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关键词： Diethyl nitrosamine   Oxidative stress   Thioacetamide   Choline-deficient diet   Renal carcinogenesis   Canagliflozin   Rats  

摘要： A novel class of antidiabetic drugs known as sodium-glucose cotransporter 2 inhibitors (SGLT2-Is) prevents the renal proximal tubules from reabsorbing glucose. While a recent study showed that SGLT2-Is may be able to slow the proliferation of cancer cells that express SGLT2, limited evidence exists regarding their effects on renal cell carcinoma (RCC). Here, we examine the ability of the SGLT2-I canagliflozin (Cana) to prevent experimentally induced kidney carcinogenesis in male rats. A total of twenty-four rats were divided into four groups, six in each: negative control, DEN/TAA control;rats (60-70 g) were fed a choline-deficient diet (CDD) for 4 weeks, then rats were subjected to four doses of 50 mg/kg diethyl nitrosamine (DEN) over 8 weeks followed by thioacetamide 100 mg/kg (TAA) intraperitoneal injections twice weekly for 15 weeks, treated groups: rats were given canagliflozin (10 and 20 mg/kg ***.) orally starting from the 24th week of the experiment till the end of the 29th week. The obtained findings showed that treatment with canagliflozin reduced renal oxidative stress and toxicity indicator levels and considerably reinforced renal antioxidant capacity. The histological changes further supported the biochemical findings. In addition, canagliflozin therapy activated AMPK and inhibited Nrf2, NLRP3 and IL-6/STAT3 pro-inflammatory pathway. Immunohistochemistry exhibited upregulation of pro-apoptotic protein caspase-3 and downregulation of PCNA expression in Cana-treated groups. Conclusion: the results showed that canagliflozin has anti-carcinogenic efficacy against renal carcinogenesis via activating AMPK and suppressing NLRP3/IL-6/STAT3 signaling pathways.

关键词： Proteomics   Sexual dimorphism   Multi-omics   Human DRG  

摘要： The peripheral nervous system (PNS) plays a critical role in pathological conditions, including chronic pain disorders, that manifest differently in men and women. To investigate this sexual dimorphism at the molecular level, we integrated quantitative proteomic profiling of human dorsal root ganglia (hDRG) and peripheral nerve tissue into the expanding omics framework of the PNS. Using data-independent acquisition (DIA) mass spectrometry, we characterized a comprehensive proteomic profile, validating tissue-specific differences between the hDRG and peripheral nerve. Through multi-omic analyses and in vitro functional assays, we identified sex-specific molecular differences, with TNF alpha signalling emerging as a key sexually dimorphic pathway with higher prominence in men. Genetic evidence from genome-wide association studies further supports the functional relevance of TNF alpha signalling in the periphery, while clinical trial data and meta-analyses indicate a sex-dependent response to TNF alpha inhibitors. Collectively, these findings underscore a functionally sexual dimorphism in the PNS, with direct implications for sensory and pain-related clinical translation.

关键词： MALAT1   miR-146a   IL-17   SIRT1   NF-kappa beta p65   Liver cirrhosis  

摘要： In liver diseases, the interplay of different noncoding RNA expressions, and inflammatory biomarkers show high context dependencies. Interrelations between these noncoding RNA and inflammatory biomarkers paved the way for the diagnosis of various diseases. Here, we analyzed the expression of MALAT1, miR-181a in liver cirrhosis and a panel of pro-inflammatory cytokines (IL-17, SIRT1 and NF-kappa beta p65). The association between all measured parameters was monitored. Fifty healthy volunteers with normal liver function, hepatic ultrasonography, and negative results for HCV and HBV participated in our study as a healthy control group. In addition, hundred and fifty patients with liver cirrhosis were included. Compared with healthy controls, miR-181a expression was significantly decreased (p < 0.01), while MALAT1 expression was significantly elevated (p < 0.01) in patients with liver cirrhosis. IL-17 and NF-kappa B p65 were significantly increased (p < 0.001), while SIRT1 was significantly decreased (p < 0.001) in cirrhotic patients compared to controls. Serum expression of SIRT1 significantly positively correlated with miR-181a and negatively associated with MALAT-1, NF-kappa beta p65, and IL-17expression levels. Our results pointed to alterations in the expression levels of miR-181a, and MALAT1 could serve as biomarkers in cirrhotic patients. Reduction of IL-17 and NF-kappa beta p65 in combination with an elevation of SIRT-1 might refer to the dual effects of miR-181a and MALAT1 in controlling inflammation in liver cirrhosis.

关键词： Atopic dermatitis   Super responder   Biologics therapy   Dupilumab   Predictive factors   Treatment optimization  

摘要： Introduction: Biologics have revolutionized the treatment of moderate-to-severe atopic dermatitis (AD), with dupilumab, an anti-interleukin-4R alpha monoclonal antibody, showing notable clinical efficacy. However, some patients achieve rapid and profound improvement-termed super responders (SRs), while others respond poorly. This study aimed to identify SRs to dupilumab in patients with AD and analyze their clinical characteristics to inform personalized treatment strategies. Methods: A retrospective analysis was conducted on patients with moderate-to-severe AD treated with dupilumab, sourced from the National Clinical Research Center for Skin and Immune Diseases in China. Clinical and follow-up data were reviewed. Categorical variables were compared using Chi-square or Fisher's exact tests, while continuous variables were compared via t-tests or Mann-Whitney U tests. Furthermore, a logistic regression model was employed to evaluate the predictive ability of clinical and demographic variables collected at baseline on the probability of becoming SRs. Results: Among 1,034 patients with AD, 125 (12.09%) were identified as SRs, achieving significant clinical improvement within 16 weeks. Further univariate analysis indicated that factors closely associated with SRs included: older age, higher body mass index, later disease onset, higher baseline scores of pruritus intensity (Peak pruritus Numerical Rating Scale, PP-NRS)/disease severity (Eczema Area and Severity Index, EASI)/quality of life (Dermatology Life Quality Index, DLQI), prior systemic therapy use, no prior biologics, elevated eosinophil count, high-dose dupilumab, shorter dosing intervals of dupilumab, and absence of concomitant therapies. Logistic regression identified moderate baseline pruritus (PP-NRS) and higher baseline DLQI scores (moderate-to-severe impact) as strong predictors of SRs (moderate pruritus Adj odds ratio (OR): 8.38, 95% confidence interval (CI) 2.56-27.42;moderate DLQI Adj OR: 11.01, 95% CI

摘要： Chronic inflammation, resulting from infections, is characterized by increased levels of cytokines including interleukin-1 (IL-1), but little is known about how IL-1 contributes to cognitive impairment, potentially via epigenetic processes. Here we demonstrate that mice chronically infected with the parasite Toxoplasma gondii exhibit impaired spatial memory, which is dependent on neuronal IL-1 signaling and mimicked by chronic exposure to IL-1 beta. Both T. gondii infection and chronic IL-1 beta drive H2A.X-dependent DNA double-strand break signaling in hippocampal neurons and invalidating neuronal H2A.X-dependent signaling blocks memory impairments caused by either exposure. Our results highlight the instrumental role of cytokine-induced double-strand-break-dependent signaling in spatial memory defects, which may be relevant to multiple brain diseases.

关键词： IL-4 inducing peptides   ESM-2 model   Protein language model   SMOTE   ENN  

摘要： Despite progress in developing antiviral drugs and vaccines, infections continue to be a significant challenge. Interleukin-4 (IL-4) is crucial for regulating immune responses and mediating allergic reactions. This research aims to improve the predictive accuracy of IL-4-inducing peptides by tackling data imbalance and enhancing feature extraction. Specifically, we introduce a new approach that utilizes SMOTE and ENN for balancing the dataset and applies a 30-layer ESM-2 model for extracting deep features. The extracted features are subsequently processed through a Gated Recurrent Unit (GRU) model, which is optimized through hyperparameter tuning. Our method achieves notable improvements, with an AUC of 0.98 and an accuracy of 93.1 %, highlighting its potential to support future immunotherapy and vaccine development efforts. The PLM-IL4 web server is freely accessible at http://***/PLM-IL4, and the datasets used in this research are also available for download from the website.

关键词： Multiple sclerosis   IFNG rs2069727 T/C   Interferon-gamma   MicroRNA   Biomarker  

摘要： Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder, with relapsing-remitting MS (RRMS) being the most common subtype. Interferon-gamma (IFN-gamma) plays a dual role in MS pathogenesis. MicroRNAs (miRNAs) have emerged as potential diagnostic biomarkers. This study examined the effect of relative expression of hsa-miR-24-3p and hsa-miR-181d-3p, plasma IFN-gamma levels, and the IFNG rs2069727 T/C variant on MS risk, evaluating their interrelationships and diagnostic potential. This case-control study comprised two overlapping groups-a genetic polymorphism group (330 RRMS, 330 healthy controls (HCs)) and a miRNA group (25 glatiramer acetate (GA)-treated RRMS patients, 25 treatment-na & iuml;ve RRMS patients, and 25 HCs)- collected at the Ankara Bilkent City Hospital Neurology Polyclinic. The IFNG rs2069727 T/C variant did not display a statistically significant disparity between RRMS patients and HCs. Significantly elevated hsa-miR-24-3p and hsa-miR-181d-3p relative expression levels were observed in GA-treated and treatment-na & iuml;ve RRMS patients compared to HCs. Conversely, age-adjusted plasma IFN-gamma concentrations were markedly lower in GA-treated and treatment-na & iuml;ve RRMS patients versus HCs. Individuals with low plasma IFN-gamma levels (<= 1.311 pg/mL) demonstrated significantly elevated hsa-miR-24-3p relative expression compared to the high IFN-gamma group (> 1.311 pg/mL). Conversely, subjects with low hsa-miR-181d-3p levels (<= 2.90) exhibited significantly higher plasma IFN-gamma concentrations relative to those with high hsa-miR-181d-3p levels (> 2.90). In the GA-treated group, EDSS negatively correlated with age-adjusted plasma IFN-gamma. This study identified age-adjusted plasma IFN-gamma, hsa-miR-24-3p, and hsa-miR-181d-3p expression as potential blood-based biomarkers for RRMS diagnosis and analyzed them alongside disability scores. The miRNAs in this study can be further evaluated as prospective therapeutic targets.

摘要： A method for designing high-affinity, specific binders to peptide–MHC complexes may improve the next generation of antigen-specific T cell-based therapeutics. © Springer Nature America, Inc. 2024.

关键词： Innate lymphoid cells   Interstitial lung disease   microbiome-driven hematopoiesis and immune development   chronic inflammation  

摘要： Advancements in vaccination and sanitation have significantly reduced the prevalence and burden of infectious diseases;however, these benefits have coincided with a marked rise in autoimmune and allergic disorders. Recent studies have investigated these linked trends through the lens of host-microbiome alterations, proposing these shifts as a potential explanatory mechanism. Previously, we demonstrated that vancomycin-induced depletion of short-chain fatty acid (SCFA) producing bacteria results in hyperactivation of ILC2s and exacerbated allergic responses. Here we investigate the effects of low-dose streptomycin on innate and adaptive immune cell populations and their activation states. Although streptomycin-treated mice exhibit normal allergic responses, they display heightened susceptibility to Th1/Th17-mediated disease, specifically hypersensitivity pneumonitis (HP). This is characterized by a two-fold increase in ILC3s and Th17 cells in the lungs, alongside activation of antigen-presenting cells (APCs) at steady state, an effect that is further amplified upon exposure to HP-inducing agents. Shotgun metagenomic analysis revealed that streptomycin-induced dysbiosis reduces microbial diversity, depletes bile acid-metabolizing bacteria, and enriches for metabolic pathways involved in branched-chain amino acid biosynthesis, including leucine, a known activator of mTORC1. Strikingly, administration of the secondary bile acid metabolite isolithocholic acid (an inverse agonist of ROR gamma t), or an IL-23 neutralizing antibody, reverses the enhanced susceptibility to HP. Inhibition of mTORC1 also significantly reduced Th17/ILC3 responses and histopathology. Our findings underscore microbial equilibrium as a key determinant of susceptibility to HP and uncover a positive feedback loop between IL-23-producing APCs and ILC3/Th17 cells that mechanistically links dysbiosis to sustained type 3 inflammation;and we identify a simple, actionable means of intervention.