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关键词： Antiulcer   Vincamine   Gastroprotection   Inflammation   Interleukin-beta (IL-1 beta)   Interleukin-6 (IL-6)   Tumor necrosis factor-alpha (TNF-alpha)  

摘要： Vincamine, a monoterpenoid alkaloid, and an active constituent of plant Catharanthus roseus Linn, has been proclaimed for antioxidant and anti-inflammatory activities. This study was designed to evaluate the gastroprotective activity of Vincamine by ameliorating gastric ulcer in BALB/c mice. The study was also designed to find the possible mechanism of gastric protection by exploring the impact of Vincamine on gastric pH, acidic content, observing histopathology and molecular expression of inflammatory mediators like Interleukin- beta (IL-1 beta), Interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF- alpha) and oxidative stress markers in the gastric tissue. A total number of 36 BALB/c mice were divided into 6 groups mainly normal control (NC) treated with normal saline, disease control (DC) treated with high dose of absolute ethanol (5ml/kg) while treatment groups involved pretreatment with low- dose Vincamine (VLD) at 10mg/kg body weight, medium-dose vincamine (VMD) at 20mg/kg body weight and high- dose vincamine (VHD) at 40mg/kg body weight before ethanol high dose administration and reference drug control, omeprazole (OMT) at the dose of 20 mg/kg body weight. Molecular expression levels of mRNA expressions of inflammatory cytokines like IL-1 beta, IL-6 and TNF- alpha were evaluated by using reverse transcription real time polymerase chain reaction method (RT-PCR). Pre-treatment of DC group with low (VLD), medium (VMD) and high doses (VHD) of vincamine improved gastric ulcer score and ameliorated histopathological parameter such as, infiltration of inflammatory cells, edema, fibrinoid necrosis, hemorrhage, and erosion score when compared to DC group. Induction of gastric model significantly increased (all P < 0.05) the mRNA expression of IL-1 beta, IL-6 and TNF- alpha in the gastric tissue when same was compared to normal control group (NC). Pretreatment of DC group with different doses of vincamine (VLD, VMD and VHD) significantly downregulated (all P < 0.0

摘要： Patients carrying specific HLA risk alleles are at higher risk for developing drug hypersensitivity reactions, yet pre-therapeutic screening is uncommon. We examined whether patients with a history of drug allergies have more HLA risk alleles to assess whether these patients are potential candidates for pre-therapeutic HLA screening. We performed a case-control study with patients who had a self-reported history of drug allergy (N = 94) and patients without such a history (N = 185). HLA regions were sequenced by use of Alloseq Tx for HLA-A -B, -C, -DP, -DQ and -DR genotypes. A logistic regression was performed to investigate whether the number of HLA risk alleles differed between cases and controls. Sequencing data of 279 patients were available for this analysis. There was no statistically significant difference in the mean number of unique HLA risk alleles between the cases and controls (5.31 vs 5.31, p = 0.9397). Therefore, patients with a self-reported history of drug allergy do not form a suitable group for pre-therapeutic screening for HLA risk alleles to prevent future drug allergies.

关键词： IL-7   TSLP   regulatory T cells   eosinophils   adipose tissue  

摘要： Regulatory T cells (Tregs) mediate tissue homeostasis and repair. The function of the interleukin-7 receptor alpha (IL-7R alpha) in nonlymphoid tissue Tregs is still unknown, although low expression of IL-7R alpha is a widely accepted marker for Tregs. Here, we show that IL-33R (ST2)-expressing Tregs in the visceral adipose tissue (VAT) express the IL-7R alpha at high levels. Treg-specific IL-7R alpha-deficient mice exhibited reduced adipose ST2+ Tregs and impaired glucose tolerance, whereas IL-7R alpha was dispensable for Tregs in lymphoid tissues. Mice deficient in thymic stromal lymphopoietin (TSLP), an additional ligand for IL-7R alpha, displayed a modest decrease in adipose ST2+ Tregs and a reduced accumulation of adipose eosinophils, accompanied by slightly impaired glucose tolerance. In the VAT, mesothelial cells expressed IL-7, whereas adipose stem cells and folate receptor beta-expressing tissue-resident macrophages expressed TSLP. Thus, this study indicates the significance of IL-7R alpha signaling in the maintenance of VAT Tregs and glucose homeostasis, revealing a novel role for IL-7 and TSLP in immunometabolism.

关键词： Parkinson's disease   Regulatory T cell   IL-2/anti-IL-2 complexes   Dopaminergic neuron   Microglia   Astrocytes  

摘要： Parkinson's disease (PD) is the second most common neurodegenerative disease, with motor and non-motor symptoms being its main clinical manifestations. Neuroinflammation has been shown to involve in pathogenesis of PD. Regulatory T cells (Tregs) in PD exhibited reduction in number and suppressive activity. Existing methods to increase the Tregs remains challenging for clinical application because of the difficulty in Tregs expanding or serious side-effects. Therefore, new approaches still need to be explored to balance the amount and activity of Tregs. In this study, we assessed the protective effects of IL-2/anti-IL-2 complexes (IL-2C) on mouse models of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). And the results showed that IL2C significantly increased the number of Tregs both in spleen and brain, accompanied by reduced nigral dopaminergic neuron loss and behavioral defects. Besides, IL-2C also attenuated neuroinflammation as observed by diminished glial activation, fewer infiltration of CD4+ and CD8+ T cells and reduced pro-inflammatory cytokines releasing in the nigral region. Moreover, the protective effects of IL-2C were abolished by pre-treatment of anti-CD25 antibody (PC61), which was used to delete the Tregs. In summary, our results demonstrate that IL2C-induced Tregs expansion attenuates the dopaminergic neurons loss and the neuroinflammatory response in vivo, suggesting that IL-2C maybe a promising therapeutic target for PD.

关键词： K27-Ubn-SAR1A   radiotherapy   STING trafficking and activation   targeting USP1   Type I IFNs  

摘要： The magnitude of Type I interferon (IFN) mediated innate immune response within the tumor microenvironment (TME) critically influences the effectiveness of radiotherapy. Unfortunately, due to a myriad of resistance mechanisms, the double-stranded DNA (dsDNA) signals produced by tumor cells postradiotherapy often induce a diminished response from immune cells. Through chemical screening targeting deubiquitinating enzymes, we identified USP1 (Ubiquitin Specific Peptidase 1) inhibitor as an enhancer of post-radiotherapy dsDNA responses. Mechanistically, within the context of immune-stimulatory cells in TME, USP1 serves as a suppressor in the stress-mediated stages of the cGAS (Cyclic GMP-AMP synthase) -STING (Stimulator of interferon genes protein) signaling pathway, specifically affecting the trafficking of STING from endoplasmic reticulum to Golgi apparatus. It is elucidated that SAR1A (Secretion associated Ras related GTPase 1A) requires K27-linked oligo-ubiquitination to assemble the STING-COP-II (Coat protein II) transport complex for STING trafficking. USP1 counteracts this activation by removing SAR1A ubiquitination, thereby blocking STING trafficking and activation. Consequently, pharmacological USP1 inhibition using ML323 sustains SAR1A ubiquitination and COP-II complex formation, significantly enhancing STING trafficking and subsequent Type I IFN production. This intervention substantially amplifies radiotherapy-induced immune activation in the TME, providing a strategic approach to overcome therapeutic resistance and synergize radiotherapy with immunotherapies.

关键词： IL-36   IL-38   Dry eye   Corneal barrier   Ectoine   Murine model  

摘要： Purpose: To explore the destructive and protective effects and therapeutic targets of IL-36 cytokines in dry eye disease using a murine dry eye model. Methods: A dry eye model was established in C57BL/6 mice exposed to desiccating stress (DS) with untreated mice as controls. A topical challenge model was performed in normal mice with exogenous rmIL-36 alpha, rhIL-38 and 2 % ectoine, or PBS vehicle. IL-36 cytokine expression was assessed by RT-qPCR and immunofluorescent (IF) staining. Corneal epithelial damage was evaluated by corneal smoothness score, Oregon Green Dextran (OGD) fluorescent staining, and tight junction barrier. Results: All members of the IL-36 family were expressed by murine ocular surface epithelium. The expression of IL-36 alpha and IL-361 was upregulated while IL-38 and IL-36RN were down regulated in ocular surface of dry eye mice. A topical challenge of rmIL-36 alpha directly destructed corneal surface with distorted smoothness, increased OGD uptake and IF intensity, and disrupted tight junction proteins ZO-1 and occludin. Co-application with rhIL38 prevented all these corneal damages by rmIL-36 alpha. Ectoine treatment reversed the pathological expression pattern of IL-36 cytokines, protected corneal epithelium from defects, and restored the tight junction barrier in DS mice, and even prevented corneal damage by rmIL-36 alpha. Conclusions: Our findings demonstrate the upregulated pro-inflammatory agonists IL-36 alpha and IL-361 with downregulated antagonists IL-38 and IL-36RA in dry eye model, which provides a previously unknown mechanism and therapeutic targets in dry eye disease. The therapeutic efficacy of ectoine may be through reversing the pathological alteration of IL-36 cytokines in dry eye mice.

关键词： HLA   HLA-DQA1*01:170   novel allele   sequencing-based typing  

摘要： HLA-DQA1*01:170 differs from HLA-DQA1*01:03:01:02 by one nucleotide substitution in codon 183 in exon 4.

关键词： HLA   HLA-B*38:123   M-leader sequence   NGS   novel allele  

摘要： HLA-B*38:123 differs from HLA-B*38:01:01:01 by a single nucleotide substitution in codon -14 in exon 1.

关键词： Rheumatoid arthritis   Tumor necrosis factor-alpha   Inflammation   Euphorbia hirta   Virtual screening through molecular docking   Molecular dynamics simulations  

摘要： Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease that is now potentially lethal and has a significant detrimental influence on people's daily lives by affecting bone joints. Inflammation plays a vital role in this type of autoimmune disorder. In rheumatoid arthritis, long-term production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 (IL-1) stimulates the immune system against cells in bone joints and helps to develop the pathogenesis of rheumatoid arthritis. So, while treating rheumatoid arthritis, we need to block these kinds of mechanisms. We employed soxhlet extraction, thin-layer chromatography (TLC), and gas chromatography-mass spectroscopy (GC-MS) to analyze the phytocompound information in E. hirta leaves. Furthermore, our research included in vitro investigations using Western blotting and mRNA expression analysis (TNF-alpha, IL-1 beta, IL-6) to affirm the anti-inflammatory effectiveness of our extract. For identifying the lead-like molecules, virtual screening and molecular dynamics simulations were used. TLC results confirmed the presence of phytocompounds in E. hirta crude through spots. The structure elucidation of the phytocompounds was confirmed by the GC-MS chromatogram. The in vitro outcomes collectively underscore the inhibitory influence of E. hirta on cell proliferation and its capacity to attenuate the expression of TNF- alpha within THP-1 cells. The results of in silico methodologies confirmed six lead-like molecules. We could conclude that phytocompounds from ethanol leaf crude have effective lead-like molecules against the TNF-alpha.

关键词： Bw-epitopes   graft versus host disease (GvHD)   haematopoietic stem cell transplantation (HSCT)   HLA-B Leader Assessment Tool (BLEAT)   human leukocyte antigen (HLA)  

摘要： High degree of variability in human leukocyte antigens (HLAs) system restricts availability of histocompatible HLA-matched-related donors, thus increasing reliance on worldwide bone marrow registries network. Nevertheless, due to limited coverage/accessibility/affordability of some ethnicities in these registries, haploidentical haematopoietic stem cell transplantation (HSCT) emerged as an alternative option, though with allorecognition-mediated graft versus host disease (GvHD) (>40% cases). A dimorphism [-21 methionine (M) or threonine (T)] in HLA-B leader peptide (exon 1) which differentially influences its HLA-E binding, plausibly regulates natural killer cell functionality, affecting GvHD vulnerability and clinically in practice for donor selection. Here, we analysed population-specific influence of this functionally relevant dimorphism on post HSCT GvHD occurrence and clinical utility (if any) towards defining donor permissibility. High resolution HLA-B genotyping data were analysed in 178 study participants, including 89 HSCT patient-donor pairs, for the frequency distribution of -21 leader dimorphism. Distribution of HLA-Bw4/Bw6 was deduced with killer cell immunoglobulin receptor ligand calculator tool in IPD-IMGT/HLA database. Though -21T (similar to 85%) was over represented in the study participants, no significant influence is observed for this variant between HLA-identical v/s haplo HSCT either with or without GvHD, at allelic and genotypic levels as well as in BLEAT (HLA-B Leader Assessment Tool)-based donor-recipient matching. Stratified analysis of -21 M/T into Bw4/Bw6 groups revealed a higher frequency of -21T + Bw4 in GvHD (+) group compared to GvHD (-) (p < 0.05), plausibly linking this haplotype with occurrence of GvHD post HSCT and importance of HLA class I-mediated NK cell functionality in GvHD.