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关键词： Interleukin inhibitors   Biologics   Fungal infections   Candidiasis   Dermatophytosis   Invasive candidiasis   Psoriasis   Invasive fungal infection   Immunosuppression   Diabetes  

关键词： Antibody   B cell   Tumor microenvironment - TME   T cell   Major histocompatibility complex - MHC  

摘要： Background Cancers persist despite expression of immunogenic neoantigens and ongoing antitumor immune responses. While some occult tumors likely are cleared by effective antitumor immune responses, the targeted antigens are not easily identifiable as those tumors spontaneously *** We used mouse models with a defined antigenic protein mimicking tumor-specific neoantigens to address the nature of these spontaneous anti-tumor immune *** BALB/c (H-2d) mice challenged with BALB/c breast tumors expressing the rat-erbB2 oncoprotein succumb to their tumors despite ongoing immune responses targeting tumor-specific model antigens. Meanwhile, congenic BALB.B (H-2b) and H-2d/H-2b F1 hybrid mice spontaneously eliminate genetically matched tumors in a major histocompatibility complex (MHC)-II dependent manner. Adoptive transfer and immune cell depletion strategies revealed CD4+ T cells and CD20+ B cells are crucial mediators of the protective response in H-2b mice. Furthermore, passive transfer of immune serum from mice rejecting their tumors confers resistance in tumor antigen-tolerant animals with an inversely proportional relationship between tumor outgrowth and the amount of rat-erbB2 specific antibody present in tumor-bearing mice. Introduction of the rat-erb2 ectodomain into other H-2b tumor models also promotes their spontaneous tumor rejection. Notably, the tumor microenvironments differ in rat-erbB2+ tumor-bearing BALB.B and BALB/c mice at the time of fate decision in the models reflecting the differences between effective and ineffective tumor immune *** We find that the effective antitumor immunity targeting neoantigens in these breast cancer models is determined by MHC-II-restricted presentation of optimal cancer-associated antigens. These responses are dependent on CD4+ T cells, B cells, and antigen-specific antibodies.

关键词： Genetic variations   haplotypes   IL-23/IL-17 pathway   polymorphisms   scleritis  

摘要： PurposeTo examine the relationship between IL-23/IL-17 pathway gene polymorphisms and scleritis susceptibility in the Chinese Han *** assessed IL-23/IL-17 pathway-related SNPs in 898 scleritis cases and 1,573 controls, employing stratified analysis to evaluate subtype-specific impacts and a discovery-validation cohort strategy to ensure genetic association ***-23 R/rs10789229 TC genotype and C allele, and the IL-21/rs2221903 TT genotype and T allele were more frequent in scleritis patients (Pc = 2.07 x 10-3-2.77 x 10-6, OR = 1.497-2.327, 95% CI = 1.216-3.219), particularly anterior scleritis (Pc = 3.88 x 10-3-2.95 x 10-6, OR = 1.507-2.378, 95% CI = 1.209-3.321). The IL-23 R/rs10789229 TT genotype and T allele, and the IL-21/rs2221903 TC genotype and C allele were found less common among scleritis patients overall (Pc = 2.07 x 10-3-4.18 x 10-6, OR = 0.436-0.668, 95% CI = 0.316-0.822) and in the anterior scleritis subgroups (Pc = 3.88 x 10-3-4.43 x 10-6, OR = 0.427-0.664, 95% CI = 0.306-0.827). The analysis of haplotypes showed a noteworthy surge of IL-23 R CCCG haplotype in both scleritis patients in general (Pc = 1.91 x 10-4) and those with anterior scleritis (Pc = 1.15 x 10-4). Conversely, the frequency of the IL-17A GAA haplotype was significantly lower among scleritis patients overall (Pc = 4.17 x 10-12) and in the anterior or posterior scleritis subgroups (Pc = 7.41 x 10-11;Pc = 0.021). Only the IL-23 R/rs10789229 variant demonstrated consistent replication in the validation *** findings suggest that specific polymorphisms of IL-23/IL-17 pathway-related genes could confer risk to the development of scleritis in the Chinese Han population. Patients with varying subtypes of scleritis exhibit somewhat similar genetic profiles.

关键词： Bronchopulmonary dysplasia   Apoptosis   Sodium propionate   IL-17   Alveolar epithelial cells  

摘要： Sodium propionate (SP) has been shown to enhance alveolar growth retardation in Bronchopulmonary Dysplasia (BPD), but the mechanism remains unclear. The aim of this study is to explore the potential mechanism of SP in the treatment of BPD by utilizing animal and cell models along with bioinformation analysis. Neonatal mice were exposed to either air (21% O2) or hyperoxia (85% O2) from the first day after birth to establish the BPD model. The neonatal mice were intraperitoneally injected with normal saline (control group) or SP (500 mg/kg, SP group) from day 8 to day 14. SP significantly reduced the inflammatory condition of alveolar septal thickening, and decreased the alveolar fusion and mitigated weight loss in BPD mice. ELISA results demonstrated that SP significantly inhibited the secretion of IL-17, IL-6 and TNF alpha. Transcriptome analysis confirmed that IL-17 signaling pathway is closely related to the therapeutic effects of SP on BPD. In addition, MX2, MMP10, IL-11, ZMAT4 and SEC1 genes were identified as key and potential targets involved in the mechanism of SP treating BPD. Meanwhile, in mouse alveolar epithelial cells, apoptosis was induced by hyperoxia, but it was reduced following SP intervention. The expression of IL-17 pathway related genes: IL-17A, IL-6, TNF alpha and cox2 was decreased in hyperoxia treated cells after SP intervention. In conclusion, through transcriptome analysis, animal and cell experiments, we explored the role of sodium propionate in attenuating apoptosis in a BPD model through IL-17 pathway.

关键词： CD52   IL-6/JAK/STAT3   Mast cell   RNA sequencing   Triple-negative breast cancer  

摘要： The aggressive nature and rapid progression of triple-negative breast cancer (TNBC), coupled with a high likelihood of recurrence and mortality, underscore the critical need for effective treatments. While immunotherapy presents promising advantages for those with triple-negative breast cancer (TNBC), its efficacy is not universal. This disparity highlights the importance of investigating survival outcomes and prognostic factors for those TNBC patients who don't respond well to immunotherapy. Our study leverages both bulk and single-cell RNA sequencing data to conduct an in-depth analysis, revealing that genes associated with mast cells (PCMT1, VDAC1, YWHAB, BRD4, BTG1, and CD52) are pivotal in prognostication for TNBC patients. Laboratory experiments have further substantiated our findings, demonstrating that the overexpression of CD52 in mast cells impedes the proliferation, invasion, and metastasis of breast cancer cells. Further anti-CD52 treatment inhibiting breast tumor growth in vivo. Additionally, we have discovered that CD52 elicits its antitumor effects by meditating the IL-6/JAK/STAT3 signaling pathway. These insights not only enhance the prognostic significance of mast cells in TNBC but also pave the way for the development of novel targeted immunotherapy strategies.

关键词： Sweroside   Psoriasis   NLRP3/Caspase-1   IL-1 beta   Anti-inflammatory  

摘要： Psoriasis is a chronic autoimmune skin disorder with no cure, posing challenges in long-term therapy and economic burden. Sweroside (SOS), an iridoid compound from Gentiana, shows promise for treatment due to its anti-inflammatory properties. In this study, SOS significantly reduced erythema, thickening, and scaling in IMQinduced psoriasiform mice, lowered serum TNF-alpha and IL-1 beta levels, and suppressed inflammatory marker expression. Molecular docking revealed strong binding to IL-1 beta and NLRP3 proteins. Western blot and RT-PCR confirmed that SOS inhibited NLRP3, Cleaved-Caspase-1, ASC, and IL-1 beta expression. SOS's inhibition of IL-1 beta production is mediated through the NLRP3/Caspase-1 pathway. Additionally, SOS regulates IL-1 beta signal transduction and precursor production, exhibiting anti-inflammatory effects linked to NF-kappa B signaling inhibition in HaCaT cells. Thus, SOS has potential as a psoriasis treatment.

摘要： Ciprofloxacin (CIP) was found to enhance pegylated G-CSF therapy (PEG, Neulasta®)-induced survival from 30% to 85% after ionizing radiation exposure. This combined therapy significantly mitigated radiation-induced brain hemorrhage through its capability to improve platelet recovery. This study tested whether this combined treatment also mitigated gastrointestinal damage from radiation. B6D2F1 female mice were exposed to 60Co γ radiation. CIP was fed daily to mice for up to 14 days. PEG was injected on day 1, and then weekly up to day 14. For the early time point study, blood, femurs, spleen, and ileum were collected on days 2, 4, 9, and 15 postirradiation. Bone marrow cells were counted; spleen weights and splenocyte counts were measured; and ileum histopathology was examined and analyzed. AKT, ERK, JNK, p38, claudin 2, NF-kB, Bax, Bcl-2, and gasdermin D were measured in ileum lysates using Western blotting while miR-34a was measured by reverse transcription followed by real-time-PCR, and citrulline was measured by colorimetric assay. In serum, interleukin-18 (IL-18) was measured by Luminex assay and complement protein 3 (C3) was detected by ELISA. The bacterial DNA load in livers was measured by real-time PCR. Radiation depleted bone marrow cells in femurs beginning day 2 through day 15 postirradiation, which was mitigated by PEG or CIP+PEG on day 9 through day 15 and by CIP on day 15, respectively. Radiation exposure led to decreased spleen weight on day 2 through day 15, while PEG or CIP+PEG significantly mitigated the reduction on day 9 through day 15. Radiation exposure reduced splenocyte counts on day 2 through day 15 postirradiation, but that was mitigated by PEG or CIP+PEG on day 15. Ileum histology showed that radiation decreased villus height on day 2 through day 15; CIP mitigated the reduction on day 15, whereas PEG+CIP mitigated it on day 2 through 15. Villus widths were increased on day 2 through day 15, while PEG+CIP effectively decreased them on day 4

摘要： BACKGROUND/AIMS:This research explores the effectiveness of a new cytotoxic T-cell epitope peptide specific for HLA-A2402 in enhancing cellular immune responses to SARS-CoV-2 infections. HLA molecules play a key role in presenting antigenic epitopes to T cells, with genetic polymorphisms resulting in varying immune responses among individuals. The study aimed to investigate whether loading this epitope peptide into dendritic cells (DCs) from HLA-A2402(+) individuals could improve immune responses. METHODS:DCs were sensitized with varying doses of the peptide (2-12 µg/mL), with optimal results observed at 8 µg/mL. T-cell responses, proliferation, differentiation, Th cytokine secretion, CTL function, and apoptotic response were compared among the HLA-A2402(+), HLA-A2402(-), PBS control, DC only, and epitope-only groups. RESULTS:A significant enhancement in DC maturation, antigen presentation, T-cell activation, and proliferation was observed in the HLA-A2402(+) group compared to the HLA-A2402(-) control. CONCLUSION:These findings suggest that HLA-A2402-restricted epitope peptides can enhance cellular immunity, offering potential for improving allele-specific SARS-CoV-2 vaccines and other molecular therapies, advancing precision medicine for infectious diseases.

关键词： FHL2   IL-1 beta   mTOR   NF-& kgreen   B   Signaling pathway   Osteoarthritis  

摘要： BackgroundThe role of nuclear translocation in osteoarthritis (OA) pathogenesis has garnered increasing attention in recent years. Extensive research has demonstrated that FHL2 acts as a nuclear transmitter through interactions with other nuclear transcription factors. We aimed to investigate the role of FHL2 in an osteoarthritis cell *** cartilage model was established by chondrocyte-like ATDC5 cells induced by 1% insulin-transferrin-selenium and then treated with interleukin-1 beta (IL-1 beta, 10 ng/mL). Lentivirus transfection was employed to suppress the expression of FHL2. Immunofluorescence and flow cytometry were used to examine nuclear transcription and apoptosis, respectively. Western blotting was performed to analyze the expression of metabolism-related proteins, autophagy-related proteins, apoptosis-related proteins, as well as proteins associated with the NF-& kgreen;B and mTOR *** elevated expression of FHL2 occurred in both the cytoplasm and the nucleus. Knockdown of FHL2 could inhibit IL-1 beta-induced phosphorylation of NF-& kgreen;B p65 and stabilize the extracellular matrix (ECM) by decreasing MMP-3 and MMP-13 expression, to suppress COL II degradation in chondrocyte-like ATDC5 cells. Meanwhile, the knockdown of FHL2-activated autophagy in IL-1 beta-treated chondrocytes through mTOR signaling, characterized by an increased LC3-II/LC3-I ratio and Beclin-1. FHL2 downregulation inhibited IL-1 beta-induced apoptosis by suppressing BAX and Caspase-3 expression, while enhancing BCL-2 protein levels. This mechanism may involve AKT phosphorylation and decreased expression of p-NF-& kgreen;B ***2 knockdown activated autophagy while suppressing inflammation, apoptosis, and ECM degradation. The mechanism underlying these processes may involve the inhibition of the mTOR and NF-& kgreen;B signaling pathways.