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关键词： IL-6   TNF-alpha   IFN-gamma   cytokine storm   COVID-19   tocilizumab  

摘要： IL-6 remains a key molecule of the cytokine storms characterizing COVID-19, exerting both proinflammatory and anti-inflammatory effects. Emerging research underscores the significance of IL-6 trans-signaling over classical signaling pathways, which has shifted the focus of therapeutic strategies. Additionally, the synergistic action of TNF-alpha and IFN-gamma has been found to induce inflammatory cell death through PANoptosis, further amplifying the severity of cytokine storms. Long COVID-19 patients, as well as those with cytokine storms triggered by other conditions, exhibit distinct laboratory profiles, indicating the need for targeted approaches to diagnosis and management. Growing evidence also highlights the gut microbiota's crucial role in modulating the immune response during COVID-19 by affecting cytokine production, adding further complexity to the disease's immunological landscape. Targeted intervention strategies should focus on specific cytokine cutoffs, though accurate cytokine quantification remains a clinical challenge. Current treatment strategies are increasingly focused on inhibiting IL-6 trans-signaling, which offers promise for more precise therapeutic approaches to manage hyperinflammatory responses in COVID-19. In light of recent discoveries, this review summarizes key research findings on cytokine storms, particularly their role in COVID-19 and other inflammatory conditions. It explores emerging therapeutic strategies targeting cytokines like IL-6, TNF-alpha, and IFN-gamma, while also addressing open questions, such as the need for better biomarkers to detect and manage cytokine storms. Additionally, the review highlights ongoing challenges in developing targeted treatments that mitigate hyperinflammation without compromising immune function, emphasizing the importance of continued research in this field.

关键词： severe obesity   LSG   interleukin-6   TNF-alpha   adiponectin  

摘要： Background and Objectives: Overweight and obesity are well-known conditions that negatively impact the health and lifestyle of an individual. Bariatric surgery is one of the most efficient weight loss techniques. Besides the main effect on the bodyweight, improvement in the levels of inflammatory biomarkers, such as interleukin 6 (IL-6), tumor necrosis factor alpha (TNFalfa), and others, has been observed. The purpose of this study was to establish the correlations between obesity-linked chronic systemic inflammation (estimated with inflammatory cytokine levels) and the weight loss process after metabolic surgery. Materials and Methods: An observational cohort study included two categories: the patients with obesity-bariatric group and the patients without obesity-control group. The study was performed between 1 February 2021 and 1 March 2023. Baseline characteristics, anthropometrics, biochemical assessment and inflammatory biomarkers were measured both before surgery and one year after the procedure, in the case of the bariatric group. The control group was assessed in the same period as the pre-surgery bariatric group. The bariatric group underwent two types of bariatric procedures: the majority underwent laparoscopic sleeve gastrectomy whereas a select few underwent one anastomosis laparoscopic gastric bypass. Results: We performed a prospective study comprising 55 Caucasian patients-from which 33 patients had morbid obesity, a mean age of 41.76 +/- 10.78 and a mean BMI of 43.34 +/- 7.51 kg/m2. The preoperative levels of IL-6 were positively correlated with waist circumference (r = 0.354, p = 0.043), weight (r = 0.549, p = 0.001) and BMI (r = 0.520, p = 0.002). After applying the Kruskal-Wallis test and Dunn's test, significant differences for IL-6 (p = 0.010) and adiponectin (p = 0.024) were obtained for values recorded pre- and post-surgery. No correlation was found between adiponectin, IL-6, TNF- alpha levels and anthropometric indices after surgery. Our stud

关键词： apache-ii score   sepsis markers   sepsis prognosis   sepsis progression   systemic inflammatory response syndrome (sirs)  

摘要： INTRODUCTION:Sepsis and systemic inflammatory response syndrome (SIRS) are significant concerns in intensive care units and contribute significantly to patient mortality. Traditional diagnostic markers such as C-reactive protein (CRP) and procalcitonin (PCT) often lack the sensitivity and specificity needed for early diagnosis and prognosis. Consequently, more reliable biomarkers are needed. This study aimed to evaluate interleukin-6 (IL-6) and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as potential biomarkers to improve diagnostic and prognostic capabilities in sepsis and SIRS. METHODS:The study comprised 64 patients diagnosed with sepsis and SIRS, admitted to the Critical Care Department of the First University Clinic (Tbilisi, Georgia). Changes in the levels of CRP, PCT, IL-6, sTREM-1, and lactate were monitored over a five-day observation period, with measurements taken on days 0, 1, 2, 3, and 5. RESULTS:We found a significant logarithmic relationship between sTREM-1 levels and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores (r = 0.922, p < 0.001), suggesting that sTREM-1 could serve as a valuable biomarker for early risk stratification in sepsis. Furthermore, sTREM-1 exhibited strong correlations with IL-6 and lactate levels, underscoring its potential as a predictor of disease severity. While CRP and PCT were more useful in tracking disease progression over time, their baseline levels were less predictive of early outcomes. CONCLUSION:Our findings highlight the potential of sTREM-1, IL-6, and lactate as early diagnostic and prognostic markers in sepsis, where sTREM-1 is a critical biomarker for identifying high-risk patients. Further studies with larger cohorts are required to validate these results and explore the sTREM-1 clinical utility in guiding therapeutic interventions in sepsis management.

摘要： Interleukin-18 (IL-18) is a vital pro-inflammatory cytokine crucial for immune regulation. Despite its significance, bibliometric analysis in this field is lacking. This study aims to quantitatively and qualitatively assess IL-18 research to construct its intellectual base and predict future hotspots. We conducted a thorough search on the Web of Science Core Collection for relevant publications between 1 January 2012 and 31 December 2022. English-language articles and reviews were included. Visual analysis was performed using various tools including VOSviewer, Citespace, and Microsoft Excel. Our analysis covers interleukin-18 (IL-18) literature from 2012 to 2022, exploring research trends comprehensively. Key institutions like Yale University and Shanghai Jiao Tong University emerged as significant contributors. Prolific authors such as Kanneganti and Dinarello made notable contributions. Main focus areas included biology, medicine, and immunology. Co-citation analysis highlighted influential works like Jianjin Shi. Hotspot keyword frequency cluster analysis revealed emerging themes like pyroptosis and psoriasis. Gene co-occurrence clustering identified genes associated with immune regulation and inflammation. GO and KEGG pathway enrichment analysis provided insights into IL-18-related biological processes and pathways. Protein-protein interaction networks identified core proteins such as IL10 and TNF. Association disease analysis linked IL-18 to various inflammatory, autoimmune, and metabolic disorders. This bibliometric review offers insights into IL-18 research trends over the past decade, guiding future investigations and serving as a reference for researchers in this field.

关键词： aplastic anaemia   clonal haematopoiesis   haematopoietic stem cells   immune suppressive treatment  

摘要： HLA loss represents the result of immune forces shaping bone marrow clonal dynamics in immune aplastic anaemia. Human leukocyte antigen (HLA)-deficient clones may rescue haematopoiesis by evading immune attacks, potentially guiding treatment strategies.

关键词： Cyanidin-3-glucoside   endothelial nitric oxide synthase   nitric oxide   protocatechuic acid   vanillic acid  

摘要： Background/Objectives: Reduced nitric oxide (NO) bioavailability secondary to excess-superoxide-driven oxidative stress is central to endothelial dysfunction. Previous studies suggest that phenolic metabolites may improve NO bioavailability, yet limited research is available in response to an inflammatory mediator. Therefore, we assessed the effects of cyanidin-3-glucoside (C3G) and its phenolic metabolites protocatechuic acid (PCA) and vanillic acid (VA) on NO bioavailability in a TNF-alpha induced inflammatory environment. Methods: Primary human umbilical vein endothelial cells (HUVECs) were supplemented with either C3G, PCA, or VA at 1 mu M for 24 h before being stimulated with TNF-alpha 20 ng/mL for an additional 24 h. Measurements included cell viability, apoptosis, reactive oxygen species (ROS), nitrite concentrations, and endothelial nitric oxide synthase (eNOS) and Akt at the mRNA and protein level. Results: Phenolic metabolites did not increase the eNOS expression or nitrite levels in the unstimulated environment;rather, the metabolites mediated NO bioavailability in response to TNF-alpha induced oxidative stress, with increased viability, eNOS mRNA, phosphorylation, and nitrite levels. Conclusions: Phenolic metabolites, in the presence of TNF-alpha, can improve NO bioavailability at physiologically relevant concentrations via the Akt-eNOS pathway. This demonstrates that the induction of inflammation is a prerequisite for phenolic metabolites to promote protective properties in endothelial cells by activating the Akt-eNOS pathway.

关键词： IL-17A   Drug metabolism   Drug-drug interactions   JAK/STAT pathway   HepaRG Cells  

摘要： The founding family member, Interleukin (IL)-17A, is commonly known as IL-17 and has garnered increasingly attention for proinflammatory functions in autoimmune disorders. Although the effects of IL-17A on hepatic important drug-metabolizing enzymes and transporters (DMETs) expression still remain unclear, it is critical to ascertain owing to the well-established alterations of the drug disposition capacity of the liver occurring during immune imbalance. The present study was designed to explore the effects and mechanisms of IL-17A on DMETs mRNA and protein expression in HepaRG cells by real-time quantitative reverse transcription polymerase chain reaction and Western blot, respectively. It is discovered that IL-17A can inhibit most DMETs mRNA expression (drug-metabolizing enzymes of CYP1A2, CYP3A4, CYP2C9, CYP2C19, GSTA1 and UGT1A1 and transporters of NTCP, OCT1, OATP1B1, BCRP and MDR1) as well as the protein expression of CYP3A4 and CYP2C19, via the janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) signaling pathway. Thus, abnormal regulation of DMETs in IL-17A-mediated immune disorders such as psoriasis may cause alterations in pharmacokinetic processes and may occasionally result in unexpected drug-drug interactions (DDIs) in clinical practice.

关键词： Balancing selection   Linkage disequilibrium   Amino acid   Population genetics   HLA-DPB1  

摘要： Although allele frequency data for most HLA loci provide strong evidence for balancing selection at the allele level, the DPB1 locus is a notable exception, with allele frequencies compatible with neutral evolution (genetic drift) or directional selection in most populations. This discrepancy is especially interesting as evidence for balancing selection has been seen at the nucleotide and amino acid (AA) sequence levels for DPB1. We describe methods used to examine the global distribution of DPB1 alleles and their constituent AA sequences. These methods allow investigation of the influence of natural selection in shaping DPP diversity in a hierarchical fashion for DPBJ alleles, all polymorphic DPBJ exon 2-encoded AA positions, as well as all pairs and trios of these AA positions. In addition, we describe how asymmetric linkage disequilibrium for all DPB1 exon 2-encoded AA pairs can be used to complement other methods. Application of these methods provides strong evidence for the operation of balancing selection on AA positions 56, 85-87, - 87, 36, 55 and 84 (listed in decreasing order of the strength of selection), but no evidence for balancing selection on DPBJ alleles.

关键词： Traf5   CD40   germinal center   B cells   antibody   T-dependent immune response   TNF receptor  

摘要： TNF receptor-associated factors (TRAFs) function as intracellular adaptor proteins utilized by members of the TNF receptor superfamily, such as CD40. Among the TRAF family proteins, TRAF5 has been identified as a potential regulator of CD40. However, it remains unclear whether TRAF5 regulates the generation of germinal center (GC) B cells and antigen-specific antibody production in the T-dependent (TD) immune response. TRAF5-deficient (Traf5-/-) and TRAF5-sufficient (Traf5+/+) mice were immunized in the footpad with 2,4,6-trinitrophenol-conjugated keyhole limpet hemocyanin (TNP-KLH) and complete Freund's adjuvant (CFA). We found that GC B cell generation and antigen-specific IgM and IgG1 production were significantly impaired in Traf5-/- mice compared to Traf5+/+ mice. The expression levels of CD40-target genes Fas and Lta, which are involved in GC formation, were significantly decreased in B220+ cells isolated from immunized Traf5-/- mice. Traf5-/- B cells showed decreased antibody production, proliferation, and induction of CD40-target genes Tnfaip3, Tnfsf4, and Cd80 in response to agonistic Fc-CD40L protein in vitro. Furthermore, administration of TNP-KLH and Fc-CD40L to Traf5-/- mice resulted in a severe loss of GC B cell development. These results highlight the crucial role of TRAF5 in driving CD40-mediated TD immune response in vivo.