Clinical and Experimental Pharmacology and Physiology最新文献

{"title":"Plasma IL4 Levels Linked to Pulmonary Hypertension Severity and Outcome","authors":"Yun Li, Yi Liu, Zhanping Liang, Shuying Jia, Yuyan Liu, Jinling Li, Jinming Liu, Jingyun Shi, Ping Yuan, Jie Zhu, Xiaohuan Xia, Jialin C. Zheng","doi":"10.1111/1440-1681.70040","DOIUrl":"https://doi.org/10.1111/1440-1681.70040","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The anti-inflammatory cytokine interleukin-4 (IL4) has been recognised as a protective factor in various cardiovascular events, yet its prognostic value in patients with pulmonary hypertension (PH) remains unclear. The study aimed to measure the levels of plasma IL4 in patients with PH and to explore their potential association with disease risk and outcomes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this observational study, we analysed the levels of plasma IL4 in 766 PH patients and 191 healthy controls in Shanghai Pulmonary Hospital from October 2009 to January 2024. To establish the correlations between plasma IL4 levels and the risk and outcomes of PH, all patients were followed up from June 2013 to June 2024. The Spearman correlation test was employed to evaluate the relationships between IL4 and right heart catheterisation parameters among patients with PH. Receiver operating characteristic (ROC) curves were generated to evaluate the diagnostic performance of IL4 for PH. The Cox proportional hazards models and Kaplan–Meier survival curves were used to assess the prognostic value of IL4 levels. Logistic regression analysis was performed to predict PH incidence. A nomogram was constructed to predict mortality, and its clinical utility was validated using decision curve analysis (DCA).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Plasma IL4 levels were significantly decreased in patients with PH compared with controls (<i>p</i> < 0.001), as well as in different PH groups (<i>p</i> < 0.05 for all). The logistic regression analyses indicated that the lower IL4 levels were associated with the high risk of PH (OR = 0.79, 95% CI: 0.716–0.872; <i>p</i> < 0.001). IL4 levels correlated inversely with NT-proBNP (<i>r</i> = −0.10, <i>p</i> < 0.05) and mPAP (<i>r</i> = −0.01, <i>p</i> < 0.05), and positively with CI (<i>r</i> = 0.12, <i>p</i> < 0.05) and PaSaO2 (<i>r</i> = 0.11, <i>p</i> < 0.05), indicating an association with disease severity. Kaplan–Meier analysis revealed that patients with IL4 ≥ 2.8774 pg/mL had a 3-year cumulative survival rate of 91.28%, compared with 82.83% for those with IL4 < 2.8774 pg/mL (log–rank <i>p</i> = 0.007). Cox regression confirmed IL4 as an independent predictor of survival (HR = 0.810, 95% CI: 0.660–0.993; <i>p</i> = 0.043). A diagnostic model combining IL4, 6MWD and NT-proBNP demonstrated good prognostic value (AUC = 0.692, <i>p</i> < 0.0001).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Plasma IL4 levels were significantly decreased in p","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 6","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/1440-1681.70040","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143818509","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":"Electroacupuncture Attenuates Cerebral Ischemia–Reperfusion Injury by Inhibiting Ferroptosis via the p53/SLC7A11 Pathway","authors":"Ziwen Hou,&nbsp;Yaoyao Liu,&nbsp;Qi Wang,&nbsp;Peng Li","doi":"10.1111/1440-1681.70036","DOIUrl":"https://doi.org/10.1111/1440-1681.70036","url":null,"abstract":"<p>Acupuncture has demonstrated efficacy in treating post-stroke complications. Electroacupuncture (EA) ameliorates neurological outcomes in cerebral ischemia models, yet its mechanisms remain unclear. This study investigated EA's role in reducing cerebral ischemia–reperfusion injury (CIRI) in a rat model, focusing on ferroptosis. A CIRI model was established via the MCAO/R method. Rats were randomly assigned to five experimental groups: Sham, MCAO/R, MCAO/R + COTI-2, MCAO/R + EA and MCAO/R + COTI-2 + EA. We evaluated neurological function with Zausinger scoring. 2,3,5-Triphenyltetrazolium chloride (TTC) staining assessed infarct size, while haematoxylin–eosin (HE) staining examined neuronal damage. Transmission electron microscopy analysed mitochondrial changes associated with ferroptosis, and Perl staining measured iron levels in neurons. The biomarkers associated with ferroptosis, including glutathione (GSH), reactive oxygen species (ROS) and malondialdehyde (MDA), were measured. The expression of <i>p53</i>, <i>SLC7A11</i> and <i>GPX4</i> was assessed by qRT-PCR and Western blot. EA enhanced neurological function, reduced the infarct size, alleviated excessive serum iron accumulation, increased antioxidant markers (GSH, GPX4) and decreased lipid peroxidation levels (ROS, MDA), attenuating lipid peroxidation. Additionally, it reversed mitochondrial morphological changes associated with ferroptosis. qRT-PCR and Western blot analyses revealed that EA downregulated <i>p53</i> expression while upregulating <i>SLC7A11</i> and <i>GPX4</i> expression. In summary, ferroptosis was activated after CIRI, and EA ameliorated neurological deficits in cerebral ischemia models by modulating the p53/SLC7A11 axis to counteract oxidative stress-induced ferroptosis, ultimately providing neuroprotective benefits.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 5","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/1440-1681.70036","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143809790","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":"Global, Regional, and National Temporal Trend and Patterns of Change in the Burden of Asthma From 1990 to 2021: An Analysis of the Global Burden of Disease Study 2021","authors":"Shuyi Mu,&nbsp;Yu Wang,&nbsp;Jie Cui,&nbsp;Linjin Chen,&nbsp;Lei Qiu,&nbsp;Cui Li,&nbsp;Yuwei Jiang,&nbsp;Zhenhui Lu,&nbsp;Zifeng Ma","doi":"10.1111/1440-1681.70039","DOIUrl":"https://doi.org/10.1111/1440-1681.70039","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Asthma presents a significant challenge to the global healthcare systems and imposes a heavy socioeconomic burden. Previous studies had geographical limitations and lacked comprehensive global analysis. The study utilises data from the 2021 Global Burden of Disease (GBD) study to assess the global, regional, and national burden of asthma from 1990 to 2021. It examines disease trends, highlights health inequalities and aims to provide scientific evidence for future public health strategies and the optimisation of resource allocation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Data from GBD 2021 were used to estimate the incidence, prevalence, mortality, and disability-adjusted life years (DALYs) of asthma across 21 global regions and 204 countries and territories from 1990 to 2021. Temporal trends were analysed, and the relationship between asthma burden and the socio-demographic index (SDI) was examined using a smoothing spline model. Analyses included the slope index of inequality and the concentration index to assess health disparities, frontier analysis to estimate achievable outcomes based on development levels, and decomposition analysis to identify the drivers of changes in DALYs number.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Over the past three decades, the age-standardised burden of asthma has declined, with age-standardised mortality and DALY rates decreasing by 46% and 44%, respectively. However, the absolute number of deaths has increased by 17%, particularly among females, especially in low and low-middle SDI regions. Significant health inequalities persist, with high-SDI regions benefiting from better asthma control, while low-SDI regions face disproportionate burdens due to healthcare disparities. Frontier analysis highlights gaps between current and optimal disease burden levels, while low-SDI regions require increased investment in asthma control. Aging, population growth, and epidemiological changes are key drivers of asthma burden trends. High body mass index (BMI) remains the leading risk factor, while smoking and occupational exposures continue to contribute significantly.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The global burden of asthma has declined, yet significant regional disparities persist, with low-SDI regions experiencing higher mortality and DALYs due to limited healthcare access and environmental risks. High BMI, smoking and occupational exposures remain key contributors, requiring targeted public health interventions and lifestyle modifications.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 5","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143778238","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":"Inhibition of Hsp90 Alleviates Necroptosis and Inflammation in Lung Epithelial Cells During Pulmonary Ischemia–Reperfusion Injury","authors":"Xiaofang Xu,&nbsp;Zhiling Lou,&nbsp;Jinsheng Li,&nbsp;Fuxiang Liang,&nbsp;Yifan Yu,&nbsp;Ming Wu","doi":"10.1111/1440-1681.70037","DOIUrl":"https://doi.org/10.1111/1440-1681.70037","url":null,"abstract":"<div>\u0000 \u0000 <p>Lung ischemia–reperfusion injury (LIRI) is a critical pathological process associated with various clinical conditions, characterised by excessive inflammatory responses and cell death, which can lead to severe respiratory dysfunction and even mortality. However, no effective therapeutic strategy is currently available. This study investigates the protective effects and underlying mechanisms of the Hsp90 inhibitor 17-dimethylaminoethylamino (17-DMAG) in LIRI. An in vivo mouse model of LIRI was established by transiently occluding the left pulmonary hilum with a microvascular clamp, followed by reperfusion. In vitro, necroptosis was induced in BEAS-2B cells using TSZ (TNF-α, Smac mimetic and z-VAD-FMK). Our results demonstrate that 17-DMAG significantly attenuates lung injury, inflammation and epithelial cell necroptosis in mice. Additionally, 17-DMAG mitigates TSZ-induced cell death and inflammatory responses in BEAS-2B cells. Mechanistically, 17-DMAG inhibits the phosphorylation of RIPK1, RIPK3 and MLKL—key necroptotic regulators and client proteins of Hsp90—thereby suppressing necroptosis and reducing the associated inflammatory response. In conclusion, 17-DMAG alleviates LIRI by inhibiting necroptosis and its consequent acute inflammatory cascade. These findings suggest that 17-DMAG may serve as a promising therapeutic candidate for LIRI treatment.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 5","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143749361","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":"Pancreatitis Independently Induced by Hypertriglyceridaemia Outlines the Immune Profiles of HTGP in Clinic","authors":"Jianxing Liu,&nbsp;Caixia Liang,&nbsp;Wenjing Yan,&nbsp;Yanfeng Zhang,&nbsp;Yi Pan,&nbsp;Yue Yang,&nbsp;Fangfang Zhang,&nbsp;Xiaojian Liu,&nbsp;Liang Jin","doi":"10.1111/1440-1681.70032","DOIUrl":"https://doi.org/10.1111/1440-1681.70032","url":null,"abstract":"<div>\u0000 \u0000 <p>Hypertriglyceridaemia (HTG) is a common and well-established aetiology of acute pancreatitis (AP). Although the underlying pathophysiology of hypertriglyceridaemic pancreatitis (HTGP) is complex, some animal models of HTAP have been successfully reproduced by repeated caerulein injections based on HTAP. However, most of the current HTGP models are critically dependent on the “two-attack” of cholecystokinin analogue, which may not be consistent with the fact of HTGP aetiologies due to ignored the initial effects of HTG in the development of HTGP. Here, we showed that HTGP could be induced by HTG independently, the HTGP mice with the typical characteristics and typical complications of pancreatitis. We found that the HTGP mice with mild pancreatic oedema, but the necrosis and immune cell infiltration were extensive. In addition, the immune cell infiltration and immune dysregulation that widely observed in HTGP patients were well reproduced in this model, including innate and adaptive immune cells. Our results suggest that the murine HTGP model independently induced by HTG could recapitulate the pathological and immunological profiles of HTGP in the clinic. More importantly, the model generated by this method could sustain a prolonged, non-life-threatening course of the disease and is suitable for research into the underlying mechanisms and for application to the preclinical evaluation of HTGP drugs.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 5","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143602772","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":"Norisoboldine Alleviates Isoproterenol-Induced Myocardial Ischemic Injury via the TLR4–MyD88-Dependent NF-κB Activation Pathway and Modulation of L-Type Calcium Channels","authors":"Xin Zhang,&nbsp;Xinliu Wang,&nbsp;Yuanyuan Wang,&nbsp;Xingyou Ma,&nbsp;Yunyun Geng,&nbsp;Shuxian Zang,&nbsp;Ziyun Ban,&nbsp;Yugai Jia,&nbsp;Yonggang Gao","doi":"10.1111/1440-1681.70033","DOIUrl":"https://doi.org/10.1111/1440-1681.70033","url":null,"abstract":"<div>\u0000 \u0000 <p>Norisoboldine (NIB) displays beneficial effects on cardiovascular diseases, although its protective role and underlying mechanisms in myocardial ischemia (MI) injury remain elusive. The aim of this study is to explore the potential cardioprotective mechanism of NIB on MI injury caused by isoproterenol (ISO). We administered NIB to SD rats at 20 and 40 mg/kg daily for 7 days in this study; this was followed by an ISO injection to induce MI injury. Parameters such as electrocardiogram readings, heart rate, serum concentrations of creatine kinase (CK) and creatine kinase-MB (CK-MB), levels of inflammatory markers, some histopathological assessments and oxidative stress markers were evaluated. We conducted Western blot analyses to evaluate protein expression related to apoptosis and the TLR4–MyD88-mediated NF-κB activation pathway. The L-type Ca²⁺ current (ICa-L) and contraction of isolated ventricular cells from rats were identified using patch-clamp methods and the IonOptix detection system. The treatment with NIB resulted in improvements in heart rate and ST-segment changes, a reduction in CK and CK-MB levels, the restoration of superoxide dismutase, catalase and glutathione levels and a decrease in malondialdehyde accumulation. Furthermore, NIB reduced the expression of inflammatory markers, lowered Ca²⁺ levels and reactive oxygen species production and improved myocardial tissue morphology. It also countered ISO-induced alterations in apoptosis and the TLR4–MyD88-dependent NF-κB activation pathway. Additionally, NIB considerably attenuated ICa-L and reduced the contractile function of cardiomyocytes. These results suggest that NIB effectively mitigates ISO-induced MI injury through anti-inflammatory, antioxidative, and anti-apoptotic mechanisms, potentially involving the TLR4–MyD88-dependent NF-κB activation pathway and calcium balance.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 4","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143497272","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":"Flavokawain A Ruthenium-p-Cymene Complex-Induced Apoptosis by the Modulation of PI3K/β-Catenin/HER2/PARP Signalling in Lung Cancer","authors":"Sakuntala Gayen,&nbsp;Souvik Roy,&nbsp;Diana Laishram,&nbsp;Soumendra Nath Bandyopadhyay,&nbsp;Swarupananda Mukherjee","doi":"10.1111/1440-1681.70030","DOIUrl":"https://doi.org/10.1111/1440-1681.70030","url":null,"abstract":"<div>\u0000 \u0000 <p>Lung cancer is most terrible cause of cancer-related death throughout the world. This study focused on the synthesis and characterisation of novel flavokawain A ruthenium-p-cymene complex and to investigate the chemotherapeutic activity against lung carcinoma via in silico, in vitro and in vivo approaches. The complex was characterised via several spectroscopic techniques. In vitro study including cell viability, transwell migration, Western blot and flow cytometric analysis have been executed on both A549 and NCI-H460 cells. The toxicological assessment was performed and subsequently anticancer activity of complex was evaluated in benzo[α]pyrene persuaded lung carcinoma in mice. The molecular docking study demonstrated the compound has greater binding ability with β-catenin, Akt, HER2 and PARP. Followed by the complex treatment, the downregulation of β-catenin, PI3K, Akt, HER2 and PARP were investigated by Western blot analysis and cell cycle arrest was determined through flow cytometry. The outcomes of in vivo experimentation represented fruitful restoration of typical lung architecture after complex treatment. Immunohistochemical analysis demonstrated the downstream of β-catenin/m-TOR/Akt and upstream of caspase-3 and p53 expression, thereby initiating apoptosis. The complex exhibited a potent chemotherapeutic activity via the alteration of tumour microenvironment by modulating PI3K/Akt/β-catenin/HER2/PARP transduction in correlates with apoptotic events in lung carcinoma.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 4","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143446720","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":"Prophylactic Effects of Rhamnetin Flavonoid on Indomethacin-Induced Gastric Ulceration by Modulating HSP 70/Bax, SOD/MDA and TNF-α/IL-10","authors":"Mohammed T. Mohammed,&nbsp;Talal Salem Al-Qaisi,&nbsp;Ahmed A. J. Jabbar,&nbsp;Mohammed M. H. M. Raouf,&nbsp;Parween AbdulSamad Ismail,&nbsp;Ramzi A. Mothana,&nbsp;Omer I. Fantoukh,&nbsp;Rawaz Rizgar hassan,&nbsp;Mahmood Ameen Abdulla,&nbsp;Musher Ismael Saleh,&nbsp;Mohammed Awad","doi":"10.1111/1440-1681.70029","DOIUrl":"https://doi.org/10.1111/1440-1681.70029","url":null,"abstract":"<div>\u0000 \u0000 <p>Rhamnetin is a naturally occurring flavonoid compound found in many wild plant species and indigenous fruits. Despite its numerous biological potentials, such as anti-inflammatory, antioxidant and antimicrobial effects, there is a lack of literature elucidating its gastroprotective action and anticipating molecular mechanism. Natural products can be a good alternative to overcome the side effects and relapses associated with anti-ulcer drugs. This study aims to elucidate rhamnetin's acute toxicity and gastroprotective effects using the indomethacin ulceration model. Animals were arbitrarily divided into five groups: a negative control group (A) and a positive control group (B), both treated with 1% carboxymethyl cellulose; a reference group (C) receiving 20 mg/kg omeprazole; and low-dose (D) and high-dose (E) rhamnetin groups receiving 30 and 60 mg/kg, respectively. After 1 h, rats in Groups B–E were subjected to indomethacin-induced ulceration. Toxicity evaluations indicated the safety of rhamnetin at doses of up to 400 mg/kg in rats, without any noticeable physiological alterations. Rhamnetin (30 and 60 mg/kg) administered orally 1 h before indomethacin-induced gastric ulcer ameliorated the stomach lesions and lowered the ulcer index area by 73.81% and 77.87%, respectively. Rhamnetin supplementation ameliorated histopathological alterations and restored gastric barriers, including gastric pH and mucin secretion. Moreover, rhamnetin-treated rats exhibited increased anti-apoptotic heat shock protein 70 and decreased Bax protein in stomach tissues. These findings were in line with lowered accumulated MDA, increased superoxide dismutase, catalase and prostaglandin E2 levels, reduced serum inflammatory mediators (TNF-α and interleukin-6) and elevated interleukin-10 cytokines. The outcomes indicate rhamnetin's cicatrising and gastroprotective effects against indomethacin-mediated ulceration, possibly due to its modulatory actions on oxidative stress, inflammation and apoptotic pathways.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 4","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143446719","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":"Corticosterone-Induced Myocardial Dysfunctions and the Cardioprotective Role of Tauroursodeoxycholic Acid: An Experimental Study in Mice","authors":"Houyuan Zhou,&nbsp;Xiaoying Chen,&nbsp;Yanlin Tao,&nbsp;Zikang Li,&nbsp;Hui Wu,&nbsp;Hailian Shi,&nbsp;Xiaojun Wu,&nbsp;Fei Huang","doi":"10.1111/1440-1681.70027","DOIUrl":"https://doi.org/10.1111/1440-1681.70027","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;Major depressive disorder increases cardiovascular risk through stress-induced elevated cortisol levels. Tauroursodeoxycholic acid (TUDCA), a bile acid, has been reported to have anti-inflammatory, anti-depressive and cardioprotective effects. However, the effects of stress-induced myocardial dysfunctions remain unclear. Our study aims to investigate corticosterone-induced myocardial dysfunctions and the role of TUDCA in rescuing such dysfunctions.&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;To achieve this, experiments were conducted on mice that had been exposed to corticosterone, with treatment involving TUDCA. We first evaluated depression-like behaviours using the open field test, forced swimming test and sucrose preference test, and assessed cardiac function using echocardiography. We then analysed the levels of norepinephrine (NE), adenosine triphosphate (ATP) and B-cell lymphoma-2 (Bcl-2)/Bcl-2 Associated X-protein (Bax) using liquid chromatography-mass spectrometry, enzyme-linked immunosorbent assay and Western blot, respectively. Finally, we investigated gene expression and signalling pathways through RNA-sequencing, which were further validated by qRT-PCR.&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;The results demonstrate that corticosterone administration induced depression-like behaviours in mice, including a significant increase in immobility time during the tail suspension test and a significant decrease in the sucrose preference rate. Additionally, it induced cardiac dysfunction in mice, including a decrease in ejection fraction and fractional shortening. Furthermore, corticosterone administration resulted in an increase in left ventricular volume-systolic and left ventricular end-systolic volume index in the mouse left ventricular myocardium. Moreover, it elevated the NE concentration in mouse serum and decreased ATP levels and the Bcl-2/Bax protein expression ratio in the mouse left ventricular tissue. Notably, these detrimental changes were rescued by TUDCA treatment. Additionally, corticosterone affected genes related to cardiac muscle contraction and mitochondrial function, while TUDCA countered this impact by modulating genes associated with muscle processes and ion transport, potentially alleviating myocardial contractile dysfunction.&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;Overall, our results suggest that corticosterone induces depression-like behaviours, cardiac dysfunction, elevated serum NE levels, reduced ATP and a decreased Bcl-2/Bax ratio, disrupting myocardial contraction and mitochondrial function. TUDCA effectively reversed these effects and mo","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 4","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380592","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":"LeuRS-Targeting Prodrug, MRX-5, Expresses Anti-Mycobacterium abscessus Activity","authors":"Anqi Li,&nbsp;Siyuan He,&nbsp;Yaping Jia,&nbsp;Junsheng Fan,&nbsp;Shicong Liu,&nbsp;Xinghai Wang,&nbsp;Zhemin Zhang,&nbsp;Haiqing Chu","doi":"10.1111/1440-1681.70024","DOIUrl":"https://doi.org/10.1111/1440-1681.70024","url":null,"abstract":"<div>\u0000 \u0000 <p><i>Mycobacterium abscessus</i> is a multi-drug resistant pathogen presenting significant treatment challenges. This study evaluated MRX-5, an oral prodrug of the leucyl-tRNA synthetase inhibitor MRX-6038, for its efficacy against <i>M. abscessus</i> both in vitro and in vivo. Stability testing of MRX-5 was conducted using liquid chromatography–tandem mass spectrometry in Middlebrook 7H9 broth at 35°C. Following this, the minimum inhibitory concentrations of MRX-5 were determined against two reference strains and 17 clinical isolates of <i>M. abscessus</i>. In the in vivo experiments, the pharmacokinetic properties of MRX-5 were assessed first, followed by efficacy testing conducted in a neutropenic BALB/c mouse model of <i>M. abscessus</i> lung infection. Remarkably, the conversion of MRX-5 to MRX-6038 in liquid broth was complete within 72 h, and MRX-5 demonstrated reduced potency compared to MRX-6038 in vitro. In vivo, MRX-5 was efficiently converted to MRX-6038, achieving an oral bioavailability of 83.95% and significant lung distribution. In the mouse model of pulmonary <i>M. abscessus</i> infection, MRX-5 effectively reduced bacterial load and exhibited antimicrobial activity comparable to that of linezolid. In conclusion, MRX-5 exhibited favourable lung distribution and in vivo efficacy against <i>M. abscessus</i>, positioning it as a promising candidate for the oral treatment of <i>M. abscessus</i> infections.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 4","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143380593","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}