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Acta Pharmaceutica Sinica B ; (6): 52-58, 2017.
Article in English | WPRIM | ID: wpr-256780


Tubulin has been shown to be an effective target for the development of cytotoxic agents against prostate cancer. Previously, we reported that Lx2-32c is an anti-tubulin agent with high binding affinity to tubulin. In this study, we investigated the potential of Lx2-32c to act as an effective cytotoxic agent in the treatment of prostate cancer. MTT assays showed that Lx2-32c was cytotoxic to all tested prostate cancer cell lines. The Lx2-32c-treated cells typically exhibited a rounded morphology associated with the onset of apoptosis, as evidenced by immunocytochemical staining. Human prostate cancer cell lines treated with Lx2-32c arrest in the G2/M phase of the cell cycle and the treatment is associated with an increased ratio of cells in the sub-G0/G1 phase as determined by flow cytometry. Furthermore, expression of the cleaved form of poly (ADP-ribose) polymerase in prostate cancer cell lines treated with Lx2-32c was shown by Western blotting assay. Xenograft implants of LNCaP and PC3-derived tumors in nude mice showed that Lx2-32c treatment significant inhibited tumor growth with effects equivalent to those of docetaxel. These findings demonstrate the potential of Lx2-32c as a candidate antitumor agent for the treatment of prostate cancer.

Article in Chinese | WPRIM | ID: wpr-503687


OBJECTIVE To investigate the delayed cytotoxicity effect of chlorpyrifos (CPF) with?drawal on primary hippocampal neurons. METHODS Hippocampal neurons were prepared from SD rat fetuses on the 17th day of gestation. Seven days after culture,neurons were exposed to CPF 10 and 30 μmol · L-1,respectively,for 72 h or for 48 h followed by CPF withdrawal for 24 h. CCK-8 kit and neuronal nuclei(NeuN), 5-bromodeoxyuridine(BrdU) and β Ⅲ tubulin immunofluorescence expression methods were used to evaluate the cell viability. RESULTS Compared with normal control, no significant cytotoxicity was found after CPF 72 h continuous exposure. However,CPF 48 h expo?sure followed by CPF withdrawal for 24 h induced evident cytotoxicity. The amount of BrdU positive and β Ⅲ tubulin positive hippocampal neurons were both decreased significantly(P<0.05),and cell survival and viability reduced after CPF withdrawal. CONCLUSION CPF exposure withdrawal can induce more seriously delayed cytotoxicity than continuous exposure in rat primary hippocampal neurons.

Pakistan Journal of Pharmaceutical Sciences. 2013; 26 (2): 315-322
in English | IMEMR | ID: emr-193730


Acetylcholinesterase inhibitors [AChEIs], including Huperzine A [HupA], have been the mainstay of treatment for Alzheimer's disease [AD]. However, AChEIs can cause gastrointestinal side effects, which has been related to the high C[max] and short t[max] after oral administration. Clinical trials have verified that extended-release formulation with lower C[max] and prolonged t[max], such as rivastigmine patch, could perform a similar efficacy with significantly improved tolerability compared with the oral formulations. In this study, we developed an extended-release microspheres formulation of HupA [called as HAM] with poly[lactide-co-glycolide] [PLGA] as drug carrier. HAM has showed the loading rate as 1.35% [w/w] and yielded 42% with mean particle size at 72.6 micro m. In vitro and in vivo pharmacokinetics studies have showed that HAM produced a relatively smooth and continuous drug concentration in 14 days. Furthermore, in vivo pharmacokinetics data have demonstrated that the C[max] was lower and the t[max] was considerably later in single intramuscular administration of HAM [1,000 micro g/kg] than the counterparts in single intragastric administration of HAT [75 micro g/kg/d]. Meanwhile, HAM has performed a continuous inhibition to brain AChE activity in normal rats and improvement of memory deficit in A beta 1-40 i.c.v. infused AD rat model for 14 days. The results have suggested that HAM has performed good extended-release properties and good prolonged pharmacological efficacy in vivo in the 2-week period, and could exert a similar efficacy with significantly lowered gastrointestinal side effects as compared with oral formulation

Article in Chinese | WPRIM | ID: wpr-422186


Objective To study the distribution and significance of free organophosphorus poisons (FOP)with different degrees of hudrosolubility in the blood and adipose tissues of poisoned rabbits.Methods Seventy two male livid blue rabbits with 2-2.5 kg body weight were divided into 3 groups as per the rabbits intoxicated with different kinds of organophosphorous given subcutaneously,namely monocrotophos(11.12 mg/kg)group,trichloffon(556.0 mg/kg)group and methyl parathion(37.05 mg/kg)group(n =24 in each).Each group was further divided into 4 subgroups(n =6,in each).Blood samples and adipose tissues were collected 1 h,6 h,24 h and 96 h after administration of organophosphorous.Blood cells and plasma were separated.Well-formed adipose tissue homogenates were made.Acetylcholinesterase(AChE)activities were assayed with dithiobisnitrobenzoic acid(DTNB)enzyme kinetic method.The levels of FOPs in blood plasma,blood cells and adipose tissues were determined with enzyme inhibition method.Results There were signiflc.ant differences in FOP concentrations of plasma,blood cells and adipose tissues among moncrotophos group,trichlorfon group and methyl pararthion group at the intervals of 1,6 and 24 hours after organophosphorous administered(all P < 0.05).There were no significant differences in FOP concentrations of moncrotophos among blood plasma,blood cells and adipose tissues at intervals of 1,6,24 and 96 hours.FOP concentrations of trichlorfon in adipose tissues were significantly higher than those in blood cells and plasma at intervals of 1,6,24 hours after organophosphorous administered(P < 0.05).There were significant differences in FOP concentrations of pararthion in blood plasma compared with blood cells and adipose tissues at intervals of 1 and 6 hours after organophosphorous administered(P < 0.05)and no difference was found over 24 hours after administration of organophosphorous(P > 0.05).The significant differences in the rates of FOP clearance from blood and adipose tissues were also found between different organophosphates(P < 0.05,moncrotophos > trichlorfon >methyl pararthion).Conclusions With the decrease in hydrosolubility of organophosphates,the increase in adipose tissue-specific retention was found and the time required for clearance from blood and adipose tissue was prolonged.Adipose tissue was the major storage site for organophosphates with low hydrosolubility.

Article in Chinese | WPRIM | ID: wpr-554432


AIM To study the effects of polydatin on free radical induced rat cortex mitochondria injury. METHODS Fe 2++VitC system was used to produce ?OH. The mitochondria was isolated. Mitochondria membrane fluidity, swelling and contents of phospholipid were determined to measure the function of mitochondria membrane. The activities of ATPase and Cytochrome C oxidase were determined to measure the ability of mitochondria energy metabolism. The activity of superoxide dismutase (SOD) and content of malondial dehyde (MDA) were determined to measure the ability of anti oxygenation. RESULTS ?OH resulted in severe neuronal mitochondria injuries and the injuries and the injuries was alleviated by Polydatin (content of 100,200,400 mg?L -1). The swelling of mitochondria was ameliorated, the decomposability of mitochondrion membrane phospholipid was decreased, the membrane fluidity of mitochondria was increased. Polydatin also significantly inhibited the decrease in SOD, Cytochrome C oxidase and ATPase activity and the increase in MDA levels caused by free radical. CONCLUSION Polydatin has a protective action against the rat neuronal mitochondria injuries induced by oxygen free radical. The mechanisms may be derived from scavenging free radicals, reducing lipid peroxides, and improving the energy metabolism.

Article in Chinese | WPRIM | ID: wpr-539026


Objective: To evaluate the distribution and degradatio n of albumin microspheres (AMS) with average diameter of 56.3 ?m injected into jugular external artery.Methods: 125 I labeled AMS we re injected into rabbit's jugular external artery. The radioactive amount of loc al tissue and internal organs was measured. 760 ml/L urografin angiography was e mployed to observe the re opening of embolized vessels after AMS infusion of e xternal jugular artery in 5 dogs. Results: The AMS was mai nly concentrated in the target area (92.23%) after injection. The micro artery was obviously embolized by AMS and re opened in 7~9 days. Conclusio n : The AMS can be used as the drug bearer with delayed releasing eff ection.