Mingxia Li, Juan Tan, Rongsen Zhang, Xiaoxiang Gong, Jun Xie, Cong Liu, Chenhao Wu, Xiaojing Li
{"title":"Sunitinib alleviates hepatic ischemia reperfusion injury by inhibiting the JAK2/STAT pathway and promoting the M2 polarization of macrophages.","authors":"Mingxia Li, Juan Tan, Rongsen Zhang, Xiaoxiang Gong, Jun Xie, Cong Liu, Chenhao Wu, Xiaojing Li","doi":"10.1080/08923973.2024.2390455","DOIUrl":"10.1080/08923973.2024.2390455","url":null,"abstract":"<p><strong>Background: </strong>Hepatic ischemia reperfusion injury (IRI) is a common liver surgery complication. This study aims to explore the effect and potential mechanism of Sunitinib - a multi-target tyrosine kinase inhibitor - on hepatic IRI.</p><p><strong>Methods: </strong>We established a hepatic IRI model using C57BL/6 mice, and integrated 40 mg/kg of Sunitinib, solely or combined with 100 μg/kg of coumermycin A1 (C-A1), in the treatment strategy. H&E staining, TUNEL assay, and detection of serum ALT and AST activities were used to assess liver damage. Further, ELISA kits and Western Blots were utilized to determine IL-1β, TNF-α, IL-6, CXCL10, and CXCL2 levels. Primary macrophages, once isolated, were cultured <i>in vitro</i> with either 2 nM of Sunitinib, or Sunitinib in conjunction with 1 μM of C-A1, to gauge their influence on macrophage polarization. qPCR and Western blot were conducted to examine the level of p-STAT1/STAT1, p-STAT3/STAT3, p-JAK2/JAK2, and M1/M2 polarization markers. To quantify immune cell infiltration, we applied Immunofluorescence.</p><p><strong>Results: </strong>Sunitinib pretreatment significantly alleviated liver injury and reduced p-STAT1/STAT1, p-STAT3/STAT3, p-JAK2/JAK2 levels. <i>In vitro</i>, Sunitinib treatment curbed M1 polarization induced by LPS + IFN-γ and bolstered M2 polarization triggered by IL-4. C-A1 application upregulated JAK2/STAT pathway phosphorylation and promoted LPS + IFN-γ-induced M1 polarization, which was reversed by Sunitinib treatment. In IL-4-stimulated macrophages, application of C-A1 activated the JAK2/STAT pathway and decreased M2-type macrophages, which was reversed by Sunitinib treatment either.</p><p><strong>Conclusion: </strong>Sunitinib is capable of guiding the polarization of macrophages toward an M2-type phenotype <i>via</i> the inhibition of the JAK2/STAT pathway, thereby exerting a protective effect on hepatic IRI.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"672-684"},"PeriodicalIF":2.9,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999843","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":"Galantamine and wedelolactone combined treatment suppresses LPS-induced NLRP3 inflammasome activation in microglial cells.","authors":"Dilek Saker,Leman Sencar,Gulfidan Coskun,Tugce Sapmaz Ercakalli,Dervis Mansuri Yilmaz,Sait Polat","doi":"10.1080/08923973.2024.2405579","DOIUrl":"https://doi.org/10.1080/08923973.2024.2405579","url":null,"abstract":"CONTEXTInflammasome NLR family pyrin domain-containing 3 (NLRP3) is associated with neurological disorders. Neuroinflammation can be suppressed by inhibiting NLRP3 inflammasome activation, decreasing neurodegenerative disorder progression. We devised a therapeutic technique that can reduce neuroinflammation induced by microglial activation, avoiding neurodegeneration. We aimed to investigate the mechanisms underlying the pharmacological effects of galantamine and wedelolactone by evaluating the response of the nuclear factor kappa B (NF-κB) signaling pathway and NLRP3 inflammasome in lipopolysaccharide (LPS)-activated N9 microglia.METHODSLPS and adenosine triphosphate were used to activate the NLRP3 inflammasome in N9 microglial cells, which were pretreated with galantamine and wedelolactone. Caspase-1, NLRP3, NF-κB, and interleukin (IL)-1β levels were measured using RT-qPCR and immunostaining.RESULTSCombined administration of galantamine and wedelolactone rescued microglial cells from LPS-induced cell death. Furthermore, treatment with galantamine and wedelolactone led to the suppression of NF-κB expression. NLRP3, caspase-1, and IL-1β levels were decreased by the combined treatment.DISCUSSION AND CONCLUSIONThe concurrent administration of galantamine and wedelolactone effectively suppresses the production of inflammatory cytokines and NLRP3 inflammasome activation in microglia. This inhibitory effect is likely linked to the NF-κB signaling pathway modulation. Therefore, this combined treatment is a potential therapeutic approach for neuroinflammatory diseases.","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":"38 1","pages":"1-10"},"PeriodicalIF":3.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259309","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":"Immunosuppressive effects of triptolide via interleukin-2/receptor signaling.","authors":"Ying Xiong,Yi Yin,Nandani Darshika Kodithuwakku,Jiagang Lv,Juan Wang,Yanxia Ding,Jiao Chen","doi":"10.1080/08923973.2024.2373219","DOIUrl":"https://doi.org/10.1080/08923973.2024.2373219","url":null,"abstract":"BACKGROUNDTriptolide (TP) has been confirmed to possess many beneficial functions including anti-inflammation and immunosuppression.OBJECTIVEThe present study aimed to explore the potential involvement of IL-2/IL-2R pathway in the immunosuppressive activities of TP.METHODSCultured CTLL-2 cells were utilized to evaluate the potential benefits of TP. Then cell viability was determined by CCK-8 assay, IFN-γ level by ELISA assay, Annexin V-FITC/PI double-staining and CD25 expression by flow cytometry, and protein expression by western blotting. Additionally, rhIL-2-driven lymphocytes following ConA activation were investigated. The interactions of TP with IL-2 and IL-2Rα were investigated by binding assays and molecular dynamics simulations.RESULTSTP treatment attenuated IFN-γ level and cell viability in both rhIL-2-induced CTLL-2 cells and rhIL-2-driven splenic lymphocytes. TP treatment increased cellular apoptosis/necrosis and cleaved PARP-1 level, while suppressed c-Myc level in rhIL-2-induced CTLL-2 cells. Additionally, TP treatment reduced CD25 expression on CTLL-2 cell surface. Notably, the phosphorylation protein levels in IL-2R signaling pathways were inhibited by TP exposure prior to rhIL-2 stimulation. SPR and BLI assays verified TP that directly bound to rhIL-2 and rmIL-2Rα, respectively. Molecular simulations suggested that TP bound at the interface of IL-2 and IL-2Rα near the hydrophobic patch composed of F62, L92 on IL-2 and L23, I46, V139 on IL-2Rα, resulting in decreased binding free energy between IL-2 and IL-2Rα.CONCLUSIONSThese findings collectively emphasized that TP interfered IL-2/IL-2Rα interactions, down-regulated IL-2Rα expression, and inhibited IL-2R signaling pathways activation, thereby leading to the immune cells being desensitized to rhIL-2 and exhibiting immunosuppressive properties.","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":"25 1","pages":"1-14"},"PeriodicalIF":3.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142259307","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":" ","pages":"425-435"},"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}
Dan Li, Song Shan, Xuhua Mao, Yiru Zhao, Beizhong Chen, Qiuyun Xiong, Desi Pan, Shengjian Huang
{"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":" ","pages":"529-537"},"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":" ","pages":"461-469"},"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}
Ehab A M El-Shoura, Souty M Z Sharkawi, Lobna A Abdelzaher, Basel A Abdel-Wahab, Yasmine H Ahmed, Asmaa Ramadan Abdel-Sattar
{"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":" ","pages":"509-520"},"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}
Isabela Gonçalves Lima, Isabele Benck Usiro Cabral da Silva, Vitória Carpentieri Pípolo, Vinicius Daher Alvares Delfino, Paulo Roberto Bignardi
{"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":" ","pages":"470-481"},"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":"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":" ","pages":"482-495"},"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}
Shweta Shrivastava, Tribhuwan Bahuguna, Sudipto Mondal, Sunil Kumar, Bijo Mathew, Manish Kumar Jeengar, V G M Naidu
{"title":"Attenuation of adjuvant-induced arthritis with carnosic acid by inhibiting mPGES-1, COX-2, and bone loss in male SD rats.","authors":"Shweta Shrivastava, Tribhuwan Bahuguna, Sudipto Mondal, Sunil Kumar, Bijo Mathew, Manish Kumar Jeengar, V G M Naidu","doi":"10.1080/08923973.2024.2377984","DOIUrl":"10.1080/08923973.2024.2377984","url":null,"abstract":"<p><strong>Objective: </strong>Rheumatoid arthritis (RA), a chronic inflammatory disease, is characterized by joint swelling, cartilage erosion, and bone destruction. This study investigated the therapeutic efficacy of Carnosic acid (CA), a natural compound with anti-inflammatory and antioxidant properties, in an adjuvant-induced arthritis model.</p><p><strong>Methods: </strong>Paw swelling and arthritis index were measured. Oxidative stress markers, including lipid peroxidation and antioxidant enzyme levels, were assessed. Synovial tissue was analyzed for pro-inflammatory markers using real-time Q-PCR and Western blotting. The expression of mPGES-1 was determined by Western blotting. Peripheral neuropathic pain was assessed using cold and mechanical allodynia tests. Bone loss was quantitatively assessed through microcomputed tomography (μCT) scanning of femurs and X-ray radiography. Indomethacin-induced gastric ulcers were evaluated. Molecular docking studies were conducted to analyze the binding affinity of CA to mPGES-1.</p><p><strong>Results: </strong>The CA treatment not only demonstrated a significant reduction in joint inflammation and paw swelling but also mitigated oxidative stress and improved the antioxidant defence system. CA inhibited microsomal prostaglandin E synthase-1 (mPGES-1) expression and the expression of pro-inflammatory molecules such as inducible nitric oxide synthase (iNOS) and cyclooxygenases-2 (COX-2), thus attenuating the arthritis symptoms without severe gastrointestinal side effects. Additionally, it inhibited the expression of pro-inflammatory molecules such as iNOS and COX-2, contributing to the reduction of arthritis symptoms. Notably, CA treatment prevented the common side effects of traditional RA treatments like corticosteroids and non-steroidal anti-inflammatory drugs (NSAIDs), including weight loss, bone degradation, and gastric ulcers.</p><p><strong>Conclusions: </strong>These findings suggest that CA, through specific enzyme inhibition, offers a compelling alternative therapeutic approach for RA. Further research is warranted to explore the potential of CA in other arthritis models and its suitability for human RA treatment.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"538-549"},"PeriodicalIF":2.9,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141626665","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}