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关键词： TLRs   DAMPs   M2 macrophage   IL-6   HSP72  

摘要： BackgroundM2-polarized macrophages aggressively modulate the tumor microenvironment and enhance tumor cell malignancy. As intracellular molecules are released by damaged or stressed cells, damage-associated molecular patterns (DAMPs) bind to toll-like receptors (TLRs) on cells in the tumor microenvironment, inducing inflammation and epithelial-mesenchymal transition. However, recent studies on the crosstalk between DAMPs and M2-polarized macrophages (M2 macrophages) during tumor progression have not provided conclusive *** investigated the role of toll-like receptors (TLRs) in IL-6 production by M2 macrophages and searched for cancer cell-derived DAMPs that can activate the TLRs responsible for IL-6 ***2 activation was required for IL-6 production by M2 macrophages. The malignancy of cancer cells was increased by the activation of this pathway. Cancer-derived HSP 72 acted as a ligand that stimulates the TLR2 signaling pathway in M2 macrophages, triggering IL-6 *** 2 stimulation in M2 macrophages enhances tumor malignancy by upregulating IL-6. Heat shock protein 72 (HSP72) is a potent TLR2 stimulator. Our findings reveal a connection between TLR2 and M2-polarized macrophages in tumor malignancy and may be useful for developing effective treatments for tumor relapse.

摘要： Chorion trophoblasts (CTCs) and immune cell-enriched decidua (DECs) comprise the maternal-fetal membrane interface called the chorio-decidual interface (CDi) which constantly gets exposed to maternal stressors without leading to labor activation. This study explored how CTCs act as a barrier at CDi. The roles of human leukocyte antigen (HLA)-G and progesterone receptor membrane component 2 (PGRMC2) in mediating immune homeostasis were also investigated. The CDi was recreated in a two-chamber microfluidic device (CDi-on-chip) with an outer chamber of primary DECs and immune cell line-derived innate immune cells and an inner chamber of wild-type or PGRMC2 or HLA-G knockout immortalized CTCs. To mimic maternal insults, DECs were treated with lipopolysaccharide, poly(I:C), or oxidative stress inducer cigarette smoke extract. Expression levels of inflammation and immunity genes via targeted RNA sequencing, production of soluble mediators, and immune cell migration into CTCs were determined. In CDi-on-chip, decidua and immune cells became inflammatory in response to insults while CTCs were refractory, highlighting their barrier function. HLA-G and PGRMC2 are found to be vital to immune homeostasis at the CDi, with PGRMC2 serving as an upstream regulator of inflammation, HLA-G expression, and mesenchymal-epithelial transition, and HLA-G serving as a frontline immunomodulatory molecule, thus preventing fetal membrane compromise. An organ-on-chip model of the maternal-fetal membrane interface reveals that HLA-G and PGRMC2 produced by chorion trophoblasts modulate inflammation, thus serving as immunological barrier to prevent membrane compromise.

关键词： Adolescent   Strength training   Oxidative stress   Hormones   IL-6  

摘要： Purpose The aim of the study was to investigate how 8-week strength training affects adolescent athletes' basal hormone concentrations, sex hormone binding globulin (SHBG), insulin-like growth factor binding protein-3 (IGFBP-3), cytokine, and oxidative stress markers. Methods Twenty adolescent handball players participated in this study. The participants were randomly divided into the strength training group (ST, n = 10) and the control group (C, n = 10). ST participates in strength training 3 sessions a week for 8 weeks and C participates only in handball training. We quantified serum basal hormone concentration, SHBG, IGFBP3, oxidative stress markers, and IL-6 in each subject's blood samples before and after 8 weeks of strength training. Results Interestingly, while insulin-like growth factor-1 (IGF-1) concentration declined in group C (p < 0.05), it did not in ST (p > 0.05). Furthermore, the basal concentration of growth hormone (GH), total testosterone (T), cortisol (Cor), total antioxidant status (TAS), and serum-free androgen index (FAI) basal concentration did not change in ST and C. Basal IGFBP-3 and SHBG concentrations decreased only in ST (p < 0.05), but not in C (p > 0.05). Serum-free testosterone (FT) levels increased in ST and C (p > 0.05). Total oxidant status (TOS) and oxidative stress index (OSI) reduced ST and C (p < 0.05). Serum interleukin-6 (IL-6) levels did not alter groups ST and C. Conclusion Strength training did not affect basal serum concentrations of T, GH, IGF-1, COR, IL-6, and TAS, but it caused a decrease in SHBG and IGFBP3 concentrations in ST. Increased basal FT concentration and improved serum TOS may not depend on strength training.

关键词： Alcohol-Related Hepatitis   Interleukin-1b   MELD   Model for End-Stage Liver Disease  

摘要： BACKGROUND AND AIMS:Short-term mortality in alcohol-related hepatitis (AH) is high, and no current therapy results in durable benefit. A role for interleukin (IL)-1β has been demonstrated in the pathogenesis of alcohol-induced steatohepatitis. This study explored the safety and efficacy of canakinumab (CAN), a monoclonal antibody targeting IL-1β, in the treatment of patients with AH. METHODS:Participants with biopsy-confirmed AH and discriminant function ≥32 but Model for End-Stage Liver Disease ≤27 were randomly allocated 1:1 to receive either CAN 3 mg/kg or placebo (PBO). Liver biopsies were taken before and 28 days after treatment. The primary endpoint was the overall histological improvement in inflammation analyzed by the modified intention-to-treat principle. RESULTS:Fifty-seven participants were randomized: 29 to CAN and 28 to PBO. Two participants had histology that did not corroborate the clinical diagnosis. Of the remaining 55 participants, paired histology data were evaluable from 48 participants. In CAN-treated participants, 14 (58%) of 24 demonstrated histological improvement compared with 10 (42%) of 24 in the PBO group (P = .25). There was no improvement in prognostic scores of liver function. Four (7%) of the 55 participants died within 90 days, 2 in each group. The number of serious adverse events was similar between CAN vs PBO. In post hoc exploratory analyses after adjustment for baseline prognostic factors, CAN therapy was associated with overall histological improvement (P = .04). CONCLUSIONS:CAN therapy in severe AH participants with Model for End-Stage Liver Disease ≤27 did not alter biochemical or clinical outcomes compared with PBO. Nonsignificant histological improvements did not translate into clinical benefit. EudraCT, Number: 2017-003724-79; ***, Number: NCT03775109.

关键词： defective ribosomal product   DRIP   antigen presentation   antigen processing   LCMV   ISG15   protein degradation   MHC  

摘要： Background Defective ribosomal products (DRiPs) are non-functional proteins rapidly degraded during or after translation being an essential source for MHC class I ligands. DRiPs are characterized to derive from a substantial subset of nascent gene products that degrade more rapidly than their corresponding native retiree pool. So far, mass spectrometry analysis revealed that a large number of HLA class I peptides derive from DRiPs. However, a specific viral DRiP on protein level was not described. In this study, we aimed to characterize and identify DRiPs derived from a viral *** Using the nucleoprotein (NP) of the lymphocytic choriomeningitis virus (LCMV) which is conjugated N-terminally to ubiquitin, or the ubiquitin-like modifiers FAT10 or ISG15 the occurrence of DRiPs was studied. The formation and degradation of DRiPs was monitored by western blot with the help of a FLAG tag. Flow cytometry and cytotoxic T cells were used to study antigen *** We identified several short lived DRiPs derived from LCMV-NP. Of note, these DRiPs could only be observed when the LCMV-NP was modified with ubiquitin or ubiquitin-like modifiers, but not in the wild type form. Using proteasome inhibitors, we could show that degradation of LCMV-NP derived DRiPs were proteasome dependent. Interestingly, the synthesis of DRiPs could be enhanced when cells were stressed with the help of FCS starvation. An enhanced NP118-126 presentation was observed when the LCMV-NP was modified with ubiquitin or ubiquitin-like modifiers, or under FCS *** Taken together, we visualize for the first time DRiPs derived from a viral protein. Furthermore, DRiPs formation, and therefore MHC-I presentation, is enhanced under cellular stress conditions. Our investigations on DRiPs in MHC class I antigen presentation open up new approaches for the development of vaccination strategies.

关键词： polymorphisms   graft-versus-host-disease   predictive models   cytokines   allogeneic transplantation  

摘要： Backgrounds Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapy for hematological malignancies, it can be associated with relevant post-transplant complications. Several reports have shown that polymorphisms in immune system genes are correlated with the development of post-transplant complications. Within this context, this work focuses on identifying novel polymorphisms in cytokine genes and developing predictive models to anticipate the risk of developing graft-versus-host disease (GVHD), transplantation-related mortality (TRM), relapse and overall survival (OS). Methods Our group developed a 132-cytokine gene panel which was tested in 90 patients who underwent an HLA-identical sibling-donor allo-HSCT. Bayesian logistic regression (BLR) models were used to select the most relevant variables. Based on the cut-off points selected for each model, patients were classified as being at high or low-risk for each of the post-transplant complications (aGVHD II-IV, aGVHD III-IV, cGVHD, mod-sev cGVHD, TRM, relapse and OS). Results A total of 737 polymorphisms were selected from the custom panel genes. Of these, 41 polymorphisms were included in the predictive models in 30 cytokine genes were selected (17 interleukins and 13 chemokines). Of these polymorphisms, 5 (12.2%) were located in coding regions, and 36 (87.8%) in non-coding regions. All models had a statistical significance of p<0.0001. Conclusion Overall, genomic polymorphisms in cytokine genes make it possible to anticipate the development all complications studied following allo-HSCT and, consequently, to optimize the clinical management of patients.

关键词： 肺炎严重度指数评分   中性粒细胞   淋巴细胞   下呼吸道感染  

摘要： 目的探讨肺炎严重度指数高危评分(PSI-HR)、中性粒细胞与淋巴细胞比值（N/L）在ICU下呼吸道感染患者病情评估中的应用价值。方法回顾性分析2020年1月至2023年7月在我院重症医学科住院的下呼吸道感染患者的临床资料。根据ICU转归将患者分为好转组和预后不良组，绘制受试者特征工作曲线（ROC）分析PSI-HR评分、PSI-HR评分死亡风险分级、PSI评分死亡风险分级、N/L以及PSI-HR评分联合N/L对下呼吸道感染患者预后评估的价值。结果好转组77例，预后不良组25例。PSI不同分级病死率分别为5级40.00%、4级18.75%、3级22.22%、2级4.76%。PSI分级与病死率无明显相关性（r=0.911，P=0.089）。PSI-HR不同分级病死率分别为6级75.00%、5级46.67%、4级28.57%、3级12.82%、2级12.12%，下呼吸道感染患者病死率与PI-HR分级呈正相关（r=0.955，P=0.011）。N/L预测下呼吸道感染死亡风险的ROC曲线下面积最大，为0.754(95%CI:0.637～0.871，P<0.001)，其次为PSI-HR评分0.744(95%CI:0.636～0.852，P<0.001)和PSI-HR分级0.706(95%CI:0.584～0.829，P=0.004)，PSI分级0.695(95%CI:0.582～0.807，P=0.004)预测效能最差。PSI-HR评分联合N/L预测患者死亡风险的ROC曲线下面积为0.828（95%CI:0.717～0.938，P<0.001）。结论PSI-HR评分死亡风险分级与下呼吸道感染患者的死亡风险有较好的相关性。PSI-HR评分联合中性粒细胞与淋巴细胞比值对ICU下呼吸道感染患者病情有更好的预测价值，优于单一指标。

关键词： Interleukin 18   Serum   Plasma   Saliva   Gingival tissue   Gingival crevicular fluid   Periodontitis  

摘要： BackgroundThe presence of a polymicrobial dysbiotic film in direct and constant contact with periodontal tissues initiates the host immune response. Interleukin 18 (IL-18) triggers up-regulates the production of other proinflammatory cytokines (TNF-alpha, IL-1 beta, IL-6), creating a vicious cycle that expands the inflammatory and destructive process in the periodontal tissue. A systematic review and meta-analysis was carried out with the main propose to investigate IL-18 expression in different biological samples from subjects with chronic *** protocol followed PRISMA guidelines and was registered in Open Science Framework (OSF):https://***/10.17605/***/BS9GM. A digital search was conducted in the databases PubMed, ScienceDirect, Google Scholar, Web of Science and Dentistry & Oral Sciences Source databases were consulted from March 15th, 2005 to February 10th, 2023. Study quality was assessed using the JBI tool for cross-sectional studies and clinical trials. A meta-analysis was performed using a random/fixed effects model to evaluate the concentration of IL-18 in serum, plasma, saliva, gingival tissue and GCF of exposure group compared to control *** search strategy provided a total of 3,156 articles, of which 18 investigations met the inclusion criteria and 15 articles were quantitatively analyzed. The total number of patients studied was 1,275 (682 cases and 593 controls). The meta-analysis revealed significantly elevated IL-18 levels of serum, saliva and GCF of subjects with chronic periodontitis compared to healthy subjects (Serum: SMD = 62.73, 95%CI: 25.43-100.03, Z = 3.29, p = 0.001*;Saliva: SMD = 243.63, 95%CI: 8.68-478.59, Z = 2.03, p = 0.042*;GCF: SMD = 150.26, 95%CI: 56.86-243.66, Z = 3.15, p = 0.02*).ConclusionIL-18 levels in serum, saliva and GCF could have the potential to be used as complementary diagnostic tools to the clinical and radiographic parameters in subjects with periodontitis.

关键词： Atopic dermatitis   Icariin   WTAP   SERPINB4   TNF-alpha/IFN-gamma  

摘要： Atopic dermatitis (AD) is a chronic inflammatory skin disorder characterized by increased sensitivity to environmental allergens and irritants. Icariin, a natural compound extracted from the herb Epimedium, has been traditionally used for its potential anti-inflammatory and antioxidant properties. This study aimed to investigate the regulatory effects of icariin on AD-like symptoms and to elucidate its underlying mechanisms. The effects of icariin on TNF-alpha/IFN-gamma-induced HaCaT cell injury were assessed using various assays, including cell counting kit-8 for cell viability, flow cytometry for reactive oxygen species (ROS) levels, and colorimetric assays for malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity. In addition, the study performed enzyme-linked immunosorbent assays to assess cytokines (IL-1 beta, IL-6, and IL-8) and chemokines (MDC, TARC, and RANTES) levels. Flow cytometry was used to quantify apoptotic rate, while a wound-healing assay was conducted to assess cell migration. The expression of WT1 associated protein (WTAP) and serpin family B member 4 (SERPINB4) at the mRNA and protein levels was determined using qRT-PCR and western blotting, respectively. The associations between WTAP and SERPINB4 were analyzed using RNA immunoprecipitation assay and m6A RNA immunoprecipitation assay. Icariin treatment significantly mitigated TNF-alpha/IFN-gamma-induced oxidative stress, inflammatory response, and apoptosis in HaCaT cells, while also reversing the inhibitory effect on cell migration. Icariin reduced the expression of WTAP in TNF-alpha/IFN-gamma-stimulated HaCaT cells. Overexpression of WTAP reversed the effects of icariin in TNF-alpha/IFN-gamma-stimulated HaCaT cells. WTAP silencing inhibited the mRNA stability of SERPINB4 through the m6A modification. SERPINB4 overexpression attenuated the effects of WTAP silencing on oxidative stress, inflammatory response, apoptosis, and migration of TNF-alpha/IFN-gamma-stimulated HaCaT cells. I

关键词： Vincamine   CLP   Hepatic injury   TNF alpha   Cleaved caspase 3   Nrf-2   Keap-1  

摘要： Sepsis is a pathological and biochemical disorder induced by numerous infections, leading to critical illness and a high mortality rate worldwide. Vincamine is an indole alkaloid compound obtained from the leaves of Vinca minor. The present study aims to investigate the hepato-protective activity of vincamine during colon ligation puncture (CLP)-induced sepsis at the molecular level. Sepsis was induced using the CLP model. Liver function enzymes such as ALT and AST were analyzed. The hepatic antioxidant status (SOD and GSH), lipid peroxidation (MDA), the pro-inflammatory cytokines (TNF alpha, IL-6, and IL-1 beta), bax, bcl2, and cleaved caspase 3 proteins were estimated. Nrf-2 and Keap-1 protein expression was evaluated using western blotting. Histopathological investigation of liver tissues was also performed. CLP-induced sepsis led to liver injury through the elevation of ALT and AST liver enzymes. Oxidative stress was initiated during CLP via the suppression of hepatic GSH content and SOD activity and the elevation of MDA. The inflammatory condition was activated by the upregulation of TNF alpha, IL-6, IL-1 beta, and Keap-1 and the downregulation of Nrf-2 proteins. The apoptosis was initiated through the activation of bax and cleaved caspase 3 protein expression and inhibition of bcl2 protein expression. However, vincamine significantly improved the hepatic histological abnormalities and decreased liver enzymes (ALT and AST). It ameliorated oxidative stress, as evidenced by reducing the hepatic MDA content and increasing the SOD activity and GSH content. Moreover, vincamine reduced the hepatic content of TNF alpha, IL-6, IL-1 beta, and Keap-1 and increased Nrf-2 protein expression. Additionally, it upregulated bcl2 protein expression and downregulated bax and cleaved caspase 3 protein expression. Vincamine exhibited hepato-protective potential during CLP-induced sepsis via the cross-connection of antioxidant, anti-inflammatory, and anti-apoptotic activities by mo