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关键词： Obese patients with PCOS   BMP-15   infertility   metabolic disorders  

摘要： Background: Obesity-related polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with infertility and metabolic dysfunction. While bone morphogenetic protein-15 (BMP-15) plays a recognized role in ovarian function, its specific impact on infertility in obese PCOS patients remains unclear Objective: This study aimed to investigate the influence of BMP-15, NOD-like receptor protein 3 (NLRP3), and interleukin-18 (IL-18) on infertility in this population and to evaluate their predictive clinical value. Methods: Clinical data from 185 obese PCOS patients were retrospectively analyzed. Univariate and logistic regression analyses identified infertility-related factors. Results: Results showed an infertility rate of 34.43%, with significant differences in BMP-15, NLRP3, IL-18, Morisky Medication Adherence Scale (MMAS-8), and Connor-Davidson Resilience Scale (CD-RISC) scores between infertility and non-infertility groups. NLRP3, IL-18, and MMAS-8 emerged as risk factors, while BMP-15 and CD-RISC were *** an obese PCOS mouse model, BMP-15 administration improved metabolic parameters, restored hormonal balance, reduced ovarian inflammation, and preserved fertility. Conclusion: These findings suggest that BMP-15 plays a protective role in PCOS-related infertility by modulating metabolic and inflammatory pathways. BMP-15 may serve as a valuable biomarker and therapeutic target for early identification and intervention in obese PCOS patients at risk of infertility.

关键词： cGAS-STING pathway   porcine   apoptosis   interferon   autophagy   caspase  

摘要： The innate immune cGAS-STING signalling pathway recognizes double-stranded DNA and induces the interferon (IFN) response, autophagy and apoptosis, exerting a broad antiviral effect. However, the mechanisms and interrelationship between STING induced downstream IFN, autophagy, and apoptosis in livestock have not been fully elucidated. Our previous study defined porcine STING (pSTING) induced IFN, autophagy and apoptosis, and showed that IFN does not affect autophagy and apoptosis, whereas autophagy inhibits both IFN and apoptosis, likely by promoting pSTING degradation. In this study, we further explored the underlying mechanism of pSTING induced apoptosis and the regulation of IFN and autophagy by apoptosis. First, pSTING induces endoplasmic reticulum (ER) stress and mitochondrial damage to activate caspases 9, 3, and 7, which drive intrinsic apoptosis. Second, pSTING triggered apoptosis inhibits the IFN response by activating caspase 7, which cleaves pIRF3 at the species specific D197/D198 site. Third, pSTING activated apoptotic caspases 9, 3, and 7 reduce the expression of ATG proteins, and cleave the ATG5-ATG12L1 complex, effectively inhibiting autophagy. Fourth, knockout of pSTING activated apoptosis heightens the IFN response and autophagy, while suppressing the replication of Herpes Simplex Virus type 1 (HSV-1), Vesicular Stomatitis Virus (VSV) and Pseudorabies Virus (PRV). This study sheds light on the molecular mechanisms of innate immunity in pigs.

关键词： Platelet transfusion refractoriness   anti-HLA antibody   anti-HLA-C autoantibody   hematologic disorders  

摘要： Objectives Platelet transfusion refractoriness (PTR) is a frustrating clinical problem, and primary and persistent (P/P) PTR who experienced persistent PTR since the first transfusion was failed to be well recognized. This study aims to investigate the incidence and risk factors for P/P PTR. Methods Patients with hematologic disorders who underwent HLA high-resolution genotyping and donor-specific HLA antibody or panel reactive antibody (PRA) testing between January 2019 and March 2023 were reviewed. Clinical data including infection history, splenomegaly, frequency and quantity of blood transfusions, and transfusions response were delineated and subsequently analyzed. Results 114 patients were included retrospectively, and 1071 transfusions were recorded. The overall incidence of PTR was 28.95% (33/114), with 63.63% (21/33) being P/P PTR. Anti class I HLA (anti-HLA-I) antibody was identified as an independent risk factor for ineffective platelet transfusion through multivariate logistic regression analysis (p = .034). Interestingly, anti-HLA-C autoantibodies were first found in six patients, and both anti-HLA-A and C autoantibodies were detected in one case, comprising a total of 10.71% (6/56) of HLA-I antibody-positive patients. Further analysis revealed that anti-HLA-C autoantibody was identified as an independent risk factor for P/P PTR (p = .039). Among patients with positive anti-HLA-C antibodies, significant differences in the effectiveness of ABO, D-matched and cross-matching transfusions were observed between patients with or without anti-HLA-C autoantibodies (p < .001 and p = .017). Notably, platelet transfusions independence was achieved by two of the four patients who received rituximab. Conclusions This work emphasized the significance of anti-HLA-C autoantibody for P/P PTR in hematological patients, and rituximab may therapeutic.

关键词： Endostar   HIF-1   MHC-I   beta 2m   lung cancer  

摘要： Endostar is a human recombinant endostatin which is an attractive anti-angiogenesis protein. Because inefficient antigen presenting MHC class I expression (which can be downregulated by HIF-1) is an important strategy for cancer immune evasion, besides its anti-angiogenesis effect, it remains unclear whether Endostar has an inhibitory effect on HIF-1 expression by upregulating MHC class I expression in cancer cells to facilitate immunotherapies, including PD-1/PD-L1 inhibitors. In this study, A549 and NCI-H1299 lung cancer cells were treated with Endostar (6.25 mu g/ml, 12.5 mu g/ml, and 25 mu g/ml, respectively). HIF-1 expression was detected by Immunocytochemistry and Western blot. Proteins of the MHC class I alpha-heavy chain and beta 2 m light chain, STAT3 and pSTAT3 were detected by Western blot. The mRNAs of MHC class I alpha-heavy chain and beta 2 m light chain were detected by RT-qPCR. It was shown that decreased expression of HIF-1 and promotion of beta 2-microglobulin were observed after Endostar treatment. In addition, elevated levels of MHC class I alpha-heavy chain mRNA and protein, as well as downregulation of STAT3 and pSTAT3, were also observed following Endostar treatment. Endostar inhibited HIF-1 expression in A549 and NCI-H1299 lung cancer cells, upregulated expression of MHC class I alpha-heavy chain and beta 2 m light chain, with the upregulation of STAT3 and pSTAT3, suggesting involvement of STAT3 pathway. It is important because only in combination with MHC class I on target cells can tumor antigenic peptides be recognized by CD8+ CTLs which destroy target cells. However, MHC class I is frequently deficient in cancer cells.

关键词： MHC I   immunopeptidome   colorectal cancer   topoisomerase inhibitor   microsatellite  

摘要： Immunotherapy options for microsatellite stable (MSS) colorectal cancer are currently very limited. The lack of detectably unique or altered immunogens in the tumor microenvironment may be a factor. Radiation and chemotherapy may enhance immunotherapy by increasing cancer cell visibility through Major Histocompatibility Complex I (MHC I) expression. To investigate this, we treated MSS and microsatellite-instable (MSI) colon cancer cells with a topoisomerase inhibitor and analyzed MHC I-associated peptides. Treatment increased peptide numbers by 5% in RKO (MSI) cells and 83% in SW620 (MSS) cells, with 40-50% of peptides being exclusive to treatment. Additionally, clustering analysis revealed a set of peptides with uniquely conserved residues displayed only in treated MSS SW620 cells. Gene Ontology analysis of MHC I-displayed proteins revealed a treatment-induced increase in extracellular vesicle- and nuclear-derived proteins, alongside reduced cytosolic protein sampling. Overall, we present evidence for treatment-inducible differential display of peptides, some of which may affect interactions and functions of immune cells. Given the multitude of factors that modulate the effects of increased MHC I expression and associated peptides, further studies are needed to elucidate the pathophysiological implications of these changes.

关键词： Autophagy   IL-10   macrophage   italic>Mycobacterium abscessus subsp. abscessus   RUBCN  

摘要： Mycobacterium abscessus subsp. abscessus (***) is a nontuberculous mycobacterium that can infect human lung macrophages, which poses a public health concern. Understanding its mechanism is crucial for developing strategies to combat *** infections. *** survives within host cells by inhibiting autophagy, a defense mechanism used against intracellular pathogens;therefore, we investigated the mechanism underlying autophagy inhibition and human lung macrophage infection by ***. This study focuses on the *** UC22 strain, which exhibits stronger inhibition of autophagic flux compared to the *** ATCC 19,977 strain. Central to this study is MAB_0676c, a protein secreted by *** UC22, and its effects on autophagic flux and the innate immune response, particularly its role in enhancing IL-10 production, a known autophagy regulator. Experiments showed that MAB_0676c expression stabilizes autophagy-related proteins while reducing LC3-LAMP2 co-localization in macrophages, thereby inhibiting autophagy and promoting bacterial growth. Furthermore, blocking IL-10 reduced both autophagy-related protein levels and the intracellular growth of MAB_0676c-expressing bacteria. Therefore, *** UC22 mediates intracellular survival by inhibiting autophagy through IL-10 production. Our study reveals bacterial immune-evasion tactics and identifies a potential therapeutic target for treating infectious diseases caused by nontuberculous mycobacteria.

关键词： IL-15 transpresentation   mRNA delivery   NK cell immunotherapy   ovarian cancer  

摘要： Ovarian cancer (OC) is the most lethal gynecological malignancy. As high numbers of Natural Killer (NK) cells in ascites associate with improved survival, the adoptive transfer of allogeneic NK cells is an attractive therapeutic strategy. An approach to further improve NK cell expansion and anti-tumor functionality post-infusion includes IL-15 transpresentation (transIL-15), which involves surface expression of the IL-15 cytokine bound to IL-15R alpha. However, others have substantiated that systemic administration of ALT/N-803, a soluble molecule mimicking transIL-15, leads to T cell-mediated rejection of the infused allogeneic NK cell product. In addition, whether transIL-15 induce superior expansion and functionality of our hematopoietic progenitor cell-derived NK cells (HPC-NK) remains understudied. Here, we propose to transfect OC cells with IL-15 and IL-15R alpha mRNA and evaluate HPC-NK cell stimulation in vitro. Co-transfection of both mRNAs resulted in surface co-expression of both components, thus mimicking the transIL-15. Importantly, co-culture of HPC-NK cells with transIL-15 OC cells resulted in superior proliferation, IFN gamma production, cytotoxicity and granzyme B secretion. Furthermore, we observed uptake of IL-15R alpha by HPC-NK cells when co-cultured with transIL-15 OC cells, which associates with NK cell long-term proliferation and survival. Superior killing and granzyme B secretion were also observed in transIL-15 OC spheroids. Our results demonstrate that local delivery of IL-15 and IL-15R alpha mRNA to OC tumors may be a safer strategy to boost HPC-NK cell therapy of OC through IL-15 transpresentation.

关键词： Calpain 2   hepatocellular carcinoma   IL-1 alpha   MDSCs   tumor microenvironment  

摘要： Tumor-promoting inflammation significantly impacts cancer progression, and targeting inflammatory cytokines has emerged as a promising therapeutic approach in clinical trials. Interleukin (IL)-1 alpha, a member of the IL-1 cytokine family, plays a crucial role in both inflammation and carcinogenesis. How IL-1 alpha is secreted in the tumor microenvironment has been poorly understood, and we previously showed that calpain 1 cleaves pro-IL-1 alpha for mature IL-1 alpha secretion, which exacerbates hepatocellular carcinoma by recruiting myeloid-derived suppressor cells. In this study, we report that calpain 2 also modulates IL-1 alpha secretion. Notably, a deficiency in calpain 2 resulted in enhanced hepatocellular carcinoma development within an IL-1 alpha-enriched tumor microenvironment. Further investigations revealed that calpain 2 deficiency increased calpain 1 expression, implying a compensatory mechanism between the two calpains. Mechanistically, calpain 2 deficiency led to increased expression of FoxO3, which is a forkhead transcription factor that promotes calpain 1 expression. Collectively, these results suggest that calpain 2 modulates calpain 1 expression, and therefore IL-1 alpha secretion through the induction of FoxO3, offering novel potential therapeutic targets for cancer treatment.

关键词： Alzheimer disease   nanobody   single-domain antibody   TNF alpha   TNF alpha inhibition   nanobody humanization  

摘要： Tumor necrosis factor-alpha (TNF alpha) is a key pro-inflammatory cytokine implicated in the pathogenesis of numerous inflammatory and autoimmune diseases, including rheumatoid arthritis, inflammatory bowel disease, and neurodegenerative disorders such as Alzheimer's disease. Effective inhibition of TNF alpha is essential for mitigating disease progression and improving patient outcomes. In this study, we present the development and comprehensive characterization of potent humanized TNF alpha inhibitory nanobodies (TNFI-Nbs) derived from camelid single-domain antibodies. In silico analysis of the original camelid nanobodies revealed low immunogenicity, which was further reduced through machine learning-guided humanization and developability optimization. The two humanized TNFI-Nb variants we developed demonstrated high anti-TNF alpha activity, achieving IC50 values in the picomolar range. Binding assays confirmed their high affinity for TNF alpha, underscoring robust neutralization capabilities. These TNFI-Nbs present valid alternatives to conventional monoclonal antibodies currently used in human therapy, offering potential advantages in potency, specificity, and reduced immunogenicity. Our findings establish a solid foundation for further preclinical development and clinical translation of TNF alpha-targeted nanobody therapies in TNF alpha-mediated diseases.

关键词： Oligomerized polyphenol   bladder cancer   complementary medicine  

摘要： Oligonol (R) (Olg) is an oligomerized polyphenol with a higher bioavailability and exhibits excellent antioxidant and anti-inflammatory properties. However, the effects and underlying mechanisms of Olg on bladder cancer are still largely unknown. The current study found that Olg markedly reduced the viability of bladder cancer cells through the induction of caspase-dependent apoptosis while exhibiting no noticeable toxicity to normal bladder cells. Combining Olg and cisplatin resulted in a synergistic cytotoxic effect on bladder cancer cells. Olg also inhibited cell migration and invasion by affecting the expression of E-cadherin, Snail, N-cadherin, and vimentin. These effects of Olg were significantly weaker in the NF-kappa B silencing cells, revealing that Olg may inhibit cell viability and motility by modulation of the TNF-alpha/NF-kappa B/Snail pathway in human bladder cancer cells. Olg acts against cancer cells and enhances cisplatin chemotherapy, and it holds great potential as an anticancer drug or complementary medicine for bladder cancer.