Antimicrobial peptides (AMPs), particularly host defense peptides (HDPs), have gained recognition for their role in host defense mechanisms, but they have also shown potential as a promising anticancer, antiviral, antiparasitic, antifungal and immunomodulatory agent. Research studies in recent years have shown HDPs play a crucial role in endothelial cell function and biology. The function of endothelial cells is impacted by HDPs’ complex interplay between cytoprotective and cytotoxic actions as they are known to modulate barrier integrity, inflammatory response and angiogenesis. This biphasic response varies and depends on the peptide structure, its concentration, and the microenvironment. These effects are mediated through key signaling pathways, including MAPK, NF-κB, and PI3K/Akt, which controls responses such as cell proliferation, apoptosis, and migration. In the present review, we have discussed the significance of the intriguing relationship between HDPs and endothelial cell physiology which suggests it potential as a therapeutic agents for the treating wounds, cardiovascular diseases, and inflammation-related endothelial damage.
{"title":"Host defense peptides at the crossroad of endothelial cell physiology: Insight into mechanistic and pharmacological implications","authors":"Vivek Kumar Garg , Hemant Joshi , Amarish Kumar Sharma , Kiran Yadav , Vikas Yadav","doi":"10.1016/j.peptides.2024.171320","DOIUrl":"10.1016/j.peptides.2024.171320","url":null,"abstract":"<div><div>Antimicrobial peptides (AMPs), particularly host defense peptides (HDPs), have gained recognition for their role in host defense mechanisms, but they have also shown potential as a promising anticancer, antiviral, antiparasitic, antifungal and immunomodulatory agent. Research studies in recent years have shown HDPs play a crucial role in endothelial cell function and biology. The function of endothelial cells is impacted by HDPs’ complex interplay between cytoprotective and cytotoxic actions as they are known to modulate barrier integrity, inflammatory response and angiogenesis. This biphasic response varies and depends on the peptide structure, its concentration, and the microenvironment. These effects are mediated through key signaling pathways, including MAPK, NF-κB, and PI3K/Akt, which controls responses such as cell proliferation, apoptosis, and migration. In the present review, we have discussed the significance of the intriguing relationship between HDPs and endothelial cell physiology which suggests it potential as a therapeutic agents for the treating wounds, cardiovascular diseases, and inflammation-related endothelial damage.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"182 ","pages":"Article 171320"},"PeriodicalIF":2.8,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142638462","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 : 2024-11-06DOI: 10.1016/j.peptides.2024.171319
J. Michael Conlon, Peter R. Flatt
{"title":"Discovery of the bioactive form of glucagon-like peptide-1: An attempt to correct some misconceptions","authors":"J. Michael Conlon, Peter R. Flatt","doi":"10.1016/j.peptides.2024.171319","DOIUrl":"10.1016/j.peptides.2024.171319","url":null,"abstract":"","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"182 ","pages":"Article 171319"},"PeriodicalIF":2.8,"publicationDate":"2024-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142625721","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 : 2024-11-01DOI: 10.1016/j.peptides.2024.171317
Othman Al Musaimi
Lasso peptides exhibit a range of bioactivities, including antiviral effects, inhibition of the glucagon receptor, blockade of the endothelin type B receptor, inhibition of myosin light chain kinase, and modulation of the atrial natriuretic factor, as well as notable antimicrobial properties. Intriguingly, lasso peptides exhibit remarkable proteolytic and thermal stability, addressing one of the key challenges that traditional peptides often face. The challenge in producing those valuable peptides remains the main hurdle in the way of producing larger quantities or even modifying them with more potent analogues. Genome mining and heterologous expression approaches have greatly facilitated the production of lasso peptides, moving beyond mere isolation techniques. This advancement not only allows for larger quantities but also enables the creation of additional analogues with improved stability and potency. This review aims to explore the unique bioactivities and stability of lasso peptides, along with recent advancements in genome mining and heterologous expression that address production challenges and open pathways for engineering potent analogues.
拉索肽具有一系列生物活性，包括抗病毒作用、抑制胰高血糖素受体、阻断 B 型内皮素受体、抑制肌球蛋白轻链激酶、调节心房利钠因子，以及显著的抗微生物特性。有趣的是，拉索肽具有显著的蛋白水解稳定性和热稳定性，解决了传统多肽经常面临的关键挑战之一。生产这些有价值的多肽所面临的挑战仍然是生产更多甚至用更强效的类似物对其进行改良的主要障碍。基因组挖掘和异源表达方法大大促进了套索肽的生产，超越了单纯的分离技术。这一进步不仅可以生产更多数量的拉索肽，还能创造出更多具有更高稳定性和效力的类似物。
{"title":"Lasso peptides realm: Insights and applications","authors":"Othman Al Musaimi","doi":"10.1016/j.peptides.2024.171317","DOIUrl":"10.1016/j.peptides.2024.171317","url":null,"abstract":"<div><div>Lasso peptides exhibit a range of bioactivities, including antiviral effects, inhibition of the glucagon receptor, blockade of the endothelin type B receptor, inhibition of myosin light chain kinase, and modulation of the atrial natriuretic factor, as well as notable antimicrobial properties. Intriguingly, lasso peptides exhibit remarkable proteolytic and thermal stability, addressing one of the key challenges that traditional peptides often face. The challenge in producing those valuable peptides remains the main hurdle in the way of producing larger quantities or even modifying them with more potent analogues. Genome mining and heterologous expression approaches have greatly facilitated the production of lasso peptides, moving beyond mere isolation techniques. This advancement not only allows for larger quantities but also enables the creation of additional analogues with improved stability and potency. This review aims to explore the unique bioactivities and stability of lasso peptides, along with recent advancements in genome mining and heterologous expression that address production challenges and open pathways for engineering potent analogues.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"182 ","pages":"Article 171317"},"PeriodicalIF":2.8,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142569247","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}
The co-evolution of social behavior and the immune system plays a critical role in individuals' adaptation to their environment. However, also need for further research on the key molecules that co-regulate social behavior and immunity. This study focused on neonatal mice that were separated from their mothers for 4 hours per day between the 6th and 16th day after birth. The results showed that these mice had lower plasma levels of IFN-γ and oxytocin, but higher levels of plasma glucocorticoids (GC), then impacting their social abilities. Additionally, maternal separation led to decreased levels of BDNF, IGF2, and CREB mRNAs in the hippocampus, while levels in the prefrontal cortex (PFC) remained unaffected. Maternal separation also resulted in increased levels of oxytocin and CRH mRNA in the hypothalamus, as well as an increase in CD45+ lymphocyte subsets in the meninges and choroid plexus (CP), with CD8+ lymphocytes in meninges and CD4+ lymphocytes in CP showing an increase. In IFN-γ-/- mice, a decrease in social preference was observed alongside lower plasma oxytocin levels. Moreover, IFN-γ-/- mice exhibited reduced numbers of oxytocin neurons in the paraventricular nucleus of the paraventricular nucleus of hypothalamus (PVN), decreased BDNF levels in the PFC and hippocampus, and alterations in CD45+ lymphocytes in CP and meninges, with an increase in CD8+ lymphocytes in meninges and CD4+ lymphocytes in CP. These findings highlight the immunological impact of social stress on IFN-γ regulation, suggesting that the immunomodulatory molecule IFN-γ may influence social behavior by affecting synaptic efficiency in brain regions such as the hippocampus and PFC, which are linked to oxytocin in the PVN.
{"title":"Maternal separation alters peripheral immune responses associated with IFN-γ and OT in mice","authors":"Yishu Zhang , HaiChao Chen , JiaXin Cao , LiPing Gao , YuHong Jing","doi":"10.1016/j.peptides.2024.171318","DOIUrl":"10.1016/j.peptides.2024.171318","url":null,"abstract":"<div><div>The co-evolution of social behavior and the immune system plays a critical role in individuals' adaptation to their environment. However, also need for further research on the key molecules that co-regulate social behavior and immunity. This study focused on neonatal mice that were separated from their mothers for 4 hours per day between the 6th and 16th day after birth. The results showed that these mice had lower plasma levels of IFN-γ and oxytocin, but higher levels of plasma glucocorticoids (GC), then impacting their social abilities. Additionally, maternal separation led to decreased levels of <em>BDNF</em>, <em>IGF2</em>, and <em>CREB</em> mRNAs in the hippocampus, while levels in the prefrontal cortex (PFC) remained unaffected. Maternal separation also resulted in increased levels of oxytocin and <em>CRH</em> mRNA in the hypothalamus, as well as an increase in CD45<sup>+</sup> lymphocyte subsets in the meninges and choroid plexus (CP), with CD8<sup>+</sup> lymphocytes in meninges and CD4<sup>+</sup> lymphocytes in CP showing an increase. In IFN-γ<sup>-/-</sup> mice, a decrease in social preference was observed alongside lower plasma oxytocin levels. Moreover, IFN-γ<sup>-/-</sup> mice exhibited reduced numbers of oxytocin neurons in the paraventricular nucleus of the paraventricular nucleus of hypothalamus (PVN), decreased <em>BDNF</em> levels in the PFC and hippocampus, and alterations in CD45<sup>+</sup> lymphocytes in CP and meninges, with an increase in CD8<sup>+</sup> lymphocytes in meninges and CD4<sup>+</sup> lymphocytes in CP. These findings highlight the immunological impact of social stress on IFN-γ regulation, suggesting that the immunomodulatory molecule IFN-γ may influence social behavior by affecting synaptic efficiency in brain regions such as the hippocampus and PFC, which are linked to oxytocin in the PVN.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"182 ","pages":"Article 171318"},"PeriodicalIF":2.8,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564342","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 : 2024-10-28DOI: 10.1016/j.peptides.2024.171312
Trinidad de los Ángeles Cordero Gil , María Soledad Moleón , Belkis Ester Marelli , Pablo Ariel Siroski
Amphibians and reptiles, like all animals, are prone to periodic infections. However, crocodilians stand out for their remarkable ability to remain generally healthy and infection-free despite frequent exposure to a wide variety of microorganisms in their habitats and often sustaining significant injuries. These animals have evolved highly active immune mechanisms that provide rapid and effective defense. This is evidenced by the superior hemolytic capacity of their plasma compared to that of other organisms. To date, several host defense peptides (HDPs) have been identified in crocodilians, including cathelicidins, beta-defensins, hepcidins, leucrocins, hemocidins, and omwaprins. These peptides exhibit potent and broad-spectrum antimicrobial, antibiofilm, antifungal, and anticancer activities. Due to the relatively low but diverse evolutionary rate of crocodilians, the HDPs found in this species offer valuable insights into proteins and mechanisms of action that are highly conserved across many animals related to immune defense. The potential applications of HDPs in modern medicine represent a promising strategy for developing new therapeutic agents. Their novelty and the vast variability with which peptide sequences can be designed and modified expand the field of application for HDPs almost infinitely. This review addresses the urgent need for innovative and more effective drugs to combat the rise of antimicrobialresistant infections and evaluates the potential of crocodilian HDPs. It presents recent advances in the identification of crocodilian HDPs, particularly antimicrobial peptides (AMPs), including previously underexplored topics such as the sequential and structural conformation of different peptide types in crocodilians and the use of bioinformatics tools to enhance native peptides
{"title":"Host defense peptides in crocodilians – A comprehensive review","authors":"Trinidad de los Ángeles Cordero Gil , María Soledad Moleón , Belkis Ester Marelli , Pablo Ariel Siroski","doi":"10.1016/j.peptides.2024.171312","DOIUrl":"10.1016/j.peptides.2024.171312","url":null,"abstract":"<div><div>Amphibians and reptiles, like all animals, are prone to periodic infections. However, crocodilians stand out for their remarkable ability to remain generally healthy and infection-free despite frequent exposure to a wide variety of microorganisms in their habitats and often sustaining significant injuries. These animals have evolved highly active immune mechanisms that provide rapid and effective defense. This is evidenced by the superior hemolytic capacity of their plasma compared to that of other organisms. To date, several host defense peptides (HDPs) have been identified in crocodilians, including cathelicidins, beta-defensins, hepcidins, leucrocins, hemocidins, and omwaprins. These peptides exhibit potent and broad-spectrum antimicrobial, antibiofilm, antifungal, and anticancer activities. Due to the relatively low but diverse evolutionary rate of crocodilians, the HDPs found in this species offer valuable insights into proteins and mechanisms of action that are highly conserved across many animals related to immune defense. The potential applications of HDPs in modern medicine represent a promising strategy for developing new therapeutic agents. Their novelty and the vast variability with which peptide sequences can be designed and modified expand the field of application for HDPs almost infinitely. This review addresses the urgent need for innovative and more effective drugs to combat the rise of antimicrobialresistant infections and evaluates the potential of crocodilian HDPs. It presents recent advances in the identification of crocodilian HDPs, particularly antimicrobial peptides (AMPs), including previously underexplored topics such as the sequential and structural conformation of different peptide types in crocodilians and the use of bioinformatics tools to enhance native peptides</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"182 ","pages":"Article 171312"},"PeriodicalIF":2.8,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142546691","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 : 2024-10-26DOI: 10.1016/j.peptides.2024.171313
M. Gonzalez-Garcia , B. Bertrand , EM Martell-Huguet , JF Espinosa-Romero , RF Vázquez , F. Morales –Vicente , F. Rosenau , LH Standker , OL Franco , AJ Otero-Gonzalez , C Muñoz-Garay
Amidst the health crisis caused by the rise of multi-resistant pathogenic microorganisms, Antimicrobial Peptides (AMPs) have emerged as a potential alternative to traditional antibiotics. In this sense, Cm-p5 is an AMP with fungistatic activity against the yeast Candida albicans. Its antimicrobial activity and selectivity have been well characterized; however, the mechanism of action is still unknown. This study used biophysical approaches to gain insight into how this peptide exerts its activity. Stability and fluidity of lipid membrane were explored by liposome leakage and Laurdan generalized polarization (GP) respectively, suggesting that Cm-p5 does not perturb lipid membranes even at very high concentrations (≥100 µm.L−1). Likewise, no depolarizing action was observed using 3,3′-propil-2,2′-thyodicarbocianine, a potential membrane fluorescent reporter, with C. albicans cells or the corresponding liposome models. Changes in liposome size were analyzed by Dynamic Light Scattering (DLS) data, indicating that Cm-p5 covers the vesicular surface slightly increasing liposome hydrodynamic size, without liposome rupture. These results were further corroborated with Langmuir monolayer isotherms, where no significant changes in lateral pressure or area per lipid were detected, indicating little or no insertion. Finally, data obtained from molecular dynamics simulations aligned with in vitro observations, whereby Cm-p5 slightly interacted with the fungal membrane model surface without causing significant perturbation. These results suggest Cm-p5 is not a pore-forming anti-fungal peptide and that other mechanisms of action on the membrane as some limitation of fungal nutrition or receptor-dependent transduction for depressing growth development should be explored.
{"title":"Cm-p5, a molluscan-derived antifungal peptide exerts its activity by a membrane surface covering in a non-penetrating mode","authors":"M. Gonzalez-Garcia , B. Bertrand , EM Martell-Huguet , JF Espinosa-Romero , RF Vázquez , F. Morales –Vicente , F. Rosenau , LH Standker , OL Franco , AJ Otero-Gonzalez , C Muñoz-Garay","doi":"10.1016/j.peptides.2024.171313","DOIUrl":"10.1016/j.peptides.2024.171313","url":null,"abstract":"<div><div>Amidst the health crisis caused by the rise of multi-resistant pathogenic microorganisms, Antimicrobial Peptides (AMPs) have emerged as a potential alternative to traditional antibiotics. In this sense, Cm-p5 is an AMP with fungistatic activity against the yeast <em>Candida albicans</em>. Its antimicrobial activity and selectivity have been well characterized; however, the mechanism of action is still unknown. This study used biophysical approaches to gain insight into how this peptide exerts its activity. Stability and fluidity of lipid membrane were explored by liposome leakage and Laurdan generalized polarization (GP) respectively, suggesting that Cm-p5 does not perturb lipid membranes even at very high concentrations (≥100 µm.L<sup>−1</sup>). Likewise, no depolarizing action was observed using 3,3′-propil-2,2′-thyodicarbocianine, a potential membrane fluorescent reporter, with <em>C. albicans</em> cells or the corresponding liposome models. Changes in liposome size were analyzed by Dynamic Light Scattering (DLS) data, indicating that Cm-p5 covers the vesicular surface slightly increasing liposome hydrodynamic size, without liposome rupture. These results were further corroborated with Langmuir monolayer isotherms, where no significant changes in lateral pressure or area per lipid were detected, indicating little or no insertion. Finally, data obtained from molecular dynamics simulations aligned with <em>in vitro</em> observations, whereby Cm-p5 slightly interacted with the fungal membrane model surface without causing significant perturbation. These results suggest Cm-p5 is not a pore-forming anti-fungal peptide and that other mechanisms of action on the membrane as some limitation of fungal nutrition or receptor-dependent transduction for depressing growth development should be explored.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"182 ","pages":"Article 171313"},"PeriodicalIF":2.8,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142554420","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}
Several cell biology studies have focused on the effects of hypoxic environments on cardiomyocytes. However, the effect of anoxic conditions on cardiomyocytes remains largely unexplored. In the present study, we investigated the direct effects of anoxia on B-type natriuretic peptide (BNP) gene expression in cardiomyocytes. Neonatal rat cardiomyocytes (NRCMs) were exposed to anoxia using an airtight chamber saturated with 95 % N2/5 % CO2. BNP mRNA levels in NRCM were substantially reduced after more than 8 h of anoxia exposure, whereas after reoxygenation, BNP gene expression levels recovered in a time-dependent manner and significantly increased after 24 h of reoxygenation. BNP mRNA levels suppressed under anoxic conditions were significantly increased by aldosterone-induced activation of sodium-proton exchanger 1 (NHE1), which was canceled by an NHE1 inhibitor, suggesting that anoxia reduces BNP gene expression, at least in part, in an NHE1-dependent manner. In summary, we found that BNP gene expression in cardiomyocytes decreases under anoxic conditions, in contrast to previous research findings that BNP expression increases under hypoxic conditions. These findings reveal a new insight that, within a single heart tissue in various cardiovascular diseases, such as myocardial infarction, the biological responses of cardiomyocytes are fundamentally different in regions of anoxia and hypoxia.
{"title":"Suppression of B-type natriuretic peptide gene expression in cardiomyocytes under anoxic conditions","authors":"Rei Yasutake, Tomohisa Nagoshi, Akira Yoshii, Hirotake Takahashi, Yuhei Oi, Haruka Kimura, Yusuke Kashiwagi, Toshikazu D. Tanaka, Yoshiro Tanaka, Michihiro Yoshimura","doi":"10.1016/j.peptides.2024.171316","DOIUrl":"10.1016/j.peptides.2024.171316","url":null,"abstract":"<div><div>Several cell biology studies have focused on the effects of hypoxic environments on cardiomyocytes. However, the effect of anoxic conditions on cardiomyocytes remains largely unexplored. In the present study, we investigated the direct effects of anoxia on B-type natriuretic peptide (BNP) gene expression in cardiomyocytes. Neonatal rat cardiomyocytes (NRCMs) were exposed to anoxia using an airtight chamber saturated with 95 % N<sub>2</sub>/5 % CO<sub>2</sub>. BNP mRNA levels in NRCM were substantially reduced after more than 8 h of anoxia exposure, whereas after reoxygenation, BNP gene expression levels recovered in a time-dependent manner and significantly increased after 24 h of reoxygenation. BNP mRNA levels suppressed under anoxic conditions were significantly increased by aldosterone-induced activation of sodium-proton exchanger 1 (NHE1), which was canceled by an NHE1 inhibitor, suggesting that anoxia reduces BNP gene expression, at least in part, in an NHE1-dependent manner. In summary, we found that BNP gene expression in cardiomyocytes decreases under anoxic conditions, in contrast to previous research findings that BNP expression increases under hypoxic conditions. These findings reveal a new insight that, within a single heart tissue in various cardiovascular diseases, such as myocardial infarction, the biological responses of cardiomyocytes are fundamentally different in regions of anoxia and hypoxia.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"182 ","pages":"Article 171316"},"PeriodicalIF":2.8,"publicationDate":"2024-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142554419","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 : 2024-10-24DOI: 10.1016/j.peptides.2024.171314
Sangmin Lee
Calcitonin peptide hormone controls calcium homeostasis by activating the calcitonin receptor. When the calcitonin receptor forms a complex with an accessory protein, the complex functions as the receptors for another peptide hormone amylin. The amylin receptors are the drug target for diabetes and obesity treatment. Since human amylin can produce aggregates, rat amylin that does not form aggregates has been commonly used for research. Interestingly, calcitonin originated from salmons was reported to interact with human amylin receptors with higher affinity/potency than endogenous rat amylin. Here, the peptide hybrid was made of a rat amylin N-terminal fragment and a salmon calcitonin C-terminal fragment. This novel hybrid peptide showed higher potency for human amylin receptor 1/2 activation by 6- to 8-fold than endogenous rat amylin. To further examine the role of the peptide C-terminal fragment in receptor activation, another hybrid peptide was made where salmon calcitonin N-terminal 21 amino acids were fused with rat amylin C-terminal 11 amino acids. The rat amylin C-terminal fragment was previously reported to have relatively low affinity for calcitonin receptor extracellular domain. As expected, this calcitonin-amylin hybrid peptide decreased the potency for calcitonin receptor activation by 3-fold compared to salmon calcitonin. The hybrid strategy used in this study significantly changed the peptide potency for amylin and calcitonin receptor activation. These results provide insight into the role of peptide C-terminal fragments in modulating amylin and calcitonin receptor activation.
降钙素肽激素通过激活降钙素受体来控制钙平衡。当降钙素受体与附属蛋白形成复合物时，该复合物就成为另一种肽类激素淀粉样蛋白的受体。淀粉素受体是治疗糖尿病和肥胖症的药物靶点。由于人类淀粉样蛋白会产生聚集体，因此研究中通常使用不会形成聚集体的大鼠淀粉样蛋白。有趣的是，有报道称源自鲑鱼的降钙素与人淀粉样蛋白受体相互作用，其亲和力/效力高于内源性大鼠淀粉样蛋白。在这里，大鼠淀粉样蛋白 N 端片段和鲑鱼降钙素 C 端片段被制成了多肽杂交肽。与内源性大鼠淀粉样蛋白相比，这种新型杂交肽对人淀粉样蛋白受体1/2的激活效力高出6至8倍。为了进一步研究肽 C 端片段在受体激活中的作用，我们又制作了另一种杂交肽，将鲑降钙素 N 端 21 个氨基酸与大鼠淀粉样蛋白 C 端 11 个氨基酸融合。之前有报道称，大鼠淀粉样蛋白 C 端片段与降钙素受体胞外结构域的亲和力相对较低。不出所料，与鲑鱼降钙素相比，这种降钙素-淀粉样蛋白杂交肽激活降钙素受体的效力降低了 3 倍。本研究采用的杂交策略显著改变了肽激活淀粉样蛋白和降钙素受体的效力。这些结果让我们了解了多肽 C 端片段在调节淀粉样蛋白和降钙素受体活化过程中的作用。
{"title":"Modulation of amylin and calcitonin receptor activation by hybrid peptides","authors":"Sangmin Lee","doi":"10.1016/j.peptides.2024.171314","DOIUrl":"10.1016/j.peptides.2024.171314","url":null,"abstract":"<div><div>Calcitonin peptide hormone controls calcium homeostasis by activating the calcitonin receptor. When the calcitonin receptor forms a complex with an accessory protein, the complex functions as the receptors for another peptide hormone amylin. The amylin receptors are the drug target for diabetes and obesity treatment. Since human amylin can produce aggregates, rat amylin that does not form aggregates has been commonly used for research. Interestingly, calcitonin originated from salmons was reported to interact with human amylin receptors with higher affinity/potency than endogenous rat amylin. Here, the peptide hybrid was made of a rat amylin N-terminal fragment and a salmon calcitonin C-terminal fragment. This novel hybrid peptide showed higher potency for human amylin receptor 1/2 activation by 6- to 8-fold than endogenous rat amylin. To further examine the role of the peptide C-terminal fragment in receptor activation, another hybrid peptide was made where salmon calcitonin N-terminal 21 amino acids were fused with rat amylin C-terminal 11 amino acids. The rat amylin C-terminal fragment was previously reported to have relatively low affinity for calcitonin receptor extracellular domain. As expected, this calcitonin-amylin hybrid peptide decreased the potency for calcitonin receptor activation by 3-fold compared to salmon calcitonin. The hybrid strategy used in this study significantly changed the peptide potency for amylin and calcitonin receptor activation. These results provide insight into the role of peptide C-terminal fragments in modulating amylin and calcitonin receptor activation.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"182 ","pages":"Article 171314"},"PeriodicalIF":2.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505460","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 : 2024-10-24DOI: 10.1016/j.peptides.2024.171315
Jinah Ha, Hyunwon Yang
This study aimed to investigate the expression and functional role of nesfatin-1, a peptide hormone traditionally associated with appetite regulation, in the human endometrium. Specifically, we examined its presence and regulatory potential in the human endometrial stromal cell line, THESC cells, focusing on the process of endometrial decidualization, which is critical for implantation and pregnancy maintenance. We found that nesfatin-1 and its binding sites were expressed in THESC cells. Furthermore, nesfatin-1 protein expression decreased after treatment with 17β-estradiol but increased upon exposure to progesterone, indicating an influence of sexsteroid hormones on nesfatin-1 expression. Notably, administration of nesfatin-1 protein to THESC cells resulted in significant upregulation of genes associated with decidualization, such as insulin-like growth factor binding protein 1 (IGFBP1) and prolactin. In addition, our research showed that nesfatin-1 promotes decidualization through the activation of the FAK/PI3K/AKT signaling pathway. These findings underscore the central role of nesfatin-1 in endometrial decidualization, and suggest its potential utility in the development of new treatments to improve fertility and pregnancy outcomes.
{"title":"Nesfatin-1 expressed in human endometrial stromal cell line (THESC) stimulates decidualization through FAK/PI3K/AKT signaling pathway","authors":"Jinah Ha, Hyunwon Yang","doi":"10.1016/j.peptides.2024.171315","DOIUrl":"10.1016/j.peptides.2024.171315","url":null,"abstract":"<div><div>This study aimed to investigate the expression and functional role of nesfatin-1, a peptide hormone traditionally associated with appetite regulation, in the human endometrium. Specifically, we examined its presence and regulatory potential in the human endometrial stromal cell line, THESC cells, focusing on the process of endometrial decidualization, which is critical for implantation and pregnancy maintenance. We found that nesfatin-1 and its binding sites were expressed in THESC cells. Furthermore, nesfatin-1 protein expression decreased after treatment with 17β-estradiol but increased upon exposure to progesterone, indicating an influence of sexsteroid hormones on nesfatin-1 expression. Notably, administration of nesfatin-1 protein to THESC cells resulted in significant upregulation of genes associated with decidualization, such as insulin-like growth factor binding protein 1 (IGFBP1) and prolactin. In addition, our research showed that nesfatin-1 promotes decidualization through the activation of the FAK/PI3K/AKT signaling pathway. These findings underscore the central role of nesfatin-1 in endometrial decidualization, and suggest its potential utility in the development of new treatments to improve fertility and pregnancy outcomes.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"182 ","pages":"Article 171315"},"PeriodicalIF":2.8,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142505461","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 : 2024-10-18DOI: 10.1016/j.peptides.2024.171311
Esther Imperlini , Federica Massaro , Angelica Grifoni , Francesco Maiurano , Anna Rita Taddei , Stefano Borocci , Francesco Buonocore , Fernando Porcelli
Antarctic fishes, living in an extreme environment and normally exposed to pathogens, are a promising source of antimicrobial peptides (AMPs). These are emerging as next-generation drugs due to their activity against multidrug resistant (MDR) bacteria. To infect hosts, beyond intrinsic/acquired resistance, MDR species also use virulence factors such as protease secretion. Hence, AMPs targeting virulence factors could represent a novel strategy to counteract the antimicrobial resistance (AMR). In this paper, we focused on a mutant peptide, named KHS-Cnd, that was obtained from the scaffold of the chionodracine (Cnd), a natural peptide identified in the icefish Chionodraco hamatus. We studied different effects caused by the peptide interaction with the cell membrane of two model bacteria, E. coli and B. cereus. First, we investigated its membranolytic activity revealing that the peptide action is more evident on E. coli, with a 69 % uptake of the used dye at 3 μM, whereas for B. cereus we found only a 65 % uptake at 6 μM. Successively, we determined the impact of this lysis on total protein concentration in the medium and an increase was estimated for both bacteria (84 % after 1 h for E. coli and 90 % for B. cereus, respectively). Moreover, we evaluated the changes in the proteolytic activity of the supernatant, that is an important aspect of bacterial resistance, showing that there was a significant reduction for both bacteria, although at higher level in the case of E. coli. The membranolytic activity was evidenced also morphologically with TEM analysis and a different alteration was evidenced for the two bacteria. Moreover, NMR metabolomics analysis showed that peptide induces changes in E. coli and B. cereus extracellular metabolites especially at the higher tested concentrations: this metabolic variation could be used as a fingerprinting of the peptide action on bacteria physiology due to its interaction with cell wall. Finally, we determined the KHS-Cnd cytotoxicity on human primary cell lines to verify its selectivity toward bacterial cell membranes and we found low toxicity until a concentration of 5 μM. Considering that the peptide exerts both membranolytic and anti-virulence activity on E. coli at 1.5 μM, we confirmed the interesting potential of this AMP as a new drug to counteract AMR.
{"title":"Membrane alteration, anti-virulence properties and metabolomic perturbation of a chionodracine-derived antimicrobial peptide, KHS-Cnd, on two bacteria models","authors":"Esther Imperlini , Federica Massaro , Angelica Grifoni , Francesco Maiurano , Anna Rita Taddei , Stefano Borocci , Francesco Buonocore , Fernando Porcelli","doi":"10.1016/j.peptides.2024.171311","DOIUrl":"10.1016/j.peptides.2024.171311","url":null,"abstract":"<div><div>Antarctic fishes, living in an extreme environment and normally exposed to pathogens, are a promising source of antimicrobial peptides (AMPs). These are emerging as next-generation drugs due to their activity against multidrug resistant (MDR) bacteria. To infect hosts, beyond intrinsic/acquired resistance, MDR species also use virulence factors such as protease secretion. Hence, AMPs targeting virulence factors could represent a novel strategy to counteract the antimicrobial resistance (AMR). In this paper, we focused on a mutant peptide, named KHS-Cnd, that was obtained from the scaffold of the chionodracine (Cnd), a natural peptide identified in the icefish <em>Chionodraco hamatus</em>. We studied different effects caused by the peptide interaction with the cell membrane of two model bacteria, <em>E. coli</em> and <em>B. cereus</em>. First, we investigated its membranolytic activity revealing that the peptide action is more evident on <em>E. coli</em>, with a 69 % uptake of the used dye at 3 μM, whereas for <em>B. cereus</em> we found only a 65 % uptake at 6 μM. Successively, we determined the impact of this lysis on total protein concentration in the medium and an increase was estimated for both bacteria (84 % after 1 h for <em>E. coli</em> and 90 % for <em>B. cereus</em>, respectively). Moreover, we evaluated the changes in the proteolytic activity of the supernatant, that is an important aspect of bacterial resistance, showing that there was a significant reduction for both bacteria, although at higher level in the case of <em>E. coli</em>. The membranolytic activity was evidenced also morphologically with TEM analysis and a different alteration was evidenced for the two bacteria. Moreover, NMR metabolomics analysis showed that peptide induces changes in <em>E. coli</em> and <em>B. cereus</em> extracellular metabolites especially at the higher tested concentrations: this metabolic variation could be used as a fingerprinting of the peptide action on bacteria physiology due to its interaction with cell wall. Finally, we determined the KHS-Cnd cytotoxicity on human primary cell lines to verify its selectivity toward bacterial cell membranes and we found low toxicity until a concentration of 5 μM. Considering that the peptide exerts both membranolytic and anti-virulence activity on <em>E. coli</em> at 1.5 μM, we confirmed the interesting potential of this AMP as a new drug to counteract AMR.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"182 ","pages":"Article 171311"},"PeriodicalIF":2.8,"publicationDate":"2024-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142471891","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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