ABSTRACT
Acute myeloid leukemia (AML) is a heterogeneous disease characterized by the accu-mulation of immature myeloid progenitor cells in the bone marrow,compromising of normal hematopoi-esis and ultimately resulting in bone marrow failure. Chemotherapy is the mainstay treatment for all AML patients,however,drug resistance and clinical relapse limits its efficacy.The 5-year survival rate of AML patients is only 26.6%.Survival rates are even lower among patients ages 65 to 74 years (5.3%)and 75 years or older(1.6%).Therefore,exploring novel therapeutic agents is urgent for improving the outcome of patients with AML. Saponins are amphipathic glycosides found in traditional Chinese medicines. In the present study, we isolated a panel of saponins from Paris forrestii (Takht.) H. Li, a unique plant found in Tibet and Yunnan provinces, China. By examining their activities in suppressing acute myeloid leukemia cell proliferation, total saponins from Paris forrestii (TSPf) displayed more potent activity than individual ones.TSPf induced more than 40% AML cell apoptosis within 24 h and decreased the viability of all leukemia cell lines. TSPf-induced apoptosis was confirmed by both Annexin V staining and caspase-3 activation.TSPf downregulated pro-survival proteins Mcl-1,Bcl-xL and Bcl-2,but upreg-ulated the expression of tumor suppressor proteins p53,p27,Bax and Beclin 1.The AKT/mTOR signaling pathway is frequently over activated in various AML cells,and TSPf was found to suppress the activa-tion of both AKT and mTOR,but had no effects on their total protein expression.This was further con-firmed by the inactivation of 4EBP-1 and p70S6K,two typical downstream signal molecules in the AKT/mTOR pathway. More specifically, TSPf-inactivated AKT/mTOR signaling was found to be associated with downregulated RNF6, a recently identified oncogene in AML. RNF6 activated AKT/mTOR, and consistently, knockdown of RNF6 led to inactivation of the AKT/mTOR pathway. Furthermore, TSPf suppressed the growth of AML xenografts in nude mice models. Oral administration of 100 mg·kg-1 body weight almost fully suppressed tumor growth within 14 d, without gross toxicity. This study thus demonstrated that TSPf displays potent anti-AML activity by suppressing the RNF6/AKT/mTOR pathway. Given its low toxicity,TSPf could be developed for the treatment of AML.
ABSTRACT
<p><b>OBJECTIVE</b>To study the effects of Erlong Zuoci Pill (, ELZCP) and its disassembled: prescriptions on gentamicin (GM)-induced ototoxicity model in vitro.</p><p><b>METHODS</b>After the spiral organ of cochleae: of newborn mice (postnatal days: 2-3) cultured for 24 h, GM alone or combined with water extracting-alcohol precipitating solution of ELZCP or with its disassembled prescriptions was added. Hair cells were observed under a fluorescence microscope after TRITC-phalloidin staining, and the cochlear hair cell loss rate was calculated by counting the whole cochlear hair cells and analyzed by whole cochlear hair cells analyzing software.</p><p><b>RESULTS</b>GM induced cochlear outer hair cells (OHCs) and inner hair cells (IHCs) injuries in a dose-dependent manner, and they were significantly different as compared with those in the normal control group (P<0.05, P<0.01). ELZCP at the concentration of 0.003-3 mg/mL could decrease the hair cells loss induced by the 0.3 mmol/L GM (P<0.05, P<0.01), the effects was in a dose-dependent manner, and the concentration of 0.3 mg/mL showed the optimal protective effect. For the ELZCP disassembled prescriptions, Liuwei-Dihuang could decrease OHC loss rate than that in the 0.3 mmol/L GM model group (P<0.05), but the OHC loss rate was still higher than that in the ELZCP group (P<0.01), which indicated that the protective effect of hair cells by Liuwei-Dihuang was not better than that of ELZCP. Poria decreased OHC loss rate from 72.1 % +/-3.7 % to 58.8 %+/- 8.2 % (P<0.05).</p><p><b>CONCLUSIONS</b>ELZCP could play a role in antagonizing the injury of cochlear hair cells induced by GM ototoxicity,: and its disassembled prescriptions, Liuwei-Dihuang was the main component to protect the cochlear hair cells from GM-induced ototoxicity, and Magnetitum combined with Radix Bupleurui could strengthen the action of the whole prescription; Poria could reduce GM-induced OHC loss.</p>
Subject(s)
Animals , Mice , Dose-Response Relationship, Drug , Drugs, Chinese Herbal , Pharmacology , Gentamicins , Toxicity , Hair Cells, Auditory, Inner , Pathology , Hair Cells, Auditory, Outer , Pathology , Organ of Corti , Pathology , Prescriptions , TabletsABSTRACT
<p><b>OBJECTIVE</b>To study the effects of four kinds of traditional Chinese herbal compound, Sini powder, Banxiahoupu soup, Ganmaidazao soup and Guizhigancaolonggumuli soup, on the experimental acute stress behaviors and the hypothalamus-pituitary-adrenal gland axis.</p><p><b>METHOD</b>Rats were divide into 7 groups: normal group, model 1 and 2 groups, Sini powder group, Banxiahoupu soup group, Ganmaidazao soup group, and Guizhigancaolonggumuli soup group. The behaviors of the rats and their CRH of the hypothalamus, ACTH of plasma and CORT of serum (by the means of radio-immunity) were detected.</p><p><b>RESULT</b>Sini powder could reduce the crossing times of open-field test( P < 0.01) and the contents of CRH and CORT (P < 0.01, P < 0.05); Banxiahoupu soup could extent the still time of tail-hanging test ( P < 0.05) and the content of CRH (P < 0.05); Ganmaidazao soup could prolong the still time (P < 0.05) and reduce the struggle times (P < 0.01) of tail-hanging test and reduce the contents of CRH, ACTH and CORT (P < 0.01, P < 0.05); Guizhigancaolonggumuli soup could reduce the crossing times of open-field test (P < 0.01) , extent the still time (P < 0.05) and reduce the struggle times ( P < 0.01) of tail-hanging test of tail-hanging test, also reduce the contents of CRH, ACTH and CORT (P < 0.01, P < 0.05).</p><p><b>CONCLUSION</b>The four kinds of traditional Chinese herbal compound can increase the ability of anti stress by affect the different taches of the hypothalamus-pituitary-adrenal gland axle and change the stress behaviors, which are based on their respective functions of regulating Qi, dispersing phlegm, tonifying Qi and warming Yang.</p>