Clinical and Experimental Pharmacology and Physiology最新文献

{"title":"A Novel Inhibitor of Methyltransferase SMYD2, AZ505 Protects Against Peritoneal Fibrosis in Mice","authors":"Taijing Xu,&nbsp;Binbin Cui,&nbsp;Feng Liu,&nbsp;Mengjun Liu,&nbsp;Xiying Hou,&nbsp;Xuan Hong,&nbsp;Hualin Qi","doi":"10.1111/1440-1681.70035","DOIUrl":"https://doi.org/10.1111/1440-1681.70035","url":null,"abstract":"<p>AZ505, a highly selective inhibitor of SMYD2, exhibits an antifibrotic effect in renal fibrosis. Its effect on peritoneal fibrosis remains unexplored. In this study, we investigated its effects on the development of peritoneal fibrosis induced by chlorhexidine gluconate (CG) in a murine model. We found that SMYD2 and trimethylated histone substrate H3K36 (H3K36me3) were highly expressed in the peritoneal tissue following CG injection, and administration of AZ505 remarkably inhibited their expression, along with attenuating CG–induced peritoneal fibrosis and expression of collagen I and fibronectin. Moreover, AZ505 also significantly reduced expression of CD31 (marker of angiogenesis) and CD68-positive macrophage infiltration in the CG-injured peritoneum. AZ505 further inhibited CG-induced epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells, manifested by decreasing expression of α-smooth muscle antigen (α-SMA) and Vimentin and restoring E-cadherin expression, accompanied by suppressing expression of two transcription factors, Snail and Twist. Finally, AZ505 inhibited CG-induced phosphorylation of AKT and increased expression of phosphatase and tensin (PTEN), a key phosphatase. These data suggest that AZ505 may protect against peritoneal fibrosis by inhibiting EMT, inflammation and angiogenesis, due to its blockade of methylation modification catalysed by SMYD2.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 7","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/1440-1681.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135790","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}

{"title":"MRGPRX2-Mediated Mast Cell Degranulation by Monomethyl Methacrylate: Unveiling a Pathway in Bone Cement Implantation Syndrome","authors":"Yasuyuki Suzuki,&nbsp;Liu Shuang,&nbsp;Erika Takemasa,&nbsp;Yasushi Takasaki,&nbsp;Toshihiro Yorozuya,&nbsp;Masaki Mogi","doi":"10.1111/1440-1681.70046","DOIUrl":"https://doi.org/10.1111/1440-1681.70046","url":null,"abstract":"<div>\u0000 \u0000 <p>Bone cement implantation syndrome is a critical complication of orthopaedic surgery, characterised by hypotension and hypoxemia. This syndrome is hypothesised to result from obstruction caused by fat droplets and the biochemical release of histamine caused by bone cement components. This study aimed to elucidate the histamine release mechanism, focusing on Mas-related G protein-coupled receptor X2 expressed on mast cells, which is hypothesised to be activated by bone cement components. Using a mast cell-deficient mouse femur fracture model, we examined bone cement's effect on serum histamine. Rat basophil-like cells expressing Mas-related G protein-coupled receptor X2 were exposed to monomethyl methacrylate, a bone cement component, to assess degranulation via <i>β</i>-hexosaminidase release. Our findings demonstrated that histamine levels significantly increased in wild-type mice post-cement application, from 27.7 ± 11.1 to 35.3 ± 12.9 ng/mL (<i>p</i> = 0.016). Furthermore, Mas-related G protein-coupled receptor X2 expressing cells showed a marked increase in <i>β</i>-hexosaminidase release upon monomethyl methacrylate stimulation (<i>p</i> = 4.30 × 10⁻⁵). These results support the hypothesis that activating Mas-related G protein-coupled receptor X2 by monomethyl methacrylate contributes to bone cement implantation syndrome via histamine release. Bone cement implantation syndrome can manifest as a condition involving either peripheral vascular embolism, the release of chemical mediators, or a combination of both. Our research elucidates the role of chemical mediators, particularly histamine-induced vasodilation, in the pathophysiology of bone cement implantation syndrome, providing valuable insights that pave the way for targeted interventions to mitigate this severe complication during orthopaedic surgery.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 7","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143944933","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}

{"title":"Sepsis Important Genes Identification Through Biologically Informed Deep Learning and Transcriptomic Analysis","authors":"Ruichen Li,&nbsp;Qiushi Wang,&nbsp;Ru Gao,&nbsp;Rutao Shen,&nbsp;Qihao Wang,&nbsp;Xiuliang Cui,&nbsp;Zhiming Jiang,&nbsp;Lijie Zhang,&nbsp;Jingjing Fang","doi":"10.1111/1440-1681.70031","DOIUrl":"https://doi.org/10.1111/1440-1681.70031","url":null,"abstract":"<div>\u0000 \u0000 <p>Sepsis is a life-threatening disease caused by the dysregulation of the immune response. It is important to identify influential genes modulating the immune response in sepsis. In this study, we used P-NET, a biologically informed explainable artificial intelligence model, to evaluate the gene importance for sepsis. About 688 important genes were identified, and these genes were enriched in pathways involved in inflammation and immune regulation, such as the PI3K-Akt signalling pathway, necroptosis and the NF-κB signalling pathway. We further selected differentially expressed genes both at bulk and single-cell levels and found TIMP1, GSTO1 and MYL6 exhibited significant different expressions in multiple cell types. Moreover, the expression levels of these 3 genes were correlated with the abundance of important immune cells, such as M-MDSC cells. Further analysis demonstrated that these three genes were highly expressed in sepsis patients with worse outcomes, such as severe, non-survived and shock sepsis patients. Using a drug repositioning strategy, we found navitoclax, curcumin and rotenone could down-regulate and bind to these genes. In conclusion, TIMP1, GSTO1 and MYL6 may serve as promising biomarkers and targets for sepsis treatment.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 7","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143939433","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}

{"title":"A Comment About Methodological Limitations on the Study by An et al.","authors":"Büyükcavlak Mustafa","doi":"10.1111/1440-1681.70047","DOIUrl":"https://doi.org/10.1111/1440-1681.70047","url":null,"abstract":"<div>\u0000 \u0000 <p>The study by An et al. provides valuable insights into rocuronium pharmacodynamics in patients with high body fat percentages (PBF). However, the lack of normalisation for acceleromyographic train-of-four (TOF) ratios raises concerns about the validity of endpoints. Due to the acceleromygraph's inherent “inverse fade” artefact, non-normalised TOF ratios may mask clinically significant residual paralysis. For example, a reported TOF of 0.9 could correspond to a true ratio of 0.75 (assuming a baseline of 1.2), overestimating recovery. This methodological gap weakens the study's conclusion on fat-free mass-based dosing advantages in high-PBF patients. Future studies should adopt TOF normalisation or electromyography (EMG)-based monitoring to improve accuracy and patient safety. Addressing this limitation would strengthen the clinical applicability of individualised neuromuscular blocking strategies.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 7","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143938998","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}

{"title":"NOTIFICATION: MiR-375-3p/YWHAZ/β-catenin Axis Regulates Migration, Invasion, EMT in Gastric Cancer Cells","authors":"","doi":"10.1111/1440-1681.70045","DOIUrl":"https://doi.org/10.1111/1440-1681.70045","url":null,"abstract":"<p>\u0000 <b>NOTIFICATION:</b> <span>F. Guo</span>, <span>Y. Gao</span>, <span>G. Sui</span>, <span>D. Jiao</span>, <span>L. Sun</span>, <span>Q. Fu</span>, and <span>C. Jin</span>, “ <span>MiR-375-3p/YWHAZ/β-catenin Axis Regulates Migration, Invasion, EMT in Gastric Cancer Cells</span>,” <i>Clinical and Experimental Pharmacology and Physiology</i> <span>46</span>, no. <span>2</span> (<span>2019</span>): <span>144</span>–<span>152</span>, https://doi.org/10.1111/1440-1681.13047.\u0000 </p><p>This notification is for the above article, published online on 24 October 2018 in Wiley Online Library (wileyonlinelibrary.com), and has been issued by agreement between the journal Editor-in-Chief, Yang Yang; and John Wiley &amp; Sons Australia Ltd. This notification has been issued in response to concerns raised by third parties [<span>1</span>]. The article mentions a non-verifiable cell line identifier, “MGC-823” in relation to Figure 1C. Within the figure, the cell line identifier is spelled “MGC-803”, which describes a verified cell line (RRID: CVCL_5334). As the authors could not be reached to clarify this discrepancy, the journal has decided to publish this notification to inform and alert readers.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/1440-1681.70045","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143888852","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}

{"title":"Reliability of Matrix-Assisted Laser Desorption-Ionisation Time-of-Flight Mass Spectrometry as a Method for Drug-Resistant Tuberculosis Gene Identification","authors":"Kaishun Zhao,&nbsp;Wei Wei,&nbsp;Lijia Yang,&nbsp;Wei Chen,&nbsp;Haiying Liang,&nbsp;Ye Jin,&nbsp;Yameng Sun,&nbsp;Jun Xu,&nbsp;Yanfang Yu","doi":"10.1111/1440-1681.70038","DOIUrl":"https://doi.org/10.1111/1440-1681.70038","url":null,"abstract":"<div>\u0000 \u0000 <p>Instances of drug-resistant tuberculosis (TB), particularly multidrug- and extensive drug-resistant TB, are escalating worldwide; therefore, there is an urgent need to explore suitable treatment strategies. This study assessed the precision of matrix-assisted laser desorption-ionisation time-of-flight mass spectrometry (MALDI-TOF MS) in detecting drug-resistant TB. We developed a multiplex MALDI-TOF MS detection assay that concurrently identifies 51 gene mutations for six commonly used medications: rifampicin (RFP), isoniazid (INH), levofloxacin (LVX), moxifloxacin (MOX), capreomycin (CPM) and amikacin (AMK). Subsequently, we evaluated the accuracy of the system by testing clinical sputum samples with known (<i>n</i> = 45) and unknown (<i>n</i> = 254) minimum inhibitory concentrations (MICs), using Sanger-sequenced genes as references. The detection system exhibited a minimum sensitivity of 88.00% and a specificity of 95.24% for the 45 known isolates. Similarly, for the 254 unknown samples, the detection system demonstrated sensitivity and specificity for mutations associated with each medication as follows: RFP—sensitivity: 98.97%, specificity: 99.36%; INH—sensitivity: 97.80%, specificity: 100.00%; LVX and MOX—sensitivity: 97.14%, specificity: 100.00%; AMK and CPM—sensitivity: 100.00%, specificity: 100.00%. The unknown samples also displayed favourable sensitivity and specificity values in the MIC validation as follows: RFP—sensitivity: 92.39%, specificity: 92.59%; INH—sensitivity: 75.21%, specificity: 99.27%; LVX—sensitivity: 75.28%, specificity: 99.39%; MOX—sensitivity: 73.24%, specificity: 91.26%; AMK—sensitivity: 94.87%, specificity: 96.74%; CPM—sensitivity: 89.47%, specificity: 95.83%. Meanwhile, our study allows for the identification of the <i>Mycobacterium tuberculosis</i> complex (MTBC). The MALDI-TOF MS exhibited remarkable accuracy in the detection of drug-resistant TB, making it a potential alternative approach for clinical TB diagnosis.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871469","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}

{"title":"Alpha-Linolenic Acid for Mitigating Neuroinflammation and Dopaminergic Neuronal Loss in Parkinson's Disease: Insights From In Vivo and In Silico Studies","authors":"Mahnoor,&nbsp;Sarwat Jahan,&nbsp;Laila Elahi,&nbsp;Muhammad Zakria,&nbsp; Rabia,&nbsp;Muhammad Ikram,&nbsp;Najeeb Ullah","doi":"10.1111/1440-1681.70043","DOIUrl":"https://doi.org/10.1111/1440-1681.70043","url":null,"abstract":"<div>\u0000 \u0000 <p>Parkinson's disease (PD) is a progressive neurodegenerative disorder characterised by dopaminergic neuronal loss and chronic neuroinflammation, leading to significant motor and non-motor deficits. This study explores the therapeutic potential of alpha-linolenic acid (ALA), a known antioxidant and anti-inflammatory agent, in a lipopolysaccharide (LPS)-induced murine model of PD. Male Balb-C mice were divided into control, LPS-treated, LPS + ALA-treated and ALA-only groups. Behavioural assessments, including the pole test, rotarod test and open field test, revealed significant motor impairments in LPS-treated mice. Co-treatment with ALA partially ameliorated motor deficits in LPS-treated mice compared to the healthy control group. However, no direct comparison was made with standard PD treatments such as levodopa. Immunohistochemistry analysis showed a 68% reduction in tyrosine hydroxylase-positive (TH+) neurons in the substantia nigra pars compacta (SNpc) of LPS-treated mice. Notably, ALA co-treatment preserved dopaminergic neurons, demonstrating its neuroprotective effects. Western blotting and ELISA revealed heightened expression of inflammatory mediators, including TNF-α, IL-1β and NF-κB, in LPS-treated mice. ALA treatment significantly reduced these markers, indicating its capacity to mitigate neuroinflammation. Molecular docking analysis revealed moderate binding affinities of ALA to NF-κB (−5.1 kcal/mol), TNF-α (−5.7 kcal/mol) and IL-1β (−3.9 kcal/mol), suggesting possible interactions with key inflammatory pathways. These interactions were comparable to known inhibitors, indicating ALA's potential for neuroprotection. This study highlights the neuroprotective and anti-inflammatory effects of ALA in reducing dopaminergic neuronal loss and mitigating neuroinflammation in an LPS-induced PD model. Although behavioural improvements were moderate, these findings underscore ALA's potential as an adjunct therapeutic candidate for PD and other neurodegenerative diseases. Further research is warranted to explore its translational applications in clinical settings.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143865971","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}

{"title":"Sex Steroid Control of Serotonergic System: Clinical Implications for Psychiatric Disorders and Addiction Treatment","authors":"Lien-Chung Wei,&nbsp;Hsien-Jane Chiu","doi":"10.1111/1440-1681.70044","DOIUrl":"https://doi.org/10.1111/1440-1681.70044","url":null,"abstract":"<div>\u0000 \u0000 <p>The seminal work by Fink et al. on sex steroid regulation of mood, cognition, and memory has profound implications for understanding sex differences in psychiatric disorders and addiction treatment. Their findings that estradiol upregulates serotonin transporter (SERT) and 5-HT2A receptor expression, along with testosterone's reliance on aromatisation for its serotonergic effects, highlight key neurobiological mechanisms underlying psychiatric conditions. These insights are particularly relevant to addiction medicine, given serotonin's modulatory role in reward pathways and substance use disorders. Recent research by Gu et al. has demonstrated that estradiol reduces serotonin reuptake by downregulating the plasma membrane monoamine transporter (PMAT) through oestrogen receptor beta (ERβ) and MAPK/ERK signalling pathways, further elucidating the neurochemical underpinnings of mood disorders. Additionally, testosterone's effects on serotonergic regulation are dependent on its conversion to estradiol via aromatase, which influences the expression of SERT and 5-HT2A receptors in critical brain regions. This process may explain sex differences in psychiatric disorders and treatment responses, particularly in mood disorders and substance use disorders. From a clinical perspective, understanding aromatase activity's role in modulating serotonergic pathways may aid in predicting treatment responses, particularly for male patients undergoing testosterone replacement therapy. Furthermore, targeting ERβ as a potential treatment strategy could provide novel therapeutic avenues for managing depression and substance use disorders in women experiencing hormonal fluctuations. These findings underscore the importance of sex-specific considerations in psychiatric and addiction treatment paradigms.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143861962","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}

{"title":"The Rough Morphotype of Mycobacterium abscessus Enhances Its Virulence Through ROS/p65/NLRP3/GSDMD-Mediated Macrophage Pyroptosis","authors":"Jingren Li,&nbsp;Juan Li,&nbsp;Anqi Li,&nbsp;Zhili Tan,&nbsp;Junsheng Fan,&nbsp;Siyuan He,&nbsp;Qi Guo,&nbsp;Liyun Xu,&nbsp;Haiqing Chu","doi":"10.1111/1440-1681.70034","DOIUrl":"https://doi.org/10.1111/1440-1681.70034","url":null,"abstract":"<div>\u0000 \u0000 <p>The rough morphotype of <i>Mycobacterium abscessus</i> exhibits significantly higher virulence compared to the smooth morphotype, yet the underlying molecular mechanisms remain incompletely understood. Pyroptosis in macrophages plays a pivotal role in lung tissue damage; however, its specific involvement in <i>Mycobacterium abscessus</i> infection remains to be fully clarified. In this study, we identified that the rough morphotype of <i>Mycobacterium abscessus</i> upregulates the ROS/p65/NLRP3/GSDMD signalling pathway, thereby mediating pyroptosis in THP-1-derived macrophages. This heightened ability to induce macrophage pyroptosis is attributed to the bacterium's capacity to sustain intracellular viability and proliferation. These findings offer valuable insights into the virulence mechanisms of <i>Mycobacterium abscessus</i> and provide a foundation for future therapeutic interventions.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143849300","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}

{"title":"Endothelin System Blockade Extenuates Sepsis-Induced Acute Heart and Kidney Injuries via Modulating ET-1/Klotho/p38-MAPK","authors":"Alaa Al-kadi,&nbsp;Aliaa F. Anter,&nbsp;Remon Roshdy Rofaeil,&nbsp;Mohamed M. Sayed-Ahmed,&nbsp;Sara Mohamed Naguib Abdel Hafez,&nbsp;Al-Shaimaa F. Ahmed","doi":"10.1111/1440-1681.70042","DOIUrl":"https://doi.org/10.1111/1440-1681.70042","url":null,"abstract":"<div>\u0000 \u0000 <p>Sepsis-induced organ failure is a major health problem, characterised by massive inflammatory and oxidative stress responses. Endothelin-1 (ET-1) is one of the peptides expressed during septicemia with proapoptotic, proinflammatory, and oxidant effects. ET-1 plays a role in heart and kidney injuries in sepsis. Accordingly, the current study was conducted to investigate, on a mechanistic basis, whether inhibition of ET-1 signalling either by blocking its receptors or inhibiting its formation attenuates sepsis-induced acute cardiorenal injuries. To analyse the role of ET-1 in sepsis, we used a cecal ligation and puncture (CLP) model of sepsis. The animals were divided into five groups: CLP non-treated group, CLP-treated groups with bosentan, ambrisentan, and phosphoramidon (30, 5, and 0.5 mg/kg, respectively), and sham-operated group. In addition to the same set of groups, survival analysis was assigned Survival rate, histopathological assessment, and cardiorenal functions were analysed. Oxidant and antioxidant activities, ET-1, IL-6, and lactate were measured. The expression of TNF-α, p38, Klotho, and caspase-3 was evaluated by immunohistochemistry. CLP caused acute cardiorenal damage, high mortality, upregulated levels of ET-1, IL-6, and lactate, as well as an imbalance in oxidant/antioxidant activities, elevated expression of TNF-α, p38, caspase-3 and reduced expression of klotho. Bosentan, ambrisentan, or phosphoramidon improved survival, reduced the levels of inflammatory and oxidative stress parameters, improved cardiorenal functions and structure, elevated the tissue contents of GSH and SOD, raised the expression of klotho protein, and reduced the cardiorenal expression of p38, TNF-α and caspase-3. Endothelin receptor antagonists (ERAs); bosentan and ambrisentan, or endothelin converting enzyme inhibitor (ECE-i) phosphoramidon, are promising agents against sepsis-induced organ damage. This was evident in their cardiorenal protective effects, up-regulation of klotho, suppression of inflammation, oxidation, apoptosis, and enhancement of the antioxidant status.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143831234","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}