Increased levels of interleukin-18 (IL-18) and high mobility group box 1 protein (HMGB1) have been reported in patients with calcific aortic valve disease (CAVD). However, the role of IL-18 and HMGB1 in the modulation of the valvular interstitial cell (VIC) phenotype remains unclear. We hypothesized that HMGB1 mediates IL-18-induced myofibroblastic transition of VICs.The expression of IL-18, HMGB1 and α-smooth muscle actin (α-SMA) in human aortic valves was evaluated by immunohistochemical staining, real-time polymerase chain reaction and immunoblotting. Plasma concentrations of IL-18 and HMGB1 were measured using the ELISA kit. Cultured human aortic VICs were used as an in vitro model.Immunohistochemistry and immunoblotting revealed increased levels of IL-18, HMGB1 and α-SMA in calcific valves. Circulating IL-18 and HMGB1 levels were also higher in CAVD patients. In vitro, IL-18 induced upregulation of HMGB1 and α-SMA in VICs. Moreover, IL-18 induced secretion of HMGB1 to the extracellular space and activation of nuclear factor kappa-B (NF-κB). Blockade of NF-κB abrogated the upregulation and release of HMGB1 induced by IL-18. Whereas HMGB1 inhibition attenuated the IL-18-induced expression of α-SMA, HMGB1 enhanced the effect of IL-18.We demonstrated for the first time that both tissue and plasma levels of IL-18 and HMGB1 were increased in patients with CAVD. Mechanically, HMGB1 mediated IL-18-induced VIC myofibroblastic transition.
Abstract Background The prevalence of vitamin D deficiency and insufficiency is extremely high in pregnant women worldwide. However, the association between single nucleotide polymorphisms (SNPs) in vitamin D metabolic pathway genes and 25‐hydroxyvitamin D (25(OH)D) concentration among Chinese pregnant women is seldom reported. The risk of adverse neonatal outcomes due to maternal vitamin D deficiency has not been well investigated. Methods A total of 815 pregnant women and 407 infants were enrolled in this study. Serum 25(OH)D concentration was detected. DNA was extracted from the maternal blood for genotyping genetic SNPs in vitamin D pathway. An XGBoost model was established based on SNPs combined with external variables. Results Mean serum 25(OH)D level was 15.67 ± 7.98 ng/mL among the pregnant women. Seventy‐five percent of pregnant women had 25(OH)D deficiency in China. SNPs of GC (rs17467825, rs4588, rs2282679, rs2298850, and rs1155563) were significantly associated with maternal 25(OH)D concentration. The influence of variants of rs17467825, rs4588, rs2282679, and rs2298850 on maternal 25(OH)D might be modified by vitamin D supplementation and sunshine exposure. An XGBoost model was established for monitoring 25(OH)D status in pregnant women and provided clinical advice to reduce the risk of 25(OH)D deficiency. Mothers with 25(OH)D deficiency hinted a risk for macrosomia. Conclusion A high prevalence of vitamin D deficiency in China has been confirmed. A clinical model was established to guide pregnant women to supplement vitamin D according to genotype. Furthermore, we suggest the effect of maternal vitamin D status on the risk of macrosomia.
Abstract Recent progress in studying copper‐dependent targets and pathways in the context of tumor treatment has provided new insights into therapeutic strategies of leveraging copper‐dependent disease vulnerabilities and pharmacological manipulation of intratumor copper transportation to improve chemotherapy. Here, we developed reactive oxygen species (ROS)‐sensitive nanoparticles loaded with copper chaperone inhibitor DC_AC50 and cisplatin(IV) prodrug. The released DC_AC50 can promote a remarkable accumulation of intracellular cisplatin and copper through inhibition of the Atox1‐ATPase pathways, thereby enhancing the chemotherapeutic effect of cisplatin and inducing significant ROS generation. Excessive ROS then elicits intense endoplasmic reticulin (ER) stress which facilitates the immunogenic cell death (ICD) spurring a sustained immune response. Our study suggests that nanoparticle‐mediated copper chaperone inhibition via DC_AC50 can restore the immunogenicity of tumor cells for enhanced chemotherapy and cancer immunotherapy.
Abstract Background Emerging metabolomics-based studies suggested links between amino acids metabolism and non-alcoholic fatty liver disease (NAFLD) risk, however, whether there exists an aetiological role of amino acid metabolism in NAFLD development remains unknown. The aim of the present study was to assess the causal relationship between circulating levels of amino acids and NAFLD risk. Methods We performed two-sample Mendelian randomisation (MR) analyses using summary level data from genome-wide association studies (GWAS) to assess causal relationships between genetically predicted circulating levels of amino acids and NAFLD risk. Data from the largest GWAS on NAFLD (8,434 cases and 770,180 controls) were used in discovery MR analysis, and from a GWAS on NAFLD (1,483 cases and 17,781 controls) where NAFLD cases were diagnosed using liver biopsy, were used in replication MR analysis. Wald ratios or multiplicative random-effect inverse variance weighted (IVW) methods were used in the main MR analysis, and weighted median and MR-Egger regression analysis were used in sensitivity analyses. We additionally performed an MR conservative analysis by restricting genetic instruments to those directly involved in amino acid metabolism pathways. Findings We found that genetically predicted higher alanine (OR=1.45, 95% CI 1.15-1.83) and lower glutamine (OR = 0.81, 95% CI 0.66-1.00) levels were associated with a higher risk of developing NAFLD. Results from MR sensitivity analyses and conservative analysis supported the main findings. Interpretation Genetically predicted higher circulating levels of alanine was associated with an increased risk of NAFLD, whereas higher glutamine was associated with a decreased risk of NAFLD. Funding This work was supported by Xinhua Hospital, Shanghai Jiao Tong University School of Medicine (2021YJRC02). Research in context Evidence before this study Recent metabolomics studies revealed associations between circulating levels of several amino acids and non-alcoholic fatty liver disease (NAFLD) risk. Most of these studies were conducted with a focus on the profiling of amino acids between individuals with NAFLD and healthy subjects, which suggested the altered amino acid metabolism might be a consequence of NAFLD rather than a causal risk factor for NAFLD. We searched PubMed for studies in any language using the search terms “amino acids” AND “Non-alcoholic fatty liver disease OR NAFLD OR fatty liver” AND “Mendelian randomisation OR Mendelian randomization”, and found few studies on the causal effects of circulating amino acids on NAFLD risk. Thus, whether there is an aetiological role of amino acids in NAFLD development remains unknown. Added value of this study In the present study, we systematically investigated the causal effects of genetically predicted circulating levels of 20 amino acids on NAFLD risk using data from large-scale genome-wide association studies in up to 778,614 individuals of European ancestry. We utilised a state-of-art causal inference approach, that is Mendelian randomisation, to construct layers of evidence. Overall, we found that among 20 amino acids, genetically predicted higher circulating levels of alanine was associated with an increased risk of NAFLD, whereas higher glutamine was associated with a decreased risk of NAFLD. Implications of all the available evidence Our study is the first to systematically assess the causal relationships between levels of plasma amino acids and the development of NAFLD using multi-omics (i.e., genomic and metabolomic) data from large-scale human studies. Our results suggest the potential for the glutamine supplementation or alanine depletion for personalized nutrition in NAFLD prevention and treatment.
3,4,5-Trisubstituted piperidine-containing compounds displayed a range of biological activities, are potential drug candidates to treatment of Alzheimer’s disease, sexual dysfunctions or obesity, heart and kidney insufficiency. However, the inherent difficulty in obtaining a variety of 3,4,5-trisubstituted piperidines has greatly hindered their systematic medicinal chemistry studies for them. In this paper, we disclose an efficient synthesis of racemic and chiral 3,4,5-trisubstituted piperidines via SN2’ reaction.
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