1.Effect of maternal subclinical hypothyroidism during pregnancy on brain development in rat offspring
Dijie LIU ; Zhongyan SHAN ; Weiping TENG ; Xiaohui YU ; Yun GAO ; Sen WANG ; Chenling FAN ; Hong WANG ; Hongmei ZHANG
Chinese Journal of Endocrinology and Metabolism 2010;26(11):936-941
Objective To explore whether maternal subclinical hypothyroidism gives rise to poor performance in the offspring and whether this is associated with the expression of several genes that are under the control of thyroid hormones. Methods Sixty female rats were divided into three groups ( each group n = 20): ( 1 )maternal subclinical hypothyroidism ( total thyroidectomy with T4 infusion), (2) maternal hypothyroidism ( total thyroidectomy without T4 infusion), and (3) control (sham operated). All rats were mated 10 days after the start of infusion. The infusion continued until 10 days postpartum. Pups were sacrificed at postnatal day 3, 7, and 21. The hippocampus was collected and tested for brain-derived neurotrophic factor (BDNF) and Rap1 protein expression by Western blotting and for BDNF and neural cell adhesion molecule ( NCAM ) mRNA expression by real-time polymerase chain reaction. On day 41-49, rat pups explored the Morris water maze. Time spent in the quadrant previously containing the plat form was recorded. Results The present study found decreases in BDNF mRNA (on day 3 ) and protein levels (on day 3 and 7 ) in hippocampi of pups from subclinical hypothyroidism dams (P<0.05). No change was observed in the levels of NCAM mRNA, whereas at day 21, expression of Rap1 protein was higher than that of control offspring. In addition, pups of subclinical hypothyroidism dams showed a trend toward depression in short-term memory (P>0.05), and long-term memory testing revealed a trend toward subclinical hypothyroidism group pups being less able to remember a fixed platform position than controls, spending less time in the proper quadrant ( P<0. 05 ). Conclusion The long-term memory deficits of pups born to maternal subclinical hypothyroidism dams are likely related with decrease in BDNF expression as well as increase in Rap1 expression in hippocampi.
2.Treatment with levothyroxine in early maternal subclinical hypothyroidism may improve the neural development of the progeny
Li LU ; Xiaohui YU ; Weiping TENG ; Zhongyan SHAN ; Dijie LIU ; Sen WANG ; Yun GAO ; Jinyuan MAO ; Chenling FAN ; Hong WANG ; Hongmei ZHANG
Chinese Journal of Endocrinology and Metabolism 2010;26(11):942-947
Objective To investigate the effect of treatment with levothyroxine in early maternal subclinical hypothyroidism (SCH) on the neural development of the progeny. Methods 75 thyroidectomized female Wistar rats were divided randomly into groups of hypothyroidism (CH), SCH, SCH treated with levothyroxine at embryonic day 10 (E10), E13, and E17. There were 15 sham operated controls. Body weight,thyroid function, and the development of progeny by morris water maze, immunohistochemistry, and Nissl's staining of progeny were made. Results Pups from SCH or CH group had significantly lower body weight than euthyroid group ( P<0. 05 ). Pups from E10, E13 or E17 groups had normal body weight compared to pups of control (P>0.05). The levels of TSH and total T4( TT4 ) of all pups were normal. The mean latencies were longer in pups from CH, SCH, and E17 group than the control (P<0.05). The mean escape latencies did not differ between the control and E10 group pups and between the control and E13 pups (P>0.05). There were changes in the cytoarchitecture of the barrel cortex and of the hippocampus ( toluidine blue-stained sections) in CH, SCH, and E17 pups. The barrel cortex of E10 or E13 pups was similar to that of control pups. The distribution of BrdUlabeled cells was more widespread in CH, SCH, and E17 pups than in control, E10, and E13 progeny.Conclusion Maternal SCH disturbs learning and memory performances, cytoarchitecture and cell migration of the pups. Treatment with levothyroxine in early maternal SCH before E13 improves the cell migration in the developing brain of the progeny.
3.Drug discovery of sclerostin inhibitors.
Sifan YU ; Dijie LI ; Ning ZHANG ; Shuaijian NI ; Meiheng SUN ; Luyao WANG ; Huan XIAO ; Dingdong LIU ; Jin LIU ; Yuanyuan YU ; Zongkang ZHANG ; Samuel Tin Yui YEUNG ; Shu ZHANG ; Aiping LU ; Zhenlin ZHANG ; Baoting ZHANG ; Ge ZHANG
Acta Pharmaceutica Sinica B 2022;12(5):2150-2170
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.