VPA/PLGA microfibers produced by coaxial electrospinning for the treatment of central nervous system injury

The central nervous system shows limited regenerative capacity after injury. Spinal cord injury (SCI) is a devastating traumatic injury resulting in loss of sensory, motor, and autonomic function distal from the level of injury. An appropriate combination of biomaterials and bioactive substances is currently thought to be a promising approach to treat this condition. Systemic administration of valproic acid (VPA) has been previously shown to promote functional recovery in animal models of SCI. In this study, VPA was encapsulated in poly(lactic-co-glycolic acid) (PLGA) microfibers by the coaxial electrospinning technique. Fibers showed continuous and cylindrical morphology, randomly oriented fibers, and compatible morphological and mechanical characteristics for application in SCI. Drug-release analysis indicated a rapid release of VPA during the first day of the in vitro test. The coaxial fibers containing VPA supported adhesion, viability, and proliferation of PC12 cells. In addition, the VPA/PLGA microfibers induced the reduction of PC12 cell viability, as has already been described in the literature. The biomaterials were implanted in rats after SCI. The groups that received the implants did not show increased functional recovery or tissue regeneration compared to the control. These results indicated the cytocompatibility of the VPA/PLGA core-shell microfibers and that it may be a promising approach to treat SCI when combined with other strategies.

HDAC Inhibition by Valproic Acid Induces Neuroprotection and Improvement of PD-like Behaviors in LRRK2 R1441G Transgenic Mice

Parkinson’s disease (PD) is one of the late-onset neurodegenerative movement disorder. Major pathological markers of PD include progressive loss of dopaminergic neurons, Lewy body formation, genetic mutations, and environmental factors. Epigenetic regulation of specific gene expression via impaired histone acetylation is associated with neuronal dysfunction in various neurodegenerative diseases. In this study, we hypothesized that histone deacetylase (HDAC) inhibitor, valproic acid (VPA), can improve motor function by enhancing cell survival in PD genetic model mice with LRRK2 R1441G mutation. To address this question, we administered VPA in LRRK2 R1441G transgenic mice to determine whether VPA affects 1) histone acetylation and HDAC expression, 2) dopaminergic neuron survival, 3) inflammatory responses, 4) motor or non-motor symptoms. As results, VPA administration increased histone acetylation level and the number of tyrosine hydroxylase (TH) positive neurons in substantia nigra of LRRK2 R1441G mice. VPA reduced iba-1 positive activated microglia and the mRNA levels of pro-inflammatory marker genes in LRRK2 R1441G mice. In addition, VPA induced the improvement of PD-like motor and non-motor behavior in LRRK2 R1441G mice. These data suggest that the inhibition of HDAC can be further studied as potential future therapeutics for PD.

VPApromotesEMTincoloncarcinomacellsvianucleartranslocationofE-cadherin / 中国肿瘤生物治疗杂志

@# Objective: To explore the effect of histone deacetylase (HDAC) inhibitor valproic acid (VPA) on the epithelial-mesenchymal transition (EMT) of colon cancer. Methods: With four colon carcinoma cell lines (DLD-1, HCT116, SW480 and HT29) as study subjects, the effect of different concentrations of VPA(0.5，5 mmol/L) on cell proliferation was detected by MTT assay. The expression level of EMT-related proteins (E-cadherin and vimentin) was detected by Western blotting; Phenotypic changes of E-cadherin and vimentin were detected by immunofluorescence staining; Cell migration and invasion ability was detected by wound healing and Transwell invasion assay, respectively. Results:After treated with different concentrations of VPAfor 48 h, low concentration of VPAmerely exerted any effect on the cell proliferation rate of four colon cancer cell lines, and thus was chosen as the experiment concentration; The results of Western blotting showed that the expression of E-cadherin was reduced (P<0.05) and vimentin was increased (P<0.05) in colon carcinoma cells by VPAtreatment (0.5 mmol/L); Immunofluorescence staining revealed membranous attenuation or nuclear translocation of E-cadherin and enhanced expression of vimentin after VPA treatment (0.5 mmol/L), and these responses occurred after 6 h and sustained until 24 h; Wound healing and Transwell invasion assay showed increased migration and invasion ability following VPA treatment (0.5 mmol/L). Conclusion: Low concentration VPA could induce the development of EMT in colon cancer cells by nuclear translocation of E-cadherin, and obviously enhance the migration and invasion ability of colon cancer cells; Thus, HDAC inhibitors, as a new type anti-cancer option, shall be carefully considered before their application in colon cancer.

POLG gene related diseases / 国际儿科学杂志

DNA polymerase γis the only known DNA polymerase in human mitochondria,and is essential for mitochondrial DNA replication and repair.DNA polymerase γ is encoded by POLG gene.POLG-related disorders resulted from mutations of POLG gene comprise a continuum of overlapping phenotypes including Alpers Huttenlocher syndrome and other five subtypes, with high prevalence rate at patients with intractable seizure.Genetic testing for POLG mutations in patients with intractable epilepsies is very important for clinical diagnostics, genetic counseling, and treatment decisions because of the increased risk for VPA-induced liver failure in patients with POLG mutations.

Experimental study on susceptibility of high risk factors related with hepatotoxicity of valproic acid / 中国药理学通报

Aim To explore the differences of pathogenesis for the hepatotoxicity induced by chronic treatment of valproic acid(VPA) in different ages,and in combination administration with inducers of liver enzyme.Methods Animal models were established by oral administration chronically with VPA at doses of 200 or 500 mg?kg~(-1) per day in 30 days for 50 Wistar rats(infant and adult rats) with inducers of liver enzyme Phenobarbital(PB) or not.Mitochondria were obtained by differential centrifugation.Levels of liver enzymes,coagulation factors,plasma ammonia,VPA and PB serum levels,and L-carnitine in sera,as well as the changes of respiratory enzymes and lipid peroxidation in hepatic mitochondria were measured.Mitochondrial membrane potential(MMP) and mRNA expression of CYP450 reductase in liver were determined by flow cytometer and in situ hybridization,and morphological changes of hepatocytes were observed under microscope with Oil-Red-O staining.Results ① In all rats treated with higher dose of VPA added with PB or not,there were no significant elevations of liver enzymes(ALT and AST).However significant abnormalities of function of blood coagulation and serum fibrinogen were shown, and the levels of plasma ammonia and L-carnitine were also changed significantly,and the changes were notable in infant rats or in those rats added with PB. ② Average contents of cytochrome aa3 in liver mitochondria of infant rats were reduced by 58.80% and 61.80% because of administration of high dose VPA and high dose VPA added with PB,but were reduced by 37.55% and 46.53% in adults.As for activities of SDH,which affected by high dose VPA in infants,were significant decreased by 44.8% and 57.9%,respectively,but still in normal range in adult groups.Activities of CCO in liver mitochondria were significantly lowered by high dose VPA or added with PB compared with controls(P

Protective function of L-carnitine against valproate-associated hepatotoxicity in infant rats and its mechanism / 重庆医科大学学报

Objective:To explore the protective function of L-carnitine against valproate-associated hepatotoxicity in infant rats and its mechanism.Methods:Rat models with VPA liver lesion were established by oral administration of VPA and PB.L-carnitine was adopted as intervention measure:to observe its protection of experiment rat livers,especially the function of liver mitochondrion.Levels of plasma ammonia,L-carnitine and coagulation factors in sera as well as the changes of respiratory enzymes in hepatic mitochondria were measured by chemical colorimetry. Mitochondrial membrane potential(MMP),and VPA and PB blood drug levels in liver were determined by flow cytometer and HPLC,respectively.and morphological changes of hepatocytes were observed under microscope with Oil-Red-O staining.Results(1)In the groups affected by VPA or VPA added with PB,the activities of SDH and CCO significantly decreased compared with control group(P

Modulation of Caspase expression by up-regulating histone acetylizad level with VPA / 中国免疫学杂志

Objective:To investigate modulation of a specific HDAC inhibitor,Valproate acid sodium(VPA),on expression of Caspase3,Caspase8,Caspase9 by inhiting HDAC,as well as apoptosis rate of cancer cells treated with VPA and the specific inhibitors of Caspase3,Caspase8,Caspase9.Methods:Heptocellular carcinoma cells-HepG2,gastric carcinoma cells-BGC-823 and breast cancer cells-MCF-7 were cultured with 0.75-4.0 mmol/L of VPA for 48 hrs in vivo,apoptosis was analyzed by flow cytometry with Annexin V/PI assay.The activities and protein expressions of Caspase3,Caspase8,Caspase9 were detected by spectrophotometry and indirect immunofluorescence technique.Results:Contrary to control groups,VPA at concentrations between 0.75 and 4.0 mmol/L induced a significant apoptosis in HepG2,BGC-823,MCF-7 cells(P0.05).The apoptosis rates of cancer cells treated with VPA and specific inhibitors of Caspase3,Caspase9 together was lower than in the groups with VPA treatment singlely(P