DR8 (DHNNPQIR) is a rapeseed-derived bioactive octapeptide with antioxidant and anti-inflammatory properties, but its therapeutic potential in chronic kidney disease (CKD) and related muscle wasting has not been defined. In this study, we investigated the anti-fibrotic and anti-atrophic efficacy of DR8 using complementary in vitro, transcriptomic, and in vivo approaches. In TGF-β1-stimulated C2C12 myoblasts and HK-2 tubular epithelial cells, DR8 significantly attenuated fibrosis and atrophy by downregulating cannabinoid receptor 1 (CNR1) and suppressing ERK-ELK1 activation, leading to restoration of myogenic regulators (MYOD, MYOG) and inhibition of proteolytic E3 ligases (MuRF-1, MAFbx). Transcriptomic analysis identified CNR1 as a key upstream target mediating these effects. In a 5/6 nephrectomized (5/6Nx) mouse model, systemic administration of DR8 significantly improved renal function, reduced collagen accumulation, and alleviated skeletal muscle fibrosis and atrophy, accompanied by suppression of CNR1-ERK-ELK1 activation in both organs. Together, these findings demonstrate that DR8 exerts strong renoprotective and myoprotective effects through selective modulation of CNR1-dependent signaling pathways, supporting its potential as a novel peptide therapeutic for CKD-associated fibrosis and muscle wasting.
{"title":"DR8 (DHNNPQIR), a rapeseed-derived peptide, mitigates fibrosis and muscle atrophy in chronic kidney disease by targeting CNR1–ERK/ELK-1 signaling","authors":"Wenli Zhang , Yidan Zuo , Diyan Xu , Yibei Lin , Yaoxue Zang , Ruyi Chen , Mingli Chen , Zhen Su","doi":"10.1016/j.peptides.2025.171456","DOIUrl":"10.1016/j.peptides.2025.171456","url":null,"abstract":"<div><div>DR8 (DHNNPQIR) is a rapeseed-derived bioactive octapeptide with antioxidant and anti-inflammatory properties, but its therapeutic potential in chronic kidney disease (CKD) and related muscle wasting has not been defined. In this study, we investigated the anti-fibrotic and anti-atrophic efficacy of DR8 using complementary in vitro, transcriptomic, and in vivo approaches. In TGF-β1-stimulated C2C12 myoblasts and HK-2 tubular epithelial cells, DR8 significantly attenuated fibrosis and atrophy by downregulating cannabinoid receptor 1 (CNR1) and suppressing ERK-ELK1 activation, leading to restoration of myogenic regulators (MYOD, MYOG) and inhibition of proteolytic E3 ligases (MuRF-1, MAFbx). Transcriptomic analysis identified CNR1 as a key upstream target mediating these effects. In a 5/6 nephrectomized (5/6Nx) mouse model, systemic administration of DR8 significantly improved renal function, reduced collagen accumulation, and alleviated skeletal muscle fibrosis and atrophy, accompanied by suppression of CNR1-ERK-ELK1 activation in both organs. Together, these findings demonstrate that DR8 exerts strong renoprotective and myoprotective effects through selective modulation of CNR1-dependent signaling pathways, supporting its potential as a novel peptide therapeutic for CKD-associated fibrosis and muscle wasting.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"194 ","pages":"Article 171456"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145669436","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 : 2025-12-01DOI: 10.1016/j.peptides.2025.171455
Jaqueline Moura da Costa , Amanda de Sá Martins de Bessa , Lara Marques Naves , Monique Machado Louredo Teles , Gustavo Rodrigues Pedrino , Elizabeth Pereira Mendes , Carlos Henrique de Castro
Angiotensin-(1−7) [Ang-(1−7)] exerts cardioprotective effects through Mas receptor activation. Endothelin-1 (ET-1) is implicated in cardiovascular pathologies. Previous studies indicate a cross-talk between angiotensin and endothelin pathways; however, it remains unclear whether Ang-(1−7) differentially modulates vascular responses to ET-1 in normotensive and hypertensive conditions. This study investigated the influence of Ang-(1−7) on ET-1–induced pressor and vascular responses in normotensive and hypertensive rats (SHR). Blood pressure was recorded in conscious animals. Vascular reactivity was assessed in isolated aortic rings, and coronary effects were assessed in isolated hearts using the Langendorff technique. ET-1 increased blood pressure and reduced heart rate only in Wistar rats, effects abolished by Ang-(1−7). In normotensive rats, Ang-(1−7) potentiated ET-1–induced vasoconstriction in endothelium-intact aortas independently of Mas receptors, but had no effect in the aorta without endothelium. In hypertensive rats, Ang-(1−7) attenuated ET-1 responses in endothelium-intact aorta via Mas receptor, whereas in endothelium-denuded vessels it potentiated the vasoconstriction. In isolated hearts, ET-1 produced a biphasic response in normotensive rats (vasodilation followed by vasoconstriction) but only vasoconstriction in hypertensive rats. Ang-(1−7) potentiated vasoconstriction in normotensive but attenuated it in hypertensive hearts, which was abolished by Mas receptor blockade. These findings demonstrate that Ang-(1−7) differentially modulates ET-1 actions in normotensive and hypertensive conditions, reinforcing RAS–endothelin cross-talk. Its counter-regulatory effect in hypertension highlights Ang-(1−7) as a promising therapeutic target in cardiovascular disease.
血管紧张素-(1−7)[Ang-(1−7)]通过激活Mas受体发挥心脏保护作用。内皮素-1 （ET-1）与心血管疾病有关。先前的研究表明血管紧张素和内皮素通路之间存在交叉对话；然而，尚不清楚Ang-(1−7)是否在正常和高血压情况下调节血管对ET-1的反应。本研究探讨了Ang-(1−7)对正常和高血压大鼠（SHR） et -1诱导的升压和血管反应的影响。在有意识的动物身上记录血压。在离体主动脉环中评估血管反应性，在离体心脏中使用Langendorff技术评估冠状动脉效应。ET-1仅在Wistar大鼠中升高血压和降低心率，Ang-的作用被Ang-消除（1−7）。在血压正常的大鼠中，Ang-(1−7)增强了et -1在内皮完整的主动脉中诱导的血管收缩，而不依赖于Mas受体，但在没有内皮的主动脉中没有作用。在高血压大鼠中，Ang-(1−7)通过Mas受体减弱内皮完好主动脉中ET-1的反应，而在内皮脱落血管中，Ang-(1−7)增强血管收缩。在离体心脏中，ET-1在正常血压大鼠中产生双相反应（血管扩张后血管收缩），但在高血压大鼠中只产生血管收缩。Ang-(1−7)在血压正常的心脏中增强血管收缩，而在高血压心脏中减弱血管收缩，这一作用被Mas受体阻断所消除。这些发现表明，在正常和高血压情况下，Ang-(1−7)调节ET-1的差异作用，加强ras -内皮素的串扰。其在高血压中的反调节作用突出了Ang-(1−7)作为心血管疾病的有前途的治疗靶点。
{"title":"Influence of the angiotensin-(1−7) on the vascular effects of the endothelin-1 in normotensive and hypertensive rats","authors":"Jaqueline Moura da Costa , Amanda de Sá Martins de Bessa , Lara Marques Naves , Monique Machado Louredo Teles , Gustavo Rodrigues Pedrino , Elizabeth Pereira Mendes , Carlos Henrique de Castro","doi":"10.1016/j.peptides.2025.171455","DOIUrl":"10.1016/j.peptides.2025.171455","url":null,"abstract":"<div><div>Angiotensin-(1−7) [Ang-(1−7)] exerts cardioprotective effects through Mas receptor activation. Endothelin-1 (ET-1) is implicated in cardiovascular pathologies. Previous studies indicate a cross-talk between angiotensin and endothelin pathways; however, it remains unclear whether Ang-(1−7) differentially modulates vascular responses to ET-1 in normotensive and hypertensive conditions. This study investigated the influence of Ang-(1−7) on ET-1–induced pressor and vascular responses in normotensive and hypertensive rats (SHR). Blood pressure was recorded in conscious animals. Vascular reactivity was assessed in isolated aortic rings, and coronary effects were assessed in isolated hearts using the Langendorff technique. ET-1 increased blood pressure and reduced heart rate only in Wistar rats, effects abolished by Ang-(1−7). In normotensive rats, Ang-(1−7) potentiated ET-1–induced vasoconstriction in endothelium-intact aortas independently of Mas receptors, but had no effect in the aorta without endothelium. In hypertensive rats, Ang-(1−7) attenuated ET-1 responses in endothelium-intact aorta via Mas receptor, whereas in endothelium-denuded vessels it potentiated the vasoconstriction. In isolated hearts, ET-1 produced a biphasic response in normotensive rats (vasodilation followed by vasoconstriction) but only vasoconstriction in hypertensive rats. Ang-(1−7) potentiated vasoconstriction in normotensive but attenuated it in hypertensive hearts, which was abolished by Mas receptor blockade. These findings demonstrate that Ang-(1−7) differentially modulates ET-1 actions in normotensive and hypertensive conditions, reinforcing RAS–endothelin cross-talk. Its counter-regulatory effect in hypertension highlights Ang-(1−7) as a promising therapeutic target in cardiovascular disease.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"195 ","pages":"Article 171455"},"PeriodicalIF":2.9,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145665498","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 : 2025-11-25DOI: 10.1016/j.peptides.2025.171454
Minyu Shi , Yuting Luan , Ziqing Zhang, Xixiang Xi, Wufeng Li
Sepsis-associated acute kidney injury (AKI) is a major cause of morbidity and mortality, and lipopolysaccharide (LPS)-induced ferroptosis is a critical mechanism of renal tubular cell injury. Follistatin-like 1 (FSTL1) is a matricellular protein implicated in inflammation and oxidative stress; however, its role in LPS-induced ferroptosis in renal tubular cells remains unknown. Human renal proximal tubular epithelial (HK-2) cells were exposed to increasing concentrations of LPS to evaluate FSTL1 expression levels. FSTL1 silencing was achieved by siRNA transfection, and its effects on PI3K/Akt signaling, apoptosis, oxidative stress, and ferroptosis were assessed using western blotting, RT-qPCR, flow cytometry, and fluorescent probes. The PI3K/Akt inhibitor LY294002 was used to validate the involvement of this pathway. FSTL1 expression was significantly upregulated by LPS in a dose-dependent manner at both the mRNA and protein levels. Silencing FSTL1 markedly increased the phosphorylation of PI3K and Akt and significantly attenuated LPS-induced apoptosis, as evidenced by increased cell viability and decreased number of Annexin V-positive cells. FSTL1 silencing also decreased reactive oxygen species and malondialdehyde levels, while enhancing superoxide dismutase activity and glutathione content. Moreover, FSTL1 silencing reduced mitochondrial ferrous iron accumulation and restored Nrf2, SLC7A11, GPX4, and FTH1, alongside decreased ACSL4 expression. These protective effects were reversed by LY294002, indicating a dependence on PI3K/Akt signaling. FSTL1 mediates LPS-induced apoptosis, oxidative stress, and ferroptosis in renal tubular cells via the PI3K/Akt pathway. Targeting FSTL1-PI3K/Akt signaling may represent a novel approach to mitigate ferroptotic injury in endotoxin-stimulated renal tubular cells, providing mechanistic insights relevant to LPS-induced tubular injury model.
{"title":"FSTL1 silencing protects against lipopolysaccharide-induced ferroptosis in renal tubular cells by regulating the PI3K/Akt pathway","authors":"Minyu Shi , Yuting Luan , Ziqing Zhang, Xixiang Xi, Wufeng Li","doi":"10.1016/j.peptides.2025.171454","DOIUrl":"10.1016/j.peptides.2025.171454","url":null,"abstract":"<div><div>Sepsis-associated acute kidney injury (AKI) is a major cause of morbidity and mortality, and lipopolysaccharide (LPS)-induced ferroptosis is a critical mechanism of renal tubular cell injury. Follistatin-like 1 (FSTL1) is a matricellular protein implicated in inflammation and oxidative stress; however, its role in LPS-induced ferroptosis in renal tubular cells remains unknown. Human renal proximal tubular epithelial (HK-2) cells were exposed to increasing concentrations of LPS to evaluate FSTL1 expression levels. FSTL1 silencing was achieved by siRNA transfection, and its effects on PI3K/Akt signaling, apoptosis, oxidative stress, and ferroptosis were assessed using western blotting, RT-qPCR, flow cytometry, and fluorescent probes. The PI3K/Akt inhibitor LY294002 was used to validate the involvement of this pathway. FSTL1 expression was significantly upregulated by LPS in a dose-dependent manner at both the mRNA and protein levels. Silencing FSTL1 markedly increased the phosphorylation of PI3K and Akt and significantly attenuated LPS-induced apoptosis, as evidenced by increased cell viability and decreased number of Annexin V-positive cells. FSTL1 silencing also decreased reactive oxygen species and malondialdehyde levels, while enhancing superoxide dismutase activity and glutathione content. Moreover, FSTL1 silencing reduced mitochondrial ferrous iron accumulation and restored Nrf2, SLC7A11, GPX4, and FTH1, alongside decreased ACSL4 expression. These protective effects were reversed by LY294002, indicating a dependence on PI3K/Akt signaling. FSTL1 mediates LPS-induced apoptosis, oxidative stress, and ferroptosis in renal tubular cells via the PI3K/Akt pathway. Targeting FSTL1-PI3K/Akt signaling may represent a novel approach to mitigate ferroptotic injury in endotoxin-stimulated renal tubular cells, providing mechanistic insights relevant to LPS-induced tubular injury model.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"194 ","pages":"Article 171454"},"PeriodicalIF":2.9,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145614541","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}
The neuropeptide FF (NPFF) system plays an important role in regulating the analgesic effects of opioids and cannabis. Incorporating NPFF pharmacophores at the C-terminus of opioid or cannabinoid peptides has emerged as a strategy to enhance analgesic potency while mitigating adverse effects. However, the development of such multi-target compounds has been limited to two systems, with no successful commercialization to date. Hence, we developed the chimeric peptide MPN-12-NH2 by incorporating the opioid peptide morphiceptin, the core sequence of pepcans NFKL, and the NPFF analog PFR(Tic)-NH2. In the mouse tail flick test, intracerebroventricular (i.c.v.) injection of MPN-12-NH2 demonstrated dose-dependent analgesic effects (ED50 = 0.71 nmol/mouse). Furthermore, molecular docking and molecular dynamics (MD) simulations were employed to elucidate the binding patterns of MPN-12-NH2 with opioid receptors, cannabinoid receptors, and neuropeptide receptors. In vitro studies revealed that MPN-12-NH2 is a multifunctional agonist of mu opioid receptors (MOR), delta opioid receptors, cannabinoid 1 receptors (CB1), CB2, and NPFF2 receptors. Subsequently, receptor antagonism studies suggested that the central analgesic effects of MPN-12-NH2 were primarily mediated by MOR, CB1, and NPFF receptors. Furthermore, we found that i.c.v. injection of MPN-12-NH2 dose-dependently alleviated pathological pain responses in the SNI, carrageenan, and acetic acid writhing models. However, MPN-12-NH2 (3 nmol/mouse, i.c.v.) did not result in addiction, analgesic tolerance, or microglial cell alterations in the PAG region. Additionally, MPN-12-NH2 effectively differentiated its analgesic effects on acute pain from its inhibitory effects on gastrointestinal motility, with an ED50 ratio of 14.21-fold. In summary, the multi-target compound MPN-12-NH2 exhibited potent analgesic activity mediated by MOR, CB1, and NPFF receptors in mice, along with a favorable side-effect profile. These findings pave a new way for the development of opioid/cannabinoid/NPFF agonists.
{"title":"MPN-12-NH2 shows potent antinociception effects by targeting opioid, cannabinoid, and neuropeptide FF receptors","authors":"Lanxia Zhou , Jing Zhang , Chenxi Mei , Zhanyu Niu , Huiming Bao , Yaofeng Zhao , Zhonghua Zhang , Dingnian Gou , Shouliang Dong","doi":"10.1016/j.peptides.2025.171453","DOIUrl":"10.1016/j.peptides.2025.171453","url":null,"abstract":"<div><div>The neuropeptide FF (NPFF) system plays an important role in regulating the analgesic effects of opioids and cannabis. Incorporating NPFF pharmacophores at the C-terminus of opioid or cannabinoid peptides has emerged as a strategy to enhance analgesic potency while mitigating adverse effects. However, the development of such multi-target compounds has been limited to two systems, with no successful commercialization to date. Hence, we developed the chimeric peptide MPN-12-NH<sub>2</sub> by incorporating the opioid peptide morphiceptin, the core sequence of pepcans NFKL, and the NPFF analog PFR(Tic)-NH<sub>2</sub>. In the mouse tail flick test, intracerebroventricular (i.c.v.) injection of MPN-12-NH<sub>2</sub> demonstrated dose-dependent analgesic effects (ED<sub>50</sub> = 0.71 nmol/mouse). Furthermore, molecular docking and molecular dynamics (MD) simulations were employed to elucidate the binding patterns of MPN-12-NH<sub>2</sub> with opioid receptors, cannabinoid receptors, and neuropeptide receptors. <em>In vitro</em> studies revealed that MPN-12-NH<sub>2</sub> is a multifunctional agonist of mu opioid receptors (MOR), delta opioid receptors, cannabinoid 1 receptors (CB1), CB2, and NPFF2 receptors. Subsequently, receptor antagonism studies suggested that the central analgesic effects of MPN-12-NH<sub>2</sub> were primarily mediated by MOR, CB1, and NPFF receptors. Furthermore, we found that i.c.v. injection of MPN-12-NH<sub>2</sub> dose-dependently alleviated pathological pain responses in the SNI, carrageenan, and acetic acid writhing models. However, MPN-12-NH<sub>2</sub> (3 nmol/mouse, i.c.v.) did not result in addiction, analgesic tolerance, or microglial cell alterations in the PAG region. Additionally, MPN-12-NH<sub>2</sub> effectively differentiated its analgesic effects on acute pain from its inhibitory effects on gastrointestinal motility, with an ED<sub>50</sub> ratio of 14.21-fold. In summary, the multi-target compound MPN-12-NH<sub>2</sub> exhibited potent analgesic activity mediated by MOR, CB1, and NPFF receptors in mice, along with a favorable side-effect profile. These findings pave a new way for the development of opioid/cannabinoid/NPFF agonists.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"194 ","pages":"Article 171453"},"PeriodicalIF":2.9,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145419366","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 : 2025-10-25DOI: 10.1016/j.peptides.2025.171450
Abdoulaye Issotina Zibrila , Asma A. Alkuhali , Meng Yuan , Zhaoshu Zeng , Md. Ahasan Ali , Ming Zeng , Amr Mostafa Elenany , Manza Manzoor , Xiaomin Wang , Ming Zhao , Lianhai Jin , Jinjun Liu
Preeclampsia (PE) is associated with increased activation and sensitivity of the Angiotensin II type 1 receptor (AT1R) and inflammation. In this work, we assessed the effect of Pyridostigmine (PYR), with reported anti-inflammatory properties, on placental AT1R in a rat model of PE with placental ischemia. AT1R expression in the placenta from pregnant women (with and without PE) was assessed. Pregnant rats underwent sham or reduced uterine perfusion pressure (RUPP) operation on gestational day 14 (GD14). Dams were treated with either losartan (20 mg/kg/day) or PYR (20 mg/kg/day) or water for five days. Blood pressure and feto-maternal data were collected and placental samples were harvested and processed for molecular analysis. The human trophoblast (HTR-8/SVneo) cell lines were stimulated with Angiotensin II to activate AT1R and treated with Acetylcholine (ACh) to simulate the effects of PYR-increased ACh on trophoblasts. RUPP upregulated the placental AT1R expression. We confirmed that losartan lowers the mean arterial pressure (MAP) in RUPP rats and showed that losartan inhibited RUPP-upregulated placental AT1R, NOX4, TNF-α, IL-1β, and NF-κBp65. On the other hand, PYR lowered the elevated MAP in RUPP and inhibited the placental expression of AT1R, NOX4, TNF-α, IL-1β and NF-κBp65 and reduced the circulating and placental AChE activities. At the cellular level, ACh reduced the angiotensin II-increased NOX4 and NF-κBp65 expressions in the HTR-8/SVneo cell line. This study has confirmed the anti-hypertensive effects of losartan and that of PYR and revealed the anti-inflammatory effect of AT1R antagonism with losartan and the ability of PYR to mitigate the expression and the signaling of placental AT1R.
{"title":"Pyridostigmine attenuates placental-ischemia-upregulated placental angiotensin II type 1 receptor in rats","authors":"Abdoulaye Issotina Zibrila , Asma A. Alkuhali , Meng Yuan , Zhaoshu Zeng , Md. Ahasan Ali , Ming Zeng , Amr Mostafa Elenany , Manza Manzoor , Xiaomin Wang , Ming Zhao , Lianhai Jin , Jinjun Liu","doi":"10.1016/j.peptides.2025.171450","DOIUrl":"10.1016/j.peptides.2025.171450","url":null,"abstract":"<div><div>Preeclampsia (PE) is associated with increased activation and sensitivity of the Angiotensin II type 1 receptor (AT1R) and inflammation. In this work, we assessed the effect of Pyridostigmine (PYR), with reported anti-inflammatory properties, on placental AT1R in a rat model of PE with placental ischemia. AT1R expression in the placenta from pregnant women (with and without PE) was assessed. Pregnant rats underwent sham or reduced uterine perfusion pressure (RUPP) operation on gestational day 14 (GD14). Dams were treated with either losartan (20 mg/kg/day) or PYR (20 mg/kg/day) or water for five days. Blood pressure and feto-maternal data were collected and placental samples were harvested and processed for molecular analysis. The human trophoblast (HTR-8/SVneo) cell lines were stimulated with Angiotensin II to activate AT1R and treated with Acetylcholine (ACh) to simulate the effects of PYR-increased ACh on trophoblasts. RUPP upregulated the placental AT1R expression. We confirmed that losartan lowers the mean arterial pressure (MAP) in RUPP rats and showed that losartan inhibited RUPP-upregulated placental AT1R, NOX4, TNF-α, IL-1β, and NF-κBp65. On the other hand, PYR lowered the elevated MAP in RUPP and inhibited the placental expression of AT1R, NOX4, TNF-α, IL-1β and NF-κBp65 and reduced the circulating and placental AChE activities. At the cellular level, ACh reduced the angiotensin II-increased NOX4 and NF-κBp65 expressions in the HTR-8/SVneo cell line. This study has confirmed the anti-hypertensive effects of losartan and that of PYR and revealed the anti-inflammatory effect of AT1R antagonism with losartan and the ability of PYR to mitigate the expression and the signaling of placental AT1R.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"194 ","pages":"Article 171450"},"PeriodicalIF":2.9,"publicationDate":"2025-10-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145419367","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 : 2025-10-16DOI: 10.1016/j.peptides.2025.171449
Sina Vahedi , Mehdi Khaksari , Shahram Sharafi , Vida Hojati , Nahid Masoudian
Lead, a neurotoxic metal, impairs hippocampal structure by inducing cell death, promoting neuroinflammation, and disrupting the oxidant–antioxidant balance. Additionally, lead-exposed animals display anxiety-like behaviors and deficits in hippocampal-dependent learning and memory. Erythropoietin (EPO), a glycoprotein hormone, stands out as a promising candidate, given its potential to enhance neuronal survival, reduce inflammation, and restore the antioxidant, offering hope for mitigating lead-induced neurodegeneration. This study examined EPO's neuroprotective effect against lead-induced hippocampal damage in male Wistar rats. Rats were divided into four groups (n = 16): control, lead acetate, and lead acetate with EPO (1000 or 2500 IU/kg). Lead (25 mg/kg) was given i.p. for 3 days; EPO was administered i.p. for 7 days after. Controls received distilled water. Spatial memory and anxiety were evaluated using the Morris water maze and elevated plus maze, respectively. Concentrations of antioxidant enzymes and TNF-α were measured using an ELISA assay. Nissl staining assessed necrotic cell death. GFAP and caspase-3 expression were evaluated by immunohistochemistry. The results indicate that EPO administration significantly ameliorated spatial memory deficits and anxiety-like behavior induced by lead exposure. EPO significantly elevates superoxide dismutase, glutathione and catalase levels (P < 0.001). It results in a notable reduction in malondialdehyde (P < 0.001) and TNF-α (P < 0.05) levels relative to the lead group. The EPO group showed reduced necrotic cell death (P < 0.01), and lower caspase-3 and GFAP-positive cell levels (P < 0.001). The research indicates that EPO provides significant neuroprotection against lead via antioxidant activity, inflammation reduction, and apoptosis suppression.
{"title":"Erythropoietin attenuates lead-induced spatial memory deficits and anxiety-like behavior by suppressing hippocampal oxidative stress, cell death inhibition, and inflammation reduction","authors":"Sina Vahedi , Mehdi Khaksari , Shahram Sharafi , Vida Hojati , Nahid Masoudian","doi":"10.1016/j.peptides.2025.171449","DOIUrl":"10.1016/j.peptides.2025.171449","url":null,"abstract":"<div><div>Lead, a neurotoxic metal, impairs hippocampal structure by inducing cell death, promoting neuroinflammation, and disrupting the oxidant–antioxidant balance. Additionally, lead-exposed animals display anxiety-like behaviors and deficits in hippocampal-dependent learning and memory. Erythropoietin (EPO), a glycoprotein hormone, stands out as a promising candidate, given its potential to enhance neuronal survival, reduce inflammation, and restore the antioxidant, offering hope for mitigating lead-induced neurodegeneration. This study examined EPO's neuroprotective effect against lead-induced hippocampal damage in male Wistar rats. Rats were divided into four groups (n = 16): control, lead acetate, and lead acetate with EPO (1000 or 2500 IU/kg). Lead (25 mg/kg) was given i.p. for 3 days; EPO was administered i.p. for 7 days after. Controls received distilled water. Spatial memory and anxiety were evaluated using the Morris water maze and elevated plus maze, respectively. Concentrations of antioxidant enzymes and TNF-α were measured using an ELISA assay. Nissl staining assessed necrotic cell death. GFAP and caspase-3 expression were evaluated by immunohistochemistry. The results indicate that EPO administration significantly ameliorated spatial memory deficits and anxiety-like behavior induced by lead exposure. EPO significantly elevates superoxide dismutase, glutathione and catalase levels (P < 0.001). It results in a notable reduction in malondialdehyde (P < 0.001) and TNF-α (P < 0.05) levels relative to the lead group. The EPO group showed reduced necrotic cell death (P < 0.01), and lower caspase-3 and GFAP-positive cell levels (P < 0.001). The research indicates that EPO provides significant neuroprotection against lead via antioxidant activity, inflammation reduction, and apoptosis suppression.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"194 ","pages":"Article 171449"},"PeriodicalIF":2.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145318424","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 : 2025-10-13DOI: 10.1016/j.peptides.2025.171448
Caroline Hansen , Josephine Fisker-Andersen , Christine Rasmussen , Frederik R. Ceutz , Jens J. Holst , Marie Winther-Sørensen , Nicolai J. Wewer Albrechtsen
Glucagon increases hepatic glucose production by activating both glycogenolysis and gluconeogenesis. Its effect on gluconeogenesis is traditionally attributed to increased expression of gluconeogenic enzyme genes. However, whether glucagon’s transcription-independent actions are sufficient to acutely stimulate hepatic glucose output remains uncertain. To investigate this, we examined the acute effects of glucagon on hepatic gluconeogenesis using an in situ perfused mouse liver model. Livers from male, freely fed C57BL/6JRj mice (11–16 weeks) were perfused via the portal vein with oxygenated Krebs–Henseleit bicarbonate buffer. Hepatic glucose output was measured every three minutes. Glucagon (10 nM) added to the perfusate rapidly increased hepatic glucose production, with a 3.6-fold rise observed within minutes. This effect was absent in overnight-fasted mice. When gluconeogenic substrates (6 mM lactate, pyruvate, or both) were added to the perfusate, acute glucose production was stimulated. Co-administration of glucagon (10 nM) further enhanced glucose output by 36–43 % (p ≤ 0.044). Repeated stimulation experiments confirmed the reproducibility and reversibility of the response. These findings demonstrate that glucagon acutely and reversibly enhances hepatic gluconeogenesis, independent of transcriptional regulation and in the absence of hepatic glycogen. Our data redefine glucagon as a rapid metabolic modulator capable of minute-to-minute control of hepatic glucose output in the fasted state. This has important implications for our understanding of glucose homeostasis during fasting, stress, and disease, and challenges conventional textbook views of glucagon’s role as solely a transcriptional regulator of gluconeogenic genes.
{"title":"Glucagon acutely stimulates hepatic gluconeogenesis","authors":"Caroline Hansen , Josephine Fisker-Andersen , Christine Rasmussen , Frederik R. Ceutz , Jens J. Holst , Marie Winther-Sørensen , Nicolai J. Wewer Albrechtsen","doi":"10.1016/j.peptides.2025.171448","DOIUrl":"10.1016/j.peptides.2025.171448","url":null,"abstract":"<div><div>Glucagon increases hepatic glucose production by activating both glycogenolysis and gluconeogenesis. Its effect on gluconeogenesis is traditionally attributed to increased expression of gluconeogenic enzyme genes. However, whether glucagon’s transcription-independent actions are sufficient to acutely stimulate hepatic glucose output remains uncertain. To investigate this, we examined the acute effects of glucagon on hepatic gluconeogenesis using an <em>in situ</em> perfused mouse liver model. Livers from male, freely fed C57BL/6JRj mice (11–16 weeks) were perfused via the portal vein with oxygenated Krebs–Henseleit bicarbonate buffer. Hepatic glucose output was measured every three minutes. Glucagon (10 nM) added to the perfusate rapidly increased hepatic glucose production, with a 3.6-fold rise observed within minutes. This effect was absent in overnight-fasted mice. When gluconeogenic substrates (6 mM lactate, pyruvate, or both) were added to the perfusate, acute glucose production was stimulated. Co-administration of glucagon (10 nM) further enhanced glucose output by 36–43 % (p ≤ 0.044). Repeated stimulation experiments confirmed the reproducibility and reversibility of the response. These findings demonstrate that glucagon acutely and reversibly enhances hepatic gluconeogenesis, independent of transcriptional regulation and in the absence of hepatic glycogen. Our data redefine glucagon as a rapid metabolic modulator capable of minute-to-minute control of hepatic glucose output in the fasted state. This has important implications for our understanding of glucose homeostasis during fasting, stress, and disease, and challenges conventional textbook views of glucagon’s role as solely a transcriptional regulator of gluconeogenic genes.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"194 ","pages":"Article 171448"},"PeriodicalIF":2.9,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145302436","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 : 2025-10-11DOI: 10.1016/j.peptides.2025.171447
Meng Yuan , Shuaiming Bao , Kejun Wu , Zixin Deng , Jiangtao Gao
This review evaluates duramycin, a lantibiotic antimicrobial peptide, focusing on its biochemical properties, biosynthetic mechanisms, structural characteristics, and therapeutic applications. We examine the critical role of lanthionine and methyllanthionine in antimicrobial efficacy and trace duramycin's development trajectory. Molecular analysis of duramycin highlights the significance of post-translational modifications and leader peptide interactions in its functionality. The peptide's mechanism of action, which involves disrupting membrane integrity through phosphatidylethanolamine binding, forms the foundation of its antimicrobial activity. We assess duramycin's clinical progress, particularly its advancement to Phase II trials for cystic fibrosis therapy, and evaluate its potential against viral infections. The review addresses challenges in production, resistance development, and clinical delivery while exploring emerging applications in cancer treatment, diagnostics, and molecular probes for studying membrane dynamics. We conclude by examining future directions for lantibiotic engineering and the broader implications of duramycin research for antimicrobial therapy and biomedicine.
{"title":"Duramycin: Exploring the therapeutic frontier of a unique lantibiotic","authors":"Meng Yuan , Shuaiming Bao , Kejun Wu , Zixin Deng , Jiangtao Gao","doi":"10.1016/j.peptides.2025.171447","DOIUrl":"10.1016/j.peptides.2025.171447","url":null,"abstract":"<div><div>This review evaluates duramycin, a lantibiotic antimicrobial peptide, focusing on its biochemical properties, biosynthetic mechanisms, structural characteristics, and therapeutic applications. We examine the critical role of lanthionine and methyllanthionine in antimicrobial efficacy and trace duramycin's development trajectory. Molecular analysis of duramycin highlights the significance of post-translational modifications and leader peptide interactions in its functionality. The peptide's mechanism of action, which involves disrupting membrane integrity through phosphatidylethanolamine binding, forms the foundation of its antimicrobial activity. We assess duramycin's clinical progress, particularly its advancement to Phase II trials for cystic fibrosis therapy, and evaluate its potential against viral infections. The review addresses challenges in production, resistance development, and clinical delivery while exploring emerging applications in cancer treatment, diagnostics, and molecular probes for studying membrane dynamics. We conclude by examining future directions for lantibiotic engineering and the broader implications of duramycin research for antimicrobial therapy and biomedicine.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"193 ","pages":"Article 171447"},"PeriodicalIF":2.9,"publicationDate":"2025-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145268935","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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