European journal of pharmacology最新文献

{"title":"Protective effects and mechanism of quercetin from Rhododendron dauricum against cerebral ischemia-reperfusion injury","authors":"Fang Fang ,&nbsp;Siwei Bao ,&nbsp;Danxia Chen ,&nbsp;Xiaofeng Duan ,&nbsp;Yuefen Zhao ,&nbsp;Yabin Ma","doi":"10.1016/j.ejphar.2024.177126","DOIUrl":"10.1016/j.ejphar.2024.177126","url":null,"abstract":"<div><h3>Methods</h3><div>This study seeks to identify the bioactive compounds within Rhododendron dauricum and explore potential mechanisms for treating cerebral I/R injury through a comprehensive analysis employing network pharmacology, complemented by experimental validation.</div></div><div><h3>Results</h3><div>The core targets associated with quercetin in the treatment of cerebral I/R injury are TNF-α, IL-6, IL-1β, and AKT1. Notably, we propose for the first time that its mode of action primarily involves the inhibition of the TNF-α/RhoA/ROCK2 pathway.</div></div><div><h3>Conclusion</h3><div>Our findings reveal that quercetin emerges as a pivotal bioactive component of Rhododendron dauricum in the context of cerebral I/R injury treatment.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177126"},"PeriodicalIF":4.2,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142616725","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A combination of peripherally restricted CB1 and CB2 cannabinoid receptor agonists reduces bladder afferent sensitisation in cystitis","authors":"Stewart Ramsay,&nbsp;Wai Ping Yew,&nbsp;Simon Brookes,&nbsp;Vladimir Zagorodnyuk","doi":"10.1016/j.ejphar.2024.177078","DOIUrl":"10.1016/j.ejphar.2024.177078","url":null,"abstract":"<div><div>Cannabinoid agonists can potentially ameliorate lower urinary tract symptoms (LUTS), including pain associated with interstitial cystitis/bladder pain syndrome (IC/BPS). This study aims to determine the contributions of the cannabinoid 1 receptors (CB₁Rs) and CB₂Rs in regulating the activity of different functional classes of afferents, comparing normal healthy bladder with bladders from guinea pigs with protamine/zymosan-induced cystitis. The mechanosensitivity of different functional afferent classes was determined by <em>ex vivo</em> single-unit extracellular recordings.</div><div>Peripherally restricted CB₁R preferential agonists, ACEA and PrNMI and peripherally restricted CB₂R selective agonists, 4Q3C and olorinab all reduced the mechanosensitivity of mucosal bladder afferents. The potency and efficacy of these synthetic cannabinoid agonists were significantly increased in cystitis compared to controls. Combined application of CB₁R agonists, ACEA or PrNMI with the CB₂R agonist, 4Q3C produced additive inhibitory effects. ACEA and PrNMI also inhibited the stretch-induced firing of high-threshold muscular bladder afferents in animals with cystitis. In contrast, low- and high-threshold muscular-mucosal bladder afferents were unaffected by the CB₁R and CB₂R agonists in control and cystitis. Our data indicated that peripherally restricted CB₁R and CB₂R agonists effectively reduce the sensitisation of probable nociceptive afferents in the bladder in cystitis. The findings also suggest a potential benefit of simultaneously targeting both the CB₁Rs and CB₂Rs to ameliorate LUTS in cystitis.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177078"},"PeriodicalIF":4.2,"publicationDate":"2024-11-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Metformin inhibits migration and epithelial-to-mesenchymal transition in non-small cell lung cancer cells through AMPK-mediated GDF15 induction","authors":"Hongyu Zhou ,&nbsp;Jun Xiao ,&nbsp;Qi Cheng,&nbsp;Wen Wang,&nbsp;He Peng,&nbsp;Xiaojian Lin,&nbsp;Jiajun Chen,&nbsp;Xingya Wang","doi":"10.1016/j.ejphar.2024.177127","DOIUrl":"10.1016/j.ejphar.2024.177127","url":null,"abstract":"<div><div>The growth differentiation factor 15 (GDF15) may serve as a biomarker of metformin, which mediates the bodyweight lowering effect of metformin. However, whether GDF15 also serves as a molecular target of metformin to inhibit carcinogenesis remains largely unknown. This study examined the role and molecular mechanisms of GDF15 in the anticancer effects of metformin in non-small cell lung cancer (NSCLC) cells, which has never been reported before. We found that metformin significantly inhibited the migration of NSCLC A549 and NCI-H460 cells and reduced the expression of epithelial-to-mesenchymal transition (EMT)-related molecules, including neuro-cadherin (N-cadherin), matrix metalloproteinase 2 (MMP2), and the zinc finger transcription factor Snail, but increased epithelial cadherin (E-cadherin) expression. Furthermore, metformin increased GDF15 and its upstream transcription factors activated transcription factor 4 (ATF4) and C/EBP-homologous protein (CHOP) expressions and increased AMP-activated protein kinase (AMPK) phosphorylation in NSCLC cells. GDF15 siRNA partially reverses the inhibitory effect of metformin on NSCLC cell migration. Moreover, metformin-induced increases in GDF15, CHOP, and ATF4 expression and the inhibition of migration were partially reversed by treatment with Compound C, a specific AMPK inhibitor. Meanwhile, metformin significantly inhibited NCI-H460 xenograft tumor growth in nude mice, increased GDF15 expression, and regulated EMT- and migration-related protein expression in xenograft tumors. In conclusion, our results provide novel insights into revealing that GDF15 can serve as a potential molecular target of metformin owing to its anti-cancer effect in NSCLC, which is mediated by AMPK activation.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177127"},"PeriodicalIF":4.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leukemia inhibitory factor receptor inhibition by EC359 reduces atherosclerotic stenosis grade in Ldlr−/− mice","authors":"Esmeralda Hemme ,&nbsp;Marie A.C. Depuydt ,&nbsp;Peter J. van Santbrink ,&nbsp;Anouk Wezel ,&nbsp;Harm J. Smeets ,&nbsp;Amanda C. Foks ,&nbsp;Johan Kuiper ,&nbsp;Ilze Bot","doi":"10.1016/j.ejphar.2024.177121","DOIUrl":"10.1016/j.ejphar.2024.177121","url":null,"abstract":"<div><div>Cytokines are involved in all stages of atherosclerosis, generally contributing to disease progression. Previously, members of the Interleukin (IL)-6 cytokine family, such as IL-6, oncostatin M, and cardiotrophin-1, have been extensively studied in atherosclerosis. However, the role of leukemia inhibitory factor (LIF), member of the IL-6 family, and its receptor (LIFR), remains to be further elucidated. Therefore, the aim of this study is to provide insight in LIF receptor signalling in atherosclerosis development.</div><div>Single-cell RNA sequencing analysis of human carotid artery plaques revealed that mast cells highly express <em>LIF</em>, whereas <em>LIFR</em> was specifically expressed on activated endothelial cells. A similar expression pattern of <em>Lifr</em> was observed in mouse atherosclerotic plaques. Next, female Western-type diet fed <em>Ldlr</em>^−/− mice were treated with LIF receptor inhibitor EC359 (5 mg/kg s.c., n = 15) or control solvent (n = 15) three times per week for eight weeks. Stenosis grade was reduced in the aortic root of EC359 treated mice compared to control mice, but treatment did not affect plaque composition. Serum cholesterol levels were significantly reduced in EC359 treated mice, likely attributed to a reduction in VLDL cholesterol levels. Furthermore, LIF receptor inhibition reduced <em>Pecam1</em> and <em>Vcam1</em> expression in the aorta. Consequently, immune cell infiltration was reduced in aortic plaques of EC359 treated mice compared to control mice.</div><div>Conclusively, we demonstrated that LIF receptor is a potential therapeutic target in atherosclerosis by reducing plaque size, attributed to lower serum cholesterol levels, reduced endothelial activation and less immune cell infiltration in the plaque.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177121"},"PeriodicalIF":4.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of lysophosphatidic acid receptor 2 attenuates neonatal chronic lung disease in mice by preserving vascular and alveolar development","authors":"Xueyu Chen ,&nbsp;Dongshan Han ,&nbsp;Yali Zeng ,&nbsp;Huitao Li ,&nbsp;Xuan Wang ,&nbsp;Zilu Huang ,&nbsp;Lingling Yang ,&nbsp;Gerry T.M. Wagenaar ,&nbsp;Bingchun Lin ,&nbsp;Chuanzhong Yang","doi":"10.1016/j.ejphar.2024.177120","DOIUrl":"10.1016/j.ejphar.2024.177120","url":null,"abstract":"<div><h3>Aim</h3><div>Bronchopulmonary dysplasia (BPD) is a common morbidity in extremely premature infants. Previous studies demonstrated the important role of lysophosphatidic acid (LPA) in inflammation in BPD. However, the role of LPA and its receptors in hyperoxia-induced vascular malformations in BPD remains to be elucidated.</div></div><div><h3>Methods and results</h3><div>Elevated plasma LPA levels were observed in mice with BPD compared to controls (792 vs. 607 ng/mL, p &lt; 0.05). Inhibition of LPA signaling protected against hyperoxia-induced lung injury in neonatal mice, demonstrated by a 2.8-fold increase in pulmonary vascular density and a 14% reduction in alveolar enlargement. <em>In vitro</em> studies showed that LPA suppressed tube formation in human umbilical vein endothelial cells (HUVECs) by approximately 50%. LPA receptor 2 (LPA₂) was identified as a functional LPA receptor in primary endothelial cells from the lungs of hyperoxic mice and in HUVECs under hyperoxic conditions. The LPA₂ antagonist H2L5186303 enhanced the tube formation ability of HUVECs exposed to LPA, both under normoxia (4-fold) and hyperoxia (5-fold). Moreover, H2L5186303 significantly protected against hyperoxia-induced vascular malformation (2-fold) and improved alveolarization in neonatal mice (12% decrease in mean linear intercept, MLI). Early growth response 1 (EGR1) was characterized as a downstream target of LPA₂, silencing EGR1 restored tube formation in HUVECs exposed to LPA and hyperoxia.</div></div><div><h3>Conclusions</h3><div>Our <em>in vitro</em> and <em>in vivo</em> findings demonstrate that the inhibition of LPA/LPA₂ signaling mitigates hyperoxia-induced pulmonary vascular malformations, suggesting the LPA/LPA₂-dependent signaling pathway has therapeutic potential for extremely premature infants with BPD.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177120"},"PeriodicalIF":4.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of GB1107, a novel galectin-3 inhibitor on pro-fibrotic signalling in the liver.","authors":"Alison C MacKinnon, Duncan C Humphries, Kimberley Herman, James A Roper, Ian Holyer, Joseph Mabbitt, Ross Mills, Ulf J Nilsson, Hakon Leffler, Anders Pedersen, Hans Schambye, Fredrik Zetterberg, Robert J Slack","doi":"10.1016/j.ejphar.2024.177077","DOIUrl":"10.1016/j.ejphar.2024.177077","url":null,"abstract":"<p><strong>Background and purpose: </strong>Galectin-3 (Gal-3) is a pro-fibrotic β-galactoside binding lectin highly expressed in fibrotic liver and implicated in hepatic fibrosis. GB1107 is a novel orally active Gal-3 small molecule inhibitor that has high affinity for Gal-3 >1000-fold selectively over other galectins. The aim of this study was to characterise GB1107 and galectin-3 in vitro and in vivo in the context of fibrosis signalling and liver disease.</p><p><strong>Experimental approach: </strong>Liver fibrosis was induced by administration of CCl₄ twice weekly by intraperitoneal injection in mice for 8 weeks. GB1107 was orally administered once daily (10 mg/kg) for the last 4 weeks of CCl₄ treatment. Fibrosis was assessed by picrosirius red staining of FFPE sections. Liver enzymes, Gal-3 and downstream biomarkers were assessed in liver and plasma. Paired-end sequencing was performed on the Nextseq 2000 platform. Pathway enrichment analysis was performed to determine enrichment of differentially expressed genes (DEGs) within Reactome pathways and Gene Ontology (GO) terms.</p><p><strong>Key results: </strong>GB1107 significantly reduced plasma transaminases and liver Gal-3 and reduced liver fibrosis. RNAseq analysis of whole liver showed that 1659 DEGs were identified with CCl₄ treatment compared to control. Pathways enriched in up-regulated genes in the CCl₄ group included those related to the extracellular matrix, collagen biosynthesis and assembly, cell cycle and the immune system. Comparing GB1107 treatment with CCl₄ control 1147 DEGs were identified. GB1107 effectively reversed the majority of the CCl₄ induced gene changes.</p><p><strong>Conclusions and implications: </strong>GB1107 attenuated liver fibrosis and highlights Gal-3 as a therapeutic target for hepatic fibrosis.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177077"},"PeriodicalIF":4.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epac1 activation optimizes cellular functions of BMSCs and promotes wound healing via Erk/ACLY/PGC-1α signaling pathway.","authors":"Xujie Wang, Kuo Shen, Yan Li, Kejia Wang, Mengdong Liu, Yage Shang, Mengyang Li, Hao Zhang, Hao Guan, Juntao Han, Dahai Hu","doi":"10.1016/j.ejphar.2024.177124","DOIUrl":"10.1016/j.ejphar.2024.177124","url":null,"abstract":"<p><p>Restrained cell function of relocated bone marrow mesenchymal stem cells (BMSCs) largely impedes the clinical benefits of BMSCs-mediated tissue repair. Exchange protein directly activated by cAMP (Epac), a novel protein discovered in cAMP signaling pathway, has a potential role in regulating cell migration and proliferation by triggering the downstream Rap signaling. However, whether and how Epac may exert effects on BMSCs' bioactivity have less been investigated. Here we showed that Epac1 was predominantly expressed in BMSCs and Epac1 activation by 8-pCPT enhanced BMSCs proliferation. 8-pCPT also altered F-actin cytoskeleton and promoted BMSCs migration. By contrast, Epac1 inhibitor ESI-09 resulted in retarded cell migration in 8-pCPT-treated BMSCs. Epac1 activation was further found to be contributed directly to the chemotactic responses induced by CXCL12. The proteomic analysis revealed that ACLY expression significantly increased and Chemokine signaling pathway was robustly activated in 8-pCPT-treated BMSCs. In addition, 8-pCPT up-regulated the protein levels of active Rap1, p-Erk, p-ACLY, VEGF-A and PGC-1α in BMSCs; however, ESI-09 prevented the increase of p-Erk, VEGF-A and PGC-1α induced by 8-pCPT, but further enhanced the p-ACLY level, which consequently stimulated an apoptosis signal as revealed by increased caspase-3 cleavage. Notably, 8-pCPT promoted VEGF paracrine of BMSCs. Finally, we demonstrated that 8-pCPT-treated BMSCs accelerated the cutaneous wound healing process in a mice wound model, while treatment with ESI-09 obviously inhibited these effects. In conclusion, this study suggests that appropriate manipulation of Epac1 may enhance the therapeutic effects of BMSCs and facilitate their future clinical applications in tissue repair.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177124"},"PeriodicalIF":4.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Trifolin attenuates hypertension-mediated cardiac injury by inhibiting cardiomyocyte apoptosis: Mechanistic insights and therapeutic potential","authors":"Fu Zhang ,&nbsp;Zhi Guo ,&nbsp;Meizhu Wu ,&nbsp;Guosheng Lin ,&nbsp;Hong Chen ,&nbsp;Huifang Zheng ,&nbsp;Dandan Zhang ,&nbsp;Miaomiao Jiang ,&nbsp;Yi Xie ,&nbsp;Youqin Chen ,&nbsp;Dawei Lian ,&nbsp;Aling Shen ,&nbsp;Jun Peng","doi":"10.1016/j.ejphar.2024.177125","DOIUrl":"10.1016/j.ejphar.2024.177125","url":null,"abstract":"<div><h3>Background</h3><div>Hypertension-induced cardiac disease is a common complication and a significant contributor to mortality in hypertensive patients, largely due to cardiomyocyte apoptosis. Although Trifolin has been identified as a potential antihypertensive compound, its therapeutic role in hypertension-induced cardiac injury remains uncertain.</div></div><div><h3>Purpose</h3><div>This study aims to evaluate the protective effects of Trifolin and explore the underlying mechanisms of its action against hypertension-induced cardiac injury.</div></div><div><h3>Methods</h3><div><em>In vivo</em>, mice were infused with Angiotensin II (AngII, 500 ng/kg/min) or saline via osmotic pumps and treated with Trifolin (0.1, 1.0, or 10.0 mg/kg/day) or Valsartan (10 mg/kg/day) for four weeks. <em>In vitro</em>, H9C2 cells were stimulated with AngII (1 μM) and treated with Trifolin (25, 50, or 100 μM). Various assays, including echocardiography, hematoxylin and eosin staining, TUNEL assay, Annexin-V/propidium iodide staining, and JC-1 staining, were used to assess Trifolin's therapeutic effects on hypertension-related cardiac injury and cardiomyocyte apoptosis. Potential pharmacological mechanisms were analyzed through network pharmacology and confirmed via Western blotting.</div></div><div><h3>Results</h3><div>Trifolin treatment improved cardiac function by increasing left ventricular ejection fraction and fractional shortening while reducing tissue disorganization in AngII-treated mice. It also reduced cardiomyocyte apoptosis, reversing the upregulation of Bax and cleaved caspase-3 and the downregulation of Bcl-2. Network pharmacology identified 314 common targets of Trifolin linked to hypertensive heart disease, with involvement in apoptosis, MAPK, PI3K/AKT, and HIF-1 signaling pathways. Trifolin treatment increased p-PI3K/PI3K and p-AKT/AKT ratios while decreasing p-ERK/ERK, p-p38 MAPK/p38 MAPK, and p-JNK/JNK ratios in both mouse and cell models.</div></div><div><h3>Conclusion</h3><div>Trifolin alleviates AngII-induced cardiac injury and cardiomyocyte apoptosis, potentially through the regulation of MAPK, PI3K/AKT, and HIF-1 signaling pathways.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177125"},"PeriodicalIF":4.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142615403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baicalin attenuates corticosterone-induced hippocampal neuronal injury by activating mitophagy in an AMPK-dependent manner","authors":"Yuan Liu ,&nbsp;Xiaohui Jin ,&nbsp;Caiyin Li ,&nbsp;Jingjing Bu ,&nbsp;Baoying Wang ,&nbsp;Ming Bai ,&nbsp;Pan Su ,&nbsp;Erping Xu ,&nbsp;Yucheng Li","doi":"10.1016/j.ejphar.2024.177091","DOIUrl":"10.1016/j.ejphar.2024.177091","url":null,"abstract":"<div><div>Defective mitophagy is closely related to the neuronal dysfunction and major depressive disorder (MDD). Our previous study found that baicalin could enhance nip-like protein (NIX)-mediated mitophagy and exhibit antidepressant effects, and predicted that AMPK may be the pharmacological target of baicalin. However, validated experiments are lacking. In the present study, we first demonstrated the effect of baicalin on hippocampal NIX-mediated mitophagy in CORT-induced depressive mice. Secondly, we transfected siRNA to knockdown AMPK, PGC-1α, and NIX respectively in HT22 cells, and detected the effects of baicalin on mitochondrial function, AMPK/PGC-1α/NIX pathway protein expression and mitophagy levels. Finally, AAV-shAMPKα was injected into hippocampal CA3 to knockdown AMPK in mice to validate the antidepressant effects of baicalin in vivo. The results showed that CORT induced depressive-like behaviors, accompanied with neuronal damage, mitochondrial injury, and inhibited mitophagy in the hippocampus, which were prevented by baicalin (20 mg/kg) treatment. In HT22 cells, baicalin remarkably ameliorated mitochondrial dysfunction and mitophagy disturbance induced by CORT, and these protective effects of baicalin were blocked by knockdown of AMPK, PGC-1α and NIX. Moreover, the beneficial effects of baicalin on depressive-like behaviors and NIX-mediated mitophagy were suppressed by knockdown of AMPKα in mice. Our present results further demonstrated that baicalin promotes NIX-mediated mitophagy and improves depression in an AMPK-dependent manner.</div></div>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":"985 ","pages":"Article 177091"},"PeriodicalIF":4.2,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617405","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteomic Alteration in Catalpol Treatment of Alzheimer's disease by regulating HSPA5/ GPX4.","authors":"Leiyu Tian, Hongwei Li, Wei Xiong, Xia Li, Shaobin Duan, Chengzhi Yang, Changhua Shi","doi":"10.1016/j.ejphar.2024.177075","DOIUrl":"https://doi.org/10.1016/j.ejphar.2024.177075","url":null,"abstract":"<p><p>Alzheimer's disease (AD), a chronic and progressive neurodegenerative disease, is characterized by the deposition of extracellular amyloid plaques and intracellular neurofibrillary tangles. Conventional anti-AD drugs exhibit high toxicity and adversely impact patients' quality of life. Therefore, novel treatments for AD are urgently required. In recent years, targeting ferroptosis through the modulation of lipid oxidation has emerged as a new approach in the treatment of neurodegenerative diseases. Catalpol, an iridoid glycoside isolated from the roots of Rehmannia glutinosa, has exhibited anti-inflammatory, antioxidant, and neuroprotective properties. Therefore, in this study, we investigated the protective effects and associated underlying mechanisms of catalpol in an APP/PS1 AD mouse model. Catalpol treatment significantly improved the cognitive capabilities and decreased Aβ_1-40 and Aβ_1-42 levels in mice. Morphological testing revealed that catalpol prevented neuronal loss and reduced mitochondrial swelling in the hippocampal CA1 region. Proteomic studies identified 2,495 hippocampus proteins whose expression was associated with the mechanism of catalpol treatment, including 44 ferroptosis-related proteins. Bioinformatic analysis revealed that catalpol significantly increased the protein levels of HSPA5 and GPX4 in the hippocampus. Additionally, catalpol modulated biological pathways related to apoptosis, cytokine-mediated signaling, and ferroptosis. The considerable upregulation of HSPA5 and GPX4 with catalpol was further confirmed through western blotting. Catalpol exhibited neuroprotective effects through a variety of mechanisms. Among these, HSPA5 and GPX4, associated with ferroptosis, may play key roles in AD pathogenesis, and present promising therapeutic targets.</p>","PeriodicalId":12004,"journal":{"name":"European journal of pharmacology","volume":" ","pages":"177075"},"PeriodicalIF":4.2,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142617512","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}