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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.

关键词： exercise and diet intervention   obesity   blood lipids   inflammation  

摘要： Background/Objectives: This study piloted a 24-week bodybuilding program combining resistance training (RT) with a dietary bulk-and-cut protocol in middle-aged adult males. Methods: Seven untrained males (33 +/- 3.0 years;BMI = 35.0 +/- 4.6 kg/m2;body fat = 36 +/- 5%) completed a 24-week intervention combining RT with a dietary protocol consisting of 12-week cycles of caloric bulking (0-12 weeks) and cutting (12-24 weeks). The participant retention rate was 64%, while compliance with training was 96.7%, and adherence to dietary cycles was over 93%. To assess the preliminary efficacy of the intervention, venous blood samples and measurements of body composition (BodPod), muscle strength, and VO2max (cycle ergometer) were collected at baseline (week 0) and following the bulking (week 12) and cutting (week 24) cycles. Circulating lipids (triglycerides, total, low-density, and high-density cholesterol), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and interleukin-10 (IL-10) were measured in serum. Results: The training led to significant increases in muscle strength, especially in the deadlift (+46%, p < 0.001) and squat (+65%, p < 0.001). Improvements in body composition were characterized by an increase in fat-free mass and a decrease in body fat percentage over the 24-week intervention (+3% and -6%, respectively, p < 0.05). Lipids, CRP, IL-6, and IL-10 did not change significantly, but there was a notable reduction in TNF-alpha (time effect p = 0.05, p eta 2 = 0.39), with 15% lower concentrations at week 24 compared to baseline, indicating reduced inflammation. Conclusions: Overall, the pilot intervention achieved high compliance and adherence rates, leading to improvements in body composition and lower resting TNF-alpha concentrations in a group of middle-aged males with obesity.

关键词： Crohn's disease   Anti-TNF alpha   Preoperative treatment   Postoperative recurrence   Loss of response  

摘要： Anti-TNF alpha antibodies are effective in controlling intestinal inflammation caused by Crohn's disease. However, many patients undergo surgery due to diminished efficacy of the antibodies during maintenance therapy. Currently, the decision between intensification of TNF alpha therapy and surgery is difficult to make. The purpose of this study was to determine the effect of preoperative treatment with anti-TNF alpha antibodies on postoperative recurrence of Crohn's disease. One hundred and fourteen consecutive patients with Crohn's disease who underwent bowel resection with anastomosis between 2009 and 2021 were retrospectively analyzed on the preoperative treatment history and perioperative information. Of the 74 patients who used anti-TNF alpha antibodies preoperatively, 43 underwent surgery after intensification of therapy following attenuation of anti-TNF alpha antibody efficacy. Time to postoperative endoscopic recurrence was significantly shorter in the group using anti-TNF alpha antibodies than in the group not using them (p = 0.0055). We found no difference in time to postoperative endoscopic recurrence between patients who underwent intensified therapy and those who underwent immediate surgery. Patients who received preoperative anti-TNF alpha antibody had a shorter time to postoperative endoscopic recurrence, but the presence or absence of intensified treatment after weakening of the anti-TNF alpha antibody effects did not affect the time to postoperative endoscopic recurrence.

关键词： myeloma   immunotherapies   immunology   micro-transplant   microchimerism  

摘要： Background Despite advances in the treatment of multiple myeloma, a proportion of patients still hardly achieve desired prognosis. Although microtransplant (MST) has proved promising results in treating several hematological malignancies, it has not been studied in multiple *** We performed a retrospective analysis of multiple myeloma patients treated with MST at our institution. Their clinical information and outcome measurements were collected. Furthermore, the fluctuation of donor microchimerism after MST, as well as the alteration of immune function before and after MST were *** Twenty patients receiving MST were enrolled from June 2008, to May 2024, with an overall response rate of 17/20. The 6-year overall survival (OS) and progression-free survival (PFS) rates were 64.7% and 35.3%, respectively, with no graft-versus-host disease or non-relapse mortality. Incidence of controlled fever and Grade I cytokine release syndrome (CRS) was 40.8%. The OS were comparable between groups with age, International Staging System stage, and Mayo Stratification of Myeloma and Risk-Adapted Therapy stage. However, earlier Durie-Salmon stage, disease in VGPR or CR status prior to MST, and an increase in total cycle number of MST were significantly associated with longer OS. Donor microchimerism was detected in all available peripheral blood samples from 14 days to 6 months post-MST. Furthermore, MST resulted in increased proportions of total CD3+ T cells, and CD4+CD8- T cells in peripheral blood, as well as improved CD4:CD8 ratio and increased proportions of Th0 *** MST extended PFS and OS, and benefit immune reconstitution in multiple myeloma patients. Therefore, MST is a promising treatment for multiple myeloma, especially those with high-risk cytogenetics.

关键词： coronary artery disease   cytokines   inflammation   ischemic heart disease  

摘要： Background: Ischemic heart disease (CAD), a leading global health burden, arises primarily from atherosclerosis, an inflammatory condition characterized by lipid accumulation and metabolic dysregulation. The precise contribution of inflammatory cytokines (IL-2, IL-6, and TNF-α) to CAD pathogenesis remains an area of significant research. Aim: The primary aim of this study is to examine the IL-2, IL-6, and TNF-α in patients with coronary artery disease (CAD) and compare them with Non-CAD individuals to evaluate their potential as diagnostic biomarkers for CAD. Methodology: A prospective observational study was conducted over 3 years, involving 100 participants divided into CAD and non-CAD groups. Blood samples were isolated and analyzed for IL-2, IL-6, and TNF-α levels utilizing ELISA kits. Biochemical parameters, including lipid profiles, were also assessed. Results: This study observed significantly elevated IL-6 in patients with CAD compared with controls, while IL-2 and TNF-α levels did not reach statistical significance. The CAD group exhibited dyslipidemia characterized by elevated triglycerides and reduced HDL. Furthermore, the CAD group demonstrated alterations in biochemical parameters, including lower albumin and calcium levels, higher urea and uric acid levels, and an elevated erythrocyte sedimentation rate. These findings suggest a systemic inflammatory state and metabolic disturbances in patients with CAD. Conclusions: This study highlights IL-6 as a potential biomarker and key player in CAD pathogenesis. These findings warrant further investigation into the therapeutic potential of targeting inflammatory pathways for cardiovascular risk reduction.

关键词： aminopeptidase   antigen processing and presentation   cancer immunotherapy   cellular stress   metabolism   ACN   acetonitrile   CALR   calreticulin   DAPI   4',6-diamidino-2-phenylindole   DCF   dichlorofluorescein   DIA   data-independent acquisition   DMEM   Dulbecco's modified Eagle medium   DMSO   Dimethyl sulfoxide   ECAR   extracellular acidification rate   ER   endoplasmic reticulum   ERAP   endoplasmic reticulum aminopeptidase   FA   formic acid   FBS   fetal bovine serum   FDR   false discovery rate   H2DCFDA   2',7'-dichlorodihydrofluorescein diacetate   HLA   human leukocyte antigen   LC-MS/MS   liquid chromatography tandem mass spectrometry   MHC-I   major histocompatibility complex class I   OCR   oxygen consumption rate   PBMC   peripheral blood mononuclear cell   PDIA3   protein disulfide isomerase family A member 3   PLC   peptide-loading complex   PSM   peptide spectrum match   RPMI   Roswell Park Memorial Institute Medium   TAP   transporter associated with antigen processing   Tht   thioflavin-T  

摘要： Endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) metabolizes peptides inside the ER and shapes the peptide repertoire available for binding to Major Histocompatibility Complex Class I molecules (MHC-I). However, it may have additional effects on cellular homeostasis, which have not been explored. To address these questions, we used both genetic silencing of ERAP1 expression as well as treatment with a selective allosteric ERAP1 inhibitor to probe changes in the immunopeptidome and proteome of the A375 melanoma cancer cell line. We observed significant immunopeptidome shifts with both methods of functional ERAP1 disruption, which were distinct for each method. Both methods of inhibition led to an enhancement, albeit slight, in tumor cell killing by stimulated human PBMCs and in significant proteomic alterations in pathways related to metabolism and cellular stress. Similar proteomic changes were also observed in the leukemia cell line THP-1. Biochemical analyses suggested that ERAP1 inhibition affected sensitivity to ER stress, reactive oxygen species production and mitochondrial metabolism. Although the proteomics shifts were significant, their potential in shaping immunopeptidome shifts was limited since only 9.6% of differentially presented peptides belonged to proteins with altered expression and only 4.0% of proteins with altered expression were represented in the immunopeptidome shifts. Taken together, our findings suggest that modulation of ERAP1 activity can generate unique immunopeptidomes, mainly due to altered peptide processing in the ER, but also induce changes in the cellular proteome and metabolic state which may have further effects on tumor cells.

关键词： HBV   HLA-Ib   rs41551813   HIF-1   genetic association   HBV outcome  

摘要： Background The natural history of HBV infection is highly heterogeneous. Failure to clear the virus during the acute phase of infection allows for viral persistence and progression to chronicity. Investigating the immune mechanisms involved in this process is crucial for effectively managing infection outcome. HLA-Ib molecules (HLA-G, HLA-E and HLA-F) play a critical role in regulating the immune response. Objectives: Primary objective we investigate the potential impact of functional polymorphisms in HLA-F*01:03 (rs1736924), HLA-E*01:01/01:03 (rs1264457), and two selected HLA-G polymorphisms in Exon 2 (+292 A > T (rs41551813) and +372 G > A (rs1130355)) on HBV infection outcome. Secondary objective: we evaluate the expression of soluble HLA-E in our cohort. Methods We evaluated these polymorphisms in a cohort of 200 patients with chronic HBV infection and 100 individuals who spontaneously resolved the infection, using SSP-PCR and Sanger sequencing. Additionally, we measured soluble HLA-E (sHLA-E) levels using ELISA. Results Our results showed a significant association of HLA-G (rs41551813) and HLA-E (rs1264457) polymorphisms with HBV infection outcome, where carriers of the A allele in both HLA-G (rs41551813) and HLA-E (rs1264457) had a significantly higher likelihood of spontaneous HBV clearance (all p < 0.01). Furthermore, we demonstrate that elevated sHLA-E expression favours HBV persistence. Additionally, our findings has revealed that the HLA-G + 292 A > T polymorphism (rs41551813) is associated with regulation of sHLA-G expression. Haplotype analysis further identified the 'TAAA' haplotype as linked to spontaneous HBV clearance. Conclusion this study demonstrates, for the first time, the critical role of HLA-Ib on HBV infection outcome, providing insights for potential therapeutic interventions.

关键词： Breast neoplasms   Cancer vaccines   Epitopes   T-Lymphocyte   Histocompatibility antigen class II   Neoantigen  

摘要： BackgroundThe high occurrence of treatment resistance in patients with hormone receptor-positive (HR +) breast cancer is a global health concern. Thus, effective immunotherapy must be developed. The public neoantigens, estrogen receptor 1 (ESR1) and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), shared by HR + and endocrine-resistant breast cancer, could be ideal targets for immunotherapy;however, their presentation by human leukocyte antigen class II (HLA II) and recognition by CD4 + T cells remain largely *** mutations in ESR1 and ten mutations in PIK3CA were subjected to major histocompatibility complex (MHC)-peptide binding analysis and enzyme-linked immunospot (ELISPOT) assays using peripheral blood mononuclear cells (PBMCs) from healthy donors carrying DRB4*01:03, or DRB4*01:03 and DPA1*02:02-DPB1*05:01 (DP5). DRB4*01:03- or DP5-restricted peptides were inferred from binding measurements and ELISPOT assays. Other DRB1 alleles that can also present these mutant peptides were identified using binding *** IFN-gamma responses by CD4 + T cells were detected for most peptides. The peptides that contain ESR1 (E380Q) and PIK3CA (N345K, E542K, E545K/A, E726K, H1047R/L/Y, and G1049R) are presumably restricted by DRB4*01:03, which is frequently found globally (carrier frequency: 35-63%), or by DRB4*01:03 and DRB1*04 alleles. Some PIK3CA (H1047R/L/Y) peptides can also be presented by DRB1*01:01, DRB1*09:01, DRB1*11:01, and DRB1*15:02. ESR1 (Y537S/N, D538G) peptides are potentially restricted by DP5, a frequently found allele in East Asian populations, and DRB1*01:01 and DRB1*15:*** in ESR1 and PIK3CA were recognized by CD4 + T cells from healthy donors through potential restriction by common HLA II alleles. Further studies are warranted to elucidate the landscape of HLA II presentation and validate the clinical applicability of these mutations for the immunotherapy of patients

关键词： Rheumatoid arthritis   Growth arrest and DNA damage 45 gamma   Interleukin 10   Collagen-induced arthritis   C-Jun N-terminal kinases  

摘要： It has been shown that Gadd45 beta alleviated K/BxN serum-induced arthritis, but in collagen-induced arthritis (CIA), it exacerbated joint inflammatory response, clinical signs, and symptoms. So far, the function of Gadd45 gamma in arthritis remains to be explored. This study aimed to investigate the role and immune regulatory mechanism of Gadd45 gamma in arthritis by intra-articular injection of a lentiviral vector encoding the Gadd45 gamma gene (LV-Gadd45 gamma) or lentiviral vectors (LV). The experiments showed that CIA increased the level of Gadd45 gamma, overexpression of Gadd45 gamma inhibited the symptoms and articular destruction of CIA, reduced the pro-inflammatory cytokine IL-1 beta, IL-6, and matrix metalloproteinases-13 (MMP-13), and increased the anti-inflammatory cytokine IL-10. In turn, high levels of IL- 10 elevated Gadd45 gamma in CIA mice, human rheumatoid synovial fibroblasts (HRSF), and RAW cell lines. Furthermore, the increasing expression of Gadd45 gamma dramatically raised IL-10 and diminished the phosphorylation of c-Jun N-terminal kinase (JNK) in CIA mice and HRSF. Mechanistic analysis showed that the attenuating effect of Gadd45 gamma on CIA may be attributed to the mutual enhancement of the expression of Gadd45 gamma and IL-10 and the inhibition of JNK activity through downregulating IL-1 beta and IL-6. The results indicate that Gadd45 gamma can act as an inflammatory suppressor and joint damage attenuator in CIA mice. Increased IL-10 levels through a positive feedback circuit between Gadd45 gamma and IL-10 and the inhibitory effect of Gadd45 gamma on JNK activity endows this protein with the ability to inhibit CIA.

关键词： Bioinformatics   Wilms tumor   Interleukin (receptors)   IL20RA   Immune infiltration   Epithelial-mesenchymal transition  

摘要： Wilms tumor (WT) is a common renal malignancy in pediatric patients. Interleukin (receptors) (IL(R)s) play significant roles in tumor biology, however, their specific involvement in WT remains inadequately understood. We employed univariate Cox regression analysis to screen for certain IL(R) genes associated with prognosis and then analyzed their expression patterns. A prognostic model was constructed based on five selected IL(R)s using the LASSO Cox regression algorithm. To further elucidate the relationship between the prognostic model and the immune microenvironment, we conducted immune-related analyses. Additionally, we performed experiments to verify the roles of IL20RA and IL19 in WT. Finally, CNV, methylation and pan-cancer analysis were performed for IL19 and IL20RA. Our analysis ultimately identified five genes associated with prognosis: IL20RA, IL19, IL24, IL11 and IL17RD. The prognostic model incorporating these five genes demonstrated robust predictive power in both training and validation cohorts. Notably, IL19 and IL20RA were found to promote epithelial-mesenchymal transition (EMT) through the STAT3/SNAIL pathway, thereby contributing to tumor progression. Furthermore, significant differences in immune function and checkpoint expression were observed between the two groups. The high-risk group exhibiting a lower TIDE score, which suggests a potentially better response to immunotherapy. This study introduces a novel IL(R)-based prognostic signature for WT, highlighting IL20RA as a potential therapeutic target. These findings offer valuable insights for future studies on WT.