Clinical and Experimental Pharmacology and Physiology最新文献

PHD3-Mediated Inhibition of Retinal Neovascularization in Retinopathy of Prematurity

IF 2.9 4区医学

Clinical and Experimental Pharmacology and Physiology Pub Date : 2025-02-06 DOI: 10.1111/1440-1681.70020

Jiawei Yu, Haifeng Liu, Yue Xing, Yuan Gao

{"title":"PHD3-Mediated Inhibition of Retinal Neovascularization in Retinopathy of Prematurity","authors":"Jiawei Yu, Haifeng Liu, Yue Xing, Yuan Gao","doi":"10.1111/1440-1681.70020","DOIUrl":"https://doi.org/10.1111/1440-1681.70020","url":null,"abstract":"<div>\u0000 \u0000 <p>Retinopathy of prematurity is characterised by abnormal retinal neovascularization in response to hypoxia stress. Prolyl 4-hydroxylase domain protein 3 (PHD3) is a well-known molecular oxygen sensor. However, the role that PHD3 plays in retinopathy of prematurity remains unclear. In this work, a mouse model of oxygen-induced retinopathy (OIR) was used for in vivo studies. Compared with the mice in room air, OIR mice showed sprouting of retinal neovascularization and increased level of PHD3. It was further found that PHD3 overexpression weakened OIR-induced retinal neovascularization and promoted cell apoptosis in the retina, indicating a mitigative effect on retinopathy. More importantly, OIR-induced upregulation of hypoxia inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGFA) was offset by PHD3 overexpression. In in vitro experiments, mouse retinal microvascular endothelial cells (MRMECs) were cultured under hypoxic conditions. The functions of endothelial cells including cell proliferation, cell migration, and tube formation ability were suppressed by PHD3, suggesting an anti-angiogenesis effect of PHD3. In line with in vivo experiments, the expression of HIF-1α and VEGFA levels declined in endothelial cells when PHD3 was overexpressed. Taken together, PHD3 alleviates retinopathy of prematurity through anti-angiogenesis, and the core mechanism may involve cell apoptosis of retina endothelial cell and HIF-1α–VEGFA axis. These findings provide exciting new insights into the pathogenesis of retinopathy of prematurity, and could offer new treatment directions.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 4","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143362273","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

Isoferulic Acid Inhibits Proliferation and Migration of Pancreatic Cancer Cells, and Promotes the Apoptosis of Pancreatic Cancer Cells in a Mitochondria-Dependent Manner Through Inhibiting NF-κB Signalling Pathway

IF 2.9 4区医学

Clinical and Experimental Pharmacology and Physiology Pub Date : 2025-01-24 DOI: 10.1111/1440-1681.70025

Suqin Sun, Rong Fan, Li Chang, Lei Gao, Chunting Liu, Dongying Liu, Shiyu Niu

{"title":"Isoferulic Acid Inhibits Proliferation and Migration of Pancreatic Cancer Cells, and Promotes the Apoptosis of Pancreatic Cancer Cells in a Mitochondria-Dependent Manner Through Inhibiting NF-κB Signalling Pathway","authors":"Suqin Sun, Rong Fan, Li Chang, Lei Gao, Chunting Liu, Dongying Liu, Shiyu Niu","doi":"10.1111/1440-1681.70025","DOIUrl":"10.1111/1440-1681.70025","url":null,"abstract":"<div>\u0000 \u0000 <p>Isoferulic acid (IA), a derivative of cinnamic acid, is derived from Danshen and exhibits anticancer properties by disrupting cancer cell activities. However, its role in pancreatic cancer, the “king of cancer”, was unknown. In this study, pancreatic cancer cells were subjected to treatment with IA (6.25, 12.5, 25 μM), and nude mice injected with pancreatic cancer cells were received IA at doses of 7.5 mg/kg/day or 30 mg/kg/day by oral administration. CCK8, Annexin V-FITC/propidium iodide (PI) double staining and TUNEL assay were conducted to evaluate the cell viability and apoptosis. Hoechst staining and comet assay was employed to measure DNA damage. Mitochondrial membrane potential (MMP) analysis was carried out to explain the mitochondrial damage. EdU and wound healing assay were performed for cell proliferation and migration detection. Immunofluorescence and western blot were used to explore the mechanism. We found that IA reduced cell viability and induced apoptosis, as evidenced by an increase in Annexin V-FITC<sup>+</sup>PI<sup>−</sup> and Annexin V-FITC<sup>+</sup>PI<sup>+</sup> cell populations, brighter TUNEL and Hoechst staining, and more percentage of tail DNA. Furthermore, IA decreased MMP and changed levels of apoptosis-related proteins. The cell proliferation and migration were inhibited by IA treatment. Mechanically, IA downregulated the phosphorylation of IĸBα and inhibited p65 nuclear translocation, consequently suppressing NF-κB pathway. In general, IA suppressed the cell proliferation and migration, and caused apoptosis of pancreatic cancer cells in a mitochondria-dependent manner through blocking NF-κB signalling pathway, indicating that IA may be a potential therapeutic strategy for pancreatic cancer.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143037489","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

RETRACTION: Pentoxifylline Prevents Epileptic Seizure via Modulating HMGB1/RAGE/TLR4 Signalling Pathway and Improves Memory in Pentylenetetrazol Kindling Rats 回退：己酮茶碱通过调节HMGB1/RAGE/TLR4信号通路预防癫痫发作，改善戊四氮点燃大鼠的记忆。

IF 2.9 4区医学

Clinical and Experimental Pharmacology and Physiology Pub Date : 2025-01-21 DOI: 10.1111/1440-1681.70023

{"title":"RETRACTION: Pentoxifylline Prevents Epileptic Seizure via Modulating HMGB1/RAGE/TLR4 Signalling Pathway and Improves Memory in Pentylenetetrazol Kindling Rats","authors":"","doi":"10.1111/1440-1681.70023","DOIUrl":"10.1111/1440-1681.70023","url":null,"abstract":"<p>\u0000 <b>RETRACTION:</b> <span>G. A. Badawi</span>, <span>M. M. Shokr</span>, <span>H. F. Zaki</span> and <span>A. F. Mohamed</span>, “ <span>Pentoxifylline Prevents Epileptic Seizure via Modulating HMGB1/RAGE/TLR4 Signalling Pathway and Improves Memory in Pentylenetetrazol Kindling Rats</span>,” <i>Clinical and Experimental Pharmacology and Physiology</i> <span>48</span>, no. <span>8</span> (<span>2021</span>): <span>1111</span><b>–</b><span>1124</span>, https://doi.org/10.1111/1440-1681.13508.\u0000 </p><p>The above article, published online on 26 April 2021 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Yang Yang; and John Wiley & Sons Australia Ltd. The retraction has been agreed following concerns raised by a third party regarding evidence of splicing of western blot bands presented in Figures 4 and 7. Following an investigation, further concerns were uncovered regarding duplication between the ‘phenytoin + PTZ’ and ‘PTX + PTZ’ bands within the HMGB1 lane in Figure 4B1 and the TLR4 lane in Figure 4C1. Additionally, the ‘HMGB1’ and ‘TLR4’ lanes across Figures 4B1 and 4C1 appear duplicated and resized with respect to each other.</p><p>The authors provided some raw data and explained that the bands in Figures 4B1, 4C1, 7A1, 7B1 and 7C1 were spliced and rearranged in order to simplify the data and maintain consistency with other results. The authors also provided an explanation for the duplicates observed within and across Figures 4B1 and 4C1. The editors were not satisfied with the explanation or raw data provided and consider the editing applied to the western blots to be inappropriate. Due to the extent and nature of the concerns, the editors have lost confidence in the results and conclusions presented in this article. The authors were informed of the retraction.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/1440-1681.70023","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143001001","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}

引用次数: 0

Molecular Mechanism of Ginsenoside Rg3 Alleviation in Osteoporosis via Modulation of KPNA2 and the NF-κB Signalling Pathway 人参皂苷Rg3通过调控KPNA2和NF-κB信号通路减轻骨质疏松的分子机制

IF 2.9 4区医学

Clinical and Experimental Pharmacology and Physiology Pub Date : 2025-01-16 DOI: 10.1111/1440-1681.70019

Xiaonan Zhang, Fenglan Huang, Jinzhu Liu, Zhenzhong Zhou, Shanyou Yuan, Haoli Jiang

{"title":"Molecular Mechanism of Ginsenoside Rg3 Alleviation in Osteoporosis via Modulation of KPNA2 and the NF-κB Signalling Pathway","authors":"Xiaonan Zhang, Fenglan Huang, Jinzhu Liu, Zhenzhong Zhou, Shanyou Yuan, Haoli Jiang","doi":"10.1111/1440-1681.70019","DOIUrl":"10.1111/1440-1681.70019","url":null,"abstract":"<div>\u0000 \u0000 <p>Osteoporosis is mainly caused by an imbalance in osteoclast and osteoblast regulation, resulting in an imbalance in bone homeostasis. Ginsenoside Rg3 (Rg3) has been reported to have a therapeutic effect on alleviating osteoporosis. Nonetheless, the underlying mechanisms have not been completely elucidated. Herein, the molecular mechanism of Rg3 alleviation in osteoporosis was further explored. An in vitro model was established utilising the receptor activator of nuclear factor-kappaB ligand (RANKL) to induce osteoclast differentiation of RAW264.7 cells. RNA-sequencing results showed that karyopherin subunit alpha 2 (KPNA2) is one of the significantly differentially expressed genes regulated by Rg3 in RANKL-induced RAW264.7 cells. Basic experiments further suggested that KPNA2 is up-regulated in a time-dependent manner in the RANKL-induced RAW264.7 cells, while Rg3 treatment reduced its expression in a dose- and time-dependent manner. Knockdown of KPNA2 inhibited osteoclast formation and the expression of related molecules, including those in the nuclear factor kappa-B (NF-κB) pathway. The NF-κB inhibitor, JSH-23, partially abolished the impact of KPNA2 overexpression on osteoclast formation, indicating KPNA2 activates NF-κB. Furthermore, KPNA2 overexpression partially abolished the inhibitory impact of Rg3 on osteoclast formation, indicating that KPNA2 is a target of Rg3. These results suggest that KPNA2 plays a role in how Rg3 influences on osteoclast differentiation and osteoporosis through the NF-κB pathway.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143000988","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

Predictive Effect of FT3 Within the Euthyroid Range on LDL-C in Patients With Type 2 Diabetes: A Cross-Sectional Analysis of Inpatients in China 甲状腺功能正常范围内FT3对2型糖尿病患者LDL-C的预测作用：中国住院患者的横断面分析

IF 2.9 4区医学

Clinical and Experimental Pharmacology and Physiology Pub Date : 2025-01-09 DOI: 10.1111/1440-1681.70021

Yujue Wang, Chi Zhang, Shangshuang Zhao, Jinmei Xu, Jun Han

{"title":"Predictive Effect of FT3 Within the Euthyroid Range on LDL-C in Patients With Type 2 Diabetes: A Cross-Sectional Analysis of Inpatients in China","authors":"Yujue Wang, Chi Zhang, Shangshuang Zhao, Jinmei Xu, Jun Han","doi":"10.1111/1440-1681.70021","DOIUrl":"10.1111/1440-1681.70021","url":null,"abstract":"<div>\u0000 \u0000 <p>Evidence regarding the relationship between free triiodothyronine (FT3) and low-density lipoprotein cholesterol (LDL-C) remains limited. This study aimed to evaluate the association between FT3 and LDL-C levels in patients with type 2 diabetes mellitus (T2DM) who exhibit normal thyroid function. Between June 2022 and October 2023, a total of 3011 inpatients with T2DM and euthyroid status were continuously and non-selectively recruited from a Chinese hospital. The average age of the included individuals was 56.92 ± 12.56 years, with 1430 (47.49%) males. The mean FT3 concentration was 4.35 ± 0.56 pmol/L. A logistic regression model was applied to analyse the relationship between the FT3 and LDL-C levels, while smooth curve fitting was employed to investigate potential nonlinear associations between these variables. This study demonstrated a positive correlation (0.05 [95% CI: 0.02–0.07; <i>p</i> = 0.0018]) and nonlinear relationship (<i>p</i> = 0.0014) between FT3 and LDL-C levels in Chinese patients with diabetes. Specifically, when FT3 was below 4.28 pmol/L, LDL-C levels increased alongside rising FT3 concentration. However, when FT3 reached or exceeded 4.28 pmol/L, LDL-C levels plateaued and tended to stabilise. These findings suggest that maintaining FT3 within the range of 2.76 to 4.28 pmol/L may be most beneficial for mitigating the progression of cardiovascular disease in patients with T2DM. Our research is important for identifying the optimal FT3 range to delay the progression of cardiovascular disease in patients with T2DM. These findings provide valuable insights to guide clinicians in preventing and managing cardiovascular disease in this population.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945234","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

Diclofenac Enhances the Response of BRAF Inhibitor to Melanoma Through ROS/p38/p53 Signaling 双氯芬酸通过ROS/p38/p53信号通路增强BRAF抑制剂对黑色素瘤的应答

IF 2.9 4区医学

Clinical and Experimental Pharmacology and Physiology Pub Date : 2025-01-09 DOI: 10.1111/1440-1681.70022

Haihong Qin, Zheng Li, Jinfeng Wu, Xiao Liu, Ruilong Wang, Jinhua Xu, Xiaohua Zhu

{"title":"Diclofenac Enhances the Response of BRAF Inhibitor to Melanoma Through ROS/p38/p53 Signaling","authors":"Haihong Qin, Zheng Li, Jinfeng Wu, Xiao Liu, Ruilong Wang, Jinhua Xu, Xiaohua Zhu","doi":"10.1111/1440-1681.70022","DOIUrl":"10.1111/1440-1681.70022","url":null,"abstract":"<div>\u0000 \u0000 <p>BRAF inhibitors (BRAFi) represent a cornerstone in melanoma therapy due to their high efficacy. However, the emergence of resistance causes a significant challenge to their clinical utility. This study aims to investigate the potential of diclofenac as a sensitizer for BRAFi therapy in melanoma and to elucidate its underlying mechanism. BRAFi-acquired resistant melanoma cell lines SK-MEL-5R and A375R were established and treated with diclofenac in combination with BRAFi PLX4032. Cell viability was assessed using the MTT assay, cell proliferation was determined by crystal violet staining, cell apoptosis was evaluated by flow cytometry, and intracellular ROS levels were measured using the DCFH-DA probe-labeled and flow cytometry. Mitochondrial membrane potential was assessed by JC-1 staining and flow cytometry, and protein expression levels were detected by western blotting. Our results demonstrated that diclofenac significantly augmented the cytotoxicity of PLX4032 and enhanced its ability to induce apoptosis in SK-MEL-5R and A375R cells. Diclofenac treatment led to the release of intracellular reactive oxygen species (ROS), consequently reducing transmembrane potential, promoting mitochondrial apoptosis, and activating the ROS downstream p38/p53 signaling pathway. Pretreatment with N-acetylcysteine significantly reversed the sensitizing effect of diclofenac on PLX4032 in SK-MEL-5R cells. These findings suggested that diclofenac sensitized BRAFi-resistant melanoma cells to BRAFi by increasing ROS release and activating p38/p53 signaling pathway. Diclofenac might serve as a promising adjunct therapy to overcome BRAFi resistance in melanoma treatment.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945242","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

Restoring Autophagy by Exercise Ameliorates Insulin Resistance Partly via Calcineurin-Driven TFEB Nuclear Translocation 运动恢复自噬部分通过钙调神经蛋白驱动的TFEB核易位改善胰岛素抵抗。

IF 2.9 4区医学

Clinical and Experimental Pharmacology and Physiology Pub Date : 2025-01-09 DOI: 10.1111/1440-1681.70010

Ping Wang, Jiaxin Li, Chun Guang Li, Xian Zhou, Xiaolong Chen, Minghua Zhu, Hongjiang Wang

{"title":"Restoring Autophagy by Exercise Ameliorates Insulin Resistance Partly via Calcineurin-Driven TFEB Nuclear Translocation","authors":"Ping Wang, Jiaxin Li, Chun Guang Li, Xian Zhou, Xiaolong Chen, Minghua Zhu, Hongjiang Wang","doi":"10.1111/1440-1681.70010","DOIUrl":"10.1111/1440-1681.70010","url":null,"abstract":"<div>\u0000 \u0000 <p>Exercise activates autophagy and lysosome system in skeletal muscle, which are known to play an important role in metabolic adaptation. However, the mechanism of exercise-activated autophagy and lysosome system in obese insulin resistance remains covert. In this study, we investigated the role of exercise-induced activation of autophagy and lysosome system in improving glucose metabolism of skeletal muscle. Male C57BL/6 mice were randomly divided into five groups: the chow diet (CD) group, the high-fat diet (HFD) group, the high-fat diet plus exercise (HFD-E) group and the HFD-E treated with calcineurin inhibitor FK506 (HFD-E-F) or saline (HFD-E-S) groups. The mice in exercise groups (HFD-E, HFD-E-F and HFD-E-S) were subjected to aerobic treadmill exercise (speed at 12 m/min for 1 h per session, 0° slope, 5 days per week for 12 weeks). Mice of HFD-E-F group were intraperitoneally administered FK506 (1 mg/kg), once each day for 2 weeks before the end of exercise. Expressions pTFEB, T-TFEB and autophagy–lysosome markers, including Beclin1, LC3, ULK1, SQSTM1, LAMP1, CTSD and CTSL proteins in gastrocnemius muscle were analysed. We demonstrated that HFD induced insulin resistance and decreased autophagy-lysosomal proteins and the exercise significantly increased transcription factor EB (TFEB) translocation from the cytoplasm to the nucleus, restored the impaired autophagy-lysosomal-related protein expressions, and improved glucose metabolism. The increase in TFEB nuclear translocation was partly blocked by the calcineurin inhibitor FK506. Our results suggest that exercise promotes autophagy and lysosome restoration by regulating calcineurin-mediated TFEB nuclear translocation, ultimately alleviating HFD-induced insulin resistance in mice skeletal muscle.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945557","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

Sirt6, Deubiquitinated and Stabilised by USP9X, Takes Essential Actions on the Pathogenesis of Experimental Autoimmune Myasthenia Gravis by Regulating CD4+ T Cells 被USP9X去泛素化并稳定的Sirt6通过调节CD4+ T细胞在实验性自身免疫性重症肌无力发病机制中发挥重要作用

IF 2.9 4区医学

Clinical and Experimental Pharmacology and Physiology Pub Date : 2025-01-05 DOI: 10.1111/1440-1681.70018

Chen Xie, Hong-Lian Zhang, Jun Yuan, Ye Zhang, Yang-Chun Liu, Quan Xu, Li-Ru Chen

{"title":"Sirt6, Deubiquitinated and Stabilised by USP9X, Takes Essential Actions on the Pathogenesis of Experimental Autoimmune Myasthenia Gravis by Regulating CD4+ T Cells","authors":"Chen Xie, Hong-Lian Zhang, Jun Yuan, Ye Zhang, Yang-Chun Liu, Quan Xu, Li-Ru Chen","doi":"10.1111/1440-1681.70018","DOIUrl":"10.1111/1440-1681.70018","url":null,"abstract":"<div>\u0000 \u0000 <p>Myasthenia gravis (MG) presents with symptoms that significantly affect patients' daily lives. Long-term MG therapies may lead to substantial side effects, predominantly due to prolonged immune suppression. Sirt6, which plays a vital role in maintaining cellular homeostasis and is recognised for its involvement in cytokine production in immune cells, has not yet been explored in relation to MG. PBMCs and CD4<sup>+</sup> T cells were isolated from blood samples. RT-qPCR, western blot and ELISA were used to assess the expression of target genes and proteins. Flow cytometry was used to identify the subsets of T helper cells. Co-IP was conducted to investigate the interaction between USP9X and Sirt6. Finally, the experimental autoimmune myasthenia gravis (EAMG) model was established. In MG patients, Sirt6 levels were downregulated compared to healthy controls. Sirt6 overexpression led to a reduction in Th1 and Th17 cell populations while augmenting Treg cells in PBMCs. USP9X interacted with Sirt6, leading to its deubiquitination and stabilisation. Elevated Sirt6 levels subsequently mitigated symptoms in the EAMG model. The stabilisation of Sirt6, mediated by USP9X, has been found to relieve symptoms of EAMG by influencing the subtypes of T helper cells. This highlights the promising potential of Sirt6 as a viable therapeutic target in the treatment of MG.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930713","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

Phillygenin Inhibits PI3K-Akt–mTOR Signalling Pathway to Prevent bleomycin-Induced Idiopathic Pulmonary Fibrosis in Mice philygenin抑制PI3K-Akt-mTOR信号通路预防博莱霉素诱导的小鼠特发性肺纤维化

IF 2.9 4区医学

Clinical and Experimental Pharmacology and Physiology Pub Date : 2025-01-02 DOI: 10.1111/1440-1681.70017

Yongjia Wei, Wenting Ni, Lizhi Zhao, Yanhong Gao, Bing Zhou, Qun Feng, Yun Ma, Limin Wang

{"title":"Phillygenin Inhibits PI3K-Akt–mTOR Signalling Pathway to Prevent bleomycin-Induced Idiopathic Pulmonary Fibrosis in Mice","authors":"Yongjia Wei, Wenting Ni, Lizhi Zhao, Yanhong Gao, Bing Zhou, Qun Feng, Yun Ma, Limin Wang","doi":"10.1111/1440-1681.70017","DOIUrl":"10.1111/1440-1681.70017","url":null,"abstract":"<div>\u0000 \u0000 <p>Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterised by irreversible lung structure and function. Phillygenin (PHI) is a lignan extracted from Forsythiae fructus with the activities of anti-inflammatory and antioxidant. This study aimed to explore the protective effect of PHI on IPF. The mouse model of IPF was established by bleomycin (BLM), and then treated with PHI. After 15 days of administration, the lung index was calculated. H&E staining, Masson staining and immunohistochemical methods were used to detect the effect of PHI on pulmonary fibrosis. MDA and SOD were tested to evaluate the effect of PHI on lung tissue oxidative stress. Western blot was used to detect the effect of PHI on the expressions of α-SMA, p-smad2, TGF- β1, Nrf2, HO-1 and NQO-1. Network pharmacology was used to identify the key signalling pathways for PHI to improve IPF, and Western blot was used to validate the result. The results showed that PHI prevented mice from BLM-induced IPF, manifested by reducing lung index, improving lung tissue pathological damage, inhibiting collagen deposition and expression of fibrosis markers including α-SMA, collagen1, p-smad2 and TGF-β1. PHI inhibited oxidative stress by upregulating the expressions of Nrf2, HO-1 and NQO-1. Network pharmacology revealed that PI3K-Akt–mTOR signalling pathway was the underlying target of PHI for IPF. Molecular docking indicated strong binding of PHI with PIK3CA, AKT1 and RELA. Western blot validated that PHI downregulated the PI3K-Akt–mTOR signalling pathway and stimulated autophagy. This study indicated that PHI prevented BLM-induced pulmonary fibrosis by inhibiting PI3K-Akt–mTOR signalling pathway.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920804","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

High Salt Exacerbates Myocardial Dysfunction In Vitro and In Vivo by Promoting SIRT1/Nrf2-Mediated Ferroptosis 高盐通过促进SIRT1/Nrf2介导的铁氧化作用加剧体外和体内心肌功能障碍

IF 2.9 4区医学

Clinical and Experimental Pharmacology and Physiology Pub Date : 2024-12-29 DOI: 10.1111/1440-1681.70016

Wu Guanji, Liu Fuqiang, You Fei, Tao Zhang, Chen Xiaolin

{"title":"High Salt Exacerbates Myocardial Dysfunction In Vitro and In Vivo by Promoting SIRT1/Nrf2-Mediated Ferroptosis","authors":"Wu Guanji, Liu Fuqiang, You Fei, Tao Zhang, Chen Xiaolin","doi":"10.1111/1440-1681.70016","DOIUrl":"10.1111/1440-1681.70016","url":null,"abstract":"<div>\u0000 \u0000 <p>Myocardial dysfunction is a crucial determinant of the development of heart failure in salt-sensitive hypertension. Ferroptosis, a programmed iron-dependent cell death, has been increasingly recognised as an important contributor to the pathophysiology of various cardiovascular diseases. This study aims to investigate the role and underlying mechanism of ferroptosis in high-salt (HS)-induced myocardial damage. Our results reveal that HS stimulation inhibited cell proliferation and promoted apoptosis in cardiomyocyte HL-1 cells in a dose-dependent manner. Ferroptotic features were observed in HS-induced HL-1 cells, including ferric iron accumulation, decreased glutathione levels, increased oxidative stress levels, upregulation of ferroptosis marker proteins PTGS2, 4HNE and FTH1 and downregulation of GPX4, all of which were reversed by treatment with the ferroptosis suppressor Fer-1. Furthermore, the administration of Fer-1 ameliorated HS-induced ferroptosis and myocardial damage in salt-sensitive Dahl SS rats. Additionally, we found that a HS diet suppressed the SIRT1/Nrf2 signalling pathway activation in our in vivo experiments. Activation of SIRT1/Nrf2 signalling by SIRT1 overexpression significantly attenuated ferroptosis in HS-induced HL-1 cells. In conclusion, our findings demonstrate that HS levels induce myocardial injury by promoting ferroptosis via the deactivation of the SIRT1/Nrf2 signalling pathway, highlighting the potential for therapeutic targeting of ferroptosis for hypertension-related cardiovascular disorders.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902682","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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