Clinical and Experimental Pharmacology and Physiology最新文献

{"title":"M2 Macrophages-Derived Exosomes Inhibited Podocyte Pyroptosis via lncRNA AFAP1-AS1/EZH2 Axis","authors":"Qing Zhan,&nbsp;Huiyun Liu,&nbsp;Minyang Zhao,&nbsp;Haihua Huang","doi":"10.1111/1440-1681.70056","DOIUrl":"https://doi.org/10.1111/1440-1681.70056","url":null,"abstract":"<div>\u0000 \u0000 <p>Macrophage infiltration was closely associated with inflammatory injury of podocytes in diabetic nephropathy (DN), while how macrophages affected podocytes remained not entirely clear. Here, we not only investigated the relationship between macrophages and high glucose (HG)-treated podocytes, but the underlying mechanisms were also explored. Transmission electron microscopy, nanoparticle tracking analysis, and western blot of CD9, CD63, CD81, and Calnexin were performed to identify exosomes; QRT-PCR was performed to detect AFAP1-AS1 expression; Western blot was performed to examine NLRP3, Cleaved caspase-1, and GSDMD-N protein levels; Immunofluorescence was performed to assess co-localisation of NLRP3 and ASC; ELISA was performed to detect IL-18 and IL-1β levels; Cytotoxicity LDH Assay Kit was performed to detect LDH level; RNA pulldown was performed to determine the interaction of AFAP1-AS1 and EZH2; ChIP was employed to determine the interaction of EZH2 and H3K27me3 in the NLRP3 promoter region. The results showed that AFAP1-AS1 expression was down-regulated in the peripheral blood of DN patients, and exosomes derived from M2 macrophages transfected with si-AFAP1-AS1 enhanced HG-induced podocyte pyroptosis via significantly elevating NLRP3, Cleaved caspase-1, and GSDMD-N protein levels, immunofluorescence intensity of NLRP3 and ASC, as well as IL-18, IL-1β, and LDH levels. Mechanistically, AFAP1-AS1 interacted with EZH2 to transcriptionally regulate H3K27me3 level in the NLRP3 promoter region, thus epigenetically repressing NLRP3 level to inhibit podocyte pyroptosis. These results may provide an important target for improving kidney injury in DN.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 9","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144635533","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":"Potential Kidney Risks Associated With Clinical Doses of Omeprazole: In Vivo and In Vitro Studies","authors":"Zibo Xiong,&nbsp;Zhiwei Lai,&nbsp;Sanmu Li,&nbsp;Hua Zhang,&nbsp;Yongqiang Wang,&nbsp;Lishan Tan,&nbsp;Guang Yang,&nbsp;Zuying Xiong","doi":"10.1111/1440-1681.70050","DOIUrl":"https://doi.org/10.1111/1440-1681.70050","url":null,"abstract":"<p>Omeprazole is a widely used proton pump inhibitor and anti-<i>Helicobacter pylori</i> drug; however, its nephrotoxicity has been controversial. This study aimed to explore the effects and mechanisms of omeprazole on the kidney. In HK2, HPC, NRK and 293 T cells, omeprazole-induced alterations in cell morphology, density and viability in a concentration-dependent manner. Excessively high concentrations (&gt; 50 μM) led to a significant increase in cell death. Interestingly, NRK seemed insensitive to omeprazole. RNA sequencing revealed significant alterations in the genomic expression profile when HK2 cells were incubated at a concentration of 5 μM, including the inhibition of proliferative, metabolic and cytokine receptor gene expression. This alteration augments the environmental susceptibility of HK2 when exposed to H₂O₂. Animal studies have shown that omeprazole (10.4 mg/kg × day, 28 days) has no significant effect on body weight, kidney or heart weight or kidney or liver function, as well as plasma calcium and vitamin D. Tissue staining revealed increased expression of the macrophage marker F4/80 in response to omeprazole. In conclusion, therapeutic-dose omeprazole administration in the short term shows no clinically relevant nephrotoxicity. However, omeprazole decreases cell proliferation and viability by disrupting gene expression; thus, the long-term use of omeprazole may increase inflammation and environmental susceptibility. These findings provide valuable insights for the clinical use of omeprazole, highlighting the need for careful consideration of its effects in the kidney.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 8","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/1440-1681.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144573761","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":"Decrease in Mitochondrial Oxidative Respiratory Function in Liver of Cricetulus barabensis Under Long and Short Photoperiods: The Role of Mitochondrial Fission and Apoptosis","authors":"Jin-Hui Xu,&nbsp;Lu-Fan Li,&nbsp;Yi-Man Liu,&nbsp;Xin-Yi Song,&nbsp;Le Chen,&nbsp;Ming-Di Wang,&nbsp;Li-Na Jiang,&nbsp;Zhe Wang","doi":"10.1111/1440-1681.70054","DOIUrl":"https://doi.org/10.1111/1440-1681.70054","url":null,"abstract":"<div>\u0000 \u0000 <p>The photoperiod is a crucial factor affecting the seasonal rhythms of mammals. Under the seasonal rhythms, the growth and development of the body are closely related to the oxidative respiratory function of mitochondria, but the influence of the single seasonal factor photoperiod on it remains unclear. In this study, mitochondrial dynamics and associated regulatory mechanisms were investigated in the livers of striped dwarf hamsters (<i>Cricetulus barabensis</i>) exposed to three distinct photoperiod regimes: short photoperiod (SP), moderate photoperiod (MP) and long photoperiod (LP). Results indicated that: (1) Liver mass responses to photoperiod varied with changes in body weight. (2) ATP synthase activity was significantly decreased under LP, whereas citrate synthase activity (CS) was selectively diminished under SP. (3) The Bcl2 associated X protein (bax) to b cell lymphoma 2 (bcl2) ratio increased under both SP and LP. (4) Dynamin-related protein 1 (DRP1) protein abundance increased under both LP and SP conditions, while mitochondrial fission factor (MFF) decreased under LP, signifying divergent remodelling of mitochondrial fission signalling. (5) Caspase3 activity unchanged under SP. In conclusion, under LP and SP treatment, the oxidative respiratory function of liver mitochondria in striped dwarf hamsters may be weakened, potentially due to increased mitochondrial membrane permeability, as indicated by an elevated bax/bcl2 ratio. Compared to long photoperiod treatment, the upregulation of the liver mitochondrial fission signalling and the lower level of apoptosis under short photoperiod conditions may help facilitate thermogenic adaptation to increased energetic demands in winter.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 8","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144514703","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":"GPR39 Activation Attenuates AngII-Induced Abdominal Aortic Aneurysm by Suppressing ETS-1 Mediated VEGF-A/VEGFR2 Signalling","authors":"Bin Liu,&nbsp;Yiming Xu,&nbsp;Yuanyuan Liu,&nbsp;Yue Zhang,&nbsp;Haiyan Mao","doi":"10.1111/1440-1681.70053","DOIUrl":"https://doi.org/10.1111/1440-1681.70053","url":null,"abstract":"<div>\u0000 \u0000 <p>Abdominal aortic aneurysm (AAA), a vascular condition that endangers life, is typified by the progressive weakening and dilation of the aortic wall. In its pathogenic process, oxidative stress and angiogenesis assume crucial functions. This research explored the function of G protein-coupled receptor 39 (GPR39) in angiotensin II (AngII)-induced AAA in ApoE−/− mice and its underlying mechanisms. A series of in vivo and in vitro experiments were performed, including AngII infusion-induced AAA in mice, histological analysis, ELISA, Western blotting, quantitative PCR, and angiogenic tube formation assays. GPR39 expression was significantly downregulated in arterial tissues of AngII-induced AAA mice, as evidenced by reduced mRNA and protein. Administration of the GPR39 agonist TC-G 1008 markedly attenuated AAA progression, reducing aneurysm incidence and size. Furthermore, TC-G 1008 alleviated oxidative stress through reducing the levels of malondialdehyde (MDA) and augmenting the activity of superoxide dismutase (SOD) as well as the levels of glutathione (GSH) in arterial tissues. TC-G 1008 also suppressed the vascular endothelial growth factor A (VEGF-A) and vascular endothelial growth factor receptor 2 (VEGF-R2) expressions in both saline- and AngII-infused mice. In vitro, TC-G 1008 inhibited AngII-induced angiogenic tube formation in human umbilical vein endothelial cells (HUVECs) and downregulated VEGF-A/VEGFR2 signalling. Mechanistically, TC-G 1008 reduced the expression of the transcription factor Ets-related transcription factor 1 (ETS-1), which is involved in VEGF-A/VEGFR2 regulation. Overexpression of ETS-1 reversed the inhibitory effects of TC-G 1008 on VEGF-A/VEGFR2 levels and angiogenic tube formation, confirming the critical role of ETS-1 in this pathway. These findings demonstrate that GPR39 activation by TC-G 1008 protects against AngII-induced AAA by mitigating oxidative stress, suppressing VEGF-A/VEGFR2 signalling, and inhibiting ETS-1-mediated angiogenesis.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 8","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144514907","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":"Frailty: An Important Determinant Influencing Glycaemic Control in Elderly Chinese Patients Diagnosed With Type 2 Diabetes","authors":"Lei Cao,&nbsp;Shuang-shuang Chen,&nbsp;Qing Xu,&nbsp;Can Chen,&nbsp;Qian-zhou Lv,&nbsp;Xiao-mu Li,&nbsp;Xiao-yu Li","doi":"10.1111/1440-1681.70049","DOIUrl":"https://doi.org/10.1111/1440-1681.70049","url":null,"abstract":"<div>\u0000 \u0000 <p>Few studies have investigated blood glucose levels and complication management in elderly patients with type 2 diabetes (T2D) at community hospitals in China. The objective of this study was to investigate the factors influencing blood glucose control in elderly patients with T2D. One thousand one hundred and fifty elderly patients (age ≥ 65 years) with T2D were involved in the study to assess blood glucose control, health status (including comorbidities and cognitive status), complication management, and adherence to medication according to the guidelines of the American Diabetes Association. The FRAIL scale was used to screen for frailty syndrome in the elderly patients. Univariate and multivariate logistic regression analyses were used to investigate the factors affecting glucose control. Among the 1150 participants, 351 (30.52%) had poor glucose control. Frailty (odds ratio [OR]:2.546; 95% confidence interval [CI]: 1.267–5.117; <i>p</i> = 0.009), male sex (OR:0.679; 95% CI: 0.522–0.884; <i>p</i> = 0.004), and insulin treatment (OR: 0.229; 95% CI: 0.165–0.317; <i>p</i> &lt; 0.001) were significantly independently associated with poor blood glucose control. In conclusion, for elderly patients with T2D, more attention should be paid to men, insulin therapy initiation and screening for frailty.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 8","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144514908","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":"Synthesis, Characterization, Molecular Dynamic Simulation and Neuroprotective Effects of Synthetic Isoxazolone Derivatives in Ethanol-Induced Neurodegeneration","authors":"Maria Awan,&nbsp;Faisal Albaqami,&nbsp;Humaira Nadeem,&nbsp;Iqra Zulfiqar,&nbsp;Najeeb Ur Rehman,&nbsp;Muhammad Ayaz,&nbsp;Mohd Faiyaz Khan,&nbsp;Fawad Ali Shah","doi":"10.1111/1440-1681.70051","DOIUrl":"https://doi.org/10.1111/1440-1681.70051","url":null,"abstract":"<div>\u0000 \u0000 <p>Alcoholism and alcohol misuse are major public health concerns, and chronic alcohol consumption negatively impacts memory and can lead to neurodegeneration and neuroinflammation. Neuroinflammation is a prevalent characteristic of all neurological diseases, induced by oxidative stress and resulting in impaired neuronal function. Thus, targeting neuroinflammation and oxidative stress can be a pivotal mechanism for attenuating memory impairment. In the current study, new isoxazolone derivatives were synthesized, and their synthetic properties were characterized using proton nuclear magnetic resonance (¹H NMR) and Fourier transform infrared (FTIR) spectroscopy. The molecular simulation studies were performed on triggering receptors expressed on myeloid cells-1 (TREM-1) and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3). Further, these derivatives were evaluated for neuroprotective potential in an ethanol-induced neuroinflammation model in male albino mice. Our results demonstrated ethanol-induced cognitive deficits, elevated inflammatory markers, ROS and altered endogenous antioxidant enzyme levels. At the same time, treatment with isoxazolone reversed the hyperactivated inflammatory markers, including NLRP3, and modulated the TREM-2 expression. Further, the antioxidant and anti-cholinesterase potential of these derivatives was also evaluated using in vitro assays. Our results suggested that these derivatives may help reduce neuroinflammation by acting on several stages of the inflammatory process in an ethanol-induced neurodegenerative model.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 8","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339457","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":"Stachydrine Protects Against Cyclophosphamide-Induced Premature Ovarian Insufficiency in Wistar Rats by Inhibiting Oxidative Stress and Apoptosis via the Activation of the Nrf2/HO-1 Signalling Pathway","authors":"Cong Feng,&nbsp;Yue Jiang,&nbsp;Yuehui Zhang,&nbsp;Yu Liu,&nbsp;Lihong Zhang","doi":"10.1111/1440-1681.70052","DOIUrl":"https://doi.org/10.1111/1440-1681.70052","url":null,"abstract":"<div>\u0000 \u0000 <p>Excessive oxidative stress and apoptosis of ovarian granulosa cells lead to severe ovarian dysfunctions and even premature ovarian insufficiency (POI). Stachydrine (STA), the main active component of <i>Leonurus japonicas</i>, possesses antioxidant and anti-apoptotic actions. However, the effects of STA on POI remain unknown. This work aimed to investigate STA's role in cyclophosphamide (CP)-induced POI. CP was intraperitoneally injected into rats for 14 days (200 mg/kg for day 1, 8 mg/kg for day 2–14) to establish a POI model, and STA (20 or 40 mg/kg/d) was orally given to rats for three weeks after CP treatment. We found that STA treatment (40 mg/kg) alleviated the estrous cycle disorder and the imbalance of serum sex hormone levels in CP-treated rats. Further, STA administration (40 mg/kg) inhibited oxidative stress and apoptosis of ovarian granulosa cells. Subsequently, human granulosa-like cells (KGN) were treated with CP (250 μM) for 48 h, followed by STA administration (1 μM) for 24 h to investigate the in vitro effects of STA. Consistently, STA treatment prevented KGN cells from CP-induced cell damage. In detail, STA treatment activated the Nrf2/HO-1 signalling pathway, thereby inhibiting the oxidative stress and cell apoptosis of CP-injured KGN cells. In conclusion, STA exerted a protective role in CP-induced POI by alleviating oxidative stress and apoptosis through activating the Nrf2/HO-1 signalling pathway, providing a new insight into POI treatment.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 8","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144339458","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":"Linarin Relieves Apoptosis, Inflammation and Oxidative Stress in LPS-Induced Acute Kidney Injury by Modulating COX2","authors":"Jia Zhang,&nbsp;Wenqi Wang,&nbsp;Yafen Liu,&nbsp;Xiaoqing Wan,&nbsp;Lin Zhang","doi":"10.1111/1440-1681.70048","DOIUrl":"https://doi.org/10.1111/1440-1681.70048","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Acute kidney injury (AKI) is a common clinical disease with a rapid decline of renal function. Linarin (LIN) is a flavonoid compound with wide application in different diseases. However, the role and relevant mechanism of LIN in AKI are not fully clear. This study aimed to investigate the function of LIN in modulating the inflammatory response and oxidative stress in lipopolysaccharide (LPS)-induced AKI models and further focused on the interaction between LIN and cyclooxygenase-2 (COX2).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>AKI model in vivo was established in mice with 10 mg/kg LPS and 60 mg/kg/day LIN. Also, the AKI model in vitro was constructed in HK2 cells with 10 μg/mL LPS and 40 μM LIN. The TUNEL assay was used for apoptosis detection in tissues. Cell viability and apoptosis were examined using the CCK-8 assay and flow cytometry. Inflammatory factors and oxidative indicators were determined via ELISA and commercial kits. Target screening was carried out using the PPI network and molecular docking. Expression analysis was performed by RT-qPCR and western blot.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>LIN protected kidney tissues from LPS-induced kidney dysfunction and pathological damage in mice. Apoptosis, inflammatory reaction and oxidative stress in LPS-induced mice were restored by LIN. LIN treatment also mitigated kidney cell apoptosis, inflammation and oxidative injury caused by LPS. COX2 (PTGS2) was selected as a hub gene for LIN and AKI through PPI network, and its interaction with LIN was proved by molecular docking. LIN could decrease the COX2 protein expression in LPS-treated HK2 cells. The protective function of LIN from LPS-induced cell injury was achieved by downregulating COX2 level.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These evidences demonstrated that LIN alleviated inflammation and oxidative stress in LPS-stimulated AKI through reducing COX2 protein level.</p>\u0000 </section>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 7","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144244693","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Novel Inhibitor of Methyltransferase SMYD2, AZ505 Protects Against Peritoneal Fibrosis in Mice","authors":"Taijing Xu,&nbsp;Binbin Cui,&nbsp;Feng Liu,&nbsp;Mengjun Liu,&nbsp;Xiying Hou,&nbsp;Xuan Hong,&nbsp;Hualin Qi","doi":"10.1111/1440-1681.70035","DOIUrl":"https://doi.org/10.1111/1440-1681.70035","url":null,"abstract":"<p>AZ505, a highly selective inhibitor of SMYD2, exhibits an antifibrotic effect in renal fibrosis. Its effect on peritoneal fibrosis remains unexplored. In this study, we investigated its effects on the development of peritoneal fibrosis induced by chlorhexidine gluconate (CG) in a murine model. We found that SMYD2 and trimethylated histone substrate H3K36 (H3K36me3) were highly expressed in the peritoneal tissue following CG injection, and administration of AZ505 remarkably inhibited their expression, along with attenuating CG–induced peritoneal fibrosis and expression of collagen I and fibronectin. Moreover, AZ505 also significantly reduced expression of CD31 (marker of angiogenesis) and CD68-positive macrophage infiltration in the CG-injured peritoneum. AZ505 further inhibited CG-induced epithelial-to-mesenchymal transition (EMT) of peritoneal mesothelial cells, manifested by decreasing expression of α-smooth muscle antigen (α-SMA) and Vimentin and restoring E-cadherin expression, accompanied by suppressing expression of two transcription factors, Snail and Twist. Finally, AZ505 inhibited CG-induced phosphorylation of AKT and increased expression of phosphatase and tensin (PTEN), a key phosphatase. These data suggest that AZ505 may protect against peritoneal fibrosis by inhibiting EMT, inflammation and angiogenesis, due to its blockade of methylation modification catalysed by SMYD2.</p>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 7","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/1440-1681.70035","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135790","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MRGPRX2-Mediated Mast Cell Degranulation by Monomethyl Methacrylate: Unveiling a Pathway in Bone Cement Implantation Syndrome","authors":"Yasuyuki Suzuki,&nbsp;Liu Shuang,&nbsp;Erika Takemasa,&nbsp;Yasushi Takasaki,&nbsp;Toshihiro Yorozuya,&nbsp;Masaki Mogi","doi":"10.1111/1440-1681.70046","DOIUrl":"https://doi.org/10.1111/1440-1681.70046","url":null,"abstract":"<div>\u0000 \u0000 <p>Bone cement implantation syndrome is a critical complication of orthopaedic surgery, characterised by hypotension and hypoxemia. This syndrome is hypothesised to result from obstruction caused by fat droplets and the biochemical release of histamine caused by bone cement components. This study aimed to elucidate the histamine release mechanism, focusing on Mas-related G protein-coupled receptor X2 expressed on mast cells, which is hypothesised to be activated by bone cement components. Using a mast cell-deficient mouse femur fracture model, we examined bone cement's effect on serum histamine. Rat basophil-like cells expressing Mas-related G protein-coupled receptor X2 were exposed to monomethyl methacrylate, a bone cement component, to assess degranulation via <i>β</i>-hexosaminidase release. Our findings demonstrated that histamine levels significantly increased in wild-type mice post-cement application, from 27.7 ± 11.1 to 35.3 ± 12.9 ng/mL (<i>p</i> = 0.016). Furthermore, Mas-related G protein-coupled receptor X2 expressing cells showed a marked increase in <i>β</i>-hexosaminidase release upon monomethyl methacrylate stimulation (<i>p</i> = 4.30 × 10⁻⁵). These results support the hypothesis that activating Mas-related G protein-coupled receptor X2 by monomethyl methacrylate contributes to bone cement implantation syndrome via histamine release. Bone cement implantation syndrome can manifest as a condition involving either peripheral vascular embolism, the release of chemical mediators, or a combination of both. Our research elucidates the role of chemical mediators, particularly histamine-induced vasodilation, in the pathophysiology of bone cement implantation syndrome, providing valuable insights that pave the way for targeted interventions to mitigate this severe complication during orthopaedic surgery.</p>\u0000 </div>","PeriodicalId":50684,"journal":{"name":"Clinical and Experimental Pharmacology and Physiology","volume":"52 7","pages":""},"PeriodicalIF":2.9,"publicationDate":"2025-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143944933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}