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关键词： CRC   Hedyotis diffusa polysaccharide   Tumor immunotherapy   Immune checkpoint inhibitors  

摘要： Colorectal cancer (CRC) is a prevalent and highly malignant tumor with a limited response to immune checkpoint inhibitor-based immunotherapy. There is an urgent need for novel immunomodulatory agents to enhance the immunotherapeutic response in CRC. Hedyotis diffusa, known for its immunomodulatory properties, has long been utilized as an adjunct in cancer treatment, positioning it as a potential source for discovering new tumor immunomodulators. In this study, we identified a polysaccharide derived from Hedyotis diffusa (HDP), comprising six monosaccharides: rhamnose, arabinose, galactose, glucose, xylose, and mannose. When combined with PD-1 and CTLA-4 inhibitors, HDP can boost systemic immunity in mice to enhance the effectiveness of immune checkpoint inhibitors in CRC therapy. HDP significantly increases the infiltration of CD4+ and CD8+ T cells into tumor microenvironment and upregulates the expression of key effector molecules derived from cytotoxic T cells. Mechanistic studies reveal that HDP activates the IL-2/IL-2R axis by upregulating IL-2 production and the expression of IL-2 receptor subunits, thereby promoting T cell proliferation. Collectively, this research introduces an innovative strategy to improve the efficacy of tumor immunotherapy by harnessing the immunomodulatory potential of polysaccharides. It also directs a roadmap for developing HDP as a promising immunomodulator for CRC treatment.

关键词： bone marrow donor   HLA-DRB1   NGS   novel allele  

摘要： Six novel HLA-DRB1 alleles are described from bone marrow volunteers from the Russian Registry.

关键词： HLA-DPA1*01:03:01:99 allele   HLA-genotyping   Illumina   next generation sequencing   novel allele  

摘要： The HLA-DPA1*01:03:01:99 allele differs from HLA-DPA1*01:03:01:04 by a single nucleotide substitution in intron 1.

关键词： CuO/ZnO particles   immunosuppressive effects on macrophages   metal (nano)-particle exposure   welding and metal fumes   workplace safety and new approach methodologies (NAM)  

摘要： Metal workers have an increased risk of severe lobar pneumonia due to exposure to metal fume particles, which lead to recent pneumococcal vaccination recommendations. To investigate the effects of metal fume-derived zinc oxide (ZnO) and copper oxide (CuO) particles on airway immune responses, human THP-1-derived macrophages are exposed in vitro to the bacterial pathogen-associated molecular patterns (PAMPs) lipopolysaccharide (LPS), lipoteichoic Acid (LTA), or peptidoglycan (PGN), together with particle suspensions. Particles are generated through metal inert gas (MIG) soldering. Spectrometric and microscopic analysis confirms CuO and ZnO as main components. Macrophage IL-6 and TNF mRNAs are quantified by qPCR and secreted protein levels by electrochemiluminescent multi-spot assay. A dose-dependent increase in macrophage TNF and IL-6 mRNA (4 h) and protein (24 h) levels following exposure to PAMPs is significantly inhibited by 2 mu g mL-1 CuO/ZnO particles (n = 5). Additionally, CuO/ZnO particles significantly inhibit TNF protein expression in unstimulated macrophages, while IL-6 protein levels are unaffected (n = 5). The presented in vitro immunotoxicity approach may extend existing new approach methodology (NAM) elements for chemical risk assessment and possibly exposure limit evaluation refinements. These findings implicate that CuO/ZnO particles suppress macrophage proinflammatory responses to PAMPs, potentially compromising lung immunity, underlining current vaccine recommendations and efforts for preventive occupational health guidelines.

关键词： haplotype   HLA   HLA-B*15:88   sequence-based typing   Taiwanese  

摘要： Two nucleotide substitutions in codon 152 of HLA-B*15:02:01:01 result in a novel allele, HLA-B*15:88.

关键词： Edible bird's nest   Peptides   Antioxidant   Anti-inflammatory   Human vascular endothelial cells  

摘要： Bioactive peptides from edible bird's nest (EBN) represent a unique natural source that exhibits various attractive bioactivities. Four EBN peptides (P1: LFWSPSVYLK, P2: GWPHLEDNYLDW, P3: NPPADLHK and P4: GDLAYLDQGHR) were previously identified with potential antioxidant and anti-inflammatory activities. However, their bioactivities at cellular levels and underlying mechanisms are poorly understood. This study aimed to investigate the antioxidant and anti-inflammatory activities of these four EBN peptides in human vascular endothelial cells (EA. hy926) and identify the mechanisms involved. Four EBN peptides were screened for their antioxidant effects (superoxide scavenging) and anti-inflammatory effects (reducing cyclooxygenase-2 (COX-2) and vascular cell adhesion molecule 1 (VCAM-1) level) in tumour necrosis factor (TNF-alpha) induced EA. hy926 cells. Stability in a gastrointestinal (GI) digestion model was assessed. The expression levels of phospho-Nrf2 (p-Nrf2), mitogen-activated protein kinase (MAPK) family proteins (p38, ERK, and JNK) and sirtuin 1 (SIRT1) were studied. Results indicated that P1, among four peptides tested, potently lowered the superoxide (38%), COX-2 (26.63%), and VCAM-1 (58.88%) levels, thus exhibiting antioxidant and anti-inflammatory activities. Importantly, P1 maintained these activities after the simulated GI digestion. Additionally, P1 significantly improved p-Nrf2 (44.30%) and SIRT1 (40.26%) levels, while inhibiting MAPK proteins [p38 (72.29%), ERK (27.22%) and JNK (50%)], indicating its potential to modulate the Nrf2 and MAPK signalling pathways. This study is the first to report the potential role of EBN peptides in protecting vascular endothelial cells from oxidative and inflammation damage.

关键词： DPA1 gene   Macaca thibetana   major histocompatibility complex  

摘要： Ten novel MHC-DPA1 alleles were identified in Tibetan macaques (Macaca thibetana).

关键词： Accelerated skin aging   Compound K   Epidermis   Inflammaging   IL-17A   UVB  

摘要： We evaluated the anti-accelerated epidermal skin aging effects of compound K (CK) on keratinocytes using IL-17A and ultraviolet B. CK restored epidermal functions and reduced the induction of pro-inflammatory cytokines by inhibiting NF-kappa B and p38 MAPK activation. CK plays a significant role in controlling accelerated epidermal skin aging.

关键词： acute-on-chronic liver failure (ACLF)   acute kidney injury (AKI)   serum   cystatin C   metallothionein  

摘要： Background/Aims: Acute-on-chronic liver failure (ACLF) is a complication of cirrhosis associated with systemic inflammation and organ dysfunction. In ACLF, the development of acute kidney injury (AKI) is associated with poor outcomes. FABP1, NGAL, Cys C and IL-18 have been shown to correlate with ACLF severity and mortality. Hence, our study aimed to evaluate the association of these biomarkers with organ dysfunctions, particularly AKI, in an Indian ACLF patient cohort. Methods: 151 study participants including ACLF (n = 91;with AKI n = 63, no-AKI n = 28), non-liver AKI (n = 30) and healthy controls (n = 30) were recruited. Serum ELISA was performed for biomarker estimation. Data interpolation and graphical representation were performed using GraphPad Prism and statistical analyses performed using STATA 14.0. Results: FABP1 and Cys C levels were higher in ACLF-AKI patients compared to ACLF no-AKI (P-value <= 0.0005). Serum Cys C levels were significantly increased in non-liver AKI compared to ACLF-AKI (P-value <= 0.001). AUROC analysis showed better performance of Cys C (AUC 0.79;95% CI (0.68-0.89)) compared to serum creatinine (AUC 0.71;95% CI (0.61-0.82)) in discriminating AKI and noAKI. Correlation analysis revealed positive correlations of FABP1 with creatinine and urea, Cys C with creatinine, urea and OF-Kidney, NGAL, and IL-18 with general markers of organ dysfunction. Plasma MTs) measured in a subset of ACLF patients were elevated in progression-to-AKI. Conclusion: Our study showed that in an Indian population of ACLF patients with a high short-term mortality, serum Cys C and FABP1 were elevated in ACLF-AKI, however did not have predictive potential for ACLF-AKI. Cys C levels were significantly higher in non-liver AKI patients vs. ACLF-AKI and correlated with markers of kidney dysfunction whereas NGAL and IL-18 represented higher inflammation and total organ dysfunction. Hence, we conclude that these biomarkers were elevated in ACLF-AKI but did not have predi

关键词： Bone inflammation   Lipopolysaccharide   TLR4   IFN gamma   IL-10   M-CSF   RANKL  

摘要： The inflammatory response in bone tissue often triggered by LPS is a complex process. Since LPS through TLR4 and in presence of IFN gamma activates osteoclast differentiation and bone resorption, therefore, suppression of osteoclastogenesis through inhibition of TLR4 vs IFN gamma mediated inflammation could be a reasonable strategy for the treatment of inflammatory bone loss. Administration of anti-TLR4 (30 mg/kg) and anti-IFN gamma antibodies (6.6 mg/kg) were utilized before LPS (5 mg/kg) challenge and subsequently mice were treated with mouse IL-10 (0.02 mg/kg). Then RBMCs were isolated from different groups of mice and stimulated (in vitro) with M-CSF (10 ng/ml) and RANKL (10 ng/ml) to induce bone marrow cell differentiation in presence of LPS (100 ng/ml). The involvement of RANKL and M-CSF in the regulation of bone inflammation underlines the intricate signaling pathways. Furthermore, the study sheds light on the potential therapeutic effects of exogenous IL-10 possibly through STAT3 signaling in the RBMCs. The use of antibodies against TLR4 and IFN gamma, in conjugation with IL-10in LPS bone damage model, appears to downregulate the activation of NF-kappa B, and reduction of many proinflammatory cytokines regulating the inflammatory cascade in RBMC. This suggests a promising avenue for the development of treatments aimed at mitigating bone inflammation associated with bacterial infections. Therefore, inhibition of TLR4 and IFN gamma could be explored as potential therapeutic agents against LPS induced bone loss.