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Zhao Y, Wang X, Teng H, Zhao T, Nadembega WMC, Fan X, Zhang W, Fan B, Chi Y, Zhao Y, Liu S. Weighted Gene Co-Expression Network Based on Transcriptomics: Unravelling the Differentiation Dynamics of 3T3-L1 Preadipocytes and the Regulatory Mechanism of Protopanaxatriol. Int J Mol Sci 2024; 25:12254. [PMID: 39596321 PMCID: PMC11594308 DOI: 10.3390/ijms252212254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2024] [Revised: 11/06/2024] [Accepted: 11/12/2024] [Indexed: 11/28/2024] Open
Abstract
The intricate regulatory mechanisms governing adipocyte differentiation are pivotal in elucidating the complex pathophysiology underlying obesity. This study aims to explore the dynamic changes in gene expression during the differentiation of 3T3-L1 adipocytes using transcriptomics methods. Protopanaxatriol (PPT) significantly inhibited adipocyte differentiation. To uncover the molecular mechanisms, we conducted an extensive transcriptomic analysis of adipocytes throughout various differentiation stages, comparing gene expression profiles before and after PPT treatment. The construction of 16 co-expression modules was achieved using weighted gene co-expression network analysis (WGCNA). The 838 differentially expressed genes in the blue module were highly correlated with PPT treatment. Further analysis revealed that PIKfyve, STAT3, JAK1, CTTN, TYK2, JAK3, STAT2, STAT5b, SOCS3, and IRF9 were core genes closely associated with adipocyte differentiation. This discovery underscores the potential pivotal function of these ten genes in regulating adipocyte differentiation. This study elucidated that PPT, an active ingredient in ginseng, could reduce lipid accumulation by inhibiting the differentiation of adipocyte precursors through the negative regulation of genes such as PIKfyve, STAT3, and JAK1. Finally, molecular docking identified potential binding sites for PPT on PIKfyve and JAK1. This study provides potential drug targets for preventing obesity and related metabolic diseases.
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Affiliation(s)
- Yaru Zhao
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130117, China; (Y.Z.); (X.W.); (H.T.); (X.F.); (W.Z.); (B.F.); (Y.C.)
- International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Changchun 130118, China; (T.Z.); (W.M.C.N.)
| | - Xv Wang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130117, China; (Y.Z.); (X.W.); (H.T.); (X.F.); (W.Z.); (B.F.); (Y.C.)
- International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Changchun 130118, China; (T.Z.); (W.M.C.N.)
| | - Hongbo Teng
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130117, China; (Y.Z.); (X.W.); (H.T.); (X.F.); (W.Z.); (B.F.); (Y.C.)
- International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Changchun 130118, China; (T.Z.); (W.M.C.N.)
| | - Tianyi Zhao
- International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Changchun 130118, China; (T.Z.); (W.M.C.N.)
| | - Wendyam Marie Christelle Nadembega
- International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Changchun 130118, China; (T.Z.); (W.M.C.N.)
| | - Xinhua Fan
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130117, China; (Y.Z.); (X.W.); (H.T.); (X.F.); (W.Z.); (B.F.); (Y.C.)
- International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Changchun 130118, China; (T.Z.); (W.M.C.N.)
| | - Wenxin Zhang
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130117, China; (Y.Z.); (X.W.); (H.T.); (X.F.); (W.Z.); (B.F.); (Y.C.)
- International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Changchun 130118, China; (T.Z.); (W.M.C.N.)
| | - Bowen Fan
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130117, China; (Y.Z.); (X.W.); (H.T.); (X.F.); (W.Z.); (B.F.); (Y.C.)
- International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Changchun 130118, China; (T.Z.); (W.M.C.N.)
| | - Yuye Chi
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130117, China; (Y.Z.); (X.W.); (H.T.); (X.F.); (W.Z.); (B.F.); (Y.C.)
| | - Yan Zhao
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130117, China; (Y.Z.); (X.W.); (H.T.); (X.F.); (W.Z.); (B.F.); (Y.C.)
- International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Changchun 130118, China; (T.Z.); (W.M.C.N.)
| | - Shuangli Liu
- College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun 130117, China; (Y.Z.); (X.W.); (H.T.); (X.F.); (W.Z.); (B.F.); (Y.C.)
- International Joint Laboratory for Development of Animal and Plant Resources for Food and Medicine, Changchun 130118, China; (T.Z.); (W.M.C.N.)
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Gui R, Ren Y, Wang Z, Li Y, Wu C, Li X, Li M, Li Y, Qian L, Xiong Y. Deciphering interleukin-18 in diabetes and its complications: Biological features, mechanisms, and therapeutic perspectives. Obes Rev 2024; 25:e13818. [PMID: 39191434 DOI: 10.1111/obr.13818] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 07/16/2024] [Accepted: 08/02/2024] [Indexed: 08/29/2024]
Abstract
Interleukin-18 (IL-18), a potent and multifunctional pro-inflammatory cytokine, plays a critical role in regulating β-cell failure, β-cell death, insulin resistance, and various complications of diabetes mellitus (DM). It exerts its effects by triggering various signaling pathways, enhancing the production of pro-inflammatory cytokines and nitric oxide (NO), as well as promoting immune cells infiltration and β-cells death. Abnormal alterations in IL-18 levels have been revealed to be strongly associated with the onset and development of DM and its complications. Targeting IL-18 may present a novel and promising approach for DM therapy. An increasing number of IL-18 inhibitors, including chemical and natural inhibitors, have been developed and have been shown to protect against DM and diabetic complications. This review provides a comprehensive understanding of the production, biological functions, action mode, and activated signaling pathways of IL-18. Next, we shed light on how IL-18 contributes to the pathogenesis of DM and its associated complications with links to its roles in the modulation of β-cell failure and death, insulin resistance in various tissues, and pancreatitis. Furthermore, the therapeutic potential of targeting IL-18 for the diagnosis and treatment of DM is also highlighted. We hope that this review will help us better understand the functions of IL-18 in the pathogenesis of DM and its complications, providing novel strategies for DM diagnosis and treatment.
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Affiliation(s)
- Runlin Gui
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Yuanyuan Ren
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Zhen Wang
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Yang Li
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Chengsong Wu
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
| | - Xiaofang Li
- Department of Gastroenterology, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Man Li
- Department of Endocrinology, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Yujia Li
- Department of Traditional Chinese Medicine, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
| | - Lu Qian
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
- Scientific Research Center, Xi'an Mental Health Center, Xi'an, Shaanxi, China
| | - Yuyan Xiong
- Key Laboratory of Resource Biology and Biotechnology in Western China, Ministry of Education, Faculty of Life Sciences and Medicine, Northwest University, Xi'an, Shaanxi, China
- Xi'an Key Laboratory of Cardiovascular and Cerebrovascular Diseases, Xi'an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi'an, Shaanxi, China
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Herrera-Uribe J, Convery O, ALmohammadi D, Weinberg FI, Stevenson NJ. The Neglected Suppressor of Cytokine Signalling (SOCS): SOCS4-7. Inflammation 2024:10.1007/s10753-024-02163-7. [PMID: 39460806 DOI: 10.1007/s10753-024-02163-7] [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: 07/22/2024] [Revised: 09/30/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024]
Abstract
SOCS proteins are essential for the regulation of oncogenic, anti-pathogenic, and proinflammatory signalling cascades, including the JAK/STAT and NF-kB pathways, where they act as negative feedback regulators. Given their powerful role in a broad spectrum of biological processes, it is surprising that the functions of many SOCS proteins have not been widely explored. While the mechanisms of action of CIS, SOCS1-3 are well-documented, information regarding SOCS4-7 remains limited. However, recent studies have begun to elucidate the regulatory functions of these proteins during infection and disease, such as influenza infection, cancer and diabetes. Therefore, this review aims to describe and discuss studies detailing our current understanding of SOCS4-7, painting a clearer picture of the biological processes these regulatory proteins maintain. Indeed, our review highlights important evidence proving that all SOCS play a role in biological processes that are essential for normal immunological homeostasis, clearance of infection and avoidance of disease. Understanding how SOCS proteins interact with other proteins or how they are dysregulated in disease is likely to provide valuable insights for advancing therapeutic approaches.
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Affiliation(s)
- Juber Herrera-Uribe
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Orla Convery
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Daniah ALmohammadi
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Fabienne Ingrid Weinberg
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Nigel J Stevenson
- Viral Immunology Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
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Huang J, Rozi R, Ma J, Fu B, Lu Z, Liu J, Ding Y. Association between higher triglyceride glucose index and increased risk of osteoarthritis: data from NHANES 2015-2020. BMC Public Health 2024; 24:758. [PMID: 38468219 PMCID: PMC10929152 DOI: 10.1186/s12889-024-18272-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Accepted: 03/04/2024] [Indexed: 03/13/2024] Open
Abstract
BACKGROUND The relationship between the triglyceride glucose (TyG) index and osteoarthritis (OA) remains unclear. The objective of this study was to examine potential associations between an elevated TyG index and an increased risk of OA prevalence. METHODS 3,921 participants with OA from the National Health and Nutrition Examination Survey (2015-2020) were included in this study. Participants were categorized into quartiles based on TyG index, which was determined using the formula: Ln [triglyceride (mg/dL) fasting blood glucose (mg/dL)/2]. Weighted multivariable regression, subgroup analyses, and threshold effect analyses were performed to calculate the independent association between TyG index and OA. RESULTS A total of 25,514 people were enrolled, with a mean TyG index of 8.48 ± 0.65. The results of multivariable logistic regression analysis after full adjustment showed a significant association between higher TyG index values and an increased risk of OA. Specifically, each incremental unit increase in the TyG index was associated with a 634% higher risk of OA [OR = 7.34; 95% CI: 2.25, 23.93; p = 0.0010]. Based on interaction tests, age, gender, BMI, and smoking status did not significantly affect the relationship between the TyG index and OA, while diabetes showed a stronger positive correlation between the TyG index and OA. CONCLUSION An increased risk of OA was associated with a higher TyG index. TyG could be a valuable predictor of OA and offer novel perspectives on the assessment and treatment of OA.
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Affiliation(s)
- Jie Huang
- Orthopedics of TCM Senior Department, The Sixth Medical Center of PLA General Hospital, 100048, Beijing, China
- Department of Orthopaedics, School of Medicine, South China University of Technology, 510006, Guangzhou, China;, China
| | - Rigbat Rozi
- Orthopedics of TCM Senior Department, The Sixth Medical Center of PLA General Hospital, 100048, Beijing, China
| | - Jingbo Ma
- Orthopedics of TCM Senior Department, The Sixth Medical Center of PLA General Hospital, 100048, Beijing, China
| | - Bensheng Fu
- Orthopedics of TCM Senior Department, The Sixth Medical Center of PLA General Hospital, 100048, Beijing, China
| | - Zhengcao Lu
- Orthopedics of TCM Senior Department, The Sixth Medical Center of PLA General Hospital, 100048, Beijing, China
- Department of Orthopaedics, School of Medicine, Jinzhou Medical University, 121001, Jinzhou, China
| | - Jiang Liu
- Orthopedics of TCM Senior Department, The Sixth Medical Center of PLA General Hospital, 100048, Beijing, China
| | - Yu Ding
- Orthopedics of TCM Senior Department, The Sixth Medical Center of PLA General Hospital, 100048, Beijing, China.
- Department of Orthopaedics, School of Medicine, South China University of Technology, 510006, Guangzhou, China;, China.
- Department of Orthopaedics, School of Medicine, Jinzhou Medical University, 121001, Jinzhou, China.
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Engin AB. Mechanism of Obesity-Related Lipotoxicity and Clinical Perspective. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:131-166. [PMID: 39287851 DOI: 10.1007/978-3-031-63657-8_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The link between cellular exposure to fatty acid species and toxicity phenotypes remains poorly understood. However, structural characterization and functional profiling of human plasma free fatty acids (FFAs) analysis has revealed that FFAs are located either in the toxic cluster or in the cluster that is transcriptionally responsive to lipotoxic stress and creates genetic risk factors. Genome-wide short hairpin RNA screen has identified more than 350 genes modulating lipotoxicity. Hypertrophic adipocytes in obese adipose are both unable to expand further to store excess lipids in the diet and are resistant to the antilipolytic action of insulin. In addition to lipolysis, the inability of packaging the excess lipids into lipid droplets causes circulating fatty acids to reach toxic levels in non-adipose tissues. Deleterious effects of accumulated lipid in non-adipose tissues are known as lipotoxicity. Although triglycerides serve a storage function for long-chain non-esterified fatty acid and their products such as ceramide and diacylglycerols (DAGs), overloading of palmitic acid fraction of saturated fatty acids (SFAs) raises ceramide levels. The excess DAG and ceramide load create harmful effects on multiple organs and systems, inducing chronic inflammation in obesity. Thus, lipotoxic inflammation results in β cells death and pancreatic islets dysfunction. Endoplasmic reticulum stress stimuli induce lipolysis by activating cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and extracellular signal-regulated kinase (Erk) 1/2 signaling in adipocytes. However, palmitic acid-induced endoplasmic reticulum stress-c-Jun N-terminal kinase (JNK)-autophagy axis in hypertrophic adipocytes is a pro-survival mechanism against endoplasmic reticulum stress and cell death induced by SFAs. Endoplasmic reticulum-localized acyl-coenzyme A (CoA): glycerol-3-phosphate acyltransferase (GPAT) enzymes are mediators of lipotoxicity, and inhibiting these enzymes has therapeutic potential for lipotoxicity. Lipotoxicity increases the number of autophagosomes, which engulf palmitic acid, and thus suppress the autophagic turnover. Fatty acid desaturation promotes palmitate detoxification and storages into triglycerides. As therapeutic targets of glucolipotoxicity, in addition to caloric restriction and exercise, there are four different pharmacological approaches, which consist of metformin, glucagon-like peptide 1 (GLP-1) receptor agonists, peroxisome proliferator-activated receptor-gamma (PPARγ) ligands thiazolidinediones, and chaperones are still used in clinical practice. Furthermore, induction of the brown fat-like phenotype with the mixture of eicosapentanoic acid and docosahexaenoic acid appears as a potential therapeutic application for treatment of lipotoxicity.
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Affiliation(s)
- Ayse Basak Engin
- Faculty of Pharmacy, Department of Toxicology, Gazi University, Hipodrom, Ankara, Turkey.
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Engin A. Protein Kinases in Obesity, and the Kinase-Targeted Therapy. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1460:199-229. [PMID: 39287853 DOI: 10.1007/978-3-031-63657-8_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/19/2024]
Abstract
The action of protein kinases and protein phosphatases is essential for multiple physiological responses. Each protein kinase displays its own unique substrate specificity and a regulatory mechanism that may be modulated by association with other proteins. Protein kinases are classified as dual-specificity kinases and dual-specificity phosphatases. Dual-specificity phosphatases are important signal transduction enzymes that regulate various cellular processes in coordination with protein kinases and play an important role in obesity. Impairment of insulin signaling in obesity is largely mediated by the activation of the inhibitor of kappa B-kinase beta and the c-Jun N-terminal kinase (JNK). Oxidative stress and endoplasmic reticulum (ER) stress activate the JNK pathway which suppresses insulin biosynthesis. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) are important for proper regulation of glucose metabolism in mammals at both the hormonal and cellular levels. Additionally, obesity-activated calcium/calmodulin dependent-protein kinase II/p38 suppresses insulin-induced protein kinase B phosphorylation by activating the ER stress effector, activating transcription factor-4. To alleviate lipotoxicity and insulin resistance, promising targets are pharmacologically inhibited. Nifedipine, calcium channel blocker, stimulates lipogenesis and adipogenesis by downregulating AMPK and upregulating mTOR, which thereby enhances lipid storage. Contrary to the nifedipine, metformin activates AMPK, increases fatty acid oxidation, suppresses fatty acid synthesis and deposition, and thus alleviates lipotoxicity. Obese adults with vascular endothelial dysfunction have greater endothelial cells activation of unfolded protein response stress sensors, RNA-dependent protein kinase-like ER eukaryotic initiation factor-2 alpha kinase (PERK), and activating transcription factor-6. The transcriptional regulation of adipogenesis in obesity is influenced by AGC (protein kinase A (PKA), PKG, PKC) family signaling kinases. Obesity may induce systemic oxidative stress and increase reactive oxygen species in adipocytes. An increase in intracellular oxidative stress can promote PKC-β activation. Activated PKC-β induces growth factor adapter Shc phosphorylation. Shc-generated peroxides reduce mitochondrial oxygen consumption and enhance triglyceride accumulation and lipotoxicity. Liraglutide attenuates mitochondrial dysfunction and reactive oxygen species generation. Co-treatment of antiobesity and antidiabetic herbal compound, berberine with antipsychotic drug olanzapine decreases the accumulation of triglyceride. While low-dose rapamycin, metformin, amlexanox, thiazolidinediones, and saroglitazar protect against insulin resistance, glucagon-like peptide-1 analog liraglutide inhibits palmitate-induced inflammation by suppressing mTOR complex 1 (mTORC1) activity and protects against lipotoxicity.
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Affiliation(s)
- Atilla Engin
- Faculty of Medicine, Department of General Surgery, Gazi University, Besevler, Ankara, Turkey.
- Mustafa Kemal Mah. 2137. Sok. 8/14, 06520, Cankaya, Ankara, Turkey.
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Yan Y, Zhou L, La R, Jiang M, Jiang D, Huang L, Xu W, Wu Q. The association between triglyceride glucose index and arthritis: a population-based study. Lipids Health Dis 2023; 22:132. [PMID: 37608322 PMCID: PMC10463930 DOI: 10.1186/s12944-023-01899-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Accepted: 08/07/2023] [Indexed: 08/24/2023] Open
Abstract
OBJECTIVES Insulin resistance is a well-established contributor to inflammation; however, the specific association between the triglyceride glucose (TyG) index, a biomarker reflecting insulin resistance, and arthritis remains unexplored. As a result, the main aim of this study was to examine the correlation between the TyG index and arthritis. METHODS This observational study used data from the National Health and Nutrition Examination Survey (NHANES), which was conducted between 2007 and 2018. To investigate the relationship between the TyG index and arthritis, various statistical analyses were employed, including weighted multivariable logistic regression analysis, subgroup analysis, curve fit analysis, and threshold effect analysis. RESULTS In total, 14,817 patients were enrolled in the trial, with 4,191 individuals (28.29%) diagnosed with arthritis. An increased risk of arthritis was found to be significantly correlated with higher TyG index values (odds ratio OR = 1.15, 95% confidence interval CI: 1.07-1.23), according to the results of multivariable logistic regression analysis after full adjustment. Subgroup analysis and interaction tests further indicated that the TyG index exhibited an additive effect when combined with other established risk factors, including age (OR = 1.29; 95% CI: 1.17-1.41), body mass index (BMI) (OR = 1.43; 95% CI: 1.24-1.69), and diabetes (OR = 1.20; 95% CI: 1.11-1.31). Additionally, curve fit analysis and threshold effect analysis demonstrated a nonlinear relationship with a breakpoint identified at 8.08 µmol/L. CONCLUSION The TyG index was positively correlated with arthritis in adults under 60 years of age in the United States who had normal weight and no diabetes. Further large-scale prospective studies are warranted for a comprehensive analysis of the role of the TyG index in arthritis.
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Affiliation(s)
- Yuxin Yan
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Liyu Zhou
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Rui La
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Ming Jiang
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Dinghua Jiang
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Lixin Huang
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China
| | - Wu Xu
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China.
| | - Qian Wu
- Department of Orthopedic Surgery, Orthopedic Institute, The First Affiliated Hospital, Suzhou Medical College, Soochow University, Suzhou, Jiangsu, China.
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Mathew D, Barillas-Cerritos J, Nedeljkovic-Kurepa A, Abraham M, Taylor MD, Deutschman CS. Phosphorylation of insulin receptor substrates (IRS-1 and IRS-2) is attenuated following cecal ligation and puncture in mice. Mol Med 2023; 29:106. [PMID: 37550630 PMCID: PMC10408057 DOI: 10.1186/s10020-023-00703-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Accepted: 07/18/2023] [Indexed: 08/09/2023] Open
Abstract
BACKGROUND Sepsis is characterized as an insulin resistant state. However, the effects of sepsis on insulin's signal transduction pathway are unknown. The molecular activity driving insulin signaling is controlled by tyrosine phosphorylation of the insulin receptor β-subunit (IRβ) and of insulin receptor substrate molecules (IRS) -1 and IRS-2. HYPOTHESIS Cecal ligation and puncture (CLP) attenuates IRβ, IRS-1 and IRS-2 phosphorylation. METHODS IACUC-approved studies conformed to ARRIVE guidelines. CLP was performed on C57BL/6 mice; separate cohorts received intraperitoneal insulin at baseline (T0) or at 23 or 47 h. post-CLP, 1 h before mice were euthanized. We measured levels of (1) glucose and insulin in serum, (2) IRβ, IRS-1 and IRS-2 in skeletal muscle and liver homogenate and (3) phospho-Irβ (pIRβ) in liver and skeletal muscle, phospho-IRS-1 (pIRS-1) in skeletal muscle and pIRS-2 in liver. Statistical significance was determined using ANOVA with Sidak's post-hoc correction. RESULTS CLP did not affect the concentrations of IRβ, IRS-1or IRS-2 in muscle or liver homogenate or of IRS-1 in liver. Muscle IRS-1 concentration at 48 h. post-CLP was higher than at T0. Post-CLP pIRS-1 levels in muscle and pIRβ and pIRS-2 levels in liver were indistinguishable from T0 levels. At 48 h. post-CLP pIRβ levels in muscle were higher than at T0. Following insulin administration, the relative abundance of pIRβ in muscle and liver at T0 and at both post-CLP time points was significantly higher than abundance in untreated controls. In T0 controls, the relative abundance of pIRS-1 in muscle and of pIRS-2 in liver following insulin administration was higher than in untreated mice. However, at both post-CLP time points, the relative abundance of pIRS-1 in muscle and of pIRS-2 in liver following insulin administration was not distinguishable from the abundance in untreated mice at the same time point. Serum glucose concentration was significantly lower than T0 at 24 h., but not 48 h., post-CLP. Glucose concentration was lower following insulin administration to T0 mice but not in post-CLP animals. Serum insulin levels were significantly higher than baseline at both post-CLP time points. CONCLUSIONS CLP impaired insulin-induced tyrosine phosphorylation of both IRS-1 in muscle and IRS-2 in liver. These findings suggest that the molecular mechanism underlying CLP-induced insulin resistance involves impaired IRS-1/IRS-2 phosphorylation.
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Affiliation(s)
- Deepa Mathew
- Department of Pediatrics, Cohen Children's Medical Center, Lake Success, NY, USA
- Institute for Molecular Medicine, Feinstein Institutes for Medical Research, Room 3140, 350 Community Dr, Manhasset, NY, 11030, USA
| | - Julia Barillas-Cerritos
- Department of Pediatrics, Cohen Children's Medical Center, Lake Success, NY, USA
- Institute for Molecular Medicine, Feinstein Institutes for Medical Research, Room 3140, 350 Community Dr, Manhasset, NY, 11030, USA
- Pediatric Endocrinology, Metabolism and Diabetes, Winthrop Pediatrics Associates, Mineola, NY, USA
| | - Ana Nedeljkovic-Kurepa
- Department of Pediatrics, Cohen Children's Medical Center, Lake Success, NY, USA
- Institute for Molecular Medicine, Feinstein Institutes for Medical Research, Room 3140, 350 Community Dr, Manhasset, NY, 11030, USA
| | - Mabel Abraham
- Department of Pediatrics, Cohen Children's Medical Center, Lake Success, NY, USA
- Institute for Molecular Medicine, Feinstein Institutes for Medical Research, Room 3140, 350 Community Dr, Manhasset, NY, 11030, USA
| | - Matthew D Taylor
- Department of Pediatrics, Cohen Children's Medical Center, Lake Success, NY, USA
- Institute for Molecular Medicine, Feinstein Institutes for Medical Research, Room 3140, 350 Community Dr, Manhasset, NY, 11030, USA
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA
| | - Clifford S Deutschman
- Department of Pediatrics, Cohen Children's Medical Center, Lake Success, NY, USA.
- Institute for Molecular Medicine, Feinstein Institutes for Medical Research, Room 3140, 350 Community Dr, Manhasset, NY, 11030, USA.
- Zucker School of Medicine at Hofstra/Northwell, Hempstead, NY, USA.
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Barrios-Nolasco A, Domínguez-López A, Miliar-García A, Cornejo-Garrido J, Jaramillo-Flores ME. Anti-Inflammatory Effect of Ethanolic Extract from Tabebuia rosea (Bertol.) DC., Quercetin, and Anti-Obesity Drugs in Adipose Tissue in Wistar Rats with Diet-Induced Obesity. Molecules 2023; 28:molecules28093801. [PMID: 37175211 PMCID: PMC10180162 DOI: 10.3390/molecules28093801] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 04/18/2023] [Accepted: 04/26/2023] [Indexed: 05/15/2023] Open
Abstract
Obesity is characterized by the excessive accumulation of fat, which triggers a low-grade chronic inflammatory process. Currently, the search for compounds with anti-obesogenic effects that help reduce body weight, as well as associated comorbidities, continues. Among this group of compounds are plant extracts and flavonoids with a great diversity of action mechanisms associated with their beneficial effects, such as anti-inflammatory effects and/or as signaling molecules. In the bark of Tabebuia rosea tree, there are different classes of metabolites with anti-inflammatory properties, such as quercetin. Therefore, the present work studied the effect of the ethanolic extract of T. rosea and quercetin on the mRNA of inflammation markers in obesity compared to the drugs currently used. Total RNA was extracted from epididymal adipose tissue of high-fat diet-induced obese Wistar rats treated with orlistat, phentermine, T. rosea extract, and quercetin. The rats treated with T. rosea and quercetin showed 36 and 31% reductions in body weight compared to the obese control, and they likewise inhibited pro-inflammatory molecules: Il6, Il1b, Il18, Lep, Hif1a, and Nfkb1 without modifying the expression of Socs1 and Socs3. Additionally, only T. rosea overexpressed Lipe. Both T. rosea and quercetin led to a reduction in the expression of pro-inflammatory genes, modifying signaling pathways, which led to the regulation of the obesity-inflammation state.
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Affiliation(s)
- Alejandro Barrios-Nolasco
- Laboratorio de Biología Celular y Productos Naturales, Escuela Nacional de Medicina y Homeopatía (ENMH), Instituto Politécnico Nacional, Guillermo Massieu Helguera 239, Col. La Escalera, Alcaldía Gustavo A. Madero, Ciudad de Mexico 07320, Mexico
| | - Aarón Domínguez-López
- Laboratorio de Biología Molecular, Escuela Superior de Medicina (ESM), Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Col. Casco de Santo Tomas, Alcaldía Miguel Hidalgo, Ciudad de Mexico 11340, Mexico
| | - Angel Miliar-García
- Laboratorio de Biología Molecular, Escuela Superior de Medicina (ESM), Instituto Politécnico Nacional, Plan de San Luis y Díaz Mirón s/n, Col. Casco de Santo Tomas, Alcaldía Miguel Hidalgo, Ciudad de Mexico 11340, Mexico
| | - Jorge Cornejo-Garrido
- Laboratorio de Biología Celular y Productos Naturales, Escuela Nacional de Medicina y Homeopatía (ENMH), Instituto Politécnico Nacional, Guillermo Massieu Helguera 239, Col. La Escalera, Alcaldía Gustavo A. Madero, Ciudad de Mexico 07320, Mexico
| | - María Eugenia Jaramillo-Flores
- Laboratorio de Polímeros, Department de Ingeniería Bioquímica, Escuela Nacional de Ciencias Biológicas (ENCB), Instituto Politécnico Nacional, Wilfrido Massieu s/n esq. Manuel I. Stampa. Col. Unidad Profesional Adolfo López Mateos, Alcaldía Gustavo A. Madero, Ciudad de Mexico 07738, Mexico
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Emamgholipour S, Esmaeili F, Shabani M, Hasanpour SZ, Pilehvari M, Zabihi-Mahmoudabadi H, Motevasseli M, Shanaki M. Alterations of SOCS1 and SOCS3 transcript levels, but not promoter methylation levels in subcutaneous adipose tissues in obese women. BMC Endocr Disord 2023; 23:7. [PMID: 36609306 PMCID: PMC9817302 DOI: 10.1186/s12902-022-01247-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 12/12/2022] [Indexed: 01/07/2023] Open
Abstract
BACKGROUND Animal model studies suggest that change in the members of the suppressor of the cytokine signaling (SOCS) family (mainly SOCS1 and SOCS3) is linked to the pathogenesis of obesity-related metabolic disorders. Moreover, epigenetic modification is involved in the transcriptional regulation of the SOCS gene family. Here, we aimed to evaluate the mRNA expression as well as gene promoter methylation of SOCS1 and SOCS3 in subcutaneous adipose tissue (SAT) from obese women compared to normal-weight subjects. We also intend to identify the possible association of SOCS1 and SOCS3 transcript levels with metabolic parameters in the context of obesity. METHODS This study was conducted on women with obesity (n = 24) [body mass index (BMI) ≥ 30 kg/m 2] and women with normal-weight (n = 22) (BMI < 25 kg/m 2). Transcript levels of SOCS1 and SOCS3 were evaluated by real-time PCR in SAT from all participants. After bisulfite treatment of DNA, methylation-specific PCR was used to assess the putative methylation of 10 CpG sites in the promoter of SOCS1 and 13 CpG sites in SOCS3 in SAT from women with obesity and normal weight. RESULTS It was found that unlike SOCS3, which disclosed an elevating expression pattern, the expression level of SOCS1 was lower in the women with obesity as compared with their non-obese counterparts (P-value = 0.03 for SOCS1 transcript level and P-value = 0.011 for SOCS3 transcript level). As for the analysis of promoter methylation, it was found that SOCS1 and SOCS3 methylation were not significantly different between the individuals with obesity and normal weight (P-value = 0.45 and P-value = 0.89). Correlation analysis indicated that the transcript level of SOCS1 mRNA expression had an inverse correlation with BMI, hs-CRP levels, HOMA-IR, and insulin levels. However, the SOCS3 transcript level showed a positive correlation with BMI, waist-to-height ratio, waist circumference, hip circumference, hs-CRP, HOMA-IR, insulin, fasting blood glucose, and total cholesterol. Interestingly, HOMA-IR is the predictor of the transcript level of SOCS1 (β = - 0.448, P-value = 0.003) and SOCS3 (β = 0.465, P-value = 0.002) in SAT of all participants. CONCLUSIONS Our findings point to alterations of SOCS1 and SOCS3 transcript levels, but not promoter methylation levels in subcutaneous adipose tissues from women with obesity. Moreover, mRNA expression of SOCS1 and SOCS3 in SAT was associated with known obesity indices, insulin resistance, and hs-CRP, suggesting the contribution of SOCS1 and SOCS3 in the pathogenesis of obesity-related metabolic abnormalities. However, further studies are required to establish this concept.
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Affiliation(s)
- Solaleh Emamgholipour
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Fataneh Esmaeili
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Student Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Maryam Shabani
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
- Department of Anatomy, School of Medicine, Tehran University of Medical Science, Tehran, Iran Sciences, Tehran, Iran
| | - Seyedeh Zahra Hasanpour
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mahsa Pilehvari
- Department of Clinical Biochemistry, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Hossein Zabihi-Mahmoudabadi
- Department of Surgery, School of Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
| | - Meysam Motevasseli
- Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mehrnoosh Shanaki
- Department of Medical Laboratory Sciences, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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11
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Acosta-Martinez M, Cabail MZ. The PI3K/Akt Pathway in Meta-Inflammation. Int J Mol Sci 2022; 23:ijms232315330. [PMID: 36499659 PMCID: PMC9740745 DOI: 10.3390/ijms232315330] [Citation(s) in RCA: 89] [Impact Index Per Article: 29.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/22/2022] [Accepted: 12/01/2022] [Indexed: 12/09/2022] Open
Abstract
Obesity is a global epidemic representing a serious public health burden as it is a major risk factor for the development of cardiovascular disease, stroke and all-cause mortality. Chronic low-grade systemic inflammation, also known as meta-inflammation, is thought to underly obesity's negative health consequences, which include insulin resistance and the development of type 2 diabetes. Meta-inflammation is characterized by the accumulation of immune cells in adipose tissue, a deregulation in the synthesis and release of adipokines and a pronounced increase in the production of proinflammatory factors. In this state, the infiltration of macrophages and their metabolic activation contributes to complex paracrine and autocrine signaling, which sustains a proinflammatory microenvironment. A key signaling pathway mediating the response of macrophages and adipocytes to a microenvironment of excessive nutrients is the phosphoinositide 3-kinase (PI3K)/Akt pathway. This multifaceted network not only transduces metabolic information but also regulates macrophages' intracellular changes, which are responsible for their phenotypic switch towards a more proinflammatory state. In the present review, we discuss how the crosstalk between macrophages and adipocytes contributes to meta-inflammation and provide an overview on the involvement of the PI3K/Akt signaling pathway, and how its impairment contributes to the development of insulin resistance.
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Affiliation(s)
- Maricedes Acosta-Martinez
- Department of Physiology and Biophysics, Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Maria Zulema Cabail
- Biological Science Department, State University of New York-College at Old Westbury, Old Westbury, NY 11568, USA
- Correspondence:
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Xiao F, Deng J, Jiao F, Hu X, Jiang H, Yuan F, Chen S, Niu Y, Jiang X, Guo F. Hepatic cytokine-inducible SH2-containing protein (CISH) regulates gluconeogenesis via cAMP-responsive element binding protein (CREB). FASEB J 2022; 36:e22541. [PMID: 36083102 DOI: 10.1096/fj.202200870r] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 08/17/2022] [Accepted: 08/29/2022] [Indexed: 11/11/2022]
Abstract
Impairment of gluconeogenesis is a key factor responsible for hyperglycemia in patients with type 2 diabetes. As an important member of the suppressors of cytokine signaling (SOCS) protein family, many physiological functions of cytokine-inducible SH2-containing protein (CISH) have been described; however, the role of hepatic CISH in gluconeogenesis is poorly understood. In the present study, we observed that hepatic CISH expression was reduced in fasted wild-type (WT) mice. Overexpression of CISH decreased glucose production in mouse primary hepatocytes, while silencing of CISH had the opposite effects. In addition, adenovirus-mediated hepatic CISH overexpression resulted in improved glucose tolerance and decreased gluconeogenesis in WT and leptin receptor-deficient diabetic (db/db) mice. In contrast, adenovirus-mediated hepatic CISH knockdown impaired glucose tolerance and increased gluconeogenesis in WT mice. We also generated liver-specific CISH knockout (LV-CISH KO) mice and discovered that these mice had a similar phenotype in glucose tolerance and gluconeogenesis as mice injected with adenoviruses that knockdown CISH expression. Mechanistically, we found that CISH overexpression decreased and CISH knockdown increased the mRNA and protein levels of glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase 1 (PEPCK), two key enzymes involved in gluconeogenesis, in vitro, and in vivo. Moreover, we discovered that the phosphorylation of cAMP-responsive element binding protein 1 (CREB), a transcription factor of G6pase and Pepck, was required for regulating gluconeogenesis by CISH. Taken together, this study identifies hepatic CISH as an important regulator of gluconeogenesis. Our results also provide important insights into the metabolic functions of the SOCS protein family and the potential targets for the treatment of diabetes.
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Affiliation(s)
- Fei Xiao
- Jinshan Hospital, State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
| | - Jiali Deng
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Fuxin Jiao
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiaoming Hu
- Jinshan Hospital, State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
| | - Haizhou Jiang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Feixiang Yuan
- Jinshan Hospital, State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
| | - Shanghai Chen
- Jinshan Hospital, State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
| | - Yuguo Niu
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Xiaoxue Jiang
- CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Feifan Guo
- Jinshan Hospital, State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China
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Hendawy AS, El-Lakkany NM, Mantawy EM, Hammam OA, Botros SS, El-Demerdash E. Vildagliptin alleviates liver fibrosis in NASH diabetic rats via modulation of insulin resistance, oxidative stress, and inflammatory cascades. Life Sci 2022; 304:120695. [PMID: 35671811 DOI: 10.1016/j.lfs.2022.120695] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 05/30/2022] [Accepted: 06/03/2022] [Indexed: 02/06/2023]
Abstract
AIMS This study investigates the therapeutic potential of Vilda in a NASH model with liver fibrosis and elucidates the underlying molecular mechanisms. MAIN METHODS To induce NASH, male Sprague-Dawley rats were fed a high-fat diet for 24 weeks with a single dose of STZ (40 mg/kg, IP). Vilda was orally administered at two doses (10 and 20 mg/kg) for 20 weeks. KEY FINDINGS The induction of NASH was validated by abnormalities in hepatotoxicity indices, lipid profile, oxidative stress markers, and pathologically by marked fat deposition in hepatic tissues together with severe inflammatory cell infiltration. Moreover, NASH-affected rats demonstrated reduced insulin sensitivity manifested as elevated fasting blood glucose levels and disrupted homeostasis model assessment for insulin resistance. Vilda, at both doses, effectively abrogated all these pathological features of NASH. Mechanistically, these hepatoprotective properties of Vilda can be attributed to its antioxidant effects, anti-inflammatory effects (by inhibiting the TNF-α, NF-κB, JNK, and JAK/STAT pathways), and insulin-sensitizing effect (by upregulating the IRS-1/PI3K/Akt pathway). Besides, Vilda successfully counteracted NASH-associated liver fibrosis by downregulating the TGF-β1 pathway. SIGNIFICANCE The hepatoprotective and antifibrotic effects of Vilda were mostly dose-dependent. Collectively, this study offered a promising therapeutic avenue for Vilda as a novel strategy for counteracting the pathological progression of NASH and associated liver fibrosis.
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Affiliation(s)
- Ahmed S Hendawy
- Department of Pharmacology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba, 30, Giza 12411, Egypt
| | - Naglaa M El-Lakkany
- Department of Pharmacology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba, 30, Giza 12411, Egypt
| | - Eman M Mantawy
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbasia, Cairo 11566, Egypt
| | - Olfat A Hammam
- Department of Pathology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba, 30, Giza 12411, Egypt
| | - Sanaa S Botros
- Department of Pharmacology, Theodor Bilharz Research Institute, Kornaish El Nile, Warrak El-Hadar, Imbaba, 30, Giza 12411, Egypt
| | - Ebtehal El-Demerdash
- Department of Pharmacology & Toxicology, Faculty of Pharmacy, Ain Shams University, Organization of African Unity Street, Abbasia, Cairo 11566, Egypt.
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New Insights into Adipokines in Gestational Diabetes Mellitus. Int J Mol Sci 2022; 23:ijms23116279. [PMID: 35682958 PMCID: PMC9181219 DOI: 10.3390/ijms23116279] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 05/27/2022] [Accepted: 06/01/2022] [Indexed: 12/12/2022] Open
Abstract
Gestational diabetes mellitus (GDM) is the most common metabolic disorder of pregnancy and has considerable short- and long-term consequences for the health of both the mother and the newborn. Within its pathophysiology, genetic, nutritional, epigenetic, immunological, and hormonal components have been described. Within the last two items, it is known that different hormones and cytokines secreted by adipose tissue, known collectively as adipokines, are involved in the metabolic alterations underlying GDM. Although the maternal circulating profile of adipokines in GDM has been extensively studied, and there are excellent reviews on the subject, it is in recent years that more progress has been made in the study of their expression in visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), placenta, and their concentrations in the umbilical circulation. Thus, this review compiles and organizes the most recent findings on the maternal and umbilical circulating profile and the levels of expression of adipokines in VAT, SAT, and placenta in GDM.
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15
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Infante M, Padilla N, Alejandro R, Caprio M, Della-Morte D, Fabbri A, Ricordi C. Diabetes-Modifying Antirheumatic Drugs: The Roles of DMARDs as Glucose-Lowering Agents. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:571. [PMID: 35629988 PMCID: PMC9143119 DOI: 10.3390/medicina58050571] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 04/14/2022] [Accepted: 04/18/2022] [Indexed: 02/06/2023]
Abstract
Systemic inflammation represents a shared pathophysiological mechanism which underlies the frequent clinical associations among chronic inflammatory rheumatic diseases (CIRDs), insulin resistance, type 2 diabetes (T2D), and chronic diabetes complications, including cardiovascular disease. Therefore, targeted anti-inflammatory therapies are attractive and highly desirable interventions to concomitantly reduce rheumatic disease activity and to improve glucose control in patients with CIRDs and comorbid T2D. Therapeutic approaches targeting inflammation may also play a role in the prevention of prediabetes and diabetes in patients with CIRDs, particularly in those with traditional risk factors and/or on high-dose corticosteroid therapy. Recently, several studies have shown that different disease-modifying antirheumatic drugs (DMARDs) used for the treatment of CIRDs exert antihyperglycemic properties by virtue of their anti-inflammatory, insulin-sensitizing, and/or insulinotropic effects. In this view, DMARDs are promising drug candidates that may potentially reduce rheumatic disease activity, ameliorate glucose control, and at the same time, prevent the development of diabetes-associated cardiovascular complications and metabolic dysfunctions. In light of their substantial antidiabetic actions, some DMARDs (such as hydroxychloroquine and anakinra) could be alternatively termed "diabetes-modifying antirheumatic drugs", since they may be repurposed for co-treatment of rheumatic diseases and comorbid T2D. However, there is a need for future randomized controlled trials to confirm the beneficial metabolic and cardiovascular effects as well as the safety profile of distinct DMARDs in the long term. This narrative review aims to discuss the current knowledge about the mechanisms behind the antihyperglycemic properties exerted by a variety of DMARDs (including synthetic and biologic DMARDs) and the potential use of these agents as antidiabetic medications in clinical settings.
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Affiliation(s)
- Marco Infante
- Clinical Cell Transplant Program (CCTP), Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL 33136, USA; (R.A.); (C.R.)
- Department of Systems Medicine, Diabetes Research Institute Federation (DRIF), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
- Section of Endocrinology, UniCamillus, Saint Camillus International University of Health Sciences, Via di Sant’Alessandro 8, 00131 Rome, Italy
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Via Cola di Rienzo 28, 00192 Rome, Italy
| | - Nathalia Padilla
- Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Colonia Centroamérica L-823, Managua 14048, Nicaragua;
| | - Rodolfo Alejandro
- Clinical Cell Transplant Program (CCTP), Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL 33136, USA; (R.A.); (C.R.)
| | - Massimiliano Caprio
- Laboratory of Cardiovascular Endocrinology, IRCCS San Raffaele Roma, Via di Val Cannuta 247, 00166 Rome, Italy;
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy;
| | - David Della-Morte
- Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Via di Val Cannuta 247, 00166 Rome, Italy;
- Department of Systems Medicine, University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy
- Department of Neurology, Evelyn F. McKnight Brain Institute, University of Miami Miller School of Medicine, 1120 NW 14th St., Miami, FL 33136, USA
| | - Andrea Fabbri
- Department of Systems Medicine, Diabetes Research Institute Federation (DRIF), University of Rome Tor Vergata, Via Montpellier 1, 00133 Rome, Italy;
| | - Camillo Ricordi
- Clinical Cell Transplant Program (CCTP), Diabetes Research Institute, University of Miami Miller School of Medicine, 1450 NW 10th Ave, Miami, FL 33136, USA; (R.A.); (C.R.)
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Jyothi CCX, Bandyopadhyay D, Sahu S, Patro BK, Nayak S. Correlation of Serum Retinol and Atherogenic Indices in Type 2 Diabetes Mellitus: A Case-Control Study. Indian J Clin Biochem 2022; 37:100-106. [PMID: 35125699 PMCID: PMC8799824 DOI: 10.1007/s12291-020-00951-0] [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: 05/11/2020] [Accepted: 12/17/2020] [Indexed: 01/03/2023]
Abstract
Dyslipidemia is an important risk factor for atherosclerosis and coronary heart disease, leading to mortality and morbidity in subjects with T2DM. This risk is higher in subjects with diabetes who are on retinoid therapy for some other indication, where hypercholesterolemia, hypertriglyceridemia, and low serum high-density lipoprotein cholesterol (HDL-C), and sudden cardiovascular deaths have been reported. Our study aimed to find the correlation of serum retinol and atherogenic index (AI) in subjects with T2DM and compare them with healthy controls. We found there was a significant difference in systolic and diastolic blood pressure, body mass index, waist circumference, waist hip ratio, total cholesterol (TC), Triglycerides (TG), non-high density lipoprotein cholesterol (non-HDL-C), the atherogenic ratio of cholesterol (ARC), atherogenic index of plasma (AIP) and AI between the two groups. There was a significant positive correlation of serum retinol with TC, TG, LDL-C, Non-HDL-C, ARC, AIP, and AI. In our study we found an association of serum retinol with atherogenic index and dyslipidemia in subjects with T2DM. Serum retinol can be a novel predictor of cardiovascular risk in subjects with T2DM.
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Affiliation(s)
| | | | - Suchanda Sahu
- Department of Biochemistry, AIIMS, Bhubaneswar, India
| | - Binod Kumar Patro
- Department of Community Medicine and Family Medicine, AIIMS, Bhubaneswar, India
| | - Saurav Nayak
- Department of Biochemistry, AIIMS, Bhubaneswar, India
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Arlien-Søborg MC, Dal J, Madsen MA, Høgild ML, Hjelholt AJ, Pedersen SB, Møller N, Jessen N, Jørgensen JOL. Reversible insulin resistance in muscle and fat unrelated to the metabolic syndrome in patients with acromegaly. EBioMedicine 2021; 75:103763. [PMID: 34929488 PMCID: PMC8688588 DOI: 10.1016/j.ebiom.2021.103763] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/22/2021] [Accepted: 12/03/2021] [Indexed: 10/27/2022] Open
Abstract
BACKGROUND Patients with active acromegaly exhibit insulin resistance despite a lean phenotype whereas controlled disease improves insulin sensitivity and increases fat mass. The mechanisms underlying this paradox remain elusive, but growth hormone (GH)-induced lipolysis plays a central role. The aim of the study was to investigative the molecular mechanisms of insulin resistance dissociated from obesity in patients with acromegaly. METHODS In a prospective study, twenty-one patients with newly diagnosed acromegaly were studied at diagnosis and after disease control obtained by either surgery alone (n=10) or somatostatin analogue (SA) treatment (n=11) with assessment of body composition (DXA scan), whole body and tissue-specific insulin sensitivity and GH and insulin signalling in adipose tissue and skeletal muscle. FINDINGS Disease control of acromegaly significantly reduced lean body mass (p<0.001) and increased fat mass (p<0.001). At diagnosis, GH signalling (pSTAT5) was constitutively activated in fat and enhanced expression of GH-regulated genes (CISH and IGF-I) were detected in muscle and fat. Insulin sensitivity in skeletal muscle, liver and adipose tissue increased after disease control regardless of treatment modality. This was associated with enhanced insulin signalling in both muscle and fat including downregulation of phosphatase and tensin homolog (PTEN) together with reduced signalling of GH and lipolytic activators in fat. INTERPRETATION In conclusion, the study support that uncontrolled lipolysis is a major feature of insulin resistance in active acromegaly, and is characterized by upregulation of PTEN and suppression of insulin signalling in both muscle and fat. FUNDING This work was supported by a grant from the Independent Research Fund, Denmark (7016-00303A) and from the Alfred Benzon Foundation, Denmark.
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Affiliation(s)
- Mai C Arlien-Søborg
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital, Denmark.
| | - Jakob Dal
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; Department of Endocrinology, Aalborg University Hospital, Denmark; Steno Diabetes Centre North, Aalborg University Hospital, Aalborg, Denmark
| | - Michael Alle Madsen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; Department of Nuclear Medicine & PET Centre, Aarhus University Hospital, Denmark
| | - Morten Lyng Høgild
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital, Denmark
| | - Astrid Johannesson Hjelholt
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital, Denmark
| | | | - Niels Møller
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital, Denmark
| | - Niels Jessen
- Steno Diabetes Centre, Aarhus, Denmark; Department of Clinical Pharmacology, University of Aarhus, Aarhus, Denmark; Department of Biomedicine, Aarhus University, Denmark
| | - Jens O L Jørgensen
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark; Medical Research Laboratory, Department of Clinical Medicine, Aarhus University Hospital, Denmark
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Jiang ZY, Zhou Y, Zhou L, Li SW, Wang BM. Identification of Key Genes and Immune Infiltrate in Nonalcoholic Steatohepatitis: A Bioinformatic Analysis. BIOMED RESEARCH INTERNATIONAL 2021; 2021:7561645. [PMID: 34552988 PMCID: PMC8452393 DOI: 10.1155/2021/7561645] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 08/25/2021] [Accepted: 08/26/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) can progress to cirrhosis and hepatic carcinoma and is closely associated with changes in the neurological environment. The discovery of new biomarkers would aid in the treatment of NASH. METHODS Data GSE89632 were downloaded from the Gene Expression Omnibus (GEO) database, and R package "limma" was used to identify differentially expressed genes (DEGs) for NASH vs. normal tissues. The STRING database was used to construct a protein-protein interaction (PPI) network, and the Cytoscape software program (Version 3.80) was used to visualize the PPI network and identify key genes. The immune infiltration of NASH was determined using the R package "CIBERSORT". RESULTS We screened 41 DEGs. GO and KEGG enrichment analyses of the DEGs revealed the enrichment of pathways related to NAFLD steatosis and inflammation. A PPI network analysis was also performed on the DEGs, and seven genes (MYC, CXCL8, FOS, SOCS1, SOCS3, IL6, and PTGS2) were identified as hub genes. An immune infiltration assessment revealed that macrophages M2, memory resting CD4+ T cells, and γΔ T cells play important roles in the immune microenvironment of NASH, which may be mediated by the seven identified hub genes.
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Affiliation(s)
- Zhen-yu Jiang
- Department of Graduate School of Tianjin Medical University, Tianjin, China
- Department of Gastroenterology, General Hospital of Tianjin Medical University, Tianjin, China
- Department of Gastroenterology, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Yi Zhou
- Department of Graduate School of Tianjin Medical University, Tianjin, China
- Department of Gastroenterology, General Hospital of Tianjin Medical University, Tianjin, China
- Department of Gastroenterology, The Second Affiliated Hospital of Baotou Medical College, Inner Mongolia University of Science and Technology, Baotou, China
| | - Lu Zhou
- Department of Gastroenterology, General Hospital of Tianjin Medical University, Tianjin, China
| | - Shao-wei Li
- Key Laboratory of Minimally Invasive Techniques & Rapid Rehabilitation of Digestive System Tumor of Zhejiang Province, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China
- Department of Gastroenterology, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China
- Institute of Digestive Disease, Taizhou Hospital of Zhejiang Province Affiliated to Wenzhou Medical University, Linhai, Zhejiang Province, China
| | - Bang-mao Wang
- Department of Gastroenterology, General Hospital of Tianjin Medical University, Tianjin, China
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19
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Léniz A, Martínez-Maqueda D, Fernández-Quintela A, Pérez-Jiménez J, Portillo MP. Potential Relationship between the Changes in Circulating microRNAs and the Improvement in Glycaemic Control Induced by Grape Pomace Supplementation. Foods 2021; 10:foods10092059. [PMID: 34574169 PMCID: PMC8470177 DOI: 10.3390/foods10092059] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 12/01/2022] Open
Abstract
MicroRNAs (miRNAs) represent important tools in medicine and nutrition as new biomarkers, and can act as mediators of nutritional and pharmacological interventions. The aim of the present study was to analyse the effect of grape pomace supplementation on the expression of seven selected miRNAs and their potential relationship with the observed positive effect on glycaemic control, in order to shed light on the mechanism underlying the beneficial effect of this dietary intervention. For this purpose, plasma samples were obtained from 49 subjects with metabolic syndrome. After supplementation with grape pomace (6 weeks), these subjects were categorised as responders (n = 23) or non-responders (n = 26) according to the changes in their fasting insulin rate. MiRNA expression at baseline and at the end of the supplementation was analysed by RT-PCR, and the MiRecords Database was used to identify potential target genes for the studied miRNAs. The increase observed in miR-23a in the whole cohort was present in both subgroups of participants. The increase in miR-181a was significant among non-responders but not responders. The decrease in miR-30c and miR-222 was found in the responders, but not in the non-responders. No changes were observed in miR-10a, miR-151a, miR-181a, and miR-let-7a expressions. After analysing these results, a potential involvement of the reduced expression of miR-30c and miR-222, two microRNAs associated with insulin resistance and diabetes, in the improvement of glycaemic control produced by grape pomace administration, can be proposed. Further research is needed to confirm the involvement of glycolytic enzymes, PI3K, AMPK, and IRS-1 in the effect of grape pomace, as suggested by the changes induced in microRNAs.
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Affiliation(s)
- Asier Léniz
- Araba Integrated Health Care Organization, Basque Health Service (Osakidetza), 01006 Vitoria-Gasteiz, Spain;
- Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain;
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28222 Madrid, Spain
- Nutrition and Obesity Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy and Lucio Lascaray Research Center, University of the Basque Country (UPV/EHU), 01008 Vitoria-Gasteiz, Spain
| | - Daniel Martínez-Maqueda
- Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), José Antonio Novais 10, 28040 Madrid, Spain; (D.M.-M.); (J.P.-J.)
- Department of Agrifood Research, Madrid Institute for Rural, Agricultural and Food Research and Development (IMIDRA), A-2 Km. 38.2, 28805 Alcalá de Henares, Spain
| | - Alfredo Fernández-Quintela
- Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain;
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28222 Madrid, Spain
- Nutrition and Obesity Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy and Lucio Lascaray Research Center, University of the Basque Country (UPV/EHU), 01008 Vitoria-Gasteiz, Spain
- Correspondence: ; Tel.: +34-945-013-066; Fax: +34-945-013-014
| | - Jara Pérez-Jiménez
- Department of Metabolism and Nutrition, Institute of Food Science, Technology and Nutrition (ICTAN-CSIC), José Antonio Novais 10, 28040 Madrid, Spain; (D.M.-M.); (J.P.-J.)
| | - María P. Portillo
- Bioaraba Health Research Institute, 01006 Vitoria-Gasteiz, Spain;
- CIBER Fisiopatología de la Obesidad y Nutrición (CIBEROBN), Instituto de Salud Carlos III (ISCIII), 28222 Madrid, Spain
- Nutrition and Obesity Group, Department of Pharmacy and Food Sciences, Faculty of Pharmacy and Lucio Lascaray Research Center, University of the Basque Country (UPV/EHU), 01008 Vitoria-Gasteiz, Spain
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20
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Abstract
The immune and endocrine systems collectively control homeostasis in the body. The endocrine system ensures that values of essential factors and nutrients such as glucose, electrolytes and vitamins are maintained within threshold values. The immune system resolves local disruptions in tissue homeostasis, caused by pathogens or malfunctioning cells. The immediate goals of these two systems do not always align. The immune system benefits from optimal access to nutrients for itself and restriction of nutrient availability to all other organs to limit pathogen replication. The endocrine system aims to ensure optimal nutrient access for all organs, limited only by the nutrients stores that the body has available. The actual state of homeostatic parameters such as blood glucose levels represents a careful balance based on regulatory signals from the immune and endocrine systems. This state is not static but continuously adjusted in response to changes in the current metabolic needs of the body, the amount of resources it has available and the level of threats it encounters. This balance is maintained by the ability of the immune and endocrine systems to interact and co-regulate systemic metabolism. In context of metabolic disease, this system is disrupted, which impairs functionality of both systems. The failure of the endocrine system to retain levels of nutrients such as glucose within threshold values impairs functionality of the immune system. In addition, metabolic stress of organs in context of obesity is perceived by the immune system as a disruption in local homeostasis, which it tries to resolve by the excretion of factors which further disrupt normal metabolic control. In this chapter, we will discuss how the immune and endocrine systems interact under homeostatic conditions and during infection with a focus on blood glucose regulation. In addition, we will discuss how this system fails in the context of metabolic disease.
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21
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Wang C, Huang X, Tian S, Huang R, Guo D, Lin H, Wang J, Wang S. High Plasma Resistin Levels Portend the Insulin Resistance-Associated Susceptibility to Early Cognitive Decline in Patients with Type 2 Diabetes Mellitus. J Alzheimers Dis 2021; 75:807-815. [PMID: 32333593 DOI: 10.3233/jad-200074] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Metabolic disorders, including insulin resistance, obesity, and hyperlipidemia occur frequently prior to hyperglycemia in patients with type 2 diabetes mellitus (T2DM) and cause mild cognitive impairment (MCI). OBJECTIVE We investigated the involvement of resistin in these metabolic abnormalities contributes to MCI in patients with T2DM. METHODS A total of 138 hospitalized patients with T2DM were enrolled and categorized into MCI and non-MCI groups according to the Montreal Cognitive Assessment (MoCA) score. Metabolic indicators and cognitive state were assessed, and plasma resistin levels were determined by ELISA. RESULTS The resistin levels and homeostasis model assessment of insulin resistance (HOMA-IR) scores of MCI and gender-stratified subgroups were significantly higher than those of controls without MCI (all p < 0.01). Correlation analysis showed that the resistin level was negatively associated with majority of cognitive domains, e.g., MoCA (r = -0.693, p < 0.001) and Mini-Mental State Examination (r = -0.571, p < 0.001), and was related to HOMA-IR (r = 0.667, p < 0.001) but not to obesity and lipid indices. Multivariable regression analysis indicated that resistin (β= -0.675, p < 0.001) and educational level (β= 0.177, p = 0.003) were independent risk factors of MoCA in patients with T2DM. CONCLUSIONS High plasma resistin levels portend the insulin resistance-related susceptibility to early cognitive decline in Chinese patients with T2DM. The involvement of this adipokine in other metabolic disorders leading to diabetic MCI and its clinical value for early disease screening must be further studied.
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Affiliation(s)
- Chenchen Wang
- School of Medicine, Southeast University, Nanjing, China
| | - Xi Huang
- Department of Endocrinology, The Affiliated ZhongDa Hospital of Southeast University, Nanjing, China
| | - Sai Tian
- School of Medicine, Southeast University, Nanjing, China
| | - Rong Huang
- School of Medicine, Southeast University, Nanjing, China
| | - Dan Guo
- School of Medicine, Southeast University, Nanjing, China
| | - Hongyan Lin
- School of Medicine, Southeast University, Nanjing, China
| | - Jiaqi Wang
- School of Medicine, Southeast University, Nanjing, China
| | - Shaohua Wang
- Department of Endocrinology, The Affiliated ZhongDa Hospital of Southeast University, Nanjing, China
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22
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Wang CR, Tsai HW. Anti- and non-tumor necrosis factor-α-targeted therapies effects on insulin resistance in rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. World J Diabetes 2021; 12:238-260. [PMID: 33758645 PMCID: PMC7958474 DOI: 10.4239/wjd.v12.i3.238] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 01/07/2021] [Accepted: 01/22/2021] [Indexed: 02/06/2023] Open
Abstract
In addition to β-cell failure with inadequate insulin secretion, the crucial mechanism leading to establishment of diabetes mellitus (DM) is the resistance of target cells to insulin, i.e. insulin resistance (IR), indicating a requirement of beyond-normal insulin concentrations to maintain euglycemic status and an ineffective strength of transduction signaling from the receptor, downstream to the substrates of insulin action. IR is a common feature of most metabolic disorders, particularly type II DM as well as some cases of type I DM. A variety of human inflammatory disorders with increased levels of proinflammatory cytokines, including tumor necrosis factor (TNF)-α, interleukin (IL)-6 and IL-1β, have been reported to be associated with an increased risk of IR. Autoimmune-mediated arthritis conditions, including rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS), with the involvement of proinflammatory cytokines as their central pathogenesis, have been demonstrated to be associated with IR, especially during the active disease state. There is an increasing trend towards using biologic agents and small molecule-targeted drugs to treat such disorders. In this review, we focus on the effects of anti-TNF-α- and non-TNF-α-targeted therapies on IR in patients with RA, PsA and AS. Anti-TNF-α therapy, IL-1 blockade, IL-6 antagonist, Janus kinase inhibitor and phospho-diesterase type 4 blocker can reduce IR and improve diabetic hyper-glycemia in autoimmune-mediated arthritis.
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Affiliation(s)
- Chrong-Reen Wang
- Department of Internal Medicine, National Cheng Kung University Hospital, Tainan 70403, Taiwan
| | - Hung-Wen Tsai
- Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan
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23
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Ahmed B, Sultana R, Greene MW. Adipose tissue and insulin resistance in obese. Biomed Pharmacother 2021; 137:111315. [PMID: 33561645 DOI: 10.1016/j.biopha.2021.111315] [Citation(s) in RCA: 397] [Impact Index Per Article: 99.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 01/19/2021] [Accepted: 01/21/2021] [Indexed: 02/08/2023] Open
Abstract
Currently, obesity has become a global health issue and is referred to as an epidemic. Dysfunctional obese adipose tissue plays a pivotal role in the development of insulin resistance. However, the mechanism of how dysfunctional obese-adipose tissue develops insulin-resistant circumstances remains poorly understood. Therefore, this review attempts to highlight the potential mechanisms behind obesity-associated insulin resistance. Multiple risk factors are directly or indirectly associated with the increased risk of obesity; among them, environmental factors, genetics, aging, gut microbiota, and diets are prominent. Once an individual becomes obese, adipocytes increase in their size; therefore, adipose tissues become larger and dysfunctional, recruit macrophages, and then these polarize to pro-inflammatory states. Enlarged adipose tissues release excess free fatty acids (FFAs), reactive oxygen species (ROS), and pro-inflammatory cytokines. Excess systemic FFAs and dietary lipids enter inside the cells of non-adipose organs such as the liver, muscle, and pancreas, and are deposited as ectopic fat, generating lipotoxicity. Toxic lipids dysregulate cellular organelles, e.g., mitochondria, endoplasmic reticulum, and lysosomes. Dysregulated organelles release excess ROS and pro-inflammation, resulting in systemic inflammation. Long term low-grade systemic inflammation prevents insulin from its action in the insulin signaling pathway, disrupts glucose homeostasis, and results in systemic dysregulation. Overall, long-term obesity and overnutrition develop into insulin resistance and chronic low-grade systemic inflammation through lipotoxicity, creating the circumstances to develop clinical conditions. This review also shows that the liver is the most sensitive organ undergoing insulin impairment faster than other organs, and thus, hepatic insulin resistance is the primary event that leads to the subsequent development of peripheral tissue insulin resistance.
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Affiliation(s)
- Bulbul Ahmed
- Department of Nutrition, Auburn University, Auburn, AL, 36849, United States.
| | - Rifat Sultana
- Department of Biology and Microbiology, South Dakota State University, Brookings, SD, 57007, United States
| | - Michael W Greene
- Department of Nutrition, Auburn University, Auburn, AL, 36849, United States
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24
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Mohamed AAR, Khater SI, Hamed Arisha A, Metwally MM, Mostafa-Hedeab G, El-Shetry ES. Chitosan-stabilized selenium nanoparticles alleviate cardio-hepatic damage in type 2 diabetes mellitus model via regulation of caspase, Bax/Bcl-2, and Fas/FasL-pathway. Gene 2021; 768:145288. [PMID: 33181259 DOI: 10.1016/j.gene.2020.145288] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/26/2020] [Accepted: 10/29/2020] [Indexed: 02/07/2023]
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25
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Chen G, Chen J, Wu J, Ren X, Li L, Lu S, Cheng T, Tan L, Liu M, Luo Q, Liang S, Nie Q, Zhang X, Luo W. Integrative Analyses of mRNA Expression Profile Reveal SOCS2 and CISH Play Important Roles in GHR Mutation-Induced Excessive Abdominal Fat Deposition in the Sex-Linked Dwarf Chicken. Front Genet 2021; 11:610605. [PMID: 33519913 PMCID: PMC7841439 DOI: 10.3389/fgene.2020.610605] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 11/30/2020] [Indexed: 01/28/2023] Open
Abstract
Sex-linked dwarf (SLD) chicken, which is caused by a recessive mutation of the growth hormone receptor (GHR), has been widely used in the Chinese broiler industry. However, it has been found that the SLD chicken has more abdominal fat deposition than normal chicken. Excessive fat deposition not only reduced the carcass quality of the broilers but also reduced the immunity of broilers to diseases. To find out the key genes and the precise regulatory pathways that were involved in the GHR mutation-induced excessive fat deposition, we used high-fat diet (HFD) and normal diet to feed the SLD chicken and normal chicken and analyzed the differentially expressed genes (DEGs) among the four groups. Results showed that the SLD chicken had more abdominal fat deposition and larger adipocytes size than normal chicken and HFD can promote abdominal fat deposition and induce adipocyte hypertrophy. RNA sequencing results of the livers and abdominal fats from the above chickens revealed that many DEGs between the SLD and normal chickens were enriched in fat metabolic pathways, such as peroxisome proliferator-activated receptor (PPAR) signaling, extracellular matrix (ECM)-receptor pathway, and fatty acid metabolism. Importantly, by constructing and analyzing the GHR-downstream regulatory network, we found that suppressor of cytokine signaling 2 (SOCS2) and cytokine-inducible SH2-containing protein (CISH) may involve in the GHR mutation-induced abdominal fat deposition in chicken. The ectopic expression of SOCS2 and CISH in liver-related cell line leghorn strain M chicken hepatoma (LMH) cell and immortalized chicken preadipocytes (ICP) revealed that these two genes can regulate fatty acid metabolism, adipocyte differentiation, and lipid droplet accumulation. Notably, overexpression of SOCS2 and CISH can rescue the hyperactive lipid metabolism and excessive lipid droplet accumulation of primary liver cell and preadipocytes that were isolated from the SLD chicken. This study found some genes and pathways involved in abdominal fat deposition of the SLD chicken and reveals that SOCS2 and CISH are two key genes involved in the GHR mutation-induced excessive fat deposition of the SLD chicken.
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Affiliation(s)
- Genghua Chen
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Jiahui Chen
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Jingwen Wu
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Xueyi Ren
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Limin Li
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Shiyi Lu
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Tian Cheng
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Liangtian Tan
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Manqing Liu
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Qingbin Luo
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Shaodong Liang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Qinghua Nie
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Xiquan Zhang
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
| | - Wen Luo
- Department of Animal Genetics, Breeding and Reproduction, College of Animal Science, South China Agricultural University, Guangzhou, China.,Key Lab of Chicken Genetics, Breeding and Reproduction, Ministry of Agriculture, South China Agricultural University, Guangzhou, China
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26
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Oghbaei H, Fattahi A, Hamidian G, Sadigh-Eteghad S, Ziaee M, Mahmoudi J. A closer look at the role of insulin for the regulation of male reproductive function. Gen Comp Endocrinol 2021; 300:113643. [PMID: 33017586 DOI: 10.1016/j.ygcen.2020.113643] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 09/16/2020] [Accepted: 09/28/2020] [Indexed: 11/25/2022]
Abstract
While insulin demonstrates to have a considerable influence on the reproductive system, there are various unanswered questions regarding its precise sites, mechanisms of action, and roles for the developing and functioning of the adult male reproductive system. Apart from its effects on glucose level, insulin has an important role in the reproductive system directly by binding on insulin and IGF receptors in the brain and testis. To date, however, the effect of insulin or its alterations on blood-testis-barrier, as an important regulator of normal spermatogenesis and fertility, has not yet been studied. This review aimed to focus on the experimental and clinical studies to describe mechanisms by which insulin affects the hypothalamic-pituitary-gonadal (HPG) axis, testicular cells, spermatozoa, and sexual behavior. Moreover, we discussed the mechanism and impact of insulin changes in type 1 (insulin deficiency along with persisted or even increased sensitivity) and 2 (insulin resistance along with increased insulin level at the early stages of disease) diabetes and obesity on the male reproductive tract.
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Affiliation(s)
- Hajar Oghbaei
- Department of Physiology, Tabriz University of Medical Sciences, Tabriz, Iran; Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Amir Fattahi
- Department of Reproductive Biology, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - GholamReza Hamidian
- Department of Basic Sciences, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Saeed Sadigh-Eteghad
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mojtaba Ziaee
- Medicinal Plants Research Center, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Javad Mahmoudi
- Neurosciences Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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27
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Han X, Chen X, Han J, Zhong Y, Li Q, An Y. MiR-324/SOCS3 Axis Protects Against Hypoxia/Reoxygenation-Induced Cardiomyocyte Injury and Regulates Myocardial Ischemia via TNF/NF-κB Signaling Pathway. Int Heart J 2020; 61:1258-1269. [PMID: 33191336 DOI: 10.1536/ihj.19-687] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
We aimed at exploring the function of microRNA-324/cytokine signaling 3 (miR-324/SOCS3) axis in hypoxia/reoxygenation (H/R) -induced cardiomyocyte injury and its underlying mechanism. The differential expression genes were analyzed based on the GSE83500 and GSE48060 datasets from the Gene Expression Omnibus (GEO) database. Then, to conduct the function enrichment analysis, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases were used. The upstream regulatory microRNAs (miRNAs) of the identified genes were predicted by miRanda, miRWalk, and TargetScan websites. MiR-324 expression was measured with quantitative real-time polymerase chain reaction (qRT-PCR). The target binding of miR-324 and SOCS3 was established by dual-luciferase reporter assay. Cardiomyocyte proliferation was analyzed by cell counting kit-8 (CCK-8) assay, whereas the apoptosis was investigated via flow cytometry. The expression of TNF pathway-related proteins was detected by western blot analysis. SOCS3 was upregulated in patients with myocardial infarction (MI), and function enrichment analyses proved that SOCS3 was enriched in TNF signaling pathway. Moreover, we found that miR-324 was the upstream regulatory miRNA of SOCS3 and negatively regulated SOCS3 expression. MiR-324 was downregulated in cardiomyocytes with H/R-induced injury, inhibiting cell proliferation. In the H/R model, SOCS3 suppresses cardiomyocyte proliferation, which was recovered by miR-324, and induces cell apoptosis, which was repressed by miR-324 via regulating the expression of cleaved caspase-3 and p P38-MAPK. MiR-324 upregulation decreased the protein levels of TNF-α, p-P65, and p-IκBα in cardiomyocytes that suffered from H/R, which was reversed with SOCS3 overexpression. MiR-324/SOCS3 axis could improve the H/R-induced injury of cardiomyocytes via regulating TNF/NF-κB signaling pathway, and this might provide a new therapy strategy for myocardial ischemia.
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Affiliation(s)
- Xuefu Han
- Department of medicine, Qingdao University.,Department of Cardiology, Weifang People's Hospital
| | - Xi Chen
- Department of Stomatology, Weifang Maternal and Child Health Hospital
| | - Jiaqi Han
- Department of medicine, Qingdao University
| | - Yu Zhong
- Department of Personnel, Weifang Maternal and Child Health Hospital
| | - Qinghua Li
- School of Public Health, Weifang Medical University
| | - Yi An
- Department of Cardiology, The Affiliated Hospital of Qingdao University.,Qingdao University
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28
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González F, Mather KJ, Considine RV, Abdelhadi OA, Acton AJ. Salicylate administration suppresses the inflammatory response to nutrients and improves ovarian function in polycystic ovary syndrome. Am J Physiol Endocrinol Metab 2020; 319:E744-E752. [PMID: 32830548 PMCID: PMC7750514 DOI: 10.1152/ajpendo.00228.2020] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Oxidative stress (OS) and inflammation are often present in polycystic ovary syndrome (PCOS). We examined the effects of salsalate treatment on nutrient-induced OS and inflammation, ovarian androgen secretion, ovulation, and insulin sensitivity in PCOS. Eight lean insulin-sensitive women with PCOS and eight age- and body composition-matched ovulatory controls for baseline comparison participated in the study. The women with PCOS underwent a 12-wk treatment of salsalate, a nonsteroidal anti-inflammatory drug, at a dose of 3 g daily. Markers of OS and inflammation were quantified in mononuclear cells (MNC) and plasma from blood drawn fasting and 2 h after saturated fat ingestion before and after treatment. Ovarian androgen secretion was assessed from blood drawn fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration before and after treatment. Ovulation was documented based on biphasic basal body temperatures and luteal range progesterone elevations. A two-step pancreatic clamp was performed pre- and posttreatment to measure basal endogenous glucose production (EGP) and the steady-state glucose disposal rate (GDR) during the euglycemic phase and markers of OS and inflammation in MNC and plasma during the hyperglycemic phase. Salsalate administration suppressed lipid- and glucose-stimulated reactive oxygen species generation, activated nuclear factor-κB and circulating tumor necrosis factor-α, normalized basal androgen levels, and lowered HCG-stimulated androgen secretion without altering EGP or GDR. Four salsalate-treated subjects responded with two consecutive ovulations. We conclude that in PCOS, salsalate-induced suppression of OS and inflammation ameliorates ovarian androgen hypersecretion and may induce ovulation while maintaining insulin action.
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Affiliation(s)
- Frank González
- Department of Obstetrics and Gynecology, University of Illinois at Chicago, College of Medicine, Chicago, Illinois
| | - Kieren J Mather
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Robert V Considine
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ola A Abdelhadi
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Anthony J Acton
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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Zhang X, Lv X, Li X, Wang Y, Lin H, Zhang J, Peng C. Dysregulated circulating SOCS3 and haptoglobin expression associated with stable coronary artery disease and acute coronary syndrome: An integrated study based on bioinformatics analysis and case-control validation. Anatol J Cardiol 2020; 24:160-174. [PMID: 32870172 PMCID: PMC7585973 DOI: 10.14744/anatoljcardiol.2020.56346] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/17/2020] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVE To extensively use blood transcriptome analysis to identify potential diagnostic and therapeutic targets for cardiovascular diseases. METHODS Two gene expression datasets (GSE59867 and GSE62646) were downloaded from GEO DataSets to identify altered blood transcriptomes in patients with ST-segment elevation myocardial infarction (STEMI) compared to stable coronary artery disease (CAD). Thereafter, several computational approaches were taken to determine functional roles and regulatory networks of differentially expressed genes (DEGs). Finally, the expression of dysregulated two hub genes-suppressor of cytokine signaling 3 (SOCS3) and haptoglobin (HP)-were validated in a case-control study. RESULTS A total of 119 DEGs were identified in the discovery phase, consisting of 71 downregulated genes and 48 upregulated genes; two hub modules consisting of two hub genes-SOCS3 and HP-were identified. In the validation phase, both SOCS3 and HP were significantly downregulated in the stable CAD and acute coronary syndrome (ACS) patients when compared with healthy controls. Meanwhile, HP was significantly upregulated in STEMI patients when compared with stable CAD patients (p=0.041). Logistic regression analysis indicated that: downregulated expression of HP correlated with increased risk of CAD [odds ratio (OR)=0.52, 95% confidence interval (CI)=0.31~0.87, p=0.013]; and downregulated expression of SOCS3 correlated with increased risk of ACS (OR=0.66, 95% CI=0.46~0.94, p=0.023) when age, gender, history of hyperlipidemia, diabetes and hypertension were included as covariates. CONCLUSION Future clarification of how SOCS3 and HP influence the pathogenesis of disease may pave the way for the development of novel diagnostic and therapeutic methods.
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Affiliation(s)
- Xunnan Zhang
- Postgraduate Training Basement of Jinzhou Medicical University, Taihe Hospital, Hubei University of Medicine; Hubei-P.R. China
| | - Xi Lv
- Postgraduate Training Basement of Jinzhou Medicical University, Taihe Hospital, Hubei University of Medicine; Hubei-P.R. China
| | - Xiandong Li
- Department of Laboratory Medicine, Taihe Hospital, Hubei University of Medicine; Hubei-P.R. China
| | - Yaping Wang
- Postgraduate Training Basement of Jinzhou Medicical University, Taihe Hospital, Hubei University of Medicine; Hubei-P.R. China
| | - Haoyu Lin
- Department of Breast and Thyroid Surgery, The First Affiliated Hospital of Shantou University Medical College; Guangdong-P.R. China
| | - Jicai Zhang
- Postgraduate Training Basement of Jinzhou Medicical University, Taihe Hospital, Hubei University of Medicine; Hubei-P.R. China
- Department of Laboratory Medicine, Taihe Hospital, Hubei University of Medicine; Hubei-P.R. China
| | - Chunyan Peng
- Department of Laboratory Medicine, Taihe Hospital, Hubei University of Medicine; Hubei-P.R. China
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine; Hubei-P.R. China
- Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Hubei-P.R. China
- Address for correspondence: Chunyan Peng, MD, Department of Laboratory Medicine, Taihe Hospital, Hubei University of Medicine, Renming road 32# Shiyan, 442000, Hubei-P.R. China Phone: +86 13636 254788 E-mail:
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Macchi C, Greco MF, Botta M, Sperandeo P, Dongiovanni P, Valenti L, Cicero AFG, Borghi C, Lupo MG, Romeo S, Corsini A, Magni P, Ferri N, Ruscica M. Leptin, Resistin, and Proprotein Convertase Subtilisin/Kexin Type 9: The Role of STAT3. THE AMERICAN JOURNAL OF PATHOLOGY 2020; 190:2226-2236. [PMID: 32798443 DOI: 10.1016/j.ajpath.2020.07.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 07/17/2020] [Accepted: 07/30/2020] [Indexed: 01/13/2023]
Abstract
In a condition of dysfunctional visceral fat depots, as in the case of obesity, alterations in adipokine levels may be detrimental for the cardiovascular system. The proinflammatory leptin and resistin adipokines have been described as possible links between obesity and atherosclerosis. The present study was aimed at evaluating whether proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein metabolism, is induced by leptin and resistin through the involvement of the inflammatory pathway of STAT3. In HepG2 cells, leptin and resistin up-regulated PCSK9 gene and protein expression, as well as the phosphorylation of STAT3. Upon STAT3 silencing, leptin and resistin lost their ability to activate PCSK9. The knockdown of STAT3 did not affect the expression of leptin and resistin receptors or that of PCSK9. The analysis of the human PCSK9 promoter region showed that the two adipokines raised PCSK9 promoter activity via the involvement of a sterol regulatory element motif. In healthy males, a positive association between circulating leptin and PCSK9 levels was found only when the body mass index was <25 kg/m2. In conclusion, this study identified STAT3 as one of the molecular regulators of leptin- and resistin-mediated transcriptional induction of PCSK9.
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Affiliation(s)
- Chiara Macchi
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
| | - Maria Francesca Greco
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Margherita Botta
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Paola Sperandeo
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy
| | - Paola Dongiovanni
- General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Luca Valenti
- Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Translational Medicine, Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Arrigo F G Cicero
- Department of Medicine and Surgery Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Claudio Borghi
- Department of Medicine and Surgery Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
| | - Maria Giovanna Lupo
- Department of Pharmaceutical and Pharmacological Sciences, Università degli Studi di Padova, Padova, Italy
| | - Stefano Romeo
- Department of Molecular and Clinical Medicine, University of Gothenburg, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Science, Magna Graecia University, Catanzaro, Italy; Department of Cardiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Alberto Corsini
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy; IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy
| | - Paolo Magni
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy; IRCCS MultiMedica, Sesto S. Giovanni, Milan, Italy
| | - Nicola Ferri
- Department of Pharmaceutical and Pharmacological Sciences, Università degli Studi di Padova, Padova, Italy
| | - Massimiliano Ruscica
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, Milan, Italy.
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Rancourt RC, Ott R, Schellong K, Ziska T, Melchior K, Henrich W, Plagemann A. Altered SOCS3 DNA methylation within exon 2 is associated with increased mRNA expression in visceral adipose tissue in gestational diabetes. Epigenetics 2020; 16:488-494. [PMID: 32752921 DOI: 10.1080/15592294.2020.1805695] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
Overweight/obesity is the main risk factor for gestational diabetes mellitus (GDM). In our cohort of pregnant women with GDM, n = 19, and without, n = 22, we previously reported a significant increase in SOCS3 mRNA expression (+62%) in visceral adipose tissue (VAT) according to GDM, without altered promoter DNA-methylation. Here, we examined methylation status of additional SOCS3 exon 2 regions in VAT and maternal blood. We found significantly altered methylation at specific CpG sites corresponding to aberrant mRNA expression levels of SOCS3 in VAT. We propose a potential regulatory element/region within exon 2; however, this region does not appear to be a good blood-marker representing VAT.
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Affiliation(s)
- Rebecca C Rancourt
- Division of 'Experimental Obstetrics', Clinic of Obstetrics, Charité- Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - Raffael Ott
- Division of 'Experimental Obstetrics', Clinic of Obstetrics, Charité- Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - Karen Schellong
- Division of 'Experimental Obstetrics', Clinic of Obstetrics, Charité- Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - Thomas Ziska
- Division of 'Experimental Obstetrics', Clinic of Obstetrics, Charité- Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - Kerstin Melchior
- Division of 'Experimental Obstetrics', Clinic of Obstetrics, Charité- Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - Wolfgang Henrich
- Clinic of Obstetrics, Charité - Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of Health, Berlin, Germany
| | - Andreas Plagemann
- Division of 'Experimental Obstetrics', Clinic of Obstetrics, Charité- Universitätsmedizin Berlin, Freie Universität Berlin, Humboldt-Universität Zu Berlin, Berlin Institute of Health, Berlin, Germany
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Exploring Therapeutic Targets to Reverse or Prevent the Transition from Metabolically Healthy to Unhealthy Obesity. Cells 2020; 9:cells9071596. [PMID: 32630256 PMCID: PMC7407965 DOI: 10.3390/cells9071596] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/24/2020] [Accepted: 06/30/2020] [Indexed: 12/14/2022] Open
Abstract
The prevalence of obesity and obesity-related metabolic comorbidities are rapidly increasing worldwide, placing a huge economic burden on health systems. Excessive nutrient supply combined with reduced physical exercise results in positive energy balance that promotes adipose tissue expansion. However, the metabolic response and pattern of fat accumulation is variable, depending on the individual’s genetic and acquired susceptibility factors. Some develop metabolically healthy obesity (MHO) and are resistant to obesity-associated metabolic diseases for some time, whereas others readily develop metabolically unhealthy obesity (MUO). An unhealthy response to excess fat accumulation could be due to susceptibility intrinsic factors (e.g., increased likelihood of dedifferentiation and/or inflammation), or by pathogenic drivers extrinsic to the adipose tissue (e.g., hyperinsulinemia), or a combination of both. This review outlines the major transcriptional factors and genes associated with adipogenesis and regulation of adipose tissue homeostasis and describes which of these are disrupted in MUO compared to MHO individuals. It also examines the potential role of pathogenic insulin hypersecretion as an extrinsic factor capable of driving the changes in adipose tissue which cause transition from MHO to MUO. On this basis, therapeutic approaches currently available and emerging to prevent and reverse the transition from MHO to MUO transition are reviewed.
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González F, Considine RV, Abdelhadi OA, Acton AJ. Inflammation Triggered by Saturated Fat Ingestion Is Linked to Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome. J Clin Endocrinol Metab 2020; 105:5788228. [PMID: 32140727 PMCID: PMC7150616 DOI: 10.1210/clinem/dgaa108] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Revised: 01/29/2020] [Accepted: 02/28/2020] [Indexed: 12/18/2022]
Abstract
CONTEXT Inflammation and insulin resistance are often present in polycystic ovary syndrome (PCOS). OBJECTIVE We determined the effect of saturated fat ingestion on mononuclear cell (MNC) nuclear factor-κB (NFκB) activation; NFκB, inhibitory-κBα (IκBα), and tumor necrosis factor-α (TNFα) gene expression; and circulating C-reactive protein (CRP) in women with PCOS. DESIGN Cross-sectional study. SETTING Academic medical center. PATIENTS Twenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity). MAIN OUTCOME MEASURES Activated NFκB, NFκB heterodimer subunits, IκBα and TNFα messenger ribonucleic acid content and NFκB p65 and IκBα protein content were quantified in mononuclear cells (MNC), and CRP was measured in plasma from blood drawn fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from oral glucose tolerance testing (ISOGTT). Androgen secretion was assessed from blood drawn fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration. RESULTS In response to saturated fat ingestion, women with PCOS regardless of weight class exhibited lipid-induced increases in activated NFκB, NFκB, and TNFα gene expression and plasma CRP and decreases in IκBα protein compared with lean control subjects. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. Lipid-stimulated NFκB activation was negatively correlated with ISOGTT, and positively correlated with HCG-stimulated androgen secretion. CONCLUSION In PCOS, increases in NFκB activation and circulating CRP and decreases in IκBα protein following saturated fat ingestion are independent of obesity. Circulating MNC and excess adipose tissue are separate and distinct contributors to inflammation in this disorder.
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Affiliation(s)
- Frank González
- Department of Obstetrics and Gynecology, University of Illinois at Chicago College of Medicine, Chicago, IL
- Correspondence and Reprint Requests: Frank González, MD, University of Illinois at Chicago College of Medicine, Department of Obstetrics and Gynecology, 820 S. Wood Street m/c 808, CSN 276, Chicago, IL 60612. E-mail:
| | - Robert V Considine
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
| | - Ola A Abdelhadi
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, IN
| | - Anthony J Acton
- Department of Medicine, Indiana University School of Medicine, Indianapolis, IN
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Gehrke N, Schattenberg JM. Metabolic Inflammation-A Role for Hepatic Inflammatory Pathways as Drivers of Comorbidities in Nonalcoholic Fatty Liver Disease? Gastroenterology 2020; 158:1929-1947.e6. [PMID: 32068022 DOI: 10.1053/j.gastro.2020.02.020] [Citation(s) in RCA: 122] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 02/05/2020] [Accepted: 02/11/2020] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) is a global and growing health concern. Emerging evidence points toward metabolic inflammation as a key process in the fatty liver that contributes to multiorgan morbidity. Key extrahepatic comorbidities that are influenced by NAFLD are type 2 diabetes, cardiovascular disease, and impaired neurocognitive function. Importantly, the presence of nonalcoholic steatohepatitis and advanced hepatic fibrosis increase the risk for systemic comorbidity in NAFLD. Although the precise nature of the crosstalk between the liver and other organs has not yet been fully elucidated, there is emerging evidence that metabolic inflammation-in part, emanating from the fatty liver-is the engine that drives cellular dysfunction, cell death, and deleterious remodeling within various body tissues. This review describes several inflammatory pathways and mediators that have been implicated as links between NAFLD and type 2 diabetes, cardiovascular disease, and neurocognitive decline.
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Affiliation(s)
- Nadine Gehrke
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center, Mainz, Germany.
| | - Jörn M Schattenberg
- Metabolic Liver Research Program, I. Department of Medicine, University Medical Center, Mainz, Germany
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Rancourt RC, Ott R, Ziska T, Schellong K, Melchior K, Henrich W, Plagemann A. Visceral Adipose Tissue Inflammatory Factors (TNF-Alpha, SOCS3) in Gestational Diabetes (GDM): Epigenetics as a Clue in GDM Pathophysiology. Int J Mol Sci 2020; 21:ijms21020479. [PMID: 31940889 PMCID: PMC7014132 DOI: 10.3390/ijms21020479] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2019] [Revised: 01/07/2020] [Accepted: 01/09/2020] [Indexed: 12/19/2022] Open
Abstract
Gestational diabetes (GDM) is among the most challenging diseases in westernized countries, affecting mother and child, immediately and in later life. Obesity is a major risk factor for GDM. However, the impact visceral obesity and related epigenetics play for GDM etiopathogenesis have hardly been considered so far. Our recent findings within the prospective ‘EaCH’ cohort study of women with GDM or normal glucose tolerance (NGT), showed the role, critical factors of insulin resistance (i.e., adiponectin, insulin receptor) may have for GDM pathophysiology with epigenetically modified expression in subcutaneous (SAT) and visceral (VAT) adipose tissues. Here we investigated the expression and promoter methylation of key inflammatory candidates, tumor necrosis factor-alpha (TNF-α) and suppressor of cytokine signaling 3 (SOCS3) in maternal adipose tissues collected during caesarian section (GDM, n = 19; NGT, n = 22). The mRNA expression of TNF-α and SOCS3 was significantly increased in VAT, but not in SAT, of GDM patients vs. NGT, accompanied by specific alterations of respective promoter methylation patterns. In conclusion, we propose a critical role of VAT and visceral obesity for the pathogenesis of GDM, with epigenetic alterations of the expression of inflammatory factors as a potential factor.
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Affiliation(s)
- Rebecca C. Rancourt
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (R.O.); (T.Z.); (K.S.); (K.M.); (A.P.)
- Correspondence:
| | - Raffael Ott
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (R.O.); (T.Z.); (K.S.); (K.M.); (A.P.)
| | - Thomas Ziska
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (R.O.); (T.Z.); (K.S.); (K.M.); (A.P.)
| | - Karen Schellong
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (R.O.); (T.Z.); (K.S.); (K.M.); (A.P.)
| | - Kerstin Melchior
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (R.O.); (T.Z.); (K.S.); (K.M.); (A.P.)
| | - Wolfgang Henrich
- Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany;
| | - Andreas Plagemann
- Division of ‘Experimental Obstetrics’, Clinic of Obstetrics, Charité—Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Campus Virchow-Klinikum, 13353 Berlin, Germany; (R.O.); (T.Z.); (K.S.); (K.M.); (A.P.)
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Fruit and vegetable intake modifies the associations between suppressor of cytokine signaling 3 genetic variants and type 2 diabetes. Eur J Nutr 2020; 59:3441-3449. [PMID: 31927672 DOI: 10.1007/s00394-020-02178-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2019] [Accepted: 01/03/2020] [Indexed: 12/13/2022]
Abstract
PURPOSE Type 2 diabetes is a complex disease determined by variable genes and environmental factors. The study was designed to investigate the effect of interactions of four polymorphisms of suppressor of cytokine signaling 3 (SOCS3) with fruit and vegetable (F&V) intake on type 2 diabetes in a rural population of China. METHODS A total of 4411 participants from the rural areas of Henan, China were included in the study. Multivariate logistic regression and restricted cubic splines were used to estimate the associations between polymorphisms and risk allele score of SOCS3 and type 2 diabetes in different groups. Haplotype analysis was conducted to examine the effects of linkage inheritance at these four loci on type 2 diabetes. RESULTS Three of the four polymorphisms showed significant associations with type 2 diabetes in the less F&V intake group after adjusting the covariates, the odds ratios (ORs) and corresponding 95% confidence intervals (95% CIs) were 1.24 (1.08-1.41) for rs4969168, 1.16 (1.02-1.32) for rs9892622, and 1.21 (1.06-1.39) for rs9914220. No significant association was detected in the more F&V intake group. The obvious dose-response relationship between the risk allele score and type 2 diabetes was also noted only in the less F&V intake group. CONCLUSIONS Variants of SOCS3 gene were associated with type 2 diabetes and the associations could be modified by the F&V intake.
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Son M, Oh S, Choi J, Jang JT, Choi CH, Park KY, Son KH, Byun K. The Phlorotannin-Rich Fraction of Ecklonia cava Extract Attenuated the Expressions of the Markers Related with Inflammation and Leptin Resistance in Adipose Tissue. Int J Endocrinol 2020; 2020:9142134. [PMID: 32215011 PMCID: PMC7081028 DOI: 10.1155/2020/9142134] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 12/26/2019] [Accepted: 01/13/2020] [Indexed: 12/11/2022] Open
Abstract
Obesity is associated with systemic chronic inflammation, and it induces central leptin resistance which blocks the appetite-suppressing effect of leptin and leptin resistance in adipocytes. In the present study, we evaluated the effects of Ecklonia cava extract (ECE), which contained rich phlorotannins, on inflammation and leptin resistance in the adipose tissue of a diet-induced obese model. Effects of ECE on fat deposition, inflammation, M1/M2 macrophage, and T-cell infiltrations were investigated, and leptin resistance and SOCS3 were also measured in adipose tissue. Furthermore, ECE attenuated the expression of inflammation-related receptors such as TLR4 and RAGE and leptin resistance by reducing SOCS3 expression, increasing expression of leptin receptor in adipose tissue, and increasing lipolysis. ECE showed antiadiposity and anti-inflammatory effects, attenuated leptin resistance, and increased lipolysis in the diet-induced obese model. This study shows that ECE is a suitable dietary supplement candidate for the prevention or treatment of obesity or obesity-associated diseases, especially inflammation-related diseases.
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Affiliation(s)
- Myeongjoo Son
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Republic of Korea
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Seyeon Oh
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Junwon Choi
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Republic of Korea
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
| | - Ji Tae Jang
- Aqua Green Technology Co., Ltd., Smart Bldg., Jeju Science Park, Jeju 63309, Republic of Korea
| | - Chang Hu Choi
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea
| | - Kook Yang Park
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea
| | - Kuk Hui Son
- Department of Thoracic and Cardiovascular Surgery, Gachon University Gil Medical Center, Gachon University, Incheon 21565, Republic of Korea
| | - Kyunghee Byun
- Department of Anatomy & Cell Biology, Gachon University College of Medicine, Incheon 21936, Republic of Korea
- Functional Cellular Networks Laboratory, College of Medicine, Department of Medicine, Graduate School and Lee Gil Ya Cancer and Diabetes Institute, Gachon University, Incheon 21999, Republic of Korea
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Pasternak Y, Ohana M, Biron-Shental T, Cohen-Hagai K, Benchetrit S, Zitman-Gal T. Thioredoxin, thioredoxin interacting protein and transducer and activator of transcription 3 in gestational diabetes. Mol Biol Rep 2019; 47:1199-1206. [PMID: 31848914 DOI: 10.1007/s11033-019-05221-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2019] [Accepted: 12/03/2019] [Indexed: 12/13/2022]
Abstract
To evaluate changes in the inflammatory response of thioredoxin (TXN), thioredoxin interacting protein (TXNIP), transducer and activator of transcription 3, NFƙB-p50 and STAT3 at the level of maternal serum, placenta, and umbilical cord blood of women with gestational diabetes mellitus type 2 (GDMA2) compared to normal pregnancies (NP). Thirty pregnant women (20 with GDMA2 and 10 NP) were recruited during admission for delivery. Blood samples were obtained from the parturients and umbilical cords, as well as placental tissue for mRNA and protein extraction. TXNIP mRNA expression was significantly increased in maternal serum of women with GDMA2 compared to NP women. TXNIP mRNA was significantly decreased in GDMA2 placentas and cord blood compared to NP. TXN/TXNIP mRNA ratio showed significantly high absolute values in placental and cord blood (2.39 and 1.66) respectively, compared to maternal ratio (1.084) (P < 0.001). TXN/TXNIP placenta protein ratio showed similar values between GDMA2 and NP (0.98 and 0.86; P = 0.7). STAT3 and its target protein SOCS3, as well as NFƙB-p50 mRNA expression were significantly increased in placentas of GDMA2. NFƙB-p50 mRNA expression was significantly decreased in cord blood compared to both maternal and placental mRNA expression. Pro-inflammatory changes are expressed by low mRNA TXN/TXNIP ratio in maternal blood of GDMA2 patients, but not in placental and umbilical cord blood samples. This, as well as the feedback role of SOCS3 in STAT3 pathway and NFƙB-p50 expression, may indicate that the placenta has a role in protecting the fetus from damage due to inflammatory response, which is common in diabetes.
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Affiliation(s)
- Yael Pasternak
- Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Meital Ohana
- Nephrology Laboratory, Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba, Israel
| | - Tal Biron-Shental
- Department of Obstetrics and Gynecology, Meir Medical Center, Kfar Saba, Israel.,Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Keren Cohen-Hagai
- Nephrology Laboratory, Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba, Israel
| | - Sydney Benchetrit
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.,Nephrology Laboratory, Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba, Israel
| | - Tali Zitman-Gal
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. .,Nephrology Laboratory, Department of Nephrology and Hypertension, Meir Medical Center, Kfar Saba, Israel.
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González F, Considine RV, Abdelhadi OA, Acton AJ. Oxidative Stress in Response to Saturated Fat Ingestion Is Linked to Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome. J Clin Endocrinol Metab 2019; 104:5360-5371. [PMID: 31298704 PMCID: PMC6773460 DOI: 10.1210/jc.2019-00987] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/27/2019] [Accepted: 07/08/2019] [Indexed: 12/29/2022]
Abstract
CONTEXT Oxidative stress and insulin resistance are often present in polycystic ovary syndrome (PCOS). OBJECTIVE We determined the effect of saturated fat ingestion on leukocytic reactive oxygen species (ROS) generation, p47phox expression, and circulating thiobarbituric acid-reactive substances (TBARS) in women with PCOS. DESIGN Cross-sectional study. SETTING Academic medical center. PATIENTS Twenty women of reproductive age with PCOS (10 lean, 10 with obesity) and 19 ovulatory control subjects (10 lean, 9 with obesity). MAIN OUTCOME MEASURES ROS generation and p47phox mRNA and protein content were quantified in leukocytes, and TBARS was measured in plasma from blood drawn while the subjects were fasting and 2, 3, and 5 hours after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (ISOGTT). Androgen secretion was assessed from blood drawn while the subjects were fasting and 24, 48, and 72 hours after human chorionic gonadotropin (HCG) administration. RESULTS Regardless of weight class, women with PCOS exhibited lipid-induced increases in leukocytic ROS generation and p47phox mRNA and protein content as well as plasma TBARS compared with lean control subjects. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. The ROS generation, p47phox, and TBARS responses were negatively correlated with ISOGTT and positively correlated with HCG-stimulated androgen secretion. CONCLUSION In PCOS, increases in ROS generation, p47phox gene expression, and circulating TBARS in response to saturated fat ingestion are independent of obesity. Circulating mononuclear cells and excess adipose tissue are separate and distinct contributors to oxidative stress in this disorder.
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Affiliation(s)
- Frank González
- Department of Obstetrics and Gynecology, University of Illinois at Chicago College of Medicine, Chicago, Illinois
- Correspondence and Reprint Requests: Frank González, MD, University of Illinois at Chicago College of Medicine, Department of Obstetrics and Gynecology, 820 South Wood Street m/c 808, CSN W233, Chicago, Illinois 60612. E-mail:
| | - Robert V Considine
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ola A Abdelhadi
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Anthony J Acton
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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Patel BM, Goyal RK. Liver and insulin resistance: New wine in old bottle!!! Eur J Pharmacol 2019; 862:172657. [DOI: 10.1016/j.ejphar.2019.172657] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 09/02/2019] [Accepted: 09/05/2019] [Indexed: 12/20/2022]
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Abdulmalek SA, Balbaa M. Synergistic effect of nano-selenium and metformin on type 2 diabetic rat model: Diabetic complications alleviation through insulin sensitivity, oxidative mediators and inflammatory markers. PLoS One 2019; 14:e0220779. [PMID: 31442295 PMCID: PMC6707613 DOI: 10.1371/journal.pone.0220779] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND OBJECTIVES In the present article, we explore a novel strategy of selenium nanoparticles (Se-NPs) for the treatment of type 2 diabetes mellitus (T2DM) by investigating the effect of Se-NPs alone and in combination with standard anti-diabetic drug metformin (MET) in high-fat diet/streptozotocin (HFD/STZ)-induced T2DM. METHODS HFD was supplemented daily to experimental rats for 8 weeks, followed by a single low dose injection of 35 mg/kg of STZ to induce T2DM. The synergistic effect of the different therapeutic strategies on diabetic complications was evaluated after the Se-NPs and MET administration for 8 weeks. Molecular and biochemical analyses were conducted to figure out the effectiveness of our treatment on insulin sensitivity, oxidative mediators and inflammatory markers. RESULTS Our observations demonstrated that HFD/STZ-induced rats have a toxic effect on serum and hepatic tissues resulted in inducing remarkable oxidative damage and hyper-inflammation with a significant disturbance in the insulin signaling pathway. Experimental animals either treated with mono-therapeutic-two doses Se-NPs (0.1 and 0.4 mg/kg) and/or MET (100 mg/kg) alone as well as the combined therapy resulted in a remarkable protective anti-diabetic effect illustrated by significant decreases in fasting blood glucose and insulin levels after 8 weeks treatment. At the same time, the levels of active insulin signaling proteins pIRS1/pAKT/pGSK-3β/pAMPK were significantly improved. Moreover, Se-NPs exhibited an anti-inflammatory effect by the mitigation of cytokine expression and a balance between oxidative stress and antioxidant status was restored. Furthermore, the anti-diabetic drug MET administration also exhibited a significant improvement in diabetic complications after the treatment period. CONCLUSION This study provides mightily the mechanism of action of combined Se-NPs and MET as a promising therapeutic alternative that synergistically alleviates most of diabetic complications and insulin resistance.
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Affiliation(s)
- Shaymaa A. Abdulmalek
- Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Mahmoud Balbaa
- Department of Biochemistry, Faculty of Science, Alexandria University, Alexandria, Egypt
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Korbecki J, Bajdak-Rusinek K. The effect of palmitic acid on inflammatory response in macrophages: an overview of molecular mechanisms. Inflamm Res 2019; 68:915-932. [PMID: 31363792 PMCID: PMC6813288 DOI: 10.1007/s00011-019-01273-5] [Citation(s) in RCA: 294] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Revised: 07/22/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
Palmitic acid is a saturated fatty acid whose blood concentration is elevated in obese patients. This causes inflammatory responses, where toll-like receptors (TLR), TLR2 and TLR4, play an important role. Nevertheless, palmitic acid is not only a TLR agonist. In the cell, this fatty acid is converted into phospholipids, diacylglycerol and ceramides. They trigger the activation of various signaling pathways that are common for LPS-mediated TLR4 activation. In particular, metabolic products of palmitic acid affect the activation of various PKCs, ER stress and cause an increase in ROS generation. Thanks to this, palmitic acid also strengthens the TLR4-induced signaling. In this review, we discuss the mechanisms of inflammatory response induced by palmitic acid. In particular, we focus on describing its effect on ER stress and IRE1α, and the mechanisms of NF-κB activation. We also present the mechanisms of inflammasome NLRP3 activation and the effect of palmitic acid on enhanced inflammatory response by increasing the expression of FABP4/aP2. Finally, we focus on the consequences of inflammatory responses, in particular, the effect of TNF-α, IL-1β and IL-6 on insulin resistance. Due to the high importance of macrophages and the production of proinflammatory cytokines by them, this work mainly focuses on these cells.
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Affiliation(s)
- Jan Korbecki
- Department of Molecular Biology, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 St., 40-752, Katowice, Poland.
| | - Karolina Bajdak-Rusinek
- Department of Medical Genetics, School of Medicine in Katowice, Medical University of Silesia, Medyków 18 St., 40-752, Katowice, Poland
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Emamalipour M, Seidi K, Jahanban‐Esfahlan A, Jahanban‐Esfahlan R. Implications of resistin in type 2 diabetes mellitus and coronary artery disease: Impairing insulin function and inducing pro‐inflammatory cytokines. J Cell Physiol 2019; 234:21758-21769. [DOI: 10.1002/jcp.28913] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Revised: 05/13/2019] [Accepted: 05/20/2019] [Indexed: 12/20/2022]
Affiliation(s)
- Melissa Emamalipour
- Department of Medical Biotechnology Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
- Student Research Committee, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Khaled Seidi
- Department of Medical Biotechnology Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
- Student Research Committee, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Ali Jahanban‐Esfahlan
- Department of Medical Biotechnology Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
- Student Research Committee, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
| | - Rana Jahanban‐Esfahlan
- Department of Medical Biotechnology Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
- Student Research Committee, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences Tabriz Iran
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Pedroso JAB, Ramos-Lobo AM, Donato J. SOCS3 as a future target to treat metabolic disorders. Hormones (Athens) 2019; 18:127-136. [PMID: 30414080 DOI: 10.1007/s42000-018-0078-5] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Accepted: 10/29/2018] [Indexed: 12/20/2022]
Abstract
The suppressors of cytokine signaling (SOCS) are a group of eight proteins responsible for preventing excessive cytokine signaling. Among this protein family, SOCS3 has received special attention. SOCS3 expression is important to control certain allergy autoimmune diseases. Furthermore, SOCS3 expression is elevated in obesity and it is involved in the inhibition of leptin and insulin signaling, two important hormones involved in the control of energy metabolism. Therefore, increased SOCS3 expression in obese individuals is associated with several metabolic disorders, including reduced energy expenditure, increased food intake and adiposity, and insulin and leptin resistance. In addition, recent studies found that SOCS3 expression regulates energy and glucose homeostasis in several metabolic conditions, such as pregnancy, caloric restriction, and refeeding. Importantly, attenuation of SOCS3 expression in most cases improves leptin and insulin sensitivity, leading to beneficial metabolic effects. This review aims to discuss the role of SOCS3 in the control of blood glucose levels as well as in energy homeostasis. The development of pharmacological compounds to inhibit SOCS3 activity and/or expression may represent a promising therapeutic approach to treat type 2 diabetes mellitus, obesity, and other metabolic imbalances.
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Affiliation(s)
- João A B Pedroso
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, 05508-000, Brazil.
| | - Angela M Ramos-Lobo
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, 05508-000, Brazil
| | - Jose Donato
- Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Av. Prof. Lineu Prestes, 1524, São Paulo, 05508-000, Brazil
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Richter F, Seifert O, Herrmann A, Pfizenmaier K, Kontermann RE. Improved monovalent TNF receptor 1-selective inhibitor with novel heterodimerizing Fc. MAbs 2019; 11:653-665. [PMID: 30929560 DOI: 10.1080/19420862.2019.1596512] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The development of alternative therapeutic strategies to tumor necrosis factor (TNF)-blocking antibodies for the treatment of inflammatory diseases has generated increasing interest. In particular, selective inhibition of TNF receptor 1 (TNFR1) promises a more precise intervention, tackling only the pro-inflammatory responses mediated by TNF while leaving regenerative and pro-survival signals transduced by TNFR2 untouched. We recently generated a monovalent anti-TNFR1 antibody fragment (Fab 13.7) as an efficient inhibitor of TNFR1. To improve the pharmacokinetic properties of Fab 13.7, the variable domains of the heavy and light chains were fused to the N-termini of newly generated heterodimerizing Fc chains. This novel Fc heterodimerization technology, designated "Fc-one/kappa" (Fc1κ) is based on interspersed constant Ig domains substituting the CH3 domains of a γ1 Fc. The interspersed immunoglobulin (Ig) domains originate from the per se heterodimerizing constant CH1 and CLκ domains and contain sequence stretches of an IgG1 CH3 domain, destined to enable interaction with the neonatal Fc receptor, and thus promote extended serum half-life. The resulting monovalent Fv-Fc1κ fusion protein (Atrosimab) retained strong binding to TNFR1 as determined by enzyme-linked immunosorbent assay and quartz crystal microbalance, and potently inhibited TNF-induced activation of TNFR1. Atrosimab lacks agonistic activity for TNFR1 on its own and in the presence of anti-human IgG antibodies and displays clearly improved pharmacokinetic properties.
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Affiliation(s)
- Fabian Richter
- a Institute of Cell Biology and Immunology , University of Stuttgart , Stuttgart , Germany.,b Stuttgart Research Center Systems Biology , University of Stuttgart , Stuttgart , Germany
| | - Oliver Seifert
- a Institute of Cell Biology and Immunology , University of Stuttgart , Stuttgart , Germany.,b Stuttgart Research Center Systems Biology , University of Stuttgart , Stuttgart , Germany
| | | | - Klaus Pfizenmaier
- a Institute of Cell Biology and Immunology , University of Stuttgart , Stuttgart , Germany.,b Stuttgart Research Center Systems Biology , University of Stuttgart , Stuttgart , Germany
| | - Roland E Kontermann
- a Institute of Cell Biology and Immunology , University of Stuttgart , Stuttgart , Germany.,b Stuttgart Research Center Systems Biology , University of Stuttgart , Stuttgart , Germany
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González F, Considine RV, Abdelhadi OA, Acton AJ. Saturated Fat Ingestion Promotes Lipopolysaccharide-Mediated Inflammation and Insulin Resistance in Polycystic Ovary Syndrome. J Clin Endocrinol Metab 2019; 104:934-946. [PMID: 30590569 PMCID: PMC6364509 DOI: 10.1210/jc.2018-01143] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2018] [Accepted: 12/19/2018] [Indexed: 11/19/2022]
Abstract
Context Inflammation and insulin resistance (IR) are often present in polycystic ovary syndrome (PCOS). Objective We determined the effect of saturated fat ingestion on circulating lipopolysaccharide (LPS) and mononuclear cell (MNC) toll-like receptor-4 (TLR-4) and suppressor of cytokine signaling-3 (SOCS-3) in women with PCOS. Design Cross-sectional study. Setting Academic medical center. Patients Nineteen reproductive-age women with PCOS (10 lean, 9 obese) and 19 ovulatory control subjects (10 lean, 9 obese). Main Outcome Measures LPS and TNFα levels were measured in plasma. TLR-4 and SOCS-3 mRNA and protein content were quantified in MNC from blood collected after fasting and 2, 3, and 5 hours after saturated fat ingestion. Insulin sensitivity was derived from an oral glucose tolerance test (ISOGTT). Androgen secretion was assessed from blood collected after fasting and 24, 48, and 72 hours after human chorionic gonadotropin (HCG) administration. Results Regardless of PCOS status, subjects who were obese had lipid-induced increases in circulating LPS and TLR-4 protein content compared with subjects who were lean. Lean and obese women with PCOS had lipid-induced increases in plasma TNFα and SOCS-3 mRNA and protein content compared with lean control subjects. Both PCOS groups had lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. The LPS and SOCS-3 responses were negatively correlated with ISOGTT and positively correlated with HCG-stimulated androgen secretion. Conclusion In PCOS, lipid-induced LPS-mediated inflammation through TLR-4 is associated with obesity and worsened by PCOS, whereas lipid-induced increases in SOCS-3 may represent an obesity-independent, TNFα-mediated mechanism of IR.
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Affiliation(s)
- Frank González
- Department of Obstetrics and Gynecology, University of Illinois at Chicago, Chicago, Illinois
| | - Robert V Considine
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Ola A Abdelhadi
- Department of Obstetrics and Gynecology, Indiana University School of Medicine, Indianapolis, Indiana
| | - Anthony J Acton
- Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
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Ye HM, Zhao T, Wu LX, Cheng J, Tan XY. Molecular characterization of nine suppressors of cytokine signaling (SOCS) genes from yellow catfish Pelteobagrus fulvidraco and their changes in mRNA expression to dietary carbohydrate levels. FISH & SHELLFISH IMMUNOLOGY 2019; 86:906-912. [PMID: 30580042 DOI: 10.1016/j.fsi.2018.12.037] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/26/2018] [Revised: 12/14/2018] [Accepted: 12/19/2018] [Indexed: 06/09/2023]
Abstract
Suppressors of cytokine signaling (SOCS) are important molecules that mediates the regulation of glucose homeostasis. Here, we cloned and characterized the full-length cDNA sequences of nine genes of the SOCS family (SOCS1, 2, 3, 3b, 5, 5b, 6, 7 and CISH) from yellow catfish P. fulvidraco, explored their mRNA abundance across the tissues and their mRNA changes to dietary carbohydrate levels. Structural analysis indicated that the nine members shared conserved functional domains to the orthologues of the mammalian SOCS members, such as SRC homology 2 and the SOCS domains. Their mRNAs were constitutively expressed in various tissues but changed among the tissues. Their mRNA expression in response to dietary carbohydrate levels were explored in the liver, muscle, intestine, testis and ovary. Dietary carbohydrate addition showed significant effects on the mRNA levels of the nine SOCS members. Moreover, their mRNA expressions in response to dietary carbohydrate levels were also tissue-dependent. These indicated that SOCS members potentially mediated the utilization of dietary carbohydrate in yellow catfish.
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Affiliation(s)
- Han-Mei Ye
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, 430070, China
| | - Tao Zhao
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, 430070, China
| | - Li-Xiang Wu
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, 430070, China
| | - Jie Cheng
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, 430070, China
| | - Xiao-Ying Tan
- Key Laboratory of Freshwater Animal Breeding, Ministry of Agriculture, Fishery College, Huazhong Agricultural University, Wuhan, 430070, China.
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Qin S, Sun D, Mu J, Ma D, Tang R, Zheng Y. Purple sweet potato color improves hippocampal insulin resistance via down-regulating SOCS3 and galectin-3 in high-fat diet mice. Behav Brain Res 2018; 359:370-377. [PMID: 30465813 DOI: 10.1016/j.bbr.2018.11.025] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 11/13/2018] [Accepted: 11/16/2018] [Indexed: 12/18/2022]
Abstract
Hippocampal insulin resistance is the key factor in cognitive deficits. The obesity induces chronic inflammation and the inflammation molecules suppressors of cytokine signaling3 (SOCS3) and galectin-3 directly impair the insulin signaling. The anti-inflammation properties of purple sweet potato color (PSPC) prompted us to investigate the effect of PSPC on cognitive impairment associated with obesity. 60 C57BL/6 mice were randomly divided into four groups: normal, high fat diets (HFD), HFD+PSPC and PSPC. The mice were fed with the HFD or normal diet for 32 weeks. The PSPC (500 mg/kg/day) was administered via oral gavage from 21 to 32 weeks. The results showed the PSPC rectified the abnormal metabolism indexes induced by HFD, including ameliorated obesity, decreased the concentration of fasting blood glucose and improved the glucose tolerance. The Morris water maze test showed the PSPC alleviated the cognitive impairment in HFD mice. The PSPC decreased the expression of Iba1, tumor necrosis factor-α, interleukin-1β, SOCS3 and galectin-3 in hippocampus of HFD mice. The insulin signaling molecules including the p-IRS1 (Tyr608), PI3K p110α and p-AKT (Ser473) were detected and the PSPC treatment improved the insulin resistance in hippocampus of HFD mice. Furthermore, the PSPC increased Bcl-2, diminished the Bak and the cleaved-caspase3 in HFD mice hippocampus. These findings indicated that PSPC could be a potential treatment to improve the cognitive impairment associated with obesity.
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Affiliation(s)
- Suping Qin
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Sciences, Jiangsu Normal University, Xuzhou, China
| | - Dexu Sun
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu, China
| | - Jingjing Mu
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Sciences, Jiangsu Normal University, Xuzhou, China
| | - Daifu Ma
- Key Laboratory of Biology and Genetic Improvement of Sweetpotato, Ministry of Agriculture, Jiangsu Xuzhou Sweetpotato Research Center, Xuzhou, China
| | - Renxian Tang
- Jiangsu Key Laboratory of Immunity and Metabolism, Xuzhou Medical University, Xuzhou, Jiangsu, China.
| | - Yuanlin Zheng
- Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Sciences, Jiangsu Normal University, Xuzhou, China.
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Liu J, Zhang HR, Hou YB, Jing XL, Song XY, Shen XP. Global gene expression analysis in liver of db/db mice treated with catalpol. Chin J Nat Med 2018; 16:590-598. [PMID: 30197124 DOI: 10.1016/s1875-5364(18)30096-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2017] [Indexed: 10/28/2022]
Abstract
Catalpol, a major bioactive component from Rehmannia glutinosa, which has been used to treat diabetes. The present study was designed to elucidate the anti-diabetic effect and mechanism of action for catalpol in db/db mice. The db/db mice were randomly divided into six groups (10/group) according to their blood glucose levels: db/db control, metformin (positive control), and four dose levels of catalpol treatment (25, 50, 100, and 200 mg·kg-1), and 10 db/m mice were used as the normal control. All the groups were administered orally for 8 weeks. The levels of fasting blood glucose (FBG), random blood glucose (RBG), glucose tolerance, insulin tolerance, and glycated serum protein (GSP) and the globe gene expression in liver tissues were analyzed. Our results showed that catalpol treatment obviously reduced water intake and food intake in a dose-dependent manner. Catalpol treatment also remarkably reduce fasting blood glucose (FBG) and random blood glucose (RBG) in a dose-dependent manner. The RBG-lowering effect of catalpol was better than that of metformin. Furthermore, catalpol significantly improved glucose tolerance and insulin tolerance via increasing insulin sensitivity. Catalpol treatment significantly decreased GSP level. The comparisons of gene expression in liver tissues among normal control mice, db/db mice and catalpol treated mice (200 and 100 mg·kg-1) indicated that there were significant increases in the expressions of 287 genes, whichwere mainly involved in lipid metabolism, response to stress, energy metabolism, and cellular processes, and significant decreases in the expressions of 520 genes, which were mainly involved in cell growth, death, immune system, and response to stress. Four genes expressed differentially were linked to glucose metabolism or insulin signaling pathways, including Irs1 (insulin receptor substrate 1), Idh2 (isocitrate dehydrogenase 2 (NADP+), mitochondrial), G6pd2 (glucose-6-phosphate dehydrogenase 2), and SOCS3 (suppressor of cytokine signaling 3). In conclusion, catalpol ecerted significant hypoglycemic effect and remarkable therapeutic effect in db/db mice via modulating various gene expressions.
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Affiliation(s)
- Jing Liu
- Tianjin Institute of Pharmaceutical Research Co., Ltd., Tianjin 300301, China; Tianjin Institute of Pharmaceutical Research Drug Safety Assessment Co., Ltd., Tianjin 300301, China
| | - He-Ran Zhang
- Tianjin Institute of Pharmaceutical Research Co., Ltd., Tianjin 300301, China
| | - Yan-Bao Hou
- Tianjin Institute of Pharmaceutical Research Drug Safety Assessment Co., Ltd., Tianjin 300301, China
| | - Xiao-Long Jing
- Tianjin Institute of Pharmaceutical Research Co., Ltd., Tianjin 300301, China; Tianjin Institute of Pharmaceutical Research Drug Safety Assessment Co., Ltd., Tianjin 300301, China
| | - Xin-Yi Song
- Qinghai Yangzong Pharmaceutical Co., Ltd., Xining 810003, China
| | - Xiu-Ping Shen
- Tianjin Institute of Pharmaceutical Research Co., Ltd., Tianjin 300301, China; Tianjin Institute of Pharmaceutical Research Drug Safety Assessment Co., Ltd., Tianjin 300301, China.
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50
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Epac1 Restores Normal Insulin Signaling through a Reduction in Inflammatory Cytokines. Mediators Inflamm 2018; 2018:3809092. [PMID: 30116147 PMCID: PMC6079497 DOI: 10.1155/2018/3809092] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Revised: 06/05/2018] [Accepted: 06/20/2018] [Indexed: 01/21/2023] Open
Abstract
We have previously reported that Epac1 reduced inflammatory cytokines, which is protective to the diabetic retina. We have also published that impaired insulin signaling occurs in the diabetic retina. A reduction in interleukin-1 beta (IL-1β) and tumor necrosis factor alpha (TNFα) by Epac1 could potentially restore normal insulin signal transduction. Confocal microscopy was performed to localize the insulin receptor in the retina of Epac1 floxed and endothelial cell-specific Epac1 knockout mice. Whole retinal lysates from Epac1 floxed and endothelial cell-specific Epac1 knockout mice were used to investigate proteins involved in the insulin signaling cascade. Primary human REC were cultured in normal and high glucose followed by Epac1 agonist treatment or transfection with IL-1β or TNFα siRNA for protein analyses of insulin signaling proteins. Decreased expression of the insulin receptor was observed in the Epac1 knockout mouse retinal vasculature compared to floxed littermates. Work in mice showed that loss of Epac1 decreased insulin signaling proteins. Treatment with an Epac1 agonist decreased p38 and JNK signaling and increased insulin signaling, as did inhibition of IL-1β or TNFα using siRNA when added to REC grown in high glucose. Taken together, Epac1 can restore normal insulin signaling in the retinal vasculature through reductions in inflammatory cytokines.
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