Pub Date : 2025-04-03DOI: 10.1016/j.peptides.2025.171393
Jens Juul Holst , Mette M. Rosenkilde
Almost since its discovery, glucagon was suspected to be formed in the gastrointestinal tract, and the L-cells were shown to contain glucagon-like immunoreactivity. This was due to the presence of two peptides that both contained the full glucagon sequence:glicentin of 69 amino acids and oxyntomodulin of 37 amino acids. While glicentin is a part of the glucagon precursor, proglucagon, and probably is inactive, oxyntomodulin, a fragment of glicentin, interacts although weakly with the glucagon as well as the GLP-1 receptor. However, in agreement with these activities, oxyntomodulin inhibited appetite and food intake in humans and inspired development of long acting, potent glucagon-GLP-1 co-agonists. Several such co-agonists are currently in clinical development and show promise because they combine GLP-1 like activities with those of glucagon agonism: additive weight loss and a stimulation of hepatic lipid metabolism with unique effectiveness on hepatic steatosis. They may therefore be effective in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD).
{"title":"Oxyntomodulin - past, present and future","authors":"Jens Juul Holst , Mette M. Rosenkilde","doi":"10.1016/j.peptides.2025.171393","DOIUrl":"10.1016/j.peptides.2025.171393","url":null,"abstract":"<div><div>Almost since its discovery, glucagon was suspected to be formed in the gastrointestinal tract, and the L-cells were shown to contain glucagon-like immunoreactivity. This was due to the presence of two peptides that both contained the full glucagon sequence:glicentin of 69 amino acids and oxyntomodulin of 37 amino acids. While glicentin is a part of the glucagon precursor, proglucagon, and probably is inactive, oxyntomodulin, a fragment of glicentin, interacts although weakly with the glucagon as well as the GLP-1 receptor. However, in agreement with these activities, oxyntomodulin inhibited appetite and food intake in humans and inspired development of long acting, potent glucagon-GLP-1 co-agonists. Several such co-agonists are currently in clinical development and show promise because they combine GLP-1 like activities with those of glucagon agonism: additive weight loss and a stimulation of hepatic lipid metabolism with unique effectiveness on hepatic steatosis. They may therefore be effective in the treatment of metabolic dysfunction-associated steatotic liver disease (MASLD).</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"188 ","pages":"Article 171393"},"PeriodicalIF":2.8,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788497","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}
Visceral hypersensitivity and impaired gut barrier function, accompanied by minor inflammation, are crucial components of the pathophysiology of irritable bowel syndrome (IBS). Research has demonstrated that corticotropin-releasing factor (CRF) and toll-like receptor 4 (TLR4) signaling mutually activate to produce proinflammatory cytokines, which modulate these gastrointestinal changes. Irisin, a myokine, has been shown to inhibit TLR4-proinflammatory cytokine signaling, thereby improving inflammation driven by obesity and metabolic syndrome. Based on this, we hypothesized that irisin could improve visceral hypersensitivity and impaired gut barrier function induced by lipopolysaccharide (LPS) or CRF (IBS rat models), and tested this hypothesis. The visceral pain threshold, triggered by colonic balloon distention, was assessed by electrophysiologically monitoring abdominal muscle contractions in male Sprague-Dawley rats. Colonic permeability was evaluated by measuring the amount of Evans blue dye absorbed within the colonic tissue. Intraperitoneal irisin prevented LPS-induced visceral hypersensitivity and colonic hyperpermeability in a dose-dependent manner. Irisin also prevented CRF-induced gastrointestinal alterations. The beneficial effects of irisin in the LPS model were reversed by compound C, an AMP-activated protein kinase (AMPK) inhibitor; NG-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor; sulpiride or domperidone, a dopamine D2 receptor antagonist; atropine and intracisternal injection of SB-334867, a selective orexin 1 receptor antagonist. Overall, these findings suggest that irisin improves visceral sensation and colonic barrier function through AMPK, NO and dopamine D2, cholinergic and brain orexin signaling in IBS model. Thus, irisin may be a promising therapeutic agent for treating IBS.
内脏过敏和肠道屏障功能受损，伴随着轻微的炎症，是肠易激综合征（IBS）病理生理学的重要组成部分。研究表明，促肾上腺皮质激素释放因子（CRF）和toll样受体4 （TLR4）信号相互激活，产生促炎细胞因子，调节这些胃肠道变化。鸢尾素是一种肌因子，已被证明可以抑制tlr4促炎细胞因子信号，从而改善肥胖和代谢综合征引起的炎症。基于此，我们假设鸢尾素可以改善脂多糖（LPS）或CRF （IBS大鼠模型）引起的内脏超敏反应和肠道屏障功能受损，并对这一假设进行了验证。通过电生理学监测雄性Sprague-Dawley大鼠腹部肌肉收缩，评估由结肠球囊膨胀引发的内脏痛阈。通过测定结肠组织内埃文斯蓝染料的吸收量来评估结肠通透性。鸢尾素以剂量依赖性的方式阻止lps诱导的内脏超敏反应和结肠高渗透性。鸢尾素还能防止crf诱导的胃肠道改变。鸢尾素在LPS模型中的有益作用被化合物C逆转，化合物C是一种amp激活的蛋白激酶（AMPK）抑制剂；NO合成抑制剂ng -硝基- l -精氨酸甲酯；舒必利或多潘立酮，多巴胺D2受体拮抗剂；阿托品和腹腔注射SB-334867，一种选择性食欲素1受体拮抗剂。综上所述，这些发现表明鸢尾素在IBS模型中通过AMPK、NO和多巴胺D2、胆碱能和脑促食欲素信号通路改善内脏感觉和结肠屏障功能。因此，鸢尾素可能是一种很有前途的治疗肠易激综合征的药物。
{"title":"Irisin prevents visceral hypersensitivity and colonic hyperpermeability in a rat model of irritable bowel syndrome","authors":"Tsukasa Nozu , Saori Miyagishi , Masatomo Ishioh , Kaoru Takakusaki , Toshikatsu Okumura","doi":"10.1016/j.peptides.2025.171394","DOIUrl":"10.1016/j.peptides.2025.171394","url":null,"abstract":"<div><div>Visceral hypersensitivity and impaired gut barrier function, accompanied by minor inflammation, are crucial components of the pathophysiology of irritable bowel syndrome (IBS). Research has demonstrated that corticotropin-releasing factor (CRF) and toll-like receptor 4 (TLR4) signaling mutually activate to produce proinflammatory cytokines, which modulate these gastrointestinal changes. Irisin, a myokine, has been shown to inhibit TLR4-proinflammatory cytokine signaling, thereby improving inflammation driven by obesity and metabolic syndrome. Based on this, we hypothesized that irisin could improve visceral hypersensitivity and impaired gut barrier function induced by lipopolysaccharide (LPS) or CRF (IBS rat models), and tested this hypothesis. The visceral pain threshold, triggered by colonic balloon distention, was assessed by electrophysiologically monitoring abdominal muscle contractions in male Sprague-Dawley rats. Colonic permeability was evaluated by measuring the amount of Evans blue dye absorbed within the colonic tissue. Intraperitoneal irisin prevented LPS-induced visceral hypersensitivity and colonic hyperpermeability in a dose-dependent manner. Irisin also prevented CRF-induced gastrointestinal alterations. The beneficial effects of irisin in the LPS model were reversed by compound C, an AMP-activated protein kinase (AMPK) inhibitor; N<sup>G</sup>-nitro-L-arginine methyl ester, a nitric oxide (NO) synthesis inhibitor; sulpiride or domperidone, a dopamine D<sub>2</sub> receptor antagonist; atropine and intracisternal injection of SB-334867, a selective orexin 1 receptor antagonist. Overall, these findings suggest that irisin improves visceral sensation and colonic barrier function through AMPK, NO and dopamine D<sub>2</sub>, cholinergic and brain orexin signaling in IBS model. Thus, irisin may be a promising therapeutic agent for treating IBS.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"188 ","pages":"Article 171394"},"PeriodicalIF":2.8,"publicationDate":"2025-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143726086","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}
Plasma arginine vasopressin (AVP) measurement is critical for diagnosing central diabetes insipidus (CDI). Conventional radioimmunoassay (RIA) is widely used for AVP quantification, but its limited sensitivity, specificity, and dynamic range have prompted exploration of alternative methods. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a promising technique for AVP measurement, offering potential advantages over RIA. This study aimed to evaluate LC-MS/MS performance for AVP quantification during hypertonic saline loading and compare its diagnostic accuracy with that of RIA in differentiating CDI patients from controls. A total of 335 plasma samples were collected from 77 individuals—23 diagnosed with CDI and 54 controls—during hypertonic saline loading. AVP concentrations were measured using both LC-MS/MS and RIA. Statistical analyses included Wilcoxon tests to compare AVP levels, correlation analysis between LC-MS/MS and RIA, and receiver operating characteristic (ROC) curve analysis to assess diagnostic performance. LC-MS/MS demonstrated a lower detection limit (0.3 pg/mL) and a broader quantification range than RIA. Regression analysis showed a strong correlation between LC-MS/MS and RIA in the control group, but no correlation in the CDI group. ROC analysis indicated that LC-MS/MS provided diagnostic accuracy comparable to RIA for distinguishing CDI patients from controls. Bland-Altman analysis showed the agreement between two methods at the low range of AVP. LC-MS/MS offers equivalent specificity and sensitivity to RIA for AVP measurement, while providing added benefits in time efficiency, cost-effectiveness, and differential diagnosis of CDI. These findings suggest that LC-MS/MS is a viable alternative to RIA for clinical AVP quantification.
{"title":"Evaluation of plasma arginine vasopressin during hypertonic saline loading: A comparison of radioimmunoassay and liquid chromatography–tandem mass spectrometry","authors":"Narantsatsral Daramjav , Junko Takagi , Fumio Nomura , Kazuo Otake , Akiyoshi Takami","doi":"10.1016/j.peptides.2025.171392","DOIUrl":"10.1016/j.peptides.2025.171392","url":null,"abstract":"<div><div>Plasma arginine vasopressin (AVP) measurement is critical for diagnosing central diabetes insipidus (CDI). Conventional radioimmunoassay (RIA) is widely used for AVP quantification, but its limited sensitivity, specificity, and dynamic range have prompted exploration of alternative methods. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) has emerged as a promising technique for AVP measurement, offering potential advantages over RIA. This study aimed to evaluate LC-MS/MS performance for AVP quantification during hypertonic saline loading and compare its diagnostic accuracy with that of RIA in differentiating CDI patients from controls. A total of 335 plasma samples were collected from 77 individuals—23 diagnosed with CDI and 54 controls—during hypertonic saline loading. AVP concentrations were measured using both LC-MS/MS and RIA. Statistical analyses included Wilcoxon tests to compare AVP levels, correlation analysis between LC-MS/MS and RIA, and receiver operating characteristic (ROC) curve analysis to assess diagnostic performance. LC-MS/MS demonstrated a lower detection limit (0.3 pg/mL) and a broader quantification range than RIA. Regression analysis showed a strong correlation between LC-MS/MS and RIA in the control group, but no correlation in the CDI group. ROC analysis indicated that LC-MS/MS provided diagnostic accuracy comparable to RIA for distinguishing CDI patients from controls. Bland-Altman analysis showed the agreement between two methods at the low range of AVP. LC-MS/MS offers equivalent specificity and sensitivity to RIA for AVP measurement, while providing added benefits in time efficiency, cost-effectiveness, and differential diagnosis of CDI. These findings suggest that LC-MS/MS is a viable alternative to RIA for clinical AVP quantification.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"187 ","pages":"Article 171392"},"PeriodicalIF":2.8,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143664016","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 : 2025-03-15DOI: 10.1016/j.peptides.2025.171391
Andrew A. Butler , Peter J. Havel
Whole-body metabolic homeostasis is regulated by physiological responses across organs and tissues to proteins and peptides (<50 amino acids) released into the interstitial and circulatory spaces. These secreted factors integrate signals of metabolic status at both the cellular and systemic level, regulate the intake and distribution of ingested and stored energy substrates across tissues, and minimize toxicity from excessive excursions in circulating concentrations of energy substrates (for example, glucotoxicity and lipotoxicity). The proteins and peptides that are known to be secreted into circulation that are involved in regulating metabolic processes represent a fraction of the secretome predicted by the Human Proteome Atlas. Many undiscovered leads for targeting new therapies for metabolic diseases may therefore exist. In this review, we discuss the biology of adropin, the peptide encoded by the Energy Homeostasis Associated (ENHO) gene. First described as a feeding-responsive, liver-secreted peptide (“hepatokine”) involved in metabolic homeostasis, > 2 decades of research indicate adropin is a stress-responsive peptide acting across multiple tissues, vascular, and organ systems. Adropin modulates the responses of liver and muscle to insulin and glucagon in regulating glucose homeostasis. Adropin inhibits hepatic glucose production and stimulates glycolysis but also inhibits tissue fibrosis and maintains vascular health in aging and metabolic disease states. Adropin is also highly expressed in the central nervous system where recent data suggest neuroprotective actions. Collectively, these results suggest the potential for targeting adropin in reducing risk of both metabolic (metabolic syndrome/type-2 diabetes) and neurodegenerative diseases in the context of aging and obesity.
{"title":"Adropin: A cardio-metabolic hormone in the periphery, a neurohormone in the brain?","authors":"Andrew A. Butler , Peter J. Havel","doi":"10.1016/j.peptides.2025.171391","DOIUrl":"10.1016/j.peptides.2025.171391","url":null,"abstract":"<div><div>Whole-body metabolic homeostasis is regulated by physiological responses across organs and tissues to proteins and peptides (<50 amino acids) released into the interstitial and circulatory spaces. These secreted factors integrate signals of metabolic status at both the cellular and systemic level, regulate the intake and distribution of ingested and stored energy substrates across tissues, and minimize toxicity from excessive excursions in circulating concentrations of energy substrates (for example, glucotoxicity and lipotoxicity). The proteins and peptides that are known to be secreted into circulation that are involved in regulating metabolic processes represent a fraction of the secretome predicted by the Human Proteome Atlas. Many undiscovered leads for targeting new therapies for metabolic diseases may therefore exist. In this review, we discuss the biology of adropin, the peptide encoded by the Energy Homeostasis Associated (<em>ENHO</em>) gene<em>.</em> First described as a feeding-responsive, liver-secreted peptide (“hepatokine”) involved in metabolic homeostasis, > 2 decades of research indicate adropin is a stress-responsive peptide acting across multiple tissues, vascular, and organ systems. Adropin modulates the responses of liver and muscle to insulin and glucagon in regulating glucose homeostasis. Adropin inhibits hepatic glucose production and stimulates glycolysis but also inhibits tissue fibrosis and maintains vascular health in aging and metabolic disease states. Adropin is also highly expressed in the central nervous system where recent data suggest neuroprotective actions. Collectively, these results suggest the potential for targeting adropin in reducing risk of both metabolic (metabolic syndrome/type-2 diabetes) and neurodegenerative diseases in the context of aging and obesity.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"187 ","pages":"Article 171391"},"PeriodicalIF":2.8,"publicationDate":"2025-03-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143649891","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 : 2025-03-11DOI: 10.1016/j.peptides.2025.171380
Clifford J. Bailey , Peter R. Flatt , J. Michael Conlon
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).
{"title":"Multifunctional incretin peptides in therapies for type 2 diabetes, obesity and associated co-morbidities","authors":"Clifford J. Bailey , Peter R. Flatt , 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}
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}
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