Clinical and Experimental Pharmacology and Physiology最新文献

{"title":"Restoring Autophagy by Exercise Ameliorates Insulin Resistance Partly via Calcineurin-Driven TFEB Nuclear Translocation","authors":"Ping Wang,&nbsp;Jiaxin Li,&nbsp;Chun Guang Li,&nbsp;Xian Zhou,&nbsp;Xiaolong Chen,&nbsp;Minghua Zhu,&nbsp;Hongjiang Wang","doi":"10.1111/1440-1681.70010","DOIUrl":"10.1111/1440-1681.70010","url":null,"abstract":"<div>\u0000 \u0000 <p>Exercise activates autophagy and lysosome system in skeletal muscle, which are known to play an important role in metabolic adaptation. However, the mechanism of exercise-activated autophagy and lysosome system in obese insulin resistance remains covert. In this study, we investigated the role of exercise-induced activation of autophagy and lysosome system in improving glucose metabolism of skeletal muscle. Male C57BL/6 mice were randomly divided into five groups: the chow diet (CD) group, the high-fat diet (HFD) group, the high-fat diet plus exercise (HFD-E) group and the HFD-E treated with calcineurin inhibitor FK506 (HFD-E-F) or saline (HFD-E-S) groups. The mice in exercise groups (HFD-E, HFD-E-F and HFD-E-S) were subjected to aerobic treadmill exercise (speed at 12 m/min for 1 h per session, 0° slope, 5 days per week for 12 weeks). Mice of HFD-E-F group were intraperitoneally administered FK506 (1 mg/kg), once each day for 2 weeks before the end of exercise. Expressions pTFEB, T-TFEB and autophagy–lysosome markers, including Beclin1, LC3, ULK1, SQSTM1, LAMP1, CTSD and CTSL proteins in gastrocnemius muscle were analysed. We demonstrated that HFD induced insulin resistance and decreased autophagy-lysosomal proteins and the exercise significantly increased transcription factor EB (TFEB) translocation from the cytoplasm to the nucleus, restored the impaired autophagy-lysosomal-related protein expressions, and improved glucose metabolism. The increase in TFEB nuclear translocation was partly blocked by the calcineurin inhibitor FK506. Our results suggest that exercise promotes autophagy and lysosome restoration by regulating calcineurin-mediated TFEB nuclear translocation, ultimately alleviating HFD-induced insulin resistance in mice skeletal muscle.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 3","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142945557","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":"Sirt6, Deubiquitinated and Stabilised by USP9X, Takes Essential Actions on the Pathogenesis of Experimental Autoimmune Myasthenia Gravis by Regulating CD4+ T Cells","authors":"Chen Xie,&nbsp;Hong-Lian Zhang,&nbsp;Jun Yuan,&nbsp;Ye Zhang,&nbsp;Yang-Chun Liu,&nbsp;Quan Xu,&nbsp;Li-Ru Chen","doi":"10.1111/1440-1681.70018","DOIUrl":"10.1111/1440-1681.70018","url":null,"abstract":"<div>\u0000 \u0000 <p>Myasthenia gravis (MG) presents with symptoms that significantly affect patients' daily lives. Long-term MG therapies may lead to substantial side effects, predominantly due to prolonged immune suppression. Sirt6, which plays a vital role in maintaining cellular homeostasis and is recognised for its involvement in cytokine production in immune cells, has not yet been explored in relation to MG. PBMCs and CD4⁺ T cells were isolated from blood samples. RT-qPCR, western blot and ELISA were used to assess the expression of target genes and proteins. Flow cytometry was used to identify the subsets of T helper cells. Co-IP was conducted to investigate the interaction between USP9X and Sirt6. Finally, the experimental autoimmune myasthenia gravis (EAMG) model was established. In MG patients, Sirt6 levels were downregulated compared to healthy controls. Sirt6 overexpression led to a reduction in Th1 and Th17 cell populations while augmenting Treg cells in PBMCs. USP9X interacted with Sirt6, leading to its deubiquitination and stabilisation. Elevated Sirt6 levels subsequently mitigated symptoms in the EAMG model. The stabilisation of Sirt6, mediated by USP9X, has been found to relieve symptoms of EAMG by influencing the subtypes of T helper cells. This highlights the promising potential of Sirt6 as a viable therapeutic target in the treatment of MG.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142930713","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 Inhibits PI3K-Akt–mTOR Signalling Pathway to Prevent bleomycin-Induced Idiopathic Pulmonary Fibrosis in Mice","authors":"Yongjia Wei,&nbsp;Wenting Ni,&nbsp;Lizhi Zhao,&nbsp;Yanhong Gao,&nbsp;Bing Zhou,&nbsp;Qun Feng,&nbsp;Yun Ma,&nbsp;Limin Wang","doi":"10.1111/1440-1681.70017","DOIUrl":"10.1111/1440-1681.70017","url":null,"abstract":"<div>\u0000 \u0000 <p>Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterised by irreversible lung structure and function. Phillygenin (PHI) is a lignan extracted from Forsythiae fructus with the activities of anti-inflammatory and antioxidant. This study aimed to explore the protective effect of PHI on IPF. The mouse model of IPF was established by bleomycin (BLM), and then treated with PHI. After 15 days of administration, the lung index was calculated. H&amp;E staining, Masson staining and immunohistochemical methods were used to detect the effect of PHI on pulmonary fibrosis. MDA and SOD were tested to evaluate the effect of PHI on lung tissue oxidative stress. Western blot was used to detect the effect of PHI on the expressions of α-SMA, p-smad2, TGF- β1, Nrf2, HO-1 and NQO-1. Network pharmacology was used to identify the key signalling pathways for PHI to improve IPF, and Western blot was used to validate the result. The results showed that PHI prevented mice from BLM-induced IPF, manifested by reducing lung index, improving lung tissue pathological damage, inhibiting collagen deposition and expression of fibrosis markers including α-SMA, collagen1, p-smad2 and TGF-β1. PHI inhibited oxidative stress by upregulating the expressions of Nrf2, HO-1 and NQO-1. Network pharmacology revealed that PI3K-Akt–mTOR signalling pathway was the underlying target of PHI for IPF. Molecular docking indicated strong binding of PHI with PIK3CA, AKT1 and RELA. Western blot validated that PHI downregulated the PI3K-Akt–mTOR signalling pathway and stimulated autophagy. This study indicated that PHI prevented BLM-induced pulmonary fibrosis by inhibiting PI3K-Akt–mTOR signalling pathway.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-01-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142920804","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 Salt Exacerbates Myocardial Dysfunction In Vitro and In Vivo by Promoting SIRT1/Nrf2-Mediated Ferroptosis","authors":"Wu Guanji,&nbsp;Liu Fuqiang,&nbsp;You Fei,&nbsp;Tao Zhang,&nbsp;Chen Xiaolin","doi":"10.1111/1440-1681.70016","DOIUrl":"10.1111/1440-1681.70016","url":null,"abstract":"<div>\u0000 \u0000 <p>Myocardial dysfunction is a crucial determinant of the development of heart failure in salt-sensitive hypertension. Ferroptosis, a programmed iron-dependent cell death, has been increasingly recognised as an important contributor to the pathophysiology of various cardiovascular diseases. This study aims to investigate the role and underlying mechanism of ferroptosis in high-salt (HS)-induced myocardial damage. Our results reveal that HS stimulation inhibited cell proliferation and promoted apoptosis in cardiomyocyte HL-1 cells in a dose-dependent manner. Ferroptotic features were observed in HS-induced HL-1 cells, including ferric iron accumulation, decreased glutathione levels, increased oxidative stress levels, upregulation of ferroptosis marker proteins PTGS2, 4HNE and FTH1 and downregulation of GPX4, all of which were reversed by treatment with the ferroptosis suppressor Fer-1. Furthermore, the administration of Fer-1 ameliorated HS-induced ferroptosis and myocardial damage in salt-sensitive Dahl SS rats. Additionally, we found that a HS diet suppressed the SIRT1/Nrf2 signalling pathway activation in our in vivo experiments. Activation of SIRT1/Nrf2 signalling by SIRT1 overexpression significantly attenuated ferroptosis in HS-induced HL-1 cells. In conclusion, our findings demonstrate that HS levels induce myocardial injury by promoting ferroptosis via the deactivation of the SIRT1/Nrf2 signalling pathway, highlighting the potential for therapeutic targeting of ferroptosis for hypertension-related cardiovascular disorders.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142902682","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 DNA Methyltransferase DNMT1 Reverses Th2 Response Polarisation and Alleviates Allergic Rhinitis","authors":"Peng Zou,&nbsp;Jianguo Li,&nbsp;Jia Li,&nbsp;Jian Wang","doi":"10.1111/1440-1681.70015","DOIUrl":"10.1111/1440-1681.70015","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Type 2 T helper (Th2) cells-mediated immune response plays vital roles in allergic rhinitis (AR), and DNA methylation is previously found to be closely related to AR development.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Aims</h3>\u0000 \u0000 <p>Our study aims to reveal the detail mechanism of DNA methylation affecting Th2 response in AR.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Mice were stimulated with ovalbumin (OVA) to induce AR symptoms, and CD4⁺ T cells were subjected to Th2 induction culture. Real-time quantitative PCR, western blot, flow cytometry, and enzyme-linked immunosorbent assay were performed to analyse the activation of Th2 response.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>DNA methyltransferase 1 (DNMT1) was significantly upregulated in OVA-induced AR model mice, and DNMT1 knockdown alleviated AR symptoms and pathological changes of nasal mucosa tissues in the model mice. DNMT1 knockdown obviously reduced the expression of GATA binding protein 3 (GATA3), the ratio of interleukin (IL)-4⁺CD4⁺ cells and the release of Th2 cytokines, but elevated the expression of T-box expressed in T cells (T-bet), the ratio of interferon (IFN)-γ⁺CD4⁺ cells and the levels of Th1 cytokines to improve Th1/Th2 imbalance in the model mice and Th2-induced CD4⁺T cells. Mechanistically, DNMT1 promoted promoter methylation of forkhead box O3 (FOXO3), inhibited FOXO3 expression and activated the nuclear factor kappa-B (NF-κB)/GATA3 signalling. FOXO3 overexpression remarkably inactivated the NF-κB/GATA3 pathway and mitigated Th2 polarisation in DNMT1-deficient and Th2-conditined CD4⁺T cells, which was reversed by a NF-κB inhibitor.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>Altogether, DNMT1 downregulated FOXO3 expression to activate the NF-κB/GATA3 pathway and promote Th2 response in AR.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817488","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":"RETRACTION: Rotenone Restrains the Proliferation, Motility and Epithelial–Mesenchymal Transition of Colon Cancer Cells and the Tumourigenesis in Nude Mice via PI3K/AKT Pathway","authors":"","doi":"10.1111/1440-1681.70014","DOIUrl":"10.1111/1440-1681.70014","url":null,"abstract":"<p>\u0000 <b>RETRACTION:</b> <span>W. Xue</span>, <span>S. Men</span>, and <span>R. Liu</span>, \" <span>Rotenone Restrains the Proliferation, Motility and Epithelial–Mesenchymal Transition of Colon Cancer Cells and the Tumourigenesis in Nude Mice via PI3K/AKT Pathway</span>,\" <i>Clinical and Experimental Pharmacology and Physiology</i> <span>47</span>, no. <span>8</span> (<span>2020</span>): <span>1484</span>–<span>1494</span>. https://doi.org/10.1111/1440-1681.13320.\u0000 </p><p>The above article, published online on 13 April 2020, in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Prof. Yang Yang; and John Wiley &amp; Sons Australia, Ltd. A third party informed the publisher that images in Figures 3D, 6A, 6D and 7A were duplicated from other articles by different author groups, some of which were used in a different scientific context. The report also detailed duplicated images within this article between Figures 2A, 4C, and 5C. Additional investigation by the journal also detected duplications of images between figures 1H and 2E and between Figures 4E and 6F. The authors did not respond to an inquiry by the publisher regarding these concerns. The retraction has been agreed to because the evidence of image duplication across different articles, each of which describe different experimental conditions, as well as image duplication within the article, fundamentally compromises the editors' confidence in the conclusions presented. The authors did not respond to our notice regarding the retraction.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/1440-1681.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794352","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":"Oroxin B Resembles Bisoprolol in Attenuating Beta1-Adrenergic Receptor Autoantibody-Induced Atrial Remodelling via the PTEN/AKT/mTOR Signalling Pathway","authors":"Na Yang,&nbsp;Huaxin Sun,&nbsp;Linqiang Xi,&nbsp;Ling Zhang,&nbsp;Yanmei Lu,&nbsp;Qianhui Wang,&nbsp;Jiaru Cao,&nbsp;Jie Song,&nbsp;Baopeng Tang,&nbsp;Luxiang Shang,&nbsp;Xianhui Zhou","doi":"10.1111/1440-1681.70011","DOIUrl":"10.1111/1440-1681.70011","url":null,"abstract":"<div>\u0000 \u0000 <p>Beta1-adrenergic receptor autoantibodies (β1-AAbs) promote atrial remodelling and ultimately lead to the development of atrial fibrillation (AF). Oroxin B is a natural flavonoid glycoside with a variety of biological activities, including anti-inflammatory and autophagy-promoting effects, and has therapeutic benefits for a variety of diseases. The aim of this study was to investigate the potential therapeutic role of Oroxin B in the development of β1-AAb-induced atrial fibrillation and to elucidate the underlying mechanisms involved. We established a rat model of β1-AAb-induced atrial fibrillation via active immunisation. The first stage was divided into three groups: the control group, the β1-AAb group and the β1-AAb + bisoprolol group. The second stage was divided into three groups: the control group, the β1-AAb group and the β1-AAb + Oroxin B group. Serum levels of β1-AAbs, atrial tissue levels of cyclic monophosphate (cAMP), atrial electrophysiological parameters, cardiac structure and function, mitochondrial structure, autophagy levels, cardiomyocyte apoptosis and myocardial fibrosis were examined. The results showed that bisoprolol, a β1-blocker, improved β1-AAb-induced atrial electrical remodelling, reduced atrial collagen deposition, ameliorated the increase in LAD and regulated the balance of autophagy and apoptosis in atrial myocytes through the PTEN/AKT/mTOR signalling pathway. Oroxin B, a PTEN agonist, can improve the impairment of autophagy homeostasis and apoptosis in atrial tissue by activating the PTEN/AKT/mTOR signalling pathway, thereby improving atrial structure and electrical remodelling. Moreover, Oroxin B may play a therapeutic role in β1AAb-induced atrial fibrillation. In conclusion, our results demonstrate the potential therapeutic role of Oroxin B in β1AAb-induced atrial fibrillation and the underlying mechanisms, suggesting that Oroxin B may be an effective antiarrhythmic medication.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 2","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142794347","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":"Fingolimod Inhibits C6 Rat Glioma Proliferation and Migration, Induces Sub-G1 Cell Cycle Arrest, Mitochondrial and Extrinsic Apoptosis In Vitro and Reduces Tumour Growth In Vivo","authors":"Safura Pournajaf,&nbsp;Nastaran Afsordeh,&nbsp;Hadi Bayat,&nbsp;Mohammad Hossein Pourgholami","doi":"10.1111/1440-1681.70012","DOIUrl":"https://doi.org/10.1111/1440-1681.70012","url":null,"abstract":"<div>\u0000 \u0000 <p>Glioblastoma multiforme (GBM), the most prevalent brain tumour, is universally fatal. GBM cells exhibit cell cycle disruption and treatment resistance, remarking an urgent need for newer treatments. Fingolimod, a sphingosine-1-phosphate receptor modulator, has been reported to have anti-cancer effects. This study investigated the therapeutic potentials of fingolimod in rat C6 cells and pursued the involved mechanism(s). Cell survival, proliferation, migration, and morphology of fingolimod-treated C6 cells were evaluated using MTT, soft-agar colony formation, wound-healing, and Giemsa staining assays. Apoptosis was investigated through acridine orange/ethidium bromide (AO/EB) and annexin V staining, and flow cytometry analysed the cell cycle. Quantitative reverse transcription PCR and western blotting were used to evaluate gene and protein expressions. An intracranial C6 rat model validated the anti-tumour effect of fingolimod. Fingolimod significantly reduced the survival and colonies of the C6 cells and delayed their gap closure. Cell shrinkage coupled with AO/EB and PI staining of the fingolimod-treated cells indicated apoptosis, subsequently confirmed by measuring the expression levels of the candidate genes involved in apoptosis and cell cycle, such as Bax/Bcl2, P53, Cytochrome C and Caspases 9/3, Fas, Fadd, Tnfrsf1a, Cdkn1a, and Ccnd1, at RNA and protein levels, indicating both extrinsic and mitochondrial apoptosis and cell cycle arrest at sub-G1 phase in fingolimod-treated cells. Furthermore, treating rats bearing intracranial C6 tumours with fingolimod led to significant suppression of intracranial tumour growth. Based on our findings, cell cycle arrest and apoptosis contribute to fingolimod antitumor effects.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 1","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142764141","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":"Biochemical Investigation of the Association of Apolipoprotein E Gene Allele Variations with Insulin Resistance and Amyloid-β Aggregation in Cardiovascular Disease","authors":"Komal Jabeen,&nbsp;Kanwal Rehman,&nbsp;Muhammad Sajid Hamid Akash,&nbsp;Amjad Hussain,&nbsp;Mudassar Shahid,&nbsp;Bushra Sadaf","doi":"10.1111/1440-1681.70007","DOIUrl":"https://doi.org/10.1111/1440-1681.70007","url":null,"abstract":"<p>This article investigates the intricate associations between apolipoprotein E (APOE) gene alleles variation, insulin resistance (IR) and amyloid-β aggregation in cardiovascular disease (CVD) patients. A cohort of 250 patients exhibiting the symptoms of CVD and 50 control subjects participated in this study. After applying the stringent inclusion and exclusion criteria, the diseased group was further stratified into three categories: CVD+ (Alzheimer's disease) AD, CVD + (diabetes mellitus) DM and CVD + DM + AD. Blood samples were collected from all recruited participants for the biochemical analyses of lipid profile, glycaemic status, liver function enzymes, inflammatory and oxidative stress biomarkers. Tetra amplification-refractory mutation system-polymerase chain reaction (ARMS-PCR) was employed for APOE gene analysis. Biochemical evaluations revealed the significant elevations in the serum levels of glucose, liver enzymes, interleukin-6 (IL-6), cholesterol, low-density lipoproteins (LDL), triglycerides (TG) and malondialdehyde (MDA) in CVD + DM + AD group. Conversely, the serum levels of insulin, HDL and hexokinase decreased in CVD + DM + AD group compared to the controls and other CVD groups. Tetra ARMS-PCR results indicated a higher percentage of the risk allele in CVD + DM + AD group when compared with the other groups. Our study elucidates the multifaceted cardiovascular risk factors contributing to IR and AD in CVD patients. Age-related risk factors, prevalence of APOE risk alleles and the impact of statin use on AD incidences were identified. These findings underscore the need for tailored preventive measures, particularly in APOEε4 and ε3/ε4 carriers with CVD. Further studies should delve into the knowledge-based protocols to comprehend the underlying mechanisms. Focusing on the therapeutic targets to prevent or delay DM and AD progression in CVDs, especially in APOEε4 carriers, is essential.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 1","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708169","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":"TLR4 Inhibitor TAK-242 Protected Henoch–Schonlein Purpura Nephritis in Rats by Regulating Inflammatory Response and Immune Competence via NF- κB/NLRP3 Signalling","authors":"Yirong Liu,&nbsp;Qiong Wu,&nbsp;Zhenxing Huang,&nbsp;Dongmei Zhou,&nbsp;Chao Cai,&nbsp;Wenliang Luo,&nbsp;Ping Feng","doi":"10.1111/1440-1681.70008","DOIUrl":"10.1111/1440-1681.70008","url":null,"abstract":"<div>\u0000 \u0000 <p>This study aimed to explore the effect of toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) signalling on Henoch–Schonlein purpura nephritis (HSPN). We established a HSPN rat model in a high-altitude hypoxic (HH) environment. Renal tissue lesions were observed by haematoxylin and Eosin (H&amp;E) staining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL), CD20-postive B cells and CD68-postive macrophage cells were detected by immunohistochemistry, T-cell activation was detected by flow cytometry and toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB)/NOD-like receptor thermal protein domain associated protein 3 (NLRP3) signalling was detected by western blot. TAK-242 inhibited the expression of TLR4/NF-κB/NLRP3 signalling related-proteins, decreased the levels of 24 h urinary protein, serum creatinine, circular immune complex (CIC) and kidney immunoglobulin A (IgA), and improved renal histopathological damage in HH-HSPN rats. Furthermore, TAK-242 attenuated the infiltration of CD20 and CD68 into the kidney and increased the percentage of CD3+, CD4+ and CD4+/CD8+ cells in the blood of HH-HSPN rats. The study revealed that suppressing TLR4/NF-κB/NLRP3 signalling improved renal function and histopathological damage, and this improvement was related to inhibiting the inflammatory response and enhancing immune competence.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 1","pages":""},"PeriodicalIF":2.9,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142675290","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}