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关键词： Harmaline   Pain   Oxidative stress   Inflammation   Nrf-2   Nitric oxide   COX-inhibition  

摘要： Harmaline, a naturally occurring beta-carboline alkaloid found in plants such as Peganum harmala and Banisteriopsis caapi, exhibits various pharmacological activities, including antioxidant and neuroprotective properties. Its free radical-scavenging ability contributes to cellular protection against oxidative stress. Based on these properties, the present study aimed to explore the antinociceptive and anti-inflammatory effects of harmaline using acetic acid-induced writhing and carrageenan-induced paw edema mice models. Mice were treated with acetic acid to induce writhing, and carrageenan was administered to induce paw edema. Following carrageenan administration, the animals were euthanized, and paw tissues were harvested for biochemical analysis. Harmaline significantly reduced the frequency of acetic acid-induced writhing and attenuated carrageenan-induced inflammation, as indicated by a decrease in paw thickness. Biochemical analysis revealed that harmaline (5 mg/kg) reduced lipid peroxidation and preserved GSH levels in paw tissues, highlighting its antioxidant effects. Furthermore, harmaline treatment lowered IL-1 beta levels and upregulated Nrf-2, indicating modulation of inflammatory and antioxidant signaling. Pre-treatment with substance P and L-arginine reversed harmaline's effects on writhing and paw edema, suggesting the involvement of cyclo-oxygenase and nitric oxide pathways. These pre-treatments also reversed the harmaline-induced reduction in TBARS and IL-1 beta levels, as well as elevation of GSH and Nrf-2 levels, further supporting the involvement of these pathways. Overall, this study demonstrates that harmaline effectively alleviates pain and inflammation through the inhibition of COX and nitric oxide pathways, alongside the activation of Nrf-2-antioxidant signaling. These findings support harmaline's potential as a therapeutic agent for pain and inflammation, warranting further research into its clinical applications.

关键词： lower-grade glioma   prognosis   NK cells   CD56(dim) NK   HLA-I   anti-tumour immunity   transcriptional signature   deconvolution  

摘要： Background: Human leukocyte antigen class I (HLA-I) plays a pivotal role in shaping anti-tumour immunity by influencing the functionality of T cells and natural killer (NK) cells within the tumour microenvironment. Methods: Here, we explored the transcriptional landscape of HLA-I molecules across various solid cancer transcriptomes from The Cancer Genome Atlas (TCGA) database and assessed the impact of HLA-I expression on the clinical significance of tumour-infiltrating CD56(dim) and CD56(bright) NK cells. Results: Our analysis revealed that high HLA-I expression correlated with reduced patient survival in the TCGA lower-grade glioma (LGG) cohort, with this association varying by histopathological subtype. We then estimated the relative abundance of 23 immune and stromal cell signatures in LGG transcriptomes using a cellular deconvolution approach, which revealed that LGG patients with low HLA-I expression and high CD56(dim) NK cell abundance had better survival outcomes compared to those with high HLA-I expression and low CD56(dim) NK cell abundance. Furthermore, HLA-I expression was positively correlated with various inhibitory NK cell receptors and negatively correlated with activating NK cell receptors, particularly those within the killer cell lectin-like receptor (KLR) gene family. High co-expression of HLA-E and NKG2A predicted poor survival outcomes in LGG patients, whereas low HLA-E and high NKG2C/E abundance predicted more favourable outcomes, suggesting a potential modulatory role of HLA-I on the tumour-infiltrating cytotoxic CD56(dim) NK cell subset. Conclusions: Overall, our study unveils a potential role for deregulated HLA-I expression in modulating the clinical impact of glioma-infiltrating CD56(dim) NK cells. These findings lay the foundation for future in-depth experimental studies to investigate the underlying mechanisms.

摘要： BACKGROUND:JAK inhibition (JAKi) is effective in seronegative spondyloarthropathy (SpA) spectrum disorders, but TYK2 inhibition failed in SpA spectrum ulcerative colitis, and tofacitinib showed minimal benefit in Crohn's Disease, which highlights the complex role for JAK-STAT signaling in different inflammatory processes. In this study, we investigated whether JAKi might paradoxically activate entheseal innate immunity and aimed to identify the key regulatory cytokines involved in this process. METHODS:Spinal entheseal tissue was activated with TLR agonists, including TLR4 and IL-1 family proteins and entheseal T cell were activated with anti-CD3/anti-CD28 plus IL-23/IL-1β. JAKi via upadacitinib (JAK1/JAK2), deucravacitinib (TYK2) and ritlecitinib (JAK3) inhibition was evaluated using multiplex cytokine assays, intracellular flow and bulk RNAseq and cytokine blocking or stimulation. RESULTS:Following IFNγ stimulation, JAK1 inhibition blocked STAT1 phosphorylation in entheseal cells and strongly blocked activated entheseal T cell TNFα, IL-17A and IL-17F production. The opposite effect was evident in entheseal myeloid cell with exaggerated TLR4 and other adjuvant-mediated cytokine production including IL-23 (~10-fold increase; p < 0.001) or TNFα (~10-fold increase; p < 0.0001). This myeloid effect was induced by upadacitinib and deucravacitinib, but not ritlecitinib, suggesting IL-10R JAK1/TYK2 signaling. Bulk RNAseq showed multifaceted impact of JAKi on myeloid activation with strong M1 type monocyte polarisation under TLR4 stimulation and JAK1 inhibition confirmed by flow cytometry. Direct IL-10 inhibition recapitulated inflammatory cytokine elevations and IL-10R agonist largely, but not completely, rescued this phenotype. CONCLUSIONS:These findings help explain the emergent efficacy of TYK2 blockade in SpA spectrum related arthritis that is not IL-10 dependent but indicates why such strategies may not be a panacea for SpA spectrum disorder related intestinal inflam

关键词： apoptosis inhibitor of macrophage   CD5L   foamy macrophage   Mycobacterium avium   lipid metabolism   interleukin 10  

摘要： Non-tuberculous mycobacteria infections, including Mycobacterium avium, are increasingly recognized as a growing public health concern, even among immunocompetent individuals. These infections are a significant cause of chronic pulmonary disease, and they are characterized by the formation of foamy macrophages (FMs) that facilitate bacterial persistence. Previously, we reported that apoptosis inhibitor of macrophage (AIM), a protein secreted by macrophages, promotes lipid droplet accumulation in M. avium-infected macrophages. However, the precise role of AIM in modulating immune responses remains unclear. This study aimed to elucidate the effect of AIM on FM formation, bacterial burden, and immune response in M. avium-infected mice by comparing AIM knockout (KO) mice with wild-type mice. Histological analysis revealed a reduction in FM formation in AIM KO mice, accompanied by decreased lipid droplet accumulation and altered expression of lipid metabolism-related genes. Furthermore, AIM KO mice exhibited a reduced bacterial load in the lungs, highlighting decreased cytokine production, including IL-1 beta, compared to wild-type mice. In addition, the analysis of the immune cells of AIM KO mice using flow cytometry revealed an increase in M1 macrophages and IFN-gamma-producing T cells, as well as a decrease in M2 macrophages and interleukin 10 (IL-10)-producing T cells. The reduced expression of CD36 and PD-L1 in macrophages from AIM KO mice further supports the skewing toward an M1 phenotype. In vitro experiments with bone marrow-derived macrophages (BMDMs) confirmed reduced bacterial growth and lipid droplet formation in AIM KO BMDMs, which was restored by AIM and IL-10 treatment. These findings suggest that AIM contributes to the promotion of FM formation by establishing an immunosuppressive environment that promotes the establishment of M. avium through IL-10 production.

关键词： DILI   Hepatotoxicity   liver injury   medications   HLA   risk   prediction  

摘要： IntroductionDrug-induced liver injury is an important adverse effect and can be caused by various medications, including novel therapeutic agents. The risk stratification of patients susceptible to DILI is a growing *** coveredThe current article highlights new studies on risk stratification regarding risk factors of DILI, prediction of liver injury, and predictors of severe outcomes. Studies on patient demographic and genetic risk factors are discussed, in addition to the potential role of concomitant medications that may affect the risk of *** opinionAlthough much is known about patient risk factors for DILI, a better combination of these factors into risk scores is needed to predict which patients are particularly susceptible. Knowledge of these risk factors might determine drug treatment in the near future, as well as the need for routine monitoring of liver tests.

关键词： Idiosyncratic adverse drug reactions   HLA   pharmacogenomics   SCARs   DILI  

摘要： IntroductionIdiosyncratic adverse drug reactions (IADRs) or drug hypersensitivity reactions (DHRs) represent a major health problem because they are unpredictable and can be severe with potential life-long or even lethal consequences. Their pathophysiology is not clear but thought to be immune mediated, supported by the significant statistical association of these reactions with specific alleles of the human leukocyte antigen (HLA) *** coveredThis comprehensive update review summarizes the currently available evidence on the role of HLA gene locus in IADRs and discusses the present understanding of the pathophysiology of IADRs. We searched the available literature in PubMed and Google Scholar with no date restriction for publications on HLA and adverse drug reactions. Findings are summarized and discussed in the context of the currently available *** opinionThe role of the immune system in IADRs and the role of pharmacogenetic testing in this field is evident. HLA genetic testing is very promising in the management of these reactions. Many obstacles seem to prevent pharmacogenetic testing to meet its full potential including cost and health care providers' education. Further work in needed to provide more evidence and allow widespread use of pharmacogenetic testing in the clinical practice.

关键词： Anti-PoRV effect   Lactobacillus plantarum   STING-IFN-I pathway  

摘要： BackgroundRotavirus infection represents a major etiology of severe diarrheal disease in neonatal and weaned piglets, causing substantial economic burdens to the global swine industry. Lactobacillus plantarum, a ubiquitous probiotic in natural ecosystems, has demonstrated multifaceted biological functions. The stimulator of the interferon gene (STING) is involved in type I interferon (IFN-I) mediated host antiviral innate immunity, which is a pivotal adaptor in response to the microbial DNA/RNA-activated signaling pathways. Emerging evidence suggests that certain probiotic strains can activate the STING-dependent pathway to induce IFN-I responses. In the present study, we successfully isolated a strain of Lactobacillus plantarum (designated LP1)from porcine intestinal contents and investigate its potential to counteract porcine rotavirus (PoRV) infection via modulation of antiviral signaling ***1 exhibited superior tolerance to simulated gastrointestinal conditions (pH 3.0 and 0.3% bile salts) compared with other isolated Lactobacillus strains. In vitro adhesion assays demonstrated that LP1effectively colonized porcine intestinal epithelial cells (IPEC-J2) without inducing cytotoxicity or apoptosis. Animal experiments also confirmed the protective effect of LP1 in mice against rotavirus, by reducing body weight loss, promoting viral clearance in feces, and alleviating intestinal mucosal damage. Mechanistic investigations identified STING-IRF3 pathway activation as the pivotal antiviral mechanism. Both phosphorylation of STING and IRF3 in LP1-treated IPEC-J2 cells accompanied by upregulated transcription and secretion of IFN-beta and interferon-stimulated genes (ISGs). Consistent findings were observed in intestinal tissues of LP1-protected mice with STING pathway activation correlating with reduction in viral titers. Crucially, STING inhibitor (C-170) administration could reverse LP1-mediated antiviral ***1 exerts potent anti-PoRV activ

关键词： electroconvulsive therapy (ECT)   treatment-resistant schizophrenia (TRS)   cytokines   interleukins   antipsychotics  

摘要： Background: Resistance to antipsychotic treatment in patients suffering from schizophrenia is linked to immune system disequilibrium. One effective therapeutic option for treatment-resistant schizophrenia is electroconvulsive therapy (ECT);however, its impact on cytokines remains poorly understood. The aim of this study is to evaluate the impact of ECT on cytokines (IL-1 beta, IP-10, IL-17, TNF alpha, IL-10, and soluble receptor for IL-2 (sIL-2R)) in TRS patients. Additionally, correlations between cytokine concentrations and schizophrenia symptoms severity are explored. Methods: Cytokine and receptor concentrations were measured in eight TRS patients before and after ECT and in 13 healthy participants from control group. The Positive and Negative Syndrome Scale (PANSS) was used to evaluate the severity of the symptoms. Results: Before ECT, TRS patients exhibited significantly higher concentrations of IL-1 ss, IL-10, IL-17, and IP-10 compared to the control group, whereas no significant differences were observed in sIL-2R and TNF-alpha. In the TRS patients, ECT induced a significant reduction in IL-10, IL-17 and IP-10 levels, while IL-1 beta, TNF-alpha, and sIL-2R remained unchanged compared to pre-ECT. ECT also led to clinical improvement in schizophrenia symptoms, as measured by PANSS. Furthermore, correlations between cytokine levels and PANSS results were found. Conclusions: The above results suggest that clinical improvement in TRS patients following ECT is associated with immune modulation, especially with the steadiness between pro- and anti-inflammatory systems. However, further research is required to elucidate these mechanisms in greater detail.

摘要： The multifaceted roles and mechanisms of necroptosis in cancer cells remain incompletely understood. Here, we demonstrate that FGFR2 inhibition potently inhibits esophageal squamous cell carcinoma (ESCC) by inducing necroptosis in a RIP1/MLKL-dependent manner and show RIP3 is dispensable in this pathway. Notably, MST1 is identified as a necroptotic pathway component that interacts with RIP1 and MLKL to promote necroptosis by phosphorylating MLKL at Thr216. Additionally, FGFR2 inhibition induces Ser518 phosphorylation and triggers ubiquitin-mediated degradation of NF2, culminating in Hippo pathway suppression. Subsequently, YAP activation promotes RIP1 and MLKL transcriptional upregulation, further amplifying necroptosis. Intriguingly, IL-8 derived from necrotic cells stimulates peripheral surviving tumor cells to increase PD-L1 expression. Dual blockade of FGFR2/PD-L1 or FGFR2/IL-8-CXCR1/2 robustly impedes tumor growth in humanized mouse xenografts. Collectively, our findings delineate an alternative FGFR2-NF2-YAP signaling-dependent necroptotic pathway and shed light on the immunoregulatory role of FGFR2, offering promising avenues for combinatorial therapeutic strategies in clinical cancer management.

关键词： Adults   Autoantibodies   Autoantibody-negative   Children   Enterovirus antibodies   HLA   Recently diagnosed   Type 1 diabetes  

摘要： This study aimed to compare the immunological and immunogenetic profiles over a spectrum of childhood- and adulthood-onset T1D at diagnosis. The cross-sectional study involved participants with recently diagnosed T1D (n = 168), aged 2.9-68.2 years. HLA-II alleles, single nucleotide polymorphisms (SNP) (rs2476601, rs3087243, rs1990760, rs13266634), thyroid and coeliac disease-related autoantibodies and anti-enterovirus antibodies (anti-EV) were analysed regarding the diabetes-associated autoantibodies' (DAA) status and the age of participants. In the longitudinal study, 19 immune checkpoint gene expression levels in children (n = 25) aged 3.6-14.5 years were measured at diagnosis and 1 year after diagnosis. The duration of symptoms before diagnosis was age-dependent. Older age increased the odds of being single DAA-positive (OR 1.05;95% CI 1.02-1.09), while anti-EV IgG positivity increased the odds of being multiple DAA-positive (adjusted OR 4.42;95% CI 1.62-12.04). The DAA-negative T1D participants were older than the DAA-positive individuals. The checkpoint gene expression levels between the two time points were similar, but exhibited more pronounced variability at the time of diagnosis. These results confirm immunological variability in recent-onset T1D cases between children and adults and stress the importance of further research to define the comprehensive immunological profile of the disease age-related subgroups.