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Ye Zhao, 1, 2 Hui-Ling Wang, 1 Tong-Tong Li, 1 Fei Yang, 1 Chi-Meng Tzeng 1 1School of Pharmaceutical Sciences, Nanjing Tech University, Nanjing 211800, People’s Republic of China; 2Jiangsu Synergetic Innovation Center for Advanced Bio-Manufacture, Nanjing Tech University, Nanjing 211800, People’s Republic of ChinaCorrespondence: Ye Zhao; Chi-Meng Tzeng Email zhaoyev@163.com; tzengchimeng@njtech.edu.cnBackground: Osteoporosis is a chronic bone metabolism disorder affecting millions of the world population. The RANKL/RANK/OPG signaling pathway has been confirmed to be the main regulator of osteoporosis. It is of great interest to identify appropriate therapeutic agents that can regulate the RANKL/RANK/OPG pathway. Baicalin (BA) is a well-known traditional Chinese medicine formula against various inflammatory diseases with a proven role of the RANKL/RANK/OPG pathway regulation. However, the potential effect of BA on osteoporosis and the mechanisms underlying this remain unclear. In the present study, we aimed to evaluate the efficacy of BA in the prevention of dexamethasone (DEX)-induced osteoporosis in zebrafish.Methods: In this study, growth and development changes of zebrafish and calcein staining were assessed with a micrograph. The expression levels of RANKL and OPG and transcription factors in response to DEX induction and BA administration were evaluated by Western blotting and qRT-PCR. In addition, the intermolecular interactions of BA and RANKL were investigated by molecular docking.Results: Results show that BA enhances the growth and development of dexamethasone (DEX)-induced osteoporosis in zebrafish larvae. Calcein staining and calcium and phosphorus determination revealed that BA ameliorates mineralization of DEX-induced osteoporosis zebrafish larvae. BA also regulates the expression of RANKL and OPG and hampers the changes in gene expression related to bone formation and resorption under the induction of DEX in zebrafish. It can be inferred by molecular docking that BA may interact directly with the extracellular domain of RANKL.Conclusion: The findings, herein, reveal that BA ameliorates DEX-induced osteoporosis by regulation of the RANK/RANKL/OPG signaling pathway.Keywords: Baicalin, osteoporosis, RANKL, RANK, OPG

Supplemental Digital Content is available in the text, Leukoaraiosis (LA) is a frequent neuroimaging finding commonly observed on brain MRIs of elderly people with prevalence ranging from 50% to 100%. Multiple susceptibility genes or genetic risk factors for LA have been identified in subjects of European descent. Here, we report the first replication study on several common and novel genetic variations in the Chinese population. In this study, a total of 244 subjects (201 LA patients and 43 controls) were enrolled according to our new and strict definition for LA. Subsequently, 6 genetic variants at 5 genes, rs3744028 in TRIM65, rs1055129 in TRIM47, rs1135889 in FBF1, rs1052053 in PMF1, and rs1801133 (C677T) and rs1801131(A1298C) in MTHFR, were selected for genotyping using polymerase chain reaction (PCR)-based pyrosequencing and restriction fragment length polymorphism (RFLP) together with capillary electrophoresis (CE) and agarose gel electrophoresis. Finally, Pearson's χ2 and multivariate logistic regression tests were used to examine the associations between the genotypes and LA. Among these candidate polymorphisms, except for rs1052053 and rs1801131, rs1135889 (P = 0.012) showed significant associations with LA in the dominant model, and the other 3 SNPs, rs3744028 (P = 0.043), rs1055129 (P = 0.038), and rs1801133 (P = 0.027), showed significant associations with LA in the recessive model. However, these differences no longer remained significant after adjusting for age, gender, hypertension, and diabetes mellitus and applying Bonferroni correction or Sidak correction for multiple testing. These results suggest that the above-mentioned genetic variants are not associated with LA risk. In summary, the study did not replicate the susceptibility of rs3744028, rs1055129, and rs1135889 at the Chr17q25 locus for LA nor did it find any other significant results for rs1052053, rs1801133, and rs1801131 in the Chinese population. It strongly indicated the ethnic differences in the genetics of LA. However, the associations of rs3744028 (TRIM65), rs1055129 (TRIM47), rs1135889 (FBF1), and rs1801133 (MTHFR) with LA before Bonferroni correction and Sidak correction for multiple testing are worth highlighting. Thus, we believe that a genome-wide association study and candidate gene association studies are needed to reassess the previous findings and screen novel risk genes for LA in China.

ATP Binding Cassette Transporter A4 (ABCB4) is a sterol export pump that regulates excretion of biliary cholesterol. We tested association between ABCB4 polymorphisms and gallstone disease using meta-analysis. In a cross-sectional study, 296 subjects were recruited from a hospital-based population. Total of 171 subjects were diagnosed as gallstone disease by abdominal ultrasonography from three cohort studies. We evaluated prevalence of ABCG8 rs11887534 (D19H) as a positive control, and the ABCB4 rs1202283 and rs2230028 polymorphisms on Chinese population were screened by meta-analysis and genotyped using TaqMan® SNP assay. Stata/SE 11.0 software and random-effects model were used in meta-analyzing 3 cohort between study heterogeneity. Four studies including three cohorts were used for final meta-analysis. In allelic model, minor alleles of ABCB4 rs1202283 (OR = 0.41, 95% CI: 0.25-0.67, P