PCC0208017, a novel small-molecule inhibitor of MARK3/MARK4, suppresses glioma progression and

Gliomas are the most common primary intracranial neoplasms among all brain malignancies, and the microtubule affinity regulating kinases (MARKs) have become potential drug targets for glioma. Here, we report a novel dual small-molecule inhibitor of MARK3 and MARK4, designated as PCC0208017. PCC0208017 strongly inhibited kinase activity against MARK3 and MARK4, and strongly reduced proliferation in three glioma cell lines. This compound attenuated glioma cell migration, glioma cell invasion, and angiogenesis. Molecular mechanism studies revealed that PCC0208017 decreased the phosphorylation of Tau, disrupted microtubule dynamics, and induced a G2/M phase cell cycle arrest. In an glioma model, PCC0208017 showed robust anti-tumor activity, blood-brain barrier permeability, and a good oral pharmacokinetic profile. Molecular docking studies showed that PCC0208017 exhibited high binding affinity to MARK3 and MARK4. Taken together, our study describes for the first time that PCC0208017, a novel MARK3/MARK4 inhibitor, might be a promising lead compound for treatment of glioma.

Lx2-32c, a novel semi-synthetic taxane, exerts antitumor activity against prostate cancer cellsand

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.

Preparation and in vitro and in vivo evaluation of HupA PLGA Microsphere

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

Changes of cortex mitochondrial function in chronic traumatic brain injury rats / 生物医学工程学杂志

This experimental study was aimed to evaluate the injurious effects of chronic traumatic brain injury on cortex mitochondrial function in rats. The head of rat was impacted by a metal sphere in a weight-drop device twice per day for 30 days, cortex mitochondria were isolated. Then the mitochondria membrane fluidity, swelling, respiratory function, the activities of mitochondria respiratory enzymes and superoxide dismutase (SOD), the levels of phospholipid, malondial dehyde (MDA) and Ca2+ were determined to analyze the function of mitochondria. The data indicated that chronic closed traumatic brain injury caused severe neuronal mitochondrial injuries. The swelling of mitochondria was aggravated, the decomposability of mitochondrial membrane phospholipid was increased, the membrane fluidity of mitochondria was decreased; the chronic closed traumatic brain injury also significantly depressed the activities of respiratory enzymes and SOD of mitochondria, increased the level of MDA and Ca2+. The chronic closed traumatic brain injury induced damage to rat cortex mitochondria. The mechanisms may be derived from the secondary increase of free radicals induced by mitochondrial membrane injury and the obstacle of rat brain energy metabolism.

Protective effect of Polydatin against rat cortex mitochondria injury induced by ?OH / 中国药理学通报

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.

Protective effect of 20(S)-ginsenoside Rg_3 against rat cortex mitochondrial injuries induced by cerebral ischemia / 中国药理学通报

Aim To study the mitochondria-protective effects of 20(S)-ginsenoside Rg_3 on focal cerebral ischemia injuries and its mechanism in rats.Methods Middle cerebral artery occlusion(MCAO) was used to induce focal cerebral ischemia model.After 24 h occlusion,cortex mitochondria was isolated and prepared for the measurement of membrane fluidity,swelling,phospholipid content,respiratory function,activities of mitochondrial respiratory enzymes and superoxide dismutase(SOD),contents of phospholipid,malondial dehyde(MDA) and Ca~(2+) to evaluate the function of mitochondrial.Results Focal cerebral ischemia resulted in severe neuronal mitochondrial injuries,which could be alleviated by iv 20(S)-ginsenoside Rg_3 5 mg?kg~(-1),10 mg?kg~(-1),and nimodipine 1.0 mg?kg~(-1).The swelling of mitochondria was ameliorated,the decomposability of membrane phospholipid was decreased,the membrane fluidity of mitochondria was increased.20(S)-ginsenoside Rg_3 also significantly inhibited the decrease in the activities of respiratory(enzymes) and SOD of mitochondrial,and the increase in MDA and Ca~(2+) levels caused by cerebral ischemia in rats.Conclusion 20(S)-ginsenoside Rg_3 showed a protective action against the cortex mitochondrial injuries in rats induced by cerebral ischemia.The mechanisms may be derived from reducing lipid peroxides,inhibiting Ca~(2+) overload,scavenging free radicals and improving the energy metabolism.