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Zhang Y, Wang J, Yang S, Kou H, Liu P. Tanshinone IIA alleviate atherosclerosis and hepatic steatosis via down-regulation of MAPKs/NF-κB signaling pathway. Int Immunopharmacol 2025; 152:114465. [PMID: 40090083 DOI: 10.1016/j.intimp.2025.114465] [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: 12/24/2024] [Revised: 03/09/2025] [Accepted: 03/09/2025] [Indexed: 03/18/2025]
Abstract
OBJECTIVES Tanshinone IIA (Tan IIA) exhibits therapeutic potential for atherosclerosis (AS) and hepatic steatosis (HS). The study aims to explore the mechanisms underlying the anti-atherosclerosis and anti-hepatic steatosis effects of Tan IIA. METHODS The LDLR-/-mice were divided into control, model, low/high Tan IIA and atorvastatin group, which fed with High-fat diet to build NAFLD-associated AS model, then administrated with 0.9 % saline, Tan IIA or atorvastatin. RAW264.7 cells divided into control, LPS, LPS plus low/high Tan IIA and LPS plus Tan IIA plus JNK activator group. The different goups' pathological changes visualized with H&E, Oil Red O and Immunofluorescence staining. The therapeutic effect of Tan IIA was reflected by lipids metabolism changes, hepatic indexes, inflammation levels. ELISA, RT-qPCR and Western blot assay were used to determine the inflammatory factors and upstream proteins. Molecular docking was used to reconfirm the importance of genes studied and locate the specific gene will study. RESULTS Tan IIA alleviated LDLR-/-mice AS and HS by reducing AS plaque area, lowering serum &liver lipid levels (TC, TG), improving liver function (AST, ALT). Tan IIA decreased serum inflammation levels (IL-1β, IL-6, TNF-α) and aorta & liver inflammatory-related cytokines levels (iNOS, VCAM-1, IL-6) and inhibited the phosphorylation of aorta & liver protein ERK1/2, JNK, p38 and NF-κB p65, which were validated in the LPS-stimulated macrophages supernatant and cells. CONCLUSIONS The study indicated that Tan IIA can alleviate atherosclerosis and hepatic steatosis via down-regulating MAPKs/NF-κB signaling pathway. This provides a potential therapeutic strategy for the co-existing situation of atherosclerosis and hepatic steatosis.
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Affiliation(s)
- Yifan Zhang
- Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiarou Wang
- Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Shuo Yang
- Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Haixin Kou
- Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Ping Liu
- Department of Cardiology, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China.
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Catana OM, Nemes AF, Cioboata R, Toma CL, Mitroi DM, Calarasu C, Streba CT. Leptin and Insulin in COPD: Unveiling the Metabolic-Inflammatory Axis-A Narrative Review. J Clin Med 2025; 14:2611. [PMID: 40283443 PMCID: PMC12027990 DOI: 10.3390/jcm14082611] [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: 02/21/2025] [Revised: 04/06/2025] [Accepted: 04/08/2025] [Indexed: 04/29/2025] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a progressive and debilitating condition characterized by airflow limitations and systemic inflammation. The interaction between the metabolic and inflammatory pathways plays a key role in disease progression, with leptin and insulin emerging as pivotal metabolic regulators. Leptin, an adipokine that regulates energy homeostasis, and insulin, the primary regulator of glucose metabolism, are both altered in COPD patients. This narrative review provides an in-depth examination of the roles of leptin and insulin in COPD pathogenesis, focusing on the molecular mechanisms through which these metabolic regulators interact with inflammatory pathways and how their dysregulation contributes to a spectrum of extrapulmonary manifestations. These disturbances not only exacerbate COPD symptoms but also increase the risk of comorbidities such as metabolic syndrome, diabetes, cardiovascular disease, or muscle wasting. By exploring the underlying mechanisms of leptin and insulin dysregulation in COPD, this review underscores the significance of the metabolic-inflammatory axis, suggesting that restoring metabolic balance through leptin and insulin modulation could offer novel therapeutic strategies for improving clinical outcomes.
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Affiliation(s)
- Oana Maria Catana
- Doctoral School, University of Medicine and Pharmacy, 200349 Craiova, Romania; (O.M.C.); (D.M.M.)
| | | | - Ramona Cioboata
- Pneumology Department, University of Medicine and Pharmacy, 200349 Craiova, Romania; (C.C.); (C.T.S.)
| | - Claudia Lucia Toma
- Pneumology Department, University of Medicine Carol Davila, 020021 Bucharest, Romania
| | - Denisa Maria Mitroi
- Doctoral School, University of Medicine and Pharmacy, 200349 Craiova, Romania; (O.M.C.); (D.M.M.)
| | - Cristina Calarasu
- Pneumology Department, University of Medicine and Pharmacy, 200349 Craiova, Romania; (C.C.); (C.T.S.)
| | - Costin Teodor Streba
- Pneumology Department, University of Medicine and Pharmacy, 200349 Craiova, Romania; (C.C.); (C.T.S.)
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Xu J, Huang Z, Shi S, Xia J, Chen G, Zhou K, Zhang Y, Bian C, Shen Y, Yin X, Lu L, Gu H. Glial maturation factor-β deficiency prevents oestrogen deficiency-induced bone loss by remodelling the actin network to suppress adipogenesis of bone marrow mesenchymal stem cells. Cell Death Dis 2024; 15:829. [PMID: 39543090 PMCID: PMC11564563 DOI: 10.1038/s41419-024-07234-z] [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: 07/27/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 11/17/2024]
Abstract
An imbalance between the adipogenesis and osteogenesis of bone marrow mesenchymal stem cells (BMSCs) is considered the basic pathogenesis of osteoporosis. Although actin cytoskeleton remodelling plays a crucial role in the differentiation of BMSCs, the role of actin cytoskeleton remodelling in the adipogenesis of BMSCs and postmenopausal osteoporosis (PMOP) has remained elusive. Glia maturation factor-beta (GMFB) has a unique role in remodelling the polymerization/depolymerization cycles of actin. We observed that GMFB expression was increased in bone tissue from both ovariectomized (OVX) rats and PMOP patients. GMFB knockout inhibited the accumulation of bone marrow adipocytes and increased bone mass in the OVX rat model. The inhibition of adipocyte differentiation in GMFB knockout BMSCs was mediated via actin cytoskeleton remodelling and the Ca2+-calcineurin-NFATc2 axis. Furthermore, we found that GMFB shRNA treatment in vivo had favourable effects on osteoporosis induced by OVX. Together, these findings suggest a pathological association of the GMFB with PMOP and highlight the potential of the GMFB as a therapeutic target for osteoporosis patients.
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Affiliation(s)
- Jun Xu
- Department of Orthopedics, Minhang Hospital, Fudan University, Shanghai, PR China
| | - Zhongyue Huang
- Department of Orthopedics, Minhang Hospital, Fudan University, Shanghai, PR China
| | - Si Shi
- Department of Rehabilitation, Tongji Hospital Affiliated to Tongji University, Tongji University School of medicine, Shanghai, PR China
| | - Jiangni Xia
- Department of Orthopedics, Minhang Hospital, Fudan University, Shanghai, PR China
| | - Guangnan Chen
- Department of Orthopedics, Minhang Hospital, Fudan University, Shanghai, PR China
| | - Kaifeng Zhou
- Department of Orthopedics, Minhang Hospital, Fudan University, Shanghai, PR China
| | - Yiming Zhang
- Department of Orthopedics, Minhang Hospital, Fudan University, Shanghai, PR China
| | - Chong Bian
- Department of Orthopedics, Minhang Hospital, Fudan University, Shanghai, PR China
| | - Yuqin Shen
- Department of Rehabilitation, Tongji Hospital Affiliated to Tongji University, Tongji University School of medicine, Shanghai, PR China
| | - Xiaofan Yin
- Department of Orthopedics, Minhang Hospital, Fudan University, Shanghai, PR China.
| | - Lixia Lu
- Department of Rehabilitation, Tongji Hospital Affiliated to Tongji University, Tongji University School of medicine, Shanghai, PR China.
- Department of Biochemistry and Molecular Biology, Tongji University School of medicine, Shanghai, PR China.
| | - Huijie Gu
- Department of Orthopedics, Minhang Hospital, Fudan University, Shanghai, PR China.
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Ghotbi S, Joukar F, Orang Goorabzarmakhi M, Shahdkar M, Maroufizadeh S, Mojtahedi K, Asgharnezhad M, Naghipour M, Mansour-Ghanaei F. Evaluation of elevated serum liver enzymes and metabolic syndrome in the PERSIAN Guilan cohort study population. Heliyon 2024; 10:e32449. [PMID: 38961895 PMCID: PMC11219353 DOI: 10.1016/j.heliyon.2024.e32449] [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: 01/16/2024] [Revised: 06/01/2024] [Accepted: 06/04/2024] [Indexed: 07/05/2024] Open
Abstract
Objective The purpose of this study is to evaluate the association between elevated serum liver enzymes and Metabolic Syndrome (MetS) in Prospective Epidemiological Research Studies of the Iranian Adults (PERSIAN) Guilan Cohort Study (PGCS) population. Methods This cross-sectional study involved 10,519 individuals between the ages of 35 and 70 enrolled in the PGCS. The gathered data encompassed demographic information, anthropometric measurements, blood pressure, and biochemical indicators. MetS was defined by the National Cholesterol Education Program-Adult Treatment Panel III criteria (NCEP-ATP III). The associations between elevated liver enzymes and MetS were examined using logistic regression analysis. Odds ratio (OR) and 95 % confidence interval (CI) were calculated. Results The prevalence of MetS was 41.8 %, and the prevalence of elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), and alkaline phosphatase (ALP) were 19.4, 4.6, 11.6, and 5.1 %, respectively. In the unadjusted model, elevated ALT, AST, and GGT were associated with increased odds of MetS (OR = 1.55, 95 % CI: 1.41-1.71; OR = 1.29, 95 % CI: 1.07-1.55, and OR = 1.90, 95 % CI: 1.69-2.14, respectively). These associations remained significant for ALT and GGT after adjustment for some demographic and clinical characteristics (aOR = 1.31, 95 % CI: 1.17-1.46 and aOR = 1.30, 95 % CI: 1.14-1.49, respectively). In addition, the odds of MetS increased with the number of elevated liver enzymes, up to almost 1.32-fold among subjects with three/four elevated liver enzymes. Conclusion The higher incidence of elevated liver enzymes was associated with an increased likelihood of MetS. Including liver markers in diagnosing and predicting MetS holds promise and is considered a possible approach.
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Affiliation(s)
- Saideh Ghotbi
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Farahnaz Joukar
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | | | - Milad Shahdkar
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Saman Maroufizadeh
- Department of Biostatistics, School of Health, Guilan University of Medical Sciences, Rasht, Iran
| | - Kourosh Mojtahedi
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Mehrnaz Asgharnezhad
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Mohammadreza Naghipour
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
| | - Fariborz Mansour-Ghanaei
- Gastrointestinal and Liver Diseases Research Center, Guilan University of Medical Sciences, Rasht, Iran
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Golmohammadi M, Meibodi SAA, Al-Hawary SIS, Gupta J, Sapaev IB, Najm MAA, Alwave M, Nazifi M, Rahmani M, Zamanian MY, Moriasi G. Neuroprotective effects of resveratrol on retinal ganglion cells in glaucoma in rodents: A narrative review. Animal Model Exp Med 2024; 7:195-207. [PMID: 38808561 PMCID: PMC11228121 DOI: 10.1002/ame2.12438] [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: 02/12/2024] [Accepted: 04/22/2024] [Indexed: 05/30/2024] Open
Abstract
Glaucoma, an irreversible optic neuropathy, primarily affects retinal ganglion cells (RGC) and causes vision loss and blindness. The damage to RGCs in glaucoma occurs by various mechanisms, including elevated intraocular pressure, oxidative stress, inflammation, and other neurodegenerative processes. As the disease progresses, the loss of RGCs leads to vision loss. Therefore, protecting RGCs from damage and promoting their survival are important goals in managing glaucoma. In this regard, resveratrol (RES), a polyphenolic phytoalexin, exerts antioxidant effects and slows down the evolution and progression of glaucoma. The present review shows that RES plays a protective role in RGCs in cases of ischemic injury and hypoxia as well as in ErbB2 protein expression in the retina. Additionally, RES plays protective roles in RGCs by promoting cell growth, reducing apoptosis, and decreasing oxidative stress in H2O2-exposed RGCs. RES was also found to inhibit oxidative stress damage in RGCs and suppress the activation of mitogen-activated protein kinase signaling pathways. RES could alleviate retinal function impairment by suppressing the hypoxia-inducible factor-1 alpha/vascular endothelial growth factor and p38/p53 axes while stimulating the PI3K/Akt pathway. Therefore, RES might exert potential therapeutic effects for managing glaucoma by protecting RGCs from damage and promoting their survival.
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Affiliation(s)
- Maryam Golmohammadi
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | | | - Jitendra Gupta
- Institute of Pharmaceutical Research, GLA University, Mathura, India
| | - Ibrohim B Sapaev
- Tashkent Institute of Irrigation and Agricultural Mechanization Engineers, Tashkent, Uzbekistan
- New Uzbekistan University, Tashkent, Uzbekistan
| | - Mazin A A Najm
- Pharmaceutical Chemistry Department, College of Pharmacy, Al-Ayen University, Thi-Qar, Iraq
| | - Marim Alwave
- Medical Technical College, Al-Farahidi University, Baghdad, Iraq
| | - Mozhgan Nazifi
- Department of Neurology, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammadreza Rahmani
- Physiology-Pharmacology Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Physiology and Pharmacology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mohammad Yasin Zamanian
- Neurophysiology Research Center, Hamadan University of Medical Sciences, Hamadan, Iran
- Department of Pharmacology and Toxicology, School of Pharmacy, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Gervason Moriasi
- Department of Medical Biochemistry, School of Medicine, College of Health Sciences, Mount Kenya University, Thika, Kenya
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Tamini S, Bondesan A, Caroli D, Sartorio A. The Lipid Accumulation Product Index (LAP) and the Cardiometabolic Index (CMI) Are Useful for Predicting the Presence and Severity of Metabolic Syndrome in Adult Patients with Obesity. J Clin Med 2024; 13:2843. [PMID: 38792386 PMCID: PMC11122168 DOI: 10.3390/jcm13102843] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2024] [Revised: 04/22/2024] [Accepted: 05/10/2024] [Indexed: 05/26/2024] Open
Abstract
Background: The concomitant occurrence of obesity and metabolic syndrome (MetS) causes a significant worsening of a patient's clinical condition. Indexes that employ anthropometric measurements alone or associated with blood parameters have been investigated for their ability to identify MetS. This study aimed to evaluate the diagnostic accuracy of three of these indexes, the body adiposity index (BAI), the lipid accumulation product index (LAP), and the cardiometabolic index (CMI), in a cohort of 1912 adult subjects with obesity. Methods and Results: MetS was found in 62.3% of the enrolled subjects, with a higher prevalence in males (72.5%) than females (60.9%). Receiver operating characteristic (ROC) analysis was used to define which index performed better. The BAI was found to be the lowest-performing index, with an ROC area of 0.50, a sensitivity of 30.31%, a specificity of 74.48%, and a likelihood ratio of 1.19. On the contrary, the LAP and the CMI showed a comparable ROC area of 0.82. The LAP had a sensitivity of 63.06%, a specificity of 86.55%, and a likelihood ratio of 4.69, while the CMI had a sensitivity of 67.59%, specificity of 81.55%, and a likelihood ratio of 3.66. The analysis was also performed in the group divided into males and females, with overlapping results. Conclusions: The LAP and the CMI performed better than the BAI in detecting MetS both in the general population with obesity and in the male/female subgroups. In the future, it will be important to validate these useful diagnostic tools in order to employ them in clinical practices.
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Affiliation(s)
- Sofia Tamini
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Adele Bondesan
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Diana Caroli
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
| | - Alessandro Sartorio
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 28824 Piancavallo-Verbania, Italy
- Istituto Auxologico Italiano, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Experimental Laboratory for Auxo-Endocrinological Research, 20145 Milan, Italy
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Branigan P, Duong YV, Abdulfattah AY, Sabu J, Mallappallil M, John S. Towards Optimal Cardiovascular Health: A Comprehensive Review of Preventive Strategies. Cureus 2024; 16:e60877. [PMID: 38910676 PMCID: PMC11192625 DOI: 10.7759/cureus.60877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/22/2024] [Indexed: 06/25/2024] Open
Abstract
Heart disease remains a prominent global health concern, with cardiovascular disease (CVD) standing as a leading cause of death worldwide. Preventing heart disease not only decreases the risk of premature death but also mitigates complications like heart attacks, strokes, and arrhythmias, thereby enhancing overall health and quality of life. The economic burden of heart disease treatment highlights the importance of implementing preventive measures, such as lifestyle changes and early interventions, which can alleviate healthcare costs. These strategies, targeting risk factors like hypertension (HTN), diabetes mellitus (DM), dyslipidemia, and obesity, not only prevent heart disease but also reduce the risk of other health issues. Herein, this review covers various preventive measures, including dietary interventions, exercise, controlling HTN, DM, cholesterol, and weight, smoking cessation, and pharmacological interventions. By critically analyzing the guidelines and leveraging robust data alongside variations in recommendations, this review aims to elucidate effective primary prevention strategies for CVD.
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Affiliation(s)
- Philip Branigan
- Department of Cardiology, State University of New York Downstate Medical Center, Brooklyn, USA
| | - Y V Duong
- Department of Cardiology, University of Debrecen Medical School, Debrecen, HUN
| | - Ammar Y Abdulfattah
- Department of Internal Medicine, State University of New York Downstate Medical Center, Brooklyn, USA
| | - Jacob Sabu
- Department of Cardiology, State University of New York Downstate Health Sciences University, Brooklyn, USA
| | - Mary Mallappallil
- Department of Nephrology, State University of New York Downstate Medical Center, Brooklyn, USA
| | - Sabu John
- Department of Cardiology, State University of New York Downstate Medical Center, Brooklyn, USA
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Dashti Z, Yousefi Z, Kiani P, Taghizadeh M, Maleki MH, Borji M, Vakili O, Shafiee SM. Autophagy and the unfolded protein response shape the non-alcoholic fatty liver landscape: decoding the labyrinth. Metabolism 2024; 154:155811. [PMID: 38309690 DOI: 10.1016/j.metabol.2024.155811] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 01/23/2024] [Accepted: 01/28/2024] [Indexed: 02/05/2024]
Abstract
The incidence of nonalcoholic fatty liver disease (NAFLD) is on the rise, mirroring a global surge in diabetes and metabolic syndrome, as its major leading causes. NAFLD represents a spectrum of liver disorders, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH), which can potentially progress to cirrhosis and hepatocellular carcinoma (HCC). Mechanistically, we know the unfolded protein response (UPR) as a protective cellular mechanism, being triggered under circumstances of endoplasmic reticulum (ER) stress. The hepatic UPR is turned on in a broad spectrum of liver diseases, including NAFLD. Recent data also defines molecular mechanisms that may underlie the existing correlation between UPR activation and NAFLD. More interestingly, subsequent studies have demonstrated an additional mechanism, i.e. autophagy, to be involved in hepatic steatosis, and thus NAFLD pathogenesis, principally by regulating the insulin sensitivity, hepatocellular injury, innate immunity, fibrosis, and carcinogenesis. All these findings suggest possible mechanistic roles for autophagy in the progression of NAFLD and its complications. Both UPR and autophagy are dynamic and interconnected fluxes that act as protective responses to minimize the harmful effects of hepatic lipid accumulation, as well as the ER stress during NAFLD. The functions of UPR and autophagy in the liver, together with findings of decreased hepatic autophagy in correlation with conditions that predispose to NAFLD, such as obesity and aging, suggest that autophagy and UPR, alone or combined, may be novel therapeutic targets against the disease. In this review, we discuss the current evidence on the interplay between autophagy and the UPR in connection to the NAFLD pathogenesis.
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Affiliation(s)
- Zahra Dashti
- Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Zeynab Yousefi
- Department of Clinical Biochemistry, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Pouria Kiani
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Motahareh Taghizadeh
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Hasan Maleki
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Mohammad Borji
- Department of Clinical Biochemistry, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Omid Vakili
- Department of Clinical Biochemistry, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan, Iran; Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
| | - Sayed Mohammad Shafiee
- Autophagy Research Center, Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.
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Boccatonda A, Del Cane L, Marola L, D’Ardes D, Lessiani G, di Gregorio N, Ferri C, Cipollone F, Serra C, Santilli F, Piscaglia F. Platelet, Antiplatelet Therapy and Metabolic Dysfunction-Associated Steatotic Liver Disease: A Narrative Review. Life (Basel) 2024; 14:473. [PMID: 38672744 PMCID: PMC11051088 DOI: 10.3390/life14040473] [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: 02/28/2024] [Revised: 03/29/2024] [Accepted: 04/03/2024] [Indexed: 04/28/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is not only related to traditional cardiovascular risk factors like type 2 diabetes mellitus and obesity, but it is also an independent risk factor for the development of cardiovascular disease. MASLD has been shown to be independently related to endothelial dysfunction and atherosclerosis. MASLD is characterized by a chronic proinflammatory response that, in turn, may induce a prothrombotic state. Several mechanisms such as endothelial and platelet dysfunction, changes in the coagulative factors, lower fibrinolytic activity can contribute to induce the prothrombotic state. Platelets are players and addresses of metabolic dysregulation; obesity and insulin resistance are related to platelet hyperactivation. Furthermore, platelets can exert a direct effect on liver cells, particularly through the release of mediators from granules. Growing data in literature support the use of antiplatelet agent as a treatment for MASLD. The use of antiplatelets drugs seems to exert beneficial effects on hepatocellular carcinoma prevention in patients with MASLD, since platelets contribute to fibrosis progression and cancer development. This review aims to summarize the main data on the role of platelets in the pathogenesis of MASLD and its main complications such as cardiovascular events and the development of liver fibrosis. Furthermore, we will examine the role of antiplatelet therapy not only in the prevention and treatment of cardiovascular events but also as a possible anti-fibrotic and anti-tumor agent.
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Affiliation(s)
- Andrea Boccatonda
- Internal Medicine, Bentivoglio Hospital, AUSL Bologna, 40010 Bentivoglio, Italy
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy;
| | - Lorenza Del Cane
- Nephrology Unit, Department of Life, Health & Environmental Sciences and Internal Medicine, University of L’Aquila, ASL Avezzano-Sulmona-L’Aquila, San Salvatore Hospital, 67100 L’Aquila, Italy; (L.D.C.); (L.M.); (N.d.G.); (C.F.)
| | - Lara Marola
- Nephrology Unit, Department of Life, Health & Environmental Sciences and Internal Medicine, University of L’Aquila, ASL Avezzano-Sulmona-L’Aquila, San Salvatore Hospital, 67100 L’Aquila, Italy; (L.D.C.); (L.M.); (N.d.G.); (C.F.)
| | - Damiano D’Ardes
- Institute of “Clinica Medica”, Department of Medicine and Aging Science, “G. D’Annunzio” University of Chieti, 66100 Chieti, Italy (F.C.)
| | | | - Nicoletta di Gregorio
- Nephrology Unit, Department of Life, Health & Environmental Sciences and Internal Medicine, University of L’Aquila, ASL Avezzano-Sulmona-L’Aquila, San Salvatore Hospital, 67100 L’Aquila, Italy; (L.D.C.); (L.M.); (N.d.G.); (C.F.)
| | - Claudio Ferri
- Nephrology Unit, Department of Life, Health & Environmental Sciences and Internal Medicine, University of L’Aquila, ASL Avezzano-Sulmona-L’Aquila, San Salvatore Hospital, 67100 L’Aquila, Italy; (L.D.C.); (L.M.); (N.d.G.); (C.F.)
| | - Francesco Cipollone
- Institute of “Clinica Medica”, Department of Medicine and Aging Science, “G. D’Annunzio” University of Chieti, 66100 Chieti, Italy (F.C.)
| | - Carla Serra
- Interventional, Diagnostic and Therapeutic Ultrasound Unit, IRCCS, Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy;
| | - Francesca Santilli
- Department of Medicine and Aging Sciences, Center for Advanced Studies and Technology, University of Chieti, 66100 Chieti, Italy;
| | - Fabio Piscaglia
- Department of Medical and Surgical Sciences, University of Bologna, 40138 Bologna, Italy;
- Division of Internal Medicine, Hepatobiliary and Immunoallergic Diseases, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
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Schwärzler J, Grabherr F, Grander C, Adolph TE, Tilg H. The pathophysiology of MASLD: an immunometabolic perspective. Expert Rev Clin Immunol 2024; 20:375-386. [PMID: 38149354 DOI: 10.1080/1744666x.2023.2294046] [Citation(s) in RCA: 25] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 12/08/2023] [Indexed: 12/28/2023]
Abstract
INTRODUCTION Metabolic-associated liver diseases have emerged pandemically across the globe and are clinically related to metabolic disorders such as obesity and type 2 diabetes. The new nomenclature and definition (i.e. metabolic dysfunction-associated steatotic liver disease - MASLD; metabolic dysfunction-associated steatohepatitis - MASH) reflect the nature of these complex systemic disorders, which are characterized by inflammation, gut dysbiosis and metabolic dysregulation. In this review, we summarize recent advantages in understanding the pathophysiology of MASLD, which we parallel to emerging therapeutic concepts. AREAS COVERED We summarize the pathophysiologic concepts of MASLD and its transition to MASH and subsequent advanced sequelae of diseases. Furthermore, we highlight how dietary constituents, microbes and associated metabolites, metabolic perturbations, and immune dysregulation fuel lipotoxicity, hepatic inflammation, liver injury, insulin resistance, and systemic inflammation. Deciphering the intricate pathophysiologic processes that contribute to the development and progression of MASLD is essential to develop targeted therapeutic approaches to combat this escalating burden for health-care systems. EXPERT OPINION The rapidly increasing prevalence of metabolic dysfunction-associated steatotic liver disease challenges health-care systems worldwide. Understanding pathophysiologic traits is crucial to improve the prevention and treatment of this disorder and to slow progression into advanced sequelae such as cirrhosis and hepatocellular carcinoma.
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Affiliation(s)
- Julian Schwärzler
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Felix Grabherr
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Christoph Grander
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Timon E Adolph
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
| | - Herbert Tilg
- Department of Internal Medicine I, Gastroenterology, Hepatology, Endocrinology & Metabolism, Medical University of Innsbruck, Innsbruck, Austria
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11
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Yang K, Song M. New Insights into the Pathogenesis of Metabolic-Associated Fatty Liver Disease (MAFLD): Gut-Liver-Heart Crosstalk. Nutrients 2023; 15:3970. [PMID: 37764755 PMCID: PMC10534946 DOI: 10.3390/nu15183970] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 09/11/2023] [Accepted: 09/13/2023] [Indexed: 09/29/2023] Open
Abstract
Metabolism-associated fatty liver disease (MAFLD) is a multifaceted disease that involves complex interactions between various organs, including the gut and heart. It is defined by hepatic lipid accumulation and is related to metabolic dysfunction, obesity, and diabetes. Understanding the intricate interplay of the gut-liver-heart crosstalk is crucial for unraveling the complexities of MAFLD and developing effective treatment and prevention strategies. The gut-liver crosstalk participates in the regulation of the metabolic and inflammatory processes through host-microbiome interactions. Gut microbiota have been associated with the development and progression of MAFLD, and its dysbiosis contributes to insulin resistance, inflammation, and oxidative stress. Metabolites derived from the gut microbiota enter the systemic circulation and influence both the liver and heart, resulting in the gut-liver-heart axis playing an important role in MAFLD. Furthermore, growing evidence suggests that insulin resistance, endothelial dysfunction, and systemic inflammation in MAFLD may contribute to an increased risk of cardiovascular disease (CVD). Additionally, the dysregulation of lipid metabolism in MAFLD may also lead to cardiac dysfunction and heart failure. Overall, the crosstalk between the liver and heart involves a complex interplay of molecular pathways that contribute to the development of CVD in patients with MAFLD. This review emphasizes the current understanding of the gut-liver-heart crosstalk as a foundation for optimizing patient outcomes with MAFLD.
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Affiliation(s)
| | - Myeongjun Song
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
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12
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Shen X, Luo K, Yuan J, Gao J, Cui B, Yu Z, Lu Z. Hepatic DDAH1 mitigates hepatic steatosis and insulin resistance in obese mice: Involvement of reduced S100A11 expression. Acta Pharm Sin B 2023; 13:3352-3364. [PMID: 37655336 PMCID: PMC10465955 DOI: 10.1016/j.apsb.2023.05.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/16/2023] [Accepted: 04/03/2023] [Indexed: 09/02/2023] Open
Abstract
Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is an important regulator of plasma asymmetric dimethylarginine (ADMA) levels, which are associated with insulin resistance in patients with nonalcoholic fatty liver disease (NAFLD). To elucidate the role of hepatic DDAH1 in the pathogenesis of NAFLD, we used hepatocyte-specific Ddah1-knockout mice (Ddah1HKO) to examine the progress of high-fat diet (HFD)-induced NAFLD. Compared to diet-matched flox/flox littermates (Ddah1f/f), Ddah1HKO mice exhibited higher serum ADMA levels. After HFD feeding for 16 weeks, Ddah1HKO mice developed more severe liver steatosis and worse insulin resistance than Ddah1f/f mice. On the contrary, overexpression of DDAH1 attenuated the NAFLD-like phenotype in HFD-fed mice and ob/ob mice. RNA-seq analysis showed that DDAH1 affects NF-κB signaling, lipid metabolic processes, and immune system processes in fatty livers. Furthermore, DDAH1 reduces S100 calcium-binding protein A11 (S100A11) possibly via NF-κB, JNK and oxidative stress-dependent manner in fatty livers. Knockdown of hepatic S100a11 by an AAV8-shS100a11 vector alleviated hepatic steatosis and insulin resistance in HFD-fed Ddah1HKO mice. In summary, our results suggested that the liver DDAH1/S100A11 axis has a marked effect on liver lipid metabolism in obese mice. Strategies to increase liver DDAH1 activity or decrease S100A11 expression could be a valuable approach for NAFLD therapy.
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Affiliation(s)
- Xiyue Shen
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
- Institute of Respiratory Medicine, Tongji University School of Medicine, Shanghai 200433, China
| | - Kai Luo
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Juntao Yuan
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Junling Gao
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Bingqing Cui
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhuoran Yu
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhongbing Lu
- College of Life Science, University of Chinese Academy of Sciences, Beijing 100049, China
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13
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Son T, Jeong I, Park J, Jun W, Kim A, Kim OK. Adipose tissue-derived exosomes contribute to obesity-associated liver diseases in long-term high-fat diet-fed mice, but not in short-term. Front Nutr 2023; 10:1162992. [PMID: 37229466 PMCID: PMC10203204 DOI: 10.3389/fnut.2023.1162992] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 04/17/2023] [Indexed: 05/27/2023] Open
Abstract
Introduction Our study aimed to investigate the changes in hepatic endoplasmic reticulum (ER) stress, inflammation, insulin signaling, and lipid metabolism during the administration of a high-fat diet (HFD) in mice in order to identify correlations between obesity and metabolic disease development in the liver. Methods We used short-, medium-, and long-term HFD periods, corresponding to 4, 8, and 12 weeks, respectively, and isolated exosomes from adipose tissue. We confirmed the effect of adipose tissue-derived exosomes on metabolic disorders in obesity in alpha mouse liver 12 (AML12) hepatocytes. Results Adipose tissue-derived exosomes from HFD mice did not affect the AML12 cells after 4 weeks, but ER stress, inflammatory response, insulin resistance, and lipid synthesis were observed after 8 and 12 weeks. Furthermore, we confirmed that an HFD increases the amount of adipose tissue-derived exosomes in mice. Consequently, we can infer that adipose tissue-derived exosomes from HFD-fed mice significantly increase ER stress, inflammatory response, insulin resistance, and lipid synthesis in AML12 cells. Discussion Our results demonstrate that obesity alters the effects of adipose tissue-derived exosomes in the liver, potentially becoming a risk factor in the development of obesity-induced liver diseases.
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Affiliation(s)
- Taesang Son
- Division of Food and Nutrition, Chonnam National University, Gwangju, Republic of Korea
| | - Inae Jeong
- Division of Food and Nutrition, Chonnam National University, Gwangju, Republic of Korea
| | - Jeongjin Park
- Division of Food and Nutrition, Chonnam National University, Gwangju, Republic of Korea
- Human Ecology Research Institute, Chonnam National University, Gwangju, Republic of Korea
| | - Woojin Jun
- Division of Food and Nutrition, Chonnam National University, Gwangju, Republic of Korea
- Human Ecology Research Institute, Chonnam National University, Gwangju, Republic of Korea
| | - Andre Kim
- Department of Pharmaceutical Engineering, Silla University, Busan, Republic of Korea
| | - Ok-Kyung Kim
- Division of Food and Nutrition, Chonnam National University, Gwangju, Republic of Korea
- Human Ecology Research Institute, Chonnam National University, Gwangju, Republic of Korea
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14
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Lee EJ, Edward OC, Seo EB, Mun EG, Jeong SJ, Ha G, Han A, Cha YS. Gochujang Ameliorates Hepatic Inflammation by Improving Dysbiosis of Gut Microbiota in High-Fat Diet-Induced Obese Mice. Microorganisms 2023; 11:microorganisms11040911. [PMID: 37110334 PMCID: PMC10141003 DOI: 10.3390/microorganisms11040911] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 03/29/2023] [Accepted: 03/30/2023] [Indexed: 04/03/2023] Open
Abstract
Abnormal fat accumulation with gut microbiota dysbiosis results in hepatic inflammation by upregulating the release of lipopolysaccharide (LPS) and inflammatory cytokine. Gochujang, a traditional fermented condiment, has beneficial effects, such as anti-colonic inflammatory effects. However, Gochujang has been controversial because of its high salt content (the Korean Paradox). Thus, the present study aimed to investigate the preventative effects of Gochujang on hepatic inflammation and related gut microbiota through discussing the Korean Paradox. The mice were divided into groups including a normal diet (ND), high-fat diet (HD), HD with salt (SALT), HD with a high percentage of beneficial microbiota Gochujang (HBM), and HD with diverse beneficial microbiota Gochujang (DBM). Gochujang markedly reduced lipid accumulation, hepatic injury, and inflammation response. Furthermore, Gochujang attenuated protein expression involved in the JNK/IκB/NF-κB pathway. Additionally, Gochujang regulated the gut microbiota-derived LPS production and Firmicutes/Bacteroidetes ratio. Gochujang regulated the levels of gut microbiota such as Bacteroides, Muribaculum, Lactobacillus, and Enterorhabdus, which were correlated with hepatic inflammation. Salt did not have foregoing effects, meaning that the salt content in Gochujang did not affect its anti-inflammatory effect. In conclusion, Gochujang showed anti-hepatic inflammation effects via reduced lipid accumulation, hepatic injury, and inflammatory response together with reorganization of gut microbiota dysbiosis regardless of salt content and the difference of micro bacteria composition.
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Affiliation(s)
- Eun-Ji Lee
- Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Olivet Chiamaka Edward
- Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Eun-Bi Seo
- Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Eun-Gyung Mun
- Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Su-Ji Jeong
- Department of R & D, Microbial Institute for Fermentation Industry, Sunchang-gun 56000, Republic of Korea
| | - Gwangsu Ha
- Department of R & D, Microbial Institute for Fermentation Industry, Sunchang-gun 56000, Republic of Korea
| | - Anna Han
- Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Republic of Korea
- K-Food Research Center, Jeonbuk National University, Jeonju 54896, Republic of Korea
| | - Youn-Soo Cha
- Department of Food Science and Human Nutrition, Jeonbuk National University, Jeonju 54896, Republic of Korea
- K-Food Research Center, Jeonbuk National University, Jeonju 54896, Republic of Korea
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15
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Khalili P, Ayoobi F, Kahkesh Pour F, Esmaeili-Nadimi A, Abassifard M, La Vecchia C, Jamali Z. Serum liver enzymes and metabolic syndrome from the Rafsanjan Cohort Study. J Investig Med 2023; 71:140-148. [PMID: 36647299 DOI: 10.1177/10815589221141830] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
Our investigation aimed at evaluating the relationship between metabolic syndrome, alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase (GGT), and alkaline phosphatase (ALP) in the Rafsanjan cohort study (RCS). We used data obtained from the RCS, as a part of the prospective epidemiological research studies in Iran. In this cross-sectional research, 9895 participants from the baseline phase of RCS who completed medical questionnaire were included. Metabolic syndrome (MetS) defined using NCEP-ATP III criteria. The relationship between elevated serum liver enzymes levels even within the normal range and metabolic syndrome was evaluated by logistic regressions. The prevalence of MetS was 34.42% in the participants of study. The mean concentrations of AST, ALT, ALP, and GGT increased with increasing MetS components. After adjusting for all potential confounders, elevated serum concentrations of ALT, AST, GGT, and ALP even within the normal range were related with an increased odds of MetS. MetS was associated with increased levels of liver enzymes even within the normal range. These results indicated the potential for elevated liver enzymes as biomarkers for the possible presence of MetS.
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Affiliation(s)
- Parvin Khalili
- Social Determinants of Health Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Epidemiology, School of Public Health, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Ayoobi
- Non-Communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Firoozeh Kahkesh Pour
- Social Determinants of Health Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Ali Esmaeili-Nadimi
- Non-Communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Mitra Abassifard
- Non-Communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.,Department of Internal Medicine, Ali ibn Abi Talib Hospital, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Carlo La Vecchia
- Department of Clinical Sciences and Community Health, Università degli Study di Milano, Milan, Italy
| | - Zahra Jamali
- Non-Communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
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16
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Zuo Q, Zhang G, He L, Ma S, Ma H, Zhai J, Wang Z, Zhang T, Wang Y, Guo Y. Canagliflozin Attenuates Hepatic Steatosis and Atherosclerosis Progression in Western Diet-Fed ApoE-Knockout Mice. Drug Des Devel Ther 2022; 16:4161-4177. [PMID: 36510490 PMCID: PMC9741490 DOI: 10.2147/dddt.s388823] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Accepted: 11/21/2022] [Indexed: 12/12/2022] Open
Abstract
Purpose To investigate the effect of canagliflozin (20 mg/kg) on hepatic steatosis and atherosclerosis, and further to explore its possible mechanism. Methods Blood glucose, blood lipid, oxidative stress response and inflammatory cytokines were examined by intraperitoneal glucose tolerance test and ELISA assay. HE and Oil Red O staining were used to estimate the extent of hepatic steatosis and atherosclerosis. RNA-seq and qRT-PCR were used to further investigate the potential mechanism. The effects of canagliflozin on autophagy were detected using transmission electron microscopy and Western blotting. The endothelial function-related markers were determined by qRT-PCR. Results Canagliflozin notably alleviated the elevation in blood glucose and insulin resistance in western diet-fed ApoE-/- mice. In ApoE-/-+Cana group, ApoE-/- mice had lower levels of TG, TC, LDL-C, TNF-α, IL-6, IL-1β, and MCP-1. HE and Oil Red O staining presented that canagliflozin restrained the atherosclerotic plaque development and lipid accumulation. RNA-seq showed that 87 DEGs were relevant to improvement of hepatic steatosis and atherosclerosis by canagliflozin. Among them, CPS1, ASS1, ASL, ARG1, MATLA, GLS2, GOT1, SREBP1, Plin5, Retreg1, and C/EBPβ were verified. KEGG enrichment analysis indicated that DEGs were mainly involved in amino acid metabolism. Besides, we observed that canagliflozin reduced the contents of aspartic acid and citrulline in liver. Western blotting showed that ASS1 and p-AMPK/AMPK was remarkably elevated after administration of canagliflozin. Correspondingly, canagliflozin down-regulated SREBP1, FAS, ACC1, HMGCR, p-mTOR/m-TOR, p-ULK1/ULK1 and p62, but up-regulated CPT1, Beclin 1 and LC3 II/LC3I. TEM showed that canagliflozin reduced the number of lipid droplets and increased the autophagosomes. Moreover, we found that canagliflozin elevated the aortic endothelial function-associated markers including ASS1, ASL and eNOS. Conclusion Canagliflozin may attenuate hepatic steatosis by improving lipid metabolism, enhancing autophagy, and reducing inflammatory response through ASS1/AMPK pathway. Besides, canagliflozin further effectively improves the aortic endothelial function, thereby suppressing atherosclerosis development.
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Affiliation(s)
- Qingjuan Zuo
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China,Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Guorui Zhang
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China,Department of Cardiology, the Third Hospital of Shijiazhuang City Affiliated to Hebei Medical University, Shijiazhuang, People’s Republic of China
| | - Lili He
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Sai Ma
- Department of Internal Medicine, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Huijuan Ma
- Department of Endocrinology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Jianlong Zhai
- Department of Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Zhongli Wang
- Department of Physical Examination Center, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Tingting Zhang
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Yan Wang
- Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China
| | - Yifang Guo
- Department of Internal Medicine, Hebei Medical University, Shijiazhuang, People’s Republic of China,Department of Geriatric Cardiology, Hebei General Hospital, Shijiazhuang, People’s Republic of China,Correspondence: Yifang Guo, Department of Geriatric Cardiology, Hebei General Hospital, No. 348, Heping West Road, Xinhua District, Shijiazhuang, Hebei, 050051, People’s Republic of China, Tel +86-15100189182, Email
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17
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Toprak K, Kaplangoray M, Palice A, Taşcanov MB, Altıparmak İH, Biçer A, Demirbağ R. Ectodysplasin A is associated with the presence and severity of coronary artery disease and poor long-term clinical outcome in patients presenting with ST-elevation myocardial infarction. Acta Clin Belg 2022:1-10. [DOI: 10.1080/17843286.2022.2140246] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Kenan Toprak
- Department of Cardiology, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | | | - Ali Palice
- Mehmet Akif Inan Training and Research Hospital, Sanlıurfa, Turkey
| | | | | | - Asuman Biçer
- Department of Cardiology, Faculty of Medicine, Harran University, Sanliurfa, Turkey
| | - Recep Demirbağ
- Department of Cardiology, Faculty of Medicine, Harran University, Sanliurfa, Turkey
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18
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Warinhomhoun S, Khine HEE, Sritularak B, Likhitwitayawuid K, Miyamoto T, Tanaka C, Punsawad C, Punpreuk Y, Sungthong R, Chaotham C. Secondary Metabolites in the Dendrobium heterocarpum Methanolic Extract and Their Impacts on Viability and Lipid Storage of 3T3-L1 Pre-Adipocytes. Nutrients 2022; 14:nu14142886. [PMID: 35889842 PMCID: PMC9317628 DOI: 10.3390/nu14142886] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 07/07/2022] [Accepted: 07/12/2022] [Indexed: 02/05/2023] Open
Abstract
Although many natural products have proven their potential to regulate obesity through the modulation of adipocyte biology, none of them has yet been approved for clinical use in obesity therapy. This work aims to isolate valuable secondary metabolites from an orchid species (Dendrobium heterocarpum) and evaluate their possible roles in the growth and differentiation of 3T3-L1 pre-adipocytes. Six compounds were isolated from the orchid’s methanolic extracts and identified as amoenylin (1), methyl 3-(4-hydroxyphenyl) propionate (2), 3,4-dihydroxy-5,4’-dimethoxybibenzyl (3), dendrocandin B (4), dendrofalconerol A (5), and syringaresinol (6). Among these phytochemicals, compounds 2, 3, and 6 exhibited lower effects on the viability of 3T3-L1 cells, offering non-cytotoxic concentrations of ≲ 10 µM. Compared to others tested, compound 3 was responsible for the maximum reduction of lipid storage in 3T3-L1 adipocytes (IC50 = 6.30 ± 0.10 µM). A set of protein expression studies unveiled that compound 3 at non-cytotoxic doses could suppress the expression of some key transcription factors in adipocyte differentiation (i.e., PPARγ and C/EBPα). Furthermore, this compound could deactivate some proteins involved in the MAPK pathways (i.e., JNK, ERK, and p38). Our findings prove that D. heterocarpum is a promising source to explore bioactive molecules capable of modulating adipocytic growth and development, which can potentially be assessed and innovated further as pharmaceutical products to defeat obesity.
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Affiliation(s)
- Sakan Warinhomhoun
- School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand; (S.W.); (C.P.)
- Center of Excellence in Marijuana, Hemp, and Kratom, Walailak University, Nakhon Si Thammarat 80160, Thailand
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (B.S.); (K.L.)
| | - Hnin Ei Ei Khine
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (H.E.E.K.); (R.S.)
| | - Boonchoo Sritularak
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (B.S.); (K.L.)
- Natural Products for Ageing and Chronic Diseases Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
| | - Kittisak Likhitwitayawuid
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (B.S.); (K.L.)
| | - Tomofumi Miyamoto
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (T.M.); (C.T.)
| | - Chiaki Tanaka
- Graduate School of Pharmaceutical Sciences, Kyushu University, Fukuoka 812-8582, Japan; (T.M.); (C.T.)
- School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama 640-8156, Japan
| | - Chuchard Punsawad
- School of Medicine, Walailak University, Nakhon Si Thammarat 80160, Thailand; (S.W.); (C.P.)
| | - Yanyong Punpreuk
- Department of Agriculture, Kasetsart University, Bangkok 10900, Thailand;
| | - Rungroch Sungthong
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (H.E.E.K.); (R.S.)
| | - Chatchai Chaotham
- Department of Biochemistry and Microbiology, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand; (H.E.E.K.); (R.S.)
- Preclinical Toxicity and Efficacy Assessment of Medicines and Chemicals Research Unit, Faculty of Pharmaceutical Sciences, Chulalongkorn University, Bangkok 10330, Thailand
- Correspondence:
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19
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Noroozi Karimabad M, Khalili P, Ayoobi F, Esmaeili-Nadimi A, La Vecchia C, Jamali Z. Serum liver enzymes and diabetes from the Rafsanjan cohort study. BMC Endocr Disord 2022; 22:127. [PMID: 35549705 PMCID: PMC9102258 DOI: 10.1186/s12902-022-01042-2] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 05/04/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND We evaluated the relation between ALT, AST, GGT and ALP with diabetes in the Rafsanjan Cohort Study. MATERIALS AND METHODS The present study is a cross-sectional research including 9991 adults participated via sampling. We used data obtained from the Rafsanjan Cohort Study (RCS), as a part of the prospective epidemiological research studies in IrAN (PERSIAN). Elevated serum levels of ALT, AST, GGT and ALP were defined according to the reference range of the laboratory in the cohort center. Serum liver enzymes levels within the normal range were categorized into quartiles, and their relationship with diabetes was evaluated by logistic regressions. FINDINGS In present study, elevated serum levels of ALT, AST, GGT, and ALP were associated with increased odds of diabetes (adjusted ORs: 1.81, 95%CI 1.51-2.17; 1.75, 95%CI 1.32-2.32; 1.77, 95%CI 1.50-2.08; 1.60, 95%CI 1.35-1.90 respectively). Also, in subjects with normal levels of ALT, GGT and ALP, a dose-response increase was shown for diabetes. CONCLUSION Elevated levels of ALT, AST, GGT and ALP are related to a higher odds of diabetes. Also, increased levels of ALT, GGT and ALP even within normal range were independently related with the increased odds of diabetes. These results indicated the potential of elevated liver enzymes as biomarkers for the possible presence of diabetes.
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Affiliation(s)
- Mojgan Noroozi Karimabad
- Molecular Medicuine Research Center, Research Institute of Basic Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Parvin Khalili
- Department of Epidemiology, School of Public Health, Social Determinants of Health Research Centre, Rafsanjan University of Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Fatemeh Ayoobi
- Occupational Safety and Health Research Center, NICICO, World Safety Organization and Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Ali Esmaeili-Nadimi
- Non-Communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
| | - Carlo La Vecchia
- Department of Clinical Sciences and Community Health, Università Degli Study Di Milano, 20133, Milan, Italy
| | - Zahra Jamali
- Non-Communicable Diseases Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran.
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20
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Wang B, Xu J, Ren Q, Cheng L, Guo F, Liang Y, Yang L, Tan Z, Fu P, Ma L. Fatty acid-binding protein 4 is a therapeutic target for septic acute kidney injury by regulating inflammatory response and cell apoptosis. Cell Death Dis 2022; 13:333. [PMID: 35410456 PMCID: PMC9001746 DOI: 10.1038/s41419-022-04794-w] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 03/14/2022] [Accepted: 03/22/2022] [Indexed: 12/16/2022]
Abstract
Sepsis is a systemic inflammatory state in response to infection, and concomitant acute kidney injury (AKI) significantly increases morbidity and mortality. Growing evidence suggests that fatty acid-binding protein 4 (FABP4) is critically involved in kidney diseases, while its role in septic AKI remains unknown. Here, FABP4 was mainly upregulated in renal tubular epithelial cells (RTECs) following cecal ligation and puncture (CLP)- or lipopolysaccharide (LPS)-induced septic AKI. FABP4 inhibition by genetic deletion or BMS309403 treatment both attenuated kidney dysfunction and pathological injury in CLP- or LPS-treated mice. Notably, RTEC-specific deletion of FABP4 also showed similar renoprotective effects. Moreover, FABP4 inhibition alleviated inflammation and apoptosis in CLP-injured kidneys and LPS-stimulated mouse tubular epithelial cells. Mechanistically, TLR4 blockage improved sepsis-induced kidney injury, as well as suppressed c-Jun phosphorylation and FABP4 expression, where c-Jun knockdown also inhibited LPS-stimulated FABP4 level. Meanwhile, FABP4 inhibition reduced the elevated phosphorylated c-Jun, while the levels of TLR4 and MyD88 were uninfluenced. Collectively, the increased FABP4 in RTECs is dependent on TLR4/c-Jun signaling activation and contributes to kidney injury, by forming a positive feedback loop with c-Jun to aggravate inflammation and apoptosis in septic AKI. Thus, FABP4 may be a therapeutic target for septic AKI.
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Affiliation(s)
- Bo Wang
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, 610041, Chengdu, China
| | - Jun Xu
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, 610041, Chengdu, China
| | - Qian Ren
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, 610041, Chengdu, China
| | - Lu Cheng
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, 610041, Chengdu, China
| | - Fan Guo
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, 610041, Chengdu, China
| | - Yan Liang
- Research Core Facility of West China Hospital, Sichuan University, 610041, Chengdu, China
| | - Letian Yang
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, 610041, Chengdu, China
| | - Zhouke Tan
- Division of Nephrology, ZunYi Medical University Affiliated Hospital, 563003, ZunYi, China
| | - Ping Fu
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, 610041, Chengdu, China.
| | - Liang Ma
- Kidney Research Institute, Division of Nephrology, West China Hospital of Sichuan University, 610041, Chengdu, China.
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21
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Koo BK, Lim S. Metabolic Syndrome and Metabolic Dysfunction‐Associated Fatty Liver Disease. CLINICAL OBESITY IN ADULTS AND CHILDREN 2022:159-177. [DOI: 10.1002/9781119695257.ch13] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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22
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Smirne C, Croce E, Di Benedetto D, Cantaluppi V, Comi C, Sainaghi PP, Minisini R, Grossini E, Pirisi M. Oxidative Stress in Non-Alcoholic Fatty Liver Disease. LIVERS 2022; 2:30-76. [DOI: 10.3390/livers2010003] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a challenging disease caused by multiple factors, which may partly explain why it still remains an orphan of adequate therapies. This review highlights the interaction between oxidative stress (OS) and disturbed lipid metabolism. Several reactive oxygen species generators, including those produced in the gastrointestinal tract, contribute to the lipotoxic hepatic (and extrahepatic) damage by fatty acids and a great variety of their biologically active metabolites in a “multiple parallel-hit model”. This leads to inflammation and fibrogenesis and contributes to NAFLD progression. The alterations of the oxidant/antioxidant balance affect also metabolism-related organelles, leading to lipid peroxidation, mitochondrial dysfunction, and endoplasmic reticulum stress. This OS-induced damage is at least partially counteracted by the physiological antioxidant response. Therefore, modulation of this defense system emerges as an interesting target to prevent NAFLD development and progression. For instance, probiotics, prebiotics, diet, and fecal microbiota transplantation represent new therapeutic approaches targeting the gut microbiota dysbiosis. The OS and its counter-regulation are under the influence of individual genetic and epigenetic factors as well. In the near future, precision medicine taking into consideration genetic or environmental epigenetic risk factors, coupled with new OS biomarkers, will likely assist in noninvasive diagnosis and monitoring of NAFLD progression and in further personalizing treatments.
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Affiliation(s)
- Carlo Smirne
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Eleonora Croce
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Davide Di Benedetto
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Vincenzo Cantaluppi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Cristoforo Comi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Pier Paolo Sainaghi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Rosalba Minisini
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Elena Grossini
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
| | - Mario Pirisi
- Department of Translational Medicine, Università del Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
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23
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Khanna D, Khanna S, Khanna P, Kahar P, Patel BM. Obesity: A Chronic Low-Grade Inflammation and Its Markers. Cureus 2022; 14:e22711. [PMID: 35386146 PMCID: PMC8967417 DOI: 10.7759/cureus.22711] [Citation(s) in RCA: 129] [Impact Index Per Article: 43.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 02/28/2022] [Indexed: 12/15/2022] Open
Abstract
As the prevalence of obesity continues to rise, the world is facing a major public health concern. Obesity is a complex disease associated with an increase in several inflammatory markers, leading to chronic low-grade inflammation. Of multifactorial etiology, it is often used as a measurement of morbidity and mortality. There remains much unknown regarding the association between obesity and inflammation. This review seeks to compile scientific literature on obesity and its associated inflammatory markers in chronic disease and further discusses the role of adipose tissue, macrophages, B-cells, T-cells, fatty acids, amino acids, adipokines, and hormones in obesity. Data were obtained using PubMed and Google Scholar. Obesity, inflammation, immune cells, hormones, fatty acids, and others were search words used to acquire relevant articles. Studies suggest brown adipose tissue is negatively associated with body mass index (BMI) and body fat percentage. Researchers also found the adipose tissue of lean individuals predominantly secretes anti-inflammatory markers, while in obese individuals more pro-inflammatory markers are secreted. Many studies found that adipose tissue in obese individuals showed a shift in immune cells from anti-inflammatory M2 macrophages to pro-inflammatory M1 macrophages, which was also correlated with insulin resistance. Obese individuals generally present with higher levels of hormones such as leptin, visfatin, and resistin. With obesity on the rise globally, it is predicted that severe obesity will become most common amongst low-income adults, black individuals, and women by 2030, making the need for intervention urgent. Further investigation into the association between obesity and inflammation is required to understand the mechanism behind this disease.
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Affiliation(s)
- Deepesh Khanna
- Foundational Sciences, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA
| | - Siya Khanna
- Foundational Sciences, Nova Southeastern University Dr. Kiran C. Patel College of Osteopathic Medicine, Fort Lauderdale, USA
| | - Pragya Khanna
- Pediatrics, Gujarat Medical Education and Research Society (GMERS) Medical College, Vadnagar, IND
| | - Payal Kahar
- Department of Health Sciences, Florida Gulf Coast University, Fort Myers, USA
| | - Bhavesh M Patel
- Pediatrics, Gujarat Medical Education and Research Society (GMERS) Medical College, Vadnagar, IND
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Di Pasqua LG, Cagna M, Berardo C, Vairetti M, Ferrigno A. Detailed Molecular Mechanisms Involved in Drug-Induced Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis: An Update. Biomedicines 2022; 10:194. [PMID: 35052872 PMCID: PMC8774221 DOI: 10.3390/biomedicines10010194] [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: 11/19/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 12/12/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) are some of the biggest public health challenges due to their spread and increasing incidence around the world. NAFLD is characterized by intrahepatic lipid deposition, accompanied by dyslipidemia, hypertension, and insulin resistance, leading to more serious complications. Among the various causes, drug administration for the treatment of numerous kinds of diseases, such as antiarrhythmic and antihypertensive drugs, promotes the onset and progression of steatosis, causing drug-induced hepatic steatosis (DIHS). Here, we reviewed in detail the major classes of drugs that cause DIHS and the specific molecular mechanisms involved in these processes. Eight classes of drugs, among the most used for the treatment of common pathologies, were considered. The most diffused mechanism whereby drugs can induce NAFLD/NASH is interfering with mitochondrial activity, inhibiting fatty acid oxidation, but other pathways involved in lipid homeostasis are also affected. PubMed research was performed to obtain significant papers published up to November 2021. The key words included the class of drugs, or the specific compound, combined with steatosis, nonalcoholic steatohepatitis, fibrosis, fatty liver and hepatic lipid deposition. Additional information was found in the citations listed in other papers, when they were not displayed in the original search.
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Affiliation(s)
- Laura Giuseppina Di Pasqua
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Marta Cagna
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Clarissa Berardo
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Mariapia Vairetti
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
| | - Andrea Ferrigno
- Unit of Cellular and Molecular Pharmacology and Toxicology, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
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Ke K, Jiang X, Zhang Y, Zhou Y, Zhao J, Zhang J, Liu Y, An M. Exploring the Mechanism of Wu Ling San plus Flavor for the Treatment of Diabetic Macular Edema Based on Network Pharmacology and Molecular Docking Techniques. Chin Med 2022. [DOI: 10.4236/cm.2022.133004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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Allencherril RP, Markides KS, Al Snih S. Liver Disease Among Mexican Americans Aged 67 Years and Older. J Prim Care Community Health 2022; 13:21501319221116231. [PMID: 35929017 PMCID: PMC9358553 DOI: 10.1177/21501319221116231] [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] [Indexed: 11/29/2022] Open
Abstract
Background: The Center for Disease Control and Prevention (CDC) reports that liver disease is a significant cause of morbidity and mortality in the US, afflicting 4.5 million people in 2018, or approximately 1.7% of the American adult population. Objective: To determine the prevalence and risk factors associated with liver disease among older Mexican Americans over 18 years of follow-up. Methods: Non-institutionalized Mexican Americans aged ≥67 years (N = 1938) from the Hispanic Established Population for the Epidemiologic Study of the Elderly (1995/96-2012/13) were studied. Measures included socio-demographic variables, self-reported liver disease, language of interview, medical conditions, hand-grip strength, physical and cognitive function, depressive symptoms, and body mass index. Generalized estimating equation models were used to estimate the odds ratio and 95% confidence interval (CI) of liver disease over time. Results: The mean age at baseline was 74.9 ± 6.0 years and 58.4% were female. The prevalence of liver disease ranged from 2.4% to 8.4%. Over time, the odds ratio of reporting liver disease was 1.17 (CI = 1.12-1.22). Older age, Spanish interview, arthritis, diabetes, heart failure, cancer, and high scores on the Mini-Mental-State-Examination were factors associated with greater odds of reporting liver disease over time. Married participants reported lower odds of liver disease over time. Conclusions: The prevalence of liver disease in this population was high, ranging from 2.4% to 8.4%. Diabetes, heart failure, arthritis, and cancer were risk factors for liver disease. Screening for liver function among patients with these morbidities may help prevent liver disease in this population with high rates of diabetes and obesity.
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Affiliation(s)
| | | | - Soham Al Snih
- The University of Texas Medical Branch, Galveston, TX, USA
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27
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Zepeda-Peña AC, Gurrola-Díaz CM, Domínguez-Rosales JA, García-López PM, Pizano-Andrade JC, Hernández-Nazará ZH, Vargas-Guerrero B. Effect of Lupinus rotundiflorus gamma conglutin treatment on JNK1 gene expression and protein activation in a rat model of type 2 diabetes. PHARMACEUTICAL BIOLOGY 2021; 59:374-380. [PMID: 33784492 PMCID: PMC8018548 DOI: 10.1080/13880209.2021.1893757] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 01/05/2021] [Accepted: 02/17/2021] [Indexed: 06/12/2023]
Abstract
CONTEXT Gamma conglutin (Cγ) from lupine species represents a potential complementary treatment for type 2 diabetes mellitus (T2DM) because of its hypoglycaemic effect. However, its underlying mechanism of action is not fully known. OBJECTIVE To evaluate whether Cγ from Lupinus rotundiflorus M. E. Jones (Fabaceae) modulates c-Jun N-terminal kinase 1 (JNK1) expression and activation in a T2DM rat model. MATERIALS AND METHODS Gamma conglutin isolated from L. rotundiflorus seeds was characterized by SDS-PAGE. Fifteen Wistar rats with streptozotocin-induced T2DM (HG) were randomized into three groups (n = 5): vehicle administration (HG-Ctrl), oral treatment with Cγ (120 mg/kg/day) (HG-Lr) for one week, and treatment with metformin (300 mg/kg/day) (HG-Met); a healthy group (Ctrl, n = 5) was included as control. The levels of glucose and biomarkers of renal and hepatic function were measured pre- and post-treatment. Hepatic Jnk1 expression and phosphorylation of JNK1 were evaluated by qRT-PCR and western blot, respectively. RESULTS Oral treatment with either Cγ or metformin reduced serum glucose level to 86.30 and 74.80 mg/dL, respectively (p ˂ 0.05), from the basal levels. Jnk1 expression was 0.65- and 0.54-fold lower (p ˂ 0.05) in the HG-Lr and HG-Met groups, respectively, than in HG-Ctrl. Treatment with Cγ decreased JNK1 phosphorylation. However, Cγ did not change the levels of kidney and liver biomarkers. DISCUSSION AND CONCLUSIONS Treatment with Cγ from L. rotundiflorus inhibited Jnk1 expression, in vivo, suggesting JNK1 as a potential therapeutic target in diabetes and revealing one mechanism underlying the hypoglycaemic effect of lupine Cγ. Nevertheless, further studies are required.
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Affiliation(s)
- Andrea Catalina Zepeda-Peña
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México
| | - Carmen Magdalena Gurrola-Díaz
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México
| | - José Alfredo Domínguez-Rosales
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México
| | - Pedro Macedonio García-López
- Departamento de Botánica y Zoología, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Zapopan, México
| | - Juan Carlos Pizano-Andrade
- Departamento de Botánica y Zoología, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Zapopan, México
| | - Zamira Helena Hernández-Nazará
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México
| | - Belinda Vargas-Guerrero
- Instituto de Investigación en Enfermedades Crónico Degenerativas, Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, México
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28
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Sohouli MH, Sayyari AA, Lari A, Nameni G, Lotfi M, Fatahi S, Saneie S, Găman MA, Moodi F, Raee P, Aghamiri S, Rayi A, Shahriari A, Moodi V. Association of dietary insulinaemic potential and odds of non-alcoholic fatty liver disease among adults: A case-control study. J Hum Nutr Diet 2021; 34:901-909. [PMID: 33586811 DOI: 10.1111/jhn.12865] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Revised: 01/09/2021] [Accepted: 01/14/2021] [Indexed: 02/06/2023]
Abstract
BACKGROUND Hyperinsulinaemia is considered as a major risk factor for the development of a myriad of chronic diseases. We examined the association between the dietary insulinaemic potential and the odds of non-alcoholic fatty liver disease (NAFLD) among Iranian adults. METHODS After being subjected to a liver ultrasound, 166 patients with NAFLD and 200 controls were included in the study. The dietary intakes and the physical activity levels of the participants were evaluated using a validated semi-quantitative food frequency questionnaire and the International Physical Activity Questionnaire (short IPAQ), respectively. The insulinaemic potential of the diet was assessed by computing the scores of the Empirical Dietary Index for Hyperinsulinemia (EDIH) and the Empirical Dietary Index for Insulin Resistance (EDIR). RESULTS Compared with the control subjects, patients with NAFLD were significantly older; had higher values for body mass index, fasting blood sugar, triglycerides, low-density lipoprotein cholesterol, total cholesterol and alanine transaminase; and were more likely to smoke. Moreover, NAFLD patients had significant lower levels of high-density lipoprotein cholesterol and were less likely to perform physical activity. The risk of NAFLD was higher in the individuals in the highest tertile of the EDIH (odds ratio [OR] = 2.79; 95% confidence interval [CI] = 1.32-5.90; p value for trend < 0.05) and EDIR (OR = 2.42; 95% CI = 1.22-4.79; p value for trend < 0.05) compared to those in the lowest tertile of these scores. CONCLUSIONS Our study indicates that a higher dietary insulinaemic potential is associated with an increased risk of NAFLD.
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Affiliation(s)
- Mohammad Hassan Sohouli
- Student Research Committee, Faculty of Public Health Branch, Iran University of Medical Sciences, Tehran, Iran
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Sayyari
- Pediatric Gastroenterology, Hepatology, and Nutrition Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abolfazl Lari
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Ghazaleh Nameni
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mojtaba Lotfi
- Department of Pediatric Endocrinology and Metabolism, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Somaye Fatahi
- Student Research Committee, Faculty of Public Health Branch, Iran University of Medical Sciences, Tehran, Iran
- Pediatric Gastroenterology, Hepatology, and Nutrition Research Center, Research Institute for Children's Health, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Solaleh Saneie
- Department of Nutrition, School of Public Health, Iran University of Medical Sciences, Tehran, Iran
| | - Mihnea-Alexandru Găman
- "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
- Center of Hematology and Bone Marrow Transplantation, Fundeni Clinical Institute, Bucharest, Romania
| | - Farzan Moodi
- School of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Pourya Raee
- Department of Biology and Anatomical Sciences, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shahin Aghamiri
- Department of medical biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Appaji Rayi
- Department of Neurology, Charleston Area Medical Center Charleston, Charleston, WV, USA
| | - Ali Shahriari
- Roozbeh Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Vihan Moodi
- School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
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Ruan S, Han C, Sheng Y, Wang J, Zhou X, Guan Q, Li W, Zhang C, Yang Y. Antcin A alleviates pyroptosis and inflammatory response in Kupffercells of non-alcoholic fatty liver disease by targeting NLRP3. Int Immunopharmacol 2021; 100:108126. [PMID: 34492534 DOI: 10.1016/j.intimp.2021.108126] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Revised: 08/27/2021] [Accepted: 08/31/2021] [Indexed: 01/22/2023]
Abstract
Pyroptosis, a pattern of inflammatory death, is regulated by NLRP3-Caspase-1 inflammasome and GSDMD-FL protein. Antcin A is a small triterpenoid molecule. In this study, Kupffer cells (KC) were used for in vitro model, which were treated with LPS and Nigericin (L/N) to induce pyroptosis. ELISA was used to determine the influence of Antcin A on the expression of inflammatory factors, IF was utilized to investigate NLRP3 and Caspase-1, PI staining was used to detect the opening level of membrane pores in KCs, C57BL/6J wild-type mice were fed with high-fat diet to construct a NAFLD model, and were simultaneously treated with Antcin A. H&E staining was used to detect hepatic pathological changes in mice, oil red staining was utilized to detect hepatic fat deposits in mice, IHC was used to detect the expression of NLRP3 and Caspase-1, Western blot was used to detect the expression levels of NLRP3 inflammasome (including NLRP3, ASC, Caspase-1, GSDMD-FL and GSDMD-NT). Pull-down assay and immunoprecipitation assay were used to detect the binding between Antcin A and NLRP3. As a result, Antcin A could significantly inhibit the occurrence of pyrolysis, decrease the expression of inflammatory factors, inhibit the activation and assembly of NLRP3 inflammasome, and significantly down-regulate the expression of NLRP3, Caspase-1 and GSDMD-NT in KCs. In NAFLD mice, Antcin A could suppress the inflammatory response in liver tissues of mice, reduce lipid deposition, down-regulate the levels of ALT and AST, and improve liver function in mice. Antcin A could also inhibit the activation of NLRP3 inflammasome in liver tissue and decrease the level of inflammatory factors. In the study of mechanism, we revealed that Antcin A could inhibit the assembly and activation of NLRP3 inflammasome by binding with NLRP3. In summary, in this study, we found that Antcin A could inhibit pyroptosis in KC and alleviate the inflammatory response of liver tissue in NAFLD by targeting NLRP3 inflammasome, which was one of the mechanisms of Anctin A in protecting liver.
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Affiliation(s)
- Shuiliang Ruan
- Department of Center Laboratory, The Second Affiliated Hospital of Jiaxing University, China
| | - Chenyang Han
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, China
| | - Yongjia Sheng
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, China
| | - Jin Wang
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, China
| | - Xiaohong Zhou
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, China
| | - Qiaobing Guan
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, China
| | - Wenyan Li
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, China
| | - Caiqun Zhang
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, China.
| | - Yi Yang
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, China.
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Lim S, Kim JW, Targher G. Links between metabolic syndrome and metabolic dysfunction-associated fatty liver disease. Trends Endocrinol Metab 2021; 32:500-514. [PMID: 33975804 DOI: 10.1016/j.tem.2021.04.008] [Citation(s) in RCA: 115] [Impact Index Per Article: 28.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/15/2021] [Accepted: 04/15/2021] [Indexed: 02/08/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic condition characterized by hepatic fat accumulation combined with underlying metabolic dysregulation. Having evolved from the previous term of nonalcoholic fatty liver disease (NAFLD), the term MAFLD more closely implicates the presence of overweight/obesity, type 2 diabetes, or metabolic dysregulation as essential pathogenic factors, leading to better identification of individuals with this metabolic liver disease. Low-grade inflammation, increased oxidative stress, mitochondrial dysfunction, and intestinal dysbiosis are also involved in its pathogenesis. MAFLD is not only associated with liver-related complications, but also with adverse cardiometabolic outcomes. Further studies are needed to assess whether the newly proposed definition of MAFLD is more accurate than the NAFLD in predicting the adverse liver-related and extrahepatic outcomes.
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Affiliation(s)
- Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Korea.
| | - Jin-Wook Kim
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seoul, Korea
| | - Giovanni Targher
- Section of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Verona, Verona, Italy.
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Jichitu A, Bungau S, Stanescu AMA, Vesa CM, Toma MM, Bustea C, Iurciuc S, Rus M, Bacalbasa N, Diaconu CC. Non-Alcoholic Fatty Liver Disease and Cardiovascular Comorbidities: Pathophysiological Links, Diagnosis, and Therapeutic Management. Diagnostics (Basel) 2021; 11:689. [PMID: 33921359 PMCID: PMC8069361 DOI: 10.3390/diagnostics11040689] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/09/2021] [Accepted: 04/11/2021] [Indexed: 02/06/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) has a growing prevalence in recent years. Its association with cardiovascular disease has been intensively studied, and certain correlations have been identified. The connection between these two entities has lately aroused interest regarding therapeutic management. In order to find the best therapeutic options, a detailed understanding of the pathophysiology that links (NAFLD) to cardiovascular comorbidities is needed. This review focuses on the pathogenic mechanisms that are behind these two diseases and on the therapeutic management available at this time.
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Affiliation(s)
- Alexandra Jichitu
- Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania; (A.J.); (C.C.D.)
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania;
| | - Ana Maria Alexandra Stanescu
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
| | - Cosmin Mihai Vesa
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (C.M.V.); (C.B.)
| | - Mirela Marioara Toma
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 410028 Oradea, Romania;
| | - Cristiana Bustea
- Department of Preclinical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania; (C.M.V.); (C.B.)
| | - Stela Iurciuc
- Department of Cardiology, Faculty of Medicine, “Victor Babeş” University of Medicine and Pharmacy, 300041 Timisoara, Romania
| | - Marius Rus
- Department of Medical Disciplines, Faculty of Medicine and Pharmacy, University of Oradea, 410073 Oradea, Romania;
| | - Nicolae Bacalbasa
- Department 13, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
- Department of Surgery, “Ion Cantacuzino” Clinical Hospital, 030167 Bucharest, Romania
| | - Camelia Cristina Diaconu
- Clinical Emergency Hospital of Bucharest, 105402 Bucharest, Romania; (A.J.); (C.C.D.)
- Department 5, Faculty of Medicine, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania;
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Zhou Y, Liu Z, Lynch EC, He L, Cheng H, Liu L, Li Z, Li J, Lawless L, Zhang KK, Xie L. Osr1 regulates hepatic inflammation and cell survival in the progression of non-alcoholic fatty liver disease. J Transl Med 2021; 101:477-489. [PMID: 33005011 PMCID: PMC7987871 DOI: 10.1038/s41374-020-00493-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/12/2020] [Accepted: 09/13/2020] [Indexed: 02/07/2023] Open
Abstract
Odd-skipped related 1 (Osr1) is a novel tumor suppressor gene in several cancer cell lines. Non-alcoholic steatohepatitis (NASH) is considered as a high-risk factor for hepatocellular carcinoma (HCC). This study is aimed to investigate the novel role of Osr1 in promoting the progression of hepatic steatosis to NASH. Following 12 weeks of diethylnitrosamine (DEN) and high-fat diet (HFD), wildtype (WT) and Osr1 heterozygous (Osr1+/-) male mice were examined for liver injuries. Osr1+/- mice displayed worsen liver injury with higher serum alanine aminotransferase levels than the WT mice. The Osr1+/- mice also revealed early signs of collagen deposition with increased hepatic Tgfb and Fn1 expression. There was overactivation of both JNK and NF-κB signaling in the Osr1+/- liver, along with accumulation of F4/80+ cells and enhanced hepatic expression of Il-1b and Il-6. Moreover, the Osr1+/- liver displayed hyperphosphorylation of AKT/mTOR signaling, associated with overexpression of Bcl-2. In addition, Osr1+/- and WT mice displayed differences in the DNA methylome of the liver cells. Specifically, Osr1-responsible CpG islands of Ccl3 and Pcgf2, genes for inflammation and macrophage infiltration, were further identified. Taken together, Osr1 plays an important role in regulating cell inflammation and survival through multiple signaling pathways and DNA methylation modification for NAFLD progression.
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Affiliation(s)
- Yi Zhou
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Zhimin Liu
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Department of Colorectal Surgery, The Sixth Affiliated Hospital of Sun Yat-sen University (Gastrointestinal and Anal Hospital of Sun Yat-sen Unversity), Guangzhou, 510655, China
| | - Ernest C Lynch
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Leya He
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Henghui Cheng
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Tongji Hospital, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China
| | - Lin Liu
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Zhen Li
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Jiangyuan Li
- Department of Statistics, Texas A&M University, College Station, TX, 77843, USA
| | - Lauren Lawless
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
| | - Ke K Zhang
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA
- Center for Epigenetics & Disease Prevention, Institute of Biosciences & Technology, College of Medicine, Texas A&M University, Houston, TX, USA
| | - Linglin Xie
- Department of Nutrition, Texas A&M University, College Station, TX, 77843, USA.
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Takata N, Ishii KA, Takayama H, Nagashimada M, Kamoshita K, Tanaka T, Kikuchi A, Takeshita Y, Matsumoto Y, Ota T, Yamamoto Y, Yamagoe S, Seki A, Sakai Y, Kaneko S, Takamura T. LECT2 as a hepatokine links liver steatosis to inflammation via activating tissue macrophages in NASH. Sci Rep 2021; 11:555. [PMID: 33436955 PMCID: PMC7804418 DOI: 10.1038/s41598-020-80689-0] [Citation(s) in RCA: 37] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Accepted: 12/10/2020] [Indexed: 12/31/2022] Open
Abstract
It remains unclear how hepatic steatosis links to inflammation. Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that senses fat in the liver and is upregulated prior to weight gain. The aim of this study was to investigate the significance of LECT2 in the development of nonalcoholic steatohepatitis (NASH). In human liver biopsy samples, elevated LECT2 mRNA levels were positively correlated with body mass index (BMI) and increased in patients who have steatosis and inflammation in the liver. LECT2 mRNA levels were also positively correlated with the mRNA levels of the inflammatory genes CCR2 and TLR4. In C57BL/6J mice fed with a high-fat diet, mRNA levels of the inflammatory cytokines Tnfa and Nos2 were significantly lower in Lect2 KO mice. In flow cytometry analyses, the number of M1-like macrophages and M1/M2 ratio were significantly lower in Lect2 KO mice than in WT mice. In KUP5, mouse kupffer cell line, LECT2 selectively enhanced the LPS-induced phosphorylation of JNK, but not that of ERK and p38. Consistently, LECT2 enhanced the LPS-induced phosphorylation of MKK4 and TAB2, upstream activators of JNK. Hepatic expression of LECT2 is upregulated in association with the inflammatory signature in human liver tissues. The elevation of LECT2 shifts liver residual macrophage to the M1-like phenotype, and contributes to the development of liver inflammation. These findings shed light on the hepatokine LECT2 as a potential therapeutic target that can dissociate liver steatosis from inflammation.
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Affiliation(s)
- Noboru Takata
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Kiyo-Aki Ishii
- Department of Integrative Medicine for Longevity, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Hiroaki Takayama
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
- Life Sciences Division, Engineering and Technology Department, Kanazawa University, Kanazawa, Ishikawa, 920-8640, Japan
| | - Mayumi Nagashimada
- Technology Department of Clinical Laboratory Science, Kanazawa University Graduate School of Medical Science and Technology, Kanazawa, Ishikawa, 920-0942, Japan
| | - Kyoko Kamoshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Takeo Tanaka
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Akihiro Kikuchi
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yumie Takeshita
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yukako Matsumoto
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Tsuguhito Ota
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yasuhiko Yamamoto
- Department of Biochemistry and Molecular Vascular Biology, Kanazawa University Graduate School of Medical Science, Kanazawa, Ishikawa, 920-8640, Japan
| | - Satoshi Yamagoe
- Department of Chemotherapy and Mycoses, National Institute of Infectious Diseases, Shinjuku-ku, Tokyo, 162-8640, Japan
| | - Akihiro Seki
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Yoshio Sakai
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Shuichi Kaneko
- Department of Gastroenterology, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan
| | - Toshinari Takamura
- Department of Endocrinology and Metabolism, Kanazawa University Graduate School of Medical Sciences, Kanazawa, Ishikawa, 920-8640, Japan.
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Saeed NM, Mansour AM, Allam S. Lycopene induces insulin signaling and alleviates fibrosis in experimental model of non-alcoholic fatty liver disease in rats. PHARMANUTRITION 2020. [DOI: 10.1016/j.phanu.2020.100225] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Jia R, Cao LP, Du JL, He Q, Gu ZY, Jeney G, Xu P, Yin GJ. Effects of high-fat diet on antioxidative status, apoptosis and inflammation in liver of tilapia (Oreochromis niloticus) via Nrf2, TLRs and JNK pathways. FISH & SHELLFISH IMMUNOLOGY 2020; 104:391-401. [PMID: 32553566 DOI: 10.1016/j.fsi.2020.06.025] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 06/09/2020] [Accepted: 06/12/2020] [Indexed: 06/11/2023]
Abstract
Fatty liver injury (or disease) is a common disease in farmed fish, but its pathogenic mechanism is not fully understood. Therefore the present study aims to investigate high-fat diet (HFD)-induced liver injury and explore the underlying mechanism in fish. The tilapia were fed on control diet and HFD for 90 days, and then the blood and liver tissues were collected to determine biochemical parameter, gene expression and protein level. The results showed that HFD feeding signally increased the levels of plasma aminotransferases and pro-inflammatory factors after 60 days. In liver and plasma, HFD feeding significantly suppressed antioxidant ability, but enhanced lipid peroxidation formation, protein oxidation and DNA damage after 60 or 90 days. Further, the Nrf2 pathway and antioxidative function-related genes were adversely changed in liver of HFD-fed tilapia after 60 and/or 90 days. Meanwhile, HFD treatment induced apoptosis via initiating mitochondrial pathway in liver after 90 days. Furthermore, after 90 days of feeding, the expression of genes or proteins related to JNK pathway and TLRs-Myd88-NF-κB pathway was clearly upregulated in HFD treatment. Similarly, the mRNA levels of inflammatory factors including tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), IL-6, IL-8 and IL-10 were also upregulated in liver of HFD-fed tilapia after 60 and/or 90 days. In conclusion, the current study suggested that HFD feeding impaired antioxidant defense system, induced apoptosis, enhanced inflammation and led to liver injury. The adverse influences of HFD in the liver might be due to the variation of Nrf2, JNK and TLRs-Myd88-NF-κB signaling pathways.
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Affiliation(s)
- Rui Jia
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
| | - Li-Ping Cao
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Jin-Liang Du
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Qin He
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Zheng-Yan Gu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China
| | - Galina Jeney
- International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; National Agricultural Research Center, Research Institute for Fisheries and Aquaculture, Anna Light 8, Szarvas, 5440, Hungary
| | - Pao Xu
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
| | - Guo-Jun Yin
- Key Laboratory of Freshwater Fisheries and Germplasm Resources Utilization, Ministry of Agriculture and Rural Affairs, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China; International Joint Research Laboratory for Fish Immunopharmacology, Freshwater Fisheries Research Center, Chinese Academy of Fishery Sciences, Wuxi, 214081, China.
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C-Jun/C7ORF41/NF-κB axis mediates hepatic inflammation and lipid accumulation in NAFLD. Biochem J 2020; 477:691-708. [PMID: 31957809 DOI: 10.1042/bcj20190799] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2019] [Revised: 01/17/2020] [Accepted: 01/20/2020] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is an expanding health problem worldwide. Although many studies have made great efforts to elucidate the pathogenesis of NAFLD, the molecular basis remains poorly understood. Here, we showed that hepatic C7ORF41, a critical regulator of innate immune response, was markedly decreased in diet or genetic-induced NAFLD model. We also demonstrated that C7ORF41 overexpression significantly ameliorated hepatic inflammation and lipid accumulation in palmitic acid (PA)-treated hepatocytes, whereas C7ORF41 knockdown showed the opposite effects. Mechanistically, we found the anti-inflammatory role of C7ORF41 was attributed to the suppression of NF-κB p65-mediated induction of inflammatory cytokines. Moreover, we demonstrated that the suppression of C7ORF41 expression in hepatocytes is due to JNK activation, which promotes c-Jun-mediated transcriptional repression of C7ORF41. In conclusion, our findings suggested that a c-Jun/C7ORF41/NF-κB regulatory network controls the inflammatory response and lipid accumulation in NAFLD and may benefit the development of novel and promising therapeutic targets for NAFLD.
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Abstract
Islet dysfunction is a hallmark of type 2 diabetes mellitus (T2DM). Compelling evidence suggests that accumulation of islet amyloid in the islets of Langerhans significantly contribute to β-cell dysfunction and diabetes. Emerging evidence implicates a role for cystic fibrosis transmembrane-conductance regulator in the regulation of insulin secretion from pancreatic islets. Impaired first-phase insulin responses and glucose homeostasis have also been reported in cystic fibrosis patients. The transforming growth factor-β protein superfamily is central regulators of pancreatic cell function, and has a key role in pancreas development and pancreatic disease, including diabetes and islet dysfunction. It is also becoming clear that islet inflammation plays a key role in the development of islet dysfunction. Inflammatory changes, including accumulation of macrophages, have been documented in type 2 diabetic islets. Islet dysfunction leads to hyperglycemia and ultimately the development of diabetes. In this review, we describe these risk factors and their associations with islet dysfunction.
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Affiliation(s)
- Fei Hu
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo, China
| | - Xiaohui Qiu
- Department of nephrology, Ningbo Medical Center Li Huili Eastern Hospital Affiliated to Ningbo University
| | - Shizhong Bu
- Diabetes Research Center, School of Medicine, Ningbo University, Ningbo, China
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Wu L, Liu Y, Zhao Y, Li M, Guo L. Targeting DUSP7 signaling alleviates hepatic steatosis, inflammation and oxidative stress in high fat diet (HFD)-fed mice via suppression of TAK1. Free Radic Biol Med 2020; 153:140-158. [PMID: 32311490 DOI: 10.1016/j.freeradbiomed.2020.04.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 04/02/2020] [Accepted: 04/09/2020] [Indexed: 02/06/2023]
Abstract
The non-alcoholic fatty liver disease (NAFLD), as a critical liver disease, is still lack of effective treatments because the molecular mechanism revealing the NAFLD pathogenesis remains unclear. Dual specific phosphatase 6 (DUSP7) shows effects on inflammatory response and is a negative feedback mechanism of the mitogen-activated protein kinase (MAPK) superfamily, which are critical factors in regulating NAFLD progression. However, the effects of DUSP7 on hepatic steatosis are still not fully understood. Here, we found that DUSP7 functioned as a negative regulator of NAFLD and in various metabolic disorders. DUSP7 expression was markedly reduced in liver samples from patients with simple hepatic steatosis or non-alcoholic steatohepatitis (NASH), as well as in liver tissues from high fat diet (HFD)-challenged mice or genetically obese (ob/ob) mice. DUSP7 knockout markedly accelerated insulin resistance, glucose intolerance, liver dysfunction, fibrosis and hepatic steatosis in HFD-fed mice. In addition, inflammatory response was significantly exacerbated in HFD-challenged mice with DUSP7 deletion, which was associated with the elevated activation of nuclear factor-κB (NF-κB) and MAPKs signaling pathways. Moreover, oxidative stress was detected in liver of HFD-induced mice, and this phenomenon was aggravated in mice with DUSP7 knockout. Importantly, we demonstrated that DUSP7 physically interacted with transforming growth factor β (TGF-β)-activated kinase (TAK1). DUSP7 deletion considerably promoted the activation of TAK1 in mice after HFD feeding, contributing to the lipid deposition, inflammatory response and reactive oxygen species (ROS) production. Taken together, DUSP7 might function as a protective factor against NAFLD development and metabolic disorder through alleviating dyslipidemia, inflammation and oxidative stress by directly interacting with TAK1 in hepatocytes, which was involved in the suppression of fibrosis. Thus, we may provide an effective strategy for the treatment of hepatic steatosis via targeting DUSP7.
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Affiliation(s)
- Liping Wu
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China.
| | - Yongcun Liu
- Department of Oncology, The First People's Hospital of Xianyang, Xianyang, 712000, China
| | - Yuan Zhao
- Department of Gerontology, Shaanxi Provincial People's Hospita, Xi'an, 710068, China
| | - Meng Li
- Department of Endocrinology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China
| | - Ling Guo
- Department of Oncology, The First People's Hospital of Xianyang, Xianyang, 712000, China
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Islam S, Rahman S, Haque T, Sumon AH, Ahmed AZM, Ali N. Prevalence of elevated liver enzymes and its association with type 2 diabetes: A cross-sectional study in Bangladeshi adults. Endocrinol Diabetes Metab 2020; 3:e00116. [PMID: 32318634 PMCID: PMC7170449 DOI: 10.1002/edm2.116] [Citation(s) in RCA: 35] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 01/22/2020] [Accepted: 01/25/2020] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Type 2 diabetes (T2D) is a major public health concern affecting millions of people worldwide. The relationship between liver enzymes and T2D has been reported in limited studies; however, there is still a lack of evidence for the Bangladeshi population. This study aimed to evaluate the prevalence of elevated liver enzymes and examine its association with the prevalence of T2D in Bangladeshi adults. METHODS A total of 270 individuals (110 diabetic and 160 nondiabetic) were enrolled in the study. Alanine and aspartate aminotransferase (ALT, AST), alkaline phosphatase (ALP) and γ-glutamyltransferase (GGT) activities were measured in blood serum collected from them. T2D was defined as fasting blood glucose (FBG) ≥126 mg/dL or self-reported recent use of insulin or antidiabetic medications. Association between liver enzymes and T2D was evaluated by multinomial logistic regression analysis. RESULTS Overall, 61.2% of participants in T2D and 37.1% of participants in the nondiabetes group had at least one or more elevated liver enzymes. The mean concentrations of serum ALT, AST, ALP and GGT were significantly higher in the T2D group compared to the nondiabetes group. The prevalence of elevated liver enzymes was significantly higher in the diabetes group compared to the nondiabetes group (P < .01). In regression analysis, serum GGT activity showed an independent association with the prevalence of T2D. CONCLUSIONS A high prevalence of elevated liver enzymes was observed in subjects having diabetes. Increased serum GGT activity was independently associated with the prevalence of T2D among Bangladeshi adults. More studies of this nature should be carried out in developing countries to get proper insights into the involvement of liver enzymes in T2D.
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Affiliation(s)
- Shiful Islam
- Department of Biochemistry and Molecular BiologyShahjalal University of Science and TechnologySylhetBangladesh
| | - Sadaqur Rahman
- Department of Biochemistry and Molecular BiologyShahjalal University of Science and TechnologySylhetBangladesh
| | - Tangigul Haque
- Department of Biochemistry and Molecular BiologyShahjalal University of Science and TechnologySylhetBangladesh
| | - Abu Hasan Sumon
- Department of Biochemistry and Molecular BiologyShahjalal University of Science and TechnologySylhetBangladesh
| | | | - Nurshad Ali
- Department of Biochemistry and Molecular BiologyShahjalal University of Science and TechnologySylhetBangladesh
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Wu YK, Hu LF, Lou DS, Wang BC, Tan J. Targeting DUSP16/TAK1 signaling alleviates hepatic dyslipidemia and inflammation in high fat diet (HFD)-challenged mice through suppressing JNK MAPK. Biochem Biophys Res Commun 2020; 524:142-149. [PMID: 31982140 DOI: 10.1016/j.bbrc.2020.01.037] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 01/03/2020] [Indexed: 12/12/2022]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is featured by hepatic steatosis, insulin resistance, lipid deposition and inflammation. However, the pathogenic mechanism of NAFLD is still poorly understood. Dual-specificity phosphatase 16 (DUSP16), a c-Jun N-terminal kinase-specific phosphatase, has been reported to negatively modulate the mitogen-activated protein kinases (MAPKs) signaling, and it has never been investigated in NAFLD progression. In the study, we identified that DUSP16 could directly interact with TAK1 in human hepatocytes. DUSP16 knockdown in the isolated primary hepatocytes stimulated by palmitate (PA) showed accelerated lipid deposition and inflammatory response, along with the exacerbated activation of c-Jun NH2-terminal kinase (JNK), Transforming growth factor β (TGF-β)-activated kinase (TAK1) and nuclear factor-κB (NF-κB) signaling pathways; however, the opposite results were detected in PA-treated hepatocytes with DUSP16 over-expression. The in vivo experiments confirmed that DUSP16 knockout significantly aggravated the metabolic disorder and insulin resistance in high fat diet (HFD)-challenged mice. In addition, HFD-provoked hepatic lipid accumulation and inflammation were further promoted in mice with DUSP16 knockout through the same molecular mechanism as detected in vitro. Herein, these findings demonstrated that DUSP16 could directly interact with TAK1 and negatively regulate JNK signaling to alleviate metabolic stress-induced hepatic steatosis, and thus could be considered as a promising new molecular target for NAFLD treatment.
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Affiliation(s)
- Ye-Kuan Wu
- Postdoctoral Research Station of Biology, Chongqing University, Chongqing, 400030, China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, China; Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, 400067, PR China
| | - Lin-Feng Hu
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, China; Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, 400067, PR China
| | - De-Shuai Lou
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, 400067, PR China
| | - Bo-Chu Wang
- Postdoctoral Research Station of Biology, Chongqing University, Chongqing, 400030, China; Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, Chongqing, 400030, China.
| | - Jun Tan
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, Chongqing, 400067, PR China; Research Center of Brain Intellectual Promotion and Development for Children Aged 0-6 Years, Chongqing University of Education, Chongqing, 400067, PR China.
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He Y, Ruganzu JB, Lin C, Ding B, Zheng Q, Wu X, Ma R, Liu Q, Wang Y, Jin H, Qian Y, Peng X, Ji S, Zhang L, Yang W, Lei X. Tanshinone IIA ameliorates cognitive deficits by inhibiting endoplasmic reticulum stress-induced apoptosis in APP/PS1 transgenic mice. Neurochem Int 2019; 133:104610. [PMID: 31778727 DOI: 10.1016/j.neuint.2019.104610] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2019] [Revised: 11/15/2019] [Accepted: 11/23/2019] [Indexed: 02/06/2023]
Abstract
Our previous data indicated that tanshinone IIA (tan IIA) improves learning and memory in a mouse model of Alzheimer's disease (AD) induced by streptozotocin via restoring cholinergic function, attenuating oxidative stress and blocking p38 MAPK signal pathway activation. This study aims to estimate whether tan IIA inhibits endoplasmic reticulum (ER) stress-induced apoptosis to prevent cognitive decline in APP/PS1 transgenic mice. Tan IIA (10 mg/kg and 30 mg/kg) was intraperitoneally administered to the six-month-old APP/PS1 mice for 30 consecutive days. β-amyloid (Aβ) plaques were measured by immunohistochemisty and Thioflavin S staining, apoptotic cells were observed by TUNEL, ER stress markers and apoptosis signaling proteins were investigated by western blotting and RT-PCR. Our results showed that tan IIA significantly ameliorates cognitive deficits and improves spatial learning ability of APP/PS1 mice in the nest-building test, novel object recognition test and Morris water maze test. Furthermore, tan IIA significantly reduced the deposition of Aβ plaques and neuronal apoptosis, and markedly prevented abnormal expression of glucose regulated protein 78 (GRP78), initiation factor 2α (eIF2α), inositol-requiring enzyme 1α (IRE1α), activating transcription factor 6 (ATF6), as well as suppressed the activation of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) pathways in the parietal cortex and hippocampus. Moreover, tan IIA induced an up-regulation of the Bcl-2/Bax ratio and down-regulation of caspase-3 protein activity. Taken together, the above findings indicated that tan IIA improves learning and memory through attenuating Aβ plaques deposition and inhibiting ER stress-induced apoptosis. These results suggested that tan IIA might become a promising therapeutic candidate drug against AD.
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Affiliation(s)
- Yingying He
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - John Bosco Ruganzu
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - Chengheng Lin
- Medical Undergraduates of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - Bo Ding
- Medical Undergraduates of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - Quzhao Zheng
- Medical Undergraduates of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - Xiangyuan Wu
- Medical Undergraduates of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - Ruiyang Ma
- Medical Undergraduates of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - Qian Liu
- Medical Undergraduates of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - Yang Wang
- Medical Undergraduates of Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - Hui Jin
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - Yihua Qian
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - Xiaoqian Peng
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - Shengfeng Ji
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China
| | - Liangliang Zhang
- Department of Critical Care Medicine, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, 710061, China
| | - Weina Yang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi province, 710061, China.
| | - Xiaomei Lei
- Department of Child Health Care, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi province, 710004, China.
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Farzaei MH, Singh AK, Kumar R, Croley CR, Pandey AK, Coy-Barrera E, Kumar Patra J, Das G, Kerry RG, Annunziata G, Tenore GC, Khan H, Micucci M, Budriesi R, Momtaz S, Nabavi SM, Bishayee A. Targeting Inflammation by Flavonoids: Novel Therapeutic Strategy for Metabolic Disorders. Int J Mol Sci 2019; 20:4957. [PMID: 31597283 PMCID: PMC6801776 DOI: 10.3390/ijms20194957] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2019] [Revised: 09/28/2019] [Accepted: 09/30/2019] [Indexed: 12/16/2022] Open
Abstract
A balanced metabolic profile is essential for normal human physiological activities. Disproportions in nutrition give rise to imbalances in metabolism that are associated with aberrant immune function and an elevated risk for inflammatory-associated disorders. Inflammation is a complex process, and numerous mediators affect inflammation-mediated disorders. The available clinical modalities do not effectively address the underlying diseases but rather relieve the symptoms. Therefore, novel targeted agents have the potential to normalize the metabolic system and, thus, provide meaningful therapy to the underlying disorder. In this connection, polyphenols, the well-known and extensively studied phytochemical moieties, were evaluated for their effective role in the restoration of metabolism via various mechanistic signaling pathways. The various flavonoids that we observed in this comprehensive review interfere with the metabolic events that induce inflammation. The mechanisms via which the polyphenols, in particular flavonoids, act provide a promising treatment option for inflammatory disorders. However, detailed clinical studies of such molecules are required to decide their clinical fate.
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Affiliation(s)
- Mohammad Hosein Farzaei
- Pharmaceutical Sciences Research Center, Health Institute, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran.
| | - Amit Kumar Singh
- Department of Biochemistry, University of Allahabad, Allahabad 211 002, India.
| | - Ramesh Kumar
- Department of Biochemistry, University of Allahabad, Allahabad 211 002, India.
| | - Courtney R Croley
- Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA.
| | - Abhay K Pandey
- Department of Biochemistry, University of Allahabad, Allahabad 211 002, India.
| | - Ericsson Coy-Barrera
- Bioorganic Chemistry Laboratory, Facultad de Ciencias Básicas y Aplicadas, Campus Nueva Granada, Universidad Militar Nueva Granada, Cajicá 250247, Colombia.
| | - Jayanta Kumar Patra
- Research Institute of Biotechnology and Medical Converged Science, Dongguk University-Seoul, Ilsandong-gu, Gyeonggi-do 10326, Korea.
| | - Gitishree Das
- Research Institute of Biotechnology and Medical Converged Science, Dongguk University-Seoul, Ilsandong-gu, Gyeonggi-do 10326, Korea.
| | - Rout George Kerry
- Post Graduate Department of Biotechnology, Utkal University, Vani Vihar, Bhubaneswar 751 004, Odisha, India.
| | - Giuseppe Annunziata
- Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131 Naples, Italy.
| | - Gian Carlo Tenore
- Department of Pharmacy, University of Naples "Federico II", Via Domenico Montesano 49, 80131 Naples, Italy.
| | - Haroon Khan
- Department of Pharmacy, Abdul Wali Khan University, Mardan 23200, Pakistan.
| | - Matteo Micucci
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy.
| | - Roberta Budriesi
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum-University of Bologna, 40126 Bologna, Italy.
| | - Saeideh Momtaz
- Medicinal Plants Research Center, Institute of Medicinal Plants, Karaj 141554364, Iran.
- Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences, Tehran University of Medical Sciences, Tehran 141556451, Iran.
| | - Seyed Mohammad Nabavi
- Applied Biotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran 1435916471, Iran.
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA.
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Untangling narcolepsy and diabetes: Pathomechanisms with eyes on therapeutic options. Brain Res 2019; 1718:212-222. [DOI: 10.1016/j.brainres.2019.04.013] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2019] [Revised: 03/23/2019] [Accepted: 04/13/2019] [Indexed: 12/14/2022]
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44
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Liu Q, Liu SS, Zhao ZZ, Zhao BT, Du SX, Jin WW, Xin YN. TRIB1 rs17321515 gene polymorphism increases the risk of coronary heart disease in general population and non-alcoholic fatty liver disease patients in Chinese Han population. Lipids Health Dis 2019; 18:165. [PMID: 31470861 PMCID: PMC6717352 DOI: 10.1186/s12944-019-1108-2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 08/15/2019] [Indexed: 02/06/2023] Open
Abstract
Background Present evidences suggested that TRIB1 rs17321515 polymorphism was tightly associated with the increased risk of NAFLD and CHD. CHD is one of the main complications of NAFLD, whether TRIB1 rs17321515 polymorphism could affect the risk of CHD in general population and NAFLD patients in Chinese Han population was remain unknown. The present study was designed to investigate the association between TRIB1 rs17321515 polymorphism and the risk of CHD in general population and NAFLD patients in Chinese Han population, and investigate the effect of TRIB1 rs17321515 polymorphism on serum lipid levels. Patients and methods TRIB1 rs17321515 gene polymorphism was genotyped using the polymerase chain reaction (PCR) in healthy controls (n = 175), CHD patients (n = 155), NAFLD patients (n = 146), and NAFLD+CHD patients (n = 156). Serum lipid profiles were determined using biochemical methods. Statistical analyses were performed using SPSS 24.0 statistical software. Results The TRIB1 rs17321515 AA+GA genotypes were the significant risk factors for the CHD in general population (OR = 1.788; 95% CI: 1.104–2.897; P = 0.018) and in the NAFLD patients (OR = 1.760; 95% CI: 1.071–2.891; P = 0.026). After adjusted for age, gender, and body mass index, the risk for CHD in general population (OR = 1.857; 95% CI: 1.116–3.089; P = 0.017) and NAFLD patients was still significant (OR = 1.723; 95% CI: 1.033–2.873; P = 0.037). In addition, TRIB1 rs17321515 A carriers possess the higher lipid profiles in the included subjects. Conclusions TRIB1 rs17321515 AA+GA genotypes were significant associated with the risk of CHD in general population and in NAFLD patients in Chinese Han population. The rs17321515 A allele increases the serum lipid profiles in included subjects.
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Affiliation(s)
- Qun Liu
- The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, 266011, China.,Department of Gastroenterology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, 266011, China
| | - Shou-Sheng Liu
- Central Laboratories, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, 266071, China.,Digestive Disease Key Laboratory of Qingdao, Qingdao, 266071, China
| | - Zhen-Zhen Zhao
- Central Laboratories, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, 266071, China.,Digestive Disease Key Laboratory of Qingdao, Qingdao, 266071, China
| | - Ben-Tian Zhao
- Department of Infectious Disease, The Affiliated Qingdao Municipal Hospital of Qingdao University, 1 Jiaozhou Road, Qingdao, 266011, Shandong Province, China
| | - Shui-Xian Du
- Department of Infectious Disease, The Affiliated Qingdao Municipal Hospital of Qingdao University, 1 Jiaozhou Road, Qingdao, 266011, Shandong Province, China
| | - Wen-Wen Jin
- Department of Infectious Disease, The Affiliated Qingdao Municipal Hospital of Qingdao University, 1 Jiaozhou Road, Qingdao, 266011, Shandong Province, China
| | - Yong-Ning Xin
- The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, 266011, China. .,Department of Infectious Disease, The Affiliated Qingdao Municipal Hospital of Qingdao University, 1 Jiaozhou Road, Qingdao, 266011, Shandong Province, China. .,Department of Gastroenterology, The Affiliated Qingdao Municipal Hospital of Qingdao University, Qingdao, 266011, China. .,Digestive Disease Key Laboratory of Qingdao, Qingdao, 266071, China.
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45
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High Molecular Weight Hyaluronan Suppresses Macrophage M1 Polarization and Enhances IL-10 Production in PM 2.5-Induced Lung Inflammation. Molecules 2019; 24:molecules24091766. [PMID: 31067702 PMCID: PMC6539614 DOI: 10.3390/molecules24091766] [Citation(s) in RCA: 46] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 05/02/2019] [Accepted: 05/04/2019] [Indexed: 12/18/2022] Open
Abstract
PM2.5 is particulate matter with a diameter of 2.5 μm or less. Airway macrophages are the key players regulating PM2.5-induced inflammation. High molecular weight hyaluronan (HMW-HA) has previously been shown to exert protective effects on PM2.5-induced acute lung injury and inflammation. However, little is known about the detailed mechanism. In this study, we aimed to determine whether HMW-HA alleviates PM2.5-induced pulmonary inflammation by modulating macrophage polarization. The levels of M1 biomarkers TNF-α, IL-1β, IL-6, CXCL1, CXCL2, NOS2 and CD86, as well as M2 biomarkers IL-10, MRC1, and Arg-1 produced by macrophages were measured by ELISA, qPCR, and flow cytometry. In addition, the amount of M1 macrophages in lung tissues was examined by immunofluorescence of CD68 and NOS2. We observed a decline in PM2.5-induced M1 polarization both in macrophages and lung tissues when HMW-HA was administered simultaneously. Meanwhile, western blot analysis revealed that PM2.5-induced JNK and p38 phosphorylation was suppressed by HMW-HA. Furthermore, in vitro and in vivo studies showed that co-stimulation with HMW-HA and PM2.5 promoted the expression and release of IL-10, but exhibited limited effects on the transcription of MRC1 and ARG1. In conclusion, our results demonstrated that HMW-HA ameliorates PM2.5-induced lung inflammation by repressing M1 polarization through JNK and p38 pathways and promoting the production of pro-resolving cytokine IL-10.
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46
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Lim S, Taskinen MR, Borén J. Crosstalk between nonalcoholic fatty liver disease and cardiometabolic syndrome. Obes Rev 2019; 20:599-611. [PMID: 30589487 DOI: 10.1111/obr.12820] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Revised: 11/13/2018] [Accepted: 11/13/2018] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a chronic condition characterized by fat accumulation combined with low-grade inflammation in the liver. A large body of clinical and experimental data shows that increased flux of free fatty acids from increased visceral adipose tissue and de novo lipogenesis can lead to NAFLD and insulin resistance. Thus, individuals with obesity, insulin resistance, and dyslipidaemia are at the greatest risk of developing NAFLD. Conversely, NAFLD is a phenotype of cardiometabolic syndrome. Notably, researchers have discovered a close association between NAFLD and impaired glucose metabolism and focused on the role of NAFLD in the development of type 2 diabetes. Moreover, recent studies provide substantial evidence for an association between NAFLD and atherosclerosis and cardiometabolic disorders. Even if NAFLD can progress into severe liver disorders including nonalcoholic steatohepatitis (NASH) and cirrhosis, the majority of subjects with NAFLD die from cardiovascular disease eventually. In this review, we propose a potential pathological link between NAFLD/NASH and cardiometabolic syndrome. The potential factors that can play a pivotal role in this link, such as inflammation, insulin resistance, alteration in lipid metabolism, oxidative stress, genetic predisposition, and gut microbiota are discussed.
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Affiliation(s)
- Soo Lim
- Department of Internal Medicine, Seoul National University College of Medicine and Seoul National University Bundang Hospital, Seongnam, South Korea
| | - Marja-Riitta Taskinen
- Heart and Lung Centre, Helsinki University Central Hospital and Research Programs' Unit, Diabetes & Obesity, University of Helsinki, Helsinki, Finland
| | - Jan Borén
- Department of Molecular and Clinical Medicine/Wallenberg Lab, University of Gothenburg and Sahlgrenska University Hospital, Gothenburg, Sweden
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Sex-associated preventive effects of low-dose aspirin on obesity and non-alcoholic fatty liver disease in mouse offspring with over-nutrition in utero. J Transl Med 2019; 99:244-259. [PMID: 30413815 PMCID: PMC6354253 DOI: 10.1038/s41374-018-0144-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 08/16/2018] [Accepted: 08/23/2018] [Indexed: 01/04/2023] Open
Abstract
Aspirin has been found to diminish hypertriglyceridemia and hyperglycemia in both obese rodents and patients with type 2 diabetes mellitus. We aimed to test whether low-dose aspirin can prevent obesity and the progression of non-alcoholic fatty liver disease (NAFLD) in high-risk subjects. We used offspring mice with maternal over-nutrition as a high-risk model of obesity and NAFLD. The offspring were given postnatal HF-diet and diethylnitrosamine (DEN) to induce obesity and NAFLD, and were treated with or without a low dose of aspirin for 12 weeks (ASP or CTL groups). Aspirin treatment reduced body weight gain, reversed glucose intolerance, and depressed hepatic lipid accumulation in female, but not in male mice. Female mice displayed re-sensitized insulin/Akt signaling and overactivated AMPK signaling, with enhanced level of hepatic PPAR-γ, Glut4, and Glut2, while male mice only enhanced hepatic PPAR-α and PPAR-γ levels. The female ASP mice had inhibited p44/42 MAPK activity and enhanced Pten expression, while male displayed activated p38 MAPK signaling. Furthermore, the female but not the male ASP mice reduced Wnt-signaling activity via both the epigenetic regulation of Apc expression and the post-transcriptional regulation of β-catenin degradation. In summary, our study demonstrates a sex-associated effect of low-dose aspirin on obesity and NAFLD prevention in female but not in male mice.
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48
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Yuting Y, Lifeng F, Qiwei H. Secreted modular calcium-binding protein 2 promotes high fat diet (HFD)-induced hepatic steatosis through enhancing lipid deposition, fibrosis and inflammation via targeting TGF-β1. Biochem Biophys Res Commun 2018; 509:48-55. [PMID: 30581002 DOI: 10.1016/j.bbrc.2018.12.006] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Accepted: 12/02/2018] [Indexed: 12/15/2022]
Abstract
The molecular mechanism revealing the pathogenesis of non-alcoholic fatty liver disease (NAFLD), one of the most common liver diseases, remains to be investigated. In the study, we found that secreted modular calcium-binding protein 2 (SMOC2), which belongs to the secreted protein acidic and rich in cysteine (SPARC) family of matricellular proteins, functioned as a positive modulator of NAFLD. SMOC2 expression was markedly up-regulated in human liver samples with NAFLD, and in hepatic tissues of mice fed with HFD. SMOC2 knockout in mice significantly attenuated metabolic disorders, insulin resistance, glucose intolerance and lipid deposition in mice challenged with HFD. Moreover, liver fibrosis induced by HFD was clearly ameliorated by SMOC2 deficiency mainly through inhibiting transforming growth factor (TGF)-β1 expression. Additionally, hepatic inflammatory response triggered by HFD was also improved in SMOC2-knockout mice via inactivating nuclear factor-κB (NF-κB). Mechanically, SMOC2 could interact with TGF-β1, and SMOC2 overexpression markedly increased TGF-β1 in mouse primary hepatocytes, which played an essential role in regulating hepatic steatosis. In conclusion, we provided proof that blocking SMOC2 might be a promising strategy for preventing NAFLD through the interaction with TGF-β1.
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Affiliation(s)
- Yun Yuting
- Department of Gastroenterology, Inner Mongolia People's Hospital, Hohhot City, 010020, China
| | - Feng Lifeng
- Department of Hepatobiliary Surgery, Shaanxi Shangluo Central Hospital, Shangluo, 726000, China
| | - Hao Qiwei
- Department of General Surgery II Ward, Second Hospital of Yulin City, Yulin, 719000, China.
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Yang W, Zhang J, Shi L, Ji S, Yang X, Zhai W, Zong H, Qian Y. Protective effects of tanshinone IIA on SH-SY5Y cells against oAβ 1-42-induced apoptosis due to prevention of endoplasmic reticulum stress. Int J Biochem Cell Biol 2018; 107:82-91. [PMID: 30578955 DOI: 10.1016/j.biocel.2018.12.011] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2018] [Revised: 12/06/2018] [Accepted: 12/18/2018] [Indexed: 12/31/2022]
Abstract
Endoplasmic reticulum (ER) stress caused by β-amyloid protein (Aβ) may play an important role in the pathogenesis of Alzheimer disease (AD). Our previous data have indicated that tanshinone IIA (tan IIA) protected primary neurons from Aβ induced neurotoxicity. To further explore the neuroprotection of tan IIA, here we study the effects of tan IIA on the ER stress response in oligomeric Aβ1-42 (oAβ1-42)-induced SH-SY5Y cell injury. Our data showed that tan IIA pretreatment could increase cell viability and inhibit apoptosis caused by oAβ1-42. Furthermore, tan IIA markedly suppressed ER dilation and prevented oAβ1-42-induced abnormal expression of glucose regulated protein 78 (GRP78), initiation factor 2α (eIF2α), activating transcription factor 6 (ATF6), as well as inhibited the activation of C/EBP homologous protein (CHOP) and c-Jun N-terminal kinase (JNK) pathways. Moreover, tan IIA ameliorated oAβ1-42-induced Bcl-2/Bax ratio reduction, prevented cytochrome c translocation into cytosol from mitochondria, reduced oAβ1-42-induced cleavage of caspase-9 and caspase-3, suppressed caspase-3/7 activity, and increased mitochondrial membrane potential (MMP) and ATP content. Meanwhile, oAβ1-42-induced cell apoptosis and activation of ER stress can also be attenuated by the inhibitor of ER stress 4-phenylbutyric acid (4-PBA). Taken together, these data indicated that tan IIA protects SH-SY5Y cells against oAβ1-42-induced apoptosis through attenuating ER stress, modulating CHOP and JNK pathways, decreasing the expression of cytochrome c, cleaved caspase-9 and cleaved caspase-3, as well as increasing the ratio of Bcl-2/Bax, MMP and ATP content. Our results strongly suggested that tan IIA may be effective in treating AD associated with ER stress.
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Affiliation(s)
- Weina Yang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, China
| | - Jianshui Zhang
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, China
| | - Lili Shi
- Department of Human Anatomy, Xi'an Medical University, 1 Xinwang road, Xi'an, 710021, China
| | - Shengfeng Ji
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, China
| | - Xiaohua Yang
- Key Laboratory of Ministry of Health for Forensic Sciences, School of Forensic Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, China
| | - Wanying Zhai
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, China
| | - Hangfan Zong
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, China
| | - Yihua Qian
- Department of Human Anatomy, Histology and Embryology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 Yanta West Road, Xi'an, 710061, China.
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Pang Y, Qi G, Jiang S, Zhou Y, Li W. 1,2-Dichloroethane-induced hepatotoxicity and apoptosis by inhibition of ERK 1/2 pathways. Can J Physiol Pharmacol 2018; 96:1119-1126. [PMID: 29852074 DOI: 10.1139/cjpp-2017-0677] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
1,2-Dichloroethane (DCE) is a ubiquitous occupational environmental contaminant. Subacute exposure to DCE can cause severe toxic encephalopathy and has obvious toxic effects on the liver. However, the toxicity of DCE on the liver and its molecular mechanism remain elusive. In the present study, we established a DCE-exposed animal model by inhalation in SD rats and used HepG2 cells in in vitro tests. The DCE-exposed groups showed hepatic dysfunction relative to the control group. Moreover, apoptotic cells and decreased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) were found in liver tissue of rats in 3 DCE-exposed groups. In vitro tests showed that short-term exposure to DCE induced apoptosis in HepG2 cells. Furthermore, the incubation of cells with DCE significantly decreased the phosphorylation of ERK1/2 in a concentration-dependent manner. Additionally, incubating HepG2 cells with epidermal growth factor, an ERK1/2 activator, significantly increased apoptosis in HepG2 cells. In conclusion, our results suggest that DCE induces apoptosis in HepG2 cells by inhibiting ERK1/2 pathways.
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Affiliation(s)
- Yaqin Pang
- a Youjiang Medical University for Nationalities, Faculty of Toxicology, School of Public Health, Baise, Guangxi, China
| | - Guangzi Qi
- a Youjiang Medical University for Nationalities, Faculty of Toxicology, School of Public Health, Baise, Guangxi, China
| | - Sili Jiang
- b Guangzhou Center for Disease Control and Prevention, Guangzhou, Guangdong, China
| | - Ying Zhou
- b Guangzhou Center for Disease Control and Prevention, Guangzhou, Guangdong, China
| | - Wenxue Li
- b Guangzhou Center for Disease Control and Prevention, Guangzhou, Guangdong, China
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