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Ameling S, Van der Auwera S, Holtfreter S, Wiechert A, Michalik S, Friedrich N, Hammer E, Völzke H, Nauck M, Grabe HJ, Bröker BM, Völker U. Cytokine atlas of the population-based cohort SHIP-TREND-0 - Associations with age, sex, and BMI. Cytokine 2025; 189:156896. [PMID: 40020520 DOI: 10.1016/j.cyto.2025.156896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Revised: 12/20/2024] [Accepted: 02/14/2025] [Indexed: 03/03/2025]
Abstract
BACKGROUND The characterization of physiological immune signatures in a population-based cohort is a prerequisite for identifying pathological immune signatures associated with inflammatory or autoimmune diseases. METHODS Here, 47 plasma cytokines, chemokines, and growth factors were quantified with a bead-based multiplex-assay (Merck HCYTA-60 K) using a FLEXMAP 3D™ instrument in 1175 individuals of the Study of Health in Pomerania (SHIP; TREND cohort, 532 men and 643 women, age: 20 to 81, BMI: 17.7 to 53.6). Associations of cytokine concentrations with age, sex, BMI, season, and blood cell parameters (BCP) were examined by multivariate regression models. RESULTS The physiological cytokine concentrations differed strongly between analytes, with median concentrations ranging from 0.6 to 7820 pg/mL. Many cytokine levels showed a large dynamic range within the study population. Higher levels of the pro-inflammatory cytokines and chemokines IL-6, IL-8, CXCL9, CXCL10, IL-12p40, CCL2, CCL4, CCL11, IL-27, FLT3LG, and TNFα were significantly associated with increasing age. The strongest age-associated effects were seen for CXCL9 (βst = 0.4, p < 0.001) and CXLC10 (βst = 0.3, p < 0.001). Significant sex differences were detected for CCL2, CCL3, CCL4, CCL11, CCL22, IL-12p40, IL-1RA, IL-18, IL-27, and TNFα levels among which CCL11 showed the strongest effect (βst = -0.24, p < 0.001) with a lower level in women compared to men. Moreover, seven cytokines and chemokines, i.e. CCL4, CCL22, CXCL10, IL-1RA, IL-18, IL-6, and TNFα, displayed higher levels with increasing BMI. Among those, the strongest effect was seen for IL-1RA (βst = 0.19, p < 0.001), CCL4 (βst = 0.16, p < 0.001) and CXCL10 (βst = 0.14, p < 0.001). Only CCL11 (βst = -0.17, p < 0.001) decreased with increasing BMI. Subjects categorized as obese exhibited significantly elevated levels of CCL4, CCL22, CXCL10, and IL-1RA, while only CCL11 showed significantly reduced levels compared to normal weight. Certain cytokines such as IL-6, IL-18, or TNFα showed decreased significance levels after adjustment for blood cell components indicating blood cell components (BCPs) as potential confounders. We observed no significant non-linear seasonal effects for the investigated cytokines. CONCLUSION The generated cytokine atlas provides detailed information on cytokine variations in the general population and will provide a reference base for disease-related studies in the future. Furthermore, BCPs should be considered as potential confounders in association studies based on plasma cytokine levels.
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Affiliation(s)
- Sabine Ameling
- Department Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Straße 8, D-17475 Greifswald, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany.
| | - Sandra Van der Auwera
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Ellernholzstraße 1, D-17475 Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany
| | - Silva Holtfreter
- Institute of Immunology, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, D-17475 Greifswald, Germany
| | - Anja Wiechert
- Department Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Straße 8, D-17475 Greifswald, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany
| | - Stephan Michalik
- Department Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Straße 8, D-17475 Greifswald, Germany
| | - Nele Friedrich
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, D-17475 Greifswald, Germany
| | - Elke Hammer
- Department Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Straße 8, D-17475 Greifswald, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany
| | - Henry Völzke
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany; Institute for Community Medicine, University Medicine Greifswald, Walther-Rathenau-Straße 48, D-17475 Greifswald, Germany
| | - Matthias Nauck
- German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany; Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, D-17475 Greifswald, Germany
| | - Hans J Grabe
- Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Ellernholzstraße 1, D-17475 Greifswald, Germany; German Centre for Neurodegenerative Diseases (DZNE), Site Rostock/Greifswald, Greifswald, Germany
| | - Barbara M Bröker
- Institute of Immunology, University Medicine Greifswald, Ferdinand-Sauerbruch-Straße, D-17475 Greifswald, Germany
| | - Uwe Völker
- Department Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Felix-Hausdorff-Straße 8, D-17475 Greifswald, Germany; German Centre for Cardiovascular Research (DZHK), Partner Site Greifswald, Greifswald, Germany
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Li X, Liu S, Wang S, Ai X, Wei L. 1-Deoxynojirimycin affects high glucose-induced pancreatic beta-cell dysfunction through regulating CEBPA expression and AMPK pathway. Biochem Cell Biol 2025; 103:1-12. [PMID: 39546764 DOI: 10.1139/bcb-2024-0128] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2024] Open
Abstract
This study aims to explore the role of 1-deoxynojirimycin (DNJ) in high glucose-induced β-cells and to further explore the molecular mechanism of DNJ effect on β-cells through network pharmacology. In the study, high glucose treatment of mouse INS-1 cells inhibited cell proliferation and insulin secretion, decreased the expression of Bcl-2 protein and Ins1 and Ins2 genes, promoted apoptosis, and increased cleaved caspase-3 and cleaved caspase-9 expression levels as well as intracellular reactive oxygen species production. DNJ treatment significantly restored the dysfunction of INS-1 cells induced by high glucose, and DNJ showed no toxicity to normal INS-1 cells. Silencing CEBPA promoted, while overexpression of CEBPA relieved the dysfunction of pancreatic β-cells induced by high glucose. DNJ treatment partially restored the pancreatic β-cell dysfunction caused by silencing CEBPA. In conclusion, DNJ can inhibit high glucose-induced pancreatic β-cell dysfunction by promoting the expression of CEBPA.
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Affiliation(s)
- Xiaoying Li
- Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province, College of Biology and Food Engineering, Huaihua University, Huaihua 418000, Hunan, China
| | - Shenggui Liu
- Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province, College of Biology and Food Engineering, Huaihua University, Huaihua 418000, Hunan, China
| | - Siqi Wang
- College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou, China
| | - Xinghui Ai
- College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou, China
| | - Lin Wei
- Key Laboratory of Research and Utilization of Ethnomedicinal Plant Resources of Hunan Province, College of Biology and Food Engineering, Huaihua University, Huaihua 418000, Hunan, China
- College of Basic Medicine, Guizhou University of Traditional Chinese Medicine, Guizhou University of Traditional Chinese Medicine, Guiyang 550025, Guizhou, China
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López-Yerena A, de Santisteban Villaplana V, Badimon L, Vilahur G, Padro T. Probiotics: A Potential Strategy for Preventing and Managing Cardiovascular Disease. Nutrients 2024; 17:52. [PMID: 39796486 PMCID: PMC11722674 DOI: 10.3390/nu17010052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/22/2024] [Accepted: 12/24/2024] [Indexed: 01/13/2025] Open
Abstract
Probiotics are gaining recognition as a viable strategy for mitigating cardiovascular risk factors. Specifically, recent studies highlight their potential benefits in managing cholesterol levels, blood pressure, and inflammation, which are critical components in the prevention of cardiovascular diseases (CVD). This comprehensive review aims to elucidate the impact of probiotic consumption on major cardiovascular risk factors, including individuals with hypertension, type II diabetes mellitus, metabolic syndrome, hypercholesterolemia, and in secondary prevention in coronary artery disease. Scientific evidence based on human studies suggests that probiotic consumption is associated with positive effects on anthropometric measures, inflammation markers, blood pressure, glucose metabolism markers, lipid profiles, and endothelial function. However, these findings should be interpreted pragmatically and acknowledge the significant variability in results. This variability may be attributed to factors such as probiotic composition (single strain or multiple strains), the characteristics of the delivery matrix (food, capsules, and sachets), the duration of the intervention, the dosage regimen, and baseline health profiles of the participants. Incorporating probiotics as part of a comprehensive and healthy lifestyle approach can be considered a feasible strategy for both the prevention and management of CVD. However, further research is needed on factors influencing the effect of probiotics, such as: (i) optimal probiotic strain(s), (ii) appropriate dosage, (iii) duration of treatment, (iv) optimal delivery vehicle, and (v) sex-specific differences.
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Affiliation(s)
- Anallely López-Yerena
- Institut Recerca Sant Pau, Sant Quinti 77-79, 08041 Barcelona, Spain; (A.L.-Y.); (V.d.S.V.); (L.B.); (G.V.)
| | - Victoria de Santisteban Villaplana
- Institut Recerca Sant Pau, Sant Quinti 77-79, 08041 Barcelona, Spain; (A.L.-Y.); (V.d.S.V.); (L.B.); (G.V.)
- School of Pharmacy and Food Sciences, University of Barcelona (UB), 08036 Barcelona, Spain
| | - Lina Badimon
- Institut Recerca Sant Pau, Sant Quinti 77-79, 08041 Barcelona, Spain; (A.L.-Y.); (V.d.S.V.); (L.B.); (G.V.)
- Centro de Investigación Biomédica en Red Cardiovascular (CIBER-CV), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Cardiovascular Research Foundation for Health Prevention and Innovation (FICSI), 08017 Barcelona, Spain
| | - Gemma Vilahur
- Institut Recerca Sant Pau, Sant Quinti 77-79, 08041 Barcelona, Spain; (A.L.-Y.); (V.d.S.V.); (L.B.); (G.V.)
- Centro de Investigación Biomédica en Red Cardiovascular (CIBER-CV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Teresa Padro
- Institut Recerca Sant Pau, Sant Quinti 77-79, 08041 Barcelona, Spain; (A.L.-Y.); (V.d.S.V.); (L.B.); (G.V.)
- Centro de Investigación Biomédica en Red Cardiovascular (CIBER-CV), Instituto de Salud Carlos III, 28029 Madrid, Spain
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Rocha M, Daniels K, Chandrasekaran S, Michopoulos V. Trauma and Posttraumatic Stress Disorder as Important Risk Factors for Gestational Metabolic Dysfunction. Am J Perinatol 2024; 41:1895-1907. [PMID: 38307105 PMCID: PMC11436347 DOI: 10.1055/a-2260-5051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2024]
Abstract
Gestational metabolic diseases adversely impact the health of pregnant persons and their offspring. Pregnant persons of color are impacted disproportionately by gestational metabolic disease, highlighting the need to identify additional risk factors contributing to racial-ethnic pregnancy-related health disparities. Trauma exposure and posttraumatic stress disorder (PTSD) are associated with increased risk for cardiometabolic disorders in nonpregnant persons, making them important factors to consider when identifying contributors to gestational metabolic morbidity and mortality health disparities. Here, we review current literature investigating trauma exposure and posttraumatic stress disorder as psychosocial risk factors for gestational metabolic disorders, inclusive of gestational diabetes, low birth weight and fetal growth restriction, gestational hypertension, and preeclampsia. We also discuss the physiological mechanisms by which trauma and PTSD may contribute to gestational metabolic disorders. Ultimately, understanding the biological underpinnings of how trauma and PTSD, which disproportionately impact people of color, influence risk for gestational metabolic dysfunction is critical to developing therapeutic interventions that reduce complications arising from gestational metabolic disease. KEY POINTS: · Gestational metabolic diseases disproportionately impact the health of pregnant persons of color.. · Trauma and PTSD are associated with increased risk for cardiometabolic disorders in nonpregnant per.. · Trauma and PTSD impact physiological cardiometabolic mechanisms implicated in gestational metabolic..
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Affiliation(s)
- Mariana Rocha
- Graduate Program in Neuroscience, Emory University, Atlanta, Georgia
| | | | - Suchitra Chandrasekaran
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia
| | - Vasiliki Michopoulos
- Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta, Georgia
- Department of Gynecology and Obstetrics, Emory University School of Medicine, Atlanta, Georgia
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Holst-Hansen T, Nielsen PY, Jensen MH, Mandrup-Poulsen T, Trusina A. Tipping-point transition from transient to persistent inflammation in pancreatic islets. NPJ Syst Biol Appl 2024; 10:102. [PMID: 39266581 PMCID: PMC11393080 DOI: 10.1038/s41540-024-00427-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Accepted: 08/19/2024] [Indexed: 09/14/2024] Open
Abstract
Type 2 diabetes (T2D) is associated with a systemic increase in the pro-inflammatory cytokine IL-1β. While transient exposure to low IL-1β concentrations improves insulin secretion and β-cell proliferation in pancreatic islets, prolonged exposure leads to impaired insulin secretion and collective β-cell death. IL-1 is secreted locally by islet-resident macrophages and β-cells; however, it is unknown if and how the two opposing modes may emerge at single islet level. We investigated the duality of IL-1β with a quantitative in silico model of the IL-1 regulatory network in pancreatic islets. We find that the network can produce either transient or persistent IL-1 responses when induced by pro-inflammatory and metabolic cues. This suggests that the duality of IL-1 may be regulated at the single islet level. We use two core feedbacks in the IL-1 regulation to explain both modes: First, a fast positive feedback in which IL-1 induces its own production through the IL-1R/IKK/NF-κB pathway. Second, a slow negative feedback where NF-κB upregulates inhibitors acting at different levels along the IL-1R/IKK/NF-κB pathway-IL-1 receptor antagonist and A20, among others. A transient response ensues when the two feedbacks are balanced. When the positive feedback dominates over the negative, islets transit into the persistent inflammation mode. Consistent with several observations, where the size of islets was implicated in its inflammatory state, we find that large islets and islets with high density of IL-1β amplifying cells are more prone to transit into persistent IL-1β mode. Our results are likely not limited to IL-1β but are general for the combined effect of multiple pro-inflammatory cytokines and chemokines. Generalizing complex regulations in terms of two feedback mechanisms of opposing nature and acting on different time scales provides a number of testable predictions. Taking islet architecture and cellular heterogeneity into consideration, further dynamic monitoring and experimental validation in actual islet samples will be crucial to verify the model predictions and enhance its utility in clinical applications.
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Affiliation(s)
| | - Pernille Yde Nielsen
- Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark
- Department of Applied Mathematics and Computer Science, Technical University of Denmark, Lyngby, Denmark
| | - Mogens H Jensen
- Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.
| | - Thomas Mandrup-Poulsen
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
| | - Ala Trusina
- Niels Bohr Institute, University of Copenhagen, Copenhagen, Denmark.
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Lin CM, Meng Q, Li YJ, Zhang SX, Luo QX, Dai ZY. Causal associations between intermediate very-low-density lipoprotein cholesterol-to-total lipids ratio and peptic ulcer: A bidirectional Mendelian randomization study. World J Clin Cases 2024; 12:5729-5738. [PMID: 39247748 PMCID: PMC11263067 DOI: 10.12998/wjcc.v12.i25.5729] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Revised: 05/27/2024] [Accepted: 06/19/2024] [Indexed: 07/12/2024] Open
Abstract
BACKGROUND Previous epidemiologic investigations have consistently demonstrated a strong association between the ratio of cholesterol to total lipids in medium very-low-density lipoprotein (VLDL) and the occurrence of peptic ulcers (PU). However, the precise causal relationship between these factors remains ambiguous. Consequently, this study aims to elucidate the potential correlation between the ratio of cholesterol to total lipids in medium VLDL and the incidence of peptic ulcer. AIM To investigate the ratio of cholesterol to total lipids in medium very-low-density lipoprotein (VLDL) association with PU via genetic methods, guiding future clinical research. METHODS Genome-wide association study (GWAS) datasets for the ratio of cholesterol to total lipids in intermediate VLDL and peptic ulcer were retrieved from the IEU OpenGWAS project (https://gwas.mrcieu.ac.uk). For the forward Mendelian randomization (MR) analysis, 72 single nucleotide polymorphisms (SNPs) were identified as instrumental variables. These SNPs were selected based on their association with the ratio of cholesterol to total lipids in intermediate VLDL, with peptic ulcer as the outcome variable. Conversely, for the inverse MR analysis, no SNPs were identified with peptic ulcer as the exposure variable and the ratio of cholesterol to total lipids in intermediate VLDL as the outcome. All MR analyses utilized inverse variance weighted (IVW) as the primary analytical method. Additionally, weighted median and MR-Egger methods were employed as supplementary analytical approaches to assess causal effects. Egger regression was used as a supplementary method to evaluate potential directional pleiotropy. Heterogeneity and multiplicity tests were conducted using the leave-one-out method to evaluate result stability and mitigate biases associated with multiple testing. RESULTS The genetically predicted ratio of cholesterol to total lipids in medium VLDL was significantly associated with an elevated risk of peptic ulcer (IVW: OR = 2.557, 95%CI = 1.274-5.132, P = 0.008). However, no causal association of peptic ulcer with the ratio of cholesterol to total lipids in medium VLDL was observed in the inverse Mendelian randomization analysis. CONCLUSION In conclusion, our study reveals a significant association between the ratio of cholesterol to total lipids in medium VLDL and an elevated risk of peptic ulcers. However, further validation through laboratory investigations and larger-scale studies is warranted to strengthen the evidence and confirm the causal relationship between these factors.
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Affiliation(s)
- Chun-Mei Lin
- Postgraduate Student, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China
| | - Qian Meng
- Postgraduate Student, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China
| | - Ying-Jun Li
- Postgraduate Student, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China
| | - Shuang-Xi Zhang
- Department of Gastroenterology, Guangzhou University of Chinese Medicine Shunde Hospital, Foshan 528300, Guangdong Province, China
| | - Qiong-Xi Luo
- Postgraduate Student, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China
| | - Zhen-Yu Dai
- Postgraduate Student, Guangzhou University of Chinese Medicine, Guangzhou 510006, Guangdong Province, China
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Kothari M, Kannan K, Sahadevan R, Retnakumar SV, Chauvin C, Bayry J, Sadhukhan S. Lipophilic derivatives of EGCG as potent α-amylase and α-glucosidase inhibitors ameliorating oxidative stress and inflammation. Bioorg Chem 2024; 153:107786. [PMID: 39244970 DOI: 10.1016/j.bioorg.2024.107786] [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: 06/25/2024] [Revised: 08/20/2024] [Accepted: 08/31/2024] [Indexed: 09/10/2024]
Abstract
Uncontrolled hyperglycemia leads to increased oxidative stress, chronic inflammation, and insulin resistance, rendering diabetes management harder to accomplish. To tackle these myriads of challenges, researchers strive to explore innovative multifaceted treatment strategies, including inhibiting carbohydrate hydrolases. Herein, we report alkyl-ether EGCG derivatives as potent α-amylase and α-glucosidase inhibitors that could simultaneously ameliorate oxidative stress and inflammation. 4″-C18 EGCG, the most promising compound, showed multifold improvement in glycaemic management compared to acarbose, with 230-fold greater inhibition (competitive) of α-glucosidase (IC50 0.81 µM) and 3-fold better inhibition of α-amylase (IC50 3.74 µM). All derivatives showed stronger antioxidant activity (IC50 6.16-15.76 µM) than vitamin C, while acarbose showed none. 4″-C18 EGCG also downregulated pro-inflammatory cytokines and showed no significant cytotoxicity up to 50 µM in primary human peripheral blood mononuclear cells (PBMC), non-cancerous cell line, 3T3-L1 and HEK 293. The in silico binding affinity analysis of 4″-C18 EGCG with α-amylase and α-glucosidase was found to exhibit a good extent of interaction as compared to acarbose. In comparison to EGCG, 4″-Cn EGCG derivatives were found to remain stable in the physiological conditions even after 24 h. Together, the reported molecules demonstrated multifaceted antidiabetic potential inhibiting carbohydrate hydrolases, reducing oxidative stress, and inflammation, which are known to aggravate diabetes.
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Affiliation(s)
- Manan Kothari
- Department of Chemistry, Indian Institute of Technology Palakkad, Kerala 678 623, India
| | - Karthika Kannan
- Department of Chemistry, Indian Institute of Technology Palakkad, Kerala 678 623, India
| | - Revathy Sahadevan
- Department of Chemistry, Indian Institute of Technology Palakkad, Kerala 678 623, India
| | - Sruthi Vijaya Retnakumar
- Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 75006 Paris, France
| | - Camille Chauvin
- Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 75006 Paris, France
| | - Jagadeesh Bayry
- Institut National de la Santé et de la Recherche Médicale, Centre de Recherche des Cordeliers, Sorbonne Université, Université de Paris, 75006 Paris, France; Department of Biological Sciences & Engineering, Indian Institute of Technology Palakkad, Kerala 678 623, India
| | - Sushabhan Sadhukhan
- Department of Chemistry, Indian Institute of Technology Palakkad, Kerala 678 623, India; Department of Biological Sciences & Engineering, Indian Institute of Technology Palakkad, Kerala 678 623, India; Physical & Chemical Biology Laboratory, Indian Institute of Technology Palakkad, Kerala 678 623, India.
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Lanka N, Acharya P, Virani S, Afreen S, Perthiani A, Sangster E, Arcia Franchini AP. Safety and Efficacy of Canakinumab for the Prevention and Control of Type 2 Diabetes Mellitus and Its Complications: A Systematic Review. Cureus 2024; 16:e67065. [PMID: 39286685 PMCID: PMC11403928 DOI: 10.7759/cureus.67065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2024] [Accepted: 08/16/2024] [Indexed: 09/19/2024] Open
Abstract
Today, diabetes mellitus (DM) is one of the leading causes of morbidity and mortality globally.In this grim context, while our current armamentarium of anti-diabetic agents is vast and increasingly available, glycemic control in a significant proportion of these patients continues to remain sub-optimal.This necessitates the exploration of other potential cellular pathways and targets to effectively manage this notorious disease and its numerous complications. Inflammatory responses are thought to be implicated in the decline of pancreatic beta-cell function, with interleukin-1 beta (IL-1β) playing an important role in these pathways. Canakinumab, a human monoclonal anti-IL-1β antibody, operates by reducing inflammation, potentially safeguarding or enhancing pancreatic beta-cell function. This systematic review aims to study the safety and efficacy of canakinumab in the prevention and control of type 2 diabetes mellitus (T2DM) and its complications. This study was conducted in accordance with the PRISMA 2020 Guidelines. PubMed including MEDLINE, Google Scholar and Cochrane Library were used as information sources and randomized clinical trials and retrospective observational studies evaluating patients with T2DM or impaired glucose tolerance with/without complications receiving canakinumab, compared with placebo or standard therapy and reporting about glycemic indicators including hemoglobin A1C (HbA1C) or blood sugar levels (BSL) or insulin levels and/or inflammatory indicators including high-sensitivity C-reactive protein (hsCRP) or interleukin-6 (IL-6) were included. Non-randomized clinical trials, animal studies, review articles, case reports, case series, studies not in the English language and those evaluating type 1 DM were excluded. In total, 271 studies were identified to be included in this study. Subsequently, 27 were found to be duplicate records and were eliminated. Manual screening of title/abstract of 244 records was done which found 207 to be ineligible and 37 studies were shortlisted. These were retrieved and full-text screening was undertaken which resulted in the exclusion of 28 reports due to the following reasons: ineligible study design (17), studies evaluating type 1 DM (three), studies evaluating anakinra (one), trial being canceled (three) and duplicate studies (four). Subsequently, a total of nine studies were included in the final review. All studies were included post quality appraisal. We found that canakinumab had a modest but mostly non-significant effect on glycemic parameters including HbA1C, while having a consistently significant reduction in systemic inflammatory parameters like hsCRP and IL-6. Additionally, it was found to have a significant reduction in incident major adverse cardiovascular events (MACE). Canakinumab was also found to be safe and well-tolerated in all patient populations. Although canakinumab did not reduce incident T2DM, an exploration of alternative pathways and targets implicated in the pathogenesis of this disease process is warranted for the prevention and control of T2DM.
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Affiliation(s)
- Nidhi Lanka
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Prakash Acharya
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Shikha Virani
- Internal Medicine, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Sumayya Afreen
- Obstetrics and Gynaecology, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Arvin Perthiani
- General Surgery, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Elizabeth Sangster
- Psychiatry and Behavioral Sciences, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
| | - Ana P Arcia Franchini
- Research, California Institute of Behavioral Neurosciences & Psychology, Fairfield, USA
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Maestas MM, Ishahak M, Augsornworawat P, Veronese-Paniagua DA, Maxwell KG, Velazco-Cruz L, Marquez E, Sun J, Shunkarova M, Gale SE, Urano F, Millman JR. Identification of unique cell type responses in pancreatic islets to stress. Nat Commun 2024; 15:5567. [PMID: 38956087 PMCID: PMC11220140 DOI: 10.1038/s41467-024-49724-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 06/14/2024] [Indexed: 07/04/2024] Open
Abstract
Diabetes involves the death or dysfunction of pancreatic β-cells. Analysis of bulk sequencing from human samples and studies using in vitro and in vivo models suggest that endoplasmic reticulum and inflammatory signaling play an important role in diabetes progression. To better characterize cell type-specific stress response, we perform multiplexed single-cell RNA sequencing to define the transcriptional signature of primary human islet cells exposed to endoplasmic reticulum and inflammatory stress. Through comprehensive pair-wise analysis of stress responses across pancreatic endocrine and exocrine cell types, we define changes in gene expression for each cell type under different diabetes-associated stressors. We find that β-, α-, and ductal cells have the greatest transcriptional response. We utilize stem cell-derived islets to study islet health through the candidate gene CIB1, which was upregulated under stress in primary human islets. Our findings provide insights into cell type-specific responses to diabetes-associated stress and establish a resource to identify targets for diabetes therapeutics.
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Affiliation(s)
- Marlie M Maestas
- Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, USA
| | - Matthew Ishahak
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, USA
| | - Punn Augsornworawat
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, 10700, Thailand
| | - Daniel A Veronese-Paniagua
- Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, USA
| | - Kristina G Maxwell
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, USA
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, USA
| | - Leonardo Velazco-Cruz
- Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, USA
| | - Erica Marquez
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, USA
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, USA
| | - Jiameng Sun
- Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, USA
| | - Mira Shunkarova
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, USA
| | - Sarah E Gale
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, USA
| | - Fumihiko Urano
- Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue, St. Louis, MO, 63110, USA
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, USA
- Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, USA
| | - Jeffrey R Millman
- Roy and Diana Vagelos Division of Biology and Biomedical Sciences, Washington University School of Medicine, MSC 8127-057-08, 660 South Euclid Avenue, St. Louis, MO, 63110, USA.
- Division of Endocrinology, Metabolism, and Lipid Research, Washington University School of Medicine, MSC 8127-057-08, St. Louis, USA.
- Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, USA.
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10
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Guan J, Abudouaini H, Lin K, Yang K. Emerging insights into the role of IL-1 inhibitors and colchicine for inflammation control in type 2 diabetes. Diabetol Metab Syndr 2024; 16:140. [PMID: 38918878 PMCID: PMC11197348 DOI: 10.1186/s13098-024-01369-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 05/30/2024] [Indexed: 06/27/2024] Open
Abstract
Type 2 diabetes mellitus (T2DM), a prevalent chronic metabolic disorder, is closely linked to persistent low-grade inflammation, significantly contributing to its development and progression. This review provides a comprehensive examination of the inflammatory mechanisms underlying T2DM, focusing on the role of the NLRP3 inflammasome and interleukin-1β (IL-1β) in mediating inflammatory responses. We discuss the therapeutic potential of IL-1 inhibitors and colchicine, highlighting their mechanisms in inhibiting the NLRP3 inflammasome and reducing IL-1β production. Recent studies indicate that these agents could effectively mitigate inflammation, offering promising avenues for the prevention and management of T2DM. By exploring the intricate connections between metabolic disturbances and chronic inflammation, this review underscores the need for novel anti-inflammatory strategies to address T2DM and its complications.
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Affiliation(s)
- Jianbin Guan
- Honghui-Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Haimiti Abudouaini
- Honghui-Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China
| | - Kaiyuan Lin
- Honghui-Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.
| | - Kaitan Yang
- Honghui-Hospital, Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.
- Truma Rehabilitation Department, Honghui-Hospital，Xi'an Jiaotong University, Xi'an, 710054, Shaanxi, China.
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11
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Wang Y, Wang X, Du C, Wang Z, Wang J, Zhou N, Wang B, Tan K, Fan Y, Cao P. Glycolysis and beyond in glucose metabolism: exploring pulmonary fibrosis at the metabolic crossroads. Front Endocrinol (Lausanne) 2024; 15:1379521. [PMID: 38854692 PMCID: PMC11157045 DOI: 10.3389/fendo.2024.1379521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Accepted: 05/07/2024] [Indexed: 06/11/2024] Open
Abstract
At present, pulmonary fibrosis (PF) is a prevalent and irreversible lung disease with limited treatment options, and idiopathic pulmonary fibrosis (IPF) is one of its most common forms. Recent research has highlighted PF as a metabolic-related disease, including dysregulated iron, mitochondria, lipid, and glucose homeostasis. Systematic reports on the regulatory roles of glucose metabolism in PF are rare. This study explores the intricate relationships and signaling pathways between glucose metabolic processes and PF, delving into how key factors involved in glucose metabolism regulate PF progression, and the interplay between them. Specifically, we examined various enzymes, such as hexokinase (HK), 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), pyruvate kinase (PK), and lactate dehydrogenase (LDH), illustrating their regulatory roles in PF. It highlights the significance of lactate, alongside the role of pyruvate dehydrogenase kinase (PDK) and glucose transporters (GLUTs) in modulating pulmonary fibrosis and glucose metabolism. Additionally, critical regulatory factors such as transforming growth factor-beta (TGF-β), interleukin-1 beta (IL-1β), and hypoxia-inducible factor 1 subunit alpha (HIF-1α) were discussed, demonstrating their impact on both PF and glucose metabolic pathways. It underscores the pivotal role of AMP-activated protein kinase (AMPK) in this interplay, drawing connections between diabetes mellitus, insulin, insulin-like growth factors, and peroxisome proliferator-activated receptor gamma (PPARγ) with PF. This study emphasizes the role of key enzymes, regulators, and glucose transporters in fibrogenesis, suggesting the potential of targeting glucose metabolism for the clinical diagnosis and treatment of PF, and proposing new promising avenues for future research and therapeutic development.
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Affiliation(s)
- Yuejiao Wang
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Hebei Research Center of the Basic Discipline of Cell Biology, Hebei Collaborative Innovation Center for Eco-Environment, Shijiazhuang, Hebei, China
| | - Xue Wang
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Hebei Research Center of the Basic Discipline of Cell Biology, Hebei Collaborative Innovation Center for Eco-Environment, Shijiazhuang, Hebei, China
| | - Chaoqi Du
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Hebei Research Center of the Basic Discipline of Cell Biology, Hebei Collaborative Innovation Center for Eco-Environment, Shijiazhuang, Hebei, China
| | - Zeming Wang
- Department of Laboratory, Hebei Provincial People’s Hospital, Shijiazhuang, Hebei, China
| | - Jiahui Wang
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Hebei Research Center of the Basic Discipline of Cell Biology, Hebei Collaborative Innovation Center for Eco-Environment, Shijiazhuang, Hebei, China
| | - Nan Zhou
- Department of Gynecology, Xingtai People’s Hospital, Xingtai, Hebei, China
| | - Baohua Wang
- Department of Thoracic Surgery, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Ke Tan
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Hebei Research Center of the Basic Discipline of Cell Biology, Hebei Collaborative Innovation Center for Eco-Environment, Shijiazhuang, Hebei, China
| | - Yumei Fan
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Hebei Research Center of the Basic Discipline of Cell Biology, Hebei Collaborative Innovation Center for Eco-Environment, Shijiazhuang, Hebei, China
| | - Pengxiu Cao
- Ministry of Education Key Laboratory of Molecular and Cellular Biology, Hebei Key Laboratory of Animal Physiology, Biochemistry and Molecular Biology, College of Life Sciences, Hebei Normal University, Hebei Research Center of the Basic Discipline of Cell Biology, Hebei Collaborative Innovation Center for Eco-Environment, Shijiazhuang, Hebei, China
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12
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Conlon JM, Owolabi BO, Flatt PR, Abdel-Wahab YHA. Amphibian host-defense peptides with potential for Type 2 diabetes therapy - an updated review. Peptides 2024; 175:171180. [PMID: 38401671 DOI: 10.1016/j.peptides.2024.171180] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Revised: 02/19/2024] [Accepted: 02/20/2024] [Indexed: 02/26/2024]
Abstract
Investigations conducted since 2018 have identified several host-defense peptides present in frog skin secretions whose properties suggest the possibility of their development into a new class of agent for Type 2 diabetes (T2D) therapy. Studies in vitro have described peptides that (a) stimulate insulin release from BRIN-BD11 clonal β-cells and isolated mouse islets, (b) display β-cell proliferative activity and protect against cytokine-mediated apoptosis and (c) stimulate production of the anti-inflammatory cytokine IL-10 and inhibit production of the pro-inflammatory cytokines TNF-α and IL-1β. Rhinophrynin-27, phylloseptin-3.2TR and temporin F are peptides with therapeutic potential. Studies in vivo carried out in db/db and high fat-fed mice have shown that twice-daily administration of [S4K]CPF-AM1 and [A14K]PGLa-AM1, analogs of peptides first isolated from the octoploid frog Xenopus amieti, over 28 days lowers circulating glucose and HbA1c concentrations, increases insulin sensitivity and improves glucose tolerance and lipid profile. Peptide treatment produced potentially beneficial changes in the expression of skeletal muscle genes involved in insulin signaling and islet genes involved in insulin secretion in these murine models of T2D. Lead compounds uncovered by the study of frog HDPs may provide a basis for the design of new types of agents that can be used, alone or in combination with existing therapies, for the treatment of T2D.
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Affiliation(s)
- J Michael Conlon
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK.
| | - Bosede O Owolabi
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Peter R Flatt
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
| | - Yasser H A Abdel-Wahab
- Diabetes Research Centre, School of Biomedical Sciences, Ulster University, Coleraine, Northern Ireland BT52 1SA, UK
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13
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Tylutka A, Walas Ł, Zembron-Lacny A. Level of IL-6, TNF, and IL-1β and age-related diseases: a systematic review and meta-analysis. Front Immunol 2024; 15:1330386. [PMID: 38495887 PMCID: PMC10943692 DOI: 10.3389/fimmu.2024.1330386] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 02/19/2024] [Indexed: 03/19/2024] Open
Abstract
Introduction Chronic low-grade inflammation is an important aspect of morbidity and mortality in older adults. The level of circulating pro-inflammatory cytokines (interleukin (IL)-6, tumor necrosis factor (TNF) or IL-1β) is a risk factor in cardiovascular and neurodegenerative diseases and is also associated with sarcopenia and frailties. The objective of this study was to assess each cytokine: IL-6, TNF, and IL-1β separately in the elderly with comorbidities against controls without diseases according to the data published in the available literature. Methods The electronic bibliographic PubMed database was systematically searched to select all the relevant studies published up to July 2023. The total number of the subjects involved in the meta-analysis included patients with diseases (n=8154) and controls (n=33967). Results The overall concentration of IL-6 was found to be higher in patients with diseases compared to controls and the difference was statistically significant, with a p-value of <0.001 (SMD, 0.16; 95% CI, 0.12-0.19). The heterogeneity was considerable with Q = 109.97 (P <0.0001) and I2 = 79.2%. The potential diagnostic usefulness of IL-6 was confirmed by odds ratio (OR) analysis (OR: 1.03, 95% CI (1.01; 1.05), p=0.0029). The concentration of both TNF and IL-1β was elevated in the control group compared to patients and amounted to SMD -0.03; 95% CI, -0.09-0.02, p-value 0.533 and SMD-0.29; 95% CI, -0.47- -0.12; p = 0.001, respectively. For TNF, however, the difference was statistically insignificant. Discussion IL-6, unlike TNF and IL-1β, could be a useful and convenient marker of peripheral inflammation in older adults with various comorbidities.
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Affiliation(s)
- Anna Tylutka
- Department of Applied and Clinical Physiology, Collegium Medicum University of Zielona Gora, Zielona Gora, Poland
| | - Łukasz Walas
- Institute of Dendrology, Polish Academy of Sciences, Kórnik, Poland
| | - Agnieszka Zembron-Lacny
- Department of Applied and Clinical Physiology, Collegium Medicum University of Zielona Gora, Zielona Gora, Poland
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14
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Zhou X, Chen R, Cai Y, Chen Q. Fecal Microbiota Transplantation: A Prospective Treatment for Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2024; 17:647-659. [PMID: 38347911 PMCID: PMC10860394 DOI: 10.2147/dmso.s447784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 01/23/2024] [Indexed: 02/15/2024] Open
Abstract
Purpose of Review The aim of this review is to summarize the role of gastrointestinal microbiome (GM) in the development of type 2 diabetes mellitus (T2DM). Besides, we discuss the feasibility of applying FMT in the treatment of T2DM and propose a series of processes to refine the use of FMT in the treatment of T2DM. Recent Findings T2DM is a metabolic disease which is connected with the GM. According to many researches, GM can produce a variety of metabolites such as bile acid, short chain fatty acids, lipopolysaccharides and trimethylamine oxide which play an important role in metabolism. FMT is a method to regulate GM and has been observed to be effective in the treatment of metabolic diseases such as T2DM in some mouse models and people. However, there is still a lack of direct evidence for the use of FMT in the treatment of T2DM, and the process of FMT is not standardized. Summary Dysregulation of GM is closely related to the development of T2DM. Promoting the conversion of GM in T2DM patients to normal population through FMT can reduce insulin resistance and lower their blood glucose level, which is an optional treatment for T2DM patients in the future. At present, the feasibility and limitations of applying FMT to the treatment of T2DM need to be further studied.
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Affiliation(s)
- Xiaolan Zhou
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| | - Rumeng Chen
- School of Life Sciences, Beijing University of Chinese Medicine, Beijing, People’s Republic of China
| | - Yichen Cai
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| | - Qiu Chen
- Department of Endocrinology, Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
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15
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Giri P, Parmar M, Ezhuthachan DD, Desai T, Dwivedi M. Promoter polymorphisms of neuropeptide Y, interleukin-1B and increased IL-1β levels are associated with rheumatoid arthritis susceptibility in South Gujarat population. HUMAN GENE 2024; 39:201251. [DOI: 10.1016/j.humgen.2023.201251] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/06/2024]
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Cacic AM, Schulz FI, Germing U, Dietrich S, Gattermann N. Molecular and clinical aspects relevant for counseling individuals with clonal hematopoiesis of indeterminate potential. Front Oncol 2023; 13:1303785. [PMID: 38162500 PMCID: PMC10754976 DOI: 10.3389/fonc.2023.1303785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Accepted: 11/28/2023] [Indexed: 01/03/2024] Open
Abstract
Clonal hematopoiesis of indeterminate potential (CHIP) has fascinated the medical community for some time. Discovered about a decade ago, this phenomenon links age-related alterations in hematopoiesis not only to the later development of hematological malignancies but also to an increased risk of early-onset cardiovascular disease and some other disorders. CHIP is detected in the blood and is characterized by clonally expanded somatic mutations in cancer-associated genes, predisposing to the development of hematologic neoplasms such as MDS and AML. CHIP-associated mutations often involve DNA damage repair genes and are frequently observed following prior cytotoxic cancer therapy. Genetic predisposition seems to be a contributing factor. It came as a surprise that CHIP significantly elevates the risk of myocardial infarction and stroke, and also contributes to heart failure and pulmonary hypertension. Meanwhile, evidence of mutant clonal macrophages in vessel walls and organ parenchyma helps to explain the pathophysiology. Besides aging, there are some risk factors promoting the appearance of CHIP, such as smoking, chronic inflammation, chronic sleep deprivation, and high birth weight. This article describes fundamental aspects of CHIP and explains its association with hematologic malignancies, cardiovascular disorders, and other medical conditions, while also exploring potential progress in the clinical management of affected individuals. While it is important to diagnose conditions that can lead to adverse, but potentially preventable, effects, it is equally important not to stress patients by confronting them with disconcerting findings that cannot be remedied. Individuals with diagnosed or suspected CHIP should receive counseling in a specialized outpatient clinic, where professionals from relevant medical specialties may help them to avoid the development of CHIP-related health problems. Unfortunately, useful treatments and clinical guidelines for managing CHIP are still largely lacking. However, there are some promising approaches regarding the management of cardiovascular disease risk. In the future, strategies aimed at restoration of gene function or inhibition of inflammatory mediators may become an option.
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Affiliation(s)
- Anna Maria Cacic
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Felicitas Isabel Schulz
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Ulrich Germing
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Sascha Dietrich
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - Norbert Gattermann
- Department of Hematology, Oncology and Clinical Immunology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine Universität Düsseldorf, Düsseldorf, Germany
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
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17
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Chen J, Peng L, Sun J, Liu J, Chu L, Yi B, Gui M, Zhang H, Tang J. Upregulation of the protein kinase Lyn is associated with renal injury in type 2 diabetes patients. Ren Fail 2023; 45:2272717. [PMID: 37870491 PMCID: PMC11001359 DOI: 10.1080/0886022x.2023.2272717] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Accepted: 10/14/2023] [Indexed: 10/24/2023] Open
Abstract
BACKGROUND The role of inflammation in the pathogenesis of type 2 diabetes mellitus (T2DM) is well established. Lyn, a member of the nonreceptor protein tyrosine kinase Src family, has been reported to modulate inflammatory signaling pathways. METHODS Lyn expression was assessed in kidney biopsies of 11 patients with diabetic kidney disease (DKD) and in kidney tissues of streptozotocin (STZ)-induced DKD mice. 102 recruited T2DM patients were divided into three groups: normoalbuminuria, microalbuminuria and macroalbuminuria. Twenty-one healthy volunteers were recruited as a control group. Clinical data, blood and urine samples of all individuals were collected for analysis. RESULTS Lyn expression was augmented in the kidneys of DKD patients and STZ-induced diabetic mice. Compared with control and normoalbuminuria groups, both mRNA and protein expression of Lyn in peripheral blood mononuclear cells (PBMCs) in the macroalbuminuria group were significantly increased (p < .05). Elevated Lyn levels were independently related to urine albumin/urine creatinine ratio and were positively associated with key inflammatory factors, namely interleukin-1β, monocyte chemoattractant protein-1, and tumor necrosis factor-α. Additionally, Lyn exhibited a noteworthy connection with renal tubular injury indicators, specifically urinary neutrophil gelatinase-associated lipocalin and urinary retinol binding protein. ROC curve analysis showed that Lyn could predict albuminuria in diabetic patients with an area under the curve of 0.844 (95% CI: 0.764-0.924). CONCLUSION Lyn levels in PBMCs exhibited a positive correlation with the severity of albuminuria, renal tubular damage, and inflammatory responses. Hence, Lyn may be a compelling candidate for predicting albuminuria levels in diabetes.
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Affiliation(s)
- Juan Chen
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China and Clinical Research Center for Critical Kidney Disease in Hunan Province
| | - Lingfeng Peng
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China and Clinical Research Center for Critical Kidney Disease in Hunan Province
| | - Jian Sun
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China and Clinical Research Center for Critical Kidney Disease in Hunan Province
| | - Jishi Liu
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China and Clinical Research Center for Critical Kidney Disease in Hunan Province
| | - Ling Chu
- Department of pathology, The Third Xiangya Hospital, Central South University, Changsha, China
| | - Bin Yi
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China and Clinical Research Center for Critical Kidney Disease in Hunan Province
| | - Ming Gui
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China and Clinical Research Center for Critical Kidney Disease in Hunan Province
| | - Hao Zhang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China and Clinical Research Center for Critical Kidney Disease in Hunan Province
| | - Juan Tang
- Department of Nephrology, The Third Xiangya Hospital, Central South University, Changsha, China and Clinical Research Center for Critical Kidney Disease in Hunan Province
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Syed NA, Bhatti A, John P. Molecular Link between Glo-1 Expression and Markers of Hyperglycemia and Oxidative Stress in Vascular Complications of Type 2 Diabetes Mellitus. Antioxidants (Basel) 2023; 12:1663. [PMID: 37759966 PMCID: PMC10525326 DOI: 10.3390/antiox12091663] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/09/2023] [Accepted: 08/21/2023] [Indexed: 09/29/2023] Open
Abstract
Chronic hyperglycemia and oxidative stress in Type 2 Diabetes Mellitus trigger cellular dysfunction via the formation of Advanced Glycation End Products (AGEs), resulting in dicarbonyl stress. Glyoxalase-1 (Glo-1) is the main defense against dicarbonyl stress. The aim of this study was to explore any cross-talk between Glo-1 and markers of hyperglycemia and oxidative stress. The siRNA-mediated downregulation of Glo-1 was performed in human microvascular endothelial cell line (HMEC-1). A Glo-1 transgenic rat model was developed. Glo-1 activity, as determined spectrophotometrically, and methylglyoxal were quantified using UPLC-MS/MS and the expression of representative markers of hyperglycemia and oxidative stress was performed using quantitative real-time PCR. A significant increase in the expression of Vascular Cell Adhesion Molecule-1 (VCAM-1) was observed in the case of the siRNA-mediated downregulation of Glo-1 in the microvasculature model under hyperglycemic conditions (p-value < 0.001), as well the as overexpression of Glo-1 in the macrovasculature (p-value = 0.0125). The expression of thioredoxin interacting protein (TXNIP) was found to be significantly upregulated in wildtype diabetic conditions vs. Glo-1 transgenic control conditions (p-value = 0.008), whereas the downregulation of Glo-1 had no impact on TXNIP expression. These findings substantiate the role of VCAM as an important marker of dicarbonyl stress (represented by Glo-1 downregulation), as well as of hyperglycemia, in diabetic vascular complications. Our findings also suggest a potential feedback loop that may exist between Glo-1 and TXNIP, as the highest expression of TXNIP is observed in cases of wildtype diabetic conditions, and the lowest expression of TXNIP is observed when Glo-1 transgene is being expressed in absence of dicarbonyl stress.
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Affiliation(s)
- Nida Ali Syed
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, Pakistan; (N.A.S.); (P.J.)
- Department of Internal Medicine, Faculty of Health, Medicine and Life Science, Maastricht University, P.O. Box 616, 6200 MD Maastricht, The Netherlands
| | - Attya Bhatti
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, Pakistan; (N.A.S.); (P.J.)
| | - Peter John
- Department of Healthcare Biotechnology, Atta-ur-Rahman School of Applied Biosciences, National University of Sciences and Technology, Islamabad 44000, Pakistan; (N.A.S.); (P.J.)
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19
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Durrani IA, Bhatti A, John P. Integrated bioinformatics analyses identifying potential biomarkers for type 2 diabetes mellitus and breast cancer: In SIK1-ness and health. PLoS One 2023; 18:e0289839. [PMID: 37556419 PMCID: PMC10411810 DOI: 10.1371/journal.pone.0289839] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 07/23/2023] [Indexed: 08/11/2023] Open
Abstract
The bidirectional causal relationship between type 2 diabetes mellitus (T2DM) and breast cancer (BC) has been established by numerous epidemiological studies. However, the underlying molecular mechanisms are not yet fully understood. Identification of hub genes implicated in T2DM-BC molecular crosstalk may help elucidate on the causative mechanisms. For this, expression series GSE29231 (T2DM-adipose tissue), GSE70905 (BC- breast adenocarcinoma biopsies) and GSE150586 (diabetes and BC breast biopsies) were extracted from Gene Expression Omnibus (GEO) database, and analyzed to obtain differentially expressed genes (DEGs). The overlapping DEGs were determined using FunRich. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and Transcription Factor (TF) analyses were performed on EnrichR software and a protein-protein interaction (PPI) network was constructed using STRING software. The network was analyzed on Cytoscape to determine hub genes and Kaplan-Meier plots were obtained. A total of 94 overlapping DEGs were identified between T2DM and BC samples. These DEGs were mainly enriched for GO terms RNA polymerase II core promoter proximal region sequence and its DNA binding, and cAMP response element binding protein, and KEGG pathways including bladder cancer, thyroid cancer and PI3K-AKT signaling. Eight hub genes were identified: interleukin 6 (IL6), tumor protein 53 (TP53), interleukin 8 (CXCL8), MYC, matrix metalloproteinase 9 (MMP9), beta-catenin 1 (CTNNB1), nitric oxide synthase 3 (NOS3) and interleukin 1 beta (IL1β). MMP9 and MYC associated unfavorably with overall survival (OS) in breast cancer patients, IL6, TP53, IL1β and CTNNB1 associated favorably, whereas NOS3 did not show any correlation with OS. Salt inducible kinase 1 (SIK1) was identified as a significant key DEG for comorbid samples when compared with BC, also dysregulated in T2DM and BC samples (adjusted p <0.05). Furthermore, four of the significant hub genes identified, including IL6, CXCL8, IL1B and MYC were also differentially expressed for comorbid samples, however at p < 0.05. Our study identifies key genes including SIK1, for comorbid state and 8 hub genes that may be implicated in T2DM-BC crosstalk. However, limitations associated with the insilico nature of this study necessitates for subsequent validation in wet lab. Hence, further investigation is crucial to study the molecular mechanisms of action underlying these genes to fully explore their potential as diagnostic and prognostic biomarkers and therapeutic targets for T2DM-BC association.
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Affiliation(s)
- Ilhaam Ayaz Durrani
- Department of Healthcare Biotechnology, Atta ur Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H12, Islamabad, Islamabad Capital Territory, Pakistan
| | - Attya Bhatti
- Department of Healthcare Biotechnology, Atta ur Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H12, Islamabad, Islamabad Capital Territory, Pakistan
| | - Peter John
- Department of Healthcare Biotechnology, Atta ur Rehman School of Applied Biosciences (ASAB), National University of Sciences and Technology (NUST), H12, Islamabad, Islamabad Capital Territory, Pakistan
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20
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Cinti S. Obese Adipocytes Have Altered Redox Homeostasis with Metabolic Consequences. Antioxidants (Basel) 2023; 12:1449. [PMID: 37507987 PMCID: PMC10376822 DOI: 10.3390/antiox12071449] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/14/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
White and brown adipose tissues are organized to form a real organ, the adipose organ, in mice and humans. White adipocytes of obese animals and humans are hypertrophic. This condition is accompanied by a series of organelle alterations and stress of the endoplasmic reticulum. This stress is mainly due to reactive oxygen species activity and accumulation, lending to NLRP3 inflammasome activation. This last causes death of adipocytes by pyroptosis and the formation of large cellular debris that must be removed by macrophages. During their chronic scavenging activity, macrophages produce several secretory products that have collateral consequences, including interference with insulin receptor activity, causing insulin resistance. The latter is accompanied by an increased noradrenergic inhibitory innervation of Langerhans islets with de-differentiation of beta cells and type 2 diabetes. The whitening of brown adipocytes could explain the different critical death size of visceral adipocytes and offer an explanation for the worse clinical consequence of visceral fat accumulation. White to brown transdifferentiation has been proven in mice and humans. Considering the energy-dispersing activity of brown adipose tissue, transdifferentiation opens new therapeutic perspectives for obesity and related disorders.
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Affiliation(s)
- Saverio Cinti
- Scientific Director Centre of Obesity, Marche Polytechnic University, Via Tronto 10a, 60126 Ancona, Italy
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21
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Abduh MS, Alzoghaibi MA, Alzoghaibi AM, Bin-Ammar A, Alotaibi MF, Kamel EM, Mahmoud AM. Arbutin ameliorates hyperglycemia, dyslipidemia and oxidative stress and modulates adipocytokines and PPARγ in high-fat diet/streptozotocin-induced diabetic rats. Life Sci 2023; 321:121612. [PMID: 36948387 DOI: 10.1016/j.lfs.2023.121612] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2023] [Revised: 03/16/2023] [Accepted: 03/17/2023] [Indexed: 03/24/2023]
Abstract
Arbutin is a glycosylated hydroquinone with antioxidant and anti-hyperglycemia effects. However, its beneficial effects in type 2 diabetes (T2D) were not clarified. This study evaluated the effect of arbutin on hyperglycemia, dyslipidemia, insulin resistance, oxidative stress, and inflammatory response in T2D. Rats induced by high fat diet and streptozotocin were treated with arbutin (25 and 50 mg/kg for 4 weeks). Diabetic rats exhibited glucose intolerance, elevated HbA1c%, reduced insulin, and high HOMA-IR. Liver glycogen and hexokinase activity were decreased in T2D rats while glucose-6-phosphatase (G6Pase), fructose-1,6- biphosphatase (FBPase), and glycogen phosphorylase were upregulated. Circulating and hepatic cholesterol and triglycerides and serum transaminases were elevated in T2D rats. Arbutin ameliorated hyperglycemia, dyslipidemia, insulin deficiency and resistance, and liver glycogen and alleviated the activity of carbohydrate-metabolizing enzymes. Both doses of arbutin decreased serum transaminases and resistin, and liver lipids, TNF-α, IL-6, malondialdehyde and nitric oxide, downregulated liver resistin and fatty acid synthase, and increased serum and liver adiponectin, and liver reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). These effects were associated with the upregulation of hepatic PPARγ. Arbutin inhibited α-glucosidase in vitro and in silico investigations revealed the ability of arbutin to bind PPARγ, hexokinase, and α-glucosidase. In conclusion, arbutin effectively ameliorated glucose intolerance, insulin resistance, dyslipidemia, inflammation, and oxidative stress, and modulated carbohydrate-metabolizing enzymes, antioxidants, adipokines and PPARγ in T2D in rats.
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Affiliation(s)
- Maisa Siddiq Abduh
- Immune Responses in Different Diseases Research Group, Department of Medical Laboratory Sciences, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah 21589, Saudi Arabia; Center of Excellence in Genomic Medicine Research, King Abdulaziz University, Jeddah 22252, Saudi Arabia
| | - Mohammed A Alzoghaibi
- Physiology Department, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | | | - Albandari Bin-Ammar
- Department of Clinical Nutrition, College of Applied Medical Sciences, University of Hail, Saudi Arabia
| | - Mohammed F Alotaibi
- Physiology Department, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia
| | - Emadeldin M Kamel
- Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt
| | - Ayman M Mahmoud
- Department of Life Sciences, Faculty of Science and Engineering, Manchester Metropolitan University, Manchester M1 5GD, UK; Physiology Division, Department of Zoology, Faculty of Science, Beni-Suef University, Beni-Suef 62514, Egypt.
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22
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Li D, Zhong J, Zhang Q, Zhang J. Effects of anti-inflammatory therapies on glycemic control in type 2 diabetes mellitus. Front Immunol 2023; 14:1125116. [PMID: 36936906 PMCID: PMC10014557 DOI: 10.3389/fimmu.2023.1125116] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Accepted: 02/15/2023] [Indexed: 03/05/2023] Open
Abstract
Background The overall evidence base of anti-inflammatory therapies in patients with type 2 diabetes mellitus (T2DM) has not been systematically evaluated. The purpose of this study was to assess the effects of anti-inflammatory therapies on glycemic control in patients with T2DM. Methods PubMed, Embase, Web of Science, and Cochrane Library were searched up to 21 September 2022 for randomized controlled trials (RCTs) with anti-inflammatory therapies targeting the proinflammatory cytokines, cytokine receptors, and inflammation-associated nuclear transcription factors in the pathogenic processes of diabetes, such as interleukin-1β (IL-1β), interleukin-1β receptor (IL-1βR), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB). We synthesized data using mean difference (MD) and 95% confidence interval (CI). Heterogeneity between studies was assessed by I2 tests. Sensitivity and subgroup analyses were also conducted. Results We included 16 RCTs comprising 3729 subjects in the meta-analyses. Anti-inflammatory therapies can significantly reduce the level of fasting plasma glucose (FPG) (MD = - 10.04; 95% CI: -17.69, - 2.40; P = 0.01), glycated haemoglobin (HbA1c) (MD = - 0.37; 95% CI: - 0.51, - 0.23; P < 0.00001), and C-reactive protein (CRP) (MD = - 1.05; 95% CI: - 1.50, - 0.60; P < 0.00001) compared with control, and therapies targeting IL-1β in combination with TNF-α have better effects on T2DM than targeting IL-1β or TNF-α alone. Subgroup analyses suggested that patients with short duration of T2DM may benefit more from anti-inflammatory therapies. Conclusion Our meta-analyses indicate that anti-inflammatory therapies targeting the pathogenic processes of diabetes can significantly reduce the level of FPG, HbA1c, and CRP in patients with T2DM.
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Affiliation(s)
- Dandan Li
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jiaxin Zhong
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Qirui Zhang
- Department of General Surgery, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jingjing Zhang
- National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, Key Laboratory of Diabetes Immunology, Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, Hunan, China
- *Correspondence: Jingjing Zhang,
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23
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Wang P, Qian H, Xiao M, Lv J. Role of signal transduction pathways in IL-1β-induced apoptosis: Pathological and therapeutic aspects. Immun Inflamm Dis 2023; 11:e762. [PMID: 36705417 PMCID: PMC9837938 DOI: 10.1002/iid3.762] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 12/20/2022] [Accepted: 12/27/2022] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND Interleukin-1β (IL-1β) is a pro-inflammatory cytokine mainly produced by monocytes and macrophages with a wide range of biological effects. Evidence has shown that IL-1β plays a vital role in the process of apoptosis; however, the specific mechanisms, by which IL-1β induces apoptosis, vary due to different cellular and experimental conditions. Therefore, this present reviewstudy aimed to systematically review the association between the molecular mechanisms of IL-1β-induced apoptosis in pathological processes and the role of signaling pathways. This article also sought to briefly investigate the potential of signaling pathway-targeted therapy in the prevention and treatment of disease. METHODS This is a literature review article. The present discourse aim is first to scrutinize and assess the available literature on IL-1β and apoptosis. The relevant studies using the keywords of "IL-1β-induced apoptosis" and "signaling pathways" were searched in the databases of PubMed, Scopus, Google Scholar, and Web of Science. Gathered relevant material, and extracted information was then assessed. RESULTS IL-1β can induce apoptosis in various types of cells under different external stimuli via the mitochondrial pathway, death receptor pathway and endoplasmic reticulum pathway, and that the different pathways are often interconnected. The NF-kB signaling pathway, p38MAPK, and JNK signaling pathways mainly play a proapoptotic part, and the ERK1/2 pathway has a bidirectional role in regulating apoptosis, while activation of the PI3K-Akt signaling pathway can inhibit apoptosis. CONCLUSION This review indicates that IL-1β-induced apoptosis plays an important role in pathogenesis and development of pathology of many inflammatory diseases. Elucidating the role of the signaling pathways will aid the development of targeted therapeutic treatments.
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Affiliation(s)
- Peixuan Wang
- Department of Pediatric Dentistry, Stomatological HospitalSouthern Medical UniversityGuangzhouChina
| | - Hong Qian
- Department of Pediatric Dentistry, Stomatological HospitalSouthern Medical UniversityGuangzhouChina
| | - Manxue Xiao
- Department of Pediatric Dentistry, Stomatological HospitalSouthern Medical UniversityGuangzhouChina
| | - Jingwen Lv
- Department of Pediatric Dentistry, Stomatological HospitalSouthern Medical UniversityGuangzhouChina
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24
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Chook CYB, Cheung YM, Ma KY, Leung FP, Zhu H, Niu QJ, Wong WT, Chen ZY. Physiological concentration of protocatechuic acid directly protects vascular endothelial function against inflammation in diabetes through Akt/eNOS pathway. Front Nutr 2023; 10:1060226. [PMID: 37025617 PMCID: PMC10070727 DOI: 10.3389/fnut.2023.1060226] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 03/06/2023] [Indexed: 04/08/2023] Open
Abstract
Background Cardiovascular diseases (CVDs) have been the major cause of mortality in type 2 diabetes. However, new approaches are still warranted since current diabetic medications, which focus mainly on glycemic control, do not effectively lower cardiovascular mortality rate in diabetic patients. Protocatechuic acid (PCA) is a phenolic acid widely distributed in garlic, onion, cauliflower and other plant-based foods. Given the anti-oxidative effects of PCA in vitro, we hypothesized that PCA would also have direct beneficial effects on endothelial function in addition to the systemic effects on vascular health demonstrated by previous studies. Methods and results Since IL-1β is the major pathological contributor to endothelial dysfunction in diabetes, the anti-inflammatory effects of PCA specific on endothelial cells were further verified by the use of IL-1β-induced inflammation model. Direct incubation of db/db mouse aortas with physiological concentration of PCA significantly ameliorated endothelium-dependent relaxation impairment, as well as reactive oxygen species overproduction mediated by diabetes. In addition to the well-studied anti-oxidative activity, PCA demonstrated strong anti-inflammatory effects by suppressing the pro-inflammatory cytokines MCP1, VCAM1 and ICAM1, as well as increasing the phosphorylation of eNOS and Akt in the inflammatory endothelial cell model induced by the key player in diabetic endothelial dysfunction IL-1β. Upon blocking of Akt phosphorylation, p-eNOS/eNOS remained low and the inhibition of pro-inflammatory cytokines by PCA ceased. Conclusion PCA exerts protection on vascular endothelial function against inflammation through Akt/eNOS pathway, suggesting daily acquisition of PCA may be encouraged for diabetic patients.
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Affiliation(s)
- Chui Yiu Bamboo Chook
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yiu Ming Cheung
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Ka Ying Ma
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Fung Ping Leung
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Hanyue Zhu
- School of Food Science and Engineering, Foshan University, Foshan, Guangdong, China
| | - Qingshan Jason Niu
- Institute for Advanced Study, Shenzhen University, Shenzhen, Guangdong, China
| | - Wing Tak Wong
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- *Correspondence: Wing Tak Wong,
| | - Zhen-Yu Chen
- School of Life Sciences, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Zhen-Yu Chen,
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25
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UPLC-ESI-QTOF-MS Profiling of Phenolic Compounds from Eriocephalus africanus: In Vitro Antioxidant, Antidiabetic, and Anti-Inflammatory Potentials. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27248912. [PMID: 36558046 PMCID: PMC9782900 DOI: 10.3390/molecules27248912] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 12/08/2022] [Accepted: 12/11/2022] [Indexed: 12/23/2022]
Abstract
The present study investigated phenolic compounds, antioxidant, antidiabetic, and the anti-inflammatory potentials of methanolic and chloroform extracts of Eriocephalus africanus. The methanolic extract included, polyphenols (112 ± 2.81 mg gallic acid equivalent (GAE)/g), flavonols (76.12 ± 7.95 mg quercetin equivalents (QE)/g); antioxidant capacity (Ferric Reducing Antioxidant Power (FRAP) (752.64 ± 89.0 μmol of ascorbic acid equivalents (AAE) per g dry weight (µmol AAE/g), 2,2-dyphenyl-1-picrylhydrazyl (DPPH) (812.18 ± 51.12 Trolox equivalents per gram of dry mass of plant extracts (μmol TE/g), TEAC (631.63 ± 17.42 µmol TE/g)), while the chloroform extract included polyphenols (39.93 ± 1.36 mg GAE/g), flavonols (44.81 ± 3.74 mg QE/g); antioxidant capacity, DPPH (58.70 ± 5.18 µmol TE/g), TEAC (118.63 ± 3.74 µmol TE/g) and FRAP (107.10 ± 2.41 µmol AAE/g). The phytochemicals profiling performed by UPLC-ESI-QTOF-MS revealed some important polyphenols, predominantly flavonoids, that could be responsible for the antioxidant capacity and biological effects. Both extracts demonstrated a dose-dependent manner of the alpha-glucosidase inhibition with an IC50 between 125 and 250 μg/mL for methanolic extract, while the chloroform extract was at 250 μg/mL. In the L6 myoblasts and C3A hepatocytes, the methanolic extract slightly increased the utilization of glucose, and both extracts exhibited a dose-dependent increase in the glucose uptake in both cell types without significantly increasing the cytotoxicity. Furthermore, both extracts exhibited an anti-inflammatory potential and the findings from the present study could serve as a baseline for further research in the development of pharmaceutical agents.
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26
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Liu X, Liu Y, Wu H, He Z, Li Z, Qin Z, Yu J, Zhu L, Wu Q, Xiao W, Shen C, Wan C, Zhang B, Zhao W. Murine diabetic models for dengue virus infection. J Med Virol 2022; 94:5943-5953. [PMID: 36000451 DOI: 10.1002/jmv.28088] [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: 06/20/2022] [Revised: 07/26/2022] [Accepted: 08/16/2022] [Indexed: 01/06/2023]
Abstract
Dengue virus (DENV) is a critical public health concern in tropical and subtropical regions worldwide. Thus, immunocompetent murine models of DENV infection with robust viremia are required for vaccine studies. Diabetes is highly prevalent worldwide, making it frequent comorbidity in patients with dengue fever. Therefore, murine models are needed to understand viral pathogenesis and disease progression. Acquired-induced and inherently diabetic C57BL/6 and db/db mice were inoculated with DENV-3 via the tail vein. After infection, both the diabetic C57BL/6 and db/db mice showed obvious weight loss with clinical manifestations. Quantitative reverse-transcription polymerase chain reaction revealed robust and replicable viremia in the two types of diabetic mice. Immunohistochemical detection showed persistent DENV-3 infection in the liver. Enzyme-linked immunosorbent assay for cytokine detection revealed that diabetic mice showed more severe inflammatory responses than did nondiabetic mice, and significant histological alterations were observed in diabetic mice. Thus, the diabetic mice were more susceptible to DENV infection than the nondiabetic mice. Taken together, we established two types of immunocompetent diabetic mice for DENV infection, which can be used to further study the mechanisms of dengue pathogenesis in diabetes and to develop antiviral pharmaceuticals and treatments.
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Affiliation(s)
- Xuling Liu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Yingfang Liu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Hao Wu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Zihan He
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Zhuoyun Li
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Zhiran Qin
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Jianhai Yu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Li Zhu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Qinghua Wu
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Weiwei Xiao
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Chenguang Shen
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Chengsong Wan
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Bao Zhang
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
| | - Wei Zhao
- BSL-3 Laboratory (Guangdong), Guangdong Provincial Key Laboratory of Tropical Disease Research, School of Public Health, Southern Medical University, Guangzhou, People's Republic of China
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Alharbi HF, Algonaiman R, Alduwayghiri R, Aljutaily T, Algheshairy RM, Almutairi AS, Alharbi RM, Alfurayh LA, Alshahwan AA, Alsadun AF, Barakat H. Exposure to Bisphenol A Substitutes, Bisphenol S and Bisphenol F, and Its Association with Developing Obesity and Diabetes Mellitus: A Narrative Review. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2022; 19:15918. [PMID: 36497992 PMCID: PMC9736995 DOI: 10.3390/ijerph192315918] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/06/2022] [Accepted: 11/21/2022] [Indexed: 05/14/2023]
Abstract
Bisphenol A, a well-known endocrine-disrupting chemical, has been replaced with its analogs bisphenol S (BPS) and bisphenol F (BPF) over the last decade due to health concerns. BPS and BPF are present in relatively high concentrations in different products, such as food products, personal care products, and sales receipts. Both BPS and BPF have similar structural and chemical properties to BPA; therefore, considerable scientific efforts have investigated the safety of their exposure. In this review, we summarize the findings of relevant epidemiological studies investigating the association between urinary concentrations of BPS and/or BPF with the incidence of obesity or diabetes. The results showed that BPS and BPF were detected in many urinary samples at median concentrations ranging from 0.03 to 0.4 µg·L-1. At this exposure level, BPS median urinary concentrations (0.4 µg·L-1) were associated with the development of obesity. At a lower exposure level (0.1-0.03 µg·L-1), two studies showed an association with developing diabetes. For BPF exposure, only one study showed an association with obesity. However, most of the reported studies only assessed BPS exposure levels. Furthermore, we also summarize the findings of experimental studies in vivo and in vitro regarding our aim; results support the possible obesogenic effects/metabolic disorders mediated by BPS and/or BPF exposure. Unexpectedly, BPS may promote worse obesogenic effects than BPA. In addition, the possible mode of action underlying the obesogenic effects of BPS might be attributed to various pathophysiological mechanisms, including estrogenic or androgenic activities, alterations in the gene expression of critical adipogenesis-related markers, and induction of oxidative stress and an inflammatory state. Furthermore, susceptibility to the adverse effects of BPS may be altered by sex differences according to the results of both epidemiological and experimental studies. However, the possible mode of action underlying these sex differences is still unclear. In conclusion, exposure to BPS or BPF may promote the development of obesity and diabetes. Future approaches are highly needed to assess the safety of BPS and BPF regarding their potential effects in promoting metabolic disturbances. Other studies in different populations and settings are highly suggested.
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Affiliation(s)
- Hend F. Alharbi
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Raya Algonaiman
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Rana Alduwayghiri
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Thamer Aljutaily
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Reham M. Algheshairy
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Abdulkarim S. Almutairi
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Razan M. Alharbi
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Leena A. Alfurayh
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Amjad A. Alshahwan
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Amjad F. Alsadun
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
| | - Hassan Barakat
- Department of Food Science and Human Nutrition, College of Agriculture and Veterinary Medicine, Qassim University, Buraydah 51452, Saudi Arabia
- Department of Food Technology, Faculty of Agriculture, Benha University, Moshtohor 13736, Egypt
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28
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Tran DT, Pottekat A, Lee K, Raghunathan M, Loguercio S, Mir SA, Paton AW, Paton JC, Arvan P, Kaufman RJ, Itkin-Ansari P. Inflammatory Cytokines Rewire the Proinsulin Interaction Network in Human Islets. J Clin Endocrinol Metab 2022; 107:3100-3110. [PMID: 36017587 PMCID: PMC10233482 DOI: 10.1210/clinem/dgac493] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Indexed: 01/19/2023]
Abstract
CONTEXT Aberrant biosynthesis and secretion of the insulin precursor proinsulin occurs in both type I and type II diabetes. Inflammatory cytokines are implicated in pancreatic islet stress and dysfunction in both forms of diabetes, but the mechanisms remain unclear. OBJECTIVE We sought to determine the effect of the diabetes-associated cytokines on proinsulin folding, trafficking, secretion, and β-cell function. METHODS Human islets were treated with interleukin-1β and interferon-γ for 48 hours, followed by analysis of interleukin-6, nitrite, proinsulin and insulin release, RNA sequencing, and unbiased profiling of the proinsulin interactome by affinity purification-mass spectrometry. RESULTS Cytokine treatment induced secretion of interleukin-6, nitrites, and insulin, as well as aberrant release of proinsulin. RNA sequencing showed that cytokines upregulated genes involved in endoplasmic reticulum stress, and, consistent with this, affinity purification-mass spectrometry revealed cytokine induced proinsulin binding to multiple endoplasmic reticulum chaperones and oxidoreductases. Moreover, increased binding to the chaperone immunoglobulin binding protein was required to maintain proper proinsulin folding in the inflammatory environment. Cytokines also regulated novel interactions between proinsulin and type 1 and type 2 diabetes genome-wide association studies candidate proteins not previously known to interact with proinsulin (eg, Ataxin-2). Finally, cytokines induced proinsulin interactions with a cluster of microtubule motor proteins and chemical destabilization of microtubules with Nocodazole exacerbated cytokine induced proinsulin secretion. CONCLUSION Together, the data shed new light on mechanisms by which diabetes-associated cytokines dysregulate β-cell function. For the first time, we show that even short-term exposure to an inflammatory environment reshapes proinsulin interactions with critical chaperones and regulators of the secretory pathway.
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Affiliation(s)
- Duc T Tran
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- Plexium, San Diego, CA, USA
| | - Anita Pottekat
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- Illumina, San Diego, CA, USA
| | - Kouta Lee
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | - Megha Raghunathan
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
| | | | - Saiful A Mir
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
- University of Calcutta, West Bengal, India
| | | | | | - Peter Arvan
- University of Michigan Medical School, Ann Arbor, MI, USA
| | - Randal J Kaufman
- Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA
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High Endogenously Synthesized N-3 Polyunsaturated Fatty Acids in Fat-1 Mice Attenuate High-Fat Diet-Induced Insulin Resistance by Inhibiting NLRP3 Inflammasome Activation via Akt/GSK-3β/TXNIP Pathway. Molecules 2022; 27:molecules27196384. [PMID: 36234919 PMCID: PMC9570616 DOI: 10.3390/molecules27196384] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 09/14/2022] [Accepted: 09/21/2022] [Indexed: 01/15/2023] Open
Abstract
High-fat (HF) diets and low-grade chronic inflammation contribute to the development of insulin resistance and type 2 diabetes (T2D), whereas n-3 polyunsaturated fatty acids (PUFAs), due to their anti-inflammatory effects, protect against insulin resistance. Interleukin (IL)-1β is implicated in insulin resistance, yet how n-3 PUFAs modulate IL-1β secretion and attenuate HF diet-induced insulin resistance remains elusive. In this study, a HF diet activated NLRP3 inflammasome via inducing reactive oxygen species (ROS) generation and promoted IL-1β production primarily from adipose tissue preadipocytes, but not from adipocytes and induced insulin resistance in wild type (WT) mice. Interestingly, endogenous synthesized n-3 polyunsaturated fatty acids (PUFAs) reversed this process in HF diet-fed fat-1 transgenic mice although the HF diet induced higher weight gain in fat-1 mice, compared with the control diet. Mechanistically, palmitic acid (PA), the main saturated fatty acid in an HF diet inactivated AMPK and led to decreased GSK-3β phosphorylation, at least partially through reducing Akt activity, which ultimately blocked the Nrf2/Trx1 antioxidant pathway and induced TXNIP cytoplasm translocation and NLRP3 inflammasome activation, whereas docosahexaenoic acid (DHA), the most abundant n-3 PUFA in fat-1 adipose tissue, reversed this process via inducing Akt activation. Our GSK-3β shRNA knockdown study further revealed that GSK-3β played a pivot role between the upstream AMPK/Akt pathway and downstream Nrf2/Trx1/TXNIP pathway. Given that NLRP3 inflammasome is implicated in the development of most inflammatory diseases, our results suggest the potential of n-3 PUFAs in the prevention or adjuvant treatment of NLRP3 inflammasome-driven diseases.
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Effects of adrenergic-stimulated lipolysis and cytokine production on in vitro mouse adipose tissue-islet interactions. Sci Rep 2022; 12:15831. [PMID: 36138030 PMCID: PMC9499973 DOI: 10.1038/s41598-022-18262-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2022] [Accepted: 08/08/2022] [Indexed: 11/08/2022] Open
Abstract
Inflammatory cytokines and non-esterified fatty acids (NEFAs) are obesity-linked factors that disturb insulin secretion. The aim of this study was to investigate whether pancreatic adipose tissue (pWAT) is able to generate a NEFA/cytokine overload within the pancreatic environment and as consequence to impact on insulin secretion. Pancreatic fat is a minor fat depot, therefore we used high-fat diet (HFD) feeding to induce pancreatic steatosis in mice. Relative Adipoq and Lep mRNA levels were higher in pWAT of HFD compared to chow diet mice. Regardless of HFD, Adipoq and Lep mRNA levels of pWAT were at least 10-times lower than those of epididymal fat (eWAT). Lipolysis stimulating receptors Adrb3 and Npr1 were expressed in pWAT and eWAT, and HFD reduced their expression in eWAT only. In accordance, HFD impaired lipolysis in eWAT but not in pWAT. Despite expression of Npr mRNA, lipolysis was stimulated solely by the adrenergic agonists, isoproterenol and adrenaline. Short term co-incubation of islets with CD/HFD pWAT did not alter insulin secretion. In the presence of CD/HFD eWAT, glucose stimulated insulin secretion only upon isoproterenol-induced lipolysis, i.e. in the presence of elevated NEFA. Isoproterenol augmented Il1b and Il6 mRNA levels both in pWAT and eWAT. These results suggest that an increased sympathetic activity enhances NEFA and cytokine load of the adipose microenvironment, including that of pancreatic fat, and by doing so it may alter beta-cell function.
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Liu Y, Liu X, Zhou W, Zhang J, Wu J, Guo S, Jia S, Wang H, Li J, Tan Y. Integrated bioinformatics analysis reveals potential mechanisms associated with intestinal flora intervention in nonalcoholic fatty liver disease. Medicine (Baltimore) 2022; 101:e30184. [PMID: 36086766 PMCID: PMC10980383 DOI: 10.1097/md.0000000000030184] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 07/07/2022] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND Nonalcoholic fatty liver disease (NAFLD) is a common chronic liver disease that imposes a huge economic burden on global public health. And the gut-liver axis theory supports the therapeutic role of intestinal flora in the development and progression of NAFLD. To this end, we designed bioinformatics study on the relationship between intestinal flora disorder and NAFLD, to explore the possible molecular mechanism of intestinal flora interfering with NAFLD. METHODS Differentially expressed genes for NAFLD were obtained from the GEO database. And the disease genes for NAFLD and intestinal flora disorder were obtained from the disease databases. The protein-protein interaction network was established by string 11.0 database and visualized by Cytoscape 3.7.2 software. Cytoscape plug-in MCODE and cytoHubba were used to screen the potential genes of intestinal flora disorder and NAFLD, to obtain potential targets for intestinal flora to interfere in the occurrence and process of NAFLD. Enrichment analysis of potential targets was carried out using R 4.0.2 software. RESULTS The results showed that 7 targets might be the key genes for intestinal flora to interfere with NAFLD. CCL2, IL6, IL1B, and FOS are mainly related to the occurrence and development mechanism of NAFLD, while PTGS2, SPINK1, and C5AR1 are mainly related to the intervention of intestinal flora in the occurrence and development of NAFLD. The gene function is mainly reflected in basic biological processes, including the regulation of metabolic process, epithelial development, and immune influence. The pathway is mainly related to signal transduction, immune regulation, and physiological metabolism. The TNF signaling pathway, AGE-RAGE signaling pathway in diabetic activity, and NF-Kappa B signaling pathways are important pathways for intestinal flora to interfere with NAFLD. According to the analysis results, there is a certain correlation between intestinal flora disorder and NAFLD. CONCLUSION It is speculated that the mechanism by which intestinal flora may interfere with the occurrence and development of NAFLD is mainly related to inflammatory response and insulin resistance. Nevertheless, further research is needed to explore the specific molecular mechanisms.
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Affiliation(s)
- Yingying Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Xinkui Liu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Wei Zhou
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jingyuan Zhang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jiarui Wu
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Siyu Guo
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Shanshan Jia
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Haojia Wang
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Jialin Li
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
| | - Yingying Tan
- Department of Clinical Chinese Pharmacy, School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, China
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Jun T, Mathew D, Sharma N, Nirenberg S, Huang HH, Kovatch P, Wherry EJ, Huang KL. Multiethnic Investigation of Risk and Immune Determinants of COVID-19 Outcomes. Front Cell Infect Microbiol 2022; 12:933190. [PMID: 35942057 PMCID: PMC9355800 DOI: 10.3389/fcimb.2022.933190] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 06/20/2022] [Indexed: 12/15/2022] Open
Abstract
Background Disparate COVID-19 outcomes have been observed between Hispanic, non-Hispanic Black, and White patients. The underlying causes for these disparities are not fully understood. Methods This was a retrospective study utilizing electronic medical record data from five hospitals within a single academic health system based in New York City. Multivariable logistic regression models were used to identify demographic, clinical, and lab values associated with in-hospital mortality. Results A total of 3,086 adult patients with self-reported race/ethnicity information presenting to the emergency department and hospitalized with COVID-19 up to April 13, 2020, were included in this study. While older age (multivariable odds ratio (OR) 1.06, 95% CI 1.05–1.07) and baseline hypoxia (multivariable OR 2.71, 95% CI 2.17–3.36) were associated with increased mortality overall and across all races/ethnicities, non-Hispanic Black (median age 67, interquartile range (IQR) 58–76) and Hispanic (median age 63, IQR 50–74) patients were younger and had different comorbidity profiles as compared to non-Hispanic White patients (median age 73, IQR 62–84; p < 0.05 for both comparisons). Among inflammatory markers associated with COVID-19 mortality, there was a significant interaction between the non-Hispanic Black population and interleukin-1-beta (interaction p-value 0.04). Conclusions This analysis of a multiethnic cohort highlights the need for inclusion and consideration of diverse populations in ongoing COVID-19 trials targeting inflammatory cytokines.
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Affiliation(s)
- Tomi Jun
- Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Divij Mathew
- Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Navya Sharma
- University of California, Santa Barbara, Santa Barbara, CA, United States
| | - Sharon Nirenberg
- Scientific Computing, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Hsin-Hui Huang
- Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Patricia Kovatch
- Scientific Computing, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Edward John Wherry
- Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
- Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
| | - Kuan-lin Huang
- Department of Genetics and Genomic Sciences, Center for Transformative Disease Modeling, Tisch Cancer Institute, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
- *Correspondence: Kuan-lin Huang,
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Overview of Transcriptomic Research on Type 2 Diabetes: Challenges and Perspectives. Genes (Basel) 2022; 13:genes13071176. [PMID: 35885959 PMCID: PMC9319211 DOI: 10.3390/genes13071176] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Revised: 06/24/2022] [Accepted: 06/28/2022] [Indexed: 02/04/2023] Open
Abstract
Type 2 diabetes (T2D) is a common chronic disease whose etiology is known to have a strong genetic component. Standard genetic approaches, although allowing for the detection of a number of gene variants associated with the disease as well as differentially expressed genes, cannot fully explain the hereditary factor in T2D. The explosive growth in the genomic sequencing technologies over the last decades provided an exceptional impetus for transcriptomic studies and new approaches to gene expression measurement, such as RNA-sequencing (RNA-seq) and single-cell technologies. The transcriptomic analysis has the potential to find new biomarkers to identify risk groups for developing T2D and its microvascular and macrovascular complications, which will significantly affect the strategies for early diagnosis, treatment, and preventing the development of complications. In this article, we focused on transcriptomic studies conducted using expression arrays, RNA-seq, and single-cell sequencing to highlight recent findings related to T2D and challenges associated with transcriptome experiments.
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Blevins HM, Xu Y, Biby S, Zhang S. The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases. Front Aging Neurosci 2022; 14:879021. [PMID: 35754962 PMCID: PMC9226403 DOI: 10.3389/fnagi.2022.879021] [Citation(s) in RCA: 183] [Impact Index Per Article: 61.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 05/12/2022] [Indexed: 12/24/2022] Open
Abstract
The NLRP3 inflammasome is a multiprotein complex that plays a pivotal role in regulating the innate immune system and inflammatory signaling. Upon activation by PAMPs and DAMPs, NLRP3 oligomerizes and activates caspase-1 which initiates the processing and release of pro-inflammatory cytokines IL-1β and IL-18. NLRP3 is the most extensively studied inflammasome to date due to its array of activators and aberrant activation in several inflammatory diseases. Studies using small molecules and biologics targeting the NLRP3 inflammasome pathway have shown positive outcomes in treating various disease pathologies by blocking chronic inflammation. In this review, we discuss the recent advances in understanding the NLRP3 mechanism, its role in disease pathology, and provide a broad review of therapeutics discovered to target the NLRP3 pathway and their challenges.
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Affiliation(s)
| | | | | | - Shijun Zhang
- Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, United States
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Haring B, Wissel S, Manson JE. Somatic Mutations and Clonal Hematopoiesis as Drivers of Age-Related Cardiovascular Risk. Curr Cardiol Rep 2022; 24:1049-1058. [PMID: 35657494 PMCID: PMC9329391 DOI: 10.1007/s11886-022-01724-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/17/2022] [Indexed: 12/01/2022]
Abstract
Purpose of Review Clonal hematopoiesis of indeterminate potential (CHIP) has been identified as a novel cardiovascular risk factor. Here we review the relationship of lifestyle and environmental risk factors predisposing to somatic mutations and CHIP and provide an overview on age-related cardiovascular outcomes. Recent Findings CHIP has been associated with accelerated atherosclerosis and cardiovascular disease in both epidemiological and experimental studies. The most commonly mutated candidate driver genes are DNMT3A, TET2, JAK2, and ASXL1. The underlying mechanisms appear predominantly related to inflammatory pathways. Although age is the dominant risk factor for developing CHIP, emerging evidence suggests that other factors such as smoking, obesity/type 2 diabetes, or an unhealthy diet play a role in the occurrence of somatic mutations. Summary Evidence suggests a strong link between vascular risk factors, somatic hematopoietic mutations, and age-related cardiovascular disease. Further studies on CHIP biology are required to identify targeted interventions for risk reduction in patients with CHIP and inform the utility of screening strategies.
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Affiliation(s)
- Bernhard Haring
- Department of Medicine III, Saarland University Hospital, Homburg, Saarland, Germany. .,Department of Medicine I, University of Würzburg, Würzburg, Bavaria, Germany. .,Department of Epidemiology and Population Health, Albert Einstein College of Medicine, Bronx, NY, USA.
| | - Stephanie Wissel
- Department of Medicine I, University of Würzburg, Würzburg, Bavaria, Germany
| | - JoAnn E Manson
- Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.,Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA
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Boi R, Ebefors K, Henricsson M, Borén J, Nyström J. Modified lipid metabolism and cytosolic phospholipase A2 activation in mesangial cells under pro-inflammatory conditions. Sci Rep 2022; 12:7322. [PMID: 35513427 PMCID: PMC9072365 DOI: 10.1038/s41598-022-10907-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2022] [Accepted: 04/08/2022] [Indexed: 02/07/2023] Open
Abstract
Diabetic kidney disease is a consequence of hyperglycemia and other complex events driven by early glomerular hemodynamic changes and a progressive expansion of the mesangium. The molecular mechanisms behind the pathophysiological alterations of the mesangium are yet to be elucidated. This study aimed at investigating whether lipid signaling might be the missing link. Stimulation of human mesangial cells with high glucose primed the inflammasome-driven interleukin 1 beta (IL-1β) secretion, which in turn stimulated platelet-derived growth factor (PDGF-BB) release. Finally, PDGF-BB increased IL-1β secretion synergistically. Both IL-1β and PDGF-BB stimulation triggered the formation of phosphorylated sphingoid bases, as shown by lipidomics, and activated cytosolic phospholipase cPLA2, sphingosine kinase 1, cyclooxygenase 2, and autotaxin. This led to the release of arachidonic acid and lysophosphatidylcholine, activating the secretion of vasodilatory prostaglandins and proliferative lysophosphatidic acids. Blocking cPLA2 release of arachidonic acid reduced mesangial cells proliferation and prostaglandin secretion. Validation was performed in silico using the Nephroseq database and a glomerular transcriptomic database. In conclusion, hyperglycemia primes glomerular inflammatory and proliferative stimuli triggering lipid metabolism modifications in human mesangial cells. The upregulation of cPLA2 was critical in this setting. Its inhibition reduced mesangial secretion of prostaglandins and proliferation, making it a potential therapeutical target.
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Affiliation(s)
- Roberto Boi
- Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Box 432, 40530, Gothenburg, Sweden
| | - Kerstin Ebefors
- Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Box 432, 40530, Gothenburg, Sweden
| | - Marcus Henricsson
- Institute of Medicine, Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Jan Borén
- Institute of Medicine, Department of Molecular and Clinical Medicine, Wallenberg Laboratory, University of Gothenburg, and Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Jenny Nyström
- Institute of Neuroscience and Physiology, Department of Physiology, Sahlgrenska Academy, University of Gothenburg, Box 432, 40530, Gothenburg, Sweden.
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Ungurianu A, Zanfirescu A, Grădinaru D, Ionescu-Tîrgoviște C, Dănciulescu Miulescu R, Margină D. Interleukins and redox impairment in type 2 diabetes mellitus: mini-review and pilot study. Curr Med Res Opin 2022; 38:511-522. [PMID: 35067142 DOI: 10.1080/03007995.2022.2033049] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
BACKGROUND Type 2 diabetes mellitus (T2DM) represents a leading cause of morbidity and premature mortality, low-grade inflammation being acknowledged as a key contributor to its development and progression. A tailored therapeutic approach, based on sensitive and specific biomarkers, could allow a more accurate analysis of disease susceptibility/prognostic and of the response to treatment. OBJECTIVES This mini-review and pilot study had two main goals: (1) reviewing the most recent literature encompassing the use of interleukins as inflammatory markers influenced by the redox imbalances in T2DM and (2) assessing parameters that conjunctly evaluate the redox impairment and inflammatory burden of T2DM patients, taking into consideration smoking status, as such group-specific biomarkers are scarcely reported in literature. METHODS Firstly, PubMed database was surveyed to select and review the relevant studies employing interleukins as T2DM biomarkers and to assess if studies using combined inflammatory-redox indices were reported. Then, routine biochemical parameters were assessed in a pilot study -T2DM patients with 3 subgroups: non-smokers, smokers and ex-smokers, were compared to a control group of non-diabetic, apparently healthy non-smokers. Protein (AOPPs, AGEs), lipid/HDL (Amplex Red-based method) oxidative damage and inflammatory status (CRP, IL-1β, IL-6, IL-10) biomarkers were assessed. Cytokine ratios and 2 oxidative-inflammatory status indices were developed (IH1 and IH2) and evaluated. RESULTS We observed significant differences in terms of serum redox and inflammatory status (AOPPs, AGEs, CRP, CRP/HDL, CRP/IL-6, IL-10/IL-6, IH1) between T2DM patients compared to control and, moreover, between the subgroups formed considering smoking status (CRP, CRP/HDL, IH1). Glycemic control strongly influenced inflammatory status biomarkers: glycemia was positively correlated with the inflammatory parameters (CRP/IL-10) and inversely with the anti-inflammatory ones (IL-10, IL-10/IL-1β ratio). CONCLUSIONS Several of the assessed parameters may possess prognostic value for diabetics, especially when comparing subgroups with a different smoking history and could prove useful in clinical practice for assessing disease progress and therapeutic efficacy.
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Affiliation(s)
- Anca Ungurianu
- Department of Biochemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Anca Zanfirescu
- Department of Pharmacology, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Daniela Grădinaru
- Department of Biochemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | | | - Rucsandra Dănciulescu Miulescu
- N. Paulescu National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania
- Department of Department of Endocrinology, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
| | - Denisa Margină
- Department of Biochemistry, Faculty of Pharmacy, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania
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Prasad M K, Mohandas S, Ramkumar KM. Role of ER stress inhibitors in the management of diabetes. Eur J Pharmacol 2022; 922:174893. [DOI: 10.1016/j.ejphar.2022.174893] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2022] [Revised: 03/07/2022] [Accepted: 03/09/2022] [Indexed: 12/14/2022]
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Jiang L, Zhou J, Zhang L, Du Y, Jiang M, Xie L, Ma Z, Chen F. The association between serum interleukin-1 beta and heparin sulphate in diabetic nephropathy patients. Glycoconj J 2022; 38:697-707. [PMID: 34997893 PMCID: PMC8821487 DOI: 10.1007/s10719-021-10035-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2021] [Revised: 12/02/2021] [Accepted: 12/17/2021] [Indexed: 12/15/2022]
Abstract
Inflammation is considered an important mechanism in the development of diabetes mellitus (DM) and persists for a long time before the occurrence of diabetic nephropathy (DN). Many studies have demonstrated that a decrease in the endothelial glycocalyx (EG) is negatively correlated with proteinuria. To elucidate whether EG damage induced by inflammasomes in DM patients leads to the occurrence of microalbuminuria (MA) and accelerates the progression of DN, this study screened 300 diagnosed DM patients. Finally, 70 type 2 diabetes patients were invited to participate in this study and were divided into two groups: the T2DM group (patients with normal MA and without diabetic retinopathy, n = 35) and the T2DN group (patients with increased MA and diabetic retinopathy, n = 35). Circulating heparin sulphate (HS, EG biomarkers) and interleukin-1 beta (IL-1β, inflammasome biomarkers) of the patients were measured by ELISA. Laboratory data were measured using routine laboratory methods. Patients in the T2DN group had increased serum HS, increased IL-1β, increased CRP, decreased haemoglobin, and increased neutrophils compared to patients in the T2DM group (all P < 0.05). Increased HS and decreased haemoglobin were independently associated with T2DN patients. ROC curves showed that the AUC of HS for the prediction of T2DN was 0.67 (P < 0.05). The combination of HS and haemoglobin yielded a significant increasement in the AUC (0.75, P < 0.001) with optimal sensitivity (71.2%) and specificity (79%). Furthermore, serum IL-1β was positively correlated with HS and was an independent associated factor of HS in the T2DN group. The relationship between HS and IL-1β was not significant in the T2DM group. Our findings surgessed the inflammasome may be associated with and promote damage to the EG during the disease course of DN that manifests as increased MA.
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Affiliation(s)
- Liqiong Jiang
- Department of Nephrology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China.
| | - Jianying Zhou
- Department of Endocrinology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Li Zhang
- Clinical Lab, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Yufeng Du
- Department of Nephrology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Mingming Jiang
- Department of Nephrology, the Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou, China
| | - Liqian Xie
- Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Zhenni Ma
- Jiangsu Institute of Hematology, the First Affiliated Hospital of Soochow University, Suzhou, China
| | - Fengling Chen
- Department of Hemodialysis Center, the First Affiliated Hospital of Soochow University, Suzhou, China.
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Nord JA, Wynia-Smith SL, Gehant AL, Jones Lipinski RA, Naatz A, Rioja I, Prinjha RK, Corbett JA, Smith BC. N-terminal BET bromodomain inhibitors disrupt a BRD4-p65 interaction and reduce inducible nitric oxide synthase transcription in pancreatic β-cells. Front Endocrinol (Lausanne) 2022; 13:923925. [PMID: 36176467 PMCID: PMC9513428 DOI: 10.3389/fendo.2022.923925] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 08/19/2022] [Indexed: 02/02/2023] Open
Abstract
Chronic inflammation of pancreatic islets is a key driver of β-cell damage that can lead to autoreactivity and the eventual onset of autoimmune diabetes (T1D). In the islet, elevated levels of proinflammatory cytokines induce the transcription of the inducible nitric oxide synthase (iNOS) gene, NOS2, ultimately resulting in increased nitric oxide (NO). Excessive or prolonged exposure to NO causes β-cell dysfunction and failure associated with defects in mitochondrial respiration. Recent studies showed that inhibition of the bromodomain and extraterminal domain (BET) family of proteins, a druggable class of epigenetic reader proteins, prevents the onset and progression of T1D in the non-obese diabetic mouse model. We hypothesized that BET proteins co-activate transcription of cytokine-induced inflammatory gene targets in β-cells and that selective, chemotherapeutic inhibition of BET bromodomains could reduce such transcription. Here, we investigated the ability of BET bromodomain small molecule inhibitors to reduce the β-cell response to the proinflammatory cytokine interleukin 1 beta (IL-1β). BET bromodomain inhibition attenuated IL-1β-induced transcription of the inflammatory mediator NOS2 and consequent iNOS protein and NO production. Reduced NOS2 transcription is consistent with inhibition of NF-κB facilitated by disrupting the interaction of a single BET family member, BRD4, with the NF-κB subunit, p65. Using recently reported selective inhibitors of the first and second BET bromodomains, inhibition of only the first bromodomain was necessary to reduce the interaction of BRD4 with p65 in β-cells. Moreover, inhibition of the first bromodomain was sufficient to mitigate IL-1β-driven decreases in mitochondrial oxygen consumption rates and β-cell viability. By identifying a role for the interaction between BRD4 and p65 in controlling the response of β-cells to proinflammatory cytokines, we provide mechanistic information on how BET bromodomain inhibition can decrease inflammation. These studies also support the potential therapeutic application of more selective BET bromodomain inhibitors in attenuating β-cell inflammation.
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Affiliation(s)
- Joshua A. Nord
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Sarah L. Wynia-Smith
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Alyssa L. Gehant
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United States
| | | | - Aaron Naatz
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Inmaculada Rioja
- Immuno-Epigenetics, Immunology Research Unit, GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom
| | - Rab K. Prinjha
- Immuno-Epigenetics, Immunology Research Unit, GlaxoSmithKline Medicines Research Centre, Stevenage, United Kingdom
| | - John A. Corbett
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Brian C. Smith
- Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, United States
- *Correspondence: Brian C. Smith,
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Zak K, Popova V, Orlenko V, Furmanova O, Tronko N. Cytokines in the blood of patients with type 2 diabetes mellitus depending on the level of overweight/obesity (literature review and own data). INTERNATIONAL JOURNAL OF ENDOCRINOLOGY (UKRAINE) 2021; 17:534-551. [DOI: 10.22141/2224-0721.17.7.2021.244969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The paper analyzes the current literature data and the results of our own researches concerning the state of the cytokine network: pro- and anti-inflammatory cytokines (interleukin (IL)1α, IL-1β, IL-4, IL-6, IL-10, IL-17 and tumor necrosis factor (TNF) α), α- and β-chemokines, including IL-8 and IL-16, as well as adipokines (leptin and adiponectin) in the peripheral blood of patients with type 2 diabetes (T2D) with normal and increased body weight/obesity. It has been shown that patients with T2D are characterized by an increased content of proinflammatory cytokines (IL-1, IL-6, IL-17, TNFα), α- and β-chemokines in the peripheral blood, including IL-8 and IL-16, as well as leptin with a decrease in adiponectin content. In lean patients (with body mass index (BMI)<25.5 kg/m2) compared to lean normoglycemic individuals from the control group (BMI<25.5kg/m2), there is a small but significant increase in IL-1β, IL-6, IL-17, TNFα and leptin, which, as BMI increases, significantly increases in severe obesity (BMI>30.0kg/m2), especially in obese women (BMI>35.0kg/m2). Similarly, an increase in proinflammatory cytokines is observed in normoglycemic people, but not as significant as in T2D. Less clear data were obtained when during determination of the anti-inflammatory cytokines IL-4 and IL-10, which is explained by a significant polymorphism of their genes, and both protective and compensatory effects on pro-inflammatory cytokine rise. In T2D patients, especially those with obesity, there is an increase in the leptin level and a decrease in the adiponectin content. The severity of the course and the percentage of mortality are closely associated with the BMI of patients. The effectiveness of the fight against an increase in the incidence of T2D should be primarily aimed at preventing obesity, and in case of already developed T2D— at reducing concomitant obesity. The analysis of the data presented also suggests that a sharp increase in the content of pro-inflammatory cytokines (so called cytokine storm) observed in patients with T2D and obesity infected with COVID-19, is a consequence of the summation and potentiation of already existing inflammatory process.
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Impact of Bariatric Surgery on Adipose Tissue Biology. J Clin Med 2021; 10:jcm10235516. [PMID: 34884217 PMCID: PMC8658722 DOI: 10.3390/jcm10235516] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 02/07/2023] Open
Abstract
Bariatric surgery (BS) procedures are actually the most effective intervention to help subjects with severe obesity achieve significant and sustained weight loss. White adipose tissue (WAT) is increasingly recognized as the largest endocrine organ. Unhealthy WAT expansion through adipocyte hypertrophy has pleiotropic effects on adipocyte function and promotes obesity-associated metabolic complications. WAT dysfunction in obesity encompasses an altered adipokine secretome, unresolved inflammation, dysregulated autophagy, inappropriate extracellular matrix remodeling and insufficient angiogenic potential. In the last 10 years, accumulating evidence suggests that BS can improve the WAT function beyond reducing the fat depot sizes. The causal relationships between improved WAT function and the health benefits of BS merits further investigation. This review summarizes the current knowledge on the short-, medium- and long-term outcomes of BS on the WAT composition and function.
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Jiao J, Wang Z, Guo Y, Liu J, Huang X, Ni X, Gao D, Sun L, Zhu X, Zhou Q, Yang Z, Yuan H. Association between IL-1B (-511)/IL-1RN (VNTR) polymorphisms and type 2 diabetes: a systematic review and meta-analysis. PeerJ 2021; 9:e12384. [PMID: 34754627 PMCID: PMC8552784 DOI: 10.7717/peerj.12384] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Accepted: 10/04/2021] [Indexed: 01/15/2023] Open
Abstract
Interleukin-1 (IL-1) plays an essential role in the immune pro-inflammatory process, which is regarded as one of many factors in the development of type 2 diabetes mellitus (T2DM). Several case-control studies have illustrated the association of the IL-1B (-511) (rs16944, Chr 2:112,837,290, C/T Intragenic, Transition Substitution) and IL-1RN (VNTR) (gene for IL-1 receptor antagonist, IL-1RA, 86 bp tandem repeats in intron 2) polymorphisms with T2DM risk. However, the results were inconsistent and inconclusive. We performed a meta-analysis (registry number: CRD42021268494) to assess the association of the IL-1B (-511) and IL-1RN (VNTR) polymorphisms with T2DM risk. Random-effects models were applied to calculate the pooled ORs (odds ratios) and 95% CIs (confidence intervals) to test the strength of the association in the overall group and subgroups stratified by ethnicity, respectively. Between-study heterogeneity and publication bias were evaluated by the Q-test, I2 statistic, Harbord test, and Peters test accordingly. Sensitivity analyses were also performed. A total of 12 publications evaluating the association of IL-1B (-511) and IL-1RN (VNTR) polymorphisms with the risk of T2DM development were included. The meta-analysis showed that IL-1RN (VNTR) was related to the increasing development of T2DM risk in the recessive model (OR = 1.62, 95% CI [1.09-2.42], Phet = 0.377, Pz = 0.018) and in the homozygous model (OR = 2.02, 95% CI [1.07-3.83], Phet = 0.085, Pz = 0.031), and the IL-1RN 2* allele was found a significant association with evaluated T2DM risk in all ethnicities (OR = 2.08, 95% CI [1.43-3.02], Phet < 0.001, Pz < 0.001) and in EA (OR = 2.01, 95% CI [1.53-2.66], Phet = 0.541, Pz < 0.001). Moreover, stratification by ethnicity revealed that IL-1B (-511) was associated with a decreased risk of T2DM in the dominant model (OR=0.76, 95% CI [0.59-0.97], Phet = 0.218, P z = 0.027) and codominant model (OR = 0.73, 95% CI [0.54-0.99], Phet = 0.141, Pz = 0.040) in the East Asian (EA) subgroup. Our results suggest that the IL-1RN 2* allele and 2*2* homozygous polymorphism are strongly associated with increasing T2DM risk and that the IL-1B (-511) T allele polymorphism is associated with decreasing T2DM risk in the EA subgroup.
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Affiliation(s)
- Juan Jiao
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, P.R. China.,Department of Clinical Laboratory, the Seventh Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Zhaoping Wang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, P.R. China
| | - Yanfei Guo
- Department of Respiratory and Critical Care Medicine, Beijing Hospital, National Center of Gerontology; Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, P.R. China
| | - Jie Liu
- Department of Clinical Laboratory, the Seventh Medical Center, Chinese PLA General Hospital, Beijing, China
| | - Xiuqing Huang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, P.R. China
| | - Xiaolin Ni
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, P.R. China
| | - Danni Gao
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, P.R. China.,Peking University Fifth School of Clinical Medicine (Beijing Hospital), Beijing, China
| | - Liang Sun
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, P.R. China
| | - Xiaoquan Zhu
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, P.R. China
| | - Qi Zhou
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, P.R. China
| | - Ze Yang
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, P.R. China
| | - Huiping Yuan
- The Key Laboratory of Geriatrics, Beijing Institute of Geriatrics, Institute of Geriatric Medicine, Chinese Academy of Medical Science, Beijing Hospital/National Center of Gerontology of National Health Commission, P.R. China
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Sasaki H, Saisho Y, Inaishi J, Itoh H. Revisiting Regulators of Human β-cell Mass to Achieve β-cell-centric Approach Toward Type 2 Diabetes. J Endocr Soc 2021; 5:bvab128. [PMID: 34405128 PMCID: PMC8361804 DOI: 10.1210/jendso/bvab128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Indexed: 02/07/2023] Open
Abstract
Type 2 diabetes (T2DM) is characterized by insulin resistance and β-cell dysfunction. Because patients with T2DM have inadequate β-cell mass (BCM) and β-cell dysfunction worsens glycemic control and makes treatment difficult, therapeutic strategies to preserve and restore BCM are needed. In rodent models, obesity increases BCM about 3-fold, but the increase in BCM in humans is limited. Besides, obesity-induced changes in BCM may show racial differences between East Asians and Caucasians. Recently, the developmental origins of health and disease hypothesis, which states that the risk of developing noncommunicable diseases including T2DM is influenced by the fetal environment, has been proposed. It is known in rodents that animals with low birthweight have reduced BCM through epigenetic modifications, making them more susceptible to diabetes in the future. Similarly, in humans, we revealed that individuals born with low birthweight have lower BCM in adulthood. Because β-cell replication is more frequently observed in the 5 years after birth, and β cells are found to be more plastic in that period, a history of childhood obesity increases BCM. BCM in patients with T2DM is reduced by 20% to 65% compared with that in individuals without T2DM. However, since BCM starts to decrease from the stage of borderline diabetes, early intervention is essential for β-cell protection. In this review, we summarize the current knowledge on regulatory factors of human BCM in health and diabetes and propose the β-cell–centric concept of diabetes to enhance a more pathophysiology-based treatment approach for T2DM.
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Affiliation(s)
- Hironobu Sasaki
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Center for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Yoshifumi Saisho
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Jun Inaishi
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.,Center for Preventive Medicine, Keio University School of Medicine, Tokyo, Japan
| | - Hiroshi Itoh
- Division of Nephrology, Endocrinology and Metabolism, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan
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Butyrate Protects Pancreatic Beta Cells from Cytokine-Induced Dysfunction. Int J Mol Sci 2021; 22:ijms221910427. [PMID: 34638768 PMCID: PMC8508700 DOI: 10.3390/ijms221910427] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 09/24/2021] [Accepted: 09/25/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic beta cell dysfunction caused by metabolic and inflammatory stress contributes to the development of type 2 diabetes (T2D). Butyrate, produced by the gut microbiota, has shown beneficial effects on glucose metabolism in animals and humans and may directly affect beta cell function, but the mechanisms are poorly described. The aim of this study was to investigate the effect of butyrate on cytokine-induced beta cell dysfunction in vitro. Mouse islets, rat INS-1E, and human EndoC-βH1 beta cells were exposed long-term to non-cytotoxic concentrations of cytokines and/or butyrate to resemble the slow onset of inflammation in T2D. Beta cell function was assessed by glucose-stimulated insulin secretion (GSIS), gene expression by qPCR and RNA-sequencing, and proliferation by incorporation of EdU into newly synthesized DNA. Butyrate protected beta cells from cytokine-induced impairment of GSIS and insulin content in the three beta cell models. Beta cell proliferation was reduced by both cytokines and butyrate. Expressions of the beta cell specific genes Ins, MafA, and Ucn3 reduced by the cytokine IL-1β were not affected by butyrate. In contrast, butyrate upregulated the expression of secretion/transport-related genes and downregulated inflammatory genes induced by IL-1β in mouse islets. In summary, butyrate prevents pro-inflammatory cytokine-induced beta cell dysfunction.
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Américo-Da-Silva L, Aguilera J, Quinteros-Waltemath O, Sánchez-Aguilera P, Russell J, Cadagan C, Meneses-Valdés R, Sánchez G, Estrada M, Jorquera G, Barrientos G, Llanos P. Activation of the NLRP3 Inflammasome Increases the IL-1β Level and Decreases GLUT4 Translocation in Skeletal Muscle during Insulin Resistance. Int J Mol Sci 2021; 22:10212. [PMID: 34638553 PMCID: PMC8508423 DOI: 10.3390/ijms221910212] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/14/2021] [Accepted: 09/15/2021] [Indexed: 12/16/2022] Open
Abstract
Low-grade chronic inflammation plays a pivotal role in the pathogenesis of insulin resistance (IR), and skeletal muscle has a central role in this condition. NLRP3 inflammasome activation pathways promote low-grade chronic inflammation in several tissues. However, a direct link between IR and NLRP3 inflammasome activation in skeletal muscle has not been reported. Here, we evaluated the NLRP3 inflammasome components and their role in GLUT4 translocation impairment in skeletal muscle during IR. Male C57BL/6J mice were fed with a normal control diet (NCD) or high-fat diet (HFD) for 8 weeks. The protein levels of NLRP3, ASC, caspase-1, gasdermin-D (GSDMD), and interleukin (IL)-1β were measured in both homogenized and isolated fibers from the flexor digitorum brevis (FDB) or soleus muscle. GLUT4 translocation was determined through GLUT4myc-eGFP electroporation of the FBD muscle. Our results, obtained using immunofluorescence, showed that adult skeletal muscle expresses the inflammasome components. In the FDB and soleus muscles, homogenates from HFD-fed mice, we found increased protein levels of NLRP3 and ASC, higher activation of caspase-1, and elevated IL-1β in its mature form, compared to NCD-fed mice. Moreover, GSDMD, a protein that mediates IL-1β secretion, was found to be increased in HFD-fed-mice muscles. Interestingly, MCC950, a specific pharmacological NLRP3 inflammasome inhibitor, promoted GLUT4 translocation in fibers isolated from the FDB muscle of NCD- and HFD-fed mice. In conclusion, we found increased NLRP3 inflammasome components in adult skeletal muscle of obese insulin-resistant animals, which might contribute to the low-grade chronic metabolic inflammation of skeletal muscle and IR development.
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Affiliation(s)
- Luan Américo-Da-Silva
- Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Santiago 8380544, Chile; (L.A.-D.-S.); (J.A.); (O.Q.-W.); (C.C.)
| | - Javiera Aguilera
- Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Santiago 8380544, Chile; (L.A.-D.-S.); (J.A.); (O.Q.-W.); (C.C.)
| | - Oscar Quinteros-Waltemath
- Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Santiago 8380544, Chile; (L.A.-D.-S.); (J.A.); (O.Q.-W.); (C.C.)
| | - Pablo Sánchez-Aguilera
- Centro de Estudios en Ejercicio, Metabolismo y Cáncer, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (P.S.-A.); (R.M.-V.)
| | - Javier Russell
- Escuela de Pedagogía en Educación Física, Facultad de Educación, Universidad Autónoma de Chile, Santiago 8900000, Chile;
| | - Cynthia Cadagan
- Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Santiago 8380544, Chile; (L.A.-D.-S.); (J.A.); (O.Q.-W.); (C.C.)
| | - Roberto Meneses-Valdés
- Centro de Estudios en Ejercicio, Metabolismo y Cáncer, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (P.S.-A.); (R.M.-V.)
| | - Gina Sánchez
- Programa de Fisiopatología, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
| | - Manuel Estrada
- Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
| | - Gonzalo Jorquera
- Centro de Neurobiología y Fisiopatología Integrativa (CENFI), Instituto de Fisiología, Facultad de Ciencias, Universidad de Valparaíso, Valparaíso 2360102, Chile;
| | - Genaro Barrientos
- Centro de Estudios en Ejercicio, Metabolismo y Cáncer, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (P.S.-A.); (R.M.-V.)
- Programa de Fisiología y Biofísica, ICBM, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile;
| | - Paola Llanos
- Instituto de Investigación en Ciencias Odontológicas, Facultad de Odontología, Universidad de Chile, Santiago 8380544, Chile; (L.A.-D.-S.); (J.A.); (O.Q.-W.); (C.C.)
- Centro de Estudios en Ejercicio, Metabolismo y Cáncer, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile; (P.S.-A.); (R.M.-V.)
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Tang Y, Kline KT, Zhong XS, Xiao Y, Lian H, Peng J, Liu X, Powell DW, Tang G, Li Q. Chronic colitis upregulates microRNAs suppressing brain-derived neurotrophic factor in the adult heart. PLoS One 2021; 16:e0257280. [PMID: 34543287 PMCID: PMC8452076 DOI: 10.1371/journal.pone.0257280] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2020] [Accepted: 08/28/2021] [Indexed: 01/08/2023] Open
Abstract
Ulcerative colitis and Crohn's disease are classified as chronic inflammatory bowel diseases (IBD) with known extraintestinal manifestations. The interplay between heart and gut in IBD has previously been noted, but the mechanisms remain elusive. Our objective was to identify microRNAs mediating molecular remodeling and resulting cardiac impairment in a rat model of colitis. To induce chronic colitis, dextran sodium sulfate (DSS) was given to adult rats for 5 days followed by 9 days with normal drinking water for 4 cycles over 8 weeks. Echocardiography was performed to evaluate heart function. DSS-induced colitis led to a significant decrease in ejection fraction, increased left ventricular mass and size, and elevated B-type natriuretic protein. MicroRNA profiling showed a total of 56 miRNAs significantly increased in the heart by colitis, 8 of which are predicted to target brain-derived neurotrophic factor (BDNF). RT-qPCR validated the increases of miR-1b, Let-7d, and miR-155. Transient transfection revealed that miR-155 significantly suppresses BDNF in H9c2 cells. Importantly, DSS colitis markedly decreased BDNF in both myocardium and serum. Levels of various proteins critical to cardiac homeostasis were also altered. Functional studies showed that BDNF increases cell viability and mitigates H2O2-induced oxidative damage in H9c2 cells, demonstrating its protective role in the adult heart. Mechanistically, cellular experiments identified IL-1β as the inflammatory mediator upregulating cardiac miR-155; this effect was confirmed in adult rats. Furthermore, IL-1β neutralizing antibody ameliorated the DSS-induced increase in miR-155 and concurrent decrease in BDNF in the adult heart, showing therapeutic potential. Our findings indicate that chronic colitis impairs heart function through an IL-1β→miR-155→BDNF signaling axis.
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Affiliation(s)
- Yanbo Tang
- Department of Gastroenterology, the First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Kevin T. Kline
- Division of Gastroenterology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX, United States of America
| | - Xiaoying S. Zhong
- Division of Gastroenterology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX, United States of America
| | - Ying Xiao
- Division of Gastroenterology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX, United States of America
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
| | - Haifeng Lian
- Department of Gastroenterology, Binzhou Medical University Hospital, Binzhou, China
| | - Jun Peng
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, China
| | - Xiaowei Liu
- Department of Gastroenterology, Xiangya Hospital, Central South University, Changsha, China
| | - Don W. Powell
- Division of Gastroenterology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX, United States of America
| | - Guodu Tang
- Department of Gastroenterology, the First Affiliated Hospital, Guangxi Medical University, Nanning, China
| | - Qingjie Li
- Division of Gastroenterology, Department of Internal Medicine, The University of Texas Medical Branch at Galveston, Galveston, TX, United States of America
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Szałabska-Rąpała K, Borymska W, Kaczmarczyk-Sedlak I. Effectiveness of Magnolol, a Lignan from Magnolia Bark, in Diabetes, Its Complications and Comorbidities-A Review. Int J Mol Sci 2021; 22:10050. [PMID: 34576213 PMCID: PMC8467064 DOI: 10.3390/ijms221810050] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/10/2021] [Accepted: 09/15/2021] [Indexed: 12/15/2022] Open
Abstract
Diabetes mellitus is a chronic metabolic disease characterized by disturbances in carbohydrate, protein, and lipid metabolism, often accompanied by oxidative stress. Diabetes treatment is a complicated process in which, in addition to the standard pharmacological action, it is necessary to append a comprehensive approach. Introducing the aspect of non-pharmacological treatment of diabetes allows one to alleviate its many adverse complications. Therefore, it seems important to look for substances that, when included in the daily diet, can improve diabetic parameters. Magnolol, a polyphenolic compound found in magnolia bark, is known for its health-promoting activities and multidirectional beneficial effects on the body. Accordingly, the goal of this review is to systematize the available scientific literature on its beneficial effects on type 2 diabetes and its complications. Taking the above into consideration, the article collects data on the favorable effects of magnolol on parameters related to glycemia, lipid metabolism, or oxidative stress in the course of diabetes. After careful analysis of many scientific articles, it can be concluded that this lignan is a promising agent supporting the conventional therapies with antidiabetic drugs in order to manage diabetes and diabetes-related diseases.
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Affiliation(s)
- Katarzyna Szałabska-Rąpała
- Doctoral School of the Medical University of Silesia in Katowice, Discipline of Pharmaceutical Sciences, Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland
| | - Weronika Borymska
- Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland; (W.B.); (I.K.-S.)
| | - Ilona Kaczmarczyk-Sedlak
- Department of Pharmacognosy and Phytochemistry, Faculty of Pharmaceutical Sciences in Sosnowiec, Medical University of Silesia, Katowice, Jagiellońska 4, 41-200 Sosnowiec, Poland; (W.B.); (I.K.-S.)
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Galangin Attenuates Liver Injury, Oxidative Stress and Inflammation, and Upregulates Nrf2/HO-1 Signaling in Streptozotocin-Induced Diabetic Rats. Processes (Basel) 2021. [DOI: 10.3390/pr9091562] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Chronic hyperglycemia increases the risk of liver damage. Oxidative stress and aberrant inflammatory response are entangled in diabetes-associated liver injury. This study evaluated the protective effect of the flavonoid galangin (Gal) on glucose intolerance, liver injury, oxidative stress, inflammatory response, and Nrf2/HO-1 signaling in diabetic rats. Diabetes was induced by streptozotocin (STZ), and the rats received Gal for six weeks. STZ-induced rats showed glucose intolerance, hypoinsulinemia, elevated glycated hemoglobin (HbA1c), and decreased liver glycogen. Gal ameliorated glucose intolerance, reduced HbA1c%, increased serum insulin and liver glycogen and hexokinase activity, and suppressed glycogen phosphorylase, glucose-6-phosphatase and fructose-1,6-biphosphatase in diabetic rats. Circulating transaminases, ALP and LDH, and liver ROS, MDA, TNF-α, IL-1β, and IL-6 were increased and GSH, SOD, and CAT were diminished in diabetic rats. In addition, diabetic rats exhibited multiple histopathological alterations and marked collagen deposition. Treatment with Gal mitigated liver injury, prevented histopathological alterations, decreased ROS, MDA, pro-inflammatory cytokines, Bax and caspase-3, and enhanced cellular antioxidants and Bcl-2. Gal downregulated hepatic Keap1 in diabetic rats and upregulated Nrf2 and HO-1 mRNA as well as HO-1 activity. Molecular modeling studies revealed the ability of Gal to bind to and inhibit NF-κB and Keap1, and also showed its binding pattern with HO-1. In conclusion, Gal ameliorates hyperglycemia, glucose intolerance, oxidative stress, inflammation, and apoptosis in diabetic rats. Gal improved carbohydrate metabolizing enzymes and upregulated Nrf2/HO-1 signaling.
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Ibrahim M, Parveen B, Zahiruddin S, Gautam G, Parveen R, Khan MA, Gupta A, Ahmad S. Analysis of polyphenols in Aegle marmelos leaf and ameliorative efficacy against diabetic mice through restoration of antioxidant and anti-inflammatory status. J Food Biochem 2021; 46:e13852. [PMID: 34250628 DOI: 10.1111/jfbc.13852] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 06/18/2021] [Accepted: 06/20/2021] [Indexed: 11/28/2022]
Abstract
The biomedical survey reports edible plant Aegle marmelos has been utilized for centuries by tribal communities in India as a dietary supplement for the management of diabetes. Herein, we have investigated cytotoxicity, cytoprotective and antidiabetic activity of characterized alkaloid-free hydroalcoholic extract of A. marmelos (AFEAM; 200 and 400 mg/kg). Identification of polyphenols and quantification of major compounds were done using UPLC-MS and HPTLC, respectively. AFEAM showed good cytocompatibility and cytoprotective potential against oxidative stress induced by hyperglycemia in HepG2 cells. The AFEAM intake had significantly ameliorated the serum blood glucose level, state of dyslipidemia, level of pro-inflammatory markers (tumor necrosis factor-α, interleukin-6, and interleukin-1β), and antioxidant (superoxide dismutase, catalase, glutathione peroxidase, and malondialdehyde) status in diabetic mice. Histological examination of the treated groups showed amelioration of damaged pancreas, liver, and kidney tissues. Conclusively, AFEAM intake might be promising dietary supplements for prediabetics as well as an adjuvant to modern treatment in diabetics. PRACTICAL APPLICATIONS: Different reports have been published on Aegle marmelos but as per our understanding till date, no study has been reported on the amelioration of diabetes due to alkaloid free hydroalcoholic extract of A. marmelos /polyphenolic content in the animal model. The result of this study indicated that A. marmelos supplementation effectively ameliorates diabetes through the restoration of antioxidant and anti-inflammatory status. This study has collated sufficient scientific evidence for the dietary application of A. marmelos in society especially for prediabetics, however, it can also be used as an adjuvant to modern treatments in diabetics.
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Affiliation(s)
- Mohammad Ibrahim
- Bioactive Natural Product Laboratory, SPER, Jamia Hamdard, New Delhi, India.,Department of Pharmacology, SPER, Jamia Hamdard, New Delhi, India
| | - Bushra Parveen
- Bioactive Natural Product Laboratory, SPER, Jamia Hamdard, New Delhi, India.,Department of Pharmacology, SPER, Jamia Hamdard, New Delhi, India
| | - Sultan Zahiruddin
- Bioactive Natural Product Laboratory, SPER, Jamia Hamdard, New Delhi, India
| | - Gaurav Gautam
- Bioactive Natural Product Laboratory, SPER, Jamia Hamdard, New Delhi, India
| | - Rabea Parveen
- Bioactive Natural Product Laboratory, SPER, Jamia Hamdard, New Delhi, India.,Department of Biosciences, Jamia Millia Islamia, New Delhi, India
| | | | - Arun Gupta
- Department of Medical Affairs and Clinical Research, Dabur India Limited, Ghaziabad, India
| | - Sayeed Ahmad
- Bioactive Natural Product Laboratory, SPER, Jamia Hamdard, New Delhi, India
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