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Multifunctional incretin peptides in therapies for type 2 diabetes, obesity and associated co-morbidities
IF 2.8 4区 医学
Peptides Pub Date : 2025-03-11 DOI: 10.1016/j.peptides.2025.171380
Clifford J. Bailey , Peter R. Flatt , J. Michael Conlon
{"title":"Multifunctional incretin peptides in therapies for type 2 diabetes, obesity and associated co-morbidities","authors":"Clifford J. Bailey ,&nbsp;Peter R. Flatt ,&nbsp;J. Michael Conlon","doi":"10.1016/j.peptides.2025.171380","DOIUrl":"10.1016/j.peptides.2025.171380","url":null,"abstract":"<div><div>Recent studies with peptide-based incretin therapies have focussed mainly on the glucagon-like peptide-1 (GLP-1) receptor agonist semaglutide and the dual agonist tirzepatide that engages receptors for GLP-1 and glucose-dependent insulinotropic polypeptide (GIP). Randomised clinical trials and ‘real-world’ studies have confirmed the marked glucose-lowering and weight-lowering efficacy of these agents across diverse populations. These include different ethnic groups, young and elderly individuals with and without diabetes and/or overweight or obesity. Recent studies have also confirmed protections against the development and progression of cardiovascular and renal diseases that are additive to the benefits conferred by improved control of blood glucose and body weight. Emerging evidence suggests that incretin therapies could additionally ameliorate fatty liver disease, chronic inflammation, sleep apnea and possibly degenerative bone disorders and cognitive decline. New incretin-based peptide therapies in development include a long-acting glucagon receptor agonist (LY3324954), dual GLP-1/glucagon receptor agonists (survodutide, pemvidutide, mazdutide, G49), triple GLP-1/GIP/glucagon receptor agonists (retatrutide, efocipegtrutide), a combination of semaglutide with the amylin analogue cagrilintide (CagriSema), a unimolecular GLP-1/amylin receptor dual agonist (amycretin), and a GIP receptor antibody with GLP-1 receptor agonism (MariTide). The creation of multi-targeting incretin-based synthetic peptides provides opportunities for improved management of type 2 diabetes and obesity as well as new therapeutic approaches to an expanding list of associated co-morbidities. The aim of the review is to acquaint the reader with developments in the field from 2023 to the present (February 2025).</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"187 ","pages":"Article 171380"},"PeriodicalIF":2.8,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143601618","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A novel regulator of NLRP3 inflammasome: Peptides
IF 2.8 4区 医学
Peptides Pub Date : 2025-03-08 DOI: 10.1016/j.peptides.2025.171381
Zhuo Zuo, Yaxing Wang, Yanwei Fang, Mengya Zhao, Zhe Wang, Zhouqi Yang, Bin Jia, Yulong Sun
{"title":"A novel regulator of NLRP3 inflammasome: Peptides","authors":"Zhuo Zuo,&nbsp;Yaxing Wang,&nbsp;Yanwei Fang,&nbsp;Mengya Zhao,&nbsp;Zhe Wang,&nbsp;Zhouqi Yang,&nbsp;Bin Jia,&nbsp;Yulong Sun","doi":"10.1016/j.peptides.2025.171381","DOIUrl":"10.1016/j.peptides.2025.171381","url":null,"abstract":"<div><div>The NLRP3 inflammasome plays a crucial role as a critical regulator of the immune response and has been implicated in the pathogenesis of numerous diseases. Peptides, known for their remarkable potency, selectivity, and low toxicity, have been extensively employed in disease treatment. Recent research has unveiled the potential of peptides in modulating the activity of the NLRP3 inflammasome. This review begins by examining the structure of the NLRP3 inflammasome, encompassing NLRP3, ASC, and Caspase-1, along with the three activation pathways: canonical, non-canonical, and alternative. Subsequently, we provide a comprehensive summary of peptide modulators targeting the NLRP3 inflammasome and elucidate their underlying mechanisms. The efficacy of these modulators has been validated through <em>in vitro</em> and <em>in vivo</em> experiments on NLRP3 inflammasome regulation. Furthermore, we conduct sequence alignment of the identified peptides and investigate their binding sites on the NLRP3 protein. This work is a foundational exploration for advancing peptides as potential therapeutic agents for NLRP3-related diseases.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"187 ","pages":"Article 171381"},"PeriodicalIF":2.8,"publicationDate":"2025-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143594028","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Corrigendum to "Oxytocin attenuates cardiac hypertrophy by improving cardiac glucose metabolism and regulating OXTR/JAK2/STAT3 axis" [Peptides 182 (2024) 171323].
IF 2.8 4区 医学
Peptides Pub Date : 2025-03-07 DOI: 10.1016/j.peptides.2025.171365
Yuqiao Yang, Jin Liu, Lingyan Wang, Wen Wu, Quan Wang, Yu Zhao, Xi Qian, Zhuoran Wang, Na Fu, Yanqiong Wang, Jinqiao Qian
{"title":"Corrigendum to \"Oxytocin attenuates cardiac hypertrophy by improving cardiac glucose metabolism and regulating OXTR/JAK2/STAT3 axis\" [Peptides 182 (2024) 171323].","authors":"Yuqiao Yang, Jin Liu, Lingyan Wang, Wen Wu, Quan Wang, Yu Zhao, Xi Qian, Zhuoran Wang, Na Fu, Yanqiong Wang, Jinqiao Qian","doi":"10.1016/j.peptides.2025.171365","DOIUrl":"https://doi.org/10.1016/j.peptides.2025.171365","url":null,"abstract":"","PeriodicalId":19765,"journal":{"name":"Peptides","volume":" ","pages":"171365"},"PeriodicalIF":2.8,"publicationDate":"2025-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143586462","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
KLF4 regulates FAM3A to promotes angiotensin II-induced proliferation and migration of vascular smooth muscle cells through the PI3K/AKT signaling pathway
IF 2.8 4区 医学
Peptides Pub Date : 2025-02-25 DOI: 10.1016/j.peptides.2025.171379
Min Zhang, Rong Lei, Liqiong Wang, Yimin Jiang, Xiaoyan Zhou, Yuquan Wang
{"title":"KLF4 regulates FAM3A to promotes angiotensin II-induced proliferation and migration of vascular smooth muscle cells through the PI3K/AKT signaling pathway","authors":"Min Zhang,&nbsp;Rong Lei,&nbsp;Liqiong Wang,&nbsp;Yimin Jiang,&nbsp;Xiaoyan Zhou,&nbsp;Yuquan Wang","doi":"10.1016/j.peptides.2025.171379","DOIUrl":"10.1016/j.peptides.2025.171379","url":null,"abstract":"<div><h3>Background</h3><div>Hypertension, a major cause of cardiovascular disease, is linked to vascular remodeling, which is influenced by phenotypic changes in vascular smooth muscle cells (VSMCs). Studies have shown that KLF4 influences vascular remodeling by promoting VSMC dedifferentiation, increasing proliferation, and enhancing inflammatory responses, while FAM3 may play a key role in VSMC migration and proliferation. Angiotensin II (Ang II) contributes to remodeling, but the mechanisms are unclear.</div></div><div><h3>Methods</h3><div>Ang II was used to stimulate VSMCs in order to evaluate the expression levels of KLF4 and FAM3A. EdU assays, transwell and scratch wound healing assays measured proliferation and migration. KLF4 knockdown and overexpression experiments were performed to examine the effects on FAM3A expression and VSMC behavior. Western blotting was conducted to analyze protein expression levels of KLF4, FAM3A, and PI3K/AKT signaling components. Bioinformatics analysis was used to predict KLF4 binding sites on the FAM3A promoter. Luciferase and CHIP assays confirmed regulation.</div></div><div><h3>Results</h3><div>Ang II stimulation increased VSMC proliferation, migration, and the expression of KLF4 and FAM3A. Knockdown of KLF4 reduced Ang II-induced proliferation and migration of VSMCs, accompanied by decreased FAM3A expression. Conversely, overexpression of KLF4 enhanced FAM3A levels, promoting VSMC proliferation and migration. Bioinformatics, luciferase reporter assays and CHIP assay confirmed that KLF4 directly binds to the FAM3A promoter. FAM3A knockdown inhibited Ang II-induced VSMC proliferation and migration by reducing PI3K/AKT pathway activation, whereas FAM3A overexpression reversed the inhibitory effects of KLF4 knockdown.</div></div><div><h3>Conclusion</h3><div>KLF4 transcriptionally regulates FAM3A, modulating Ang II-induced VSMC proliferation and migration through the PI3K/AKT signaling pathway.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"187 ","pages":"Article 171379"},"PeriodicalIF":2.8,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143524094","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A murine model of obesity with hyperinsulinemia and hepatic steatosis involving neurosecretory protein GL gene and a low-fat/medium-sucrose diet
IF 2.8 4区 医学
Peptides Pub Date : 2025-02-23 DOI: 10.1016/j.peptides.2025.171376
Yuki Narimatsu , Masaki Kato , Eiko Iwakoshi-Ukena, Megumi Furumitsu, Kazuyoshi Ukena
{"title":"A murine model of obesity with hyperinsulinemia and hepatic steatosis involving neurosecretory protein GL gene and a low-fat/medium-sucrose diet","authors":"Yuki Narimatsu ,&nbsp;Masaki Kato ,&nbsp;Eiko Iwakoshi-Ukena,&nbsp;Megumi Furumitsu,&nbsp;Kazuyoshi Ukena","doi":"10.1016/j.peptides.2025.171376","DOIUrl":"10.1016/j.peptides.2025.171376","url":null,"abstract":"<div><div>Metabolic dysfunction-associated steatotic liver disease (MASLD) featuring hepatic steatosis and insulin dysregulation is becoming a common cause of chronic hepatic diseases. Although the involvement of endocrine disruption in the onset and progression of MASLD is thought to be critical, there are limited effective animal models reflecting hyperinsulinemia and hepatic steatosis. Here, we propose a MASLD mouse model that combines neuropeptide effects and dietary nutrition. We employed chronic overexpression of the gene encoding neurosecretory protein GL (NPGL) in the hypothalamus of ICR mice under a low-fat/medium-sucrose diet (LFMSD). <em>Npgl</em> overexpression promoted fat accumulation in the white adipose tissues in 2 weeks. Basal insulin levels were increased and pancreatic islets expanded following <em>Npgl</em> overexpression. Histological and molecular biological approaches revealed that <em>Npgl</em> overexpression enhanced de novo lipogenesis, leading to hepatic steatosis. Nine-week overexpression of <em>Npgl</em> exacerbated obesity and hyperinsulinemia, resulting in hyperglycemia. Moreover, prolonged <em>Npgl</em> overexpression aggravated fat accumulation in the liver with a change in the lipid metabolic pathway. These findings suggest that <em>Npgl</em> overexpression readily leads to obesity with hyperinsulinemia and hepatic steatosis in ICR mice under an LFMSD.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"186 ","pages":"Article 171376"},"PeriodicalIF":2.8,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143493201","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cholecystokinin - portrayal of an unfolding peptide messenger system
IF 2.8 4区 医学
Peptides Pub Date : 2025-02-19 DOI: 10.1016/j.peptides.2025.171369
Jens F. Rehfeld
{"title":"Cholecystokinin - portrayal of an unfolding peptide messenger system","authors":"Jens F. Rehfeld","doi":"10.1016/j.peptides.2025.171369","DOIUrl":"10.1016/j.peptides.2025.171369","url":null,"abstract":"<div><div>This review describes how the classic gut hormone, cholecystokinin (CCK), should be comprehended in 2025. In the early physiological tradition of studying gastrointestinal hormones, the hormones were named after the function that lead to their discovery. Hence, in 1928, the hormonal factor in the upper gut that regulated gallbladder contraction was called cholecystokinin. In 1968, Viktor Mutt and Erik Jorpes identified the porcine structure of this factor as an O-sulfated and carboxyamidated peptide of 33 amino acid residues (CCK-33). Its C-terminal bioactive heptapeptide amide turned out to be homologous to that of the antral hormone, gastrin. The structure allowed <em>in vitro</em> synthesis of peptide fragments for physiological studies and for production of CCK-antibodies for immunoassays and immunohistochemistry. Today, these tools have revealed CCK to be highly complex: CCK is a heterogenous, multifunctional peptide messenger system, widely expressed both in and outside the gut. Thus, the CCK gene encodes six different bioactive peptides (CCK-83, −58, −33, −22, −8, and −5) that are expressed in a cell-specific manner in O-sulfated and non-sulfated forms. Moreover, CCK peptides are not only hormones. They are also potent neurotransmitters, paracrine growth and satiety factors, anti-inflammatory cytokines, incretins, potential fertility factors and useful tumor-markers. Moreover, CCK has a phylogenetic history of nearly 600 million years. Particular interest has been given to the neuroscience of CCK, because CCK is the predominant peptide transmitter in the brain, expressed in amounts that surpass any other neuropeptide. Vice versa, the brain is the main production site of CCK in mammals.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"186 ","pages":"Article 171369"},"PeriodicalIF":2.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143454816","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Erythropoietin improves spatial and nonspatial memory defects by suppressing oxidative damage, inflammation and apoptosis against ethanol neurotoxicity in the developing male rat hippocampus
IF 2.8 4区 医学
Peptides Pub Date : 2025-02-19 DOI: 10.1016/j.peptides.2025.171368
Raheleh Rafaiee , Fahimeh Mohseni , Mehdi khaksari , Behzad Garmabi , Alireza Masoudi , Zhaleh Jamali , Shima Mohammadi , Alieh Bashghareh
{"title":"Erythropoietin improves spatial and nonspatial memory defects by suppressing oxidative damage, inflammation and apoptosis against ethanol neurotoxicity in the developing male rat hippocampus","authors":"Raheleh Rafaiee ,&nbsp;Fahimeh Mohseni ,&nbsp;Mehdi khaksari ,&nbsp;Behzad Garmabi ,&nbsp;Alireza Masoudi ,&nbsp;Zhaleh Jamali ,&nbsp;Shima Mohammadi ,&nbsp;Alieh Bashghareh","doi":"10.1016/j.peptides.2025.171368","DOIUrl":"10.1016/j.peptides.2025.171368","url":null,"abstract":"<div><div>Excessive prenatal exposure to ethanol leads to a condition called fetal alcohol spectrum disorder (FASD). The neurotoxicity of alcohol causes changes in the hippocampus of animals during this time, resulting in impaired hippocampus-related functions, including memory/learning and cognition.The liver and kidneys produce erythropoietin (EPO). The synthesis of EPO by immature neurons also plays a decisive role in the embryonic stage. Also, exogenous EPO exerts its neurocognitive effects in the developing brain under pathophysiological conditions. The aim of this study was to investigate the protective effects of EPO administration after ethanol-induced increased neurodevelopmental toxicity. Male Wistar rat pups were intubated with a dose of 5/27 g/kg/day ethanol from postnatal day 2–10, similar to the last trimester of gestation in humans. Immediately thereafter, EPO (1000 /2000 U/kg, s.c.) were injected. Spatial memory was tested with the Morris water maze (days 36–40) and non-spatial recognition memory with the novel object task (days 39–40). Concentrations of antioxidant enzymes and TNF-α (ELISA) and caspase-3 (immunohistochemical staining) was then performed. The current study shows that EPO administration significantly attenuates spatial and nonspatial memory impairment (P &lt; 0.001). EPO dramatically decreased the amount of caspase 3 positive cells in the CA1 area of the hippocampus (P &lt; 0.01). EPO increased total superoxide dismutase activity (P &lt; 0.05), glutathione concentrations (P &lt; 0.05) and catalase levels (P &lt; 0.001). EPO also attenuated the production of TNF-α and malondialdehyde (P &lt; 0.05). Given EPO's protective effect against ethanol-induced increased neurotoxicity, it is a viable treatment option for FASD, although more research is needed.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"186 ","pages":"Article 171368"},"PeriodicalIF":2.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143463490","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The role of leptin and ghrelin in the regulation of appetite in obesity
IF 2.8 4区 医学
Peptides Pub Date : 2025-02-19 DOI: 10.1016/j.peptides.2025.171367
Kinga Skoracka , Szymon Hryhorowicz , Piotr Schulz , Agnieszka Zawada , Alicja Ewa Ratajczak-Pawłowska , Anna Maria Rychter , Ryszard Słomski , Agnieszka Dobrowolska , Iwona Krela-Kaźmierczak
{"title":"The role of leptin and ghrelin in the regulation of appetite in obesity","authors":"Kinga Skoracka ,&nbsp;Szymon Hryhorowicz ,&nbsp;Piotr Schulz ,&nbsp;Agnieszka Zawada ,&nbsp;Alicja Ewa Ratajczak-Pawłowska ,&nbsp;Anna Maria Rychter ,&nbsp;Ryszard Słomski ,&nbsp;Agnieszka Dobrowolska ,&nbsp;Iwona Krela-Kaźmierczak","doi":"10.1016/j.peptides.2025.171367","DOIUrl":"10.1016/j.peptides.2025.171367","url":null,"abstract":"<div><div>Leptin and ghrelin are two key hormones that play opposing roles in the regulation of appetite and energy balance. Ghrelin stimulates appetite and food intake following binding to receptors and the subsequent activation of orexigenic neurons in the arcuate nucleus. Leptin, conversely, has been demonstrated to suppress appetite and reduce food intake. This occurs through the inhibition of ghrelin-activated neurons, while simultaneously activating those that promote satiety and increase energy expenditure. A lack of biological response despite elevated leptin levels, which is known as leptin resistance, is observed in individuals with excess body weight and represents a significant challenge. As the dysregulation of ghrelin and leptin signalling has been linked to the development of obesity and other metabolic disorders, an in-depth understanding of the genetic determinants affecting these two hormones may facilitate a more comprehensive grasp of the intricate interactions that underpin the pathogenesis of obesity.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"186 ","pages":"Article 171367"},"PeriodicalIF":2.8,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143464091","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Dulaglutide accelerates diabetic wound healing by suppressing Nrf2-dependent ferroptosis in diabetic mice
IF 2.8 4区 医学
Peptides Pub Date : 2025-02-13 DOI: 10.1016/j.peptides.2025.171366
Liuqing Xi , Juan Du , Yan Lu , Wen Xue , Yuxuan Xia , Tingxu Chen , Yang Xiao , Nuo Xu , Yansheng Wang , Jianfang Gao , Wenyi Li , Shan Huang
{"title":"Dulaglutide accelerates diabetic wound healing by suppressing Nrf2-dependent ferroptosis in diabetic mice","authors":"Liuqing Xi ,&nbsp;Juan Du ,&nbsp;Yan Lu ,&nbsp;Wen Xue ,&nbsp;Yuxuan Xia ,&nbsp;Tingxu Chen ,&nbsp;Yang Xiao ,&nbsp;Nuo Xu ,&nbsp;Yansheng Wang ,&nbsp;Jianfang Gao ,&nbsp;Wenyi Li ,&nbsp;Shan Huang","doi":"10.1016/j.peptides.2025.171366","DOIUrl":"10.1016/j.peptides.2025.171366","url":null,"abstract":"<div><div>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are frequently utilized to treat type 2 diabetes mellitus (T2DM). Several GLP-1RAs (Exendin-4 and liraglutide) have been shown to accelerate diabetic wound healing. The major aim of the study was to investigate the roles of dulaglutide in wound healing in diabetic mice and identify the underlying mechanism involved. Round-shape, full-thickness wounds were created on the backs of <em>db</em>/<em>db</em> diabetic mice. Subsequently, dulaglutide was delivered via subcutaneous injections surrounding the wound’s perimeter, and the wound closure rates were monitored. <em>In vitro</em>, keratinocytes were treated with dulaglutide under high glucose (HG) conditions, and cell viability was assessed by cell counting kit-8 (CCK-8) and EdU assays. The roles of dulaglutide in ferroptosis were assessed by measuring the levels of Fe<sup>2 +</sup> and oxidative stress, as well as the expression of ferroptosis markers. The results demonstrated that dulaglutide treatment increased the expression of vascular endothelial growth factor (VEGF) and the proliferation marker Ki67, thereby accelerating wound healing in diabetic mice. <em>In vitro</em>, dulaglutide promoted HaCaT cell proliferation and migration under HG conditions. Exposure of HaCaT cells to HG resulted in ferroptosis <em>in vivo</em> and <em>in vitro</em>, as evidenced by the significant increase in Fe<sup>2+</sup>, reactive oxygen species (ROS), and malondialdehyde (MDA) levels and the decrease in glutathione (GSH) and superoxide dismutase (SOD) levels. All these effects were reversed by dulaglutide. Mechanistically, dulaglutide activated NFE2-related factor 2 (Nrf2) signaling under HG conditions, which increased glutathione peroxidase (Gpx4) and solute carrier family 7-member 11 (Slc7a11) expression, thereby inhibiting ferroptosis. In summary, these results demonstrate dulaglutide as a promising agent for treating diabetic wounds by regulating Nrf2-dependent ferroptosis.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"185 ","pages":"Article 171366"},"PeriodicalIF":2.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143425934","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The intricate relationship between circadian rhythms and gastrointestinal peptides in obesity
IF 2.8 4区 医学
Peptides Pub Date : 2025-02-08 DOI: 10.1016/j.peptides.2025.171356
Filipe M. Ribeiro , Luiz Arnaldo , Lana P. Milhomem , Samuel S. Aguiar , Octavio L. Franco
{"title":"The intricate relationship between circadian rhythms and gastrointestinal peptides in obesity","authors":"Filipe M. Ribeiro ,&nbsp;Luiz Arnaldo ,&nbsp;Lana P. Milhomem ,&nbsp;Samuel S. Aguiar ,&nbsp;Octavio L. Franco","doi":"10.1016/j.peptides.2025.171356","DOIUrl":"10.1016/j.peptides.2025.171356","url":null,"abstract":"<div><div>There are different molecular pathways that regulate appetite, particularly the role of the hypothalamus, circadian rhythms, and gastrointestinal peptides. The hypothalamus integrates signals from orexigenic peptides like neuropeptide Y (NPY) and agouti-related protein (AgRP), which stimulate appetite, and anorexigenic peptides such as pro-opiomelanocortin (POMC) and cocaine- and amphetamine-regulated transcript (CART), which promote satiety. These signals are influenced by peripheral hormones like leptin, ghrelin, insulin, and cortisol, as well as gut peptides including glucagon-like peptide-1 (GLP-1), peptide YY (PYY), and cholecystokinin (CCK). The circadian rhythm, regulated by proteins like circadian locomotor output cycles kaput (CLOCK) and brain and muscle ARNT-like 1 (BMAL1), modulates the secretion of these peptides, aligning feeding behaviors with the sleep-wake cycle. In obesity, these regulatory systems are disrupted, leading to leptin resistance, increased ghrelin sensitivity, and altered gut peptide secretion. This results in heightened appetite and impaired satiety, contributing to overeating and metabolic dysfunction. Additionally, circadian disruptions further impair metabolic processes, exacerbating obesity. The present article underscores the importance of understanding the molecular interplay between circadian rhythms and gastrointestinal peptides, particularly in the context of obesity. While some molecular interactions, such as the regulation of GLP-1 and PYY by reverberation of circadian rhythm α (REV-ERBα) and retinoic acid-related orphan receptor α (RORα), are well-established, clinical studies are scarce. Future research is expected to explore these pathways in obesity management, especially with the rise of incretin-based treatments like semaglutide. A deeper understanding of hypothalamic molecular mechanisms could lead to novel pharmacological and non-pharmacological therapies for obesity.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"185 ","pages":"Article 171356"},"PeriodicalIF":2.8,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
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