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关键词： EPA   DHA   Myogenic IL-6   Lipid metabolism   TRPV1/Ca2+   AMPK/STAT3  

摘要： Lipid metabolism disorder serve as a critical starting point for the development of chronic non-communicable diseases (NCDs). Eicosapentaenoic acid (EPA) and Docosahexaenoic acid (DHA) are known for their lipid-lowering properties, but few studies have revealed their differences from the perspective of skeletal muscle endocrinology. Myogenic IL-6 has garnered significant attention for its role in energy distribution. The primary aim of this study was to investigate the effects and mechanisms of EPA and DHA on myogenic IL-6 and lipid metabolism disorders in mice, and to clarify the association between the alleviation of lipid metabolism disorders and myogenic IL-6 mediated by EPA/DHA. We found that EPA and DHA not only prevented high-fat diet- induced lipid metabolism disorders, but also up-regulated the expression of myogenic IL-6 by activating TRPV1/Ca2+ signaling in skeletal muscle. However, the lipid metabolism prevention effect mediated by EPA was weakened after knockout gene of myogenic IL-6, with its body weight and body fat increased and a large amounts of lipid deposited in the blood, liver, and adipocytes. Meanwhile, there no significantly differences of AMPK/STAT3 signaling in adipose tissue between groups after knockout gene of myogenic IL-6. Based on the results above, we concluded that EPA and DHA can stimulate the production of myogenic IL-6 through TRPV1/Ca2+ signaling in skeletal muscle. The prevention effect of lipid metabolism disorders by EPA, but not DHA, relies on myogenic IL-6, with the underlying mechanism may involving the enhancement of AMPK/STAT3 signaling mediated by myogenic IL-6 in adipose tissues. (c) 2024 Published by Elsevier Inc.

关键词： Peritoneal macrophages   M1 and M2 macrophages   Interleukins   Liposomes   IL-2   IL-2R alpha   Apoptosis   Inflammation  

摘要： Inflammatory diseases pose a global challenge due to the critical role of macrophages in their pathogenesis. This study evaluated the effects of cationic liposomes encapsulating IL-2 (LIP-IL-2) on murine peritoneal macrophages (MP) polarized towards M1 and M2 phenotypes. M1 MP (CD86+), which overexpressed IL-2R alpha and CD14 receptors, underwent apoptosis following LIP-IL-2 treatment, whereas M2 MP (CD206+) were unaffected. Furthermore, LIP-IL-2 significantly reduced the secretion of pro-inflammatory cytokines, including IL-6, TNF-alpha, IFN-gamma, and IL-12, exclusively in M1 macrophages. These findings suggest that LIP-IL-2 could serve as a promising therapeutic tool for chronic inflammatory diseases by selectively inducing apoptosis in pro-inflammatory M1 macrophages without affecting M2 ones, opening avenues for targeted therapies in diseases where chronic macrophage-mediated inflammation is a key factor.

关键词： Unconventional T cell receptor   gamma S TCR   Superantigen   SEA   TRGV9/TRDV2  

摘要： Bacterial toxins, called superantigens, are produced by Staphylococcus aureus and are known to activate gamma S T cells. gamma S T cells contribute to long-lasting immunity against bacterial skin infections caused by S. aureus. gamma S T cells are a distinct subgroup of T cells containing the T cell receptor (TCR) gamma and S chains. The gamma S TCR harbouring the variable chains TRGV9/TRDV2 is the most common TCR in human peripheral blood and is known to be activated by superantigens and are also promising candidates for tumor immunotherapy. However, detailed analyses of antigen binding to gamma S TCR have been severely hampered by difficulties in producing large amounts of gamma S TCR. In this study, we report a protocol to produce recombinant gamma S TCR (TRGV9/TRDV2) by fusing the variable domains gamma S TCR with the constant domains of alpha(3 TCR. Subsequently, binding analyses were executed applying microscale thermophoresis showing a clear binding between superantigen and the gamma S TCR in the micro molar range. In addition, the superantigen SEA was shown to induce cytokine expression in gamma S T cells with moderate MHC dependence, suggesting that other receptors can act as antigen presenting molecules upon gamma S T cell activation. These results pave the way towards a better understanding of superantigen recognition by the gamma S T cells and facilitates the future use of gamma S TCR in cellular tumor immunotherapy.

关键词： Oral Squamous Cell Carcinoma (OSCC)   Salivary TNF alpha   Gold nanoparticles (AuNPs)   Antibody-based detection   And predictive biomarkers  

摘要： Objectives: To assess the efficacy of the AuNP-enhanced ELISA in the detection of salivary TNF-alpha in OSCC and evaluate its predictive value for survival. Design: A longitudinal study was conducted on 40 OSCC patients and 10 healthy controls. Saliva was collected at a regular interval and TNF alpha levels were measured using ELISA and AuNP-enhanced ELISA. Descriptive statistics were carried out for demographic, clinical, and biomarker data. The efficacy of ELISA and AuNPenhanced ELISA was estimated and compared using the ROC curve. Kaplan-Meier survival analysis and Cox proportional hazards models were used to assess the survival outcome. A neural network model was performed to estimate TNF-alpha levels over time in OSCC patients. Results: OSCC patients (ELISA is 47.52 f 20.23 and Gold nano-enhanced ELISA is 57.63 f 24.99) exhibited significantly elevated TNF alpha levels compared to controls (ELISA is 10.13 f 3.07and Gold nano-enhanced ELISA is 12.07 f 3.66). Gold nano-enhanced ELISA (AUC of 0.995) demonstrated superior sensitivity than ELISA (AUC of 0.986), while Gold nano-enhanced ELISA achieves an even higher in detecting elevated TNF alpha levels. KaplanMeier analysis shows that Gold nano-enhanced ELISA outperforms ELISA in capturing survival trends, with better survival for TNF-alpha levels above the cutoff at 9 months (70 % vs. 60 %) and 24 months (40 % vs. 0 %). The neural network model poorly predicted TNF- levels over the period (AUC = 0.447). Conclusions: The gold nano-enhanced TNF alpha detection method is effective in detecting TNF alpha levels between OSCC patients and controls, demonstrating superior sensitivity in identifying survival trends over time compared to traditional ELISA.

关键词： Autoimmunity   Shared epitope   Cardiovascular disease  

摘要： Objective: Rheumatoid arthritis (RA) has been considered an independent risk factor for cardiovascular disease (CVD), where RA and CVD later manifest following genetic predisposition and an extended preclinical phase. The HLA-DRB1 Shared Epitope (SE) alleles predispose for RA and are associated with higher risk of CV mortality in RA patients, but have not been evaluated in a community-living population. Thus, we evaluated whether HLA-DRB1 (SE) alleles were associated with subclinical CVD, CV events, and mortality in the MultiEthnic Study of Atherosclerosis (MESA). Methods: We performed HLA typing in 955 MESA participants and evaluated associations of SE alleles with coronary artery calcium (CAC) and abdominal aortic calcium (AAC);risk difference for CAC, AAC severity, and carotid intima media thickness (cIMT);and associations of SE with all-cause mortality, CVD and nonCVD death, and CV events. Results: Among 955 participants, 30 % were HLA-DRB1 SE positive. SE positivity was not significantly associated with higher risk of CAC, AAC, cIMT, CV events, or mortality. DRB1*10:01 demonstrated 2.63-fold higher risk for CAC (95 % CI 1.17-5.99);DRB1*14:02 demonstrated 42 % higher risk for AAC (95 % CI 1.17-1.74);and DRB1*04:05 demonstrated 24 % lower risk for AAC (95 % CI 0.58-0.99). Conclusion: In a multi-ethnic community-living population, HLA-DRB1 SE alleles were not associated with subclinical CVD, CV events, or mortality. However, individual allele-associations with subclinical CVD suggested variability in risk.

关键词： Methicillin-resistant staphylococcus aureus   Brazilin   SaeR   Hla  

摘要： Background: Methicillin-resistant Staphylococcus aureus (MRSA) is a super-resistant bacterium with strong pathogenicity, causing broad range of infections in various tissues. alpha-Hemolysin (Hla) is the main virulence factor of S. aureus. Brazilin (BN), is a homoisoflavonoid derivative, obtained from the wood of Caesalpinia echinata Lam (Brazil-wood), Caesalpinia sappan L (Leguminosae), and Caesalpinia violacea Standl, has been proven to exert excellent antibacterial and anti-virulence effects against S. aureus. However, the underlying mechanisms remain still unclear. Objective: This study aims to evaluate the inhibitory effect of BN on MRSA virulence and pathogenicity and elucidate its underlying mechanisms. Methods: Rabbit erythrocytes were used to evaluate the effect of BN on hemocytolysis. The potential target of BN was screened by transcriptomic sequencing and verified by qRT-PCR, western blot (WB), and molecular interaction experiments. The effects of BN on MRSA toxicity and pathogenicity were both validated using A549 cell and mouse skin abscess model caused by MRSA. Results: BN attenuated the hemolytic activity of MRSA by inhibiting Hla secretion. It was also found that BN blocks its binding to the P1 promoter of the sae operon, and then reduced its transcript level. Remarkably, Delta saeR strain exhibits significantly reduced hemolytic activity due to impaired regulation of Hla and no extra inhibitory effect was observed in the samples treated with BN. Moreover, BN relieved A549 cell damage and mouse skin abscess induced by MRSA by inhibiting SaeR. Conclusion: These findings reveal, for the first time, BN can alleviate MRSA virulence and pathogenicity by decreasing the secretion of the Hla via inhibiting SaeR. Overall, this study suggests that BN could be a candidate for being submitted to further studies with the aim of its development as a new antibiotic against MRSA.

关键词： HLA   Haploidentical stem cell transplant   Donor-specific antibodies   Graft failure   Reduced-intensity conditioning  

摘要： Background: Donor-specific (DSA) anti-HLA antibodies can adversely influence outcomes of haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Methods: Patients who received a haplo-HSCT from a sibling after reduced-intensity conditioning (RIC) and had a virtual cross match against donor's HLA typing performed and a positive single-antigen microspherebased immunoassay test were studied. DSA were considered positive with a mean fluorescence intensity (MFI) >= 1000. Results: Anti-HLA DSA >= 1000, median 2623 (range 1000-13,235) MFI were documented in 27/65 (42 %) patients. In 14 (21.5 %) patients, antibodies were anti-HLA class I, in 18 (27.7 %) anti-HLA class II, and in 6 (9.2 %) against both. Overall (OS) and event-free survival (EFS) were lower in patients with anti-HLA Class I DSA (p = 0.026 and p = 0.037, respectively). One-year mortality was higher with anti-HLA DSA of any class (p = 0.009). Nine (64.3 %) of 14 patients with DSA anti-HLA class I died, vs. 11/18 (61 %) with class II DSA (p = 0.238). Anti-HLA DSA were not associated with graft failure (GF) in the cohort. There was no difference in relapse or acute or chronic GVHD in patients with and without DSA. Conclusion: Anti-HLA Class I DSA > 1000 MFI after haplo-HSCT was associated with lower OS and EFS and higher one-year mortality, but no with GF, acute or chronic GVHD, or relapse.

关键词： Inflammatory bowel disease (IBD)   Human mesenchymal stem cells (MSCs)   Bone marrow (BM)   Uterine myometrium (Ut) MSCs   Major Histocompatibility Complex (MHC)   Interferon-gamma (IFN-gamma)  

摘要： The clinical efficacy of mesenchymal stem cell (MSC) therapy for inflammatory bowel disease (IBD) is inconsistent and often fails to match promising preclinical findings. To improve outcome, we compared MSCs isolated from human uterine myometrium (Ut), a readily-available tissue source from a unique immune niche, to bone marrow (BM) MSCs, the most common source, in a murine IBD model with mechanisms underlying differential effects. In this study, human BMMSCs and UtMSCs were intravenously administered to mice with dextran sulfate sodium-induced colitis and evaluated for disease activity, microbiome composition, and cellular immunity. Bioinformatics analyses including patient data were performed to further specify involved mechanisms with subsequent functional validation performed. We found that UtMSC but not BMMSC treatment significantly reversed disease parameters by improving microbiome and reducing mesenteric lymph node IFN-gamma and IL-17Asecreting T cells. Transcriptomic analysis revealed UtMSCs had reduced MHC II pathway activation compared to BMMSCs. Functional validation confirmed UtMSCs compared to BMMSCs expressed lower IFN-gamma receptors, prevent MHC II-mediated human unstimulated T cell activation, and modulated stimulated T helper (Th) cells away from effector phenotypes while increasing regulatory T cells (Tregs) and IL-10 levels. Bioinformatics from IBD patients resistant to non-T cell-specific therapies implicated persistent MHC II-mediated Th1/Th17 activation as key drivers of disease. Overall, UtMSCs outperformed BMMSCs in improving microbiota, avoiding IFN-gamma responses, and modulating overall Th responses, suggesting this MSC source may offer more significant effectiveness for IBD and Th1/Th17-mediated conditions. Our findings also highlight that understanding MSC sourcespecific therapeutic mechanisms is crucial for optimizing clinical therapies.

关键词： Celiac disease   Gluten-free diet   Osteoclastogenesis   Bone metabolism   Osteoporosis  

摘要： The etiology of bone loss in celiac disease (CeD) remains a clinical challenge, with uncertainties present such as the extent of involvement of malabsorption and inflammation-induced osteoresorption processes in development of osteopenia/osteoporosis (OPN/OP), or reasons for failure to achieve healthy bone mass (BMD) even after long-term gluten-free diet (GFD) treatment. This observational prospective study explores the in vitro osteoclastogenic potential of peripheral blood precursors originating from adult active (newly diagnosed and untreated) celiac disease patients (aCeD) and describes the longitudinal changes in osteoclastogenesis after long-term adherence to GFD. To find connections between in vitro observations and in vivo bone metabolism changes, serum levels of 25(OH)D3, PTH, bCTX, PINP, CRP, IL-6, RANKL and OPG were measured before and after GFD and levels of these markers were correlated with the rate of osteoclastogenesis in vitro . OPG and IL-6 showed associations with BMD and/or presence of OPN/OP. Patients after GFD (CeD-GFD) exhibited improved BMD and increased serum 25(OH)D3 levels, alongside reduced bCTX and PINP levels. Compared to healthy donors, aCeD osteoclast genesis in vitro was higher and, surprisingly, remained elevated even in CeD-GFD patients. Negative correlation was found between osteoclastogenesis rate and serum OPG in aCeD, while osteoclastogenesis rate positively correlated with PTH in CeD-GFD. These results highlight OPG as marker for risk of OPN/OP in CeD and suggest that improvement of BMD after GFD is a result of uncoupling between bone metabolism and osteoresorptive action of osteoclasts after GFD. (c) 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

关键词： HLA typing   Quality control software   Transplantation   Catching data entry errors   Interpretation of real-time PCR HLA assays   Sequencing data  

摘要： HLA (human leukocyte antigen) typing is performed on both organ donors and recipients to ensure compatibility and thus maximize graft and patient survival. In the US, the final assigned HLA typing is then entered, often manually, into the DonorNet system managed by United Network for Organ Sharing (UNOS), where it is used to generate a list of potential recipients. For deceased donor organs, HLA typing is most often performed via real-time PCR (rtPCR), which is rapid and robust but requires human interpretation. Human error in that interpretation or in the data entry process (regardless of whether the typing is generated by rtPCR or sequencing) can have severe consequences including organ wastage due to inappropriate matching and graft rejection. UNOS requires laboratories to validate the accuracy of their DonorNet submission. To address this need, we have developed DonorCheck (https://***/PankratzLab/DonorCheck/), an open-source and userfriendly software application written in Java that validates DonorNet field entries against the original donor HLA typing source report. DonorCheck helps HLA laboratories independently validate their interpretation of rtPCR data (including accounting for allele, P-group, and serotype lookup) and the HLA data entry into DonorNet, reduce data entry errors, and enhance patient safety.