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关键词： Apoptosis   Autophagy   Caspases   Cancerous colorectal epithelia   IL-17a   Mucinosis  

摘要： Background/Aims. IL17-producing Th17 represent a distinct subset of T-cells. The link between IL-17a and the colorectal cancer (CRC) microenvironment has been widely accepted. However, the role of IL-17a in epithelial cell apoptosis, autophagy, mucinosis, ultrastructural changes, and their potential correlations with CRC remains unclear. Materials and Methods. Out of 2890 patients with CRC, 200 were divided into four groups (stage I-IV) and 50 into non-CRC/healthy/control. We investigated the relationship between IL-17a, apoptosis, autophagy, and mucinosis in patients with stage I-IV CRC ( in vitro/vivo). In addition to many (para)clinical assessments, IL-17a load in blood and the tumor microenvironment (TME) in patients with CRC were assessed. To examine these associations, the effect of IL-17a on CRC cells was evaluated using qPCR, Western blotting, ELISA, bioluminescence, flow cytometry, and immunohistochemistry (IHC), and ultrastructural changes in the colonic epithelia were assessed by scanning and transmission electron microscopy. Results. IL-17a is overexpressed in stage I-IV in the TME and in stage III-IV in the blood of patients with CRC. IL-17a upregulated apoptosis (caspases, cytochrome c (CYC), higher Bax:Bcl2 ratio), autophagy (SIRT1 and LC3), and the cell cycle (TP53, APC-1) and downregulated B3GALNT2 and mucins and led to morphological and nuclear changes in CRC epithelia. Conclusions. IL-17a is abundantly expressed in the CRC microenvironment, and IL-17aIL-17aR interactions play a critical role in the control of apoptosis and mucinosis. The observed remarkable association of IL-17a and apoptosis in adenocarcinoma provides valuable insight into the clinical implications of Th17/IL-17 in CRC. (c) 2025 Instituto Mexicano del Seguro Social (IMSS). Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： MHC   HLA alleles   Mexican population   Disease associations   Systematic review  

摘要： Background. The major histocompatibility complex (MHC) plays a crucial role in immune responses and is associated with disease susceptibility. This study systematically reviews MHC class I and class II allele frequencies and their associations with diseases in the Mexican population from 1979 to 2023. Methods. A systematic review following PRISMA guidelines was conducted. Reports were obtained from the Allele Frequency Net Database and PubMed using keywords related to HLA and Mexican populations. A total of 776 reports were screened, and 214 were retained for final analysis. Seventy-six studies comprising allele frequency data from over 20,000 individuals across Mexican states and indigenous communities were analyzed. In addition, over 138 articles were examined to identify alleles associated with various diseases. Results. The analysis identified 117 alleles whose frequencies varied regionally within Mexico. While DPA1*01, DPB1*04:01, and DQA1*03 were predominant, DRB1*04, DQB1*03, and DQA1*05 were also prominent but variable. Certain alleles, such as A*02, B*35, C*04, and C*07, were relatively common in the population. Numerous disease correlations were uncovered, such as B*27's strong association with spondyloarthropathies. DRB1*15:01 and DRB1*04 conferred an increase in multiple sclerosis, while DRB1*04 may protect against some skin diseases. Conclusion. This review improves the understanding of MHC allele frequencies and disease associations in Mexicans, highlighting genetic diversity. The findings lay the groundwork for future research on genetic predispositions and health outcomes, aiding healthcare strategies in this diverse population. Further studies are needed to address data gaps and refine genetic profiles for targeted medical applications. (c) 2025 The Author(s). Published by Elsevier Inc. on behalf of Instituto Mexicano del Seguro Social (IMSS). This is an open access article under the CC BY license (http://***/licenses/by/4.0/)

关键词： Psoriatic arthritis   TNF-a inhibitor   Flare   Tapering   Ultrasonography  

摘要： Objective: Dose reduction of biologic drugs in patients with psoriatic arthritis (PsA) who are in Minimal Disease Activity (MDA) is now considered a feasible option. This study evaluated which baseline clinical and ultrasonographic (US) factors may be predictive of disease activity after anti-TNF-a spacing. Methods: This observational, prospective, multicentre, 12-month study enrolled consecutive adult patients with PsA taking TNF-a inhibitors and in stable MDA who accepted to reduce their dose therapy by doubling the administration interval. Data collection included demographics, personal history, clinical disease characteristics, and joints and entheses US features. Patients maintaining the MDA were compared with those who experienced a disease flare during the 12 months of follow-up. The statistical analysis included the comparison between groups and the search of the factors associated with persistence of MDA. Results: Of the evaluable 72 patients (29 females and 43 males), 55 (76.4%) maintained a state of MDA while 17 (23.6%) experienced a disease relapse. Baseline values of DAPSA<2 and of BASDAI<1.5, and lower BASDAI and DAS28 values were significantly associated with maintenance of MDA. The multivariate analysis showed that baseline values of DAPSA< 2 and of BASDAI < 1.5 were predictive of persistence of MDA. Baseline US findings were not associated with the outcome of disease activity. Conclusions: In this study, anti-TNF-a spacing proved to be feasible in most of the PsA patients in a stable MDA. The only factor predictive of persistence of remission was a very low clinical disease activity at baseline. (c) 2025 Socioto Fran oaise de Rhumatologie. Published by Elsevier Masson SAS. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： Postbiotics   Inflammatory bowel disease   Tryptophan metabolism   Gut microbiota  

摘要： Inactivated probiotics, due to their high safety, effectiveness, stability, and resilience, are increasingly used for treating various diseases. To assess the efficacy of inactivated Bifidobacterium bifidum M1-3 in alleviating dextran sulfate sodium salt (DSS)-induced colitis, we compared the effects of live probiotics and inactivated probiotics at different concentrations on colitis in male C57BL/6J mice. Additionally, we explored potential mechanisms by analyzing changes in gut microbiota composition, tryptophan metabolites, and the AhR/IL-22 signaling pathway. Our study demonstrated that administering high doses (2 x 109 CFU/mL) of heat-inactivated probiotics by gavage for 14 days effectively alleviated DSS-induced colitis in mice, with effects comparable to those of live probiotics. This effect was attributed to the modulation of gut microbiota, with an increase in beneficial bacteria like Muribaculaceae, Alistipes, and Ruminococcaceae, and a reduction in harmful microbes such as Escherichia/ Shigella spp. Additionally, the inactivated probiotics enhanced tryptophan metabolism, leading to elevated levels of metabolites including indole-3-lactic acid, indole-3-propionic acid, indole acrylic acid, and indole, which subsequently activated the AhR/IL-22 signaling pathway. Our results confirmed the effectiveness of heat-inactivated Bifidobacterium bifidum M1-3 in alleviating colitis, demonstrating a dose-dependent response. The soluble capsular polysaccharides in the bacterial lysate supernatant are the potentially effective components of Bifidobacterium bifidum M1-3. This finding provides a theoretical basis for developing novel probiotic products containing heat-inactivated Bifidobacterium bifidum M1-3.

摘要： Production of recombinant human leukocyte antigen class I (HLA-I) proteins in vitro is fundamental for molecular immunology. However, HLA-I protein refolding has remained inefficient due to challenges in the assembling of the trimolecular complex. Here, we compare various in vitro refolding methods that address the challenges of intrachain disulfide bond formation and assembly of the complex between the light and heavy chains in the presence of the target peptide. We developed methods that uncouple the oxidation of disulfide bond formation of both subunits of HLA-I, followed by renaturation to promote complex formation. CuSO4-catalyzed air oxidation enhances correct disulfide bond formation when the protein is solubilized with N-lauryl-sarcosine (sarkosyl);however, careful removal of sarkosyl did not prevent heavy chain aggregation. We modified the classical method of HLA-I refolding by pre-oxidizing the (32m light chain before adding the HLAI heavy chain and peptide. This method yielded successful complex refolding for HLA-A*02:01/GILGFVFTL at 24.2 % efficiency, and HLA-C*12:03/KAYNVTQAF at 14.5 % efficiency. Our results suggest that pre-folded (32m improves refolding efficiency of HLA-I molecules. This work presents novel approaches to HLA-I refolding that may be applied to other difficult-to-fold protein complexes.

关键词： Celastrol   Melanoma   CD8+T cell   MHC-I   JAK/STAT1   SHP2  

摘要： Background: Celastrol (CEL) has demonstrated promising anti-cancer properties, yet its specific mechanisms against melanoma remain insufficient. This study investigated the CEL's anti-tumor effects and determined its potential mechanisms in the regulation of MHC-I expression in melanoma. In addition, we also tested its efficacy in sensitizing immune checkpoint inhibitors (ICIs) to melanoma. Methods: CEL's anti-tumor activity was evaluated in B16F10 melanoma-bearing C57BL/6 mice across five groups (control, CEL 0.5 mg/kg, CEL 1 mg/kg, CEL 2 mg/kg, and ICIs), the tumor volume, histopathology, and body weight were assessed. Mechanistic insights were obtained through network pharmacology and RNA sequencing in B16F10 cells. Differential gene and pathway analysis were validated using qRT-PCR, Western blotting, and flow cytometry. CD8+T cell activation and cytotoxicity were analyzed in co-culture with CEL-pretreated B16F10 cells using flow cytometry and ELISA. CEL's interaction with potential targets was determined by molecular docking, surface plasmon resonance (SPR), and siRNA. The synergistic effect of CEL combined with ICIs was confirmed in B16F10-bearing C57BL/6 mice, and tumor-infiltrating T cells were assessed by flow cytometry across four groups (control, CEL, ICIs, CEL+ICIs). Results: CEL exhibited a significant anti-tumor effect in B16F10 melanoma-bearing mice. Mechanistically, CELpretreated B16F10 cells notably enhanced CD8+T cell activation and promoted IFN gamma and TNF alpha secretion, leading to B16F10 cell death. CEL upregulated MHC-I expression through activation of the JAK/STAT1 pathway in B16F10 cells. The binding assay revealed that CEL interacted with SHP2, with an affinity of 37.93 mu M. When SHP2 was silenced in B16F10 cells by siRNA, CEL failed to induce MHC-I upregulation. Moreover, CEL combined with ICIs produced superior antitumor efficacy compared to ICIs alone, which was accompanied by increased CD8+T cell infiltration in melanoma. Conclusion:

关键词： Cytokines   Survivin   Cytorisk index   Breast cancer  

摘要： Introduction: Breast cancer is one of the most prevalent cancers afflicting women. Immuno-oncology is an upcoming field which has established the role of immunocompetent cells and cytokines in the pathogenesis and progression of multiple cancers including breast cancer. Methods: The study comprised of three groups- Group Icytologically confirmed breast cancer, group II- benign breast disease, group IIInormal healthy controls. Survivin, IL-4 and IL-6 levels were estimated and a novel indexcytorisk index calculated. The breast cancer patients were followed up and the histopathological markers of tumour aggression were correlated with the cytorisk index calculated at the time of diagnosis. Results: The median Cytorisk Index values were: control group - 90.86 (IQR: 33.29-167.37), benign group - 0.004 (IQR: 0.002-0.012), and malignant group - 31.91 (IQR: 9.61-73.19). Pearson's correlation analysis between the Cytorisk Index and lymphovascular invasion (LV1) and perineural invasion (PN1) status revealed a statistically significant positive correlation (p = 0.016) Conclusion: The significance of our findings lies in the Cytorisk Index's ability to serve as a noninvasive biomarker for distinguishing between benign breast tumors, malignant breast tumors, and healthy individuals during the initial stages of tumor detection. The positive correlation with the histopathological markers of disease aggression highlights the importance of this index as an important marker of breast cancer prognostication.

关键词： osteosarcoma   KRAS   IL-17A   metastasis   MMPs  

摘要： Dysregulation of Kirsten rat sarcoma virus (KRAS) plays crucial roles in many tumors. It is reported that KRAS could promote proliferation of osteosarcoma (OS) cells. Nonetheless, the contribution of KRAS to the invasion and spread of OS is still not well understood. This study aimed to investigate KRAS-driven metastasis and the mechanisms behind it in human OS. Tissue microarrays were utilized to assess KRAS expression and its relationship with clinicopathological characteristics. The migratory and invasive abilities of OS cells were evaluated through wound-healing assays and transwell analysis. Furthermore, the regulatory mechanisms of KRAS in human OS were analyzed using RNA sequencing, tandem mass tags assays, multiple immunofluorescence assays, micro-CT, and bioluminescence imaging. In vivo experiments were conducted using established lung metastatic models. Our data showed that downregulation of KRAS in human OS cells could inhibit cell migration and invasion in vitro and in vivo (tumor metastasis model by tail vein injection in BALB/c nude mice). We identify IL-17A, a crucial marker of IL-17 signal pathway, as a downstream target of KRAS. The reduction of KRAS may suppress matrix metalloproteinase (MMP1), MMP3, and MMP9, which are recognized as proteins associated with tumor metastasis, through a mechanism dependent on IL-17 signaling. In summary, these findings indicate that KRAS could serve as a potential biomarker for therapeutic strategies in human OS. Mechanistically, our data revealed that KRAS knockdown affects tumor metastasis by inactivating IL-17 signal pathway via IL-17A-dependent manner. Kirsten rat sarcoma virus (KRAS) is a gene that plays important roles in many types of cancer. In this study, we investigated how KRAS affects the spread of osteosarcoma (OS), a type of bone cancer. We found that reducing the activity of KRAS in OS cells can slow down their ability to migrate and invade other parts of the body. We also identified a protein called

关键词： il17ra   il17rc   Evolution   m6A   Antiviral immunity   Miichthys miiuy  

摘要： Interleukin-17 receptor A (IL17RA) and IL17RC form a receptor complex critical for initiating IL-17A-mediated immune responses, a hallmark of T helper 17 (Th17) cells. In this study, il17ra and il17rc were identified in miiuy croaker (Miichthys miiuy) and bioinformatics analysis revealed their evolutionary and structural conservation, underscoring their roles in immunity. However, there has been little research on the IL-17 receptor family from the perspective of N6-methyladenosine (m6A) modifications. Using methylated RNA immunoprecipitation sequencing (MeRIP-seq), we identified strong m6A modifications on the last exons of il17ra and il17rc, validated by MeRIP-PCR. Poly(I:C) stimulation significantly upregulated il17ra and il17rc expression, while reducing their m6A modification levels, implicating these changes in antiviral immunity. Interestingly, cycloleucine (CL), a well-known methylation inhibitor, did not alter the expression of il17ra and il17rc but promoted the nuclear-to-cytoplasmic transport of il17ra mRNA, potentially influencing its translation process. These findings provide valuable insights into the regulatory roles of m6A modifications in il17ra and il17rc function and highlight their importance in the antiviral immune response.