Drug discovery of sclerostin inhibitors

Sclerostin, a protein secreted from osteocytes, negatively regulates the WNT signaling pathway by binding to the LRP5/6 co-receptors and further inhibits bone formation and promotes bone resorption. Sclerostin contributes to musculoskeletal system-related diseases, making it a promising therapeutic target for the treatment of WNT-related bone diseases. Additionally, emerging evidence indicates that sclerostin contributes to the development of cancers, obesity, and diabetes, suggesting that it may be a promising therapeutic target for these diseases. Notably, cardiovascular diseases are related to the protective role of sclerostin. In this review, we summarize three distinct types of inhibitors targeting sclerostin, monoclonal antibodies, aptamers, and small-molecule inhibitors, from which monoclonal antibodies have been developed. As the first-in-class sclerostin inhibitor approved by the U.S. FDA, the monoclonal antibody romosozumab has demonstrated excellent effectiveness in the treatment of postmenopausal osteoporosis; however, it conferred high cardiovascular risk in clinical trials. Furthermore, romosozumab could only be administered by injection, which may cause compliance issues for patients who prefer oral therapy. Considering these above safety and compliance concerns, we therefore present relevant discussion and offer perspectives on the development of next-generation sclerostin inhibitors by following several ways, such as concomitant medication, artificial intelligence-based strategy, druggable modification, and bispecific inhibitors strategy.

Study on Characteristics of Distribution of TCM Syndrome Types in 106 Cases of Acute Coronary Syndrome / 中医杂志

simple Qi-deficiency syndrome.The symptoms with incidence of over 50% in the Yang-deficiency and accompanied syndromes group were in the following order:precordial pain, oppressed feeling in chest,palpitation,short breath,aversion to cold,cold limbs,weakness,lassitude in loin and knee,polyuria at night.Conclusion:Acute coronary syndrome has complicated pathogenesis,deficiency with excess,and Yang-deficiency,cold accumulation and blood stasis are the main pathogenesis of the disease.

Different impact on echocardiography in assessment of cardiac function of mouse under anesthetic or unanesthetic condition / 中华超声影像学杂志

Objective To compare echocardiographic parameters of left ventricular function in mice under anaesthesia with those in conscious condition.Methods Forty mice were randomized to anesthetic group and nonanesthetic group,all mice were examined in conscious state at baseline,then anesthetic group had intraperitoneal injection of ketamine and xylazine,the non-anesthetic group received intraperitoneal injection of the same volume of saline.Echocardiography was performed every 10min and every 15min after 30min time point until 60min.ResultsAnesthetic agent strikingly brought down heart function of mice.The nadir of heart rate,fractional shortening(FS),cardiac output(CO) occurred during 10-20min period and could not be restored to normal value at baseline even after 60min.Left ventricular end-diastolic diameter(LVEDD) and left ventricular end-systolic diameter(LVESD) increased to maximum at 20min point,then decreased to value at baseline until 60min.LVEDD could be restored to baseline value while LVESD remained larger than baseline at 60min.Coefficient of variation of echocardiographic measurement in non-anesthetic group was smaller than those in anethetic group.FS and heart rate of all mice were highly corrrelated by regression analysis(r=(0.884),P

A novel cDNA clone related with rat liver regeneration / 中国病理生理杂志

AIM: To study a novel gene that probably related with liver regeneration, which was found by representational difference analysis(RDA). METHODS: cDNA sequence, tissue distribution and functions of the novel gene were studied by slot blot, Northern blot, RT-PCR, cDNA library screening and sequence analyzing. RESULTS: Two full-length clones were isolated from cDNA library of rat fetal livers and the sequence analysis identified that the positive cDNA encoded 76 amino acids only; Using the cDNA as a probe, the novel gene showed a specific liver distribution, a moment increasing expression in one hour after partial hepatectomy (PH) and high expression in fetal liver or liver tumor by Northern blot; EGF quickly induced its high expression in primary culture rat hepatocytes(FCS free).CONCLUSION: These results show that the novel gene is an early phase response gene that is closely related to a liver regeneration adjustment. It may encode peptide or has longer sequence at N tip.