] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 08/04/2023] [Accepted: 08/15/2023] [Indexed: 09/10/2023] Open
Abstract
Osteoarthritis (OA) represents the foremost degenerative joint disease observed in a clinical context. The escalating issue of population aging significantly exacerbates the prevalence of OA, thereby imposing an immense annual economic burden on societies worldwide. The current therapeutic landscape falls short in offering reliable pharmaceutical interventions and efficient treatment methodologies to tackle this growing problem. However, the scientific community continues to dedicate significant efforts towards advancing OA treatment research. Contemporary studies have discovered that the progression of OA may be slowed through the strategic influence on peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated receptors within the nuclear hormone receptor family. The three distinctive subtypes-PPARα, PPARβ/δ, and PPARγ-find expression across a broad range of cellular terminals, thus managing a multitude of intracellular metabolic operations. The activation of PPARγ and PPARα has been shown to efficaciously modulate the NF-κB signaling pathway, AP-1, and other oxidative stress-responsive signaling conduits, leading to the inhibition of inflammatory responses. Furthermore, the activation of PPARγ and PPARα may confer protection to chondrocytes by exerting control over its autophagic behavior. In summation, both PPARγ and PPARα have emerged as promising potential targets for the development of effective OA treatments.
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Affiliation(s)
- Weibei Sheng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Qichang Wang
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Haotian Qin
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Siyang Cao
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Yihao Wei
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Jian Weng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Fei Yu
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
| | - Hui Zeng
- National & Local Joint Engineering Research Center of Orthopaedic Biomaterials, Peking University Shenzhen Hospital, Shenzhen 518036, China
- Department of Bone & Joint Surgery, Peking University Shenzhen Hospital, Shenzhen 518036, China
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Bandyopadhyay S, Samajdar SS, Das S. Effects of saroglitazar in the treatment of non-alcoholic fatty liver disease or non-alcoholic steatohepatitis: A systematic review and meta-analysis. Clin Res Hepatol Gastroenterol 2023; 47:102174. [PMID: 37380128 DOI: 10.1016/j.clinre.2023.102174] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2023] [Revised: 06/14/2023] [Accepted: 06/26/2023] [Indexed: 06/30/2023]
Abstract
AIM This systematic review and meta-analysis was conducted to evaluate the efficacy and safety of 4 mg saroglitazar treatment in patients with non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH). METHODS PubMed, Embase, Scopus, Cochrane CENTRAL, medRxiv (pre-print), bioRxiv (pre-print), and ClinicalTrials.gov databases were searched for relevant studies. The primary outcome was the change in the serum alanine transaminase (ALT) level. The secondary outcomes were changes in liver stiffness, liver function test parameters, and metabolic parameters. Pooled mean differences were calculated using random-effects models. RESULTS Of 331 studies that were screened, ten were included. Treatment with adjunct saroglitazar showed a reduction in ALT [mean difference: 26.01 U/L (95% CI: 10.67 to 41.35); p = 0.009; i2: 98%; moderate GRADE evidence] and aspartate transaminase [mean difference: 19.68 U/L (95% CI: 8.93 to 30.43); p<0.001; i2: 97%; moderate GRADE evidence] levels. There was a significant improvement in liver stiffness [mean difference: 2.22 kPa (95% CI: 0.80 to 3.63); p = 0.002; i2: 99%; moderate GRADE evidence]. There were significant improvements in glycated hemoglobin [mean difference: 0.59% (95% CI: 0.32 to 0.86); p<0.001; i2: 78%; moderate GRADE evidence], total cholesterol [mean difference: 19.20 (95% CI: 1.54 to 36.87); p = 0.03; i2: 95%; moderate GRADE evidence], and triglyceride [mean difference: 105.49 mg/dL (95% CI: 11.18 to 199.80); p = 0.03; i2: 100%; moderate GRADE evidence] levels. Saroglitazar treatment was safe. CONCLUSION Treatment with adjunct 4 mg saroglitazar could significantly improve liver enzymes, reduce liver stiffness, and improve metabolic parameters (serum glucose and lipid profile) in patients with NAFLD or NASH.
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Affiliation(s)
| | - Shambo Samrat Samajdar
- Department of Clinical and Experimental Pharmacology, Calcutta School of Tropical Medicine, Kolkata, India
| | - Saibal Das
- Indian Council of Medical Research - Centre for Ageing and Mental Health, Kolkata, India; Department of Global Public Health, Karolinska Institutet, Stockholm, Sweden
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18
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Souza-Tavares H, Miranda CS, Vasques-Monteiro IML, Sandoval C, Santana-Oliveira DA, Silva-Veiga FM, Fernandes-da-Silva A, Souza-Mello V. Peroxisome proliferator-activated receptors as targets to treat metabolic diseases: Focus on the adipose tissue, liver, and pancreas. World J Gastroenterol 2023; 29:4136-4155. [PMID: 37475842 PMCID: PMC10354577 DOI: 10.3748/wjg.v29.i26.4136] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2023] [Revised: 05/26/2023] [Accepted: 06/13/2023] [Indexed: 07/10/2023] Open
Abstract
The world is experiencing reflections of the intersection of two pandemics: Obesity and coronavirus disease 2019. The prevalence of obesity has tripled since 1975 worldwide, representing substantial public health costs due to its comorbidities. The adipose tissue is the initial site of obesity impairments. During excessive energy intake, it undergoes hyperplasia and hypertrophy until overt inflammation and insulin resistance turn adipocytes into dysfunctional cells that send lipotoxic signals to other organs. The pancreas is one of the organs most affected by obesity. Once lipotoxicity becomes chronic, there is an increase in insulin secretion by pancreatic beta cells, a surrogate for type 2 diabetes mellitus (T2DM). These alterations threaten the survival of the pancreatic islets, which tend to become dysfunctional, reaching exhaustion in the long term. As for the liver, lipotoxicity favors lipogenesis and impairs beta-oxidation, resulting in hepatic steatosis. This silent disease affects around 30% of the worldwide population and can evolve into end-stage liver disease. Although therapy for hepatic steatosis remains to be defined, peroxisome proliferator-activated receptors (PPARs) activation copes with T2DM management. Peroxisome PPARs are transcription factors found at the intersection of several metabolic pathways, leading to insulin resistance relief, improved thermogenesis, and expressive hepatic steatosis mitigation by increasing mitochondrial beta-oxidation. This review aimed to update the potential of PPAR agonists as targets to treat metabolic diseases, focusing on adipose tissue plasticity and hepatic and pancreatic remodeling.
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Affiliation(s)
| | | | | | - Cristian Sandoval
- Escuela de Tecnología Médica, Facultad de Salud, Universidad Santo Tomás, Osorno 5310431, Chile
- Departamento de Ciencias Preclínicas, Universidad de la Frontera, Temuco 4780000, Chile
| | | | | | | | - Vanessa Souza-Mello
- Department of Anatomy, Rio de Janeiro State University, Rio de Janeiro 20551030, Brazil
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19
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Niranjan S, Phillips BE, Giannoukakis N. Uncoupling hepatic insulin resistance - hepatic inflammation to improve insulin sensitivity and to prevent impaired metabolism-associated fatty liver disease in type 2 diabetes. Front Endocrinol (Lausanne) 2023; 14:1193373. [PMID: 37396181 PMCID: PMC10313404 DOI: 10.3389/fendo.2023.1193373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2023] [Accepted: 06/01/2023] [Indexed: 07/04/2023] Open
Abstract
Diabetes mellitus is a metabolic disease clinically-characterized as acute and chronic hyperglycemia. It is emerging as one of the common conditions associated with incident liver disease in the US. The mechanism by which diabetes drives liver disease has become an intense topic of discussion and a highly sought-after therapeutic target. Insulin resistance (IR) appears early in the progression of type 2 diabetes (T2D), particularly in obese individuals. One of the co-morbid conditions of obesity-associated diabetes that is on the rise globally is referred to as non-alcoholic fatty liver disease (NAFLD). IR is one of a number of known and suspected mechanism that underlie the progression of NAFLD which concurrently exhibits hepatic inflammation, particularly enriched in cells of the innate arm of the immune system. In this review we focus on the known mechanisms that are suspected to play a role in the cause-effect relationship between hepatic IR and hepatic inflammation and its role in the progression of T2D-associated NAFLD. Uncoupling hepatic IR/hepatic inflammation may break an intra-hepatic vicious cycle, facilitating the attenuation or prevention of NAFLD with a concurrent restoration of physiologic glycemic control. As part of this review, we therefore also assess the potential of a number of existing and emerging therapeutic interventions that can target both conditions simultaneously as treatment options to break this cycle.
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Affiliation(s)
- Sitara Niranjan
- Department of Internal Medicine, Allegheny Health Network, Pittsburgh, PA, United States
| | - Brett E. Phillips
- Department of Internal Medicine, Allegheny Health Network, Pittsburgh, PA, United States
| | - Nick Giannoukakis
- Department of Biological Sciences, Carnegie Mellon University, Pittsburgh, PA, United States
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20
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Zang L, Liu X, Xie X, Zhou X, Pan Y, Dai J. Exposure to per- and polyfluoroalkyl substances in early pregnancy, risk of gestational diabetes mellitus, potential pathways, and influencing factors in pregnant women: A nested case-control study. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2023; 326:121504. [PMID: 36965679 DOI: 10.1016/j.envpol.2023.121504] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/27/2023] [Accepted: 03/22/2023] [Indexed: 06/18/2023]
Abstract
Although previous studies have reported an association between maternal serum perfluoroalkyl substance (PFAS) exposure and gestational diabetes mellitus (GDM) risk, results have been inconsistent. Few studies have focused on the combined effects of emerging and legacy PFASs on glucose homeostasis while humans are always exposed to multiple PFASs simultaneously. Moreover, the potential pathways by which PFAS exposure induces GDM are unclear. A total of 295 GDM cases and 295 controls were enrolled from a prospective cohort of 2700 pregnant women in Shanghai, China. In total, 16 PFASs were determined in maternal spot serum samples in early pregnancy. We used conditional logistic regression, multiple linear regression, and Bayesian kernel machine regression (BKMR) to examine individual and joint effects of PFAS exposure on GDM risk and oral glucose tolerance test outcomes. The mediating effects of maternal serum biochemical parameters, including thyroid and liver function were further assessed. Maternal perfluorooctanoic acid (PFOA) exposure was associated with an increased risk of GDM (odds ratio (OR) = 1.68; 95% confidence interval (95% CI): 1.10, 2.57), consistent with higher concentrations in GDM cases than controls. Based on mediation analysis, an increase in the free triiodothyronine to free thyroxine ratio partially explained the effect of this association. For continuous glycemic outcomes, positive associations were observed between several PFASs and 1-h and 2-h glucose levels. In BKMR, PFAS mixture exposure showed a positive trend with GDM incidence, although the CIs were wide. These associations were more pronounced among women with normal pre-pregnancy body mass index (BMI). Mixed PFAS congeners may affect glucose homeostasis by increasing 1-h glucose levels, with perfluorononanoic acid found to be a main contributor. Exposure to PFASs was associated with increased risk of GDM and disturbance in glucose homeostasis, especially in normal weight women. The PFAS-associated disruption of maternal thyroid function may alter glucose homeostasis.
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Affiliation(s)
- Lu Zang
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China; University of Chinese Academy of Sciences, Beijing, 100049, China; State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, School of Environmental Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Xiaorui Liu
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Xianjing Xie
- The International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200030, China
| | - Xuming Zhou
- Key Laboratory of Animal Ecology and Conservation Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Yitao Pan
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, School of Environmental Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
| | - Jiayin Dai
- State Environmental Protection Key Laboratory of Environmental Health Impact Assessment of Emerging Contaminants, School of Environmental Science and Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
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21
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Pan D, Song Y, Liu S, Zeng X, Pang Q, Zhang Y, Wu H, Tan HJJ, Liao Q, Liang J, Huang D, Qiu X. Association between perfluoroalkyl and polyfluoroalkyl substances exposure and fetal overgrowth: A prospective birth cohort study conducted in China. ENVIRONMENTAL RESEARCH 2023:116175. [PMID: 37257750 DOI: 10.1016/j.envres.2023.116175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 05/07/2023] [Accepted: 05/15/2023] [Indexed: 06/02/2023]
Abstract
BACKGROUND Prenatal exposure to perfluoroalkyl and polyfluoroalkyl substances (PFASs) has been associated with gestational diabetes mellitus, obesity or overweight in childhood, but data on fetal overgrowth outcomes including macrosomia and large for gestational age (LGA) and among gestational age diverse infants remain scarce. OBJECTIVE To evaluate the association between maternal PFASs exposure and macrosomia and LGA, with exploration of the interaction between PFASs exposure and gestational age on fetal overgrowth. METHODS A total of 1441 mother-infants pairs from Guangxi Zhuang Birth Cohort of China were analyzed. Nine PFASs were measured in maternal serum using ultra-high liquid performance chromatographytandem mass spectrometry. Multivaraible logistical regression and generalized additive models were performed for individual PFAS exposures, piecewise regression analysis was used to estimate the breakpoint values for the non-linear dose-response relationships. Bayesian Kernel Machine Regression was performed for PFASs mixture. RESULTS In single pollutant models, maternal PFDA and PFOA exposure showed U-shaped relationship with macrosomia and LGA. When PFDA concentration exceeded 0.32 ng/mL was significantly positively associated with risks of LGA and macrosomia (OR=4.66, 95%CI: 1.26, 17.17; OR=14.43, 95%CI: 2.64, 79.02; respectively), while a negatively association was observed when level below 0.32 ng/mL. When PFOA concentration exceeded 1.20 ng/mL was significantly associated with increased risk of macrosomia (OR=7.75, 95%CI: 1.36, 44.06). In mixed exposure models, mixture of PFASs was positively associated with macrosomia, as well as associated with LGA when all the PFASs were at their 30th percentile or below. The maximum risk of LGA was reached when concentrations of PFUnA, PFDA, or PFBS were at the highest concentrations and the gestational age at the minimum of this study. CONCLUSIONS Maternal exposure to PFDA, PFOA and PFASs mixture were non-monotonically associated with macrosomia and LGA, the direction of the associations depends on the level of exposure.
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Affiliation(s)
- Dongxiang Pan
- Department of Epidemiology and Health Statistics, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Yanye Song
- The Third Affiliated Hospital of Guangxi Medical University, Nanning, 530031, Guangxi, China
| | - Shun Liu
- Department of Child and Adolescent Health & Maternal and Child Health, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Xiaoyun Zeng
- Department of Epidemiology and Health Statistics, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Qiang Pang
- Department of Cardiology, Debao Maternal and Child Health Hospital, Debao, 533700, Guangxi, China
| | - Yuanxiao Zhang
- Obstetrical Department, Pingguo Maternal and Child Health Hospital, Pingguo, 531400, Guangxi, China
| | - Huiping Wu
- Obstetrical Department, Jingxi People's Hospital, Jingxi, 533800, Guangxi, China
| | - Hui Juan Jennifer Tan
- Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore
| | - Qian Liao
- Department of Epidemiology and Health Statistics, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Jun Liang
- Department of Epidemiology and Health Statistics, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China
| | - Dongping Huang
- Department of Sanitary Chemistry, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
| | - Xiaoqiang Qiu
- Department of Epidemiology and Health Statistics, School of Public Health, Guangxi Medical University, Nanning, 530021, Guangxi, China.
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22
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Lin WR, Liu KH, Ling TC, Wang MC, Lin WH. Role of antidiabetic agents in type 2 diabetes patients with chronic kidney disease. World J Diabetes 2023; 14:352-363. [PMID: 37122432 PMCID: PMC10130897 DOI: 10.4239/wjd.v14.i4.352] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2022] [Revised: 01/10/2023] [Accepted: 04/04/2023] [Indexed: 04/12/2023] Open
Abstract
Insulin resistance is a condition in which the target tissues have a decreased response to insulin signaling, resulting in glucose uptake defect, and an increased blood sugar level. Pancreatic beta cells thus enhance insulin production to compensate. This situation may cause further beta cell dysfunction and failure, which can lead diabetes mellitus (DM). Insulin resistance is thus an important cause of the development of type 2 DM. Insulin resistance has also been found to have a strong relationship with cardiovascular disease and is common in chronic kidney disease (CKD) patients. The mechanisms of insulin resistance in CKD are complex and multifactorial. They include physical inactivity, inflammation and oxidative stress, metabolic acidosis, vitamin D deficiency, adipose tissue dysfunction, uremic toxins, and renin-angiotensin-aldosterone system activation. Currently, available anti-diabetic agents, such as biguanides, sulfonylureas, thiazolidinediones, alfa-glucosidase inhibitors, glucagon-like peptide-1-based agents, and sodium-glucose co-transporter-2 inhibitors, have different effects on insulin resistance. In this short review, we describe the potential mechanisms of insulin resistance in CKD patients. We also review the interaction of currently available anti-diabetic medications with insulin resistance.
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Affiliation(s)
- Wei-Ren Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Kuan-Hung Liu
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Tsai-Chieh Ling
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Ming-Cheng Wang
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
| | - Wei-Hung Lin
- Division of Nephrology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 704, Taiwan
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23
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Tao L, Dryden P, Lowe A, Wang G, Achuthkumar A, Chang T, Reese TA. WY14643 Increases Herpesvirus Replication and Inhibits IFNβ Production Independently of PPARα Expression. Microbiol Spectr 2023; 11:e0233722. [PMID: 36715509 PMCID: PMC10100363 DOI: 10.1128/spectrum.02337-22] [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: 06/28/2022] [Accepted: 01/06/2023] [Indexed: 01/31/2023] Open
Abstract
Peroxisome proliferator activated receptor (PPAR) agonists are commonly used to treat metabolic disorders in humans because they regulate fatty acid oxidation and cholesterol metabolism. In addition to their roles in controlling metabolism, PPAR agonists also regulate inflammation and are immunosuppressive in models of autoimmunity. We aimed to test whether activation of PPARα with clinically relevant ligands could impact gammaherpesvirus infection using murine gammaherpesvirus-68 (MHV68, MuHV-4). We found that PPAR agonists WY14643 and fenofibrate increased herpesvirus replication in vitro. In vivo, WY14643 increased viral replication and caused lethality in mice. Unexpectedly, these effects proved independent of PPARα. We found that WY14643 suppressed production of type I interferon after MHV68 infection in vitro and in vivo. Taken together, our data indicate that caution should be employed when using PPARα agonists in immuno-metabolic studies, as they can have off-target effects on viral replication through the inhibition of type I interferon production. IMPORTANCE PPAR agonists are used clinically to treat both metabolic and inflammatory disorders. Because viruses are known to rewire host metabolism to their own benefit, the intersection of immunity, metabolism, and virology is an important research area. Our article is an important contribution to this field for two reasons. First, it shows a role for PPARα agonists in altering virus replication. Second, it shows that PPARα agonists can affect virus replication in a manner independent of their predicted target. This knowledge is valuable for anyone seeking to use PPARα agonists as a research tool.
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Affiliation(s)
- Lili Tao
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Phillip Dryden
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Alexandria Lowe
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Guoxun Wang
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Amritha Achuthkumar
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Tyron Chang
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Tiffany A. Reese
- Department of Immunology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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24
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Malik J, Ahmed S, Momin SS, Shaikh S, Alafnan A, Alanazi J, Said Almermesh MH, Anwar S. Drug Repurposing: A New Hope in Drug Discovery for Prostate Cancer. ACS OMEGA 2023; 8:56-73. [PMID: 36643505 PMCID: PMC9835086 DOI: 10.1021/acsomega.2c05821] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Accepted: 11/24/2022] [Indexed: 06/12/2023]
Abstract
Prostate cancer (PCA), the most common cancer in men, accounted for 1.3 million new incidences in 2018. An increase in incidences is an issue of concern that should be addressed. Of all the reported prostate cancers, 85% were detected in stages III and IV, making them difficult to treat. Conventional drugs gradually lose their efficacy due to the developed resistance against them, thus requiring newer therapeutic agents to be used as monotherapy or combination. Recent research regarding treatment options has attained remarkable speed and development. Therefore, in this context, drug repurposing comes into the picture, which is defined as the "investigation of the off-patent, approved and marketed drugs for a novel therapeutic indication" which saves at least 30% of the time and cost, reducing the cost of treatment for patients, which usually runs high in cancer patients. The anticancer property of cardiac glycosides in cancers was tested in the early 1980s. The trend then shifts toward treating prostate cancer by repurposing other cardiovascular drugs. The current review mainly emphasizes the advantageous antiprostate cancer profile of conventional CVS drugs like cardiac glycosides, RAAS inhibitors, statins, heparin, and beta-blockers with underlying mechanisms.
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Affiliation(s)
- Jonaid
Ahmad Malik
- Department
of Pharmacology and Toxicology, National
Institute of Pharmaceutical Education and Research, Guwahati 781003, India
- Biomedical
Engineering, Indian Institute of Technology
(IIT), Ropar, Punjab 140001, India
| | - Sakeel Ahmed
- Department
of Pharmacology and Toxicology, National
Institute of Pharmaceutical Education and Research, Ahmedabad, Gujarat 382355, India
| | - Sadiya Sikandar Momin
- Department
of Pharmaceutics, Annasaheb Dange College of B. Pharmacy, Ashta, Shivaji University, Sangli, Maharastra 416301, India
| | - Sijal Shaikh
- Sandip Institute
of Pharmaceutical Sciences, Savitribai Phule
Pune University, Nashik, Maharashtra 422213, India
| | - Ahmed Alafnan
- Department
of Pharmacology and Toxicology, University
of Hail, Hail 81422, Saudi Arabia
| | - Jowaher Alanazi
- Department
of Pharmacology and Toxicology, University
of Hail, Hail 81422, Saudi Arabia
| | | | - Sirajudheen Anwar
- Department
of Pharmacology and Toxicology, University
of Hail, Hail 81422, Saudi Arabia
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25
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Zivko C, Witt F, Koeberle A, Fuhrmann G, Luciani P. Formulating elafibranor and obeticholic acid with phospholipids decreases drug-induced association of SPARC to extracellular vesicles from LX-2 human hepatic stellate cells. Eur J Pharm Biopharm 2023; 182:32-40. [PMID: 36470521 DOI: 10.1016/j.ejpb.2022.11.025] [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: 07/26/2022] [Revised: 11/17/2022] [Accepted: 11/29/2022] [Indexed: 12/03/2022]
Abstract
Chronic hepatic diseases often compromise liver function and are directly responsible for up to two million yearly deaths world-wide. There are yet no treatment options to solve this global medical need. Experimental drugs elafibranor (Ela) and obeticholic acid (OA) appeared promising in numerous earlier studies, but they recently struggled to show significant benefits in patients. Little is known on the drugs' impact on hepatic stellate cells (HSCs), key players in liver fibrogenesis. We recently reported a beneficial effect of polyenylphosphatidylcholines (PPCs)-rich formulations in reverting fibrogenic features of HSCs, including differences in their extracellular vesicles (EVs). Here, we newly formulated Ela and OA in PPC liposomes and evaluated their performance on the LX-2 (human HSC) cell line through our rigorous methods of EV-analysis, now expanded to include lipidomics. We show that direct treatments with Ela and OA increase EV-associated secreted protein acidic and cysteine rich (SPARC), a matricellular protein overexpressed in fibrogenesis. However, our results suggest that this potentially damaging drugs' action to HSCs could be mitigated when delivering them with lipid-based formulations, most notably with a PPC-rich phospholipid inducing specific changes in the cellular and EV phospholipid composition. Thus, EV analysis substantially deepens evaluations of drug performances and delivery strategies.
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Affiliation(s)
- Cristina Zivko
- Institute of Pharmacy, Friedrich Schiller University of Jena, Jena, Germany; Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland
| | - Finja Witt
- Michael Popp Institute, University of Innsbruck, Innsbruck, Austria
| | - Andreas Koeberle
- Michael Popp Institute, University of Innsbruck, Innsbruck, Austria
| | - Gregor Fuhrmann
- Helmholtz Institute for Pharmaceutical Research Saarland, Department of Pharmacy, Saarland University, Saarbrücken, Germany; Department of Biology, Friedrich-Alexander-University Erlangen, Erlangen, Germany.
| | - Paola Luciani
- Institute of Pharmacy, Friedrich Schiller University of Jena, Jena, Germany; Department of Chemistry, Biochemistry and Pharmaceutical Sciences, University of Bern, Bern, Switzerland.
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26
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Durga DR, Mounika N, Mudimala P, Adela R. Efficacy and Safety of Saroglitazar in Patients with Cardiometabolic Diseases: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. Clin Drug Investig 2022; 42:1049-1064. [PMID: 36329293 DOI: 10.1007/s40261-022-01219-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/19/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND AND OBJECTIVE The incidence of cardiometabolic diseases is increasing because of an increase in the standard of living. Currently, clinical treatment strategies for cardiometabolic diseases mainly focus on maintaining glycemic and lipid profiles. The objective of this systematic review and meta-analysis was to evaluate the efficacy and safety of saroglitazar in patients with metabolic disease and provide evidence for clinical decision making. METHODS We searched electronic databases (PubMed, Cochrane Central Register of Controlled Trials [CENTRAL], and Google Scholar) for randomized controlled trials that examined saroglitazar for the treatment of patients with cardiometabolic disease. A total of seven randomized controlled trials were included for the qualitative and quantitative synthesis. Mean difference (MD) and risk ratio with a 95% confidence interval (CI) were applied for continuous and dichotomous data, respectively. RESULTS The overall effect of saroglitazar showed significant changes in triglycerides, total cholesterol, low-density lipoprotein, non-high-density lipoprotein, high-density lipoprotein, very low-density lipoprotein, alkaline phosphatase, and gamma-glutamyl transferase levels [MD: - 40.50; 95% CI - 58.09 to - 22.92; p < 0.00001; I2 = 78%], [MD: - 7.49; 95% CI - 11.33 to - 3.65; p = 0.0001; I2 = 41%], [MD: - 3.53; 95% CI - 6.91 to - 0.15; p = 0.04; I2 = 19%], [MD: - 8.08; 95% CI - 15.63 to - 0.54; p = 0.04; I2 = 58%], [MD: 2.04; 95% CI 0.17 to 3.92; p = 0.03; I2 = 69%], [MD: - 6.10; 95% CI - 9.40 to - 2.80; p = 0.0003; I2 = 65%], [MD: - 5.89; 95% CI - 7.50 to - 4.28; p < 0.00001; I2 = 98%], and [MD: - 1.64; 95% CI - 2.83 to - 0.45; p = 0.007; I2 = 95%], respectively. A subgroup analysis showed favorable outcomes with sarogiltazar 4 mg. There was a statistically non-significant reduced risk of adverse event occurrence in the saroglitazar treatment group. CONCLUSIONS Our study results conclude that the overall effect of saroglitazar was beneficial only in terms of lipid profiles and liver function parameters, whereas saroglitazar 4 mg showed a better therapeutic role in maintaining lipid and glycemic parameters in patients with cardiometabolic disease.
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Affiliation(s)
- Devarapalli Ranjani Durga
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research-Guwahati, Sila Katamur (Halugurisuk), Changsari, Kamrup District, Guwahati, Assam, 781101, India
| | - Nadella Mounika
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research-Guwahati, Sila Katamur (Halugurisuk), Changsari, Kamrup District, Guwahati, Assam, 781101, India
| | - Pravallika Mudimala
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research-Guwahati, Sila Katamur (Halugurisuk), Changsari, Kamrup District, Guwahati, Assam, 781101, India
| | - Ramu Adela
- Department of Pharmacy Practice, National Institute of Pharmaceutical Education and Research-Guwahati, Sila Katamur (Halugurisuk), Changsari, Kamrup District, Guwahati, Assam, 781101, India.
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27
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Gan AM, Tracz-Gaszewska Z, Ellert-Miklaszewska A, Navrulin VO, Ntambi JM, Dobrzyn P. Stearoyl-CoA Desaturase Regulates Angiogenesis and Energy Metabolism in Ischemic Cardiomyocytes. Int J Mol Sci 2022; 23:ijms231810459. [PMID: 36142371 PMCID: PMC9499489 DOI: 10.3390/ijms231810459] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Revised: 09/05/2022] [Accepted: 09/07/2022] [Indexed: 11/21/2022] Open
Abstract
New blood vessel formation is a key component of the cardiac repair process after myocardial infarction (MI). Hypoxia following MI is a major driver of angiogenesis in the myocardium. Hypoxia-inducible factor 1α (HIF1α) is the key regulator of proangiogenic signaling. The present study found that stearoyl-CoA desaturase (SCD) significantly contributed to the induction of angiogenesis in the hypoxic myocardium independently of HIF1α expression. The pharmacological inhibition of SCD activity in HL-1 cardiomyocytes and SCD knockout in an animal model disturbed the expression and secretion of proangiogenic factors including vascular endothelial growth factor-A, proinflammatory cytokines (interleukin-1β, interleukin-6, tumor necrosis factor α, monocyte chemoattractant protein-1, and Rantes), metalloproteinase-9, and platelet-derived growth factor in ischemic cardiomyocytes. These disturbances affected the proangiogenic potential of ischemic cardiomyocytes after SCD depletion. Together with the most abundant SCD1 isoform, the heart-specific SCD4 isoform emerged as an important regulator of new blood vessel formation in the murine post-MI myocardium. We also provide evidence that SCD shapes energy metabolism of the ischemic heart by maintaining the shift from fatty acids to glucose as the substrate that is used for adenosine triphosphate production. Furthermore, we propose that the regulation of the proangiogenic properties of hypoxic cardiomyocytes by key modulators of metabolic signaling such as adenosine monophosphate kinase, protein kinase B (AKT), and peroxisome-proliferator-activated receptor-γ coactivator 1α/peroxisome proliferator-activated receptor α depends on SCD to some extent. Thus, our results reveal a novel mechanism that links SCD to cardiac repair processes after MI.
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Affiliation(s)
- Ana-Maria Gan
- Laboratory of Molecular Medical Biochemistry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland
| | - Zuzanna Tracz-Gaszewska
- Laboratory of Molecular Medical Biochemistry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland
| | - Aleksandra Ellert-Miklaszewska
- Laboratory of Molecular Neurobiology, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland
| | - Viktor O. Navrulin
- Laboratory of Molecular Medical Biochemistry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland
| | - James M. Ntambi
- Departments of Biochemistry and Nutritional Sciences, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Pawel Dobrzyn
- Laboratory of Molecular Medical Biochemistry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, 02-093 Warsaw, Poland
- Correspondence:
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28
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Oh E, Kang JH, Jo KW, Shin WS, Jeong YH, Kang B, Rho TY, Jeon SY, Lee J, Song IS, Kim KT. Synthetic PPAR Agonist DTMB Alleviates Alzheimer's Disease Pathology by Inhibition of Chronic Microglial Inflammation in 5xFAD Mice. Neurotherapeutics 2022; 19:1546-1565. [PMID: 35917087 PMCID: PMC9606171 DOI: 10.1007/s13311-022-01275-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/06/2022] [Indexed: 12/05/2022] Open
Abstract
Abnormal productions of amyloid beta (Aβ) plaque and chronic neuroinflammation are commonly observed in the brain of patients with Alzheimer's disease, and both of which induce neuronal cell death, loss of memory, and cognitive dysfunction. However, many of the drugs targeting the production of Aβ peptides have been unsuccessful in treating Alzheimer's disease. In this study, we identified synthetic novel peroxisome proliferator-activating receptor (PPAR) agonist, DTMB, which can ameliorate the chronic inflammation and Aβ pathological progression of Alzheimer's disease. We discovered that DTMB attenuated the proinflammatory cytokine production of microglia by reducing the protein level of NF-κB. DTMB also improved the learning and memory defects and reduced the amount of Aβ plaque in the brain of 5xFAD mice. This reduction in Aβ pathology was attributed to the changes in gliosis and chronic inflammation level. Additionally, bulk RNA-sequencing showed that genes related to inflammation and cognitive function were changed in the hippocampus and cortex of DTMB-treated mice. Our findings demonstrate that DTMB has the potential to be a novel therapeutic agent for Alzheimer's disease.
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Affiliation(s)
- Eunji Oh
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Nam-gu, Pohang, 790-784 Republic of Korea
| | - Jeong-Hwa Kang
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Nam-gu, Pohang, 790-784 Republic of Korea
| | - Kyung Won Jo
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Nam-gu, Pohang, 790-784 Republic of Korea
| | - Won-Sik Shin
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Nam-gu, Pohang, 790-784 Republic of Korea
| | - Young-Hun Jeong
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Nam-gu, Pohang, 790-784 Republic of Korea
| | - Byunghee Kang
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Nam-gu, Pohang, 790-784 Republic of Korea
| | - Tae-Young Rho
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Nam-gu, Pohang, 790-784 Republic of Korea
| | - So Yeon Jeon
- College of Pharmacy, Dankook University, Cheonan, 31116 Republic of Korea
| | - Jihoon Lee
- College of Pharmacy, Kyungpook National University, Daegu, 41566 Republic of Korea
| | - Im-Sook Song
- College of Pharmacy, Kyungpook National University, Daegu, 41566 Republic of Korea
| | - Kyong-Tai Kim
- Department of Life Sciences, Pohang University of Science and Technology (POSTECH), 77 Cheongam-Ro, Nam-gu, Pohang, 790-784 Republic of Korea
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García-Ortegón M, Simm GNC, Tripp AJ, Hernández-Lobato JM, Bender A, Bacallado S. DOCKSTRING: Easy Molecular Docking Yields Better Benchmarks for Ligand Design. J Chem Inf Model 2022; 62:3486-3502. [PMID: 35849793 PMCID: PMC9364321 DOI: 10.1021/acs.jcim.1c01334] [Citation(s) in RCA: 33] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Indexed: 01/05/2023]
Abstract
The field of machine learning for drug discovery is witnessing an explosion of novel methods. These methods are often benchmarked on simple physicochemical properties such as solubility or general druglikeness, which can be readily computed. However, these properties are poor representatives of objective functions in drug design, mainly because they do not depend on the candidate compound's interaction with the target. By contrast, molecular docking is a widely applied method in drug discovery to estimate binding affinities. However, docking studies require a significant amount of domain knowledge to set up correctly, which hampers adoption. Here, we present dockstring, a bundle for meaningful and robust comparison of ML models using docking scores. dockstring consists of three components: (1) an open-source Python package for straightforward computation of docking scores, (2) an extensive dataset of docking scores and poses of more than 260,000 molecules for 58 medically relevant targets, and (3) a set of pharmaceutically relevant benchmark tasks such as virtual screening or de novo design of selective kinase inhibitors. The Python package implements a robust ligand and target preparation protocol that allows nonexperts to obtain meaningful docking scores. Our dataset is the first to include docking poses, as well as the first of its size that is a full matrix, thus facilitating experiments in multiobjective optimization and transfer learning. Overall, our results indicate that docking scores are a more realistic evaluation objective than simple physicochemical properties, yielding benchmark tasks that are more challenging and more closely related to real problems in drug discovery.
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Affiliation(s)
- Miguel García-Ortegón
- Statistical
Laboratory, Centre for Mathematical Sciences, University of Cambridge, Wilberforce Rd., Cambridge CB3 0WB, United Kingdom
| | - Gregor N. C. Simm
- Department
of Engineering, University of Cambridge, Trumpington St., Cambridge CB2 1PZ, United Kingdom
| | - Austin J. Tripp
- Department
of Engineering, University of Cambridge, Trumpington St., Cambridge CB2 1PZ, United Kingdom
| | | | - Andreas Bender
- Yusuf
Hamied Department of Chemistry, University
of Cambridge, Lensfield
Rd., Cambridge CB2 1EW, United Kingdom
| | - Sergio Bacallado
- Statistical
Laboratory, Centre for Mathematical Sciences, University of Cambridge, Wilberforce Rd., Cambridge CB3 0WB, United Kingdom
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30
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Ying Q, Ronca A, Chan DC, Pang J, Favari E, Watts GF. Effect of a PCSK9 inhibitor and a statin on cholesterol efflux capacity: A limitation of current cholesterol-lowering treatments? Eur J Clin Invest 2022; 52:e13766. [PMID: 35294778 PMCID: PMC9541635 DOI: 10.1111/eci.13766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Accepted: 03/06/2022] [Indexed: 11/30/2022]
Abstract
BACKGROUND Cellular cholesterol efflux is a key step in reverse cholesterol transport that may impact on atherosclerotic cardiovascular risk. The process may be reliant on the availability of apolipoprotein (apo) B-100-containing lipoproteins to accept cholesterol from high-density lipoprotein. Evolocumab and atorvastatin are known to lower plasma apoB-100-containing lipoproteins that could impact on cholesterol efflux capacity (CEC). METHODS We conducted a 2-by-2 factorial trial of the effects of subcutaneous evolocumab (420 mg every 2 weeks) and atorvastatin (80 mg daily) for 8 weeks on CEC in 81 healthy, normolipidaemic men. The capacity of whole plasma and apoB-depleted plasma, including ATP-binding cassette transporter A1 (ABCA1)-mediated and passive diffusion, to efflux cholesterol, was measured. RESULTS Evolocumab and atorvastatin independently decreased whole plasma CEC (main effect p < .01 for both). However, there were no significant effects of evolocumab and atorvastatin on apoB-depleted plasma, ABCA1-mediated and passive diffusion-mediated CEC (p > .05 in all). In the three intervention groups combined, the reduction in whole plasma CEC was significantly correlated with the corresponding reduction in plasma apoB-100 concentration (r = .339, p < .01). In the evolocumab monotherapy group, the reduction in whole plasma CEC was also significantly correlated with the corresponding reduction in plasma lipoprotein(a) concentration (r = .487, p < .05). CONCLUSIONS In normolipidaemic men, evolocumab and atorvastatin decrease the capacity of whole plasma to efflux cellular cholesterol. These effects may be chiefly owing to a fall in the availability of apoB-100-containing lipoproteins. Reduction in circulating lipoprotein(a) may also contribute to the decrease in whole plasma cholesterol efflux with evolocumab monotherapy.
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Affiliation(s)
- Qidi Ying
- Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia
| | - Annalisa Ronca
- Department of Food and Drug, University of Parma, Parma, Italy
| | - Dick C Chan
- Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia
| | - Jing Pang
- Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia
| | - Elda Favari
- Department of Food and Drug, University of Parma, Parma, Italy
| | - Gerald F Watts
- Medical School, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia.,Lipid Disorders Clinic, Department of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, Western Australia, Australia
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31
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Chen X, Zhao H, Meng F, Zhou L, Pang X, Lu Z, Lu Y. Ameliorated effects of a lipopeptide surfactin on insulin resistance in vitro and in vivo. Food Sci Nutr 2022; 10:2455-2469. [PMID: 35844917 PMCID: PMC9281957 DOI: 10.1002/fsn3.2852] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 02/24/2022] [Accepted: 03/15/2022] [Indexed: 01/21/2023] Open
Abstract
Surfactin, produced by Bacillus amyloliquefaciens fmb50, was used to treat insulin-resistant (IR) hepatocyte. It was found that surfactin increased glucose consumption in insulin-resistant HepG2 (IR-HepG2) cells and ameliorated IR by increasing glucose transporter 4 (GLUT4) protein expression and AMP-activated protein kinase (AMPK) mRNA expression, promoting GLUT4 translocation and activating phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) in IR-HepG2 cells. Meanwhile, surfactin downregulated protein expression of phosphoenolpyruvate carboxy kinase (PEPCK) and glucose-6-phosphatase (G6Pase), further inhibiting hepatic gluconeogenesis. In addition, surfactin played important roles in eliminating reactive oxygen species (ROS), improving mitochondrial dysfunction, and inhibiting proinflammatory mediators. We observed that surfactin promoted glucose consumption, meanwhile increased translocation and protein expression of GLUT4 in Caco-2 cells. These results confirmed the conclusion in hepatic cells. Furthermore, surfactin supplement decreased body weight, food intake, and fasting blood glucose of type 2 diabetes mellitus (T2DM) mice induced by streptozotocin (STZ)/high-fat diet (HFD). Our data indicated that surfactin ameliorated insulin resistance and lowered blood glucose in intro and in vivo.
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Affiliation(s)
- Xiaoyu Chen
- College of Food Science and TechnologyNanjing Agricultural UniversityNanjingJiangsu ProvinceChina
| | - Hongyuan Zhao
- College of Food Science and TechnologyNanjing Agricultural UniversityNanjingJiangsu ProvinceChina
| | - Fanqiang Meng
- College of Food Science and TechnologyNanjing Agricultural UniversityNanjingJiangsu ProvinceChina
| | - Libang Zhou
- College of Food Science and TechnologyNanjing Agricultural UniversityNanjingJiangsu ProvinceChina
| | - Xinyi Pang
- College of Food Science and EngineeringNanjing University of Finance and EconomicsNanjingJiangsu ProvinceChina
| | - Zhaoxin Lu
- College of Food Science and TechnologyNanjing Agricultural UniversityNanjingJiangsu ProvinceChina
| | - Yingjian Lu
- College of Food Science and EngineeringNanjing University of Finance and EconomicsNanjingJiangsu ProvinceChina
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32
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Aging-related changes in metabolic indicators in female rats and their management with Tinospora cordifolia. Biogerontology 2022; 23:363-380. [PMID: 35488997 DOI: 10.1007/s10522-022-09962-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2022] [Accepted: 04/12/2022] [Indexed: 12/24/2022]
Abstract
Conflicting reports of HRT necessitates exploration of therapeutic interventions with the least side effects to preserve metabolic homeodynamics in women later in life. The current study was designed to elucidate the cumulative effects of aging and/or high fat diet (HFD) on some metabolic indicators and their management by Tinospora cordifolia stem powder (TCP) using middle-aged acyclic and young adult cyclic female rats as the model system. Animals were fed on either normal chow or HFD supplemented with or without TCP. Blood and liver tissue were collected for biochemical, and histological studies as well as for expression of proteins regulating lipid metabolism. Animals fed with TCP supplemented normal chow feed showed bodyweight management over 12-weeks despite their high feed and calories intake compared to young and age-matched controls as well as HFD-fed animals. TCP dose used was not toxic and rather prevented age-associated liver dysfunctions and ameliorated dyslipidemia and oxidative stress, normalized blood glucose, insulin, leptin, and secretary pro-inflammatory cytokines. Further, bodyweight management effect of TCP was observed to target AMPK signalling pathway as the mediator of lipogenesis, sterol biosynthesis, lipolysis, and β-oxidation of fatty acids. These findings suggest that TCP supplementation in diet may be a potential interventional strategy to ameliorate aging-associated hepatic and metabolic dysfunctions and to promote healthy aging.
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33
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Durai P, Beeraka NM, Ramachandrappa HVP, Krishnan P, Gudur P, Raghavendra NM, Ravanappa PKB. Advances in PPARs Molecular Dynamics and Glitazones as a Repurposing Therapeutic Strategy through Mitochondrial Redox Dynamics against Neurodegeneration. Curr Neuropharmacol 2022; 20:893-915. [PMID: 34751120 PMCID: PMC9881103 DOI: 10.2174/1570159x19666211109141330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 08/20/2021] [Accepted: 09/17/2021] [Indexed: 11/22/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) activity has significant implications for the development of novel therapeutic modalities against neurodegenerative diseases. Although PPAR-α, PPAR-β/δ, and PPAR-γ nuclear receptor expressions are significantly reported in the brain, their implications in brain physiology and other neurodegenerative diseases still require extensive studies. PPAR signaling can modulate various cell signaling mechanisms involved in the cells contributing to on- and off-target actions selectively to promote therapeutic effects as well as the adverse effects of PPAR ligands. Both natural and synthetic ligands for the PPARα, PPARγ, and PPARβ/δ have been reported. PPARα (WY 14.643) and PPARγ agonists can confer neuroprotection by modulating mitochondrial dynamics through the redox system. The pharmacological effect of these agonists may deliver effective clinical responses by protecting vulnerable neurons from Aβ toxicity in Alzheimer's disease (AD) patients. Therefore, the current review delineated the ligands' interaction with 3D-PPARs to modulate neuroprotection, and also deciphered the efficacy of numerous drugs, viz. Aβ aggregation inhibitors, vaccines, and γ-secretase inhibitors against AD; this review elucidated the role of PPAR and their receptor isoforms in neural systems, and neurodegeneration in human beings. Further, we have substantially discussed the efficacy of PPREs as potent transcription factors in the brain, and the role of PPAR agonists in neurotransmission, PPAR gamma coactivator-1α (PGC-1α) and mitochondrial dynamics in neuroprotection during AD conditions. This review concludes with the statement that the development of novel PPARs agonists may benefit patients with neurodegeneration, mainly AD patients, which may help mitigate the pathophysiology of dementia, subsequently improving overall the patient's quality of life.
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Affiliation(s)
- Priya Durai
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru 570 015, India and JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
| | - Narasimha M. Beeraka
- Center of Excellence in Regenerative Medicine and Molecular Biology (CEMR), Department of Biochemistry, JSS Medical College, JSS Academy of Higher Education & Research, Mysuru 570 015, Karnataka, India;,I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow 119146, Russia
| | - Hemanth Vikram Poola Ramachandrappa
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru 570 015, India and JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
| | | | - Pranesh Gudur
- Swamy Vivekananda Yoga Anusandhana Samsthana Deemed University, Bengaluru 560 105, India
| | | | - Prashantha Kumar Bommenahally Ravanappa
- Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru 570 015, India and JSS Academy of Higher Education & Research, Mysuru, Karnataka, India;,Address correspondence to this author at the Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Mysuru 570 015, India and JSS Academy of Higher Education & Research (JSS AHER), Mysuru, Karnataka, India; E-mail:
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34
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Stanzione R, Forte M, Cotugno M, Bianchi F, Marchitti S, Busceti CL, Fornai F, Rubattu S. Uncoupling Protein 2 as a Pathogenic Determinant and Therapeutic Target in Cardiovascular and Metabolic Diseases. Curr Neuropharmacol 2022; 20:662-674. [PMID: 33882809 PMCID: PMC9878956 DOI: 10.2174/1570159x19666210421094204] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 03/10/2021] [Accepted: 04/16/2021] [Indexed: 11/22/2022] Open
Abstract
Uncoupling protein 2 (UCP2) is a mitochondrial protein that acts as an anion carrier. It is involved in the regulation of several processes, including mitochondrial membrane potential, generation of reactive oxygen species within the inner mitochondrial membrane and calcium homeostasis. UCP2 expression can be regulated at different levels: genetic (gene variants), transcriptional [by peroxisome proliferator-activated receptors (PPARs) and microRNAs], and post-translational. Experimental evidence indicates that activation of UCP2 expression through the AMPK/PPAR-α axis exerts a protective effect toward renal damage and stroke occurrence in an animal model of ischemic stroke (IS) associated with hypertension. UCP2 plays a key role in heart diseases (myocardial infarction and cardiac hypertrophy) and metabolic disorders (obesity and diabetes). In humans, UCP2 genetic variants (-866G/A and Ala55Val) associate with an increased risk of type 2 diabetes mellitus and IS development. Over the last few years, many agents that modulate UCP2 expression have been identified. Some of them are natural compounds of plant origin, such as Brassica oleracea, curcumin, berberine and resveratrol. Other molecules, currently used in clinical practice, include anti-diabetic (gliptin) and chemotherapeutic (doxorubicin and taxol) drugs. This evidence highlights the relevant role of UCP2 for the treatment of a wide range of diseases, which affect the national health systems of Western countries. We will review current knowledge on the physiological and pathological implications of UCP2 with particular regard to cardiovascular and metabolic disorders and will focus on the available therapeutic approaches affecting UCP2 level for the treatment of human diseases.
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Affiliation(s)
- Rosita Stanzione
- IRCCS Neuromed, Pozzilli Isernia, Italy,,Address correspondence to these authors at the IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Is, Italy; Tel: +390865915224/23; Fax: +390865927575; E-mail: and Clinical and Molecular Medicine Department, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S.Andrea, 00189 Rome, Italy; Tel: +390865915224/23; Fax: +390865927575; E-mail:
| | | | | | | | | | | | - Francesco Fornai
- IRCCS Neuromed, Pozzilli Isernia, Italy,,Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Speranza Rubattu
- IRCCS Neuromed, Pozzilli Isernia, Italy,,Department of Clinical and Molecular Medicine, School of Medicine and Psychology, Sapienza University of Rome, Rome, Italy,Address correspondence to these authors at the IRCCS Neuromed, Località Camerelle, 86077 Pozzilli, Is, Italy; Tel: +390865915224/23; Fax: +390865927575; E-mail: and Clinical and Molecular Medicine Department, School of Medicine and Psychology, Sapienza University of Rome, Ospedale S.Andrea, 00189 Rome, Italy; Tel: +390865915224/23; Fax: +390865927575; E-mail:
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35
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Synthesis, in-vivo anti-diabetic & anticancer activities and molecular modelling studies of tetrahydrobenzo[d]thiazole tethered nicotinohydrazide derivatives. ARAB J CHEM 2022. [DOI: 10.1016/j.arabjc.2021.103546] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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36
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Gheitasi I, Savari F, Akbari G, Mohammadi J, Fallahzadeh AR, Sadeghi H. Molecular Mechanisms of Hawthorn Extracts in Multiple Organs Disorders in Underlying of Diabetes: A Review. Int J Endocrinol 2022; 2022:2002768. [PMID: 35711333 PMCID: PMC9197671 DOI: 10.1155/2022/2002768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Accepted: 05/08/2022] [Indexed: 12/15/2022] Open
Abstract
Diabetes mellitus (DM) is one of the most important metabolic disorders associated with chronic hyperglycemia and occurs when the body cannot manage insulin secretion, insulin action, or both. Autoimmune destruction of pancreatic beta cells and insulin resistance are the major pathophysiological factors of types 1 and 2 of DM, respectively. Prolonged hyperglycemia leads to multiple organs dysfunctions, including nephropathy, neuropathy, cardiomyopathy, gastropathy, and micro- and macrovascular disorders. The basis of the metabolic abnormalities in carbohydrate, fat, and protein in diabetes is insufficient action of insulin on various target tissues. Medicinal plants are rich sources of bioactive chemical compounds with therapeutic effects. The beneficial effects of leaves, fruits, and flowers extracts of Crataegus oxyacantha, commonly called hawthorn, belonging to the Rosaceae family, are widely used as hawthorn-derived medicines. Data in this review have been collected from the scientific articles published in databases such as Science Direct, Scopus, PubMed, Web of Science, and Scientific Information Database from 2000 to 2021. Based on this review, hawthorn extracts appear both therapeutic and protective effects against diabetic-related complications in various organs through molecular mechanisms, such as decreasing triglyceride, cholesterol, very low density lipoprotein and increasing the antioxidant activity of superoxide dismutase, catalase, glutathione peroxidase, total antioxidant capacity, decreasing malondialdehyde level, and attenuating tumor necrosis factor alpha, interleukin 6 and sirtuin 1/AMP-activated protein kinase (AMPK)/nuclear factor kappa B (NF-κB) pathway and increasing the phosphorylation of glucose transporter 4, insulin receptor substrate 1, AKT and phosphoinositide 3-kinases, and attenuating blood sugar and regulation of insulin secretion, insulin resistance, and improvement of histopathological changes in pancreatic beta cells. Collectively, hawthorn can be considered as one new target for the research and development of innovative drugs for the prevention or treatment of DM and related problems.
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Affiliation(s)
- Izadpanah Gheitasi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Feryal Savari
- Department of Basic Sciences, Shoushtar Faculty of Medical Sciences, Shoushtar, Iran
| | - Ghaidafeh Akbari
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Jamshid Mohammadi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Ali Reza Fallahzadeh
- Cellular and Molecular Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
| | - Hossein Sadeghi
- Medicinal Plants Research Center, Yasuj University of Medical Sciences, Yasuj, Iran
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37
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Low CH, Mohamad H, Mustafa SFZ, Mohd KS, Mat Nafi NE. Synthesis and computational study of 4-hydroxylbenzamide analogous as potential anti-breast cancer agent. ARAB J CHEM 2022. [DOI: 10.1016/j.arabjc.2021.103510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
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38
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Mastrototaro L, Roden M. Insulin resistance and insulin sensitizing agents. Metabolism 2021; 125:154892. [PMID: 34563556 DOI: 10.1016/j.metabol.2021.154892] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2021] [Revised: 09/08/2021] [Accepted: 09/20/2021] [Indexed: 02/06/2023]
Abstract
Insulin resistance is a common feature of obesity and type 2 diabetes, but novel approaches of diabetes subtyping (clustering) revealed variable degrees of insulin resistance in people with diabetes. Specifically, the severe insulin resistant diabetes (SIRD) subtype not only exhibits metabolic abnormalities, but also bears a higher risk for cardiovascular, renal and hepatic comorbidities. In humans, insulin resistance comprises dysfunctional adipose tissue, lipotoxic insulin signaling followed by glucotoxicity, oxidative stress and low-grade inflammation. Recent studies show that aside from metabolites (free fatty acids, amino acids) and signaling proteins (myokines, adipokines, hepatokines) also exosomes with their cargo (proteins, mRNA and microRNA) contribute to altered crosstalk between skeletal muscle, liver and adipose tissue during the development of insulin resistance. Reduction of fat mass mainly, but not exclusively, explains the success of lifestyle modification and bariatric surgery to improve insulin sensitivity. Moreover, some older antihyperglycemic drugs (metformin, thiazolidinediones), but also novel therapeutic concepts (new peroxisome proliferator-activated receptor agonists, incretin mimetics, sodium glucose cotransporter inhibitors, modulators of energy metabolism) can directly or indirectly reduce insulin resistance. This review summarizes molecular mechanisms underlying insulin resistance including the roles of exosomes and microRNAs, as well as strategies for the management of insulin resistance in humans.
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Affiliation(s)
- Lucia Mastrototaro
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany
| | - Michael Roden
- Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich-Heine University Düsseldorf, Düsseldorf, Germany; German Center for Diabetes Research, Partner Düsseldorf, München-Neuherberg, Germany; Department of Endocrinology and Diabetology, Medical Faculty and University Hospital, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
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39
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Imig JD, Merk D, Proschak E. Multi-Target Drugs for Kidney Diseases. KIDNEY360 2021; 2:1645-1653. [PMID: 35372984 PMCID: PMC8785794 DOI: 10.34067/kid.0003582021] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 08/02/2021] [Indexed: 02/04/2023]
Abstract
Kidney diseases such as AKI, CKD, and GN can lead to dialysis and the need for kidney transplantation. The pathologies for kidney diseases are extremely complex, progress at different rates, and involve several cell types and cell signaling pathways. Complex kidney diseases require therapeutics that can act on multiple targets. In the past 10 years, in silico design of drugs has allowed for multi-target drugs to progress quickly from concept to reality. Several multi-target drugs have been made successfully to target AA pathways and transcription factors for the treatment of inflammatory, fibrotic, and metabolic diseases. Multi-target drugs have also demonstrated great potential to treat diabetic nephropathy and fibrotic kidney disease. These drugs act by decreasing renal TGF-β signaling, inflammation, mitochondrial dysfunction, and oxidative stress. There are several other recently developed multi-target drugs that have yet to be tested for their ability to combat kidney diseases. Overall, there is excellent potential for multi-target drugs that act on several cell types and signaling pathways to treat kidney diseases.
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Affiliation(s)
- John D. Imig
- Drug Discovery Center and Cardiovascular Center, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Daniel Merk
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany
| | - Eugen Proschak
- Institute of Pharmaceutical Chemistry, Goethe University Frankfurt, Frankfurt, Germany
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40
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Xie Y, Liu Z, Liu K, Qi H, Peng W, Cao H, Liu X, Li B, Wen F, Zhang F, Zhang L. Candidate Gene Polymorphisms Influence the Susceptibility to Salt Sensitivity of Blood Pressure in a Han Chinese Population: Risk Factors as Mediators. Front Genet 2021; 12:675230. [PMID: 34671380 PMCID: PMC8521039 DOI: 10.3389/fgene.2021.675230] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 08/26/2021] [Indexed: 01/13/2023] Open
Abstract
Genome-wide association studies suggest that there is a significant genetic susceptibility to salt sensitivity of blood pressure (SSBP), but it still needs to be verified in varied and large sample populations. We attempted to verify the associations between single-nucleotide polymorphisms (SNPs) in candidate genes and SSBP and to estimate their interaction with potential risk factors. A total of 29 candidate SNPs were genotyped in the 2,057 northern Han Chinese population from the Systems Epidemiology Study on Salt Sensitivity. A modified Sullivan’s acute oral saline load and diuresis shrinkage test (MSAOSL-DST) was used to identify SSBP. A generalized linear model was conducted to analyze the association between SNPs and SSBP, and Bonferroni correction was used for multiple testing. Mediation analysis was utilized to explore the mediation effect of risk factors. Eleven SNPs in eight genes (PRKG1, CYBA, BCAT1, SLC8A1, AGTR1, SELE, CYP4A11, and VSNL1) were identified to be significantly associated with one or more SSBP phenotypes (P < 0.05). Four SNPs (PRKG1/rs1904694 and rs7897633, CYP4A11/rs1126742, and CYBA/rs4673) were still significantly associated after Bonferroni correction (P < 0.0007) adjusted for age, sex, fasting blood glucose, total cholesterol, salt-eating habit, physical activity, and hypertension. Stratified analysis showed that CYBA/rs4673 was significantly associated with SSBP in hypertensive subjects (P < 0.0015) and CYP4A11/rs1126742 was significantly associated with SSBP in normotensive subjects (P < 0.0015). Subjects carrying both CYBA/rs4673-AA and AGTR1/rs2638360-GG alleles have a higher genetic predisposition to salt sensitivity due to the potential gene co-expression interaction. Expression quantitative trait loci analysis (eQTL) suggested that the above positive four SNPs showed cis-eQTL effects on the gene expression levels. Mediation analysis suggested that several risk factors were mediators of the relation between SNP and SSBP. This study suggests that the genetic variants in eight genes might contribute to the susceptibility to SSBP, and other risk factors may be the mediators.
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Affiliation(s)
- Yunyi Xie
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Zheng Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Kuo Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Han Qi
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Wenjuan Peng
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Han Cao
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Xiaohui Liu
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Bingxiao Li
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Fuyuan Wen
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Fengxu Zhang
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
| | - Ling Zhang
- Department of Epidemiology and Health Statistics, School of Public Health, Capital Medical University, Beijing Municipal Key Laboratory of Clinical Epidemiology, Beijing, China
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Boudalia S, Bousbia A, Boumaaza B, Oudir M, Canivenc Lavier MC. Relationship between endocrine disruptors and obesity with a focus on bisphenol A: a narrative review. BIOIMPACTS 2021; 11:289-300. [PMID: 34631491 PMCID: PMC8494257 DOI: 10.34172/bi.2021.33] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/10/2019] [Revised: 04/25/2020] [Accepted: 05/10/2020] [Indexed: 11/09/2022]
Abstract
Introduction: Scientific data suggest that early exposure to endocrine-disrupting chemicals (EDCs) affect -repro, -neuro, -metabolic systems, to which are added other notions such as mixtures, window and duration of exposure, trans-generational effects, and epigenetic mechanisms. Methods: In the present narrative review, we studied the relationship between exposure to EDCs with the appearance and development of obesity. Results: Exposure to EDCs like Bisphenol A during the early stages of development has been shown to lead to weight gain and obesity. EDCs can interfere with endocrine signaling, affect adipocytes differentiation and endocrine function and disrupt metabolic processes, especially if exposure occurs at very low doses, in the mixture, during early development stages for several generations. Conclusion: Exposure to EDCs is positively associated with obesity development. Moreover, the use of integrative approaches which mimicking environmental conditions are necessary and recommended to evaluate EDCs' effects in future studies.
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Affiliation(s)
- Sofiane Boudalia
- Faculté des Sciences de la Nature et de la Vie et Sciences de la Terre et de l'Univers, Université 8 Mai 1945 Guelma BP 4010 Guelma 24000, Algérie.,Laboratoire de Biologie, Eau et Environnement, Université 8 Mai 1945 Guelma BP 4010 Guelma 24000, Algérie
| | - Aissam Bousbia
- Faculté des Sciences de la Nature et de la Vie et Sciences de la Terre et de l'Univers, Université 8 Mai 1945 Guelma BP 4010 Guelma 24000, Algérie.,Laboratoire de Biologie, Eau et Environnement, Université 8 Mai 1945 Guelma BP 4010 Guelma 24000, Algérie
| | - Boualem Boumaaza
- Laboratoire de Biologie, Eau et Environnement, Université 8 Mai 1945 Guelma BP 4010 Guelma 24000, Algérie.,Département des Sciences Agronomiques, Faculté des Sciences de la Nature et de la Vie, Université Ibn Khaldoun, Tiaret 14000, Algérie
| | - Malha Oudir
- Laboratoire de Génie Chimique, Département de Génie des Procédés, Faculté de Technologie, Université Saâd Dahlab, USDB. BP 270, Route de Soumâa, 09000 Blida, Algérie
| | - Marie Chantal Canivenc Lavier
- Centre des Sciences du Goût et de l'Alimentation, INRA, CNRS, Université de Bourgogne - Franche-Comté, Dijon, 21000, France
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Ghahramani N, Shodja J, Rafat SA, Panahi B, Hasanpur K. Integrative Systems Biology Analysis Elucidates Mastitis Disease Underlying Functional Modules in Dairy Cattle. Front Genet 2021; 12:712306. [PMID: 34691146 PMCID: PMC8531812 DOI: 10.3389/fgene.2021.712306] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Accepted: 08/30/2021] [Indexed: 11/13/2022] Open
Abstract
Background: Mastitis is the most prevalent disease in dairy cattle and one of the most significant bovine pathologies affecting milk production, animal health, and reproduction. In addition, mastitis is the most common, expensive, and contagious infection in the dairy industry. Methods: A meta-analysis of microarray and RNA-seq data was conducted to identify candidate genes and functional modules associated with mastitis disease. The results were then applied to systems biology analysis via weighted gene coexpression network analysis (WGCNA), Gene Ontology, enrichment analysis for the Kyoto Encyclopedia of Genes and Genomes (KEGG), and modeling using machine-learning algorithms. Results: Microarray and RNA-seq datasets were generated for 2,089 and 2,794 meta-genes, respectively. Between microarray and RNA-seq datasets, a total of 360 meta-genes were found that were significantly enriched as "peroxisome," "NOD-like receptor signaling pathway," "IL-17 signaling pathway," and "TNF signaling pathway" KEGG pathways. The turquoise module (n = 214 genes) and the brown module (n = 57 genes) were identified as critical functional modules associated with mastitis through WGCNA. PRDX5, RAB5C, ACTN4, SLC25A16, MAPK6, CD53, NCKAP1L, ARHGEF2, COL9A1, and PTPRC genes were detected as hub genes in identified functional modules. Finally, using attribute weighting and machine-learning methods, hub genes that are sufficiently informative in Escherichia coli mastitis were used to optimize predictive models. The constructed model proposed the optimal approach for the meta-genes and validated several high-ranked genes as biomarkers for E. coli mastitis using the decision tree (DT) method. Conclusion: The candidate genes and pathways proposed in this study may shed new light on the underlying molecular mechanisms of mastitis disease and suggest new approaches for diagnosing and treating E. coli mastitis in dairy cattle.
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Affiliation(s)
- Nooshin Ghahramani
- Department of Animal Science, Faculty of Agriculture, University of Tabriz, Tabriz, Iran
| | - Jalil Shodja
- Department of Animal Science, Faculty of Agriculture, University of Tabriz, Tabriz, Iran
| | - Seyed Abbas Rafat
- Department of Animal Science, Faculty of Agriculture, University of Tabriz, Tabriz, Iran
| | - Bahman Panahi
- Department of Genomics, Branch for Northwest & West Region, Agricultural Biotechnology Research Institute of Iran (ABRII), Agricultural Research, Education and Extension Organization (AREEO), Tabriz, Iran
| | - Karim Hasanpur
- Department of Animal Science, Faculty of Agriculture, University of Tabriz, Tabriz, Iran
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Yudhani RD, Nugrahaningsih DAA, Sholikhah EN, Mustofa M. The Molecular Mechanisms of Hypoglycemic Properties and Safety Profiles of Swietenia Macrophylla Seeds Extract: A Review. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.6972] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/06/2022] Open
Abstract
BACKGROUND: Insulin resistance (IR) is known as the root cause of type 2 diabetes; hence, it is a substantial therapeutic target. Nowadays, studies have shifted the focus to natural ingredients that have been utilized as a traditional diabetes treatment, including Swietenia macrophylla. Accumulating evidence supports the hypoglycemic activities of S. macrophylla seeds extract, although its molecular mechanisms have yet to be well-established.
AIM: This review focuses on the hypoglycemic molecular mechanisms of S. macrophylla seeds extract and its safety profiles.
METHODS: An extensive search of the latest literature was conducted from four main databases (PubMed, Scopus, Science Direct, and Google Scholar) using several keywords: “swietenia macrophylla, seeds, and diabetes;” “swietenia macrophylla, seeds, and oxidative stress;” “swietenia macrophylla, seeds, and inflammation;” “swietenia macrophylla, seeds, and GLUT4;” and “swietenia macrophylla, seeds, and toxicities.”
RESULTS: The hypoglycemic activities occur through modulating several pathways associated with IR and T2D pathogenesis. The seeds extract of S. macrophylla modulates oxidative stress by decreasing malondialdehyde (MDA), oxidized low-density lipoprotein, and thiobarbituric acid-reactive substances while increasing antioxidant enzymes (superoxide dismutase, glutathione peroxidase, and catalase). Another propose mechanism is the modulating of the inflammatory pathway by attenuating nuclear factor kappa β, tumor necrosis factor α, inducible nitric oxide synthase, and cyclooxygenase 2. Some studies have shown that the extract can also control phosphatidylinositol-3-kinase/ Akt (PI3K/Akt) pathway by inducing glucose transporter 4, while suppressing phosphoenolpyruvate carboxykinase. Moreover, in vitro cytotoxicity and in vivo toxicity studies supported the safety profile of S. macrophylla seeds extract with the LD50 higher than 2000 mg/kg.
CONCLUSION: The potential of S. macrophylla seeds as antidiabetic candidate is supported by many studies that have documented their non-toxic and hypoglycemic effects, which involve several molecular pathways.
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Von Dentz M, Gambato G, Ferrari A, Fontana RC, Rodrigues E, Salvador M, Camassola M, Jahn MP. Antihyperlipidemic effect of the hydroalcoholic extract of Basidiomycete Pycnoporus sanguineus (Fr.) Murr. in streptozotocin-induced diabetic rats. ADVANCES IN TRADITIONAL MEDICINE 2021. [DOI: 10.1007/s13596-020-00459-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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Efficacy of elafibranor in patients with liver abnormalities especially non-alcoholic steatohepatitis: a systematic review and meta-analysis. Clin J Gastroenterol 2021; 14:1579-1586. [PMID: 34370218 DOI: 10.1007/s12328-021-01491-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2021] [Accepted: 07/26/2021] [Indexed: 10/20/2022]
Abstract
BACKGROUND Dyslipidemia is a very common medical disorder affecting nearly 33.5% of US adults over 20 years of age. It represents the major risk factor for non-alcoholic fatty liver (NAFLD) and cardiovascular diseases, which is the most common cause of death worldwide. Elafibranor is a peroxisome proliferator-activated receptor (PPAR) alpha and delta dual agonist. A novel dual peroxisome proliferator-activated receptor alpha/delta (PPAR-α/δ), elafibranor, the agonist is an emerging therapy with promising hepatoprotective results. OBJECTIVES To estimate the efficacy of elafibranor in patients with liver abnormalities especially non-alcoholic steatohepatitis (NASH). METHODS We searched the following databases: PubMed, SCOPUS, Web of Science, and Cochrane Library for relevant clinical trials assessing the use of silymarin in patients with NAFLD. Risk of bias assessment was performed using Cochrane's risk of bias tool. We included the following outcomes: alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), HOMA-IR, total cholesterol (TC), triglyceride (TG), HDL-cholesterol (HDL-C), and LDL-cholesterol (LDL-C). RESULTS We included four clinical trials. We found that elafibranor significantly reduced the levels of ALT {MD = - 4.60 [- 8.17, - 1.04], (P = 0.01)}, GGT {MD = - 16.57 [- 26.59, - 6.56], (P < 0.01)}, TC {MD = - 0.37 [- 0.66, - 0.08], (P = 0.01)}, TG {MD = - 0.37 [- 0.51, - 0.24], (P < 0.01)}, ALP {(MD = - 14.45 [- 18.99, - 9.91], (P < 0.01)}, and LDL {MD = - 0.20 [- 0.33, - 0.07], (P = 0.003)}. There was no significant difference regarding HOMA-IR {MD = - 0.32 [- 0.88, 0.24], (P = 0.26) and AST (P = 0.53). CONCLUSION PPAR-alpha/delta dual agonist, elafibranor, is a promising drug that improves most metabolic parameters in dyslipidemic patients.
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Ding N, Karvonen-Gutierrez CA, Herman WH, Calafat AM, Mukherjee B, Park SK. Associations of perfluoroalkyl and polyfluoroalkyl substances (PFAS) and PFAS mixtures with adipokines in midlife women. Int J Hyg Environ Health 2021; 235:113777. [PMID: 34090141 DOI: 10.1016/j.ijheh.2021.113777] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 05/11/2021] [Accepted: 05/21/2021] [Indexed: 02/08/2023]
Abstract
BACKGROUND Perfluoroalkyl and polyfluoroalkyl substances (PFAS) exposure have been associated with obesity and related comorbidities, possibly through disrupting signaling pathways of adipokines. Both leptin and adiponectin can modulate metabolic processes. However, the effects of PFAS on adipokines are not well understood. OBJECTIVE We determined if serum PFAS concentrations were associated with adipokine profiles in midlife women. METHODS We examined 1245 women aged 45-56 years from the Study of Women's Health Across the Nation. Concentrations of 11 PFAS were quantified in baseline serum samples collected in 1999-2000. Linear and branched perfluorooctane sulfonic acid isomers (n-PFOS and Sm-PFOS) and their sum (PFOS), linear perfluorooctanoic acid (n-PFOA), perfluorononanoic acid (PFNA), perfluorohexane sulfonic acid (PFHxS), 2-(N-methyl-perfluorooctane sulfonamido) acetic acid (MeFOSAA), and 2-(N-ethyl-perfluorooctane sulfonamido) acetic acid (EtFOSAA) with detection frequencies >60% were included in the analysis. Adipokines including leptin, soluble leptin receptor (sOB-R), free leptin index (FLI, the ratio of leptin to sOB-R), total and high molecular weight (HMW) adiponectin were assessed in 2002-2003. We utilized multivariable linear regressions and Bayesian kernel machine regression (BKMR) to assess individual and overall joint effects of PFAS on adipokines with adjustment for age, race/ethnicity, study site, education, smoking status, physical activity, menopausal status, and waist circumference. RESULTS A doubling of PFAS concentrations was associated with 7.8% (95% CI: 2.5%, 13.4%) higher FLI for PFOS, 9.4% (95% CI: 3.7%, 15.3%) for n-PFOA, 5.5% (95% CI: 2.2%, 9.0%) for EtFOSAA and 7.4% (95% CI: 2.8%, 12.2%) for MeFOSAA. Similar associations were found for leptin. Only EtFOSAA was associated with lower sOB-R concentrations (-1.4%, 95% CI: -2.7%, -0.1%). Results remained in women with overweight or obesity but not those with normal weight or underweight. No statistically significant associations were observed with total or HMW adiponectin, except for PFNA with total and HMW adiponectin observed in women with normal weight or underweight. In BKMR analysis, women with PFAS concentrations at the median and the 90th percentile had 30.9% (95% CI: 15.6%, 48.3%) and 52.1% (95% CI: 27.9%, 81.0%) higher FLI, respectively, compared with those with concentrations fixed at the 10th percentile. CONCLUSION Some PFAS may alter circulating levels of leptin. Understanding associations between PFAS and adipokines may help elucidate whether PFAS can influence obesity and metabolic disease.
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Affiliation(s)
- Ning Ding
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | | | - William H Herman
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA; Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Antonia M Calafat
- Division of Laboratory Sciences, National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Bhramar Mukherjee
- Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI, USA
| | - Sung Kyun Park
- Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA; Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.
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Mazzini GS, Khoraki J, Browning MG, Wu J, Zhou H, Price ET, Wolfe LG, Mangino MJ, Campos GM. Gastric Bypass Increases Circulating Bile Acids and Activates Hepatic Farnesoid X Receptor (FXR) but Requires Intact Peroxisome Proliferator Activator Receptor Alpha (PPARα) Signaling to Significantly Reduce Liver Fat Content. J Gastrointest Surg 2021; 25:871-879. [PMID: 33555523 DOI: 10.1007/s11605-021-04908-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Accepted: 01/06/2021] [Indexed: 01/31/2023]
Abstract
BACKGROUND We interrogate effects of gastric bypass (RYGB), compared with a low-calorie diet, on bile acid (BA), liver fat, and FXR, PPARα, and targets in rats with obesity and non-alcoholic fatty liver disease (NAFLD). METHODS Male Wistar rats received a high-fat diet (obese/NAFLD, n=24) or standard chow (lean, n=8) for 12 weeks. Obese/NAFLD rats had RYGB (n=11), sham operation pair-fed to RYGB (pair-fed sham, n=8), or sham operation (sham, n=5). Lean rats had sham operation (lean sham, n=8). Post-operatively, five RYGB rats received PPARα antagonist GW6417. Sacrifice occurred at 7 weeks. We measured weight changes, fasting total plasma BA, and liver % steatosis, triglycerides, and mRNA expression of the nuclear receptors FXR, PPARα, and their targets SHP and CPT-I. RESULTS At sacrifice, obese sham was heavier (p<0.01) than all other groups that had lost similar weight loss. Obese sham had lower BA levels and lower hepatic FXR, SHP, and CPT-I mRNA expression than lean sham (P<0.05, for all comparisons). RYGB had increased BA levels compared with obese and pair-fed sham (P<0.05, for both), while pair-fed sham had BA levels, similar to obese sham. Compared with pair-fed sham, RYGB animals had increased liver FXR and PPARα expression and signaling (P<0.05). Percentage of steatosis was lower in RYGB and lean sham, relative to obese and pair-fed sham (P<0.05, for all comparisons). PPARα inhibition after RYGB resulted in similar weight loss but higher liver triglyceride content (P=0.01) compared with RYGB alone. CONCLUSIONS RYGB led to greater liver fat loss than low-calorie diet, an effect associated to increased fasting BA levels and increased expression of modulators of liver fat oxidation, FXR, and PPARα. However, intact PPARα signaling was necessary for resolution of NAFLD after RYGB.
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Affiliation(s)
- Guilherme S Mazzini
- Division of Bariatric and Gastrointestinal Surgery, Department of Surgery, Virginia Commonwealth University, 1200 E. Broad Street, Richmond, VA, USA
- Division of Gastrointestinal Surgery, Hospital de Clínicas de Porto Alegre, 2350 Ramiro Barcelos Street, Porto Alegre, RS, Brazil
| | - Jad Khoraki
- Division of Bariatric and Gastrointestinal Surgery, Department of Surgery, Virginia Commonwealth University, 1200 E. Broad Street, Richmond, VA, USA
| | - Matthew G Browning
- Division of Bariatric and Gastrointestinal Surgery, Department of Surgery, Virginia Commonwealth University, 1200 E. Broad Street, Richmond, VA, USA
| | - Jilin Wu
- Division of Bariatric and Gastrointestinal Surgery, Department of Surgery, Virginia Commonwealth University, 1200 E. Broad Street, Richmond, VA, USA
| | - Huiping Zhou
- Central Virginia Veterans Affairs Health Care System, Department of Microbiology and Immunology, Virginia Commonwealth University, 1220 E. Broad Street, Richmond, VA, USA
| | - Elvin T Price
- Department of Pharmacotherapy & Outcomes Science, School of Pharmacy, Virginia Commonwealth University, 410 N 12th Street, Richmond, VA, USA
| | - Luke G Wolfe
- Division of Bariatric and Gastrointestinal Surgery, Department of Surgery, Virginia Commonwealth University, 1200 E. Broad Street, Richmond, VA, USA
| | - Martin J Mangino
- Division of Bariatric and Gastrointestinal Surgery, Department of Surgery, Virginia Commonwealth University, 1200 E. Broad Street, Richmond, VA, USA
| | - Guilherme M Campos
- Division of Bariatric and Gastrointestinal Surgery, Department of Surgery, Virginia Commonwealth University, 1200 E. Broad Street, Richmond, VA, USA.
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Gutiérrez-Cuevas J, Sandoval-Rodriguez A, Meza-Rios A, Monroy-Ramírez HC, Galicia-Moreno M, García-Bañuelos J, Santos A, Armendariz-Borunda J. Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge. Cells 2021; 10:629. [PMID: 33809061 PMCID: PMC8000147 DOI: 10.3390/cells10030629] [Citation(s) in RCA: 62] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Revised: 02/26/2021] [Accepted: 03/03/2021] [Indexed: 02/07/2023] Open
Abstract
Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.
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Affiliation(s)
- Jorge Gutiérrez-Cuevas
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Jalisco 44340, Mexico; (J.G.-C.); (A.S.-R.); (H.C.M.-R.); (M.G.-M.); (J.G.-B.)
| | - Ana Sandoval-Rodriguez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Jalisco 44340, Mexico; (J.G.-C.); (A.S.-R.); (H.C.M.-R.); (M.G.-M.); (J.G.-B.)
| | - Alejandra Meza-Rios
- Tecnologico de Monterrey, Campus Guadalajara, Zapopan, School of Medicine and Health Sciences, Jalisco 45201, Mexico; (A.M.-R.); (A.S.)
| | - Hugo Christian Monroy-Ramírez
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Jalisco 44340, Mexico; (J.G.-C.); (A.S.-R.); (H.C.M.-R.); (M.G.-M.); (J.G.-B.)
| | - Marina Galicia-Moreno
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Jalisco 44340, Mexico; (J.G.-C.); (A.S.-R.); (H.C.M.-R.); (M.G.-M.); (J.G.-B.)
| | - Jesús García-Bañuelos
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Jalisco 44340, Mexico; (J.G.-C.); (A.S.-R.); (H.C.M.-R.); (M.G.-M.); (J.G.-B.)
| | - Arturo Santos
- Tecnologico de Monterrey, Campus Guadalajara, Zapopan, School of Medicine and Health Sciences, Jalisco 45201, Mexico; (A.M.-R.); (A.S.)
| | - Juan Armendariz-Borunda
- Department of Molecular Biology and Genomics, Institute for Molecular Biology in Medicine and Gene Therapy, University of Guadalajara, CUCS, Jalisco 44340, Mexico; (J.G.-C.); (A.S.-R.); (H.C.M.-R.); (M.G.-M.); (J.G.-B.)
- Tecnologico de Monterrey, Campus Guadalajara, Zapopan, School of Medicine and Health Sciences, Jalisco 45201, Mexico; (A.M.-R.); (A.S.)
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Cohen ED, Yee M, Porter GA, Ritzer E, McDavid AN, Brookes PS, Pryhuber GS, O’Reilly MA. Neonatal hyperoxia inhibits proliferation and survival of atrial cardiomyocytes by suppressing fatty acid synthesis. JCI Insight 2021; 6:140785. [PMID: 33507880 PMCID: PMC8021108 DOI: 10.1172/jci.insight.140785] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Accepted: 01/27/2021] [Indexed: 12/12/2022] Open
Abstract
Preterm birth increases the risk for pulmonary hypertension and heart failure in adulthood. Oxygen therapy can damage the immature cardiopulmonary system and may be partially responsible for the cardiovascular disease in adults born preterm. We previously showed that exposing newborn mice to hyperoxia causes pulmonary hypertension by 1 year of age that is preceded by a poorly understood loss of pulmonary vein cardiomyocyte proliferation. We now show that hyperoxia also reduces cardiomyocyte proliferation and survival in the left atrium and causes diastolic heart failure by disrupting its filling of the left ventricle. Transcriptomic profiling showed that neonatal hyperoxia permanently suppressed fatty acid synthase (Fasn), stearoyl-CoA desaturase 1 (Scd1), and other fatty acid synthesis genes in the atria of mice, the HL-1 line of mouse atrial cardiomyocytes, and left atrial tissue explanted from human infants. Suppressing Fasn or Scd1 reduced HL-1 cell proliferation and increased cell death, while overexpressing these genes maintained their expansion in hyperoxia, suggesting that oxygen directly inhibits atrial cardiomyocyte proliferation and survival by repressing Fasn and Scd1. Pharmacologic interventions that restore Fasn, Scd1, and other fatty acid synthesis genes in atrial cardiomyocytes may, thus, provide a way of ameliorating the adverse effects of supplemental oxygen on preterm infants.
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Affiliation(s)
| | | | | | | | | | - Paul S. Brookes
- Department of Anesthesiology, School of Medicine and Dentistry, The University of Rochester, Rochester, New York, USA
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Yang CC, Yang CM. Chinese Herbs and Repurposing Old Drugs as Therapeutic Agents in the Regulation of Oxidative Stress and Inflammation in Pulmonary Diseases. J Inflamm Res 2021; 14:657-687. [PMID: 33707963 PMCID: PMC7940992 DOI: 10.2147/jir.s293135] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Accepted: 01/14/2021] [Indexed: 12/12/2022] Open
Abstract
Several pro-inflammatory factors and proteins have been characterized that are involved in the pathogenesis of inflammatory diseases, including acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma, induced by oxidative stress, cytokines, bacterial toxins, and viruses. Reactive oxygen species (ROS) act as secondary messengers and are products of normal cellular metabolism. Under physiological conditions, ROS protect cells against oxidative stress through the maintenance of cellular redox homeostasis, which is important for proliferation, viability, cell activation, and organ function. However, overproduction of ROS is most frequently due to excessive stimulation of either the mitochondrial electron transport chain and xanthine oxidase or reduced nicotinamide adenine dinucleotide phosphate (NADPH) by pro-inflammatory cytokines, such as interleukin-1β and tumor necrosis factor α. NADPH oxidase activation and ROS overproduction could further induce numerous inflammatory target proteins that are potentially mediated via Nox/ROS-related transcription factors triggered by various intracellular signaling pathways. Thus, oxidative stress is considered important in pulmonary inflammatory processes. Previous studies have demonstrated that redox signals can induce pulmonary inflammatory diseases. Thus, therapeutic strategies directly targeting oxidative stress may be effective for pulmonary inflammatory diseases. Therefore, drugs with anti-inflammatory and anti-oxidative properties may be beneficial to these diseases. Recent studies have suggested that traditional Chinese medicines, statins, and peroxisome proliferation-activated receptor agonists could modulate inflammation-related signaling processes and may be beneficial for pulmonary inflammatory diseases. In particular, several herbal medicines have attracted attention for the management of pulmonary inflammatory diseases. Therefore, we reviewed the pharmacological effects of these drugs to dissect how they induce host defense mechanisms against oxidative injury to combat pulmonary inflammation. Moreover, the cytotoxicity of oxidative stress and apoptotic cell death can be protected via the induction of HO-1 by these drugs. The main objective of this review is to focus on Chinese herbs and old drugs to develop anti-inflammatory drugs able to induce HO-1 expression for the management of pulmonary inflammatory diseases.
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Affiliation(s)
- Chien-Chung Yang
- Department of Traditional Chinese Medicine, Chang Gung Memorial Hospital at Tao-Yuan, Kwei-San, Tao-Yuan, 33302, Taiwan.,School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Kwei-San, Tao-Yuan, 33302, Taiwan
| | - Chuen-Mao Yang
- Department of Pharmacology, College of Medicine, China Medical University, Taichung, 40402, Taiwan.,Ph.D. Program for Biotech Pharmaceutical Industry, China Medical University, Taichung, 40402, Taiwan.,Department of Post-Baccalaureate Veterinary Medicine, College of Medical and Health Science, Asia University, Taichung, 41354, Taiwan
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