Immunopharmacology and Immunotoxicology最新文献

{"title":"Mavorixafor: a CXCR4 antagonist for WHIM syndrome.","authors":"Canyu Chen, Bo Xu, Weiyi Li, Jixiang Chen, Zunbo He, Jiecan Zhou","doi":"10.1080/08923973.2025.2491551","DOIUrl":"10.1080/08923973.2025.2491551","url":null,"abstract":"<p><strong>Background: </strong>WHIM syndrome is a rare primary immune deficiency and chronic neutropenia caused by overactivation of the C-X-C motif chemokine receptor 4/C-X-C motif chemokine ligand 12 (CXCR4/CXCL12) signaling pathway. On April 26th, 2024, Xolremdi (mavorixafor) capsules received its approval from US FDA, is the first targeted treatment specifically for patients aged ≥12 years with WHIM syndrome. Mavorixafor, as a selective CXCR4 antagonist, is able to increase the number of mature neutrophils and lymphocytes in the blood.</p><p><strong>Objective: </strong>This review is to describe the pharmacological properties of mavorixafor and evaluate its clinical efficacy and safety profile.</p><p><strong>Methods: </strong>A literature search was conducted using keywords mavorixafor, XOLREMDI, AMD070, AMD11070, X4P-001, WHIM Syndrome, and CXCR4/CXCL12 on Web of Science, Google Scholar, and PubMed. Drug information was obtained from the FDA website.</p><p><strong>Results: </strong>In the pivotal 52-week phase III trial, time above absolute neutrophil count threshold (TAT_ANC) values in the mavorixafor group were higher than those in the placebo group at 4 different time points (15.04 h vs 2.75 h; <i>p</i> < 0.0001), and mavorixafor group had lower infection frequency, severity and duration. The most common adverse events are thrombocytopenia, pityriasis, rash, rhinitis, epistaxis, vomiting, and dizziness.</p><p><strong>Conclusion: </strong>Mavorixafor 400mg daily effectively increases WBC count, reduces disease symptoms and infection burden in WHIM syndrome patients ≥12 years. Future clinical programs will continue to evaluate the safety and efficacy of mavorixafor in patients with chronic neutropenic disease.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"385-391"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144002951","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":"The anti-inflammatory effects of vitamin B6 on neuroinflammation and neuronal damage caused by 1,2-diacetylbenzene in BV2 microglial and sH-SY5Y cells.","authors":"Hai Duc Nguyen, Won Hee Jo, Ngoc Hong Minh Hoang, Min-Sun Kim","doi":"10.1080/08923973.2025.2469216","DOIUrl":"10.1080/08923973.2025.2469216","url":null,"abstract":"<p><strong>Background: </strong>The pathophysiology of cognitive impairment has recently focused on 1,2-Diacetylbenzene (DAB), B vitamins, tau hyperphosphorylation, and neuroinflammation. While past evidence shows that vitamin B6 influences the immune system, the molecular processes behind DAB-induced neuroinflammation and cognitive impairment remain largely unknown. This study aimed to assess the protective roles of vitamin B6 against DAB-induced toxicity in BV2 microglial and SH-SY5Y cells.</p><p><strong>Methods: </strong><i>In vitro</i> approaches included Western blot, qRT-PCR, cell viability assays, immunocytochemistry, reactive oxygen species, and nitrite assays. For <i>in silico</i> analysis, we utilized Metascape, Cytoscape, MIENTURNET, and molecular docking.</p><p><strong>Results: </strong>Vitamin B6 suppressed the TLR4/NF-κB pathway and the TREM-1/DAP12/NLRP3/caspase-1/IL1B pathway in DAB-activated BV2 cells. Additionally, it reduced reactive oxygen species and nitric oxide levels while increasing Nrf2 and IL10 production. In SH-SY5Y cells, vitamin B6 inhibited GSK-3β Tyr216, tau hyperphosphorylation, and β-amyloid production. The <i>in silico</i> analysis identified 'positive regulation of NF-κB transcription factor activity,' 'regulation of IL-6 production,' and 'positive regulation of adaptive immune response' as key molecular mechanisms linked with DAB-induced cognitive impairment and targeted by vitamin B6. Core genes, miRNAs, and transcription factors included IL1β, IL6, IL10, TNF, hsa-miR-155-5p, hsa-miR-203a-3p, hsa-miR-106a-5p, hsa-miR-26a-5p, CEBPB, and PXR.</p><p><strong>Conclusion: </strong>Our findings indicate that vitamin B6 may protect against DAB-induced cognitive impairment by attenuating key inflammatory pathways, reducing oxidative stress, and inhibiting tau hyperphosphorylation, β-amyloid production, and GSK-3β Tyr216 phosphorylation. This highlights its potential as a therapeutic agent for cognitive impairment.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"273-286"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143648434","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":"Evaluating the impact of amitriptyline on Nitric Oxide signaling in rat models of neuropathic pain.","authors":"Hamid Reza Mohammadi, Zahra Haghighatian, Behrouz Beiranvand, Peyman Amanolahi Baharvand, Amin Hasanvand","doi":"10.1080/08923973.2025.2481870","DOIUrl":"10.1080/08923973.2025.2481870","url":null,"abstract":"<p><strong>Introduction: </strong>Nitric oxide (NO) plays a crucial role in the induction of neuropathic pain by stimulating the production of inflammatory cytokines. Additionally, research indicates that amitriptyline can inhibit nitric oxide production. In this study, we examined the inhibitory role of the nitric oxide signaling pathway through the administration of amitriptyline in the treatment of neuropathic pain.</p><p><strong>Methods: </strong>Forty rats were randomly assigned to five groups, with eight animals in each group: (1) Sham-operated, (2) Chronic constriction injury (CCI), (3) CCI plus amitriptyline, (4) CCI plus amitriptyline and L-arginine, and (5) CCI plus amitriptyline and L-NAME. Behavioral tests, including thermal hyperalgesia, cold allodynia, and mechanical allodynia, were conducted on the fourth, seventh, and fourteenth days following CCI induction. On the final day, spinal cord samples were collected to assess the levels of inflammatory cytokines. Additionally, the sciatic nerve was isolated on the same day for histological examination.</p><p><strong>Results: </strong>The results indicated that the administration of amitriptyline can reduce levels of inflammatory cytokines and improve symptoms of neuropathic pain. It should be noted that the simultaneous use of L-NAME and amitriptyline increases the therapeutic impacts of amitriptyline. However, the beneficial effects of amitriptyline are reduced by the nitric oxide stimulation induced by L-arginine.</p><p><strong>Conclusion: </strong>It was determined that one of the mechanisms by which amitriptyline ameliorates neuropathic pain is the inhibition of the nitric oxide signaling pathway. In this study, this effect was associated with a reduction in the release of inflammatory cytokines and a decrease in inflammation surrounding the nerve.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"345-353"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772239","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":"Vitamin D and canagliflozin combination alleviates Parkinson's disease in rats through modulation of RAC1/NF-κB/Nrf2 interaction.","authors":"Sara Kamal Rizk, Eman A Ali, AlZahraa A M Sheref, Sara G Tayel, Sara A El Derbaly","doi":"10.1080/08923973.2025.2481849","DOIUrl":"10.1080/08923973.2025.2481849","url":null,"abstract":"<p><strong>Objective: </strong>Oxidative stress and neuroinflammation are crucial factors in the pathogenesis of Parkinson's disease (PD). Vitamin D (Vit D) and canagliflozin (CAN) are known to have anti-inflammatory and antioxidant properties. Together, they target key molecular pathways involved in PD, including oxidative stress and neuroinflammation, specifically, the small GTPase protein (RAC1)/nuclear factor-kappa B (NF-κB)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling, which regulates brain's oxidative stress and inflammation. This study investigates the effects of Vit D and CAN alone and in combination in a rat model of PD.</p><p><strong>Materials and methods: </strong>Fifty male Wistar rats were assigned to five groups (<i>n</i> = 10), including control, rotenone (ROT), Vit D + ROT, CAN + ROT, and Vit D + CAN + ROT. We assessed weight changes, brain weight, neurobehavioral functions, biochemical markers, and immunohistopathology of brain tissues.</p><p><strong>Results: </strong>The results showed that Vit D treatment was more effective than CAN in alleviating PD symptoms, with the combination of Vit D and CAN offering the best therapeutic outcome. This combination therapy significantly improved serum Vit D, striatal dopamine (DA) levels, antioxidant status (reduced glutathione (GSH) and catalase (CAT), reduced oxidative stress (malondialdehyde (MDA)), and ameliorated inflammation (tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), and interleukin 10 (IL-10)). Additionally, the combination therapy modulated the expression of RAC1, NF-κB, Nrf2, vitamin D receptors (VDR), and vitamin D-binding protein (DBP) and immunoexpression of tyrosine hydroxylase (TH), and α-synuclein (α-SYN).</p><p><strong>Conclusion: </strong>These findings suggest that Vit D and CAN synergistically modulate the RAC1/NF-κB/Nrf2 pathway, leading to improved neuroprotection in PD.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"328-344"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709755","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 impact of diosmin and perindopril in amikacin-induced nephrotoxicity rat model: modulation of SIRT1/p53/C-FOS, NF-κB-p65, and keap-1/Nrf2/HO-1 signaling pathways.","authors":"Nashwa Abdelaala, Ehab A M El-Shoura, Marwa M Khalaf, Dalia Zafaar, Ahmed A N Ahmed, Ahmed M Atwa, Basel A Abdel-Wahab, Yasmine H Ahmed, Ahmed Abomandour, Esraa A Salem","doi":"10.1080/08923973.2025.2469220","DOIUrl":"10.1080/08923973.2025.2469220","url":null,"abstract":"<p><strong>Purpose: </strong>Amikacin (AMC), an aminoglycoside antibiotic known for its rapid and potent bactericidal activity, is also associated with nephrotoxicity. Diosmin and perindopril have been reported to improve renal function and hold promise as therapeutic agents for preventing drug-induced nephrotoxicity. This study aimed to investigate the protective effect of Diosmin and perindopril, either alone or in combination, against renal damage induced by AMC toxicity and to elucidate the underlying mechanisms.</p><p><strong>Materials and methods: </strong>The researchers evaluated the impact of Diosmin (50 mg/kg, orally) and perindopril (2 mg/kg, intraperitoneally) on AMC-induced kidney injury (1.2 g/kg, intraperitoneally) in rats. Invasive blood pressure, serum kidney function and toxicity parameters, oxidative stress biomarkers, and inflammatory cytokine levels in serum and renal tissue were assessed. Histopathological changes in the kidney were examined using hematoxylin and eosin (H&E) staining, electron microscopy, and immunohistochemical analysis. The molecular mechanisms underlying the protective effect of the combination pretreatment on kidney injury were investigated using enzyme-linked immunosorbent assay (ELISA) and Western blotting techniques.</p><p><strong>Results: </strong>The findings demonstrated that the combination therapy improved kidney function by attenuating pathological changes observed in H&E staining including tubular necrosis and glomerular damage, in addition to reducing levels of kidney function including serum levels of creatinine compared to the AMC group, blood urea nitrogen (BUN) uric acid, and albumin. Mean arterial blood pressure, and toxicity markers including Kidney Injury Molecule-1 (KIM-1), Cystatin-c were also decreased in samples of combination group compared to AMC group. Furthermore, the protective combination therapy downregulated NF-κB-p65, P53, Keap-1, and C-FOS, while upregulating Mammalian sirtuin 1 (SIRT1), inhibitor of nuclear factor kappa B (Iκβ), nuclear factor erythroid 2-related factor 2 (Nrf2), and Heme oxygenase-1 (HO-1) levels.</p><p><strong>Conclusions: </strong>The findings reveal the potential clinical application of combining Diosmin and perindopril to reduce AMC-induced nephrotoxicity, which requires further research in clinical settings.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"287-304"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143523318","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":"Dapagliflozin alleviates thioacetamide induced-liver fibrosis in rats via controlling the Nrf2/HO-1 and TLR4/TGF-β1/PI3K signaling pathways.","authors":"Nourhan Hussien Hassan, Gehan M Kamel, Hany M Fayed, Reda M S Korany, Amer Ramadan","doi":"10.1080/08923973.2025.2496661","DOIUrl":"10.1080/08923973.2025.2496661","url":null,"abstract":"<p><strong>Objectives: </strong>Because liver fibrosis causes several insults that can result in death, it is regarded as an epidemic health issue. As \"an inhibitor of the sodium-glucose cotransporter-2 (SGLT2),\" Dapagliflozin (Dapa) is one of the newest anti-diabetic drugs used to treat type 2 diabetes mellitus. Dapa's antioxidant, anti-inflammatory, and antifibrotic properties produced positive impacts in numerous human and animal models. Due to Dapa's previously documented properties, we planned this investigation to elucidate the protective function of Dapa in male rat liver fibrosis caused by thioacetamide (TAA) as well as the expected pathways.</p><p><strong>Methods: </strong>There were four groups of 24 rats: a control group, a TAA group that received (100 mg/kg b.wt intraperitoneally twice a week for 6 weeks), \"TAA + Dapa\" groups that given oral Dapa at (1 and 2 mg/kg b.wt. for 4 weeks in addition to TAA injections).</p><p><strong>Results: </strong>It was shown that TAA injections increased toll-like receptor 4 (TLR4) (509.6%), tumor necrosis factor (TNF-<i>α</i>) (298.8%), alanine aminotransferase (ALT), aspartate aminotransferase (AST), malondialdehyde (MDA), interleukin-6 (IL-6) (330.9%), phosphotidylinositol-3-kinase (PI3K) (428.9% %), and transforming growth factor-beta (TGF-<i>β</i>1) (416.6%) levels. All of these markers were considerably reduced by Dapa treatment. In addition, reduced glutathione (GSH), nuclear factor erythroid 2-related factor 2 (Nrf2) (79%), albumin, Heme-oxygenase 1 (HO-1) (69%), and superoxide dismutase (SOD) were all decreased after TAA injection; however, they were restored by Dapa administration. The Dapa-treated groups had higher Nrf2 and HO-1 gene expressions, based on the results of PCR. Biochemical outcomes were validated by histopathological results. Immunohistopathological study revealed that DAPA treatment decreased caspase-3 and alpha-smooth Muscle Actin (<i>α</i>SMA) expression.</p><p><strong>Conclusion: </strong>Due to its interactions with the Nrf2/HO-1 and TLR4 pathways, our research showed that Dapa had antioxidant and anti-inflammatory qualities against TAA-induced liver fibrosis.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"392-405"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143998874","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":"Pro-inflammatory effects of all-trans retinoic acid in experimental acute inflammation - insights into eosinophil and neutrophil dynamics.","authors":"Bruno Marques Vieira, Daniela Masid-de-Brito, Lucas Everton Simões, Francisco Leonardo da Silva Medeiro, Juliana Macedo Monte Vianna Pires, Maria Ignez Capella Gaspar-Elsas, Pedro Paulo Xavier-Elsas","doi":"10.1080/08923973.2025.2489402","DOIUrl":"10.1080/08923973.2025.2489402","url":null,"abstract":"<p><strong>Context: </strong>All-trans retinoic acid (ATRA), a metabolite of vitamin A, regulates embryogenesis, regeneration, hematopoiesis, differentiation, and apoptosis. It also exerts immunomodulatory effects and is used in inflammatory disease models.</p><p><strong>Objective: </strong>This study aimed to investigate the paradoxical pro-inflammatory effects of ATRA on eosinophil and neutrophil recruitment and activation.</p><p><strong>Materials and methods: </strong>We used thioglycolate- and zymosan-induced peritonitis models in mice to evaluate leukocyte recruitment following ATRA treatment. The roles of inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF), and the 5-lipoxygenase (5-LO) pathway were assessed using genetically deficient mice and pharmacological inhibitors.</p><p><strong>Results and discussion: </strong>ATRA increased total leukocyte, eosinophil, and neutrophil counts in peritoneal exudates, enhancing the response to both thioglycolate and zymosan. The effects were microenvironment-dependent and likely mediated by local release of pro-inflammatory cytokines and chemokines. iNOS was required for eosinophil recruitment, while TNF contributed to both eosinophil and neutrophil recruitment. The 5-LO pathway was essential for eosinophil involvement. These findings suggest that ATRA can paradoxically enhance inflammation by modulating innate immune cell responses.</p><p><strong>Conclusions: </strong>ATRA promotes inflammation through iNOS, TNF, and 5-LO-dependent pathways, revealing complex mechanisms of immune modulation with potential relevance for inflammatory disease management.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"375-384"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144063540","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":"Kindlin-2 silencing promoted apoptosis and cell cycle arrest through the fas/FasL pathway in hepatocellular carcinoma.","authors":"Weiwei Yu, Yan Wang, Shugang Wang","doi":"10.1080/08923973.2025.2506696","DOIUrl":"10.1080/08923973.2025.2506696","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the role of Kindlin-2 in HCC and its underlying molecular mechanisms, focusing on its regulation of the Fas/FasL signaling pathway.</p><p><strong>Materials and methods: </strong>In vitro, Hep3B and HepG2 cells were treated with Kindlin-2 siRNA, a Fas activator, and a combination of Kindlin-2 siRNA and Fas siRNA. Cell proliferation, apoptosis, and cell cycle progression were evaluated using CCK-8 assays and flow cytometry, while the expression of associated proteins was analyzed through Western blotting. In vivo, a nude mouse xenograft model was established, and the expression levels of apoptosis and cell cycle proteins were assessed using Western blotting and immunohistochemistry.</p><p><strong>Results: </strong>Silencing Kindlin-2 significantly upregulated the expression of Fas and Fas ligand (FasL), activating the Fas/FasL signaling pathway. This activation promoted the recruitment of FADD, leading to the activation of caspase-8 and caspase-3, inducing apoptosis and causing G1 phase cell cycle arrest.</p><p><strong>Discussion and conclusion: </strong>This study revealed that Kindlin-2 inhibited apoptosis in HCC by negatively regulating the Fas/FasL signaling pathway. Kindlin-2 reduced apoptosis in HCC cells by suppressing the activation of the Fas/FasL pathway, thereby promoting tumor progression.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"429-439"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144110582","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":"The protective effects of a single dose myricetin application on CLP-induced rat sepsis model by analyzing some immune mechanisms.","authors":"Ismail Can, Ali Guraslan, Omer Faruk Baser, Gulfem Nur Yıldız, Ihsan Toplaoglu, Selina Aksak Karamese, Murat Karamese","doi":"10.1080/08923973.2025.2469227","DOIUrl":"10.1080/08923973.2025.2469227","url":null,"abstract":"<p><strong>Introduction: </strong>In this study, our aim was to investigate the protective effects of myricetin (single dose-100 mg/kg) on CLP-induced rat sepsis model by analyzing some immune mechanisms including inflammation and oxidative stress by different techniques such as Immunohistochemistry, ELISA, tissue biochemistry and Western Blotting.</p><p><strong>Methods: </strong>Twenty-eight Wistar albino rats were divided into 4 groups. The pro-inflammatory and anti-inflammatory cytokine levels were measured by ELISA technique. CD68 and Nuclear-Factor-Kappa-B (NF-κB) positivity rates were detected by IHC. Some of oxidative stress parameters were measured by tissue biochemistry, while Toll-like receptor-4 (TLR4) expression others were detected by Western blot technique.</p><p><strong>Results: </strong>Sepsis caused a significant increase in all pro-inflammatory cytokine and oxidant levels. Also, it led to an increase in the positivity of CD68 and NF-κB markers as well as the expression levels of TNF-alpha, IL-1-beta, TLR4, Keap-1. However, single dose myricetin application normalized pro-inflammatory cytokine levels, increased anti-oxidant and anti-inflammatory cytokine levels, decreased positivity of CD68 and NF-κB and increased NRF2 and HO-1 expressions.</p><p><strong>Discussion: </strong>As a conclusion, the beneficial effect of myricetin on lung injury also involved inhibition of TLR4/NF-κB pathway, suppression of proinflammatory cytokines and induction of anti-inflammatory cytokine production, regulation of oxidant and anti-oxidant system parameters, and activating the NRF2/Keap1/HO-1 pathway.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"305-316"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143448940","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":"Protective effect of roflumilast on cyclophosphamide-induced ovarian toxicity in rats: role of SIRT1/Nrf2/nF-ĸB pathway.","authors":"Salma A El-Marasy, Hadir Farouk, Marwa S Khattab, Marwan Abdelbaset","doi":"10.1080/08923973.2025.2482804","DOIUrl":"10.1080/08923973.2025.2482804","url":null,"abstract":"<p><strong>Objective: </strong>This study aimed to investigate the possible protective effect of roflumilast (RFL) on cyclophosphamide (CP)-induced ovarian toxicity as well as the possible underlying mechanism.</p><p><strong>Material and methods: </strong>Female Wistar rats received the vehicle (<i>n</i> = 6) or CP (200 mg/kg, i.p.). The other 2 groups (<i>n</i> = 6 for each) were orally pretreated with RFL at dosages of 0.5 and 1 mg/kg, respectively, for 14 days and then after one hour of RFL administration on the 14th day, rats were intraperitoneally administered a single dose of CP. Serum and tissue samples were collected. Biochemical, real-time polymerase chain reaction, histopathological and immunohistopathological examination were carried out.</p><p><strong>Results: </strong>RFL significantly elevated serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) compared to the CP group. RFL remarkably elevated ovarian contents of Sirtuin-1 (SIRT1), heme oxygenase-1 (HO-1), and reduced nuclear factor-kappa B (NF-ĸb) p65/NF-ĸB ratio as compared to control CP group. Compared to the CP group, RFL significantly elevated Nrf2 gene expression, reduced malondialdehyde (MDA), and elevated the reduced glutathione (GSH) ovarian content. It also reduced the protein expression of TNF-α and caspase-3.</p><p><strong>Conclusion: </strong>It can be concluded that RFL (0.5 and 1 mg/kg) protected rats against CP-induced ovarian toxicity <i>via</i> altering the SIRT1/Nrf2/NF-ĸB pathway, ameliorating histopathological changes in addition to its anti-apoptotic effect.</p>","PeriodicalId":13420,"journal":{"name":"Immunopharmacology and Immunotoxicology","volume":" ","pages":"354-363"},"PeriodicalIF":2.9,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143709753","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}