Clinical and Experimental Pharmacology and Physiology最新文献

{"title":"Caffeic acid phenethyl ester ameliorates colistin-induced nephrotoxicity in rats via modulation of FOXO1/Nrf2/Sirt1 axis","authors":"Mohammed Z. Nasrullah,&nbsp;Thikryat Neamtalllah,&nbsp;Mohannad Alshibani,&nbsp;Alaa A. Bagalagel,&nbsp;Ahmad O. Noor,&nbsp;Hussain T. Bakhsh,&nbsp;Ashraf B. Abdel-Naim","doi":"10.1111/1440-1681.70000","DOIUrl":"10.1111/1440-1681.70000","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Colistin (Cst) is one of the antimicrobial peptides and is reserved for use against multi-drug-resistant Gram-negative bacteria. However, the clinical value of Cst is limited by its nephrotoxic adverse effects. Caffeic acid phenethyl ester (CAPE) is a honeybee propolis flavonoid recognised for its diverse pharmacological potential. It has demonstrated d antioxidant and anti-inflammatory properties, as well as protective effects against chemically induced toxicity in variuos biological systems. This study aimed to investigate the impact of CAPE on nephrotoxicity induced in rats by Cst.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Animals were randomly divided into five groups. Group 1 served as control, group 2 received CAPE (10 mg/kg) orally, group 3 received Cst IP, group 4 received Cst + CAPE (5 mg/kg) and group 5 received Cst + CAPE (10 mg/kg). All treatments were given daily for 10 consecutive days.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CAPE notably attenuated Cst-inducednephrotoxicity as shown by reducing urea serum levels, creatinine, cystatin C, urinary protein contents and urinary N-acetyl-β-D-glucosaminidase (NAG). This was confirmed by histological investigations that indicated amelioration of histopathological changes in the kidney architecture as well as the deposition of collagen in renal tissues. CAPE exhibited antioxidant effects supported by the prevention of rise in Cst-induced lipid peroxidation and depletion of superoxide dismutase and catalase enzymatic activities. In addition, CAPE inhibited the expression of the inflammatory markers including tumour necrosis factor-α, nuclear factor kappa B and interleukin-6. These actions were associated with modulation of messenger ribonucleic acid (mRNA) expression of <i>Bax</i> and <i>Bcl-2</i> in favour of anti-apoptosis. CAPE inhibited Cst-induced rise in forkhead box O1 (FOXO1) expression and downregulation of nuclear factor erythroid 2–related factor 2 (Nrf2) and Sirtuin 1 (Sirt1) immune-expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>CAPE protects against nephrotoxicity induced by Cst in ratsprimarily through its antioxidant, antiinflammatory and antiapoptotic activities. These pritective effects are mediated via modulation of FOXO1/Nrf2/Sirt1 axis.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"51 12","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496165","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":"Gross saponins of Tribulus terrestris attenuate rheumatoid arthritis by promoting apoptosis of fibroblast-like synoviocytes and reducing inflammation by inhibiting MAPK signalling pathway","authors":"Xinghai Cheng,&nbsp;Yuantao Su,&nbsp;Ningzheng Dong,&nbsp;Meng Liu,&nbsp;Mengting Wang,&nbsp;Tiantian Zhou,&nbsp;Haibin Zhou","doi":"10.1111/1440-1681.13925","DOIUrl":"10.1111/1440-1681.13925","url":null,"abstract":"<p>Among the numerous treatment options for rheumatoid arthritis (RA), the promotion of synoviocyte apoptosis and inhibition of inflammation are considered the most effective. However, the potential pro-apoptotic effects of gross saponins of <i>Tribulus terrestris</i> (GSTT), which are natural saponins derived from the herb <i>Tribulus terrestris</i> L., on rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) and their essential molecular mechanisms remain unclear. The aim of the present study was to investigate the influence of different concentrations of GSTT on RA-FLSs using various assays, including cell counting kit-8 (CCK-8), reverse transcription polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), flow cytometry, terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) and western blot analysis. These assessments were conducted to evaluate the cell viability, changes in the levels of inflammatory cytokines, apoptosis rates and alterations in protein expression related to this process. In vivo, arthritis clinical score, haematoxylin and eosin (HE) staining and ELISA were used to assess paw inflammation, histopathology and serum inflammatory cytokine changes. Our findings demonstrated that GSTT substantially promotes the apoptosis of RA-FLSs and reduces pro-inflammatory cytokine levels. GSTT also reduced the Bcl-2/Bax ratio and inhibited JNK and p38 phosphorylation. Furthermore, GSTT exhibits positive effects on RA by improving clinical scores, reducing synovial inflammatory infiltration and lowering serum pro-inflammatory cytokine levels. Therefore, by promoting the apoptosis of RA-FLSs and suppressing inflammation through the inhibition of the MAPK signalling pathway, GSTT is a promising therapeutic intervention for RA.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"51 12","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142496166","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":"Regulatory mechanism of TRIM21 in sepsis-induced acute lung injury by promoting IRF1 ubiquitination","authors":"Wenjie Ma,&nbsp;Jie Zheng,&nbsp;Bin Wu,&nbsp;Meitang Wang,&nbsp;Zhoujun Kang","doi":"10.1111/1440-1681.13911","DOIUrl":"10.1111/1440-1681.13911","url":null,"abstract":"<p>Sepsis-induced acute lung injury (ALI) is characterized by inflammatory damage to pulmonary endothelial and epithelial cells. The aim of this study is to probe the significance and mechanism of tripartite motif-containing protein 21 (<i>TRIM21</i>) in sepsis-induced ALI. The sepsis-induced ALI mouse model was established by cecum ligation and puncture. The mice were infected with lentivirus and treated with proteasome inhibitor MG132. The lung respiratory damage, levels of interleukin-6 (IL-6), tumour necrosis factor α (TNF-α), IL-10 and pathological changes were observed. The expression levels of <i>TRIM21</i>, interferon regulatory factors 1 (<i>IRF1</i>) and triggering receptor expressed on myeloid cells 2 (<i>TREM2</i>) were measured and their interactions were analysed. The ubiquitination level of <i>IRF1</i> was detected. <i>TRIM21</i> and <i>TREM2</i> were downregulated and <i>IRF1</i> was upregulated in sepsis-induced ALI mice. <i>TRIM21</i> overexpression eased inflammation and lung injury. <i>TRIM21</i> promoted <i>IRF1</i> degradation via ubiquitination modification. <i>IRF1</i> bonded to the <i>TREM2</i> promoter to inhibit its transcription. Overexpression of <i>IRF1</i> or silencing <i>TREM2</i> reversed the improvement of <i>TRIM21</i> overexpression on lung injury in mice. In conclusion, <i>TRIM21</i> reduced <i>IRF1</i> expression by ubiquitination to improve <i>TREM2</i> expression and ameliorate sepsis-induced ALI.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"51 11","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364629","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":"AEBP1 restores osteoblastic differentiation under dexamethasone treatment by activating PI3K/AKT signalling","authors":"Rilong Jin,&nbsp;Chen Li,&nbsp;Yute Yang,&nbsp;Jie Xie","doi":"10.1111/1440-1681.13923","DOIUrl":"10.1111/1440-1681.13923","url":null,"abstract":"<p>Adipocyte enhancer-binding protein 1 (AEBP1) is closely implicated in osteoblastic differentiation and bone fracture; this research aimed to investigate the effect of AEBP1 on restoring osteoblastic differentiation under dexamethasone (Dex) treatment, and its interaction with the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway. Pre-osteoblastic MC3T3-E1 cells were cultured in osteogenic medium and treated by Dex to mimic steroid-induced osteonecrosis cellular model. They were then further transfected with control or AEBP1-overexpressed lentiviral vectors. Finally, cells were treated with the PI3K inhibitor LY294002, with or without AEBP1-overexpressed lentiviral vectors. AEBP1 expression showed a downward trend in MC3T3-E1 cells under Dex treatment in a dose-dependent manner. AEBP1-overexpressed lentiviral vectors increased relative cell viability, alkaline phosphatase (ALP) staining, Alizarin red staining and osteoblastic differentiation markers including osteocalcin (OCN), osteopontin (OPN), collagen type I alpha 1 (COL1A1), runt-related transcription factor 2 (RUNX2) and bone morphogenetic protein 2 (BMP2), but decreased cell apoptosis rate in MC3T3-E1 cells under Dex treatment; besides, AEBP1-overexpressed lentiviral vectors positively regulated p-PI3K and p-AKT expressions. Furthermore, LY294002 treatment decreased relative cell viability, Alizarin red staining, osteoblastic differentiation markers including OCN, OPN, RUNX2 and BMP, increased cell apoptosis rate and did not affect ALP staining in MC3T3-E1 cells under Dex treatment; meanwhile, LY294002 treatment weakened the effect of AEBP1 overexpression vectors on the above cell functions. AEBP1 restores osteoblastic differentiation under Dex treatment by activating the PI3K/AKT pathway.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"51 11","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142364628","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":"Agomelatine-loaded nanostructured lipid carriers alleviate neuropathic pain in rats by Nrf2/HO-1 signalling pathway","authors":"Sundas Firdoos,&nbsp;Rongji Dai,&nbsp;Zahid Younas,&nbsp;Fawad Ali Shah,&nbsp;Maleeha Gul,&nbsp;Madiha Rasheed","doi":"10.1111/1440-1681.13922","DOIUrl":"10.1111/1440-1681.13922","url":null,"abstract":"<p>Neuropathic pain arises from impairments or malfunctions within the nervous system, resulting in atypical transmission and interpretation of pain signals. In the present study, we examined the neuroprotective effects of agomelatine (AGM) and agomelatine-loaded nanostructured lipid carriers (AGM-NLCs) in neuropathic animal models induced by chronic constriction injury (CCI) of the sciatic nerve. Male Sprague Dawley rats were divided into seven experimental groups to compare the effects of AGM and AGM-NLCs, which were administered at 20 mg/kg for 14 consecutive days after CCI. Our finding demonstrated that CCI triggered the onset of analgesia in these animals, corroborated by mechanical allodynia and thermal hyperalgesia. Furthermore, CCI induced an elevation in inflammatory mediators such as interleukin (IL)-1β and inducible nitric oxide synthase (iNOS), and downregulated heme oxygenase-1 (HO-1) and nuclear factor E2-related factor (Nrf2). Treatment with AGM and AGM-NLCs reversed inflammatory cascades and elevated antioxidant enzyme levels, leading to a reduction in paw withdrawal latency and threshold in rats. To further investigate the effect of AGM and AGM-NLCs, all-trans retinoic acid (ATRA) was administered, which antagonizes Nrf2. ATRA substantially downregulated Nrf2 expression and exacerbated thermal hyperalgesia, whereas Nrf2 and HO-1 expressions were significantly upregulated after AGM-NLCs administration. Overall, the results demonstrated that AGM-NLCs offer promising antinociceptive and anti-inflammatory properties in alleviating neuropathic pain symptoms, which can be attributed to improved drug delivery and therapeutic outcomes compared with AGM alone.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"51 11","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142342731","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":"Propofol attenuates prostate cancer progression by upregulating TRHDE-AS1 expression, and METTL14 could mediate its m6A modification","authors":"Zhuo Chen,&nbsp;Quanfu Li,&nbsp;Zhong Li,&nbsp;Guangjun Hu","doi":"10.1111/1440-1681.13924","DOIUrl":"https://doi.org/10.1111/1440-1681.13924","url":null,"abstract":"<p>Propofol has become a microtubule-stabilizing drug for prostate cancer (PC) therapy, but propofol resistance impairs the therapeutic effect. This study aimed to explore the regulatory mechanism of propofol in the pathogenesis of PC through mechanisms involving N6-methyladenosine (m6A) modification. The changes in PC cell malignancy were evaluated by means of transwell, cell counting kit 8 (CCK-8), western blotting and tumour xenograft model assays. Long noncoding RNA TRHDE-AS1 and m6A methyltransferase METTL14 expression levels were determined via reverse transcription quantitative polymerase chain reaction (RT-qPCR). The m6A modification of TRHDE-AS1 which was mediated by METTL14 was confirmed by conducting methylated RNA immunoprecipitation (MeRIP) assay. We observed that propofol (200 μM) inhibited PC cell malignancy in vivo and in vitro, elucidating that it impaired cell proliferation, migration and tumour growth but induced apoptosis. TRHDE-AS1 expression was observed to be lower in PC cells and tissues, and propofol induced TRHDE-AS1 upregulation in PC cells. Propofol was capable of reversing the tumour-promoting effect of TRHDE-AS1 knockdown in PC cells. Additionally, METTL14 was upstream of TRHDE-AS1 to induce m6A modification of TRHDE-AS1 in PC cells. Collectively, our results show that propofol prevents PC progression by upregulating TRHDE-AS1 expression and METTL14 is involved in the m6A modification of TRHDE-AS1. These findings suggest that TRHDE-AS1 may be a potential therapeutic target for the improvement of propofol's therapeutic effect.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"51 11","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142324651","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":"Phillygenin attenuates cell apoptosis and microglia activation in cerebral ischaemia–reperfusion rats through activation of peroxisome proliferator-activated receptor γ","authors":"Chaojun Yan,&nbsp;Guangwei Sun,&nbsp;Changlong Hu,&nbsp;Tao Qiu,&nbsp;Meng Wang,&nbsp;Yongzhong Fan","doi":"10.1111/1440-1681.13917","DOIUrl":"https://doi.org/10.1111/1440-1681.13917","url":null,"abstract":"<p>Ischaemic stroke is a common condition that can lead to cerebral ischaemia–reperfusion injury. Phillygenin (PHI), a natural bioactive compound derived from <i>Forsythia suspensa</i>, has been shown to play a crucial role in regulating inflammation across various diseases. However, its specific regulatory effects in ischaemic stroke progression remain unclear. In this study, we established a middle cerebral artery occlusion (MCAO) rat model. Treatment with PHI (50 or 100 mg/kg) significantly reduced cerebral infarction in MCAO rats. PHI treatment also mitigated the increased inflammatory response observed in these rats. Additionally, PHI suppressed microglial activation by reducing iNOS expression, a marker of M1-type polarization of microglia, and attenuated increased brain tissue apoptosis in MCAO rats. Furthermore, PHI's anti-inflammatory effects in MCAO rats were abrogated upon co-administration with GW9662, a peroxisome proliferator-activated receptor γ (PPARγ) inhibitor. In summary, PHI attenuated microglial activation and apoptosis in cerebral ischaemia–reperfusion injury through PPARγ activation, suggesting its potential as a therapeutic agent for mitigating cerebral ischaemia–reperfusion injury.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"51 11","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142244933","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":"High-sensitivity C-reactive protein to high-density lipoprotein cholesterol ratio predicts long-term adverse outcomes in patients who underwent percutaneous coronary intervention: A prospective cohort study","authors":"Xin-Ya Dai,&nbsp;Zheng-Kai Xue,&nbsp;Xiao-Wen Wang,&nbsp;Kang-Yin Chen,&nbsp;Su-Tao Hu,&nbsp;Gary Tse,&nbsp;Seung-Woon Rha,&nbsp;Tong Liu","doi":"10.1111/1440-1681.13919","DOIUrl":"https://doi.org/10.1111/1440-1681.13919","url":null,"abstract":"<p>High-sensitivity C-reactive protein (hsCRP) to high-density lipoprotein cholesterol (HDL-C) ratio (CHR) is associated with coronary artery disease (CAD), but its predictive value for long-term adverse outcomes in patients with CAD following percutaneous coronary intervention (PCI) remains unexplored and is the subject of this study. Patients with CAD who underwent PCI at the Korea University Guro Hospital-Percutaneous Coronary Intervention (KUGH-PCI) Registry since 2004 were included. Patients were categorized into tertiles according to their CHR. The end points were all-cause mortality (ACM), cardiac mortality (CM) and major adverse cardiac events (MACEs). Kaplan–Meier analysis, multivariate Cox regression, restricted cubic spline (RCS) and sensitivity analyses were performed. A total of 3260 patients were included and divided into Group 1 (CHR &lt;0.830, <i>N</i> = 1089), Group 2 (CHR = 0.830–3.782, <i>N</i> = 1085) and Group 3 (CHR &gt;3.782, <i>N</i> = 1086). Higher CHR tertiles were associated with progressively greater risks of ACM, CM and MACEs (log-rank, <i>p</i> &lt; 0.001). Multivariate Cox regression showed that patients in the highest tertile had greater risks of ACM (HR: 2.127 [1.452–3.117]), CM (HR: 3.575 [1.938–6.593]) and MACEs (HR: 1.337 [1.089–1.641]) than those in the lowest tertile. RCS analyses did not reveal a significant non-linear relationship between CHR and ACM, CM or MACEs. The significant associations remained significant in the sensitivity analyses, RCS analyses with or without extreme values, subgroup analyses and multiple imputations for missing data. Elevated CHR is a novel, independent risk factor for long-term ACM, CM and MACEs in CAD patients following PCI.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"51 11","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142234931","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":"β-Adrenergic receptor signalling pathway mediated antiarrhythmic activity of s-limonene in the rat heart","authors":"Joyce Francielle Ferreira Santos,&nbsp;Diego Santos de Souza,&nbsp;Karina Oliveira Mota,&nbsp;Sandra Valéria Santos de Cerqueira,&nbsp;Aimée Obolari Durço,&nbsp;Seyi Elijah Elasoru,&nbsp;Daniella Santos Nascimento,&nbsp;Danilo Roman-Campos,&nbsp;Cácia Oliveira Dantas,&nbsp;Carla Maria Lins de Vasconcelos","doi":"10.1111/1440-1681.13915","DOIUrl":"10.1111/1440-1681.13915","url":null,"abstract":"<p>S-Limonene (s-Lim) is a monocyclic monoterpene found in a variety of plants and has been shown to present antioxidant and cardioprotective activity in experimental models of myocardial infarction. The aim of this study was to evaluate the potential mechanism by which s-Lim exerts its antiarrhythmic effect, focusing on the blockade of β-adrenoceptor (β-AR) and its effects on various in vivo and in vitro parameters, including electrocardiogram (ECG) measurements, left ventricular developed pressure (LVDP), the β-adrenergic pathway, sarcomeric shortening and L-type calcium current (I_Ca,L). In isolated hearts, 10 μM of s-Lim did not alter the ECG profile or LVPD. s-Lim increased the heart rate corrected QT interval (QTc) (10.8%) at 50 μM and reduced heart rate at the concentrations of 30 (12.4%) and 50 μM (16.6%). s-Lim (10 μM) also inhibited the adrenergic response evoked by isoproterenol (ISO) (1 μM) reducing the increased of heart rate, LVDP and ECG changes. In ventricular cardiomyocyte, s-Lim antagonized the effect of dobutamine by preventing the increase of sarcomeric shortening, demonstrating a similar effect to atenolol (blocker β1-AR). In vivo, s-Lim antagonized the effect of ISO (agonists β1-AR), presenting a similar effect to propranolol (a non-selective blocker β-AR). In ventricular cardiomyocyte, s-Lim did not alter the voltage dependence for I_Ca,L activation or the I_Ca,L density. In addition, s-Lim did not affect changes in the ECG effect mediated by 5 μM forskolin (an activator of adenylate cyclase). In an in vivo caffeine/ISO-induced arrhythmia model, s-Lim (1 mg/kg) presented antiarrhythmic action verified by a reduced arrhythmia score, heart rate, and occurrence of ventricular premature beats and inappropriate sinus tachycardia. These findings indicate that the antiarrhythmic activity of s-Lim is related to blockade of β-AR in the heart.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"51 10","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124935","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":"Adenylate cyclase 1 knockdown attenuates pirarubicin-induced cardiotoxicity","authors":"Wenqing Zhang,&nbsp;Zhiyun Shu,&nbsp;Peng Huang,&nbsp;HongYuan Cheng,&nbsp;Jiahua Ji,&nbsp;Dexian Wei,&nbsp;Liqun Ren","doi":"10.1111/1440-1681.13920","DOIUrl":"10.1111/1440-1681.13920","url":null,"abstract":"<p>This study aimed to investigate the effects and possible mechanisms of adenylate cyclase 1 (ADCY1) on pirarubicin-induced cardiomyocyte injury. HL-1 cells were treated with pirarubicin (THP) to induce intracellular toxicity, and the extent of damage to mouse cardiomyocytes was assessed using CCK-8, Edu, flow cytometry, ROS, ELISA, RT-qPCR and western blotting. THP treatment reduced the viability of HL-1 cells, inhibited proliferation, induced apoptosis and triggered oxidative stress. In addition, the RT-qPCR results revealed that ADCY1 expression was significantly elevated in HL-1 cells, and molecular docking showed a direct interaction between ADCY1 and THP. Western blotting showed that ADCY1, phospho-protein kinase A and GRIN2D expression were also significantly elevated. Knockdown of ADCY1 attenuated THP-induced cardiotoxicity, possibly by regulating the ADCY1/PKA/GRIN2D pathway.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"51 10","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142124934","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}