Cytokine最新文献

{"title":"Shared molecular biomarkers and therapeutic targets in rheumatoid arthritis and osteoarthritis: Focus on EIF3B, KHSRP, NCL, PDCD1LG2, and SLC25A37","authors":"Hui Li ,&nbsp;Zhenxue Long ,&nbsp;Chengguang Wei ,&nbsp;Tingyuan Zhang ,&nbsp;Dalang Fang ,&nbsp;Shuliang Hua","doi":"10.1016/j.cyto.2025.156988","DOIUrl":"10.1016/j.cyto.2025.156988","url":null,"abstract":"<div><div>Rheumatoid arthritis (RA) and osteoarthritis (OA) are the most common joint diseases globally, posing major public health challenges. Although they are often distinguished from each other in clinical diagnoses, we hypothesize that RA and OA could have overlapping molecular pathways. Hence, this study was designed to explore the shared molecular changes and potential therapeutic targets for RA and OA. Transcriptome data were obtained from the Gene Expression Omnibus (GEO) database (GSE51588, GSE12021 and GSE55235), which included 117 synovial membrane samples (33 healthy, 50 OA, and 34 RA). Differentially expressed genes (DEGs) were identified using the “limma” package in R, and functional enrichment analyses were conducted using Gene ontology and Kyoto Encyclopedia of Genes and Genomes frameworks. Protein-protein interaction networks were constructed through STRING, and further analyzed using GeneMANIA. Immune cell infiltration in RA and OA samples was evaluated using the CIBERSORT algorithm; microRNA-messenger RNA interactions were predicted through miRanda, miRDB, miRWalk, and TargetScan databases; and lncRNAs targets were identified via the SpongeScan database. Gene-drug interactions were analyzed using DGIdb, and the results were validated in RA and OA mouse models via immunohistochemistry and western blot. In RA and OA, 38 DEGs were identified, including 23 downregulated and 15 upregulated genes (FDR &lt; 0.05, |log2FC| &gt; 0), associated with key pathways such as ubiquitin-mediated proteolysis, mTOR, JAK-STAT, and Wnt signaling. Hub genes, including EIF3B, KHSRP, nucleolin (NCL), PDCD1LG2, SLC25A37, demonstrated significant differential expression (<em>p</em> &lt; 0.05). In addition, the receiver operating characteristic (ROC) curve analysis indicated good diagnostic potential, with areas under the curve (AUC) values ranging from 0.795 to 0.958. Furthermore, immune cell infiltration analysis revealed significant involvement of plasma cells, T cells, monocytes, and dendritic cells (<em>p</em> &lt; 0.05). Several hub genes were targeted by existing drugs, such as NCL by AS1411, and PDCD1LG2 by Pembrolizumab. In vivo validation revealed that EIF3B, KHSRP, NCL, and PDCD1LG2 were downregulated in both RA and OA mouse models compared to controls (<em>p</em> &lt; 0.01), with EIF3B exhibiting higher expression in RA than in OA (<em>p</em> &lt; 0.01). Mitoferrin 1 expression showed no significant differences among groups. These findings suggest that RA and OA share common molecular pathways that may serve as promising diagnostic biomarkers and therapeutic targets.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"193 ","pages":"Article 156988"},"PeriodicalIF":3.7,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513481","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Insulin growth factor 2 contributes to adipose stem cell-derived exosome mediated angiogenesis against hind-limb ischemia injury","authors":"Xiang Li ,&nbsp;Qiang Chen ,&nbsp;Ran Li ,&nbsp;Bo Shao ,&nbsp;Dong-sheng Cui ,&nbsp;Shao-hua Ren ,&nbsp;Hong-da Wang ,&nbsp;Yi-ni Xu ,&nbsp;Zhao-bo Wang ,&nbsp;Xiao-dong Wang ,&nbsp;Kui Ye ,&nbsp;Xiang-chen Dai ,&nbsp;Hao Wang","doi":"10.1016/j.cyto.2025.156984","DOIUrl":"10.1016/j.cyto.2025.156984","url":null,"abstract":"<div><div>Critical limb ischemia is a severe stage when hypoperfusion occurs in patients with lower extremity arteriosclerotic obliterans. Exosomes have emerged as a key therapeutic agent for lower extremity ischemia. However, how these exosomes take effects on ischemic limb is still unknown. Insulin-like growth factor II (IGF2) is a key protein responsible for guiding angiogenesis. Mouse ischemic limb was injected with phosphate buffer saline (PBS), exosomes from murine adipose-derived stem cells (ADSC-Exo) and IGF2-specific knockout of ADSC-Exo (IGF2^−/−-Exo), respectively, then blood flow was detected at 21 days after injection. The level of dynamic limb movement and impairment were assessed by ambulatory impairment and tissue damage scores. Laser Doppler imaging was performed to measure the blood flow of the ischemic limbs. Molecular biology experiment is performed to investigate the mechanism of ADSC-Exo mediated limb protection against ischemia injury. Compared with the untreated group, ADSC-Exo injection significantly promoted blood perfusion of ischemic hind limbs, while knockout of IGF2 weakened the therapeutic effect of the ADSC-Exo. The fluorescence intensity of CD31⁺ in the IGF2^−/−-Exo-treated group was lower than that in the ADSC-Exo group. Tubular structures of endothelial cells in ADSC-Exo-treated group were significantly more than those in PBS-treated group, while endothelial cells in IGF2^−/−-Exo-treated group formed fewer tubular structures than those in ADSC-Exo-treated group. The protein levels of p-PI3K, p-AKT and p-eNOS in endothelial cells were upregulated by ADSC-Exo whereas IGF2-knockout impaired this promotion to activation states. Our study demonstrated that IGF2-expressing ADSC-Exo exerted a potent pro-proliferative and angiogenic effects against limb ischemia injury associated with the PI3K-Akt-eNOS pathway.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"193 ","pages":"Article 156984"},"PeriodicalIF":3.7,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513482","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterising high-resolution dynamics of inflammatory and SCFA responses to food consumption in healthy men: A pilot biomarker discovery study","authors":"C.V. Hall ,&nbsp;L. Garnier ,&nbsp;M. Gencoglu ,&nbsp;E. Varesio ,&nbsp;S. Tardy ,&nbsp;D. Brito Salgado ,&nbsp;L. Scapozza ,&nbsp;M. Marizzoni ,&nbsp;G.B. Frisoni ,&nbsp;T. Gurry","doi":"10.1016/j.cyto.2025.156990","DOIUrl":"10.1016/j.cyto.2025.156990","url":null,"abstract":"<div><div>Understanding inflammatory responses after food consumption and at fasting is crucial for assessing the impact of diet on long-term health. To study these responses meaningfully, biomarkers must be responsive to food intake, consistent across individuals, and predictive of future health outcomes. Preliminary data suggest that anti-inflammatory short-chain fatty acids (SCFAs), produced by the microbiota from prebiotic fibre, might be relevant biomarkers in the food-induced inflammatory reaction, but data on their timing, magnitude, dynamics at fasting and during the postprandial state, and relationship with other biomarkers are currently lacking. This knowledge gap impacts our ability to identify reliable biomarkers that can be used as surrogate outcomes in dietary interventions and research focused on reducing chronic disease risk. In this biomarker discovery study, we aimed to identify meal-responsive inflammatory biomarkers and assess plasma SCFAs pharmacokinetics following meal intake. Three healthy male participants consumed three isoenergetic meals with different theoretical pro-inflammatory potential, one per week over a three-week period: an anti-inflammatory meal (Meal A), a pro-inflammatory meal (Meal B), and a pro-inflammatory meal with a butyrate-promoting prebiotic fibre supplement (Meal C). For each meal condition, blood samples were taken continually over a 30-h period, and inflammatory cytokines and plasma SCFAs were measured. Cytokine biomarker dynamics were classified based on their response to meals. We identified 26 meal-responsive biomarkers, with three—CST5, FGF-19, and ST1A1—showing consistent postprandial changes across participants. The study also revealed significant interindividual variability, with 23 biomarkers displaying highly personalised responses to food intake. Quantitative analysis of plasma SCFA concentrations indicated non-trivial dynamics, but a clear accumulation of butyrate, acetate, and propionate in plasma during a 25-h period following meal intake. Our findings highlight the complexity of the postprandial response, emphasising the need for thoughtful consideration of study design, including the choice and sampling rate of biomarkers. The identified biomarkers offer potential for future research and clinical applications, improving the understanding of diet-induced inflammation and its role in chronic disease prevention.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"193 ","pages":"Article 156990"},"PeriodicalIF":3.7,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144513483","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Associations of FAAH rs324420 with serum lipid profiles are diversified by a high-carbohydrate diet in healthy Chinese adolescents","authors":"Yi Lin Shen,&nbsp;Jia Jing Cai,&nbsp;Jun Tao Ren,&nbsp;Xue Cheng Li,&nbsp;Yan Zhi Yi,&nbsp;Ke Xin Jia,&nbsp;Jun Yi Liu,&nbsp;Qi Wei Guo,&nbsp;Jia Lin","doi":"10.1016/j.cyto.2025.156986","DOIUrl":"10.1016/j.cyto.2025.156986","url":null,"abstract":"<div><h3>Objectives</h3><div>The present study is to investigate changes of serum lipid profiles in the healthy Chinese adolescents with different genotypes of rs324420 polymorphism at fatty acid amide hydrolase (FAAH) gene (<em>FAAH</em>) after a high-carbohydrate (HC) diet.</div></div><div><h3>Methods</h3><div>Fifty-one healthy university students (24 males and 27 females, aged 22.87 ± 1.82 years) were recruited by advertisements. The subjects were given a washout diet of 54.1 % carbohydrate for 7 days, followed by a HC diet of 70.1 % carbohydrate for 6 days. The anthropometric and biological parameters including serum lipid levels were analyzed using routine methods at baseline, after washout diet and after HC diet. Body mass index (BMI) and the ratios of LDL-C/HDL-C, TC/HDL-C and TG/HDL-C were calculated. Meanwhile, <em>FAAH</em> rs324420 was genotyped by polymerase chain reaction-restriction fragment length polymorphism technique and verified by DNA sequencing.</div></div><div><h3>Results</h3><div>After HC diet, all individuals exhibited reduced LDL-C, TC, LDL-C/HDL-C, and TC/HDL-C. Although TC lowering effect of HC diet was not dependent on gender and <em>FAAH</em> rs324420 polymorphism, CC homozygotes might be more susceptible than A allele carriers to the reduced TC/HDL-C after HC diet only in males. Moreover, LDL-C/HDL-C declined only in male CC homozygotes, while TG increased exclusively only in female CC homozygotes after HC diet.</div></div><div><h3>Conclusions</h3><div>These results indicate that the HC diet has the potential to induce distinct alterations in serum lipid levels and their ratios among healthy Chinese Han adolescents with different genders and genotypes of <em>FAAH</em> rs324420.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"193 ","pages":"Article 156986"},"PeriodicalIF":3.7,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144514122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GDF15 upregulation in Parkinson's disease: Compensatory mechanisms and causal insights","authors":"Sultan M. Alshahrani ,&nbsp;Hayder M. Al-Kuraishy ,&nbsp;Ali K. Albuhadily ,&nbsp;Ali I. Al-Gareeb ,&nbsp;Ahmed M. Abdelaziz ,&nbsp;Athanasios Alexiou ,&nbsp;Marios Papadakis ,&nbsp;Mubarak Alruwaili ,&nbsp;Gaber El-Saber Batiha","doi":"10.1016/j.cyto.2025.156983","DOIUrl":"10.1016/j.cyto.2025.156983","url":null,"abstract":"<div><div>Parkinson's disease (PD) is a prevalent long-term neurodegenerative condition resulting from the impairment of dopaminergic neurons (DNS) in the substantia nigra (SN). It is closely tied to inflammatory processes and oxidative stress, which worsen as PD neuropathology advances. Consequently, biomarkers linked to inflammation and oxidative stress may aid in diagnosing and monitoring PD progression. Growth differentiation factor 15 (GDF15) has emerged as a novel diagnostic biomarker for PD, though the exact reason for its elevation in PD remains unclear. This review seeks to investigate the cause-effect link between PD and heightened GDF15 levels. GDF15, part of the transforming growth factor-beta (TGF-β) family, exerts its effects through activation of the glial cell line-derived neurotrophic factor family receptor alpha-like (GFRAL). It serves a critical neuroprotective function in various brain disorders, including PD, where it enhances DNS survival, mitochondrial efficiency, and cellular energy metabolism. During PD progression, DNS degeneration may stimulate the release of anti-inflammatory GDF15 to counteract neuronal damage, though the precise mechanisms require further exploration. Elevated GDF15 levels in PD could reflect a response to cellular stress and mitochondrial dysfunction in DNS. GDF15 appears to suppress PD-related neuroinflammation by inhibiting the NLRP3 inflammasome, NF-κB signaling, and pro-inflammatory cytokine production. This suggests that increased GDF15 expression in PD may act as a compensatory mechanism to mitigate oxidative stress, mitochondrial impairment, and inflammatory pathways. As such, therapeutic strategies targeting GDF15 activation could hold promise for managing PD pathology. Further research is needed to clarify its regulatory pathways and therapeutic potential.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"193 ","pages":"Article 156983"},"PeriodicalIF":3.7,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144501837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of FGF19 in regulating mitochondrial dynamics and macrophage polarization through FGFR4/AMPKα-p38/MAPK Axis in bleomycin-induced pulmonary fibrosis","authors":"Yang Li ,&nbsp;Hong Zhang ,&nbsp;Bing Li ,&nbsp;Xin Yi ,&nbsp;Xinri Zhang","doi":"10.1016/j.cyto.2025.156978","DOIUrl":"10.1016/j.cyto.2025.156978","url":null,"abstract":"<div><h3>Background</h3><div>In the bleomycin (BLM)-induced pulmonary fibrosis model, macrophage polarization and mitochondrial dynamic imbalance are critical drivers of fibrogenesis. Although fibroblast growth factor 19 (FGF19) has been reported to alleviate fibrosis, its mechanism of regulating mitochondrial dynamics and macrophage polarization through the FGFR4/AMPKα-p38/MAPK axis remains unclear.</div></div><div><h3>Objective</h3><div>To investigate whether FGF19 mitigates alveolar epithelial injury and pulmonary fibrosis by restoring mitochondrial fusion/fission balance and modulating macrophage phenotype switching.</div></div><div><h3>Methods</h3><div>A BLM-induced C57BL/6 mouse fibrosis model was employed, with lung-specific FGF19 overexpression via lentivirus. An in vitro RAW264.7 macrophage-alveolar epithelial cell coculture system was used to assess mitochondrial morphology (transmission electron microscopy), mtDNA content (qPCR), protein expression (MFN1/2, Drp1-pSer616; Western blot), and macrophage polarization (flow cytometry). Pharmacological inhibition (SB203580, a p38/MAPK inhibitor) and MFN1/MFN2 siRNA knockdown were applied to validate pathway specificity.</div></div><div><h3>Results</h3><div>(1) FGF19 overexpression significantly attenuated BLM-induced alveolar destruction, collagen deposition, and inflammatory infiltration (H&amp;E, <em>P</em> &lt; 0.01); (2) FGF19 activated the FGFR4/AMPKα-p38/MAPK pathway, upregulated mitochondrial fusion proteins MFN1/2 (<em>P</em> &lt; 0.01), suppressed Drp1 phosphorylation (Ser616)-mediated fission (<em>P</em> &lt; 0.05), and shifted macrophages toward an M2 phenotype (CD206↑, <em>P</em> &lt; 0.01); (3) p38/MAPK inhibition or MFN1/2 knockdown reversed FGF19-driven M2 polarization (P &lt; 0.01); (4) FGF19 reduced alveolar epithelial apoptosis (Annexin V-FITC, P &lt; 0.01) and inflammatory cytokine release (TNF-α, IL-6; ELISA, P &lt; 0.01) by inhibiting M1 polarization.</div></div><div><h3>Conclusion</h3><div>FGF19 alleviates pulmonary fibrosis by restoring mitochondrial dynamics via the FGFR4/AMPKα-p38/MAPK axis, thereby inhibiting M1 macrophage polarization and epithelial injury. These findings highlight FGF19 as a potential therapeutic target for antifibrotic interventions.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"193 ","pages":"Article 156978"},"PeriodicalIF":3.7,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interleukin-18 (IL-18) engineered for half-life extension and resistance to IL-18 binding protein (IL-18BP) to enhance anti-cancer therapeutic potential","authors":"Kristiana H. Dreaden,&nbsp;Su-Ping Pearson,&nbsp;Pinar S. Gurel,&nbsp;Robert G. Newman,&nbsp;Yanchun Zhao,&nbsp;Chunhua Wang,&nbsp;Joshua F. Heiber,&nbsp;Sarah S. Donatelli,&nbsp;Jean Chamoun,&nbsp;Mark M. Whitmore","doi":"10.1016/j.cyto.2025.156979","DOIUrl":"10.1016/j.cyto.2025.156979","url":null,"abstract":"<div><div>Recombinant interleukin-18 (IL-18) holds promise as a therapeutic for oncology, as a robust activator of adaptive and innate immune cells and a potent producer of IFN-γ. However, clinical success has been limited due to rapid upregulation of the natural IL-18 inhibitor, IL-18 binding protein (IL-18BP), and fast systemic clearance of active IL-18, unbound to IL-18BP. To overcome these limitations, human IL-18 and mouse orthologs were engineered with resistance to IL-18BP and extended half-life by fusion to an Fc scaffold, with the goal of creating an improved IL-18-based therapeutic. IL-18 variants with a range of potencies showed no detectable binding to IL-18BP and retained full biological activity in the presence of super-physiological levels of IL-18BP. Pharmacokinetic studies comparing the mouse orthologs with a “naked” IL-18BP resistant tool IL-18 variant confirmed the importance of half-life extension. Importantly, the mouse Fc orthologs exhibited stronger and more durable T_H1 cytokine production and expansion of cytotoxic NK cells and effector CD8⁺ T cells when compared to the naked IL-18 variant. Remarkably, mouse engineered IL-18 variants administered once a week demonstrated strong tumor growth inhibition and improved survival compared to vehicle treated mice in multiple syngeneic tumor models. Human IL-18 variants dosed in humanized mice mirrored in vivo findings from mouse orthologs, displaying extended pharmacokinetics and durable upregulation of serum T_H1 cytokines. These promising preclinical results highlight engineered IL-18 solutions that resist IL-18BP binding and extend half-life, unlocking its full potential for sustained anti-cancer immune responses.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"193 ","pages":"Article 156979"},"PeriodicalIF":3.7,"publicationDate":"2025-06-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144335964","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of acute heat exposure on monocyte phenotype following exhaustive exercise: An ex vivo study","authors":"Lucas de Lima Schipper ,&nbsp;Igor Martins da Silva ,&nbsp;Bruna Marmett ,&nbsp;Paula Coelho Teixeira ,&nbsp;Fabio Santos de Lira ,&nbsp;Gilson Pires Dorneles ,&nbsp;Pedro R.T. Romão","doi":"10.1016/j.cyto.2025.156982","DOIUrl":"10.1016/j.cyto.2025.156982","url":null,"abstract":"<div><div><strong>Background/Aim:</strong> This study aimed to evaluate the effects of ex vivo whole blood heat therapy on monocyte inflammatory response following exhaustive exercise in young individuals. <strong>Methods:</strong> Eight recreationally endurance trained individuals (27.2 ± 3.1 years old, VO₂Peak 53.1 ± 2.1 mL/kg/min) performed a strenuous step-up/step-down protocol until exhaustion. Blood samples were collected pre and post exercise and incubated 37 °C or 40 °C during 2 h. Flow cytometry was used to assess TLR-4 expression, NF-kB activation, mitochondrial membrane potential and TNF-alpha expression in CD14+ monocytes. <strong>Results:</strong> Post exercise, TLR-4 expression and NF-kB activation increased at 37 °C (<em>p</em> &lt; 0.001), but heat therapy at 40 °C significantly reduced these responses (<em>p</em> &lt; 0.01). MMP decreased after exercise at both temperatures but was significantly lower at 37 °C than 40 °C (<em>p</em> &lt; 0.05). TNF-a levels showed a trend toward returning to baseline with heat therapy. <strong>Conclusion:</strong> Ex vivo heat therapy reduces monocyte mediated inflammation after exercise, induced muscle damage, suggesting its potential as a recovery strategy to strenuous exercise sessions.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"193 ","pages":"Article 156982"},"PeriodicalIF":3.7,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144321089","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATM and ATR inhibition increases radiosensitivity and cGAS-STING activation in prostate cancer","authors":"Nina van Campen,&nbsp;Vera E. Mekers,&nbsp;Maaike W. Looman,&nbsp;Lune van den Bogaard,&nbsp;Esther D. Kers-Rebel,&nbsp;Wenny J.M. Peeters,&nbsp;Esther Fernández Merino,&nbsp;Fabian Schuurmans,&nbsp;Robert Jan Smeenk,&nbsp;Marcel Verheij,&nbsp;Marleen Ansems,&nbsp;Gosse J. Adema","doi":"10.1016/j.cyto.2025.156980","DOIUrl":"10.1016/j.cyto.2025.156980","url":null,"abstract":"<div><div>Despite the availability of multiple effective therapies for localized prostate cancer, many patients still progress to incurable metastasized castration resistant prostate cancer (mCRPC). About 23 % of mCRPC patients carry alterations in DNA damage response (DDR) genes, including the protein kinases Ataxia telangiectasia mutated (ATM). DDR gene mutations have been shown to increase radiosensitivity and responses to immunotherapy. Here, we aimed to investigate the effect of inhibiting ATM and Ataxia telangiectasia and Rad3 related (ATR) on the radiosensitivity and subsequent activation of the cGAS-STING pathway in three prostate cancer cell lines. The data demonstrate that ATM and ATR inhibition leads to increased radiosensitivity in the PC3 and DU145 cell lines and that simultaneous inhibition of ATM and ATR results in enhanced cell death after irradiation. Furthermore, ATM blockade or combined ATM and ATR inhibition, but not ATR inhibition alone, significantly enhances radiation-induced cGAMP levels and a gene expression signature induced by the cytokine type I interferon. This work highlights the promising effects of ATM and ATR inhibition in combination with radiotherapy in prostate cancer and offers opportunities for exploring the use of radiotherapy and immunotherapy combinations in mCRPC.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"193 ","pages":"Article 156980"},"PeriodicalIF":3.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144297729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Leishmania donovani infection-driven high levels of IL-10 causes hypoalbuminemia in human visceral leishmaniasis","authors":"Bharat Singh ,&nbsp;Sheetal Saini ,&nbsp;Smita Kumari ,&nbsp;Arunim Shah ,&nbsp;Kulwant Singh ,&nbsp;Chandra Prakash Chaturvedi ,&nbsp;Anuradha Dube ,&nbsp;Amogh A. Sahatrabuddhe ,&nbsp;Chandreshwar P. Thakur ,&nbsp;Ambak K. Rai","doi":"10.1016/j.cyto.2025.156981","DOIUrl":"10.1016/j.cyto.2025.156981","url":null,"abstract":"<div><div>Visceral leishmaniasis, caused by <em>Leishmania donovani</em> is characterized by clinicopathological features like hepatomegaly with loss of liver function, etc. Albumin is an essential parameter of liver function, performing various tasks like maintaining osmotic balance in blood vessels, preventing tissue fluid leakage, carrier properties, etc. Human VL patients and <em>Leishmania donovani</em>-infected hamsters (ExVL) were tested for their albumin levels. IL-10 derived from <em>Leishmania donovani</em>-infected monocytes and recombinant IL-10 were tested on HepG2 cells for CEBP-β and albumin expression with IL-10 blocking and JAK1/STAT3 inhibition. CEBP-β binding onto the albumin promoter and its silencing were performed to confirm its role in albumin expression. Low albumin, i.e., hypoalbuminemia, was found in visceral leishmaniasis and ExVL. Its levels were inversely associated with parasitic load and hepatic IL-10 in both models. When treated with <em>Leishmania donovani-driven</em> IL-10 from the infected monocytes and recombinant IL-10, there was a significant decrease in albumin expression from HepG2 cells in a JAK1/STAT3-dependent manner. To further explore the molecular mechanism behind hypoalbuminemia in Visceral leishmaniasis, CEBP-β, a transcription factor having three isoforms (LAP1, LAP2, and LIP), was shown to increase upon recombinant IL-10 treatment and bind to the D site of the albumin promoter using Chromatin immunoprecipitation PCR. shRNA silencing results confirm CEBP-β-mediated decrease in albumin levels. Our findings showed that increased hepatic IL-10 upon <em>Leishmania donovani</em> infection reduces albumin levels in a JAK1/STAT3 and CEBP-β-dependent manner.</div></div>","PeriodicalId":297,"journal":{"name":"Cytokine","volume":"193 ","pages":"Article 156981"},"PeriodicalIF":3.7,"publicationDate":"2025-06-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144297731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}