Pub Date : 2025-03-08DOI: 10.1016/j.peptides.2025.171381
Zhuo Zuo, Yaxing Wang, Yanwei Fang, Mengya Zhao, Zhe Wang, Zhouqi Yang, Bin Jia, Yulong Sun
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 in vitro and in vivo 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.
{"title":"A novel regulator of NLRP3 inflammasome: Peptides","authors":"Zhuo Zuo, Yaxing Wang, Yanwei Fang, Mengya Zhao, Zhe Wang, Zhouqi Yang, Bin Jia, 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}
Pub Date : 2025-02-25DOI: 10.1016/j.peptides.2025.171379
Min Zhang, Rong Lei, Liqiong Wang, Yimin Jiang, Xiaoyan Zhou, Yuquan Wang
Background
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.
Methods
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.
Results
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.
Conclusion
KLF4 transcriptionally regulates FAM3A, modulating Ang II-induced VSMC proliferation and migration through the PI3K/AKT signaling pathway.
{"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, Rong Lei, Liqiong Wang, Yimin Jiang, Xiaoyan Zhou, 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}
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). Npgl overexpression promoted fat accumulation in the white adipose tissues in 2 weeks. Basal insulin levels were increased and pancreatic islets expanded following Npgl overexpression. Histological and molecular biological approaches revealed that Npgl overexpression enhanced de novo lipogenesis, leading to hepatic steatosis. Nine-week overexpression of Npgl exacerbated obesity and hyperinsulinemia, resulting in hyperglycemia. Moreover, prolonged Npgl overexpression aggravated fat accumulation in the liver with a change in the lipid metabolic pathway. These findings suggest that Npgl overexpression readily leads to obesity with hyperinsulinemia and hepatic steatosis in ICR mice under an LFMSD.
{"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 , Masaki Kato , Eiko Iwakoshi-Ukena, Megumi Furumitsu, 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}
Pub Date : 2025-02-19DOI: 10.1016/j.peptides.2025.171369
Jens F. Rehfeld
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 in vitro 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.
{"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}
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 < 0.001). EPO dramatically decreased the amount of caspase 3 positive cells in the CA1 area of the hippocampus (P < 0.01). EPO increased total superoxide dismutase activity (P < 0.05), glutathione concentrations (P < 0.05) and catalase levels (P < 0.001). EPO also attenuated the production of TNF-α and malondialdehyde (P < 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.
{"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 , Fahimeh Mohseni , Mehdi khaksari , Behzad Garmabi , Alireza Masoudi , Zhaleh Jamali , Shima Mohammadi , 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 < 0.001). EPO dramatically decreased the amount of caspase 3 positive cells in the CA1 area of the hippocampus (P < 0.01). EPO increased total superoxide dismutase activity (P < 0.05), glutathione concentrations (P < 0.05) and catalase levels (P < 0.001). EPO also attenuated the production of TNF-α and malondialdehyde (P < 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}
Pub Date : 2025-02-19DOI: 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
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.
{"title":"The role of leptin and ghrelin in the regulation of appetite in obesity","authors":"Kinga Skoracka , Szymon Hryhorowicz , Piotr Schulz , Agnieszka Zawada , Alicja Ewa Ratajczak-Pawłowska , Anna Maria Rychter , Ryszard Słomski , Agnieszka Dobrowolska , 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}
Pub Date : 2025-02-13DOI: 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
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 db/db diabetic mice. Subsequently, dulaglutide was delivered via subcutaneous injections surrounding the wound’s perimeter, and the wound closure rates were monitored. In vitro, 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 Fe2 + 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. In vitro, dulaglutide promoted HaCaT cell proliferation and migration under HG conditions. Exposure of HaCaT cells to HG resulted in ferroptosis in vivo and in vitro, as evidenced by the significant increase in Fe2+, 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.
{"title":"Dulaglutide accelerates diabetic wound healing by suppressing Nrf2-dependent ferroptosis in diabetic mice","authors":"Liuqing Xi , Juan Du , Yan Lu , Wen Xue , Yuxuan Xia , Tingxu Chen , Yang Xiao , Nuo Xu , Yansheng Wang , Jianfang Gao , Wenyi Li , 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}
Pub Date : 2025-02-08DOI: 10.1016/j.peptides.2025.171356
Filipe M. Ribeiro , Luiz Arnaldo , Lana P. Milhomem , Samuel S. Aguiar , Octavio L. Franco
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.
{"title":"The intricate relationship between circadian rhythms and gastrointestinal peptides in obesity","authors":"Filipe M. Ribeiro , Luiz Arnaldo , Lana P. Milhomem , Samuel S. Aguiar , 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}
Pub Date : 2025-02-06DOI: 10.1016/j.peptides.2025.171354
Yajing Mi , Pengtao Jiang , Jing Luan , Lin Feng , Dian Zhang , Xingchun Gao
Glioma is a prevalent form of primary malignant central nervous system tumor, characterized by its cellular invasiveness, rapid growth, and the presence of the blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB). Current therapeutic approaches, such as chemotherapy and radiotherapy, have shown limited efficacy in achieving significant antitumor effects. Therefore, there is an urgent demand for new treatments. Therapeutic peptides represent an innovative class of pharmaceutical agents with lower immunogenicity and toxicity. They are easily modifiable via chemical means and possess deep tissue penetration capabilities which reduce side effects and drug resistance. These unique pharmacokinetic characteristics make peptides a rapidly growing class of new therapeutics that have demonstrated significant progress in glioma treatment. This review outlines the efforts and accomplishments in peptide-based therapeutic strategies for glioma. These therapeutic peptides can be classified into four types based on their anti-tumor function: tumor-homing peptides, inhibitor/antagonist peptides targeting cell surface receptors, interference peptides, and peptide vaccines. Furthermore, we briefly summarize the results from clinical trials of therapeutic peptides in glioma, which shows that peptide-based therapeutic strategies exhibit great potential as multifunctional players in glioma therapy.
{"title":"Peptide‑based therapeutic strategies for glioma: Current state and prospects","authors":"Yajing Mi , Pengtao Jiang , Jing Luan , Lin Feng , Dian Zhang , Xingchun Gao","doi":"10.1016/j.peptides.2025.171354","DOIUrl":"10.1016/j.peptides.2025.171354","url":null,"abstract":"<div><div>Glioma is a prevalent form of primary malignant central nervous system tumor, characterized by its cellular invasiveness, rapid growth, and the presence of the blood-brain barrier (BBB)/blood-brain tumor barrier (BBTB). Current therapeutic approaches, such as chemotherapy and radiotherapy, have shown limited efficacy in achieving significant antitumor effects. Therefore, there is an urgent demand for new treatments. Therapeutic peptides represent an innovative class of pharmaceutical agents with lower immunogenicity and toxicity. They are easily modifiable via chemical means and possess deep tissue penetration capabilities which reduce side effects and drug resistance. These unique pharmacokinetic characteristics make peptides a rapidly growing class of new therapeutics that have demonstrated significant progress in glioma treatment. This review outlines the efforts and accomplishments in peptide-based therapeutic strategies for glioma. These therapeutic peptides can be classified into four types based on their anti-tumor function: tumor-homing peptides, inhibitor/antagonist peptides targeting cell surface receptors, interference peptides, and peptide vaccines. Furthermore, we briefly summarize the results from clinical trials of therapeutic peptides in glioma, which shows that peptide-based therapeutic strategies exhibit great potential as multifunctional players in glioma therapy.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"185 ","pages":"Article 171354"},"PeriodicalIF":2.8,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143372529","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}
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