The present study aimed at investigating the effects of Puerarin(PR), a major isoflavonoid isolated from the Chinese medicinal herb Puerariae radix, on bone metabolism and the underlying mechanism of action. The in vi...The present study aimed at investigating the effects of Puerarin(PR), a major isoflavonoid isolated from the Chinese medicinal herb Puerariae radix, on bone metabolism and the underlying mechanism of action. The in vivo assay, female mice were ovariectomized(OVX), and the OVX mice were fed with a diet containing low, middle, and high doses of PR(2, 4, and 8 mg·d^(-1), respectively) or 17β-estradiol(E_2, 0.03 μg·d^(-1)) for 4 weeks. In OVX mice, the uterine weight declined, and intake of PR at any dose did not affect uterine weight, compared with the control. The total femoral bone mineral density(BMD) was significantly reduced by OVX, which was reversed by intake of the diet with PR at any dose, especially at the low dose. In the in vitro assay, RAW264.7 cells were used for studying the direct effect of PR on the formation of osteoclasts. PR reduced the formation of tartrate resistant acid phosphatase(TRAP)-positive multi-nucleated cells in the RAW 264.7 cells induced by receptor activator for nuclear factor-κB Ligand(RANKL). MC3T3-E1 cells were used for studying the effects of PR on the expression of osteoprotegerin(OPG) and RANKL m RNA expression in osteoblasts. The expression of OPG m RNA and RANKL m RNA was detected by RT-PCR on Days of 5, 7, 10, and 12 after PR exposure. PR time-dependently enhanced the expression of OPG m RNA and reduced the expression of RANKL m RNA in MC3T3-E1 cells. In conclusion, our results suggest that PR can effectively prevent bone loss in OVX mice without any hyperplastic effect on the uterus, and the antiosteoporosis activity of PR may be related to its effects on the formation of osteoclasts and the expression of RANKL OPG in osteoblasts.展开更多
急性髓性白血病(acute myeloid leukemia,AML)是一种当下常见且难治的血液系统恶性肿瘤,由于其高度异质性和易产生耐药,所以需要不断开发新结构、新机制的治疗药物。核输出蛋白1(exportin 1,XPO1)是核质转运的重要转运受体,其在肿瘤细...急性髓性白血病(acute myeloid leukemia,AML)是一种当下常见且难治的血液系统恶性肿瘤,由于其高度异质性和易产生耐药,所以需要不断开发新结构、新机制的治疗药物。核输出蛋白1(exportin 1,XPO1)是核质转运的重要转运受体,其在肿瘤细胞中高度表达,现已成为抗肿瘤药研发的全新靶标。第一代XPO1抑制剂selinexor近日获美国食品药品管理局(Food and Drug Administration,FDA)批准上市,但存在毒性较大等问题,而由Karyopharm制药公司研发的第二代口服XPO1抑制剂eltanexor,在临床及临床前研究中表现出不易穿透血脑屏障,毒性低和耐受性强等优势,本文就其靶标特点、作用机制、基本信息和临床前试验情况作一概述。展开更多
胃肠道间质瘤(gastrointestinal stromal tumor,GIST)是一类位于消化道的间叶细胞肿瘤。对于不可切除、转移或复发的GIST患者,伊马替尼、舒尼替尼和瑞戈非尼分别是其标准的一、二和三线治疗药物。由于GIST患者在治疗过程中易出现耐药现...胃肠道间质瘤(gastrointestinal stromal tumor,GIST)是一类位于消化道的间叶细胞肿瘤。对于不可切除、转移或复发的GIST患者,伊马替尼、舒尼替尼和瑞戈非尼分别是其标准的一、二和三线治疗药物。由于GIST患者在治疗过程中易出现耐药现象,尤其是对于三线治疗失败后的患者,目前尚无有效的治疗药物。Ripretinib是由Deciphera制药公司研发的一种KIT/PDGFRα激酶开关调控抑制剂,其在一项Ⅲ期临床研究(注册号:NCT03353753;代号:INVICTUS)中无进展生存期(progression-free survival,PFS)为6.3个月,总生存期(overall survival,OS)为15.1个月。该公司已向美国食品药品监督管理局(Food and Drug Administration,FDA)提交该药的新药上市申请(new drug application,NDA),其有望成为晚期GIST患者多线治疗后新的治疗选择。本文就ripretinib的基本信息、作用机制、临床前研究和临床试验情况作一概述。展开更多
基金supported by a grant from the National Natural Science Foundation of China(No.30873290)
文摘The present study aimed at investigating the effects of Puerarin(PR), a major isoflavonoid isolated from the Chinese medicinal herb Puerariae radix, on bone metabolism and the underlying mechanism of action. The in vivo assay, female mice were ovariectomized(OVX), and the OVX mice were fed with a diet containing low, middle, and high doses of PR(2, 4, and 8 mg·d^(-1), respectively) or 17β-estradiol(E_2, 0.03 μg·d^(-1)) for 4 weeks. In OVX mice, the uterine weight declined, and intake of PR at any dose did not affect uterine weight, compared with the control. The total femoral bone mineral density(BMD) was significantly reduced by OVX, which was reversed by intake of the diet with PR at any dose, especially at the low dose. In the in vitro assay, RAW264.7 cells were used for studying the direct effect of PR on the formation of osteoclasts. PR reduced the formation of tartrate resistant acid phosphatase(TRAP)-positive multi-nucleated cells in the RAW 264.7 cells induced by receptor activator for nuclear factor-κB Ligand(RANKL). MC3T3-E1 cells were used for studying the effects of PR on the expression of osteoprotegerin(OPG) and RANKL m RNA expression in osteoblasts. The expression of OPG m RNA and RANKL m RNA was detected by RT-PCR on Days of 5, 7, 10, and 12 after PR exposure. PR time-dependently enhanced the expression of OPG m RNA and reduced the expression of RANKL m RNA in MC3T3-E1 cells. In conclusion, our results suggest that PR can effectively prevent bone loss in OVX mice without any hyperplastic effect on the uterus, and the antiosteoporosis activity of PR may be related to its effects on the formation of osteoclasts and the expression of RANKL OPG in osteoblasts.
文摘急性髓性白血病(acute myeloid leukemia,AML)是一种当下常见且难治的血液系统恶性肿瘤,由于其高度异质性和易产生耐药,所以需要不断开发新结构、新机制的治疗药物。核输出蛋白1(exportin 1,XPO1)是核质转运的重要转运受体,其在肿瘤细胞中高度表达,现已成为抗肿瘤药研发的全新靶标。第一代XPO1抑制剂selinexor近日获美国食品药品管理局(Food and Drug Administration,FDA)批准上市,但存在毒性较大等问题,而由Karyopharm制药公司研发的第二代口服XPO1抑制剂eltanexor,在临床及临床前研究中表现出不易穿透血脑屏障,毒性低和耐受性强等优势,本文就其靶标特点、作用机制、基本信息和临床前试验情况作一概述。
文摘胃肠道间质瘤(gastrointestinal stromal tumor,GIST)是一类位于消化道的间叶细胞肿瘤。对于不可切除、转移或复发的GIST患者,伊马替尼、舒尼替尼和瑞戈非尼分别是其标准的一、二和三线治疗药物。由于GIST患者在治疗过程中易出现耐药现象,尤其是对于三线治疗失败后的患者,目前尚无有效的治疗药物。Ripretinib是由Deciphera制药公司研发的一种KIT/PDGFRα激酶开关调控抑制剂,其在一项Ⅲ期临床研究(注册号:NCT03353753;代号:INVICTUS)中无进展生存期(progression-free survival,PFS)为6.3个月,总生存期(overall survival,OS)为15.1个月。该公司已向美国食品药品监督管理局(Food and Drug Administration,FDA)提交该药的新药上市申请(new drug application,NDA),其有望成为晚期GIST患者多线治疗后新的治疗选择。本文就ripretinib的基本信息、作用机制、临床前研究和临床试验情况作一概述。
