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关键词： Candida albicans   Fungal keratitis   IL-36γ   PEDF   miR-204-5p  

摘要： Fungal keratitis caused by Candida albicans (CA) is a common, disabling eye disease with a complex immune response system, affecting diagnosis, treatment, and prognosis. The specific regulatory roles and interactions of IL-36γ and pigment epithelium-derived factor (PEDF) in this disease remain largely unclarified. Additionally, the influence of miR-204-5p on the expression and anti-inflammatory functions of IL-36γ and PEDF in CA keratitis is insufficiently explored. Therefore, research focused on understanding the disease's pathogenesis and immune regulation. Human corneal epithelial cells treated with heat-killed CA showed anti-inflammatory responses from IL36γ and PEDF, confirmed via western blot, PCR, and ELISA. Transfection of small interfering RNA and recombinant protein granules showed PEDF exerts immunoprotected regulatory mechanisms by inhibiting NF-κB via PPARγ. Analysis of multiple miRNA target gene prediction databases and literature revealed that miR-204-5p is differentially expressed in fungal keratitis. PCR and dual luciferase reporter assays confirmed that miR-204-5p directly binds to PEDF mRNA, negatively regulating IL36γ and PEDF expression. Consequently, both PEDF and IL-36 γ exhibit anti-inflammatory effects in CA keratitis. PEDF may inhibit the NF-κB signaling pathway through the PPAR γ pathway. In addition, miR-204-5p inhibits the mRNA expression of IL-36 γ and PEDF, exacerbating inflammation. This provides a theoretical basis for new methods and drug targets for the prevention and treatment of CA keratitis, and promotes the clinical application of IL-36 γ/PEDF.

关键词： Clostridium butyricum   IL-22/Reg3 pathway   gut microbiota   intestinal barrier   short-chain fatty acids   traumatic brain injury  

摘要： Traumatic brain injury (TBI) disrupts the intestinal barrier, linking brain trauma to systemic inflammation and secondary complications. This study investigated the role of gut microbiota and its metabolites in intestinal barrier dysfunction following TBI, using a controlled cortical impact mouse model. TBI-induced gut dysbiosis was characterized by reduced microbial diversity and a loss of butyrate-producing bacteria, which led to decreased levels of short-chain fatty acids (SCFAs), particularly butyric acid. This disruption compromised the interleukin-22/regenerating islet-derived protein 3 (IL-22/Reg3) signaling pathway, which is essential for maintaining gut barrier integrity. Supplementation with restored butyric acid production, enhanced IL-22/Reg3 expression, and alleviated TBI-induced intestinal permeability. These findings identify the SCFA/IL-22/Reg3 axis as a key mediator of gut barrier homeostasis after TBI and highlight the potential therapeutic role of butyrate-producing probiotics in managing TBI-associated intestinal complications.

关键词： Elephantopus scaber L   Atopic dermatitis   Keratinocyte   Th2 chemokines   MKP-1  

摘要： Ethnopharmacological relevance: Atopic dermatitis (AD) is an inflammatory skin disease. Elephantopus scaber L. (E. scaber) is a traditional Chinese medicine for treating inflammatory skin diseases. However, the effects and mechanisms of *** on AD remain unclear. Aim of the study: To evaluate the effects and underlying mechanisms of the ethanol extract of *** (ESE) on AD. Methods: MC903 (calcipotriol) was painted on the ears of mice for continuous 9 days. The application area exhibited AD-like skin lesions, and the degree of cutaneous inflammation was evaluated. Histopathology assessed epidermal thickness and mast cell infiltration. Cytokine and chemokine levels in inflamed skin were measured by ELISA. TNF-alpha/IFN-gamma-activated human keratinocytes (HaCaT) were used for in vitro studies. The cells were transfected with reporter plasmids for AP-1, NF-kappa B, or STAT1 signaling assay. RT-qPCR and Western blot were used for determining the transcription and translation levels of chemokines. Results: MC903 caused AD-like skin lesions, while local application of ESE decreased ear (epidermal) thickness, reduced the dermatitis score, and lowered the number of mast cells. Furthermore, it suppressed the levels of IgE, Th2-related cytokines (IL-4 and IL-13), and chemokines (CCL22, TSLP, and CCL2) in inflamed skin. In TNF alpha/IFN-gamma-activated HaCaT cells, ESE reduced the transcription and translation levels of multiple chemokines. Furthermore, it inhibited the activation of AP-1 signaling by enhancing the expression of MKP-1 to reduce the phosphorylation levels of p38 and JNK. Conclusion: ESE alleviates the skin lesions of AD mice through suppressing Th2-related chemokines and cytokines. In vitro, it reduces the levels of Th2-related chemokines in TNF-alpha/IFN-gamma-activated HaCaT cells, which is attributed to the inhibition of MKP-1-mediated AP-1 signaling.

关键词： FAS   IFN   PD-L1   PLK   TGF-β  

摘要： Cancer immunotherapy has transformed treatment but faces challenges such as immune evasion and toxicity. Polo-like kinases (PLKs), frequently dysregulated in tumors, are emerging as key immune modulators. Combining PLK inhibition with immunotherapy may overcome resistance, enhance antitumor responses, and improve clinical outcomes, offering an optimally efficient strategy for cancer treatment.

关键词： Cytotoxicity   IL-7   PD-L1 nano-antibody   TIGIT   Tumor microenvironment   Tumor-infiltrating lymphocytes  

摘要： Cancer represents a pressing global health concern, characterized by a substantial number of unmet clinical needs. Cell therapy has emerged as a promising and efficacious approach for cancer treatment, particularly tumor-infiltrating lymphocytes (TILs), which have demonstrated remarkable improvements in patients' overall survival rates across various clinical studies. However, the tumor microenvironment exerts a adverse effect on TILs, leading to their rapid exhaustion and functional disorder. Consequently, this impedes their ability to effectively eradicate tumors and thus hinders the achievement of the anticipated therapeutic efficacy. Here, we employed lentiviral vector-mediated genetic engineering to manipulate TILs for the expression of TIGIT shRNA, IL-7-PD-L1 nano-antibody fusion protein, and the 'molecular switch' HuEGFRt. The engineered TILs exhibited higher viability, reinforced cell expansion, and reduced reliance on IL-2. The stem-like proportion of engineered TILs is significantly augmented, and their activation level is enhanced when co-cultured with tumor cells. Meanwhile, the engineered TILs exert sustained cytotoxicity after repeated stimulation from tumor cells. The use of Cetuximab has been demonstrated in vitro to induce specific apoptosis of engineered TILs through HuEGFRt, thereby ensuring safety throughout the treatment process. In the mouse tumor model, following infusion of engineered TILs, the tumor volume significantly reduced, once again demonstrating the effectiveness of engineered TILs. The findings of our study demonstrate the exceptional performance of engineered TILs, which undoubtedly holds great promise for the clinical application of engineered TILs, ultimately benefiting a larger population of cancer patients.

关键词： ANCA   T cells   glomerulonephritis   immunotherapy   interleukin-2  

摘要： BACKGROUND AND HYPOTHESIS:Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a major cause of glomerulonephritis (GN) and kidney failure and current therapies are often limited by significant toxicity and limitations. Regulatory T cells (Tregs) play a cruical role in maintaining immune tolerance, and their dysfunction has been implicated in AAV pathogenesis. Low dose interleukin-2 (IL-2) has emerged as a promising strategy to selectively expand Tregs and restore immune balance in several autoimmune diseases. However, low dose IL-2's therapeutic potential in AAV remains unclear, warranting further investigation into its immunoregulatory effects in experimental AAV models. METHODS:We tested the therapeutic efficacy of low dose IL-2 therapy (25 000 international units/day)in an experimental murine model of AAV, specifically anti-myeloperoxidase (MPO) GN, using C57BL/6 J mice. Both passive and active models of anti-MPO GN were used to assess IL-2's effects across different disease settings. RESULTS:In GN induced by passive transfer of anti-MPO antibodies, low dose IL-2 increased intrarenal Treg numbers, limited macrophage recruitment and reduced macrophage pro-inflammatory phenotype in kidneys, demonstrating anti-inflammatory effects on innate immunity. However, these immunological changes did not translate into improvement in kidney injury. In T cell mediated active anti-MPO GN induced by MPO immunization and triggered by anti-glomerular basement membrane globulin, preventative IL-2 therapy increased splenic Tregs, attenuated anti-MPO specific Th1/Th17 responses and limited structural and functional kidney injury. In established autoimmunity, mice treated with low dose IL-2 from 12 days after MPO immunization also developed expanded splenic Tregs. However, effector T cell responses were also enhanced and glomerular injury was increased. To more specifically target Tregs and minimize low dose IL-2's potential to promote effector leukocytes, we ad

关键词： Atopic dermatitis   Kocuria rhizophila   Skin barrier dysfunction   Skin microbiome   Staphylococcus aureus   AD   Atopicdermatitis   AQP   Aquaporin   ASVs   Amplicon Sequence Variants   CASP   Caspase   CCE   Cornifiedcellenvelope   CDSN   Corneodesmosin   Cla   Claudin   CSTA   CystatinA   DEGs   Differentiallyexpressedgenes   DSP   Desmoplakin   EASI   Eczema Areaand SeverityIndex   ECM   Extracellularmatrix   ELOVL   Elongationofverylongchainfattyacidsprotein   FLG   Filaggrin   FN   Fibronectin   H&E   HematoxylinandEosin   HKKR   Heat-killedKocuriarhizophilaKACC14745T   IF   Immunofluorescence   IL   Interleukin   IVL   Involucrin   JAM-A   JunctionaladhesionmoleculeA   K.rhizophila   Kocuriarhizophila   KRT   Keratin   LCE   Latecornifiedenvelope   LTA   Lipoteichoicacid   MMP   Matrixmetalloproteinase   NO   Nitricoxide   OCC   Occludin   PA   ProteinA   PKP   Plakophilin   PPL   Periplakin   RA   Relativeabundance   S.aureus   Staphylococcusaureus   SCORAD   ScoringAtopicDermatitis   SMPD   sphingomyelinphosphodiesterase   SPT   serinepalmitoyltransferase   ST14   ST14transmembraneserineproteasematriptase   STAT   Signaltransducerandactivatoroftranscription   TCHH   Trichohyalin   TEER   Transepithelialelectricalresistance   TEWL   Transepidermalwaterloss   TNF-a   Tumornecrosisfactoralpha   TSLP   Thymicstromallymphopoietin   ZO   Zonulaoccluens  

摘要： Background Recent findings suggest skin microbiota is closely linked to the aggravation of atopic dermatitis (AD) and skin barrier dysfunction. Methods This prospective cross-sectional study included 52 children: 35 with AD flare (F) and non-flare (NF), and 17 without AD (non-AD). Microbes in the skin samples from the three groups were analyzed using 16S rRNA amplicon sequencing. We estimated the anti-virulence of Kocuria rhizophila in the skin microbiome of children. The effects of K. rhizophila were evaluated in human skin cell models with AD-like damage caused by Staphylococcus aureus secretory toxins, including protein A (PA), lipoteichoic acid, and protease V8. Results Taxonomic classification revealed significant phylum-level differences among the three groups. Alpha-diversity indices tended to decrease in the AD-F group compared with the non-AD group but were higher in the AD-NF group. The AD group had a high relative abundance of S. aureus , but S. aureus was almost absent in the non-AD group and exhibited a marked decrease in the AD-NF group; K. rhizophila was negatively correlated with AD severity. Heat-killed K. rhizophila (HKKR) treatment upregulated gene expression of the tight junction protein zonula occludens- 1 and critical components of the cornified cell envelope, involucrin and filaggrin, while downregulating the expression of the pro-inflammatory cytokines interleukin ( IL )- 1b and IL-6 . Transcriptomic analysis revealed that HKKR treatment was associated with skin barrier functions, cell–cell junctions, and immune responses. Conclusions K. rhizophila may be associated with the mitigation of skin barrier dysfunction and inflammation in S. aureus infection, highlighting its potential for AD treatment.

关键词： 猫疱疹病毒   gB蛋白   优势抗原表位   串联表达   间接ELISA  

摘要： 为建立检测猫疱疹病毒特异性抗体的血清学检测方法，将主要保护性抗原gB基因的显性表位进行串联表达，然后以串联重组蛋白作为包被抗原，建立间接ELISA检测方法。通过棋盘法，优化并确定血清稀释比例和抗原包被浓度。在此基础上，对其他实验条件进行了进一步优化。结果显示，该方法的最佳包被抗原浓度为0.5 μg/mL，待测血清的最佳稀释倍数为1:1 000。酶标二抗的最佳稀释度确定为1:10 000，其相应的反应条件为37℃孵育1 h；TMB底物的显色时间为15 min（37℃避光）。特异性评估显示，该方法与FPV和FCV阳性血清无交叉反应。灵敏度试验表明，该检测方法对猫疱疹病毒阳性血清的最低检测限为1:20 480。稳定性试验表明，组内和组间的变异系数均小于5%。选用48份猫血清用本研究建立的间接ELISA法与全病毒建立的ELISA方法进行平行比较。并选择20份血清与市售的Biogal 试剂盒进行对比。与全病毒包被的ELISA总体符合率为98%，与Biogal试剂盒总体符合率为95%。基于串联表达的重组gB蛋白为包被抗原建立的间接ELISA方法可用于检测猫疱疹病毒特异性抗体，并为未来评估疫苗效力提供了有力的技术支持。

关键词： Blood group   COVID-19   Correlation   Genotyping   HLA   Public health   Severity  

摘要： The COVID-19 pandemic gave insight into how host genetics influence the ability to get infected and how severe the infection will be if contracted. Among these, the HLA polymorphisms and ABO blood groups are known to influence the immune system. This study examines the correlation between HLA-B genotypes, blood groups, and the severity of COVID-19. A total of 984 COVID-19 patient samples and control samples were collected from different regions of Pakistan. Throat and nasopharyngeal swabs were obtained for molecular detection of SARS-CoV-2, and blood samples were collected for HLA-B genotyping and ABO blood group analysis. Genomic DNA was extracted using the Phenol-Chloroform method, and HLA-B genotyping was performed using the OLERUP SSP HLA typing kit. The study identified a significant association between HLA-B07:02 and increased COVID-19 susceptibility (OR: 2.5, 95% CI: 1.6-3.9, p < 0.001), whereas HLA-B15:01 was associated with a protective effect (OR: 0.6, 95% CI: 0.4-0.9, p = 0.01). Blood group A was also linked to higher infection risk, while blood group O conferred protection. A strong correlation was observed between co-morbidities (hypertension, diabetes) and severe COVID-19 outcomes. This study provides convincing evidence that HLA-B polymorphisms and ABO blood groups play a significant role in COVID-19 susceptibility and severity.