Clinical and Experimental Pharmacology and Physiology最新文献

{"title":"Tabersonine Alleviates Cerebral Ischemia/Reperfusion Injury Partly via Repressing the SLC6A2/NF-κB Signalling Pathway","authors":"Li Zhang,&nbsp;Liji Chen,&nbsp;Juhua Chen,&nbsp;Xuehua Ge,&nbsp;Yingchun Yu,&nbsp;Panpan Sun,&nbsp;Yonglan Ruan","doi":"10.1111/1440-1681.70101","DOIUrl":"10.1111/1440-1681.70101","url":null,"abstract":"<div>\u0000 \u0000 <p>The study aimed to investigate the neuroprotective functions and the underlying regulatory mechanisms of Tabersonine in cerebral ischemia/reperfusion (I/R) injury. Oxygen–glucose deprivation/reoxygenation (OGD/R)-treated neural cells were used as a cell model under I/R context. Cell counting kit 8 (CCK8) assay and enzyme-linked immunosorbent assay (ELISA) were used to assess the cell viability and the release levels of inflammatory cytokines (interleukin-1β (IL-1β), IL-6 and tumour necrosis factor α (TNF-α)) of treated neural cells. The apoptotic proportions of treated neural cells were analysed by flow cytometry, and the intracellular levels of reactive oxygen species (ROS) and superoxide dismutase (SOD) were quantified by corresponding kits. In this study, molecular docking analysis identified solute carrier family 6 member 2 (SLC6A2) as a potential target of Tabersonine in cerebral infarction, demonstrating a high binding affinity of −7.4 kcal/mol. Tabersonine treatment increased neural cell viability, repressed apoptosis and reduced the release levels of IL-1β, IL-6 and TNF-α under OGD/R stress. Moreover, Tabersonine treatment reduced ROS levels and increased SOD expression in neural cells under OGD/R treatment. In contrast to the protective effect of SLC6A2 knockdown, its overexpression counteracted the neuroprotection conferred by Tabersonine. Tabersonine also inactivated the NF-κB pathway partially via SLC6A2. Furthermore, Tabersonine pretreatment demonstrated significant neuroprotective effects in MCAO/R rats, as evidenced by reduced brain edema and attenuated neural inflammation and apoptosis. In conclusion, Tabersonine can alleviate neural impairment in cerebral I/R injury partially by inactivating the NF-κB pathway through SLC6A2.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145905874","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":"Cellular Pharmacology of Bupivacaine in Lung Fibroblasts: Role of Intracellular Calcium Signalling and Chelation","authors":"Wei-Zhe Liang,&nbsp;Gwo-Ching Sun","doi":"10.1111/1440-1681.70078","DOIUrl":"10.1111/1440-1681.70078","url":null,"abstract":"<div>\u0000 \u0000 <p>Bupivacaine, a commonly used aminoamide local anaesthetic, exerts cellular effects beyond anaesthesia. However, its effects on calcium (Ca²⁺) signalling and the physiological responses of lung fibroblasts remain insufficiently characterised. This study aimed to determine whether bupivacaine disrupts intracellular Ca²⁺ homeostasis and induces cytotoxicity in IMR-90 human foetal lung fibroblasts via Ca²⁺-dependent mechanisms. Cell viability was assessed using the CCK-8 assay, and intracellular Ca²⁺ levels ([Ca²⁺]ᵢ) were monitored in fura-2-loaded cells. Pharmacological inhibitors were used to dissect the signalling pathways involved. Bupivacaine (20–60 μM) caused a concentration-dependent rise in [Ca²⁺]ᵢ and a corresponding decline in cell viability. These effects were significantly attenuated by pre-treatment with the Ca²⁺ chelator BAPTA-AM, indicating a Ca²⁺-dependent cytotoxic mechanism. Mechanistically, bupivacaine induced Ca²⁺ influx through store-operated Ca²⁺ entry (SOCE), involving protein kinase C (PKC), and triggered Ca²⁺ release from the endoplasmic reticulum (ER) via a phospholipase C (PLC)-dependent pathway. Mn²⁺ quenching assays confirmed SOCE as the primary route of Ca²⁺ entry. Bupivacaine disrupts Ca²⁺ signalling through both extracellular influx and intracellular release, contributing to pulmonary cytotoxicity. These findings underscore the relevance of Ca²⁺ homeostasis in anaesthetic-related lung injury and suggest that Ca²⁺ chelation may be a potential protective strategy.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145862307","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":"METTL3-Mediated m6A Modification Facilitates pri-miR-221 Maturation to Regulate Macrophage M1/M2 Polarisation and Immune Inflammation in Rheumatoid Arthritis","authors":"Xiangping Gong,&nbsp;Wei Li,&nbsp;Xiaohui Wu,&nbsp;Lirong Mao","doi":"10.1111/1440-1681.70099","DOIUrl":"10.1111/1440-1681.70099","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>Rheumatoid arthritis (RA) pathogenesis involves dysregulated macrophage polarisation, yet the epigenetic mechanisms governing this process remain poorly understood. This study investigates how METTL3 promotes pri-miR-221 maturation via m6A modification to regulate macrophage M1/M2 polarisation and immune inflammation in RA.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>METTL3 mRNA levels in serum from RA patients and healthy controls were detected by RT-qPCR and their correlations with C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were analysed. Peripheral blood mononuclear cells (PBMCs) were isolated, differentiated into macrophages and assessed for METTL3 expression using RT-qPCR and Western blot. M1/M2 polarisation was evaluated via marker genes (iNOS, Arg-1) and released cytokines (IL-6, TNF-α for M1; TGF-β1, IL-10 for M2) using Western blot and ELISA, and verified by immunofluorescence (CD68+/CD86+ for M1; CD68+/CD206+ for M2). Methylated RNA immunoprecipitation and RNA stability assays were used to identify METTL3-mediated m6A modification of pri-miR-221, while RNA immunoprecipitation was conducted to confirm YTHDF1/2/3-pri-miR-221 interactions. In vivo, a rat RA model was established, with METTL3 expression and ankle pathology analysed via immunohistochemistry, haematoxylin–eosin and Safranin O-fast green staining.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>METTL3 was significantly upregulated in RA serum, isolated PBMCs and derived macrophages, positively correlating with CRP and ESR. METTL3 knockdown in macrophages reduced M1 markers and increased M2 markers, indicating METTL3 knockdown promoted M2 polarisation and inhibited M1 polarisation. METTL3 stabilised pri-miR-221 via m6A, and pri-miR-221 overexpression reversed the effect of METTL3 knockdown on M2 polarisation. In RA rats, METTL3 was elevated, exacerbating ankle joint destruction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>METTL3 knockdown suppresses m6A-dependent pri-miR-221 maturation, rebalancing macrophage polarisation and attenuating ankle joint destruction in RA.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145803325","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":"Bharangin, A Diterpenoid, Enhances the Sensitivity of Pancreatic Cancer Cells to Gemcitabine Through Involvement of Long Non-Coding RNAs and Nuclear Factor-κB","authors":"Nikee Awasthee,&nbsp;Anusmita Shekher,&nbsp;Ankit Srivastava,&nbsp;Subash Chandra Gupta","doi":"10.1111/1440-1681.70097","DOIUrl":"10.1111/1440-1681.70097","url":null,"abstract":"<div>\u0000 \u0000 <p>Pancreatic cancer (PaCa) manifests as an aggressive tumour due to the late occurrence of early symptoms. The overall 5-year survival rate of PaCa is merely 2%–9%. Bharangin (BG), a diterpenoid quinonemethide known for its anti-cancer activities, was investigated in a preclinical PaCa model. A dose- and time-dependent suppression in the viability of PaCa cells was observed by BG. The diterpenoid suppressed the level of tumorigenic proteins in PaCa cells. As evident from phosphatidylserine externalisation, acridine orange (AO)/propidium iodide (PI) staining, cell cycle analysis and DNA laddering, BG was found to induce apoptosis in PaCa cells. An accumulation in the sub-G1 population was observed by BG. The diterpenoid induced depolarization in the mitochondrial membrane potential and enhanced the PaCa cells' sensitivity to gemcitabine (GEM). The cancer-associated lncRNAs were also modulated by both BG and GEM in PaCa cells. BG also suppressed the p65 nuclear translocation induced by TNF-α in PaCa cells. Overall, BG exhibits activities in PaCa cells. The suppression of NF-κB activation and the modulation of lncRNAs expression may provide a basis for further exploration of BG as a therapeutic agent in PaCa.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145707607","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":"COX17 Attenuates Diabetes-Associated Retinal Injury by Improving Mitochondrial Function","authors":"Hai-Yan Lian,&nbsp;Zhen-De Deng,&nbsp;Ming Yan,&nbsp;Zhen Huang,&nbsp;Ya Ye,&nbsp;Yan-Ping Song","doi":"10.1111/1440-1681.70098","DOIUrl":"10.1111/1440-1681.70098","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>Diabetic retinopathy (DR), a common complication of diabetes, is a leading cause of blindness globally. Cytochrome C oxidase copper chaperone (COX17) is important for Cytochrome C oxidase assembly, and COX17 overexpression is reported to improve mitochondrial function in renal tissue. This study aimed to explore whether COX17 alleviated DR by regulating mitochondrial function.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Diabetes was induced in rats by a single intraperitoneal injection of 65 mg/kg streptozotocin (STZ). Overexpression of COX17 was performed by infection of adeno-associated virus into the vitreous body of rats 2 weeks after STZ injection. Human retinal microvascular endothelial cells (HRMECs) were cultured with high-glucose (HG) medium (20 mM <span>d</span>-glucose). Immunofluorescence assay, enzymatic histochemistry assay, CCK-8 assay, DCFH-DA staining, flow cytometry, western blot, and real-time PCR were performed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>COX17 expression was decreased in the retinal tissues of diabetic rats and HG-stimulated HRMECs. COX17 overexpression alleviated retinal neovascularisation and increased retinal thickness in diabetic rats. COX17 overexpression decreased ROS and apoptosis and increased Cytochrome C oxidase activity, mtDNA copy number, ATP content, and mitochondrial membrane potential (MMP) in both the retinal tissues of diabetic rats and HG-induced HRMECs. Overexpression of COX17 effectively reduced cell apoptosis and increased cell viability. Overexpression of COX17 increased mtDNA in HG-induced HRMECs.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Overall, our study suggested that COX17 overexpression exerted protective effects in the retinas of diabetic rats and in HRMECs by stabilising mitochondrial function.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145676550","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":"Esculin Facilitates Aerobic Glycolysis via the Wnt/β-Catenin/HIF-1α Pathway to Reduce the Progression of Gastric Cancer","authors":"Qing Shang,&nbsp;Jing Wang,&nbsp;Xiaolei Wang,&nbsp;Haipeng Wang","doi":"10.1111/1440-1681.70096","DOIUrl":"10.1111/1440-1681.70096","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Gastric cancer (GC) is a complex pathogenesis closely related to various signalling pathways. Esculin, as a natural compound, possesses anti-oxidation, anti-inflammatory, and anti-tumour influences, and has shown promising application prospects in research on colorectal cancer (CRC) and others. However, the specific impact of Esculin on GC remains unclear. This article explores the action mechanism of Esculin in gastric cancer, which not only helps to understand its anti-cancer properties but may also offer novel approaches and strategies for treating GC.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Using the CCK-8 method to screen the concentration of Esculin that does not affect the viability of normal gastric mucosal cells GES-1. At this concentration, the changes in viability, proliferation level, migration ability, invasion ability, and apoptosis level of HGC-27 and AGS were measured. The levels of related proteins were detected through Western blot. Subsequent use of the glycolysis inhibitor 3-BrPA, the Wnt signalling pathway activator SKL2001, and the inhibitor LiCl interfered with GC cells. The impact of Esculin on aerobic glycolysis in cells was assessed by measuring glucose uptake levels, pyruvate production levels, lactate generation levels, ATP production levels, and extracellular acidification rate (ECAR). The regulatory effect of Esculin on the Wnt/β-catenin/HIF-1α pathway was evaluated through immunofluorescence and Western blot. Injecting HGC-27 cells to build a xenograft tumour model and evaluating the effect of Esculin gavage on tumour growth in mice.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Esculin at concentrations of 0, 20, 40, and 80 μM is non-toxic to GES-1. An increase in the concentration of Esculin correlates with a continuous decline in the viability of four GC cell lines, with GC cells showing the highest significance. The levels of proliferation, migration, and invasion in both cell lines significantly decrease with increasing concentrations of Esculin, while the apoptosis rate significantly increases. 80 μM of Esculin can significantly inhibit glucose absorption, pyruvate production, lactate, and ATP generation in cells, leading to a significant decrease in ECAR; at the same time, it significantly inhibits the expression of proteins in the Wnt/β-catenin/HIF-1α signalling pathway. Administering 20 mg/kg of Esculin by gavage can significantly suppress tumour growth in mice, concurrently leading to a reduction of proteins associated with the Wnt/β-catenin/HIF-1α pathway within the tumour tissue.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusion&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Esculin inhibit","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667250","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":"METTL14 Inhibits Human Lung Microvascular Endothelial Cell From Ferroptosis in Septic Lung Injury by Regulating N6-Methyladenosine-Modified ACSL4 Level","authors":"Xiao Gui,&nbsp;Yongyang Tian,&nbsp;Haiyuan Zhu,&nbsp;Lilin Wang,&nbsp;Jinhui Wang,&nbsp;Ruimiao Wu,&nbsp;Fangzhou Gan","doi":"10.1111/1440-1681.70095","DOIUrl":"https://doi.org/10.1111/1440-1681.70095","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>N⁶-methyladenosine (m⁶A) RNA modification is involved in numerous physiological and pathological processes. However, the specific role of m⁶A modification in septic lung injury remains unknown.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Here, caecal ligation and puncture (CLP) operation was performed to induce septic lung injury in mice, and the establishment of the animal model was verified by haematoxylin and eosin (H&amp;E) staining of lung tissues. The mRNA levels of m⁶A writers in blood samples from septic lung injury model mice were assessed. The intracellular concentrations of Fe²⁺, glutathione (GSH), malondialdehyde (MDA) and reactive oxygen species (ROS) were quantified to evaluate ferroptosis in HULEC-5a cells. In addition, the mitochondrial ultrastructure of HULEC-5a cells was observed by transmission electron microscopy (TEM). The MeRIP assay was performed to detect the m⁶A modification of ACSL4 mRNA. The binding of ACSL4 to METTL14 was verified using RIP and dual luciferase gene reporter assays.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>In this study, METTL14 was identified as aberrantly downregulated in septic lung injury models. Highly expressed METTL14 significantly protected HULEC-5a cells from LPS-induced ferroptosis. Meanwhile, METTL14 increased m⁶A methylation of ACSL4 mRNA and inhibited ACSL4 mRNA levels by suppressing its stability. Mechanistically, METTL14 mediates the m⁶A modification of ACSL4 in a manner dependent on the m⁶A reader protein YTHDC1. These findings support a role for METTL14-mediated modification of ACSL4 and the subsequent suppression of ferroptosis in the pathogenesis of septic lung injury.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our data support that ferroptosis-induced damage is a pathogenic event during septic lung injury and that targeting METTL14 may have therapeutic potential for the treatment of septic lung injury.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145619281","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":"Apelin-13 Attenuates Right Ventricular Hypertrophy and Pulmonary Fibrosis in a Monocrotaline Model of Pulmonary Hypertension","authors":"Önder Öztürk,&nbsp;Rahime Aslankoc,&nbsp;Mustafa Saygın,&nbsp;Ozlem Ozmen,&nbsp;Yusuf. S. Sirin,&nbsp;Oguzhan Kavrik","doi":"10.1111/1440-1681.70094","DOIUrl":"https://doi.org/10.1111/1440-1681.70094","url":null,"abstract":"<div>\u0000 \u0000 <p>Pulmonary hypertension (PH) is a progressive and fatal disease characterised by pulmonary vascular remodelling, right ventricular hypertrophy, and increased pulmonary arterial pressure. Apelin, an endogenous ligand of the APJ receptor, exerts cardioprotective and vasoprotective effects and has been proposed as a potential therapeutic agent in PH. This study aimed to investigate the therapeutic effects of Apelin-13 on hemodynamic, histomorphological, and molecular alterations in a monocrotaline (MCT)-induced PH rat model. Male Wistar rats were divided into four groups: control, MCT, MCT + Apelin-13, and sham-Apelin. A single intraperitoneal injection of MCT (60 mg/kg) was used to induce PH. Apelin-13 was administered intraperitoneally for 21 days. Hemodynamic parameters (<i>P</i>_max, <i>P</i>_min, mPAP, EDP, <i>dP</i>/<i>dt</i>_max, <i>dP</i>/<i>dt</i>_min, MAP), morphometric indices (RVHI, PAWTR, PAVR), histological and immunohistochemical analyses (Apelin-13, ACE, Caspase-3, IL-1β) were evaluated. MCT administration significantly increased pulmonary arterial pressure, right ventricular hypertrophy, and vascular wall thickness, while reducing Apelin-13 and ACE expression and elevating Caspase-3 and IL-1β levels. Apelin-13 treatment markedly attenuated these pathological alterations by lowering right ventricular overload, improving vascular remodelling, restoring Apelin-13 and ACE expression, and reducing apoptotic and inflammatory markers. Apelin-13 exerts multifaceted protective effects in MCT-induced PH by modulating hemodynamic load, vascular structure, and inflammatory-apoptotic pathways. These findings provide novel evidence supporting Apelin-13 as a promising therapeutic candidate for PH and warrant further studies to explore its long-term efficacy and translational potential.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572275","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":"In Vitro Antibacterial Activity of Myxin Against Mycobacterium abscessus","authors":"Zihao Liu,&nbsp;Xiaoyu Wan,&nbsp;Anqi Li,&nbsp;Zhili Tan,&nbsp;Siyuan He,&nbsp;Yaping Jia,&nbsp;Yani Lin,&nbsp;Rong li,&nbsp;Yuheng Qian,&nbsp;Liyun Xu,&nbsp;Bing Li","doi":"10.1111/1440-1681.70091","DOIUrl":"https://doi.org/10.1111/1440-1681.70091","url":null,"abstract":"<div>\u0000 \u0000 <p>Nontuberculous mycobacteria (NTM) infections, especially those caused by <i>Mycobacterium abscessus</i>, are extremely difficult to treat due to the organisms' intrinsic resistance to many antimicrobials. Myxin is a naturally occurring phenazine-5,10-dioxide antibiotic from <i>Sorangium</i> sp., notable for its broad-spectrum antimicrobial activity. In this study, we determined the susceptibilities of Myxin against 11 NTM reference strains and 194 clinical <i>M. abscessus</i> isolates using microdilution assays. Additionally, time-kill kinetic experiments were performed to distinguish the clearing efficiency of Myxin in broth. We also evaluated the efficacy of Myxin against intracellular <i>M. abscessus</i> in THP-1 macrophages. Checkerboard assays assessed the interactions between Myxin and eight clinically important anti-NTM antibiotics. Myxin demonstrated potent activity against <i>M. abscessus</i> with low MIC values (MIC₅₀ = 0.125 mg/L and MIC₉₀ = 0.5 mg/L). Treatment with 20 × MIC of Myxin in 7H9 broth resulted in up to 10 log₁₀ CFU/mL reduction after 4 days of incubation. An intracellular concentration-dependent bactericidal effect of Myxin was observed in THP-1 macrophages. Myxin exhibited no antagonism in combination with standard anti-NTM drugs. As such, Myxin represents a promising candidate for the treatment of <i>M. abscessus</i> and other NTM infections.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572558","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":"Dexmedetomidine Alleviates Sleep Rhythm Abnormalities in Chronic Sleep-Deprived Mice via Modulation of SIK3/HDAC4/5 Signalling","authors":"Zhengye Wang,&nbsp;Yitong Ding,&nbsp;Yonghong Zhou,&nbsp;Zhouquan Wu","doi":"10.1111/1440-1681.70086","DOIUrl":"https://doi.org/10.1111/1440-1681.70086","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Sleep deprivation (SD) often disrupts normal sleep patterns, leading to anxiety-like behaviours and cognitive impairments. Dexmedetomidine (DEX), a highly selective α-2 adrenergic agonist, has been reported to improve postoperative sleep quality and alleviate cognitive deficits. Evidence indicates that DEX can regulate the expression of histone deacetylase 5 (HDAC5), a substrate of the sleep-regulating molecule salt-inducible kinase 3 (SIK3). However, its specific role and the underlying mechanisms in regulating sleep structure remain unclear. This study aims to examine DEX's effects and potential mechanisms in regulating sleep structure in sleep-deprived mice.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>C57BL/6J mice were subjected to chronic sleep deprivation (CSD) for 20 h (from 5 to 1 PM the next day), followed by administration of DEX at 1 and 3 PM daily for 7 consecutive days. Emotional behaviours were evaluated using the open-field test. Sleep patterns were assessed during the recovery period using EEG/EMG. Golgi-Cox staining was used to determine neuronal dendritic damage. Western blotting was employed to detect the SIK3/HDAC4/5 pathway-related protein levels.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CSD disrupted the sleep structure of mice during the recovery period and induced anxiety-like behaviour and neuronal dendritic damage. DEX administration alleviated the above effects caused by CSD. Mechanistically, DEX activated SIK3/HDAC4/5 signalling in CSD mice, while inhibition of SIK3 with a specific inhibitor attenuated DEX's effects on the pathway activation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>DEX can alleviate sleep rhythm disturbances caused by CSD in mice possibly via modulation of the SIK3/HDAC4/5 pathway, thereby improving anxiety-like behaviours and cognitive function.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"53 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2025-11-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145572276","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}