Peptides最新文献_第2页

IF 2.9 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-12-01 DOI: 10.1016/S0196-9781(25)00121-4

引用次数: 0

FSTL1 silencing protects against lipopolysaccharide-induced ferroptosis in renal tubular cells by regulating the PI3K/Akt pathway FSTL1沉默可通过调节PI3K/Akt通路防止脂多糖诱导的肾小管细胞铁凋亡

IF 2.9 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-11-25 DOI: 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.

脓毒症相关的急性肾损伤（AKI）是发病率和死亡率的主要原因，脂多糖（LPS）诱导的铁上吊是肾小管细胞损伤的重要机制。卵泡抑素样1 （FSTL1）是一种与炎症和氧化应激有关的基质细胞蛋白；然而，其在脂多糖诱导的肾小管细胞铁下垂中的作用尚不清楚。将人肾近端小管上皮细胞（HK-2）暴露于浓度增加的LPS中，以评估FSTL1的表达水平。通过转染siRNA实现FSTL1的沉默，并使用western blotting、RT-qPCR、流式细胞术和荧光探针评估其对PI3K/Akt信号传导、细胞凋亡、氧化应激和铁死亡的影响。使用PI3K/Akt抑制剂LY294002来验证该途径的参与。在mRNA和蛋白水平上，LPS显著上调FSTL1的表达，并呈剂量依赖性。沉默FSTL1可显著提高PI3K和Akt的磷酸化水平，并显著减弱lps诱导的细胞凋亡，这可以通过增加细胞活力和减少Annexin v阳性细胞数量来证明。FSTL1沉默也降低了活性氧和丙二醛水平，同时提高了超氧化物歧化酶活性和谷胱甘肽含量。此外，FSTL1的沉默减少了线粒体亚铁的积累，恢复了Nrf2、SLC7A11、GPX4和FTH1，同时降低了ACSL4的表达。LY294002逆转了这些保护作用，表明其依赖于PI3K/Akt信号。FSTL1通过PI3K/Akt通路介导lps诱导的肾小管细胞凋亡、氧化应激和铁下垂。靶向FSTL1-PI3K/Akt信号通路可能是减轻内毒素刺激的肾小管细胞铁致损伤的新途径，为lps诱导的肾小管损伤模型提供了相关的机制见解。

{"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}

引用次数: 0

MPN-12-NH2 shows potent antinociception effects by targeting opioid, cannabinoid, and neuropeptide FF receptors MPN-12-NH2通过靶向阿片、大麻素和神经肽FF受体显示出有效的抗痛觉作用

IF 2.9 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-10-30 DOI: 10.1016/j.peptides.2025.171453

Lanxia Zhou , Jing Zhang , Chenxi Mei , Zhanyu Niu , Huiming Bao , Yaofeng Zhao , Zhonghua Zhang , Dingnian Gou , Shouliang Dong

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.

神经肽FF （NPFF）系统在调节阿片类药物和大麻的镇痛作用中起重要作用。在阿片或大麻素肽的c端加入NPFF药效团已成为增强镇痛效力同时减轻不良反应的一种策略。然而，这种多靶点化合物的开发仅限于两种体系，迄今尚未成功商业化。因此，我们将阿片肽morphiceptin、pepans核心序列NFKL和NPFF类似物PFR(Tic)-NH2结合，构建了嵌合肽MPN-12-NH2。在小鼠甩尾实验中，脑室内注射MPN-12-NH2具有剂量依赖性的镇痛作用（ED50 = 0.71 nmol/只）。此外，通过分子对接和分子动力学（MD）模拟来阐明MPN-12-NH2与阿片受体、大麻素受体和神经肽受体的结合模式。体外研究表明MPN-12-NH2是mu阿片样受体（MOR）、delta阿片样受体、大麻素1受体（CB1）、CB2和NPFF2受体的多功能激动剂。随后，受体拮抗研究表明MPN-12-NH2的中枢镇痛作用主要由MOR、CB1和NPFF受体介导。此外，我们发现静脉注射MPN-12-NH2剂量依赖性地减轻了SNI、卡拉胶和醋酸扭体模型的病理性疼痛反应。然而，MPN-12-NH2 （3 nmol/小鼠，i.c.v）不会导致PAG区域的成瘾、镇痛耐受性或小胶质细胞改变。此外，MPN-12-NH2对急性疼痛的镇痛作用与对胃肠运动的抑制作用有效区分，ED50比值为14.21倍。综上所述，多靶点化合物MPN-12-NH2在小鼠中表现出由MOR、CB1和NPFF受体介导的强效镇痛活性，同时具有良好的副作用。这些发现为阿片类药物/大麻素/NPFF激动剂的开发开辟了新的道路。

{"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}

引用次数: 0

Pyridostigmine attenuates placental-ischemia-upregulated placental angiotensin II type 1 receptor in rats 吡地斯的明减轻大鼠胎盘缺血-胎盘血管紧张素II型1受体上调

IF 2.9 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-10-25 DOI: 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.

子痫前期（PE）与血管紧张素II型1受体（AT1R）的激活和敏感性增加以及炎症有关。在这项工作中，我们评估了吡哆斯的明（PYR）对大鼠PE伴胎盘缺血模型中胎盘AT1R的影响，PYR具有报道的抗炎特性。评估孕妇胎盘中AT1R的表达（有无PE）。妊娠大鼠在妊娠第14天（GD14）进行假或降低子宫灌注压（RUPP）手术。用氯沙坦（20 mg/kg/day）或PYR（20 mg/kg/day）或水处理水坝5天。采集血压和胎母数据，采集胎盘样本并进行分子分析。用血管紧张素II刺激人滋养细胞（HTR-8/SVneo）细胞株激活AT1R，并用乙酰胆碱（ACh）处理以模拟pyr升高的ACh对滋养细胞的影响。RUPP上调胎盘AT1R的表达。我们证实氯沙坦降低RUPP大鼠的平均动脉压（MAP），并显示氯沙坦抑制RUPP上调的胎盘AT1R、NOX4、TNF-α、IL-1β和NF-κBp65。另一方面，PYR降低了RUPP中升高的MAP，抑制了胎盘中AT1R、NOX4、TNF-α、IL-1β和NF-κBp65的表达，降低了循环和胎盘中的AChE活性。在细胞水平上，乙酰胆碱降低HTR-8/SVneo细胞系血管紧张素ii的表达，增加NOX4和NF-κBp65的表达。本研究证实了氯沙坦和PYR的降压作用，揭示了氯沙坦拮抗AT1R的抗炎作用以及PYR减轻胎盘AT1R的表达和信号通路的能力。

{"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}

引用次数: 0

Erythropoietin attenuates lead-induced spatial memory deficits and anxiety-like behavior by suppressing hippocampal oxidative stress, cell death inhibition, and inflammation reduction 促红细胞生成素通过抑制海马氧化应激、细胞死亡抑制和炎症减轻铅诱导的空间记忆缺陷和焦虑样行为。

IF 2.9 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-10-16 DOI: 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.

铅是一种神经毒性金属，通过诱导细胞死亡、促进神经炎症和破坏氧化-抗氧化平衡而损害海马结构。此外，铅暴露的动物表现出焦虑样行为和海马依赖学习和记忆的缺陷。促红细胞生成素（EPO）是一种糖蛋白激素，具有增强神经元存活、减少炎症和恢复抗氧化能力的潜力，为减轻铅诱导的神经变性提供了希望。本研究探讨了EPO对铅诱导的雄性Wistar大鼠海马损伤的神经保护作用。将大鼠分为4组（n=16）：对照组、醋酸铅组、醋酸铅加EPO组（1000或2500 IU/kg）。铅（25mg/kg）灌胃3天；EPO连续7天ig。对照组接受蒸馏水。空间记忆和焦虑分别采用Morris水迷宫和升高+迷宫进行评估。采用ELISA法测定抗氧化酶和TNF-α浓度。尼氏染色评估坏死细胞死亡情况。免疫组织化学检测GFAP和caspase-3的表达。结果表明，EPO可显著改善铅暴露引起的空间记忆缺陷和焦虑样行为。EPO显著提高超氧化物歧化酶、谷胱甘肽和过氧化氢酶水平（P < 0.001）。与铅组相比，丙二醛（P < 0.001）和TNF-α (P < 0.05)水平显著降低。EPO组坏死细胞死亡明显减少(P

{"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}

引用次数: 0

Glucagon acutely stimulates hepatic gluconeogenesis 胰高血糖素急性刺激肝脏糖异生。

IF 2.9 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-10-13 DOI: 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.

胰高血糖素通过激活糖原分解和糖异生来增加肝脏葡萄糖的产生。其对糖异生的影响传统上归因于糖异生酶基因的表达增加。然而，胰高血糖素的转录非依赖性作用是否足以急性刺激肝脏葡萄糖输出仍不确定。为了研究这一点，我们用原位灌注的小鼠肝脏模型检测了胰高血糖素对肝脏糖异生的急性影响。从自由饲养的C57BL/6JRj雄性小鼠（11-16周龄）分离肝脏，经门静脉灌注含氧的Krebs-Henseleit碳酸氢盐缓冲液。每三分钟测量一次肝葡萄糖输出量。灌注液中加入胰高血糖素（10nM）迅速增加肝脏葡萄糖产量，几分钟内增加3.6倍。这种效果在一夜禁食、糖原耗尽的小鼠中不存在。当向灌注液中加入糖异生底物（6mM乳酸、丙酮酸或两者）时，刺激急性葡萄糖生成。同时给药胰高血糖素（10nM）可使葡萄糖输出量增加36-43% (p≤0.044)，而单独给药胰高血糖素无效果。反复的刺激实验证实了该反应的可重复性和可逆性。这些研究结果表明，胰高血糖素在没有肝糖原的情况下，不依赖于转录调节，急性地、可逆地促进肝脏糖异生。我们的数据将胰高血糖素重新定义为一种快速代谢调节剂，能够在禁食状态下每分钟控制肝脏葡萄糖输出。这对我们理解空腹、应激和疾病期间的葡萄糖稳态具有重要意义，并挑战了传统教科书中关于胰高血糖素仅作为糖异生基因转录调节剂的观点。

{"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}

引用次数: 0

Duramycin: Exploring the therapeutic frontier of a unique lantibiotic 杜拉霉素：探索一种独特抗生素的治疗前沿

IF 2.9 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-10-11 DOI: 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.

本文综述了一种新型抗菌肽杜拉米霉素的生物化学特性、生物合成机制、结构特点和治疗应用。我们研究了硫代氨酸和甲基硫代氨酸在抗菌功效中的关键作用，并追踪了杜拉霉素的发展轨迹。杜拉霉素的分子分析强调了翻译后修饰和先导肽相互作用在其功能中的重要性。肽的作用机制包括通过磷脂酰乙醇胺结合破坏膜的完整性，这是其抗菌活性的基础。我们评估了duramycin的临床进展，特别是其用于囊性纤维化治疗的II期试验的进展，并评估了其抗病毒感染的潜力。这篇综述讨论了在生产、耐药发展和临床递送方面的挑战，同时探索了在癌症治疗、诊断和研究膜动力学的分子探针方面的新兴应用。最后，我们探讨了抗生素工程的未来方向，以及杜拉霉素研究在抗菌治疗和生物医学方面的更广泛意义。

{"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}

引用次数: 0

Bioactive peptide HX-12C enhances fibroblast function through TGF-β/Smad signaling pathway and promotes wound healing in vitro and in vivo 生物活性肽HX-12C通过TGF-β/Smad信号通路增强成纤维细胞功能，促进体外和体内伤口愈合

IF 2.9 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-10-10 DOI: 10.1016/j.peptides.2025.171446

Yujing Wang , Baisheng Wang , Yiyang Li , Zhenmin Cao , Zuodong Qin , Xiaofang Luo , Kun Li

Closure of skin wounds is essential for resistance to pathogens. Collagen synthesis dominated by fibroblasts, re-epithelialization driven by keratinocytes, and angiogenesis governed by vascular endothelial cell lumen formation all play crucial roles in wound healing. Our previous study revealed that the small peptide HX-12C modified from the antimicrobial peptide Temporin had favorable antimicrobial activity and that a hydrogel complex containing HX-12C accelerates the healing of infected wounds. Here, we demonstrated that HX-12C promoted the proliferation, migration and collagen synthesis of fibroblasts, the proliferation of keratinocytes and the proliferation and migration of vascular endothelial cells in vitro, and accelerated the healing of mice skin wounds in vivo. Moreover, we found that HX-12C activated collagen synthesis in fibroblasts early by activating the TGF-β/Smad signaling axis. Thus, we suggested that HX-12C is a promising candidate for clinical application with therapeutic potential to promote wound healing.

皮肤伤口的愈合对抵抗病原体至关重要。成纤维细胞主导的胶原合成，角质形成细胞驱动的再上皮化，血管内皮细胞管腔形成控制的血管生成，都在伤口愈合中起着至关重要的作用。我们之前的研究表明，由抗菌肽Temporin修饰的小肽HX-12C具有良好的抗菌活性，并且含有HX-12C的水凝胶复合物可以加速感染伤口的愈合。本研究证明HX-12C在体外促进成纤维细胞的增殖、迁移和胶原合成，促进角质形成细胞的增殖和血管内皮细胞的增殖和迁移，并在体内加速小鼠皮肤伤口的愈合。此外，我们发现HX-12C通过激活TGF-β/Smad信号轴，在成纤维细胞早期激活胶原合成。因此，我们认为HX-12C具有促进伤口愈合的治疗潜力，具有很好的临床应用前景。

{"title":"Bioactive peptide HX-12C enhances fibroblast function through TGF-β/Smad signaling pathway and promotes wound healing in vitro and in vivo","authors":"Yujing Wang , Baisheng Wang , Yiyang Li , Zhenmin Cao , Zuodong Qin , Xiaofang Luo , Kun Li","doi":"10.1016/j.peptides.2025.171446","DOIUrl":"10.1016/j.peptides.2025.171446","url":null,"abstract":"<div><div>Closure of skin wounds is essential for resistance to pathogens. Collagen synthesis dominated by fibroblasts, re-epithelialization driven by keratinocytes, and angiogenesis governed by vascular endothelial cell lumen formation all play crucial roles in wound healing. Our previous study revealed that the small peptide HX-12C modified from the antimicrobial peptide Temporin had favorable antimicrobial activity and that a hydrogel complex containing HX-12C accelerates the healing of infected wounds. Here, we demonstrated that HX-12C promoted the proliferation, migration and collagen synthesis of fibroblasts, the proliferation of keratinocytes and the proliferation and migration of vascular endothelial cells <em>in vitro</em>, and accelerated the healing of mice skin wounds <em>in vivo</em>. Moreover, we found that HX-12C activated collagen synthesis in fibroblasts early by activating the TGF-β/Smad signaling axis. Thus, we suggested that HX-12C is a promising candidate for clinical application with therapeutic potential to promote wound healing.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"193 ","pages":"Article 171446"},"PeriodicalIF":2.9,"publicationDate":"2025-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145268936","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Relaxin-2 counteracts TNF-α-induced senescence in human primary chondrocytes by enhancing telomerase activity and modulating SIRT1/p53 signaling 松弛素-2通过增强端粒酶活性和调节SIRT1/p53信号传导抑制TNF-α-诱导的人原代软骨细胞衰老

IF 2.9 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-10-03 DOI: 10.1016/j.peptides.2025.171445

Jinfeng Pei, Guohui Wang, Minwei Yang, Liwei Liu

The pro-inflammatory cytokine TNF-α plays a crucial role in promoting cellular senescence in chondrocytes, contributing to the pathological progression of osteoarthritis (OA). Relaxin-2, a biologically active peptide hormone with diverse effects, has been investigated for its potential protective role against TNF-α-induced cellular senescence in human primary chondrocytes. In this study, human primary chondrocytes were exposed to TNF-α (10 ng/mL) with and without the presence of recombinant human relaxin-2 (rh relaxin-2). SA-β-gal staining indicated that rh relaxin-2 effectively mitigated TNF-α-induced cellular senescence in these cells. Furthermore, rh relaxin-2 enhanced telomerase activity and prevented cell cycle arrest at the G0/G1 phase induced by TNF-α. Additionally, rh relaxin-2 reduced the expression levels of plasminogen activator Inhibitor-1 (PAI-1) and p21, key regulators of cellular senescence. Interestingly, TNF-α increased K382 acetylation of p53 but decreased SIRT1 expression. Notably, knocking down SIRT1 negated the protective effects of rh relaxin-2 on cellular senescence, suggesting that SIRT1 is involved in mediating the protective effects of rh relaxin-2. These findings provide new insights into the potential therapeutic use of rh relaxin-2 for OA treatment through a novel mechanism.

促炎细胞因子TNF-α在促进软骨细胞衰老中起关键作用，促进骨关节炎（OA）的病理进展。松弛素-2是一种具有多种作用的生物活性肽激素，其对TNF-α-诱导的人原代软骨细胞衰老的潜在保护作用已被研究。在这项研究中，人原代软骨细胞暴露于TNF-α (10ng/mL)中，同时存在和不存在重组人松弛素-2 （rh松弛素-2）。SA-β-gal染色表明rh松弛素-2可有效缓解TNF-α-诱导的细胞衰老。此外，rh松弛素-2增强端粒酶活性，防止TNF-α诱导的细胞周期阻滞在G0/G1期。此外，rh松弛素-2降低了纤溶酶原激活物抑制剂-1 （PAI-1）和p21的表达水平，p21是细胞衰老的关键调节因子。有趣的是，TNF-α增加了p53的K382乙酰化，但降低了SIRT1的表达。值得注意的是，敲低SIRT1会使rh relaxin-2对细胞衰老的保护作用失效，这表明SIRT1参与介导rh relaxin-2的保护作用。这些发现通过一种新的机制为rh松弛素-2在OA治疗中的潜在治疗用途提供了新的见解。

{"title":"Relaxin-2 counteracts TNF-α-induced senescence in human primary chondrocytes by enhancing telomerase activity and modulating SIRT1/p53 signaling","authors":"Jinfeng Pei, Guohui Wang, Minwei Yang, Liwei Liu","doi":"10.1016/j.peptides.2025.171445","DOIUrl":"10.1016/j.peptides.2025.171445","url":null,"abstract":"<div><div>The pro-inflammatory cytokine TNF-α plays a crucial role in promoting cellular senescence in chondrocytes, contributing to the pathological progression of osteoarthritis (OA). Relaxin-2, a biologically active peptide hormone with diverse effects, has been investigated for its potential protective role against TNF-α-induced cellular senescence in human primary chondrocytes. In this study, human primary chondrocytes were exposed to TNF-α (10 ng/mL) with and without the presence of recombinant human relaxin-2 (rh relaxin-2). SA-β-gal staining indicated that rh relaxin-2 effectively mitigated TNF-α-induced cellular senescence in these cells. Furthermore, rh relaxin-2 enhanced telomerase activity and prevented cell cycle arrest at the G0/G1 phase induced by TNF-α. Additionally, rh relaxin-2 reduced the expression levels of plasminogen activator Inhibitor-1 (PAI-1) and p21, key regulators of cellular senescence. Interestingly, TNF-α increased K382 acetylation of p53 but decreased SIRT1 expression. Notably, knocking down SIRT1 negated the protective effects of rh relaxin-2 on cellular senescence, suggesting that SIRT1 is involved in mediating the protective effects of rh relaxin-2. These findings provide new insights into the potential therapeutic use of rh relaxin-2 for OA treatment through a novel mechanism.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"194 ","pages":"Article 171445"},"PeriodicalIF":2.9,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145233179","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Salusin-α preserves glomerular endothelial barrier function in hypertension via YAP/ZO-1 signaling pathway Salusin-α通过YAP/ZO-1信号通路保护高血压患者肾小球内皮屏障功能

IF 2.9 4区医学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Peptides

Pub Date : 2025-09-17 DOI: 10.1016/j.peptides.2025.171441

Lang Li , Huan Wang , ChunYu Zhao

Hypertensive nephropathy (HN) is a leading cause of end-stage renal disease, driven by glomerular endothelial barrier dysfunction, inflammation, and tight junction impairment. Salusin-α, an endogenous bioactive peptide with cardiovascular protective properties, has emerged as a potential regulator of renal homeostasis, but its role in hypertensive renal injury remains unclear. This study investigated the protective effects of Salusin-α on glomerular endothelial barrier function and its underlying mechanism via the YAP/ZO-1 signaling pathway. Male C57BL/6 mice were randomized into control, angiotensin II/high-salt (ANG/HS)-induced hypertensive, and ANG/HS + Salusin-α (1 or 2 μg/kg) groups. Hypertensive mice exhibited reduced serum and renal Salusin-α levels (∼43 % and ∼55 %, respectively), increased renal inflammation (IL-1β, TNF-α, MCP-1 upregulated 2.6–3.1-fold), albuminuria (82.6 vs. 19.3 μg/day in controls), and ZO-1 downregulation (∼51 %). Salusin-α treatment dose-dependently restored ZO-1 expression (95 % of control levels at 2 μg/kg) and reduced albuminuria (∼48 %). In human renal glomerular endothelial cells (HRGECs), Salusin-α (10 nM) mitigated ANG/HS-induced barrier dysfunction (FITC-dextran flux reduced from 41.3 % to 19.6 %; TEER restored from 105.2 to 169.8 Ω·cm²) by inhibiting YAP nuclear translocation (∼52 % reduction) and preserving ZO-1. Critically, YAP overexpression abolished Salusin-α’s protective effects on ZO-1 and barrier integrity. These findings demonstrate that Salusin-α alleviates hypertensive renal injury by suppressing YAP-mediated ZO-1 degradation, thereby preserving glomerular endothelial barrier function and reducing inflammation. The study identifies Salusin-α as a novel therapeutic candidate targeting the YAP/ZO-1 axis in hypertensive nephropathy.

高血压肾病（HN）是终末期肾脏疾病的主要原因，由肾小球内皮屏障功能障碍、炎症和紧密连接损伤驱动。Salusin-α是一种具有心血管保护作用的内源性生物活性肽，已被认为是肾脏稳态的潜在调节剂，但其在高血压肾损伤中的作用尚不清楚。本研究通过YAP/ZO-1信号通路探讨Salusin-α对肾小球内皮屏障功能的保护作用及其机制。雄性C57BL/6小鼠随机分为对照组、血管紧张素II/高盐（ANG/HS）致高血压组和ANG/HS + Salusin-α（1或2μg/kg）组。高血压小鼠表现出血清和肾脏Salusin-α水平降低（分别为~43%和~55%），肾脏炎症（IL-1β、TNF-α、MCP-1上调2.6-3.1倍），蛋白尿（82.6比19.3μg/d）和ZO-1下调（~51%）。Salusin-α剂量依赖性地恢复了ZO-1表达（2μg/kg时为对照水平的95%），并减少了蛋白尿（~48%）。在人肾小球内皮细胞（HRGECs）中，Salusin-α (10nM)通过抑制YAP核转位（减少约52%）和保留ZO-1，减轻了ANG/ hs诱导的屏障功能障碍（fitc -葡聚糖通量从41.3%降低到19.6%；TEER从105.2恢复到169.8 Ω·cm²）。重要的是，YAP过表达破坏了Salusin-α对ZO-1和屏障完整性的保护作用。这些结果表明Salusin-α通过抑制yap介导的ZO-1降解，从而维持肾小球内皮屏障功能，减轻炎症，从而减轻高血压肾损伤。该研究确定Salusin-α作为一种新的靶向YAP/ZO-1轴治疗高血压肾病的候选药物。

{"title":"Salusin-α preserves glomerular endothelial barrier function in hypertension via YAP/ZO-1 signaling pathway","authors":"Lang Li , Huan Wang , ChunYu Zhao","doi":"10.1016/j.peptides.2025.171441","DOIUrl":"10.1016/j.peptides.2025.171441","url":null,"abstract":"<div><div>Hypertensive nephropathy (HN) is a leading cause of end-stage renal disease, driven by glomerular endothelial barrier dysfunction, inflammation, and tight junction impairment. Salusin-α, an endogenous bioactive peptide with cardiovascular protective properties, has emerged as a potential regulator of renal homeostasis, but its role in hypertensive renal injury remains unclear. This study investigated the protective effects of Salusin-α on glomerular endothelial barrier function and its underlying mechanism via the YAP/ZO-1 signaling pathway. Male C57BL/6 mice were randomized into control, angiotensin II/high-salt (ANG/HS)-induced hypertensive, and ANG/HS + Salusin-α (1 or 2 μg/kg) groups. Hypertensive mice exhibited reduced serum and renal Salusin-α levels (∼43 % and ∼55 %, respectively), increased renal inflammation (IL-1β, TNF-α, MCP-1 upregulated 2.6–3.1-fold), albuminuria (82.6 vs. 19.3 μg/day in controls), and ZO-1 downregulation (∼51 %). Salusin-α treatment dose-dependently restored ZO-1 expression (95 % of control levels at 2 μg/kg) and reduced albuminuria (∼48 %). In human renal glomerular endothelial cells (HRGECs), Salusin-α (10 nM) mitigated ANG/HS-induced barrier dysfunction (FITC-dextran flux reduced from 41.3 % to 19.6 %; TEER restored from 105.2 to 169.8 Ω·cm²) by inhibiting YAP nuclear translocation (∼52 % reduction) and preserving ZO-1. Critically, YAP overexpression abolished Salusin-α’s protective effects on ZO-1 and barrier integrity. These findings demonstrate that Salusin-α alleviates hypertensive renal injury by suppressing YAP-mediated ZO-1 degradation, thereby preserving glomerular endothelial barrier function and reducing inflammation. The study identifies Salusin-α as a novel therapeutic candidate targeting the YAP/ZO-1 axis in hypertensive nephropathy.</div></div>","PeriodicalId":19765,"journal":{"name":"Peptides","volume":"193 ","pages":"Article 171441"},"PeriodicalIF":2.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0