No abstract

Traditional Chinese Medicine (TCM), with a history of thousands of years of clinical practice, is gaining more and more attention and application worldwide. And TCM-based new drug development, especially for the treatment of complex diseases is promising. However, owing to the TCM’s diverse ingredients and their complex interaction with human body, it is still quite difficult to uncover its molecular mechanism, which greatly hinders the TCM modernization and internationalization. Here we developed the first online Bioinformatics Analysis Tool for Molecular mechANism of TCM (BATMAN-TCM). Its main functions include 1) TCM ingredients’ target prediction; 2) functional analyses of targets including biological pathway, Gene Ontology functional term and disease enrichment analyses; 3) the visualization of ingredient-target-pathway/disease association network and KEGG biological pathway with highlighted targets; 4) comparison analysis of multiple TCMs. Finally, we applied BATMAN-TCM to Qishen Yiqi dripping Pill (QSYQ) and combined with subsequent experimental validation to reveal the functions of renin-angiotensin system responsible for QSYQ’s cardioprotective effects for the first time. BATMAN-TCM will contribute to the understanding of the “multi-component, multi-target and multi-pathway” combinational therapeutic mechanism of TCM, and provide valuable clues for subsequent experimental validation, accelerating the elucidation of TCM’s molecular mechanism. BATMAN-TCM is available at http://bionet.ncpsb.org/batman-tcm.

Emerging evidence indicates that microRNAs (miRNAs) have important roles in regulating osteogenic differentiation and bone formation. Thus far, no study has established the pathophysiological role for miRNAs identified in human osteoporotic bone specimens. Here we found that elevated miR-214 levels correlated with a lower degree of bone formation in bone specimens from aged patients with fractures. We also found that osteoblast-specific manipulation of miR-214 levels by miR-214 antagomir treatment in miR-214 transgenic, ovariectomized, or hindlimb-unloaded mice revealed an inhibitory role of miR-214 in regulating bone formation. Further, in vitro osteoblast activity and matrix mineralization were promoted by antagomir-214 and decreased by agomir-214, and miR-214 directly targeted ATF4 to inhibit osteoblast activity. These data suggest that miR-214 has a crucial role in suppressing bone formation and that miR-214 inhibition in osteoblasts may be a potential anabolic strategy for ameliorating osteoporosis.

To identify genetic susceptibility loci for nasopharyngeal carcinoma (NPC), a genome-wide association study was performed using 464,328 autosomal SNPs in 1,583 NPC affected individuals (cases) and 1,894 controls of southern Chinese descent. The top 49 SNPs from the genome-wide association study were genotyped in 3,507 cases and 3,063 controls of southern Chinese descent from Guangdong and Guangxi. The seven supportive SNPs were further confirmed by transmission disequilibrium test analysis in 279 trios from Guangdong. We identified three new susceptibility loci, TNFRSF19 on 13q12 (rs9510787, Pcombined=1.53x10(-9), odds ratio (OR)=1.20), MDS1-EVI1 on 3q26 (rs6774494, Pcombined=1.34x10(-8), OR=0.84) and the CDKN2A-CDKN2B gene cluster on 9p21 (rs1412829, Pcombined=4.84x10(-7), OR=0.78). Furthermore, we confirmed the role of HLA by revealing independent associations at rs2860580 (Pcombined=4.88x10(-67), OR=0.58), rs2894207 (Pcombined=3.42x10(-33), OR=0.61) and rs28421666 (Pcombined=2.49x10(-18), OR=0.67). Our findings provide new insights into the pathogenesis of NPC by highlighting the involvement of pathways related to TNFRSF19 and MDS1-EVI1 in addition to HLA molecules.

Metabolic skeletal disorders associated with impaired bone formation are a major clinical challenge. One approach to treat these defects is to silence bone-formation-inhibitory genes by small interference RNAs (siRNAs) in osteogenic-lineage cells that occupy the niche surrounding the bone-formation surfaces. We developed a targeting system involving dioleoyl trimethylammonium propane (DOTAP)-based cationic liposomes attached to six repetitive sequences of aspartate, serine, serine ((AspSerSer)(6)) for delivering siRNAs specifically to bone-formation surfaces. Using this system, we encapsulated an osteogenic siRNA that targets casein kinase-2 interacting protein-1 (encoded by Plekho1, also known as Plekho1). In vivo systemic delivery of Plekho1 siRNA in rats using our system resulted in the selective enrichment of the siRNAs in osteogenic cells and the subsequent depletion of Plekho1. A bioimaging analysis further showed that this approach markedly promoted bone formation, enhanced the bone micro-architecture and increased the bone mass in both healthy and osteoporotic rats. These results indicate (AspSerSer)(6)-liposome as a promising targeted delivery system for RNA interference-based bone anabolic therapy.