Immunopharmacology and Immunotoxicology最新文献

{"title":"Clinical features, treatment, and outcome of nivolumab-induced cholangitis.","authors":"Yang He, Zhiqiang Fan, Wei Sun, Linqi Ouyang, Chunjiang Wang","doi":"10.1080/08923973.2024.2402338","DOIUrl":"10.1080/08923973.2024.2402338","url":null,"abstract":"<p><strong>Background: </strong>Cholangitis is an uncommon and severe adverse reaction of nivolumab with unclear clinical features. The purpose of this study was to investigate the clinicopathological features, imaging, and treatment of nivolumab-induced cholangitis.</p><p><strong>Methods: </strong>Case reports, case series, and clinical studies of nivolumab-induced cholangitis were retrospectively analyzed by searching Chinese and English databases from January 1, 2017 to December 31, 2023.</p><p><strong>Results: </strong>Thirty-eight patients entered the study. The median number of cycles of cholangitis onset was seven cycles after administration (range 1, 28) and the median time was 11 days (range 78, 390). Abdominal pain (42.1%) and fever (18.4%) were the most important initial symptoms. Some patients (15.8%) showed elevated liver enzymes without any clinical symptoms. The median alkaline phosphatase level was 1721 IU/L (range 126, 9118), and the median γ-glutamyltranspeptidase level was 829 IU/L (range 104, 3442). Anti-nuclear antibodies, anti-mitochondrial antibodies, and IgG4 typically show negative results. Imaging shows extrahepatic bile duct and intrahepatic bile duct dilation, hypertrophy, and stenosis. Liver biopsy and biliary tract biopsy mainly found CD8 inflammatory cell infiltration. Systemic steroids (84.2%) and ursodeoxycholic acid (UDCA) (34.2%) were administered, and 24 patients (63.2%) had poor to moderate response to steroids. Thirty-one patients (81.6%) improved and seven patients (18.4%) did not improve.</p><p><strong>Conclusions: </strong>Clinicians must remain vigilant for patients experiencing cholestasis while on nivolumab and should assess for cholangitis and carry out appropriate imaging tests. Considering the excellent efficacy of UCDA in cholangitis, steroids combined with UDCA may be a viable treatment option in cases where steroids are ineffective for cholangitis.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153917","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":"Aloin alleviates corneal injury in alkali burn via inhibiting neutrophil extracellular traps and promoting Nrf2.","authors":"Zhongxiu Zhao, Yan Wen, Yanli Peng, Weili Wang, Huafeng Ma","doi":"10.1080/08923973.2024.2402365","DOIUrl":"https://doi.org/10.1080/08923973.2024.2402365","url":null,"abstract":"<p><strong>Objective: </strong>Ocular chemical burns are a leading cause of blindness. The cornea is injured by alkali-induced oxidative disturbances and an inflammatory response. The aim of this study was to evaluate the protective effects of aloin, an antioxidant, and anti-inflammatory compound, on corneal alkali burn.</p><p><strong>Materials and methods: </strong>Mice eyes were injured by NaOH and subsequently treated with aloin eye drop and intraperitoneal injection. Pathological characteristics of the eyes were examined, and corneal samples were collected for further analysis.</p><p><strong>Results: </strong>Aloin diminished neutrophil infiltration and the production of proinflammatory cytokines. Aloin also attenuated apoptosis in human corneal epithelial cells (HCEs) by reducing oxidative stress through the activation of the Nrf2 pathway. Additionally, aloin suppressed the formation of neutrophil extracellular traps (NETs) and inhibited their deposition on the cornea. Moreover, aloin mitigated alkali-induced apoptosis in HCEs caused by NETs.</p><p><strong>Conclusions: </strong>These findings suggest that aloin has potential as an antioxidant and anti-inflammatory compound for treating corneal alkali burn by inhibiting NETs formation and promoting Nrf2.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142286185","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":"Neuroprotection of isoorientin against microglia activation induced by lipopolysaccharide via regulating GSK3β, NF-κb and Nrf2/HO-1 pathways.","authors":"Xiaoqin Tan, Mindie Cao, Yijing Zhao, Lang Yi, Yingui Li, Changhong He, Qing X Li, Yan Dong","doi":"10.1080/08923973.2024.2399249","DOIUrl":"https://doi.org/10.1080/08923973.2024.2399249","url":null,"abstract":"<p><p><b>Background:</b> Isoorientin (ISO), a flavone C-glycoside, is a glycogen synthase kinase 3β (GSK3β) substrate-competitive inhibitor. ISO has potential in treatment of Alzheimer's disease (AD). An excessive activation of GSK3β can lead to neuroinflammation causing neuronal damage. Microglia cells, as resident immune cells of the central nervous system, mediate neuroinflammation. Here, we studied the effects of ISO on microglial activation to alleviate neuroinflammation.</p><p><p><b>Methods:</b> Effects of ISO were observed upon the stimulation of mouse microglia BV2 or SIM-A9 cells by lipopolysaccharide (LPS). Lithium chloride (LiCl) was the positive control as a GSK3β inhibitor. The release of TNF-α and NO were analyzed by ELISA and Griess assays, while expressions of COX-2, Iba-1, BDNF, GSK3β, NF-κB p65, IκB, Nrf2 and HO-1 were detected by Western blotting. In the co-culture model of SIM-A9 cells and differentiated SH-SY5Y human neuroblastoma cells, effects of ISO on microglia-mediated neuronal damage were evaluated with the MTS assay.</p><p><p><b>Results:</b> ISO significantly inhibited the production of TNF-α (<i>p</i> < 0.01), NO (<i>p</i> < 0.001) and the expression of COX-2 (<i>p</i> < 0.01) and Iba-1 (<i>p</i> < 0.05) induced by LPS, and increased BDNF. The cell viability of SH-SY5Y was inhibited by LPS in the co-culture, which was prevented by ISO pretreatment. ISO increased the expression of p-GSK3β (Ser9), IκB and HO-1 in the cytoplasm, decreased NF-κB p65 and increased Nrf2 in the nucleus compared with the LPS group.</p><p><p><b>Conclusion:</b> ISO attenuated the activation of microglia through regulating the GSK3β, NF-κB and Nrf2/HO-1 signaling pathways to exert neuroprotection.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142153918","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":"Emulsified isoflurane pretreatment attenuates myocardial ischemia-reperfusion injuries by suppressing toll-like Receptor-4.","authors":"Zujin Xu, Zhen Li, Shuxian Chen, Yali Zhu, Yanlin Wang, Jia Zhan, Yun Wu","doi":"10.1080/08923973.2024.2399266","DOIUrl":"https://doi.org/10.1080/08923973.2024.2399266","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the mechanism of emulsified isoflurane in reducing myocardial ischemia-reperfusion injury (MIRI).</p><p><strong>Materials and methods: </strong>Forty-eight healthy male Sprague-Dawley rats were randomly divided into four groups (<i>n</i> = 12). In the sham group (group S) and ischemia-reperfusion group (group I/R), saline (4 ml/kg/h) was administered intravenously for 30 min. In intralipid group (group L), intralipid (4 ml/kg/h) was administered intravenously. In the emulsified isoflurane group (group EI), emulsified isoflurane (4 ml/kg/h) was administered intravenously. The infusion was then discontinued for 15 min during the washout period. Apart from group S, ischemia was produced by occlusion of the left anterior descending artery (LADA) for 30 min. After 30 min of occlusion, all groups received reperfusion for two hours.</p><p><strong>Results: </strong>Creatine kinase MB (CK-MB), cardiac troponin I (cTnI), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were measured by enzyme-linked immunosorbent assay (ELISA). Myocardial infarct size was measured using triphenyl tetrazolium chloride staining. According to the result, pretreatment with emulsified isoflurane attenuated CK-MB and cTnI concentrations (<i>p</i> < 0.05). And serum TNF-α and IL-6 levels and infarct size in the emulsified isoflurane group obviously decreased. An obvious decrease in the expression of the toll-like receptor-4 (TLR-4) mRNA in group EI was observed compared with group I/R.</p><p><strong>Discussion and conclusion: </strong>Emulsified isoflurane precondition had a potent cardioprotective effect against myocardial ischemia-reperfusion injury. The mechanisms involved may be related to the decrease in the expression of TLR-4 and the reduced inflammatory response.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142132617","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":"Anti-inflammatory effect of proanthocyanidins from blueberry through NF-κβ/NLRP3 signaling pathway <i>in vivo</i> and <i>in vitro</i>.","authors":"Xinyao Liu, Lulu Zang, Jiabao Yu, Jinjin Yu, Siqi Wang, Lili Zhou, Huixin Song, Yajing Ma, Xiaofeng Niu, Weifeng Li","doi":"10.1080/08923973.2024.2358770","DOIUrl":"10.1080/08923973.2024.2358770","url":null,"abstract":"<p><strong>Background: </strong>Systemic inflammatory response syndrome (SIRS) is an uncontrolled systemic inflammatory response. Proanthocyanidins (PC) is a general term of polyphenol compounds widely existed in blueberry fruits and can treat inflammation-related diseases. This study aimed to explore the regulatory effect of PC on lipopolysaccharide (LPS)-induced systemic inflammation and its potential mechanism, providing effective strategies for the further development of PC.</p><p><strong>Methods: </strong>Here, RAW264.7 macrophages were stimulated with LPS to establish an inflammation model <i>in vitro</i>, while endotoxin shock mouse models were constructed by LPS <i>in vivo</i>. The function of PC was investigated by MTT, ELISA kits, H&E staining, immunohistochemistry, and Western blot analysis.</p><p><strong>Results: </strong>Functionally, PC could demonstrate the potential to mitigate mortality in mice with endotoxin shock, as well as attenuated the levels of inflammatory cytokines (IL-6, TNF-α) and biochemical indicators (AST, ALT, CRE and BUN). Moreover, it had a significant protective effect on lung and kidney tissues damage. Mechanistically, PC exerted anti-inflammatory effects by inhibiting the activation of the NF-κB/NLRP3 signaling pathway.</p><p><strong>Conclusion: </strong>PC might have the potential ability of anti-inflammatory effects <i>via</i> modulation of the NF-κB/NLRP3 signaling pathway.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141075950","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":"CS12192, a novel JAK3/JAK1/TBK1 inhibitor, attenuates autoimmune dermatoses in murine models.","authors":"Dan Li, Song Shan, Xuhua Mao, Yiru Zhao, Beizhong Chen, Qiuyun Xiong, Desi Pan, Shengjian Huang","doi":"10.1080/08923973.2024.2373223","DOIUrl":"10.1080/08923973.2024.2373223","url":null,"abstract":"<p><strong>Objective: </strong>Autoimmune dermatosis (AID) occurs when the body's immune system attacks skin or tissue, leading to various types of skin disorders or injuries. Recent studies show that Janus kinases (JAKs) play critical roles in autoimmune diseases including AID by regulating multiple cytokine signaling pathways. CS12192, a novel JAK3/JAK1/TBK1 inhibitor, has been reported to exert ameliorative effects in rheumatoid arthritis. However, the efficacy of CS12192 on AID is undetermined. This study aims to investigate the therapeutic efficacy of CS12192 on psoriasis (PSO), systemic lupus erythematosus (SLE) and atopic dermatitis (AD) in mouse models.</p><p><strong>Methods: </strong>Interleukin-23 (IL-23)-induced PSO model, spontaneous SLE model of MRL/MpJ-Faslpr/J (MRL/lpr) mice, and oxazolone (OXA) and dinitrochlorobenzene (DNCB)-induced murine AD models were used for the evaluation of curative effects of CS12192, respectively. The skin lesion, biochemical parameters, ear thickness, ear weight and histopathology were assessed accordingly.</p><p><strong>Results: </strong>In PSO model, mice treated with CS12192 show reduced ear thickness and ear weight as compared with vehicle. In SLE model, CS12192 ameliorates cutaneous parameters such as lymphadenectasis and skin lesion but not systematic parameters such as proteinuria concentration and score, serum dsDNA and BUN concentration. In AD models, CS12192 dose-dependently improves ear swelling and reduces histological scores, exerting equivalent efficacy with baricitinib, a marketed JAK1/JAK2 inhibitor.</p><p><strong>Conclusion: </strong>Our findings suggest that the novel JAK3/JAK1/TBK1 inhibitor CS12192 is potentially to alleviate autoimmune dermatosis.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450405","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":"Is resveratrol really effective in kidney disease?: A different perspective than ever before.","authors":"Sümeyye Kemaneci, Alev Keser, Özlem Özmen","doi":"10.1080/08923973.2024.2360067","DOIUrl":"10.1080/08923973.2024.2360067","url":null,"abstract":"<p><strong>Background: </strong>Chronic kidney disease (CKD) is a global health problem and it is stated that the use of resveratrol supplement contributes to the protection of kidney health. In this study, it was aimed to evaluate the effect of resveratrol supplementation on kidney function, inflammation and histopathological findings in rats with experimental adenine-induced kidney damage.</p><p><strong>Methods: </strong>Three different groups of 10 randomly selected rats were formed. The first group was the negative control group, the second group was the uremic control group (KDG), and the third group was the group in which uremia was created and resveratrol was applied (RG). Kidney damage was induced by administration of 200 mg/kg adenine. Resveratrol supplementation was administered at 20 mg/kg after kidney damage. Serum urea, creatinine, indoxyl sulfate (IS), p-cresol, glomerular filtration rate, C-reactive protein (CRP); interleukin (IL)-6 and tumor necrosis factor (TNF)-α gene expression levels and histopathological findings were evaluated.</p><p><strong>Results: </strong>It was determined that resveratrol supplement applied after the formation of connective tissue in renal failure didn't have an improvement effect on the urine amount, kidney function and inflammatory parameters and histopathological changes (<i>p</i> > 0.05). Just, the increase in the CRP value of KDG (<i>p</i> < 0.05) was not observed in RG.</p><p><strong>Conclusion: </strong>The findings suggest that resveratrol administered after kidney damage with adenine has no effect on kidney disease.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141175588","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":"Acute kidney injury associated with anti-PD-1 and anti-PD-L1 drugs: a meta-analysis of randomized clinical trials.","authors":"Isabela Gonçalves Lima, Isabele Benck Usiro Cabral da Silva, Vitória Carpentieri Pípolo, Vinicius Daher Alvares Delfino, Paulo Roberto Bignardi","doi":"10.1080/08923973.2024.2360071","DOIUrl":"10.1080/08923973.2024.2360071","url":null,"abstract":"<p><strong>Background: </strong>Immune Checkpoint Inhibitors (ICI) have been widely used in treating different types of cancer. They increase survival in many oncologic patients and enable cancer-specific therapy. Acute Kidney Injury (AKI) is one of the adverse effects associated with using ICI, where knowledge of the prevalence and renal histological findings are still reasons for discussion.</p><p><strong>Objective: </strong>Therefore, this meta-analysis evaluates the association between ICI use and AKI.</p><p><strong>Methods: </strong>The search was performed in PubMed, Lilacs, and Cochrane platforms. Studies published up to December 1, 2022, were included.</p><p><strong>Results: </strong>A total of 16 studies met the established PICOT criteria and were included in this review. Comparing the ICI plus chemotherapy against chemotherapy alone, the relative risk (RR) for AKI's development with ICI use was 2.89 (95%CI 1.37-6.10). In the analyses by class and drug type, programmed cell death 1 monoclonal antibody (anti-PD-1) showed an increased risk of 2.11 (95%CI 1.26-3.52), and pembrolizumab demonstrated a risk of AKI (RR= 2.77, 95%CI 1.46-5.26). Likewise, regarding the severity of AKI, AKI grade 3 or higher was more common in the ICI plus chemotherapy compared to the chemotherapy group: 3.66 (95%CI 1.19-11.30), while the subgroup analyses pooled studies comparing ICI alone versus chemotherapy alone in the control group did not demonstrate an association with AKI.</p><p><strong>Conclusions: </strong>These findings suggest that ICI use is associated with an increased risk of AKI and that anti-PD-1 use is associated with a higher incidence of renal adverse events than programmed cell death ligand 1 monoclonal antibody (anti-PD-L1). Studies with adequate power and well-defined criteria for acute interstitial nephritis, nowadays taken as a synonym for AKI related to ICI, are necessary.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141199836","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":"Reno-protective effect of fenofibrate and febuxostat against vancomycin-induced acute renal injury in rats: Targeting PPARγ/NF-κB/COX-II and AMPK/Nrf2/HO-1 signaling pathways.","authors":"Ehab A M El-Shoura, Souty M Z Sharkawi, Lobna A Abdelzaher, Basel A Abdel-Wahab, Yasmine H Ahmed, Asmaa Ramadan Abdel-Sattar","doi":"10.1080/08923973.2024.2373216","DOIUrl":"10.1080/08923973.2024.2373216","url":null,"abstract":"<p><strong>Background: </strong>Vancomycin (VCM) is used clinically to treat serious infections caused by multi-resistant Gram-positive bacteria, although its use is severely constrained by nephrotoxicity. This study investigated the possible nephroprotective effect of febuxostat (FX) and/or fenofibrate (FENO) and their possible underlying mechanisms against VCM-induced nephrotoxicity in a rat model.</p><p><strong>Methods: </strong>Male Wistar rats were randomly allocated into five groups; Control, VCM, FX, FENO, and combination groups. Nephrotoxicity was evaluated histopathologically and biochemically. The oxidative stress biomarkers (SOD, MDA, GSH, total nitrite, GPx, MPO), the apoptotic marker, renal Bcl-2 associated X protein (Bax), and inflammatory and kidney injury markers (IL-1β, IL-6, TNF-α, Nrf2, OH-1, kappa-light-chain-enhancer of activated B cells (NF-κB), NADPH oxidase, Kim-1, COX-II, NGAL, Cys-C were also evaluated.</p><p><strong>Results: </strong>VCM resulted in significant elevation in markers of kidney damage, oxidative stress, apoptosis, and inflammatory markers. Co-administration of VCM with either/or FX and FENO significantly mitigated nephrotoxicity and associated oxidative stress, inflammatory and apoptotic markers. In comparison to either treatment alone, a more notable improvement was observed with the FX and FENO combination regimen.</p><p><strong>Conclusion: </strong>Our findings show that FX, FENO, and their combination regimen have a nephroprotective impact on VCM-induced kidney injury by suppressing oxidative stress, apoptosis, and the inflammatory response. Renal recovery from VCM-induced injury was accomplished by activation of Nrf2/HO-1 signaling and inhibition of NF-κB expression. This study highlights the importance of FX and FENO as effective therapies for reducing nephrotoxicity in VCM-treated patients.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141450406","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":"Study on the mechanism of glucocorticoid receptor mitochondrial translocation and glucocorticoid-induced apoptosis in macrophages.","authors":"Xiaoqing Zhao, Xinglan Huang, Caifeng Huang, Xingrong Wang, Yuqi Yang, Ruonan Dang, Suiying Zhang, Yuqiong Deng, Peng Yan, Yiye Zhou, Ping Fan, Xiping Cheng","doi":"10.1080/08923973.2024.2366867","DOIUrl":"10.1080/08923973.2024.2366867","url":null,"abstract":"<p><strong>Objective: </strong>Our research aimed to investigate the therapeutic effects of Tubastatin-A, a glucocorticoid receptor (GR) mitochondrial translocation inhibitor, and mitoquinone (MitoQ), an antioxidant, on attenuating dexamethasone (DEX)-induced macrophage apoptosis.</p><p><strong>Methods: </strong>We treated RAW264.7 macrophages with different combinations of DEX and either Tubastatin-A or MitoQ. Parameters such as mitochondrial GR translocation, mitochondrial reactive oxygen species levels, mitochondrial membrane potential, mitochondrial permeability transition pore opening, cytochrome C efflux to the cytosol, and apoptosis were subsequently evaluated in the different treatment groups <i>via</i> qRT-PCR, western blotting, and immunofluorescence assays.</p><p><strong>Results: </strong>DEX intervention increased the translocation of GRs into the mitochondria, while reducing the expression of the mitochondrial gene MT-CO1 and the activity of mitochondrial respiratory chain complex IV in macrophages. In addition, DEX administration increased mtROS levels, mitochondrial permeability transition pore opening, and mitochondrial cytochrome C release in macrophages, which promoted their apoptosis. We found that Tubastatin-A inhibited mitochondrial GR translocation and reversed the DEX-induced increase in GR levels within the mitochondria. Furthermore, Tubastatin-A mitigated various mitochondrial changes induced by DEX, including reducing the efflux of mitochondrial cytochrome C and inhibiting macrophage apoptosis. Similarly, MitoQ exerted its effects on macrophage apoptosis by reducing mtROS levels through the mitochondrial pathway.</p><p><strong>Conclusions: </strong>The DEX-mediated translocation of GR into mitochondria disrupts the mitochondrial function of macrophages, which induces their apoptosis. By inhibiting mitochondrial translocation of GR and reducing mtROS levels, Tubastatin-A and MitoQ can effectively attenuate macrophage apoptosis, which has clinical implications for reducing the notable side effects associated with glucocorticoid use.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141305857","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}