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Liu N, Yan WT, Xiong K. Plantamajoside: A potentially novel botanical agent for diabetes mellitus management. World J Diabetes 2025; 16:104311. [DOI: 10.4239/wjd.v16.i5.104311] [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: 12/17/2024] [Revised: 02/08/2025] [Accepted: 02/20/2025] [Indexed: 04/25/2025] Open
Abstract
Diabetes mellitus (DM) and its associated complications are metabolic disorders characterized by hyperglycemia, leading to high morbidity and reduced quality of life worldwide. This global healthcare problem imposes substantial personal and social burdens that warrant comprehensive and in-depth investigation. Plantamajoside (PMS), a naturally bioactive ingredient derived from the traditional Chinese medicinal herb Plantaginis Herba, exhibits a range of pharmacological properties, including anti-inflammatory, antioxidative, and antitumor effects, and has been traditionally utilized in clinical applications such as removing phlegm and clearing heat. However, the potential biological impact of PMS on DM remains largely unexplored. Recent research by Wang et al reported the therapeutic potential of PMS in type 2 DM (T2DM) and elucidated the underlying molecular mechanisms. Specifically, PMS mitigates endoplasmic reticulum stress and apoptosis of pancreatic β-cells by upregulating DnaJ heat shock protein family (Hsp40) member C1, thereby alleviating pancreatic β-cell damage and ameliorating T2DM progression. Given the novel and protective effect of PMS on pancreatic β-cells, this natural ingredient emerges as an innovative and promising therapeutic strategy for improving DM outcomes. PMS has been shown to modulate key signaling pathways involved in multiple types of regulated cell death (RCD), such as apoptosis and autophagy. Various forms of RCD, including apoptosis, ferroptosis, pyroptosis, autophagy, and PANoptosis, contribute to the pathogenesis of DM and its associated complications. There is significant potential for PMS to exert protective effects on β-cells against these forms of RCD and to provide a multitarget approach to DM therapy. Therefore, further exploration into whether PMS shields pancreatic β-cells from these types of RCD, coupled with elucidating the underlying molecular mechanisms, will facilitate the development of more effective therapeutic strategies for DM. Additionally, further investigation on PMS in conjunction with other therapeutic approaches is warranted to enhance therapeutic efficacy for DM.
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Affiliation(s)
- Na Liu
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
| | - Wei-Tao Yan
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
| | - Kun Xiong
- Department of Anatomy and Neurobiology, School of Basic Medical Science, Central South University, Changsha 410013, Hunan Province, China
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Lin KA, Su CC, Liu SH, Lee KI, Fang KM, Tang CH, Kuo CY, Chang KC, Ke JA, Huang CF, Chen YW, Yang CY. Antimony induces mitochondria-dependent and ER stress-triggered apoptosis via the oxidative stress-activated JNK signaling pathway in pancreatic islet β-cells. Toxicology 2025; 516:154188. [PMID: 40368022 DOI: 10.1016/j.tox.2025.154188] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 04/30/2025] [Accepted: 05/11/2025] [Indexed: 05/16/2025]
Abstract
Antimony (Sb), a silvery-white metal, is a heavy metal of particular prevalence that has the ability to result in adverse effects in humans through environmental exposure resulting from natural processes and human activities. Epidemiological studies have suggested that Sb has an association with the potential for diabetes mellitus (DM) development. However, the mechanisms by which Sb exerts toxicological effects on pancreatic islet β-cells are still not clear. In this investigation, Sb exposure significantly inhibited rat pancreatic islet β-cell-derived RIN-m5F cell viability and insulin secretion, while inducing mitochondria-dependent apoptotic signals, inclusive of increased apoptotic cell populations, caspase-3 activity, the expression of PARP and caspase-3/-7/-9, and mitochondrial dysfunction. RIN-m5F cells exposure to Sb also led to the triggering of endoplasmic reticulum (ER) stress via the induction of a number of vital molecules, including CHOP, XBP-1s, and caspase-12. In Sb-exposed RIN-m5F cells, 4-PBA pretreatment (an inhibitor of ER stress) significantly suppressed protein expression related to ER stress and events of an apoptotic nature. Furthermore, exposure to Sb resulted in the significant activation of AMPKα, ERK1/2, and JNK signaling, as well as reactive oxygen species (ROS) generation. Pretreatment with SP600125 (an inhibitor of JNK) and antioxidant NAC, but not PD98059 (an inhibitor of ERK) or compound C (an inhibitor of AMPK), effectively abrogated the cytotoxicity, ER stress responses, mitochondrial dysfunction, apoptotic events, insulin secretion inhibition, and JNK activation in Sb-exposed rat pancreatic islet β-cells. However, SP600125 did not prevent ROS generation, which was inhibited by the antioxidant NAC. Collectively, the results demonstrate exposure to Sb to exert β-cell cytotoxicity through oxidative stress-activated JNK signaling downstream-regulated mitochondria-dependent and ER stress-triggered cell apoptotic pathways, eventually resulting in the death of rat pancreatic islet β-cells.
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Affiliation(s)
- Ken-An Lin
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404, Taiwan
| | - Chin-Chuan Su
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua County, Changhua County 500, Taiwan; Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 402, Taiwan
| | - Shing-Hwa Liu
- Institute of Toxicology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
| | - Kuan-I Lee
- Department of Emergency, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung 427, Taiwan
| | - Kai-Min Fang
- Department of Otolaryngology, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
| | - Chih-Hsin Tang
- Graduate Institute of Biomedical Sciences, College of Medicine, China Medical University, Taichung 404, Taiwan
| | - Chun-Ying Kuo
- Department of Otorhinolaryngology, Head and Neck Surgery, Changhua Christian Hospital, Changhua County, Changhua County 500, Taiwan
| | - Kai-Chih Chang
- Center for Digestive Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung 404, Taiwan
| | - Jun-An Ke
- Department of Medical Education, Changhua Christian Hospital Changhua City 500, Taiwan
| | - Chun-Fa Huang
- School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung 404, Taiwan; Department of Nursing, College of Medical and Health Science, Asia University, Taichung 413, Taiwan
| | - Ya-Wen Chen
- Department of Physiology, School of Medicine, College of Medicine, China Medical University, Taichung 404, Taiwan.
| | - Ching-Yao Yang
- Department of Surgery, College of Medicine, National Taiwan University, Taipei 100, Taiwan; Department of Surgery, National Taiwan University Hospital, Taipei 100, Taiwan.
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Zhou B, Zhou N, Jiang J, Zhang X, Zhao X, Duan Y, Zhang Y. Exosomal miR-25 from Mesenchymal stem cells inhibits T cells migration and Alleviates Type 1 diabetes mellitus by Targeting CXCR3 models. Gene 2025; 936:149098. [PMID: 39547359 DOI: 10.1016/j.gene.2024.149098] [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: 07/25/2024] [Revised: 10/10/2024] [Accepted: 11/12/2024] [Indexed: 11/17/2024]
Abstract
Mesenchymal stem cells (MSCs) have demonstrated promising therapeutic potential in the treatment of type 1 diabetes mellitus (T1DM); however, the underlying mechanism remains unclear. The primary pathological mechanism of T1DM involves activated T cells infiltrating the pancreas, leading to islet inflammation and the destruction of β-cells. However, the question of whether exosomes derived from MSCs can suppress the migration of T cells to the pancreas in the context of T1DM remains unresolved. In this study, we observed that miR-25 was highly expressed in MSCs exosomes and associated with signaling pathways related to cell migration. In vitro assay, we synthesized a miR-25 mimic and transiently transfected it into activated T cells, which revealed that miR-25 can effectively reduce the expression of CXCR3. Additionally, according to the in vivo T1DM mouse model, we found that there was a significant increase in miR-25 levels in T1DM mice treated with MSCs and the number of T cells decreased. Overall, our findings suggest that MSCs exosomes containing miR-25 can impede the infiltration of activated T cells into the pancreas in T1DM by repressing CXCR3 expression in these cells.
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MESH Headings
- MicroRNAs/genetics
- MicroRNAs/metabolism
- Animals
- Mesenchymal Stem Cells/metabolism
- Exosomes/metabolism
- Exosomes/genetics
- Diabetes Mellitus, Type 1/therapy
- Diabetes Mellitus, Type 1/genetics
- Diabetes Mellitus, Type 1/metabolism
- Receptors, CXCR3/metabolism
- Receptors, CXCR3/genetics
- Mice
- Cell Movement
- T-Lymphocytes/metabolism
- T-Lymphocytes/immunology
- Humans
- Mice, Inbred C57BL
- Diabetes Mellitus, Experimental/therapy
- Diabetes Mellitus, Experimental/genetics
- Diabetes Mellitus, Experimental/metabolism
- Male
- Disease Models, Animal
- Pancreas/metabolism
- Pancreas/pathology
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Affiliation(s)
- Bin Zhou
- Department of Neonatology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China; Department of Stem Cell and Regenerative Medicine, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Na Zhou
- Department of Pediatrics, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Jiaxi Jiang
- Department of dermatology, People's Liberation Army 95829 Military Hospital, Wuhan 430014, China
| | - Xiaru Zhang
- Department of Stem Cell and Regenerative Medicine, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Xinfeng Zhao
- Department of Stem Cell and Regenerative Medicine, Beijing Institute of Radiation Medicine, Beijing 100850, China
| | - Yang Duan
- Department of Neonatology, The Second Hospital of Tianjin Medical University, Tianjin 300211, China.
| | - Yi Zhang
- Department of Stem Cell and Regenerative Medicine, Beijing Institute of Radiation Medicine, Beijing 100850, China.
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Dai L, Wang Q. Targeting ferroptosis: opportunities and challenges of mesenchymal stem cell therapy for type 1 diabetes mellitus. Stem Cell Res Ther 2025; 16:47. [PMID: 39901210 PMCID: PMC11792594 DOI: 10.1186/s13287-025-04188-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/24/2025] [Indexed: 02/05/2025] Open
Abstract
Type 1 diabetes mellitus (T1DM) is characterized by progressive β-cell death, leading to β-cell loss and insufficient insulin secretion. Mesenchymal stem cells (MSCs) transplantation is currently one of the most promising methods for β-cell replacement therapy. However, recent studies have shown that ferroptosis is not only one of the key mechanisms of β-cell death, but also one of the reasons for extensive cell death within a short period of time after MSCs transplantation. Ferroptosis is a new type of regulated cell death (RCD) characterized by iron-dependent accumulation of lipid peroxides. Due to the weak antioxidant capacity of β-cells, they are susceptible to cytotoxic stimuli such as oxidative stress (OS), and are therefore susceptible to ferroptosis. Transplanted MSCs are also extremely susceptible to perturbations in their microenvironment, especially OS, which can weaken their antioxidant capacity and induce MSCs death through ferroptosis. In the pathophysiological process of T1DM, a large amount of reactive oxygen species (ROS) are produced, causing OS. Therefore, targeting ferroptosis may be a key way to protect β-cells and improve the therapeutic effect of MSCs transplantation. This review reviews the research related to ferroptosis of β-cells and MSCs, and summarizes the currently developed strategies that help inhibit cell ferroptosis. This study aims to help understand the ferroptosis mechanism of β-cell death and MSCs death after transplantation, emphasize the importance of targeting ferroptosis for protecting β-cells and improving the survival and function of transplanted MSCs, and provide a new research direction for stem cells transplantation therapy of T1DM in the future.
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Affiliation(s)
- Le Dai
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, 126 Xiantai Avenue, Changchun City, Jilin Province, China
| | - Qing Wang
- Department of Endocrinology, China-Japan Union Hospital of Jilin University, 126 Xiantai Avenue, Changchun City, Jilin Province, China.
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Liu G, Yang J, Li R, Li W, Liu D, Zhang N, Zhao Y, He Z, Gu S. Roles of N 6-methyladenosine in LncRNA changes and oxidative damage in cadmium-induced pancreatic β-cells. Toxicology 2025; 511:154053. [PMID: 39798863 DOI: 10.1016/j.tox.2025.154053] [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: 10/14/2024] [Revised: 01/06/2025] [Accepted: 01/08/2025] [Indexed: 01/15/2025]
Abstract
N6-methyladenosine (m6A) modification and LncRNAs play crucial regulatory roles in various pathophysiological processes, yet roles of m6A modification and the relationship between m6A modification and LncRNAs in cadmium-induced oxidative damage of pancreatic β-cells have not been fully elucidated. In this study, m6A agonist entacapone and inhibitor 3-deazadenosine were used to identify the effects of m6A on cadmium-induced oxidative damage as well as LncRNA changes. Our results indicate that elevated levels of m6A modification by entacapone can rescue the cell viability and attenuate the cell apoptosis, while the inhibition levels of m6A modification can exacerbate the cell death. Furthermore, the elevation of m6A modification can recover cadmium-induced oxidative damage to pancreatic β-cells, which characterized as inhibition the ROS accumulation, MDA contents, protein expressions of Nrf2 and Ho-1, while elevation the expressions of Sod1 and Gclc. On the contrary, the reduction levels of m6A modification can exacerbate the cadmium-induced oxidative damage. More importantly, six significantly differentially expressed LncRNAs were selected according to our preliminary sequencing data (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE253072) and there is a clear correlation between the levels of these LncRNAs and m6A modification after cadmium treatment. Interestingly, the intervention of m6A modification levels can significantly affect the levels of these LncRNAs. In detail, the stimulation of m6A modification reversed the changes of cadmium-induced LncRNAs, while the m6A modification inhibition can significantly exacerbate the changes of cadmium-induced LncRNAs. In conclusion, our data revealed critical roles of m6A modification in cadmium-induced LncRNAs and oxidative damage. Our findings point to a new direction for future studies on the molecular mechanisms of pancreatic β-cell damage induced by cadmium.
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Affiliation(s)
- Guofen Liu
- School of Public Health, Dali University, Dali, Yunnan, China; Yiyang Vocational and Technical College, Yiyang, Hunan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China
| | - Jie Yang
- College of Engineering, Dali University, Dali, Yunnan, China
| | - Rongxian Li
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China
| | - Wenhong Li
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China
| | - De Liu
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China
| | - Nan Zhang
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China
| | - Yuan Zhao
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China
| | - Zuoshun He
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China
| | - Shiyan Gu
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China.
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6
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Lei L, Chen M, Qin C, Cai L, Liang B. Arsenic exposure accelerates type 1 diabetes mellitus progression via pyroptosis pathway in mice. Chem Biol Interact 2025; 406:111348. [PMID: 39675543 DOI: 10.1016/j.cbi.2024.111348] [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: 08/20/2024] [Revised: 11/05/2024] [Accepted: 12/12/2024] [Indexed: 12/17/2024]
Abstract
The relationship between arsenic exposure and the development of diabetes mellitus has garnered significant interest in recent years. However, current experimental studies have not definitively established the role of arsenic in the onset of diabetes mellitus. To investigate this relationship specifically concerning type 1 diabetes mellitus, Streptozocin (STZ) was utilized as an inducer to initiate the fundamental pathological changes associated with the disease. A high dose of STZ (50 mg/kg) served as the positive control, while a low dose of STZ (20 mg/kg) was administered in combination with arsenic at varying doses. The objective was to determine whether arsenic enhances the effects of STZ, thereby leading to an expedited onset and progression of type 1 diabetes mellitus. The preliminary investigation into the impact of arsenic exposure on experimental type 1 diabetic mice focused on the NLRP3/Caspase-1/GSDMD mediated pyroptosis pathway. The results showed that fasting blood glucose (FBG) was increased, glucose tolerance was impaired, insulin sensitivity was decreased, fasting serum insulin and the homeostatic model assessment-β (HOMA-β) were significantly reduced, hair arsenic content was increased, reactive oxygen species(ROS), interleukin (IL)-1β and IL-18 contents were increased, and the pathological morphology of pancreas was more serious in the combined group. Moreover, the expression levels of proteins associated with the NLRP3/Caspase-1/GSDMD-mediated pyroptosis pathway were elevated in the combined group. This study illustrates that exposure to arsenic, combined with low-dose STZ, not only leads to pancreatic injury in mice, impacting insulin secretion and causing elevated blood glucose levels, thereby hastening the progression of type 1 diabetes, but also induces pyroptosis in pancreatic tissues by influencing the NLRP3/Caspase-1/GSDMD signaling pathway, further facilitating the development of type 1 diabetes.
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Affiliation(s)
- Lichao Lei
- School of Basic Medicine, Guizhou Medical University, Guian New District, 561113, Guizhou, China
| | - Mengling Chen
- School of Basic Medicine, Guizhou Medical University, Guian New District, 561113, Guizhou, China
| | - Chuan Qin
- School of Basic Medicine, Guizhou Medical University, Guian New District, 561113, Guizhou, China
| | - Linli Cai
- School of Basic Medicine, Guizhou Medical University, Guian New District, 561113, Guizhou, China
| | - Bing Liang
- School of Basic Medicine, Guizhou Medical University, Guian New District, 561113, Guizhou, China; The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, Department of Toxicology, School of Public Health, Guizhou Medical University, Guian New District, 561113, Guizhou, China.
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7
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Moya-Gudiño V, Altamirano-Bustamante NF, Revilla-Monsalve C, Altamirano-Bustamante MM. Decoding the Contribution of IAPP Amyloid Aggregation to Beta Cell Dysfunction: A Systematic Review and Epistemic Meta-Analysis of Type 1 Diabetes. Int J Mol Sci 2025; 26:767. [PMID: 39859479 PMCID: PMC11766435 DOI: 10.3390/ijms26020767] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Revised: 12/30/2024] [Accepted: 12/31/2024] [Indexed: 01/27/2025] Open
Abstract
Diabetes Mellitus Type 1 (DM1) is an autoimmune disease characterized by the destruction of beta cells in the pancreas. Although amyloid formation has been well-studied in Diabetes Mellitus Type 2 (DM2), its role in DM1 remains unclear. Understanding how islet amyloid polypeptide (IAPP) contributes to beta cell dysfunction and death in DM1 could provide critical insights into disease mechanisms and pave the way for novel diagnostic and therapeutic strategies. A systematic review and epistemic meta-analysis was conducted using a modified PICO framework, focusing on studies related to DM1 and the IAPP aggregation process. Searches in PubMed, BIREME, and Web of Science yielded 37 relevant articles, which were analyzed and individually evaluated based on specific quality criteria. Studies that experimentally identified the formation of IAPP oligomers in DM1 were selected, along with relevant review articles. Experimental studies from human and animal models detected the presence of IAPP oligomers in DM1 patients, as well as in nonobese diabetic (NOD) and homozygous mice. Techniques like Western Blot (WB), Transmission Electron Microscopy (TEM) and Congo red staining detected various oligomers sizes, with smaller ones showing higher cytotoxicity. IAPP oligomers have been detected in the pancreatic islets of DM1 patients, contributing to beta cell damage and disease progression.
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Affiliation(s)
- Valeria Moya-Gudiño
- Unidad de Investigación en Enfermedades Metabólicas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (V.M.-G.); (C.R.-M.)
| | | | - Cristina Revilla-Monsalve
- Unidad de Investigación en Enfermedades Metabólicas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (V.M.-G.); (C.R.-M.)
| | - Myriam M. Altamirano-Bustamante
- Unidad de Investigación en Enfermedades Metabólicas, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City 06720, Mexico; (V.M.-G.); (C.R.-M.)
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Ren Y, Hu X, Qi M, Zhu W, Li J, Yang S, Dai C. Tangningtongluo Tablet ameliorates pancreatic damage in diabetic mice by inducing autophagy and inhibiting the PI3K/Akt/mTOR signaling pathway. Int Immunopharmacol 2024; 142:113032. [PMID: 39236456 DOI: 10.1016/j.intimp.2024.113032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2024] [Revised: 07/20/2024] [Accepted: 08/25/2024] [Indexed: 09/07/2024]
Abstract
BACKGROUND Diabetes is a metabolic disease characterized by hyperglycaemia. Tangningtongluo Tablet (TNTL) is an inpatient formula extensively utilized to treat diabetes mellitus (DM), but the protective mechanism is not clear. This study aimed to investigate the relevant mechanisms by which TNTL affects pancreatic damage in diabetic mice and autophagy. METHODS The impact of TNTL on pancreatic damage in diabetic mice in vitro and in vivo was investigated via glucose and lipid metabolism analyses, HE staining, CCK-8, TUNEL staining, Annexin V/PI, and Western blotting. Molecular docking and Western blotting were used to verify the results of network pharmacological analysis, which was carried out to explore the mechanism by which TNTL affects DM. The autophagosome levels were visualized via RFP-GFP-LC3 and transmission electron microscopy, and lysosomal function was evaluated via Lysotracker red staining. Western blot, immunohistochemistry and immunofluorescence staining were used to detect the expression of the autophagy proteins LC3, p62 and LAMP2. RESULTS Compared with the model group, TNTL protected pancreas from oxidative stress, decreased the level of MDA, increased the levels of SOD and GSH-px, induced the occurrence of autophagy and decreased the levels of apoptotic factors. Moreover, TNTL inhibited the protein expression of p-PI3K, p-Akt and p-mTOR, increased the levels of LC3 and LAMP2 and decreased the level of p62, and the autophagy inhibitor CQ blocked the protective effect of TNTL on pancreatic damage in diabetic mice. CONCLUSION These results demonstrated that TNTL ameliorated pancreatic damage in diabetic mice by inhibiting the PI3K/Akt/mTOR signaling and regulating autophagy.
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Affiliation(s)
- Ying Ren
- College of Basic Medicine, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Xiangka Hu
- Institute of Materia Medica, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Mushuang Qi
- College of Basic Medicine, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Wanjun Zhu
- College of Basic Medicine, Jinzhou Medical University, Jinzhou, Liaoning 121001, China
| | - Jin Li
- The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, China; School of Medicine, Xiamen University, Xiamen, Fujian 361005, China
| | - Shuyu Yang
- The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, China; School of Medicine, Xiamen University, Xiamen, Fujian 361005, China.
| | - Chunmei Dai
- Institute of Materia Medica, Jinzhou Medical University, Jinzhou, Liaoning 121001, China.
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Johnson-Pitt A, Catchpole B, Davison LJ. Exocrine pancreatic inflammation in canine diabetes mellitus - An active offender? Vet J 2024; 308:106241. [PMID: 39243807 DOI: 10.1016/j.tvjl.2024.106241] [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: 06/05/2024] [Revised: 08/27/2024] [Accepted: 09/01/2024] [Indexed: 09/09/2024]
Abstract
The purpose of this review is to examine the current scientific literature regarding the interplay between the exocrine and endocrine pancreas, specifically the role of the exocrine pancreas in the pathogenesis of canine diabetes mellitus. β-cell death caused by exocrine pancreatic inflammation is thought to be an under-recognised contributor to diabetes mellitus in dogs, with up to 30 % of canine diabetic patients with concurrent evidence of pancreatitis at post-mortem examination. Current diagnostics for pancreatitis are imprecise, and treatments for both diseases individually have their own limitations: diabetes through daily insulin injections, which has both welfare and financial implications for the stakeholders, and pancreatitis through treatment of clinical signs, such as analgesia and anti-emetics, rather than targeted treatment of the underlying cause. This review will consider the evidence for exocrine pancreatic inflammation making an active contribution to pancreatic β-cell loss and insulin-deficiency diabetes in the dog and explore current and potential future diagnostic and treatment avenues to improve outcomes for these patients.
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Affiliation(s)
- Arielle Johnson-Pitt
- Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire AL9 7TA, UK.
| | - Brian Catchpole
- Department of Pathobiology and Population Sciences, The Royal Veterinary College, Hertfordshire AL9 7TA, UK
| | - Lucy J Davison
- Department of Clinical Science and Services, The Royal Veterinary College, Hertfordshire AL9 7TA, UK; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford OX1 3PT, UK
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Ahmed I, Chakraborty R, Faizy AF, Moin S. Exploring the key role of DNA methylation as an epigenetic modulator in oxidative stress related islet cell injury in patients with type 2 diabetes mellitus: a review. J Diabetes Metab Disord 2024; 23:1699-1718. [PMID: 39610516 PMCID: PMC11599646 DOI: 10.1007/s40200-024-01496-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 08/21/2024] [Indexed: 11/30/2024]
Abstract
Type 2 diabetes mellitus (T2DM) is a multifactorial metabolic disorder characterised by impaired insulin secretion and action, often exacerbated by oxidative stress. Recent research has highlighted the intricate involvement of epigenetic mechanisms, particularly DNA methylation, in the pathogenesis of T2DM. This review aims to elucidate the role of DNA methylation as an epigenetic modifier in oxidative stress-mediated beta cell dysfunction, a key component of T2DM pathophysiology. Oxidative stress, arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defence mechanisms, is a hallmark feature of T2DM. Beta cells, responsible for insulin secretion, are particularly vulnerable to oxidative damage due to their low antioxidant capacity. Emerging evidence suggests that oxidative stress can induce aberrant DNA methylation patterns in beta cells, leading to altered gene expression profiles associated with insulin secretion and cell survival. Furthermore, studies have identified specific genes involved in beta cell function and survival that undergo DNA methylation changes in response to oxidative stress in T2DM. These epigenetic modifications can perpetuate beta cell dysfunction by dysregulating key pathways essential for insulin secretion, such as the insulin signalling cascade and mitochondrial function. Understanding the interplay between DNA methylation, oxidative stress, and beta cell dysfunction holds promise for developing novel therapeutic strategies for T2DM. Targeting aberrant DNA methylation patterns may offer new avenues for restoring beta cell function and improving glycemic control in patients with T2DM. However, further research is needed to elucidate the complex mechanisms underlying epigenetic regulation in T2DM and to translate these findings into clinical interventions.
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Affiliation(s)
- Istiaque Ahmed
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Ritoja Chakraborty
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Abul Faiz Faizy
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
| | - Shagufta Moin
- Department of Biochemistry, Faculty of Medicine, Jawaharlal Nehru Medical College and Hospital Aligarh Muslim University, Aligarh, Uttar Pradesh 202002 India
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11
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Ajiboye BO, Famusiwa CD, Oyedare DI, Julius BP, Adewole ZO, Ojo OA, Akindele AFI, Hosseinzadeh H, Brai BIC, Oyinloye BE, Vitalini S, Iriti M. Effect of Hibiscus sabdariffa L. leaf flavonoid-rich extract on Nrf-2 and HO-1 pathways in liver damage of streptozotocin-induced diabetic rats. Z NATURFORSCH C 2024:znc-2024-0182. [PMID: 39565955 DOI: 10.1515/znc-2024-0182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2024] [Accepted: 10/30/2024] [Indexed: 11/22/2024]
Abstract
This study investigated the effects of flavonoid-rich extract from Hibiscus sabdariffa L. (Malvaceae) leaves on liver damage in streptozotocin-induced diabetic rats by evaluating various biochemical parameters, including the molecular gene expressions of Nrf-2 and HO-1 as well as histological parameters. The extract was found to significantly reduce liver damage, as evidenced by lower levels of fragmented DNA and protein carbonyl concentrations. Oxidative stress markers, including malondialdehyde (MDA) level, were also significantly (p < 0.05) decreased, while antioxidant biomarkers, like reduced glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione-S-transferase (GST) were enhanced. Additionally, the extract improved the activities of key liver enzymes, including phosphatases and transaminases, and increased albumin levels. Importantly, the study demonstrated that H. sabdariffa extract effectively regulated the expression of Nrf-2 and HO-1, suggesting a significant role in mitigating liver damage. These findings highlight its potential as a therapeutic agent for liver protection in diabetic conditions.
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Affiliation(s)
- Basiru Olaitan Ajiboye
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Courage Dele Famusiwa
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Damilola Ifeoluwa Oyedare
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Biola Paul Julius
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Zainab Odunola Adewole
- Phytomedicine and Molecular Toxicology Research Laboratory, Department of Biochemistry, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Oluwafemi Adeleke Ojo
- Phytomedicine, Molecular Toxicology, and Computational Biochemistry Research Laboratory (PMTCB-RL), Department of Biochemistry, Bowen University, Iwo, 232101, Osun, Nigeria
| | - Ajoke Fehintola Idayat Akindele
- Department of Biosciences and Biotechnology, Environmental Management and Toxicology Unit, Faculty of Sciences, University of Medical Sciences, Ondo City, Ondo State, Nigeria
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bartholomew I C Brai
- Nutritional Biochemistry and Membrane Biochemistry, and Toxicology, Federal University Oye-Ekiti, Oye-Ekiti, Ekiti, Nigeria
| | - Babatunji Emmanuel Oyinloye
- Institute of Drug Research and Development, SE Bogoro Center, Afe Babalola University, Ado-Ekiti, Nigeria
- Phytomedicine, Biochemical Toxicology and Biotechnology Research Laboratories, Department of Biochemistry, College of Sciences, Afe Babalola University, Ado-Ekiti, Ekiti, Nigeria
- Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and Microbiology, University of Zululand, KwaDlangezwa, South Africa
| | - Sara Vitalini
- Department of Biomedical, Surgical and Dental Sciences, Università Degli Studi di Milano, Via G. Celoria 2, 20133, Milan, Italy
| | - Marcello Iriti
- Department of Biomedical, Surgical and Dental Sciences, Università Degli Studi di Milano, Via G. Celoria 2, 20133, Milan, Italy
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12
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Li X, Hong L, Ru M, Cai R, Meng Y, Wang B, Diao H, Li L, Wu Z. S100A8/A9-activated IFNγ + NK cells trigger β-cell necroptosis in hepatitis B virus-associated liver cirrhosis. Cell Mol Life Sci 2024; 81:345. [PMID: 39133305 PMCID: PMC11335268 DOI: 10.1007/s00018-024-05365-2] [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: 03/16/2024] [Revised: 06/19/2024] [Accepted: 07/15/2024] [Indexed: 08/13/2024]
Abstract
BACKGROUND AND AIMS Hepatitis B virus (HBV)-associated liver cirrhosis (LC), a common condition with high incidence and mortality rates, is often associated with diabetes mellitus (DM). However, the molecular mechanisms underlying impaired glucose regulation during HBV-associated LC remain unclear. METHODS Data from 63 patients with LC and 62 patients with LC-associated DM were analysed. Co-culture of NK cells and islet β cell lines were used to study the glucose regulation mechanism. A mouse model of LC was used to verify the effect of S100A8/A9 on the glucose regulation. RESULTS Higher levels of interferon (IFN)-γ derived from natural killer (NK) cells and lower levels of insulin emerged in the peripheral blood of patients with both LC and DM compared with those from patients with LC only. IFN-γ derived from NK cells facilitated β cell necroptosis and impaired insulin production. Furthermore, S100A8/A9 elevation in patients with both LC and DM was found to upregulate IFN-γ production in NK cells. Consistently, in the mouse model for LC, mice treated with carbon tetrachloride (CCL4) and S100A8/A9 exhibited increased blood glucose, impaired insulin production, increased IFN-γ, and increased β cells necroptosis compared with those treated with CCL4. Mechanistically, S100A8/A9 activated the p38 MAPK pathway to increase IFN-γ production in NK cells. These effects were diminished after blocking RAGE. CONCLUSION Together, the data indicate that IFN-γ produced by NK cells induces β cell necroptosis via the S100A8/A9-RAGE-p38 MAPK axis in patients with LC and DM. Reduced levels of S100A8/A9, NK cells, and IFN-γ could be valuable for the treatment of LC with DM. Accumulation of S100A8/A9 in patients with LC may indicate the emergence of DM.
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Affiliation(s)
- Xuehui Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Liang Hong
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - MingHui Ru
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Rui Cai
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Yuting Meng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China
| | - Baohua Wang
- Department of Ultrasound, College of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou, Zhejiang, 310000, People's Republic of China
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
| | - Lanjuan Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
- Jinan Microecological Biomedicine Shandong Laboratory, Jinan, People's Republic of China.
| | - Zhongwen Wu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People's Republic of China.
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13
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Zheng Z, Yang S, Dai W, Xue P, Sun Y, Wang J, Zhang X, Lin J, Kong J. The role of pyroptosis in metabolism and metabolic disease. Biomed Pharmacother 2024; 176:116863. [PMID: 38850650 DOI: 10.1016/j.biopha.2024.116863] [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: 03/01/2024] [Revised: 05/27/2024] [Accepted: 06/03/2024] [Indexed: 06/10/2024] Open
Abstract
Pyroptosis is a lytic and pro-inflammatory form of regulated cell death characterized by the formation of membrane pores mediated by the gasdermin protein family. Two main activation pathways have been documented: the caspase-1-dependent canonical pathway and the caspase-4/5/11-dependent noncanonical pathway. Pyroptosis leads to cell swelling, lysis, and the subsequent release of inflammatory mediators, including interleukin-1β (IL-1β) and interleukin-18 (IL-18). Chronic inflammation is a well-established foundation and driver for the development of metabolic diseases. Conversely, metabolic pathway dysregulation can also induce cellular pyroptosis. Recent studies have highlighted the significant role of pyroptosis modulation in various metabolic diseases, including type 2 diabetes mellitus, obesity, and metabolic (dysfunction) associated fatty liver disease. These findings suggest that pyroptosis may serve as a promising novel therapeutic target for metabolic diseases. This paper reviews an in-depth study of the current advancements in understanding the role of pyroptosis in the progression of metabolic diseases.
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Affiliation(s)
- Zhuyuan Zheng
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, PR China
| | - Shaojie Yang
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, PR China
| | - Wanlin Dai
- Innovation Institute of China Medical University, Shenyang 110122, PR China
| | - Pengwei Xue
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, PR China
| | - Yang Sun
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, PR China
| | - Jingnan Wang
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, PR China
| | - Xiaolin Zhang
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, PR China
| | - Jiang Lin
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, PR China
| | - Jing Kong
- Biliary Surgery (2nd General) Unit, Department of General Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, PR China.
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14
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Kelepouras K, Saggau J, Varanda AB, Zrilic M, Kiefer C, Rakhsh-Khorshid H, Lisewski I, Uranga-Murillo I, Arias M, Pardo J, Tonnus W, Linkermann A, Annibaldi A, Walczak H, Liccardi G. The importance of murine phospho-MLKL-S345 in situ detection for necroptosis assessment in vivo. Cell Death Differ 2024; 31:897-909. [PMID: 38783091 PMCID: PMC11239901 DOI: 10.1038/s41418-024-01313-6] [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: 12/20/2023] [Revised: 05/02/2024] [Accepted: 05/07/2024] [Indexed: 05/25/2024] Open
Abstract
Necroptosis is a caspase-independent modality of cell death implicated in many inflammatory pathologies. The execution of this pathway requires the formation of a cytosolic platform that comprises RIPK1 and RIPK3 which, in turn, mediates the phosphorylation of the pseudokinase MLKL (S345 in mouse). The activation of this executioner is followed by its oligomerisation and accumulation at the plasma-membrane where it leads to cell death via plasma-membrane destabilisation and consequent permeabilisation. While the biochemical and cellular characterisation of these events have been amply investigated, the study of necroptosis involvement in vivo in animal models is currently limited to the use of Mlkl-/- or Ripk3-/- mice. Yet, even in many of the models in which the involvement of necroptosis in disease aetiology has been genetically demonstrated, the fundamental in vivo characterisation regarding the question as to which tissue(s) and specific cell type(s) therein is/are affected by the pathogenic necroptotic death are missing. Here, we describe and validate an immunohistochemistry and immunofluorescence-based method to reliably detect the phosphorylation of mouse MLKL at serine 345 (pMLKL-S345). We first validate the method using tissues derived from mice in which Caspase-8 (Casp8) or FADD are specifically deleted from keratinocytes, or intestinal epithelial cells, respectively. We next demonstrate the presence of necroptotic activation in the lungs of SARS-CoV-infected mice and in the skin and spleen of mice bearing a Sharpin inactivating mutation. Finally, we exclude necroptosis occurrence in the intestines of mice subjected to TNF-induced septic shock. Importantly, by directly comparing the staining of pMLKL-345 with that of cleaved Caspase-3 staining in some of these models, we identify spatio-temporal and functional differences between necroptosis and apoptosis supporting a role of RIPK3 in inflammation independently of MLKL versus the role of RIPK3 in activation of necroptosis.
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Grants
- Wellcome Trust
- G.L. is funded by the Center for Biochemistry, Univeristy of Cologne - 956400, Köln Fortune, CANcer TARgeting (CANTAR) project NW21-062A, two collaborative research center grants: SFB1399-413326622 Project C06, SFB1530-455784452 Project A03 both funded by the Deutsche Forschungsgemeinschaft (DFG)) and associated to the collaborative SFB1403 also funded by the DFG
- H.W. is funded by the Alexander von Humboldt Foundation, a Wellcome Trust Investigator Award (214342/Z/18/Z), a Medical Research Council Grant (MR/S00811X/1), a Cancer Research UK Programme Grant (A27323) and three collaborative research center grants (SFB1399, Project C06, SFB1530-455784452, Project A03 and SFB1403–414786233) funded by the Deutsche Forschungsgemeinschaft (DFG) and CANcer TARgeting (CANTAR) funded by Netzwerke 2021.
- AA is funded by the Center for Molecular Medine Cologne (CMMC) Junior Research Group program, Deutsche Forschungsgemeinschaft (DFG) (project number AN1717/1-1), the Jürgen Manchot Stiftung foundation, the collaborative research center SFB1530 (Project A5, ID: 455784452)
- JP is funded by FEDER (Fondo Europeo de Desarrollo Regional), Gobierno de Aragón (Group B29_23R), CIBERINFEC (CB21/13/00087), Ministerio de Ciencia, Innovación y Universidades (MCNU)/Agencia Estatal de Investigación (PID2020-113963RBI00)
- MA is funded by a Postdoctoral Juan de la Cierva Contract.
- Work in the Linkermann Lab was funded by the German Research Foundation SFB-TRR205, SFB-TRR 127, SPP2306, and a Heisenberg-Professorship to A.L., project number 324141047, and the international research training group (IRTG) 2251. It was further supported by the BMBF (FERROPath consortium), the TU Dresden / Kings College London transcampus initiative and the DFG-Sachbeihilfe LI 2107/10-1.
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Affiliation(s)
- Konstantinos Kelepouras
- Genome Instability, Inflammation and Cell Death Laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, 50931, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany
| | - Julia Saggau
- Genome Instability, Inflammation and Cell Death Laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, 50931, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany
- Cell Death, Inflammation and Immunity Laboratory, CECAD Cluster of Excellence, University of Cologne, 50931, Cologne, Germany
- Cell Death, Inflammation and Immunity Laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, 50931, Cologne, Germany
| | - Ana Beatriz Varanda
- Cell Death, Inflammation and Immunity Laboratory, CECAD Cluster of Excellence, University of Cologne, 50931, Cologne, Germany
- Cell Death, Inflammation and Immunity Laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, 50931, Cologne, Germany
| | - Matea Zrilic
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany
| | - Christine Kiefer
- Genome Instability, Inflammation and Cell Death Laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, 50931, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany
| | - Hassan Rakhsh-Khorshid
- Genome Instability, Inflammation and Cell Death Laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, 50931, Cologne, Germany
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany
| | - Ina Lisewski
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany
| | - Iratxe Uranga-Murillo
- Department of Microbiology, Radiology, Paediatry and Public Heath, Faculty of Medicine, University of Zaragoza/IIS, Aragon, Spain
- Centro de Investigacion Biomedica en Red de Enfermedades infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Maykel Arias
- Department of Microbiology, Radiology, Paediatry and Public Heath, Faculty of Medicine, University of Zaragoza/IIS, Aragon, Spain
- Centro de Investigacion Biomedica en Red de Enfermedades infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Julian Pardo
- Department of Microbiology, Radiology, Paediatry and Public Heath, Faculty of Medicine, University of Zaragoza/IIS, Aragon, Spain
- Centro de Investigacion Biomedica en Red de Enfermedades infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain
| | - Wulf Tonnus
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
| | - Andreas Linkermann
- Division of Nephrology, Department of Internal Medicine 3, University Hospital Carl Gustav Carus at the Technische Universität Dresden, Dresden, Germany
- Division of Nephrology, Department of Medicine, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Alessandro Annibaldi
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany
| | - Henning Walczak
- Cell Death, Inflammation and Immunity Laboratory, CECAD Cluster of Excellence, University of Cologne, 50931, Cologne, Germany
- Cell Death, Inflammation and Immunity Laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, 50931, Cologne, Germany
- Centre for Cell Death, Cancer and Inflammation, UCL Cancer Institute, University College London, WC1E 6BT, London, UK
| | - Gianmaria Liccardi
- Genome Instability, Inflammation and Cell Death Laboratory, Institute of Biochemistry I, Centre for Biochemistry, Faculty of Medicine, University of Cologne, 50931, Cologne, Germany.
- Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931, Cologne, Germany.
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15
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Ortega-Cuellar D, González-Sánchez I, Piñón-Zárate G, Cerbón MA, De la Rosa V, Franco-Juárez Y, Castell-Rodríguez A, Islas LD, Coronel-Cruz C. Protector Role of Cx30.2 in Pancreatic β-Cell against Glucotoxicity-Induced Apoptosis. BIOLOGY 2024; 13:468. [PMID: 39056663 PMCID: PMC11273625 DOI: 10.3390/biology13070468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/07/2024] [Accepted: 06/16/2024] [Indexed: 07/28/2024]
Abstract
Glucotoxicity may exert its deleterious effects on pancreatic β-cell function via a myriad of mechanisms, leading to impaired insulin secretion and, eventually, type 2 diabetes. β-cell communication requires gap junction channels to be present among these cells. Gap junctions are constituted by transmembrane proteins of the connexins (Cxs) family. Two Cx genes have been identified in β cells, Cx36 and Cx30.2. We have found evidence that the glucose concentration on its own is sufficient to regulate Cx30.2 gene expression in mouse islets. In this work, we examine the involvement of the Cx30.2 protein in the survival of β cells (RIN-m5F). METHODS RIN-m5F cells were cultured in 5 mM D-glucose (normal) or 30 mM D-glucose (high glucose) for 24 h. Cx30.2 siRNAs was used to downregulate Cx30.2 expression. Apoptosis was measured by means of TUNEL, an annexin V staining method, and the cleaved form of the caspase-3 protein was determined using Western blot. RESULTS High glucose did not induce apoptosis in RIN-m5F β cells after 24 h; interestingly, high glucose increased the Cx30.2 total protein levels. Moreover, this work found that the downregulation of Cx30.2 expression in high glucose promoted apoptosis in RIN-m5F cells. CONCLUSION The data suggest that the upregulation of Cx30.2 protects β cells from hyperglycemia-induced apoptosis. Furthermore, Cx30.2 may be a promising avenue of therapeutic investigation for the treatment of glucose metabolic disorders.
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Affiliation(s)
- Daniel Ortega-Cuellar
- Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico; (D.O.-C.); (Y.F.-J.)
| | - Ignacio González-Sánchez
- Departamento de Biología, Facultad de Química, UNAM, Mexico City 04510, Mexico; (I.G.-S.); (M.A.C.)
| | - Gabriela Piñón-Zárate
- Departamento de Biología Celular y Tisular, Facultad de Medicina, UNAM, Mexico City 04510, Mexico; (G.P.-Z.); (A.C.-R.)
| | - Marco A. Cerbón
- Departamento de Biología, Facultad de Química, UNAM, Mexico City 04510, Mexico; (I.G.-S.); (M.A.C.)
| | - Víctor De la Rosa
- Departamento de Fisiología, Facultad de Medicina, UNAM, Mexico City 04510, Mexico; (V.D.l.R.); (L.D.I.)
| | - Yuliana Franco-Juárez
- Laboratorio de Nutrición Experimental, Instituto Nacional de Pediatría, Secretaría de Salud, Mexico City 04530, Mexico; (D.O.-C.); (Y.F.-J.)
| | - Andrés Castell-Rodríguez
- Departamento de Biología Celular y Tisular, Facultad de Medicina, UNAM, Mexico City 04510, Mexico; (G.P.-Z.); (A.C.-R.)
| | - León D. Islas
- Departamento de Fisiología, Facultad de Medicina, UNAM, Mexico City 04510, Mexico; (V.D.l.R.); (L.D.I.)
| | - Cristina Coronel-Cruz
- Departamento de Biología Celular y Tisular, Facultad de Medicina, UNAM, Mexico City 04510, Mexico; (G.P.-Z.); (A.C.-R.)
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16
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Lv J, Su M, Wang Y, Yang J, Liang Y, Chen L, Lei L. Yunvjian decoction mitigates hyperglycemia in rats induced by a high-fat diet and streptozotocin via reducing oxidative stress in pancreatic beta cells. JOURNAL OF ETHNOPHARMACOLOGY 2024; 327:118045. [PMID: 38479546 DOI: 10.1016/j.jep.2024.118045] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/21/2023] [Revised: 02/27/2024] [Accepted: 03/10/2024] [Indexed: 03/19/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Yunvjian (YNJ), a traditional Chinese herbal formula first reported in Jing Yue Quan Shu, is commonly used in the clinical treatment of type 2 diabetes mellitus (T2DM). However, the mechanism by which YNJ affects T2DM remains unclear. AIM OF THE STUDY This study aimed to assess the therapeutic effects of YNJ on T2DM and explore the potential mechanism involved. MATERIALS AND METHODS High-performance liquid chromatography (HPLC) was used to identify the chemical compounds of YNJ. The anti-T2DM effects of YNJ were observed in a high-fat diet/streptozotocin induced rat model. The type 2 diabetic rats were prepared as follows: rats were fed a high-fat diet for four weeks and then intraperitoneally injected with a low dose (30 mg/kg) of streptozotocin. YNJ and the positive control metformin were used in these experiments. Biochemical assays were implemented to determine the fasting blood glucose, glucose tolerance, insulin sensitivity, serum lipid levels, and oxidative stress index of the pancreas. Hematoxylin-eosin (H&E) staining was used to assess histopathological alterations in the pancreas. The mechanism by which YNJ affects T2DM was evaluated in INS-1 cells treated with glucose and high sodium palmitate. YNJ-supplemented serum was used in these experiments. Methyl thiazolyl tetrazolium assays, enzyme-linked immunosorbent assays, Nile red staining, flow cytometric analysis, and Western blotting were used to assess apoptosis, insulin secretion, lipid accumulation, reactive oxygen species production, and protein levels. RESULTS Five major compounds were identified in YNJ. In high-fat diet/streptozotocin-induced diabetic rats, YNJ-M notably decreased fasting blood glucose and lipid levels; ameliorated glucose tolerance, insulin sensitivity, and islet morphology; reduced Malondialdehyde levels; and restored superoxide dismutase activity in the pancreatic islets. Furthermore, the effect of YNJ-M was significantly greater than that of YNJ-L, and YNJ-H had little effect on diabetic rats. In vitro experiments revealed that YNJ-supplemented serum (10%, 15%, and 20%) dramatically suppressed apoptosis, mitigated intracellular lipid accumulation and reduced intracellular oxidative stress levels in a dose-dependent manner. Additionally, YNJ-supplemented serum increased the protein expression of Nuclear factor erythroid 2-related factor 2, Heme oxygenase-1, and superoxide dismutase 1 and inhibited the protein expression of Kelch-like ECH-associated protein 1. CONCLUSION YNJ ameliorates high-fat diet/streptozotocin induced experimental T2DM. The underlying mechanism involves reducing oxidative stress in pancreatic beta cells. The findings of this study provide scientific justification for the application of the traditional medicine YNJ in treating T2DM.
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Affiliation(s)
- Jie Lv
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang, 712083, China; Department of Pharmacology, Shaanxi University of Chinese Medicine & Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine & Engineering Research Center of Brain Health Industry of Chinese Medicine, Universities of Shaanxi Province, Xianyang, 712046, China.
| | - Meng Su
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang, 712083, China; Department of Pharmacology, Shaanxi University of Chinese Medicine & Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine & Engineering Research Center of Brain Health Industry of Chinese Medicine, Universities of Shaanxi Province, Xianyang, 712046, China.
| | - Yansong Wang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang, 712083, China; Department of Pharmacology, Shaanxi University of Chinese Medicine & Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine & Engineering Research Center of Brain Health Industry of Chinese Medicine, Universities of Shaanxi Province, Xianyang, 712046, China
| | - Juan Yang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang, 712083, China; Department of Pharmacology, Shaanxi University of Chinese Medicine & Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine & Engineering Research Center of Brain Health Industry of Chinese Medicine, Universities of Shaanxi Province, Xianyang, 712046, China
| | - Yanni Liang
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang, 712083, China; Department of Pharmacology, Shaanxi University of Chinese Medicine & Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine & Engineering Research Center of Brain Health Industry of Chinese Medicine, Universities of Shaanxi Province, Xianyang, 712046, China
| | - Lin Chen
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang, 712083, China; Department of Pharmacology, Shaanxi University of Chinese Medicine & Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine & Engineering Research Center of Brain Health Industry of Chinese Medicine, Universities of Shaanxi Province, Xianyang, 712046, China
| | - Liyan Lei
- Co-construction Collaborative Innovation Center for Chinese Medicine Resources Industrialization by Shaanxi & Education Ministry, State Key Laboratory of Research & Development of Characteristic Qin Medicine Resources (Cultivation), Shaanxi University of Chinese Medicine, Xianyang, 712083, China; Department of Pharmacology, Shaanxi University of Chinese Medicine & Key Laboratory of Pharmacodynamics and Material Basis of Chinese Medicine of Shaanxi Administration of Traditional Chinese Medicine & Engineering Research Center of Brain Health Industry of Chinese Medicine, Universities of Shaanxi Province, Xianyang, 712046, China.
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Pang H, Huang G, Xie Z, Zhou Z. The role of regulated necrosis in diabetes and its complications. J Mol Med (Berl) 2024; 102:495-505. [PMID: 38393662 DOI: 10.1007/s00109-024-02421-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 12/21/2023] [Accepted: 01/16/2024] [Indexed: 02/25/2024]
Abstract
Morphologically, cell death can be divided into apoptosis and necrosis. Apoptosis, which is a type of regulated cell death, is well tolerated by the immune system and is responsible for hemostasis and cellular turnover under physiological conditions. In contrast, necrosis is defined as a form of passive cell death that leads to a dramatic inflammatory response (also referred to as necroinflammation) and causes organ dysfunction under pathological conditions. Recently, a novel form of cell death named regulated necrosis (such as necroptosis, pyroptosis, and ferroptosis) was discovered. Distinct from apoptosis, regulated necrosis is modulated by multiple internal or external factors, but meanwhile, it results in inflammation and immune response. Accumulating evidence has indicated that regulated necrosis is associated with multiple diseases, including diabetes. Diabetes is characterized by hyperglycemia caused by insulin deficiency and/or insulin resistance, and long-term high glucose leads to various diabetes-related complications. Here, we summarize the mechanisms of necroptosis, pyroptosis, and ferroptosis, and introduce recent advances in characterizing the associations between these three types of regulated necrosis and diabetes and its complications.
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Affiliation(s)
- Haipeng Pang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Gan Huang
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China
| | - Zhiguo Xie
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
| | - Zhiguang Zhou
- National Clinical Research Center for Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan, China.
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18
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Xu W, Wang H, Sun Q, Hua T, Bai J, Zhang Q, Liu Q, Ni X. TXNIP-NLRP3-GSDMD axis-mediated inflammation and pyroptosis of islet β-cells is involved in cigarette smoke-induced hyperglycemia, which is alleviated by andrographolide. ENVIRONMENTAL TOXICOLOGY 2024; 39:1415-1428. [PMID: 37987454 DOI: 10.1002/tox.24046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 10/25/2023] [Accepted: 10/31/2023] [Indexed: 11/22/2023]
Abstract
Epidemiologic surveys have indicated that cigarette smoking is an important risk factor for diabetes, but its mechanisms remain unclear. Andrographolide, an herb traditionally utilized in medicine, provides anti-inflammatory benefits for various diseases. In the present work, 265 patients with Type 2 diabetes (T2D) were investigated, and male C57BL/6 mice were exposed to cigareete smoke (CS) and/or to intraperitoneally injected andrographolide for 3 months. To elucidate the mechanism of CS-induced hyperglycemia and the protective mechanism of andrographolide, MIN6 cells were exposed to cigarette smoke extract (CSE) and/or to andrographolide. Our data from 265 patients with T2D showed that urinary creatinine and serum inflammatory cytokines (interleukin 6 (IL-6), IL-8, IL-1β, and tumor necrosis factor α (TNF-α)) increased with smoking pack-years. In a mouse model, CS induced hyperglycemia, decreased insulin secretion, and elevated inflammation and pyroptosis in β-cells of mice. Treatment of mice with andrographolide preserved pancreatic function by reducing the expression of inflammatory cytokines; the expression of TXNIP, NLRP3, cleaved caspase 1, IL-1β; and the N-terminal of gasdermin D (GSDMD) protein. For MIN6 cells, CSE caused increasing secretion of the inflammatory cytokines IL-6 and IL-1β, and the expression of TXNIP and pyroptosis-related proteins; however, andrographolide alleviated these changes. Furthermore, silencing of TXNIP showed that the blocking effect of andrographolide may be mediated by TXNIP. In sum, our results indicate that CS induces hyperglycemia through TXNIP-NLRP3-GSDMD axis-mediated inflammation and pyroptosis of islet β-cells and that andrographolide is a potential therapeutic agent for CS-induced hyperglycemia.
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Affiliation(s)
- Wenchao Xu
- The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, People's Republic of China
- Changzhou Center for Disease Control and Prevention, Changzhou Advanced Institute of Public Health, Nanjing Medical University, Changzhou, People's Republic of China
| | - Hailan Wang
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China
- Environmental health effects and risk assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou, People's Republic of China
| | - Qian Sun
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, Dongguan, People's Republic of China
| | - Tianqi Hua
- Changzhou Center for Disease Control and Prevention, Changzhou Advanced Institute of Public Health, Nanjing Medical University, Changzhou, People's Republic of China
| | - Jun Bai
- Environmental health effects and risk assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou, People's Republic of China
| | - Qingbi Zhang
- Environmental health effects and risk assessment Key Laboratory of Luzhou, School of Public Health, Southwest Medical University, Luzhou, People's Republic of China
| | - Qizhan Liu
- The Key Laboratory of Modern Toxicology, Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China
| | - Xinye Ni
- The Affiliated Changzhou Second People's Hospital of Nanjing Medical University, Changzhou Medical Center, Nanjing Medical University, Changzhou, People's Republic of China
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19
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Fletcher JD, Olsson GE, Zhang YC, Burkhardt BR. Oral gavage delivery of Cornus officinalis extract delays type 1 diabetes onset and hyperglycemia in non-obese diabetic (NOD) mice. FEBS Open Bio 2024; 14:434-443. [PMID: 38129973 PMCID: PMC10909980 DOI: 10.1002/2211-5463.13758] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 12/12/2023] [Accepted: 12/20/2023] [Indexed: 12/23/2023] Open
Abstract
Type 1 diabetes (T1D) is an autoimmune disease initiated by genetic predisposition and environmental influences, which result in the specific destruction of insulin-producing pancreatic β-cells. Currently, there are over 1.6 million cases of T1D in the United States with a worldwide incidence rate that has been increasing since 1990. Here, we examined the effect of Cornus officinalis (CO), a well-known ethnopharmacological agent, on a T1D model of the non-obese diabetic (NOD) mouse. A measured dose of CO extract was delivered into 10-week-old NOD mice by oral gavage for 15 weeks. T1D incidence and hyperglycemia were significantly lower in the CO-treated group as compared to the water gavage (WT) and a no handling or treatment control group (NHT) following treatment. T1D onset per group was 30%, 60% and 86% for the CO, WT and NHT groups, respectively. Circulating C-peptide was higher, and pancreatic insulitis was decreased in non-T1D CO-treated mice. Our findings suggest that CO may have therapeutic potential as both a safe and effective interventional agent to slow early stage T1D progression.
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Affiliation(s)
- Justin D. Fletcher
- Department of Molecular BiosciencesUniversity of South FloridaTampaFLUSA
| | - Grace E. Olsson
- Department of Molecular BiosciencesUniversity of South FloridaTampaFLUSA
| | | | - Brant R. Burkhardt
- Department of Molecular BiosciencesUniversity of South FloridaTampaFLUSA
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20
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Smink AM, Medina JD, de Haan BJ, García AJ, de Vos P. Necrostatin-1 releasing nanoparticles: In vitro and in vivo efficacy for supporting immunoisolated islet transplantation outcomes. J Biomed Mater Res A 2024; 112:288-295. [PMID: 37776226 DOI: 10.1002/jbm.a.37623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 09/18/2023] [Accepted: 09/20/2023] [Indexed: 10/02/2023]
Abstract
Immunoisolation of pancreatic islets in alginate microcapsules allows for transplantation in the absence of immunosuppression but graft survival time is still limited. This limited graft survival is caused by a combination of tissue responses to the encapsulating biomaterial and islets. A significant loss of islet cells occurs in the immediate period after transplantation and is caused by a high susceptibility of islet cells to inflammatory stress during this period. Here we investigated whether necrostatin-1 (Nec-1), a necroptosis inhibitor, can reduce the loss of islet cells under stress in vitro and in vivo. To this end, we developed a Nec-1 controlled-release system using poly (D,L-lactide-co-glycolide) (PLGA) nanoparticles (NPs) as the application of Nec-1 in vivo is limited by low stability and possible side effects. The PLGA NPs stably released Nec-1 for 6 days in vitro and protected beta cells against hypoxia-induced cell death in vitro. Treatment with these Nec-1 NPs at days 0, 6, and 12 post-islet transplantation in streptozotocin-diabetic mice confirmed the absence of side effects as graft survival was similar in encapsulated islet grafts in the absence and presence of Nec-1. However, we found no further prolongation of graft survival of encapsulated grafts which might be explained by the high biocompatibility of the alginate encapsulation system that provoked a very mild tissue response. We expect that the Nec-1-releasing NPs could find application to immunoisolation systems that elicit stronger inflammatory responses, such as macrodevices and vasculogenic biomaterials.
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Affiliation(s)
- Alexandra M Smink
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Juan D Medina
- Petit Institute for Bioengineering and Bioscience, Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Bart J de Haan
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Andrés J García
- Petit Institute for Bioengineering and Bioscience, Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, USA
| | - Paul de Vos
- Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Yang X, Deng H, Lv J, Chen X, Zeng L, Weng J, Liang H, Xu W. Comparison of changes in adipokine and inflammatory cytokine levels in patients with newly diagnosed type 2 diabetes treated with exenatide, insulin, or pioglitazone: A post-hoc study of the CONFIDENCE trial. Heliyon 2024; 10:e23309. [PMID: 38169889 PMCID: PMC10758788 DOI: 10.1016/j.heliyon.2023.e23309] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2023] [Revised: 11/23/2023] [Accepted: 11/30/2023] [Indexed: 01/05/2024] Open
Abstract
Background Adipokines and inflammatory cytokines (ADICs) play important roles in type 2 diabetes mellitus (T2DM). This study aimed to compare the changes of ADIC levels (ΔADICs) in patients with newly diagnosed T2DM treated with different antihyperglycemic agents, and further investigate the impact of these changes on metabolic indices, β-cell function and insulin resistance (IR). Methods Four hundred and sixteen patients with newly diagnosed T2DM from 25 centers in China randomly received 48-week intervention with exenatide, insulin or pioglitazone. Anthropometric and laboratory data, indices of β-cell function and IR, and levels of AIDCs, including interleukin-1 beta (IL-1β), interferon-gamma (IFN-γ), leptin, and fibroblast growth factor 21 (FGF21) were detected at baseline and the end of the study. Results In total, 281 participants (68 % male, age: 50.3 ± 9.4 years) completed the study. After 48- week treatment, IL-1β and IFN-γ were significantly decreased with exenatide treatment (P < 0.001 and P = 0.001, respectively), but increased with insulin (P = 0.009 and P = 0.026, respectively). However, pioglitazone treatment had no impact on ADICs. No significant change in leptin or FGF21 was detected with any of the treatments. After adjustment for baseline values and changes of body weight, waist and HbA1c, the between-group differences were found in ΔIL-1β (exenatide vs. insulin: P = 0.048; and exenatide vs. pioglitazone: P = 0.003, respectively) and ΔIFN-γ (exenatide vs. insulin: P = 0.049; and exenatide vs. pioglitazone: P < 0.001, respectively). Multiple linear regression analysis indicated that Δweight was associated with ΔIL-1β (β = 0.753; 95 % CI, 0.137-1.369; P = 0.017). After adjusting for treatment effects, Δweight was also be correlated with ΔFGF21 (β = 1.097; 95%CI, 0.250-1.944; P = 0.012); furthermore, ΔHOMA-IR was correlated with Δleptin (β = 0.078; 95%CI, 0.008-0.147; P = 0.029) as well. However, ΔHOMA-IR was not significantly associated with ΔIL-1β after adjusting for treatment effects (P = 0.513). Conclusion Exenatide treatment led to significant changes of inflammatory cytokines levels (IL-1β and IFN-γ), but not adipokines (leptin and FGF21), in newly diagnosed T2DM patients. The exenatide-mediated improvement in weight and IR may be associated with a decrease in inflammatory cytokine levels.
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Affiliation(s)
- Xubin Yang
- Department of Endocrinology and Metabolism, the 3rd Affiliated Hospital of Sun Yat-sen University. NO.600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Hongrong Deng
- Department of Endocrinology and Metabolism, the 3rd Affiliated Hospital of Sun Yat-sen University. NO.600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Jing Lv
- Department of Endocrinology and Metabolism, the 3rd Affiliated Hospital of Sun Yat-sen University. NO.600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Xueyan Chen
- Department of Endocrinology and Metabolism, the 3rd Affiliated Hospital of Sun Yat-sen University. NO.600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Longyi Zeng
- Department of Endocrinology and Metabolism, the 3rd Affiliated Hospital of Sun Yat-sen University. NO.600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
| | - Jianping Weng
- Department of Endocrinology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China (USTC), Hefei, China
| | - Hua Liang
- Department of Endocrinology and Metabolism, Shunde Hospital of Southern Medical University (The First People's Hospital of Shunde), Foshan, China
| | - Wen Xu
- Department of Endocrinology and Metabolism, the 3rd Affiliated Hospital of Sun Yat-sen University. NO.600, Tianhe Road, Tianhe District, Guangzhou, Guangdong, 510630, China
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22
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Sultana A, Borgohain R, Rayaji A, Saha D, Kumar Das B. Promising Phytoconstituents in Diabetes-related Wounds: Mechanistic Insights and Implications. Curr Diabetes Rev 2024; 21:e270224227477. [PMID: 38424430 DOI: 10.2174/0115733998279112240129074457] [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: 09/11/2023] [Revised: 01/05/2024] [Accepted: 01/16/2024] [Indexed: 03/02/2024]
Abstract
BACKGROUND The onset of diabetes mellitus (DM), a metabolic disorder characterized by high blood glucose levels and disrupted glucose metabolism, results in 20% of people with diabetes suffering from diabetes-related wounds worldwide. A minor wound, such as a cut or abrasion, can lead to infections and complications in diabetic patients. We must understand the mechanism/s contributing to this delayed wound healing to develop effective prevention strategies. The potential benefits of bioactive phytochemicals for diabetic wound healing have been reported in numerous studies. METHOD A bioactive compound may have multiple actions, including antioxidants, antiinflammatory, antimicrobial, and angiogenesis. Compounds derived from these plants have shown promising results in wound healing, inflammation reduction, collagen synthesis, and neovascularization improvement. RESULTS Consequently, this review provides an update to our understanding of how phytoconstituents promote wound healing in diabetics. A thorough literature review was conducted on diabetes, wound healing, and phytoconstituents for this study. Only English publications until June 2023 were included in the search, which used multiple search engines and the main keywords. Summing up, phytochemical-based interventions might improve the quality of life for diabetics by improving wound healing. CONCLUSION However, to fully understand the efficacy and safety of these phytochemicals in managing diabetic wounds, more research and clinical trials are needed.
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Affiliation(s)
- Arjina Sultana
- Department of Pharmacology, School of Pharmaceutical Sciences, Girijananda Chowdhury University, Azara, Guwahati 781017, Assam, India
| | - Ranadeep Borgohain
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Girijananda Chowdhury University, Azara, Guwahati 781017, Assam, India
| | - Ashwini Rayaji
- Department of Pharmaceutical Chemistry, KRE's Karnataka College of Pharmacy, Bidar 585403, Karnataka, India
| | - Dipankar Saha
- Department of Pharmacology, School of Pharmaceutical Sciences, Girijananda Chowdhury University, Azara, Guwahati 781017, Assam, India
| | - Bhrigu Kumar Das
- Department of Pharmacology, School of Pharmaceutical Sciences, Girijananda Chowdhury University, Azara, Guwahati 781017, Assam, India
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23
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Khin PP, Lee JH, Jun HS. Pancreatic Beta-cell Dysfunction in Type 2 Diabetes. EUR J INFLAMM 2023. [DOI: 10.1177/1721727x231154152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Pancreatic β-cells produce and secrete insulin to maintain blood glucose levels within a narrow range. Defects in the function and mass of β-cells play a significant role in the development and progression of diabetes. Increased β-cell deficiency and β-cell apoptosis are observed in the pancreatic islets of patients with type 2 diabetes. At an early stage, β-cells adapt to insulin resistance, and their insulin secretion increases, but they eventually become exhausted, and the β-cell mass decreases. Various causal factors, such as high glucose, free fatty acids, inflammatory cytokines, and islet amyloid polypeptides, contribute to the impairment of β-cell function. Therefore, the maintenance of β-cell function is a logical approach for the treatment and prevention of diabetes. In this review, we provide an overview of the role of these risk factors in pancreatic β-cell loss and the associated mechanisms. A better understanding of the molecular mechanisms underlying pancreatic β-cell loss will provide an opportunity to identify novel therapeutic targets for type 2 diabetes.
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Affiliation(s)
- Phyu Phyu Khin
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155, Gaetbeol-ro, Yeonsu-gu, Incheon 21999, Republic of Korea
| | - Jong Han Lee
- Department of Marine Bio-industry, Hanseo University, Seosan, Korea
| | - Hee-Sook Jun
- Lee Gil Ya Cancer and Diabetes Institute, Gachon University, 155, Gaetbeol-ro, Yeonsu-gu, Incheon 21999, Republic of Korea
- College of Pharmacy and Gachon Institute of Pharmaceutical Science, Gachon University, 191, Hambangmoe-ro, Yeonsu-gu, Incheon 21936, Republic of Korea
- Gachon Medical Research Institute, Gil Hospital, 21, Namdong-daero 774, beon-gil, Namdong-gu, Incheon, 21565, Republic of Korea
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Yu Q, Chen Y, Zhao Y, Huang S, Xin X, Jiang L, Wang H, Wu W, Qu L, Xiang C, Wang S, Liu G, Yang L. Nephropathy Is Aggravated by Fatty Acids in Diabetic Kidney Disease through Tubular Epithelial Cell Necroptosis and Is Alleviated by an RIPK-1 Inhibitor. KIDNEY DISEASES (BASEL, SWITZERLAND) 2023; 9:408-423. [PMID: 37927402 PMCID: PMC10624943 DOI: 10.1159/000529995] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Accepted: 02/16/2023] [Indexed: 11/07/2023]
Abstract
Introduction Diabetic kidney disease (DKD), one of the leading causes of end-stage renal disease, has complex pathogenic mechanisms and few effective clinical therapies. DKD progression is accompanied by the loss of renal resident cells, followed by chronic inflammation and extracellular matrix deposition. Necroptosis is a newly discovered form of regulated cell death and is a major form of intrinsic cell loss in certain diabetic complications such as cardiomyopathy, intestinal disease, and retinal neuropathy; however, its significance in DKD is largely unknown. Methods In this study, the expression of necroptosis marker phosphorylated MLKL (p-MLKL) in renal biopsy tissues of patients with DKD was detected using immunofluorescence and semiquantified using immunohistochemistry. The effects of different disease-causing factors on necroptosis activation in human HK-2 cells were evaluated using immunofluorescence and Western blotting. db/db diabetic mice were fed a high-fat diet to establish an animal model of DKD with significant renal tubule damage. Mice were treated with the RIPK1 inhibitor RIPA-56 to evaluate its renal protective effects. mRNA transcriptome sequencing was used to explore the changes in signaling pathways after RIPA-56 treatment. Oil red O staining and electron macroscopy were used to observe lipid droplet accumulation in renal biopsy tissues and mouse kidney tissues. Results Immunostaining of phosphorylated RIPK1/RIPK3/MLKL verified the occurrence of necroptosis in renal tubular epithelial cells of patients with DKD. The level of the necroptosis marker p-MLKL correlated positively with the severity of renal functional, pathological damages, and lipid droplet accumulation in patients with DKD. High glucose and fatty acids were the main factors causing necroptosis in human renal tubular HK-2 cells. Renal function deterioration and renal pathological injury were accelerated, and the necroptosis pathway was activated in db/db mice fed a high-fat diet. Application of RIPA-56 effectively reduced the degree of renal injury, inhibited the necroptosis pathway activation, and reduced necroinflammation and lipid droplet accumulation in the renal tissues of db/db mice fed a high-fat diet. Conclusion The present study revealed the role of necroptosis in the progression of DKD and might provide a new therapeutic target for the treatment of DKD.
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Affiliation(s)
- Qi Yu
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Ying Chen
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Youlu Zhao
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Shuo Huang
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Xiaohong Xin
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Lei Jiang
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Hui Wang
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China
| | - Wenyan Wu
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Lei Qu
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
| | - Chengang Xiang
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Suxia Wang
- Laboratory of Electron Microscopy, Pathological Center, Peking University First Hospital, Beijing, China
| | - Gang Liu
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
| | - Li Yang
- Renal Division, Renal Pathology Center, Peking University First Hospital, Beijing, China
- Institute of Nephrology, Peking University, Beijing, China
- Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, China
- Key Laboratory of CKD Prevention and Treatment (Peking University), Ministry of Education of China, Beijing, China
- Research Units of Diagnosis and Treatment of Immune-mediated Kidney Diseases, Chinese Academy of Medical Sciences, Beijing, China
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Gu J, Xu Y, Hua D, Chen Z. Role of artesunate in autoimmune diseases and signaling pathways. Immunotherapy 2023; 15:1183-1193. [PMID: 37431601 DOI: 10.2217/imt-2023-0052] [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: 07/12/2023] Open
Abstract
Artesunate (ART) is a derivative of artemisinin. Compared with artemisinin, ART has excellent water solubility, high stability and oral bioavailability. In this review, the application of ART in classic autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and ulcerative colitis is summarized. ART exhibited similar or even better efficacy than other highly effective immunosuppressive agents, such as methotrexate and cyclophosphamide. In addition, ART exerts its pharmacological effects mainly by inhibiting the production of inflammatory factors, reactive oxygen species, autoantibodies and the migration of cells to reduce damage to tissues or organs. Moreover, ART widely affected the NF-κB, PI3K/Akt, JAK/STAT and MAPK pathways to exert pharmacological effects.
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Affiliation(s)
- Jingsai Gu
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, 430000, China
| | - Yishuang Xu
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, 430000, China
| | - Dihao Hua
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, 430000, China
| | - Zhen Chen
- Department of Ophthalmology, Renmin Hospital of Wuhan University, Wuhan, 430000, China
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Nandeshwar, Rout J, Panda SM, Tripathy U. Phytoconstituents of Ashwagandha as potential inhibitors of human islet amyloid polypeptide (hIAPP): an in silico investigation. J Biomol Struct Dyn 2023; 42:11020-11036. [PMID: 37753786 DOI: 10.1080/07391102.2023.2259491] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Accepted: 09/09/2023] [Indexed: 09/28/2023]
Abstract
Amylin or human islet amyloid polypeptide (hIAPP) is a small peptide co-secreted with insulin. Its peripheral aggregation on the lipid bilayer leads to fibril formation. The formation of hIAPP fibrils is hypothesized to rupture the membrane of β -cells, which culminates in β-cell death. Following additional studies, amylin fibril formation is a hallmark of T2DM and is also implicitly responsible for Alzheimer's disease. This study reports the virtual screening of 1000 phytoconstituents of traditional Indian medicinal plants to get potential inhibitors of amylin, which will likely restrict and block amyloid aggregation, preventing the progression of T2DM and Alzheimer's illness. The compounds having drug-likeness properties (acquired from ADMET calculations) and highest binding affinities (from molecular docking) are subjected to molecular dynamics (MD) simulation to investigate the temporal stability of the conformations of the complexes. This study discovers that Withaferin A and Withacoagulin have the highest binding affinity for amylin, and their stability with amylin was verified further by parameters such as RMSD, RMSF, number of H-bonds and MMPBSA. Individual principle component analysis (PCA) confirms the stable complex formation of amylin with Withaferin A and Withacoagulin. We strongly believe that wet-lab experiments and clinical trials will help to validate our computational findings.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Nandeshwar
- Department of Physics, Indian Institute of Technology (Indian School of Mines), Dhanbad, Jharkhand, India
| | - Janmejaya Rout
- Department of Physics, Indian Institute of Technology (Indian School of Mines), Dhanbad, Jharkhand, India
| | - Smita Manjari Panda
- Department of Physics, Indian Institute of Technology (Indian School of Mines), Dhanbad, Jharkhand, India
| | - Umakanta Tripathy
- Department of Physics, Indian Institute of Technology (Indian School of Mines), Dhanbad, Jharkhand, India
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27
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Zhou L, Liu J, Zhou M. A comprehensive meta-analysis on the association between vitamin C intake and gestational diabetes mellitus: Insights and novel perspectives. Medicine (Baltimore) 2023; 102:e34740. [PMID: 37565861 PMCID: PMC10419659 DOI: 10.1097/md.0000000000034740] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Accepted: 07/24/2023] [Indexed: 08/12/2023] Open
Abstract
BACKGROUND Gestational Diabetes Mellitus (GDM) is a significant health concern in pregnant women and their offspring. Although Vitamin C is known to play a role in maintaining normal physiological processes, its relationship with GDM has not been fully elucidated. METHODS We conducted a systematic review and meta-analysis following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, analyzing data from 15 studies selected from PubMed, Embase, Web of Science, and the Cochrane Library up to May 16, 2023. These studies were selected based on inclusion criteria such as study design, outcome of interest, exposure factor, and data extractability. Quality assessment was performed using the Newcastle-Ottawa Scale. We assessed the heterogeneity between studies and conducted a sensitivity analysis. RESULTS Data from 10,131 subjects, including 1304 diagnosed GDM cases, were analyzed. The meta-analysis showed that women in the low Vitamin C exposure group had higher odds of developing GDM (odds ratio 2.72, 95% CI:1.24-4.19). There was a greater likelihood of increased GDM risk with lower Vitamin C exposure (standardized mean difference: -0.71, 95% CI [-1.07 -0.36]). Subgroup analysis revealed that both internal and external Vitamin C exposure, along with exposure during the second or third trimester of pregnancy, was associated with higher GDM incidence rates under low Vitamin C exposure. Sensitivity analysis confirmed the robustness of the results, and no significant publication bias was detected. CONCLUSION Low Vitamin C exposure during pregnancy may increase the risk of GDM. Given these findings, it could be beneficial for pregnant women to increase their intake of Vitamin C-rich foods and to ensure adequate blood Vitamin C levels as a preventive measure against GDM.
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Affiliation(s)
- Lili Zhou
- Department of Gynecology, The First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin Province, China
| | - Junbo Liu
- Department of Gynecology, The First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin Province, China
| | - Min Zhou
- Department of Gynecology, The First Affiliated Hospital to Changchun University of Chinese Medicine, Changchun, Jilin Province, China
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28
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ZHU B, YU N, WANG L, TIAN Y, WU M, ZHAO Z. Synergistic effect of schizandrin A and DNase I knockdown on high glucose induced beta cell apoptosis by decreasing intracellular calcium concentration. J TRADIT CHIN MED 2023; 43:661-666. [PMID: 37454250 PMCID: PMC10320450 DOI: 10.19852/j.cnki.jtcm.2023.04.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Accepted: 07/08/2022] [Indexed: 07/18/2023]
Abstract
OBJECTIVE To explore the synergistic effect of deoxyribonuclease I (DNase I) knockdown combined with Schizandrin A (Sch A) in protecting islet beta-cells (β-cells) from apoptosis under high-glucose (HG) conditions. METHODS The concentration of Sch A was detected by Cell Counting Kit-8 (CCK-8). High glucose-cultured rat insulinoma beta cell line (RIN-M5F) cells were treated with Sch A and transfected with DNase I small interfering RNA (siRNA). Cell apoptosis rate and apoptosis-related protein level were examined by flow cytometry and Western blot method respectively. In addition, Na-K-adenosine triphosphatease (Na-K-ATPase) and Ca-Mg-ATPase activity, cell membrane potential, and intracellular Ca concentration was also examined respectively. RESULTS Our study revealed that HG stimulation can cause a significant increase in DNase I level and cell apoptosis rate. However, Sch A combined with DNase I knockdown can significantly decrease the cell apoptosis rate and apoptosis-related protein levels such as BAX ( 0.05) and Caspase-3 ( 0.01). In addition, we also found that the combination of Sch A and DNase I knockdown can dramatically increase cell membrane potential level, Na-K-ATPase, and Ca-Mg-ATPase activity. Meanwhile, intracellular Ca concentration was also found to be significantly decreased by the synergistic effect of Sch A and DNase I knockdown. CONCLUSION Overall, our study reveals a synergistic effect of Sch A and DNase I knockdown in protecting β-cells from HG-induced apoptosis.
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Affiliation(s)
- Bin ZHU
- 1 Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Ning YU
- 2 Accreditation Center of Traditional Chinese Medicine Physician of National Administration of Traditional Chinese Medicine, Beijing 100120, China
| | - Lei WANG
- 3 Department of Endocrinology, the Third Affiliated Hospital of Beijing University of Chinese Medicine, Beijing 100050, China
| | - Yue TIAN
- 1 Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Mingfen WU
- 1 Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
| | - Zhigang ZHAO
- 1 Department of Pharmacy, Beijing Tiantan Hospital, Capital Medical University, Beijing 100070, China
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Nguyen TT, Wei S, Nguyen TH, Jo Y, Zhang Y, Park W, Gariani K, Oh CM, Kim HH, Ha KT, Park KS, Park R, Lee IK, Shong M, Houtkooper RH, Ryu D. Mitochondria-associated programmed cell death as a therapeutic target for age-related disease. Exp Mol Med 2023; 55:1595-1619. [PMID: 37612409 PMCID: PMC10474116 DOI: 10.1038/s12276-023-01046-5] [Citation(s) in RCA: 104] [Impact Index Per Article: 52.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2023] [Revised: 04/24/2023] [Accepted: 04/27/2023] [Indexed: 08/25/2023] Open
Abstract
Mitochondria, ubiquitous double-membrane-bound organelles, regulate energy production, support cellular activities, harbor metabolic pathways, and, paradoxically, mediate cell fate. Evidence has shown mitochondria as points of convergence for diverse cell death-inducing pathways that trigger the various mechanisms underlying apoptotic and nonapoptotic programmed cell death. Thus, dysfunctional cellular pathways eventually lead or contribute to various age-related diseases, such as neurodegenerative, cardiovascular and metabolic diseases. Thus, mitochondrion-associated programmed cell death-based treatments show great therapeutic potential, providing novel insights in clinical trials. This review discusses mitochondrial quality control networks with activity triggered by stimuli and that maintain cellular homeostasis via mitohormesis, the mitochondrial unfolded protein response, and mitophagy. The review also presents details on various forms of mitochondria-associated programmed cell death, including apoptosis, necroptosis, ferroptosis, pyroptosis, parthanatos, and paraptosis, and highlights their involvement in age-related disease pathogenesis, collectively suggesting therapeutic directions for further research.
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Affiliation(s)
- Thanh T Nguyen
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea
| | - Shibo Wei
- Department of Precision Medicine, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Thu Ha Nguyen
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, 26426, Republic of Korea
| | - Yunju Jo
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea
| | - Yan Zhang
- Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, 16419, Republic of Korea
| | - Wonyoung Park
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, 50612, Republic of Korea
| | - Karim Gariani
- Service of Endocrinology, Diabetes, Nutrition and Patient Therapeutic Education, Geneva University Hospitals, Geneva, 1205, Switzerland
| | - Chang-Myung Oh
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea
| | - Hyeon Ho Kim
- Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Sungkyunkwan University, Seoul, 06351, Republic of Korea
| | - Ki-Tae Ha
- Department of Korean Medical Science, School of Korean Medicine, Pusan National University, Yangsan, 50612, Republic of Korea
| | - Kyu Sang Park
- Department of Physiology, Yonsei University Wonju College of Medicine, Wonju, 26426, Republic of Korea
| | - Raekil Park
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea
| | - In-Kyu Lee
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, 41944, Republic of Korea
| | - Minho Shong
- Department of Internal Medicine, Chungnam National University School of Medicine, Daejeon, 35015, Republic of Korea
| | - Riekelt H Houtkooper
- Laboratory Genetic Metabolic Diseases, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
- Amsterdam Gastroenterology Endocrinology and Metabolism, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
- Amsterdam Cardiovascular Sciences, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, 1105 AZ, Amsterdam, The Netherlands.
| | - Dongryeol Ryu
- Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST), Gwangju, 61005, Republic of Korea.
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30
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Zhirong Z, Li H, Yi L, Lichen Z, Ruiwu D. Ferroptosis in pancreatic diseases: potential opportunities and challenges that require attention. Hum Cell 2023; 36:1233-1243. [PMID: 36929283 DOI: 10.1007/s13577-023-00894-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 03/07/2023] [Indexed: 03/18/2023]
Abstract
The pancreas is an abdominal organ with both endocrine and exocrine functions, and patients with pancreatic diseases suffer tremendously. The regulated cell death of various cells in the pancreas is thought to play a key role in disease development. As one of the newly discovered regulated cell death modalities, ferroptosis has the potential for therapeutic applications in the study of multiple diseases. Ferroptosis has been observed in several pancreatic diseases, but its role in pancreatic diseases has not been systematically elucidated or reviewed. Understanding the occurrence of ferroptosis in various pancreatic diseases after damage to the different cell types is crucial in determining disease progression, evaluating targeted therapies, and predicting disease prognosis. Herein, we summarize the research progress associated with ferroptosis in four common pancreatic diseases, namely acute pancreatitis, chronic pancreatitis, pancreatic ductal adenocarcinoma, and diabetes mellitus. Furthermore, the elucidation of ferroptosis in rare pancreatic diseases may provide sociological benefits in the future.
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Affiliation(s)
- Zhao Zhirong
- General Surgery Center, General Hospital of Western Theater Command, No. 270, Rongdu Rd, Jinniu District, Chengdu, 610083, Sichuan, China
- College of Medicine, Southwest Jiaotong University, Chengdu, China
| | - Han Li
- Ultrasound Medical Center, Sichuan Clinical Research Center for Cancer, Sichuan Cancer Hospital & Institute, Sichuan Cancer Center, Affiliated Cancer Hospital of University of Electronic Science and Technology of China, Chengdu, Sichuan, China
| | - Liu Yi
- School of Medicine, Jianghan University, Wuhan, 430056, Hubei, China
| | - Zhou Lichen
- General Surgery Center, General Hospital of Western Theater Command, No. 270, Rongdu Rd, Jinniu District, Chengdu, 610083, Sichuan, China
- Pancreatic Injury and Repair Key Laboratory of Sichuan Province, General Hospital of Western Theater Command, Chengdu, Sichuan, China
| | - Dai Ruiwu
- General Surgery Center, General Hospital of Western Theater Command, No. 270, Rongdu Rd, Jinniu District, Chengdu, 610083, Sichuan, China.
- College of Medicine, Southwest Jiaotong University, Chengdu, China.
- Pancreatic Injury and Repair Key Laboratory of Sichuan Province, General Hospital of Western Theater Command, Chengdu, Sichuan, China.
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Prasad MK, Mohandas S, Ramkumar KM. Dysfunctions, molecular mechanisms, and therapeutic strategies of pancreatic β-cells in diabetes. Apoptosis 2023:10.1007/s10495-023-01854-0. [PMID: 37273039 DOI: 10.1007/s10495-023-01854-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/08/2023] [Indexed: 06/06/2023]
Abstract
Pancreatic beta-cell death has been established as a critical mediator in the progression of type 1 and type 2 diabetes mellitus. Beta-cell death is associated with exacerbating hyperglycemia and insulin resistance and paves the way for the progression of DM and its complications. Apoptosis has been considered the primary mechanism of beta-cell death in diabetes. However, recent pieces of evidence have implicated the substantial involvement of several other novel modes of cell death, including autophagy, pyroptosis, necroptosis, and ferroptosis. These distinct mechanisms are characterized by their unique biochemical features and often precipitate damage through the induction of cellular stressors, including endoplasmic reticulum stress, oxidative stress, and inflammation. Experimental studies were identified from PubMed literature on different modes of beta cell death during the onset of diabetes mellitus. This review summarizes current knowledge on the crucial pathways implicated in pancreatic beta cell death. The article also focuses on applying natural compounds as potential treatment strategies in inhibiting these cell death pathways.
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Affiliation(s)
- Murali Krishna Prasad
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Sundhar Mohandas
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India
| | - Kunka Mohanram Ramkumar
- Department of Biotechnology, School of Bioengineering, SRM Institute of Science and Technology, Kattankulathur, 603 203, Tamil Nadu, India.
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32
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Linares-Pineda TM, Gutiérrez-Repiso C, Peña-Montero N, Molina-Vega M, Rubio FL, Arana MS, Tinahones FJ, Picón-César MJ, Morcillo S. Higher β cell death in pregnant women, measured by DNA methylation patterns of cell-free DNA, compared to new-onset type 1 and type 2 diabetes subjects: a cross-sectional study. Diabetol Metab Syndr 2023; 15:115. [PMID: 37264478 DOI: 10.1186/s13098-023-01096-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 05/23/2023] [Indexed: 06/03/2023] Open
Abstract
Diabetes is a metabolic disorder of glucose homeostasis in which β cell destruction occurs silently and is detected mainly when symptoms appear. In the last few years, it has emerged a great interest in developing markers capable of detecting pancreatic β cell death focused on improving early diagnosis and getting a better treatment response, mainly in type 1 diabetes. But other types of diabetes would also benefit from early detection of β cell death. Differentially methylated circulating DNA is being studied as minimally invasive biomarker of cell death. We aimed to explore whether the unmethylated/methylated ratio of the insulin and amylin genes might be a good biomarker of β cell death in different types of diabetes. A lower index ∆Ct indicates a higher rate of β-cell death. Plasma samples from subjects without diabetes, pregnant women, pregnant with gestational diabetes (GDM), type 1 diabetes and type 2 diabetes were analyzed. A qPCR reaction with specific primers for both methylated and unmethylated fragments of insulin and amylin genes were carried out. Pregnant women, GDM and non- GDM, showed a higher β-cell death for both markers (∆INS = 3.8 ± 2.1 and ∆Amylin = 8.5 ± 3.6), whereas T1D presented lower rate (∆INS = 6.2 ± 2.1 and ∆Amylin = 10.7 ± 2.9) comparable to healthy subjects. The insulin methylation index was associated with the newborn birth weight (r = 0.46; p = 0.033) and with insulin resistance (r = -0.533; p = 0.027) in the GDM group. The higher rate of β-cell death was observed in pregnant women independently of their metabolic status. These indexes could be a good indicator of β cell death in processes caused by defects on insulin secretion, insulin action, or both.
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Affiliation(s)
- Teresa María Linares-Pineda
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
| | - Carolina Gutiérrez-Repiso
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
| | - Nerea Peña-Montero
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
| | - María Molina-Vega
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
| | - Fuensanta Lima Rubio
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
| | - María Suárez Arana
- Department of Obstetrics and Gynecology, Hospital Regional Universitario de Málaga, IBIMA, Málaga, Spain
| | - Francisco J Tinahones
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain
- Departamento de Medicina y Dermatología, Universidad de Málaga, Málaga, Spain
| | - María José Picón-César
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain.
| | - Sonsoles Morcillo
- Unidad de Gestión Clínica de Endocrinología y Nutrición del Hospital Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain.
- Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBERobn), Instituto de Salud Carlos III, Madrid, Spain.
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Liu X, Xie X, Li D, Liu Z, Zhang B, Zang Y, Yuan H, Shen C. Sirt3-dependent regulation of mitochondrial oxidative stress and apoptosis contributes to the dysfunction of pancreatic islets after severe burns. Free Radic Biol Med 2023; 198:59-67. [PMID: 36738799 DOI: 10.1016/j.freeradbiomed.2023.01.027] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 01/24/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023]
Abstract
BACKGROUND Severe burns are often complicated with hyperglycemia caused by mitochondrial oxidative stress-related pancreatic islet dysfunction. Silent information regulator of transcription 3 (Sirt3) can regulate mitochondrial oxidative stress. However, the role and mechanism of Sirt3 on islet function after severe burns remain unclear. Therefore, this study aimed to investigate whether Sirt3 played a role in both mitochondrial oxidative stress in islets and mediating islet function post severe burns. METHODS A mouse model of 30% total body surface area full-thickness burn and an in vitro MIN6 cell hypoxia model were established. Sirt3 KO mice were used to demonstrate further the role of Sirt3 in maintaining redox homeostasis and regulating islet function. Fasting blood glucose and glucose-stimulated insulin secretion (GSIS) were detected to assess the islet function. The levels of mitochondrial ROS and deacetylation, and the activities of Mn-SOD and IDH2 were measured to evaluate oxidative stress. The mitochondrial membrane potential (MMP)was detected and the apoptosis rate measured. RESULTS In vitro MIN6 cells, the hypoxia treatment significantly reduced Sirt3 expression, resulting in increased deacetylation of Mn-SOD and IDH2, which further led to a higher level of mitochondrial ROS. In addition, hypoxia reduced MMP and increased apoptosis rate, which impaired GSIS eventually. Knockdown of Sirt3 caused similar alterations. The hypoxia-induced high level of mitochondrial ROS and apoptosis and impaired GSIS could be reversed by overexpression of Sirt3. Similarly, after severe burns, the expression of Sirt3 in islets decreased significantly with a high level of deacetylation of Mn-SOD, IDH2, mitochondrial ROS and apoptosis, and islet dysfunction. Oxidative stress and apoptosis also occurred in islets of Sirt3 KO mice, accompanied by islet dysfunction. CONCLUSIONS Sirt3 and downstream signalling are critical in modulating the islet function post severe burns by regulating mitochondrial oxidative stress and apoptosis.
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Affiliation(s)
- Xinzhu Liu
- Department of Burns and Plastic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, 100048, China
| | - Xiaoye Xie
- Department of Burns and Plastic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, 100048, China
| | - Dawei Li
- Department of Burns and Plastic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, 100048, China
| | - Zhaoxing Liu
- Department of Burns and Plastic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, 100048, China
| | - Bohan Zhang
- Department of Burns and Plastic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, 100048, China
| | - Yu Zang
- Department of Burns and Plastic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, 100048, China
| | - Huageng Yuan
- Department of Burns and Plastic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, 100048, China
| | - Chuan'an Shen
- Department of Burns and Plastic Surgery, The Fourth Medical Center, Chinese PLA General Hospital, Beijing, 100048, China.
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Alur V, Raju V, Vastrad B, Vastrad C, Kavatagimath S, Kotturshetti S. Bioinformatics Analysis of Next Generation Sequencing Data Identifies Molecular Biomarkers Associated With Type 2 Diabetes Mellitus. Clin Med Insights Endocrinol Diabetes 2023; 16:11795514231155635. [PMID: 36844983 PMCID: PMC9944228 DOI: 10.1177/11795514231155635] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Accepted: 01/19/2023] [Indexed: 02/23/2023] Open
Abstract
Background Type 2 diabetes mellitus (T2DM) is the most common metabolic disorder. The aim of the present investigation was to identify gene signature specific to T2DM. Methods The next generation sequencing (NGS) dataset GSE81608 was retrieved from the gene expression omnibus (GEO) database and analyzed to identify the differentially expressed genes (DEGs) between T2DM and normal controls. Then, Gene Ontology (GO) and pathway enrichment analysis, protein-protein interaction (PPI) network, modules, miRNA (micro RNA)-hub gene regulatory network construction and TF (transcription factor)-hub gene regulatory network construction, and topological analysis were performed. Receiver operating characteristic curve (ROC) analysis was also performed to verify the prognostic value of hub genes. Results A total of 927 DEGs (461 were up regulated and 466 down regulated genes) were identified in T2DM. GO and REACTOME results showed that DEGs mainly enriched in protein metabolic process, establishment of localization, metabolism of proteins, and metabolism. The top centrality hub genes APP, MYH9, TCTN2, USP7, SYNPO, GRB2, HSP90AB1, UBC, HSPA5, and SQSTM1 were screened out as the critical genes. ROC analysis provides prognostic value of hub genes. Conclusion The potential crucial genes, especially APP, MYH9, TCTN2, USP7, SYNPO, GRB2, HSP90AB1, UBC, HSPA5, and SQSTM1, might be linked with risk of T2DM. Our study provided novel insights of T2DM into genetics, molecular pathogenesis, and novel therapeutic targets.
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Affiliation(s)
- Varun Alur
- Department of Endocrinology, J.J.M
Medical College, Davanagere, Karnataka, India
| | - Varshita Raju
- Department of Obstetrics and
Gynecology, J.J.M Medical College, Davanagere, Karnataka, India
| | - Basavaraj Vastrad
- Department of Pharmaceutical Chemistry,
K.L.E. College of Pharmacy, Gadag, Karnataka, India
| | | | - Satish Kavatagimath
- Department of Pharmacognosy, K.L.E.
College of Pharmacy, Belagavi, Karnataka, India
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Liu T, Zou X, Ruze R, Xu Q. Bariatric Surgery: Targeting pancreatic β cells to treat type II diabetes. Front Endocrinol (Lausanne) 2023; 14:1031610. [PMID: 36875493 PMCID: PMC9975540 DOI: 10.3389/fendo.2023.1031610] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Accepted: 01/19/2023] [Indexed: 02/17/2023] Open
Abstract
Pancreatic β-cell function impairment and insulin resistance are central to the development of obesity-related type 2 diabetes mellitus (T2DM). Bariatric surgery (BS) is a practical treatment approach to treat morbid obesity and achieve lasting T2DM remission. Traditionally, sustained postoperative glycemic control was considered a direct result of decreased nutrient intake and weight loss. However, mounting evidence in recent years implicated a weight-independent mechanism that involves pancreatic islet reconstruction and improved β-cell function. In this article, we summarize the role of β-cell in the pathogenesis of T2DM, review recent research progress focusing on the impact of Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG) on pancreatic β-cell pathophysiology, and finally discuss therapeutics that have the potential to assist in the treatment effect of surgery and prevent T2D relapse.
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Affiliation(s)
- Tiantong Liu
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
- School of Medicine, Tsinghua University, Beijing, China
| | - Xi Zou
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Rexiati Ruze
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
- Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Qiang Xu
- Department of General Surgery, Peking Union Medical College Hospital, Beijing, China
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Song Y, He C, Jiang Y, Yang M, Xu Z, Yuan L, Zhang W, Xu Y. Bulk and single-cell transcriptome analyses of islet tissue unravel gene signatures associated with pyroptosis and immune infiltration in type 2 diabetes. Front Endocrinol (Lausanne) 2023; 14:1132194. [PMID: 36967805 PMCID: PMC10034023 DOI: 10.3389/fendo.2023.1132194] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 02/21/2023] [Indexed: 03/12/2023] Open
Abstract
INTRODUCTION Type 2 diabetes (T2D) is a common chronic heterogeneous metabolic disorder. However, the roles of pyroptosis and infiltrating immune cells in islet dysfunction of patients with T2D have yet to be explored. In this study, we aimed to explore potential crucial genes and pathways associated with pyroptosis and immune infiltration in T2D. METHODS To achieve this, we performed a conjoint analysis of three bulk RNA-seq datasets of islets to identify T2D-related differentially expressed genes (DEGs). After grouping the islet samples according to their ESTIMATE immune scores, we identified immune- and T2D-related DEGs. A clinical prediction model based on pyroptosis-related genes for T2D was constructed. Weighted gene co-expression network analysis was performed to identify genes positively correlated with pyroptosis-related pathways. A protein-protein interaction network was established to identify pyroptosis-related hub genes. We constructed miRNA and transcriptional networks based on the pyroptosis-related hub genes and performed functional analyses. Single-cell RNA-seq (scRNA-seq) was conducted using the GSE153885 dataset. Dimensionality was reduced using principal component analysis and t-distributed statistical neighbor embedding, and cells were clustered using Seurat. Different cell types were subjected to differential gene expression analysis and gene set enrichment analysis (GSEA). Cell-cell communication and pseudotime trajectory analyses were conducted using the samples from patients with T2D. RESULTS We identified 17 pyroptosis-related hub genes. We determined the abundance of 13 immune cell types in the merged matrix and found that these cell types were correlated with the 17 pyroptosis-related hub genes. Analysis of the scRNA-seq dataset of 1892 islet samples from patients with T2D and controls revealed 11 clusters. INS and IAPP were determined to be pyroptosis-related and candidate hub genes among the 11 clusters. GSEA of the 11 clusters demonstrated that the myc, G2M checkpoint, and E2F pathways were significantly upregulated in clusters with several differentially enriched pathways. DISCUSSION This study elucidates the gene signatures associated with pyroptosis and immune infiltration in T2D and provides a critical resource for understanding of islet dysfunction and T2D pathogenesis.
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Affiliation(s)
- Yaxian Song
- Department of Endocrinology, Yunnan Province Clinical Medical Center for Endocrine and Metabolic Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Chen He
- Department of Geriatric Medicine, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yan Jiang
- Department of Endocrinology, Yunnan Province Clinical Medical Center for Endocrine and Metabolic Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Mengshi Yang
- Department of Endocrinology, Yunnan Province Clinical Medical Center for Endocrine and Metabolic Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Zhao Xu
- Department of Endocrinology, Yunnan Province Clinical Medical Center for Endocrine and Metabolic Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Lingyan Yuan
- Department of Endocrinology, Yunnan Province Clinical Medical Center for Endocrine and Metabolic Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Wenhua Zhang
- Department of Endocrinology, Yunnan Province Clinical Medical Center for Endocrine and Metabolic Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Yushan Xu
- Department of Endocrinology, Yunnan Province Clinical Medical Center for Endocrine and Metabolic Disease, The First Affiliated Hospital of Kunming Medical University, Kunming, China
- *Correspondence: Yushan Xu,
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Stem-Cell-Derived β-Like Cells with a Functional PTPN2 Knockout Display Increased Immunogenicity. Cells 2022; 11:cells11233845. [PMID: 36497105 PMCID: PMC9737324 DOI: 10.3390/cells11233845] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 11/17/2022] [Accepted: 11/25/2022] [Indexed: 12/02/2022] Open
Abstract
Type 1 diabetes is a polygenic disease that results in an autoimmune response directed against insulin-producing beta cells. PTPN2 is a known high-risk type 1 diabetes associated gene expressed in both immune- and pancreatic beta cells, but how genes affect the development of autoimmune diabetes is largely unknown. We employed CRISPR/Cas9 technology to generate a functional knockout of PTPN2 in human pluripotent stem cells (hPSC) followed by differentiating stem-cell-derived beta-like cells (sBC) and detailed phenotypical analyses. The differentiation efficiency of PTPN2 knockout (PTPN2 KO) sBC is comparable to wild-type (WT) control sBC. Global transcriptomics and protein assays revealed the increased expression of HLA Class I molecules in PTPN2 KO sBC at a steady state and upon exposure to proinflammatory culture conditions, indicating a potential for the increased immune recognition of human beta cells upon differential PTPN2 expression. sBC co-culture with autoreactive preproinsulin-reactive T cell transductants confirmed increased immune stimulations by PTPN2 KO sBC compared to WT sBC. Taken together, our results suggest that the dysregulation of PTPN2 expression in human beta cell may prime autoimmune T cell reactivity and thereby contribute to the development of type 1 diabetes.
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Kokorev OV, Khlusov IA, Marchenko ES, Yasenchuk YF, Dambaev GT. Experimental Correction of Homeostasis Changes during Alloxan-Induced Diabetes by Implantation of Islet Cells Cultured in Fibrous TiNi-Based Scaffold. Bull Exp Biol Med 2022; 174:89-94. [PMID: 36437326 DOI: 10.1007/s10517-022-05654-5] [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: 04/29/2022] [Indexed: 11/29/2022]
Abstract
The use of fibrous scaffolds made of titanium nickelide and carrying islet cells (IC) after a course of alloxan administration was studied in vivo. Scanning electron microscopy showed good adhesion of IC in the pore space of the scaffolds. In 28 days, mature tissue comprising both cellular and fibrous components filled the inner space of the scaffold by 90%. The advantage of intraperitoneal implantation of IC in vitro seeded in fibrous titanium nickelide scaffolds in comparison with injection of IC (6×105 cells) to Wistar rats was demonstrated in the dynamics of pancreatic function recovery (normalization of blood glucose and glycosylated hemoglobin concentrations by day 21 of the experiment), regeneration of the white hematopoietic lineage cells, and lengthening (by 2 times) of the lifespan of animals with alloxan-induced diabetes. Injection of IC improved rat survival by only 40%. Thus, the hybrid tissue-engineered construct (fibrous titanium nickelide scaffold+IC) is biocompatible when administered intraperitoneally, stimulates regeneration in rats with alloxan-induced diabetes, improves blood glucose utilization processes, and restores suppressed leukopoiesis. It is assumed that hepatocytes can be the main target cells of the hybrid tissue-engineering construct.
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Affiliation(s)
- O V Kokorev
- Siberian State Medical University, Ministry of Health of the Russian Federation, Tomsk, Russia. .,National Research Tomsk State University, Tomsk, Russia.
| | - I A Khlusov
- Siberian State Medical University, Ministry of Health of the Russian Federation, Tomsk, Russia
| | - E S Marchenko
- National Research Tomsk State University, Tomsk, Russia
| | | | - G Ts Dambaev
- Siberian State Medical University, Ministry of Health of the Russian Federation, Tomsk, Russia
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Wei H, Cui D. Pyroptosis and Insulin Resistance in Metabolic Organs. Int J Mol Sci 2022; 23:11638. [PMID: 36232938 PMCID: PMC9570443 DOI: 10.3390/ijms231911638] [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] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 09/27/2022] [Accepted: 09/28/2022] [Indexed: 11/09/2022] Open
Abstract
Skeletal muscle serves as the optimal effective organ to balance glucose homeostasis, but insulin resistance (IR) in skeletal muscle breaks this balance by impeding glucose uptake and causes metabolic disorders. IR in skeletal muscle is caused by multiple factors, and it has been reported that systemic low-grade inflammation is related to skeletal muscle IR, though its molecular mechanisms need to be ulteriorly studied. Pyroptosis is a novel inflammatory-mediated type of cell death. It has recently been reported that pyroptosis is associated with a decline in insulin sensitivity in skeletal muscle. The appropriate occurrence of pyroptosis positively eliminates pathogenic factors, whereas its excessive activation may aggravate inflammatory responses and expedite disease progression. The relationship between pyroptosis and IR in skeletal muscle and its underlined mechanism need to be further illustrated. The role of pyroptosis during the process of IR alleviation induced by non-drug interventions, such as exercise, also needs to be clarified. In this paper, we review and describe the molecular mechanisms of pyroptosis and further comb the roles of its relevant key factors in skeletal muscle IR, aiming to propose a novel theoretical basis for the relationship between pyroptosis and muscle IR and provide new research targets for the improvement of IR-related diseases.
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Affiliation(s)
| | - Di Cui
- College of Physical Education, Hunan University, Changsha 410012, China
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Zhou F, Deng J, Banfield L, Thabane L, Sadeghirad B, Samaan MC. Pharmacotherapy in paediatric type 2 diabetes mellitus: a protocol for a systematic review and network meta-analysis of randomised trials. BMJ Open 2022; 12:e065287. [PMID: 36167361 PMCID: PMC9516159 DOI: 10.1136/bmjopen-2022-065287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2022] [Accepted: 09/08/2022] [Indexed: 12/04/2022] Open
Abstract
INTRODUCTION The rates of type 2 diabetes mellitus (T2DM) in children and adolescents have risen globally over the past few years. While a few diabetes pharmacotherapies have been used in this population, their comparative benefits and harms are unclear. Thus, we will conduct a systematic review and network meta-analysis (NMA) of randomised controlled trials (RCTs) to compare the efficacy and safety of pharmacotherapies for managing paediatric T2DM. METHODS AND ANALYSIS We will include RCTs that enrolled T2DM patients ≤18 years of age and who were randomised to monotherapy or combination pharmacotherapies with or without lifestyle interventions. Comparator groups will include placebo or non-pharmacological treatments including lifestyle interventions.Treatment outcomes will include change from baseline in glycated haemoglobin A1c, body mass index z-score, weight, systolic/diastolic blood pressure, fasting plasma glucose, fasting insulin and lipid profiles, T2DM-related complications, as well as the incidence of treatment-related adverse events.Literature searches will be conducted in Medline, Embase, CINAHL, CENTRAL and Web of Science. We will also search the grey literature and the reference list of included trials and relevant reviews. Two reviewers will assess the eligibility of articles identified through our searches and will extract data from eligible studies independently. We will use a modified Cochrane instrument to evaluate the risk of bias. Disagreements will be resolved through consensus or arbitration by a third reviewer.A frequentist random-effects model will be used for conducting NMA. The quality of evidence will be assessed using the Confidence in Network Meta-Analysis platform. We will assess the effect modification through network meta-regression and subgroup analyses for sex, age at study inclusion, duration of T2DM, follow-up duration and risk of bias ratings. ETHICS AND DISSEMINATION This study will not require ethics approval. We will disseminate our findings through publication in a peer-reviewed journal and conference presentations. PROSPERO REGISTRATION NUMBER CRD42022310100.
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Affiliation(s)
- Fangwen Zhou
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster University, Hamilton, Ontario, Canada
| | - Jiawen Deng
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster University, Hamilton, Ontario, Canada
| | - Laura Banfield
- Health Sciences Library, McMaster University, Hamilton, Ontario, Canada
| | - Lehana Thabane
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
- Department of Anesthesia, McMaster University, Hamilton, Ontario, Canada
- Biostatistics Unit, St. Joseph's Healthcare Hamilton, Hamilton, Ontario, Canada
| | - Behnam Sadeghirad
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - M Constantine Samaan
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
- Division of Pediatric Endocrinology, McMaster University, Hamilton, Ontario, Canada
- Michael G. De Groote School of Medicine, McMaster University, Hamilton, Ontario, Canada
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Yuan J, Li S, Peng H, Ma Y, Li L, Fu L, Liu J, Jiang H. Artesunate protects pancreatic β-cells from streptozotocin-induced diabetes via inhibition of the NLRP3/caspase-1/GSDMD pathway. Gen Comp Endocrinol 2022; 326:114068. [PMID: 35671834 DOI: 10.1016/j.ygcen.2022.114068] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 05/16/2022] [Accepted: 06/02/2022] [Indexed: 01/03/2023]
Abstract
BACKGROUND Reports in recent years have shown that pancreatic β-cell pyroptosis represents a critical mechanism involved with the progressive failure of pancreatic function. Previous research from our laboratory has indicated that artemether can increase the number of cells in pancreatic islets of db/db mice. In this study, we further examined whether artesunate (ART) protects pancreatic β-cells from the damage of streptozotocin (STZ) by inhibiting pyroptosis. MATERIALS AND METHODS In vitro, MIN6 cells exposed to 1 mM STZ were treated with ART (0.8 or 1.6 μM). The effects of ART on STZ-treated cells were evaluated through CCK-8 assay, flow cytometry and western blot, and further compared the effects of ART with the NLRP3 inhibitor, Mcc950 upon pyroptosis pathway proteins using western blot. In vivo, Male C57 mice were administered with a single intraperitoneal injection of STZ, and those with confirmed diabetes mellitus were given ART (0.5 or 1.0 mg/ml in drinking water) for 18 days. The effects of ART on STZ-induced diabetes were assessed by the observation of the general situation, glucose tolerance test, hematoxylin-eosin (HE) staining and immunohistochemistry. RESULTS In MIN6 cells treated with STZ, we found that ART increased cell viability, decreased the number of late apoptotic cells (including pyroptosis cells) and inhibited the expression of proteins associated with the pyroptosis pathway. In STZ-induced animal model, the administration of ART reduced blood glucose levels, improved the consumption status within this diabetic mouse model and inhibited the expression of proteins include in the pyroptosis pathway in mice pancreats. CONCLUSIONS Inhibition of pyroptosis may be a critical mechanism through which artesunate exerts protective effects upon pancreatic β cells.
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Affiliation(s)
- Jingya Yuan
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China
| | - Shipeng Li
- Department of General Surgery, Jiaozuo People's Hospital, Jiaozuo 454002, China
| | - Huifang Peng
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China
| | - Yujin Ma
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China
| | - Liping Li
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China
| | - Liujun Fu
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China
| | - Jie Liu
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China
| | - Hongwei Jiang
- Department of Metabolism and Endocrinology, Endocrine and Metabolic Disease Center, The First Affiliated Hospital, and College of Clinical Medicine of Henan University of Science and Technology, Luoyang 471003, China; Luoyang sub-center of National Clinical Research Center for Metabolic Diseases, Luoyang 471003, China; Medical Key Laboratory of Hereditary Rare Diseases of Henan, Luoyang 471003, China.
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Bronczek GA, Soares GM, Marmentini C, Boschero AC, Costa-Júnior JM. Resistance Training Improves Beta Cell Glucose Sensing and Survival in Diabetic Models. Int J Mol Sci 2022; 23:ijms23169427. [PMID: 36012692 PMCID: PMC9409046 DOI: 10.3390/ijms23169427] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2022] [Revised: 08/15/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
Resistance training increases insulin secretion and beta cell function in healthy mice. Here, we explored the effects of resistance training on beta cell glucose sensing and survival by using in vitro and in vivo diabetic models. A pancreatic beta cell line (INS-1E), incubated with serum from trained mice, displayed increased insulin secretion, which could be linked with increased expression of glucose transporter 2 (GLUT2) and glucokinase (GCK). When cells were exposed to pro-inflammatory cytokines (in vitro type 1 diabetes), trained serum preserved both insulin secretion and GCK expression, reduced expression of proteins related to apoptotic pathways, and also protected cells from cytokine-induced apoptosis. Using 8-week-old C57BL/6 mice, turned diabetic by multiple low doses of streptozotocin, we observed that resistance training increased muscle mass and fat deposition, reduced fasting and fed glycemia, and improved glucose tolerance. These findings may be explained by the increased fasting and fed insulinemia, along with increased beta cell mass and beta cell number per islet, observed in diabetic-trained mice compared to diabetic sedentary mice. In conclusion, we believe that resistance training stimulates the release of humoral factors which can turn beta cells more resistant to harmful conditions and improve their response to a glucose stimulus.
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Affiliation(s)
- Gabriela Alves Bronczek
- Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas 13083-864, Brazil
| | - Gabriela Moreira Soares
- Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas 13083-864, Brazil
| | - Carine Marmentini
- Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas 13083-864, Brazil
| | - Antonio Carlos Boschero
- Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas 13083-864, Brazil
| | - José Maria Costa-Júnior
- Obesity and Comorbidities Research Center, Institute of Biology, University of Campinas (UNICAMP), Campinas 13083-864, Brazil
- Center for Diabetes Research, Division of Endocrinology, Erasmus Hospital, Universite Libre de Bruxelles (ULB), 1070 Brussels, Belgium
- Correspondence: ; Tel.: +32-455-11-02-04
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He X, Wang C, Zhu Y, Jiang X, Qiu Y, Yin F, Xiong W, Liu B, Huang Y. Spirulina compounds show hypoglycemic activity and intestinal flora regulation in type 2 diabetes mellitus mice. ALGAL RES 2022. [DOI: 10.1016/j.algal.2022.102791] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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Mariadoss AVA, Sivakumar AS, Lee CH, Kim SJ. Diabetes mellitus and diabetic foot ulcer: Etiology, biochemical and molecular based treatment strategies via gene and nanotherapy. Biomed Pharmacother 2022; 151:113134. [PMID: 35617802 DOI: 10.1016/j.biopha.2022.113134] [Citation(s) in RCA: 56] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 05/05/2022] [Accepted: 05/15/2022] [Indexed: 12/06/2022] Open
Abstract
Diabetes mellitus (DM) is a collection of metabolic and pathophysiological disorders manifested with high glucose levels in the blood due to the inability of β-pancreatic cells to secrete an adequate amount of insulin or insensitivity of insulin towards receptor to oxidize blood glucose. Nevertheless, the preceding definition is only applicable to people who do not have inherited or metabolic disorders. Suppose a person who has been diagnosed with Type 1 or Type 2DM sustains an injury and the treatment of the damage is complicated and prolonged. In that case, the injury is referred to as a diabetic foot ulcer (DFU). In the presence of many proliferating macrophages in the injury site for an extended period causes the damage to worsen and become a diabetic wound. In this review, the scientific information and therapeutic management of DM/DFU with nanomedicine, and other related data were collected (Web of Science and PubMed) from January 2000 to January 2022. Most of the articles revealed that standard drugs are usually prescribed along with hypoglycaemic medications. Conversely, such drugs stabilize the glucose transporters and homeostasis for a limited period, resulting in side effects such as kidney damage/failure, absorption/gastrointestinal problems, and hypoglycemic issues. In this paper, we review the current basic and clinical evidence about the potential of medicinal plants, gene therapy, chemical/green synthesized nanoparticles to improving the metabolic profile, and facilitating the DM and DFU associated complications. Preclinical studies also reported lower plasma glucose with molecular targets in DM and DFU. Research is underway to explore chemical/green synthesized nanoparticle-based medications to avoid such side effects. Hence, the present review is intended to address the current challenges, recently recognized factors responsible for DM and DFU, their pathophysiology, insulin receptors associated with DM, medications in trend, and related complications.
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Affiliation(s)
- Arokia Vijaya Anand Mariadoss
- Department of Orthopaedic Surgery, Dongtan Sacred Heart Hospital, Hallym University, College of Medicine, Hwaseong, Republic of Korea
| | - Allur Subramaniyan Sivakumar
- Department of Orthopaedic Surgery, Dongtan Sacred Heart Hospital, Hallym University, College of Medicine, Hwaseong, Republic of Korea
| | - Chang-Hun Lee
- Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology, Daegu, Republic of Korea
| | - Sung Jae Kim
- Department of Orthopaedic Surgery, Dongtan Sacred Heart Hospital, Hallym University, College of Medicine, Hwaseong, Republic of Korea.
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Abdulhadi HL, Dabdoub BR, Ali LH, Othman AI, Amer ME, El-Missiry MA. Punicalagin protects against the development of pancreatic injury and insulitis in rats with induced T1DM by reducing inflammation and oxidative stress. Mol Cell Biochem 2022; 477:2817-2828. [PMID: 35666430 DOI: 10.1007/s11010-022-04478-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 05/13/2022] [Indexed: 01/07/2023]
Abstract
Pancreatic inflammation and oxidative damage remain major concerns in type 1 diabetes mellitus (T1DM). Punicalagin, a major polyphenol in pomegranates, exhibited antioxidant and protective effects on several organs in case of T1DM; however, no study has yet explored the protective effects of punicalagin on the pancreas and islets of Langerhans. T1DM was induced by injecting 40 mg/kg streptozotocin (STZ) intraperitoneally. Punicalagin (1 mg/kg ip) was injected daily for 15 days after T1DM induction. In diabetic rats, punicalagin treatment lowered the levels of inflammatory biomarkers (monocyte chemoattractant protein-1 and C-reactive protein) and adhesion molecules (E-selectin, intercellular adhesion molecule, and vascular cell adhesion molecule) while activating myeloperoxidase activity. Treatment of diabetic rats with punicalagin improved glutathione content and superoxide dismutase, catalase, and glutathione peroxidase activities; upregulated serum paraoxonase-1 activity; and prevented the elevation lipid peroxidation and protein oxidation products in the pancreas. Furthermore, punicalagin protected the pancreas against STZ-induced histopathological alterations and increased immune-reactive β-cells while reducing leucocyte infiltration into the islets of Langerhans, leading to normalized blood glucose and insulin levels. These findings indicated that punicalagin might protect against the development of insulitis in T1DM. In conclusion, punicalagin exerts a strong protective effect on the pancreas against oxidative injury and inflammation in STZ-induced experimental T1DM. The present results recommend punicalagin as a potential adjuvant for reducing diabetes-associated insulitis.
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Affiliation(s)
- Haitham L Abdulhadi
- Biology Department, College of Education for Pure Sciences, University of Anbar, Anbar, Ramadi, Iraq
| | - Banan R Dabdoub
- Biology Department, College of Education for Pure Sciences, University of Mosul, Mosul, Iraq
| | - Loay H Ali
- Biology Department, College of Education for Pure Sciences, University of Anbar, Anbar, Ramadi, Iraq
| | - Azza I Othman
- Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt
| | - Maggie E Amer
- Zoology Department, Faculty of Science, Mansoura University, Mansoura, Egypt.
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46
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Small J, Joblin-Mills A, Carbone K, Kost-Alimova M, Ayukawa K, Khodier C, Dancik V, Clemons PA, Munkacsi AB, Wagner BK. Phenotypic Screening for Small Molecules that Protect β-Cells from Glucolipotoxicity. ACS Chem Biol 2022; 17:1131-1142. [PMID: 35439415 PMCID: PMC9127801 DOI: 10.1021/acschembio.2c00052] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Accepted: 03/14/2022] [Indexed: 11/29/2022]
Abstract
Type 2 diabetes is marked by progressive β-cell failure, leading to loss of β-cell mass. Increased levels of circulating glucose and free fatty acids associated with obesity lead to β-cell glucolipotoxicity. There are currently no therapeutic options to address this facet of β-cell loss in obese type 2 diabetes patients. To identify small molecules capable of protecting β-cells, we performed a high-throughput screen of 20,876 compounds in the rat insulinoma cell line INS-1E in the presence of elevated glucose and palmitate. We found 312 glucolipotoxicity-protective small molecules (1.49% hit rate) capable of restoring INS-1E viability, and we focused on 17 with known biological targets. 16 of the 17 compounds were kinase inhibitors with activity against specific families including but not limited to cyclin-dependent kinases (CDK), PI-3 kinase (PI3K), Janus kinase (JAK), and Rho-associated kinase 2 (ROCK2). 7 of the 16 kinase inhibitors were PI3K inhibitors. Validation studies in dissociated human islets identified 10 of the 17 compounds, namely, KD025, ETP-45658, BMS-536924, AT-9283, PF-03814735, torin-2, AZD5438, CP-640186, ETP-46464, and GSK2126458 that reduced glucolipotoxicity-induced β-cell death. These 10 compounds decreased markers of glucolipotoxicity including caspase activation, mitochondrial depolarization, and increased calcium flux. Together, these results provide a path forward toward identifying novel treatments to preserve β-cell viability in the face of glucolipotoxicity.
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Affiliation(s)
- Jonnell
C. Small
- Chemical
Biology and Therapeutics Science Program, Broad Institute, Cambridge, Massachusetts 02142, United States
- Chemistry
Biology Program, Harvard Medical School, Boston, Massachusetts 02115, United States
| | - Aidan Joblin-Mills
- School
of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, Victoria University of Wellington, Wellington 6140, New Zealand
| | - Kaycee Carbone
- Chemical
Biology and Therapeutics Science Program, Broad Institute, Cambridge, Massachusetts 02142, United States
| | - Maria Kost-Alimova
- Center
for the Development of Therapeutics, Broad
Institute, Cambridge, Massachusetts 02142, United States
| | - Kumiko Ayukawa
- Chemical
Biology and Therapeutics Science Program, Broad Institute, Cambridge, Massachusetts 02142, United States
- JT
Pharmaceuticals Inc., Takatsuki 569-1125, Osaka, Japan
| | - Carol Khodier
- Center
for the Development of Therapeutics, Broad
Institute, Cambridge, Massachusetts 02142, United States
| | - Vlado Dancik
- Chemical
Biology and Therapeutics Science Program, Broad Institute, Cambridge, Massachusetts 02142, United States
| | - Paul A. Clemons
- Chemical
Biology and Therapeutics Science Program, Broad Institute, Cambridge, Massachusetts 02142, United States
| | - Andrew B. Munkacsi
- School
of Biological Sciences and Maurice Wilkins Centre for Molecular Biodiscovery, Victoria University of Wellington, Wellington 6140, New Zealand
| | - Bridget K. Wagner
- Chemical
Biology and Therapeutics Science Program, Broad Institute, Cambridge, Massachusetts 02142, United States
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47
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Li Y, Deng X, Zhuang W, Li Y, Xue H, Lv X, Zhu S. Tanshinone IIA down-regulates -transforming growth factor beta 1 to relieve renal tubular epithelial cell inflammation and pyroptosis caused by high glucose. Bioengineered 2022; 13:12224-12236. [PMID: 35577353 PMCID: PMC9275952 DOI: 10.1080/21655979.2022.2074619] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Diabetic nephropathy (DN) is a microvascular disease caused by diabetes. Tanshinone IIA has been indicated to ameliorate streptozotocin-induced DN. This study explores the effect of tanshinone IIA on high glucose-induced renal tubular epithelial cell pyroptosis and inflammation. High glucose-stimulated HK-2 cells were used as the in-vitro model of DN and were treated with tanshinone IIA at concentrations of 1, 5, 10 μM for 24 h with the same doses of tolbutamide as the control. After tanshinone IIA treatment, HK-2 cells were transfected with pcDNA-transforming growth factor beta 1 (TGFB1) or sh-TGFB1 for 48 h. RT-qPCR was used to detect the mRNA levels of TNF-α, IL-6, IL-1β, and IL-18. Cell apoptosis and pyroptosis were detected by flow cytometry and cell immunofluorescence. Bioinformatics screening predicted that tanshinone IIA might be an effective component of Salvia miltiorrhiza Bunge (Labiatae) for the treatment of DN. Tanshinone IIA exerted a protective effect in the in-vitro model of DN by suppressing inflammation and pyroptosis via the TGFB1-dependent pathway. Tanshinone IIA inhibited high glucose-induced renal tubular epithelial cell inflammation and cell death through pyroptosis by regulating TGFB1, indicating the therapeutic potential of tanshinone IIA for DN treatment.
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Affiliation(s)
- Ying Li
- Department of Endocrinology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, China
| | - Xu Deng
- Department of Endocrinology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, China
| | - Wenlong Zhuang
- Department of General Surgery, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, China
| | - Yong Li
- Department of General Surgery, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, China
| | - Hui Xue
- Department of Endocrinology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, China
| | - Xin Lv
- Department of Endocrinology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, China
| | - Shuqin Zhu
- Department of Endocrinology, The Affiliated Suqian First People's Hospital of Nanjing Medical University, Suqian, China
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48
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Baumel-Alterzon S, Katz LS, Brill G, Jean-Pierre C, Li Y, Tse I, Biswal S, Garcia-Ocaña A, Scott DK. Nrf2 Regulates β-Cell Mass by Suppressing β-Cell Death and Promoting β-Cell Proliferation. Diabetes 2022; 71:989-1011. [PMID: 35192689 PMCID: PMC9044139 DOI: 10.2337/db21-0581] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Accepted: 02/15/2022] [Indexed: 01/05/2023]
Abstract
Finding therapies that can protect and expand functional β-cell mass is a major goal of diabetes research. Here, we generated β-cell-specific conditional knockout and gain-of-function mouse models and used human islet transplant experiments to examine how manipulating Nrf2 levels affects β-cell survival, proliferation, and mass. Depletion of Nrf2 in β-cells results in decreased glucose-stimulated β-cell proliferation ex vivo and decreased adaptive β-cell proliferation and β-cell mass expansion after a high-fat diet in vivo. Nrf2 protects β-cells from apoptosis after a high-fat diet. Nrf2 loss of function decreases Pdx1 abundance and insulin content. Activating Nrf2 in a β-cell-specific manner increases β-cell proliferation and mass and improves glucose tolerance. Human islets transplanted under the kidney capsule of immunocompromised mice and treated systemically with bardoxolone methyl, an Nrf2 activator, display increased β-cell proliferation. Thus, by managing reactive oxygen species levels, Nrf2 regulates β-cell mass and is an exciting therapeutic target for expanding and protecting β-cell mass in diabetes.
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Affiliation(s)
- Sharon Baumel-Alterzon
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Liora S. Katz
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Gabriel Brill
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Clairete Jean-Pierre
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Yansui Li
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Isabelle Tse
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Shyam Biswal
- Department of Environmental Health and Engineering, Johns Hopkins University, Baltimore, MD
| | - Adolfo Garcia-Ocaña
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Donald K. Scott
- Diabetes, Obesity and Metabolism Institute, Icahn School of Medicine at Mount Sinai, New York, NY
- Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, NY
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49
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Oudbor L, Mokhtari Z, Dastghaib S, Mokarram P, Rajani HF, Barazesh M, Salami S. Aqueous extract of Stevia rebaudiana (Bertoni) Bertoni abrogates death-related signaling pathways via boosting the expression profile of oxidative defense systems. J Food Biochem 2022; 46:e14151. [PMID: 35365911 DOI: 10.1111/jfbc.14151] [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: 11/13/2021] [Revised: 02/19/2022] [Accepted: 02/23/2022] [Indexed: 12/01/2022]
Abstract
Indigenous inhabitants of South America and other areas have been using stevia as a traditional medicine for years, but its impact on cell signaling pathways has not been well studied yet. We evaluated the impacts of aqueous extract of Stevia rebaudiana (Bertoni) Bertoni on the expression of the selected genes involved in significant cell death modalities, including p53-DNA damage and the cellular antioxidative defense in pancreatic tissues in STZ-induced diabetic rats and murine pancreatic cell lines. The in vivo study revealed that aqueous extract of Stevia significantly upregulated the expression of GSTM1 and P1 and GPX (4.67, 12.08, and 2.81 fold, respectively; all p < .05) along with significant downregulation of the genes which were upregulated by STZ, including apoptotic genes caspase-3 and -9 (-9.80 and -4.16 fold, p < .05, respectively) and necroptotic genes, RIP1K, 2 K, and 3 K (-9.48, -2.70, and -12.9 fold, respectively, all p < .05). In vitro studies also revealed comparable results. In conclusion, the observed clinical improvements in diabetic rats are the result of overexpression of major genes of antioxidative defense systems in the course of a significant downregulation of major cell death modalities. PRACTICAL APPLICATIONS: The popularity of noncaloric sweeteners, including stevia, has rocketed in recent years, but the consumption of stevia as traditional medicine has a long history. The findings of the current study provide strong mechanistic lines of evidence supporting the beneficial biological effects of stevia as a noncaloric sweetener in diabetes.
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Affiliation(s)
- Leila Oudbor
- Cell Death and Differentiation Signaling Research Lab, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Zohreh Mokhtari
- Cell Death and Differentiation Signaling Research Lab, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sanaz Dastghaib
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Pooneh Mokarram
- Department of Clinical Biochemistry, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Huda Fatima Rajani
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahdi Barazesh
- School of Paramedical Sciences, Gerash Faculty of Medical Sciences, Gerash, Iran
| | - Siamak Salami
- Cell Death and Differentiation Signaling Research Lab, Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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50
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Merabet N, Lucassen PJ, Crielaard L, Stronks K, Quax R, Sloot PMA, la Fleur SE, Nicolaou M. How exposure to chronic stress contributes to the development of type 2 diabetes: A complexity science approach. Front Neuroendocrinol 2022; 65:100972. [PMID: 34929260 DOI: 10.1016/j.yfrne.2021.100972] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/24/2021] [Accepted: 12/12/2021] [Indexed: 11/18/2022]
Abstract
Chronic stress contributes to the onset of type 2 diabetes (T2D), yet the underlying etiological mechanisms are not fully understood. Responses to stress are influenced by earlier experiences, sex, emotions and cognition, and involve a complex network of neurotransmitters and hormones, that affect multiple biological systems. In addition, the systems activated by stress can be altered by behavioral, metabolic and environmental factors. The impact of stress on metabolic health can thus be considered an emergent process, involving different types of interactions between multiple variables, that are driven by non-linear dynamics at different spatiotemporal scales. To obtain a more comprehensive picture of the links between chronic stress and T2D, we followed a complexity science approach to build a causal loop diagram (CLD) connecting the various mediators and processes involved in stress responses relevant for T2D pathogenesis. This CLD could help develop novel computational models and formulate new hypotheses regarding disease etiology.
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Affiliation(s)
- Nadège Merabet
- Department of Public and Occupational Health, Amsterdam UMC, University of Amsterdam, Amsterdam Public Health Research Institute, Meibergdreef 9, Amsterdam, the Netherlands; Institute for Advanced Study, University of Amsterdam, Amsterdam 1012 GC, the Netherlands; Centre for Urban Mental Health, University of Amsterdam, Amsterdam 1012 GC, the Netherlands
| | - Paul J Lucassen
- Centre for Urban Mental Health, University of Amsterdam, Amsterdam 1012 GC, the Netherlands; Brain Plasticity Group, Swammerdam Institute for Life Sciences, Faculty of Science, University of Amsterdam, Amsterdam 1098 XH, the Netherlands
| | - Loes Crielaard
- Department of Public and Occupational Health, Amsterdam UMC, University of Amsterdam, Amsterdam Public Health Research Institute, Meibergdreef 9, Amsterdam, the Netherlands; Institute for Advanced Study, University of Amsterdam, Amsterdam 1012 GC, the Netherlands
| | - Karien Stronks
- Department of Public and Occupational Health, Amsterdam UMC, University of Amsterdam, Amsterdam Public Health Research Institute, Meibergdreef 9, Amsterdam, the Netherlands; Institute for Advanced Study, University of Amsterdam, Amsterdam 1012 GC, the Netherlands; Centre for Urban Mental Health, University of Amsterdam, Amsterdam 1012 GC, the Netherlands
| | - Rick Quax
- Institute for Advanced Study, University of Amsterdam, Amsterdam 1012 GC, the Netherlands; Computational Science Lab, University of Amsterdam, Amsterdam 1098 XH, the Netherlands
| | - Peter M A Sloot
- Institute for Advanced Study, University of Amsterdam, Amsterdam 1012 GC, the Netherlands; Centre for Urban Mental Health, University of Amsterdam, Amsterdam 1012 GC, the Netherlands; Computational Science Lab, University of Amsterdam, Amsterdam 1098 XH, the Netherlands; National Centre of Cognitive Research, ITMO University, St. Petersburg, Russian Federation
| | - Susanne E la Fleur
- Department of Endocrinology and Metabolism & Laboratory of Endocrinology, Department of Clinical Chemistry, Amsterdam Neuroscience, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands; Metabolism and Reward Group, Netherlands Institute for Neuroscience, an Institute of the Royal Netherlands Academy of Arts and Sciences, Meibergdreef 47, Amsterdam, the Netherlands.
| | - Mary Nicolaou
- Department of Public and Occupational Health, Amsterdam UMC, University of Amsterdam, Amsterdam Public Health Research Institute, Meibergdreef 9, Amsterdam, the Netherlands; Institute for Advanced Study, University of Amsterdam, Amsterdam 1012 GC, the Netherlands; Centre for Urban Mental Health, University of Amsterdam, Amsterdam 1012 GC, the Netherlands.
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