Coenzyme Q10 Supplementation Increases Removal of the ATXN3 Polyglutamine Repeat, Reducing Cerebellar Degeneration and Improving Motor Dysfunction in Murine Spinocerebellar Ataxia Type 3.

Coenzyme Q10 (CoQ10), a well-known antioxidant, has been explored as a treatment in several neurodegenerative diseases, but its utility in spinocerebellar ataxia type 3 (SCA3) has not been explored. Herein, the protective effect of CoQ10 was examined using a transgenic mouse model of SCA3 onset. These results demonstrated that a diet supplemented with CoQ10 significantly improved murine locomotion, revealed by rotarod and open-field tests, compared with untreated controls. Additionally, a histological analysis showed the stratification of cerebellar layers indistinguishable from that of wild-type littermates. The increased survival of Purkinje cells was reflected by the reduced abundance of TUNEL-positive nuclei and apoptosis markers of activated p53, as well as lower levels of cleaved caspase 3 and cleaved poly-ADP-ribose polymerase. CoQ10 effects were related to the facilitation of the autophagy-mediated clearance of mutant ataxin-3 protein, as evidenced by the increased expression of heat shock protein 27 and autophagic markers p62, Beclin-1 and LC3II. The expression of antioxidant enzymes heme oxygenase 1 (HO-1), glutathione peroxidase 1 (GPx1) and superoxide dismutase 1 (SOD1) and 2 (SOD2), but not of glutathione peroxidase 2 (GPx2), were restored in 84Q SCA3 mice treated with CoQ10 to levels even higher than those measured in wild-type control mice. Furthermore, CoQ10 treatment also prevented skeletal muscle weight loss and muscle atrophy in diseased mice, revealed by significantly increased muscle fiber area and upregulated muscle protein synthesis pathways. In summary, our results demonstrated biochemical and pharmacological bases for the possible use of CoQ10 in SCA3 therapy.

Radical Scavenging and Antiproliferative Effects of Cordycepin-Rich Ethanol Extract from Brown Rice-Cultivated Cordyceps militaris (Ascomycetes) Mycelium on Breast Cancer Cell Lines.

The yield and efficacy of bioactive compounds from Cordyceps militaris fruiting bodies and its fermented grains usually vary with the strain used. In this study, we compared the antiproliferative, apoptotic, and antioxidative properties of ethanolic extracts of fruiting bodies and solid-stated fermented rice (FRE) from two wild-type strains of C. militaris applied to human breast cancer cell lines. We observed that FRE of the Zhangzhou strain (FRE-Z) produced a high level of cordycepin and exhibited comprehensive in vitro antioxidant activity against the oxidation of 2,2-diphenyl-1-picrylhydrazyl, superoxide, and hydroxyl radicals and low-density lipoprotein. Only FRE-Z exhibited dose-dependent inhibition of cell proliferation in MCF-7 (0.7 mg/mL) and MDA-MB-231 cells (1 mg/mL) after culturing for 24 h. The antiproliferative effects of FRE-Z were associated with an early stage of apoptosis induction at 4 h of treatment with 0.5 mg/mL FRE-Z in MCF-7 cells. The antiproliferative effect was determined to occur through p53 activation but not through the release of mitochondrial apoptosis-inducing factor or caspase-9 activation for an initial culture period of 16 h. In addition to a transient increase in cellular antioxidant enzyme, Cu/Zn superoxide dismutase was identified in MCF-7 cells after 2 h of treatment with FRE-Z. Therefore, FRE-Z, which exhibits various dose- and exposure time-dependent activities, has potential application in breast cancer chemoprevention.

Andrographolide inhibits hypoxia-induced HIF-1α-driven endothelin 1 secretion by activating Nrf2/HO-1 and promoting the expression of prolyl hydroxylases 2/3 in human endothelial cells.

Andrographolide, the main bioactive component of the medicinal plant Andrographis paniculata, has been shown to possess potent anti-inflammatory activity. Endothelin 1 (ET-1), a potent vasoconstrictor peptide produced by vascular endothelial cells, displays proinflammatory property. Hypoxia-inducible factor 1α (HIF-1α), the regulatory member of the transcription factor heterodimer HIF-1α/ß, is one of the most important molecules that responds to hypoxia. Changes in cellular HIF-1α protein level are the result of altered gene transcription and protein stability, with the latter being dependent on prolyl hydroxylases (PHDs). In this study, inhibition of pro-inflammatory ET-1 expression and changes of HIF-1α gene transcription and protein stability under hypoxia by andrographolide in EA.hy926 endothelial-like cells were investigated. Hypoxic conditions were created using the hypoxia-mimetic agent CoCl2. We found that hypoxia stimulated the production of reactive oxygen species (ROS), the expression of HIF-1α mRNA and protein, and the expression and secretion of ET-1. These effects, however, were attenuated by co-exposure to andrographolide, bilirubin, and RuCO. Silencing Nrf2 and heme oxygenase 1 (HO-1) reversed the inhibitory effects of andrographolide on hypxoia-induced HIF-1α mRNA and protein expression. Moreover, andrographolide increased the expression of prolyl hydroxylases (PHD) 2/3, which hydroxylate HIF-1α and promotes HIF-1α proteasome degradation, with an increase in HIF-1α hydroxylation was noted under hypoxia. Inhibition of p38 MAPK abrogated the hypoxia-induced increases in HIF-1α mRNA and protein expression as well as ET-1 mRNA expression and secretion. Taken together, these results suggest that andrographolide suppresses hypoxia-induced pro-inflammatory ET-1 expression by activating Nrf2/HO-1, inhibiting p38 MAPK signaling, and promoting PHD2/3 expression. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 918-930, 2017.

Polygonum cuspidatum and its active components inhibit replication of the influenza virus through toll-like receptor 9-induced interferon beta expression.

Influenza virus infection is a global public health issue. The effectiveness of antiviral therapies for influenza has been limited by the emergence of drug-resistant viral strains. Therefore, there is an urgent need to identify novel antiviral therapies. Here we tested the effects of 300 traditional Chinese medicines on the replication of various influenza virus strains in a lung cell line, A549, using an influenza-specific luciferase reporter assay. Of the traditional medicines tested, Polygonum cuspidatum (PC) and its active components, resveratrol and emodin, were found to attenuate influenza viral replication in A549 cells. Furthermore, they preferentially inhibited the replication of influenza A virus, including clinical strains isolated in 2009 and 2011 in Taiwan and the laboratory strain A/WSN/33 (H1N1). In addition to inhibiting the expression of hemagglutinin and neuraminidase, PC, emodin, and resveratrol also increased the expression of interferon beta (IFN-ß) through Toll-like receptor 9 (TLR9). Moreover, the anti-viral activity of IFN-ß or resveratrol was reduced when the A549 cells were treated with neutralizing anti-IFN-ß antibodies or a TLR9 inhibitor, suggesting that IFN-ß likely acts synergistically with resveratrol to inhibit H1N1 replication. This potential antiviral mechanism, involving direct inhibition of virus replication and simultaneous activation of the host immune response, has not been previously described for a single antiviral molecule. In conclusion, our data support the use of PC, resveratrol or emodin for inhibiting influenza virus replication directly and via TLR-9-induced IFN-ß production.

Indigofera suffruticosa Mill extracts up-regulate the expression of the π class of glutathione S-transferase and NAD(P)H: quinone oxidoreductase 1 in rat Clone 9 liver cells.

Because induction of phase II detoxification enzyme is important for chemoprevention, we study the effects of Indigofera suffruticosa Mill, a medicinal herb, on the expression of π class of glutathione S-transferase (GSTP) and NAD(P)H: quinone oxidoreductase 1 (NQO1) in rat Clone 9 liver cells. Both water and ethanolic extracts of I. suffruticosa significantly increased the expression and enzyme activities of GSTP and NQO1. I. suffruticosa extracts up-regulated GSTP promoter activity and the binding affinity of nuclear factor erythroid 2-related factor 2 (Nrf2) with the GSTP enhancer I oligonucleotide. Moreover, I. suffruticosa extracts increased nuclear Nrf2 accumulation as well as ARE transcriptional activity. The level of phospho-ERK was augmented by I. suffruticosa extracts, and the ERK inhibitor PD98059 abolished the I. suffruticosa extract-induced ERK activation and GSTP and NQO-1 expression. Moreover, I. suffruticosa extracts, especially the ethanolic extract increased the glutathione level in mouse liver and red blood cells as well as Clone 9 liver cells. The efficacy of I. suffruticosa extracts in induction of phase II detoxification enzymes and glutathione content implies that I. suffruticosa could be considered as a potential chemopreventive agent.

Nationwide population-based epidemiologic study on cerebellar ataxia in Taiwan.

AIMS: To conduct the first nationwide population-based epidemiologic study on cerebellar ataxia in Taiwan. METHODS: Cerebellar ataxia cases were identified from the National Health Insurance Research Database by using the corresponding International Classification of Diseases, Ninth Revision (ICD-9) codes, from January 2005 to December 2007. Age- and sex-specific incidences were estimated by dividing the number of new cases by the population data. RESULTS: During the study, 934 cases were identified (average annual incidence: 0.91/100,000). No significant difference was noted in the incidence in men and women. The majority of the patients were middle-aged or elderly. CONCLUSION: The average annual incidence rate of cerebellar ataxia in Taiwan was 0.91/100,000, without a significant difference between the genders.

Proton magnetic resonance spectroscopy in Kennedy disease.

The purpose of this study was to investigate the metabolic abnormalities in Kennedy disease (KD) patients using proton magnetic resonance spectroscopy. Five patients with KD showing typical phenotype were compared with eight age-matched, healthy control subjects. Relative metabolite concentrations for N-acetyl-aspartate (NAA), choline (Cho) and phosphocreatine (Cr) and lactate (Lac) were measured in the motor cortex and the brainstem area. In the motor cortex, NAA/Cr ratio was significantly reduced in KD patients (P=0.04). In the brainstem area, metabolic ratios including NAA/Cho, NAA/Cr and Cho/Cr failed to show significant difference between KD patients and normal controls. No pathologic Lac signal was noted in patients and controls. These findings corroborate a previous study indicating an involvement of the motor cortices in patients with KD.

Methylenetetrahydrofolate reductase polymorphism determines the plasma homocysteine-lowering effect of large-dose folic acid supplementation in patients with cardiovascular disease.

OBJECTIVE: The polymorphism of the gene encoding methylenetetrahydrofolate reductase (MTHFR) and folic acid nutritional status play important roles in atherosclerosis. The present study investigated the total homocysteine-lowering effect of folic acid in response to the MTHFR genotype in patients who have cardiovascular disease. METHODS: Twenty-three patients who had cardiovascular disease (ages 44 to 88 y) were supplemented with 5 mg of folic acid/d for 8 wk. Blood samples were collected before and after supplementation for the measurement of folic acid. The presence of the 677C-->T mutation was assessed by polymerase chain reaction followed by restriction enzyme analysis. RESULTS: After the 8 wk of folic acid supplementation, plasma total homocysteine decreased 40% in patients who had the TT genotype, 23% in those who had the CT genotype, 10% in those who had the CC genotype, and 27% in carriers of the T allele. The plasma total homocysteine-lowering effect of folic acid was significant only in patients who had the CT genotype and in carriers of the T allele. CONCLUSIONS: The MTHFR polymorphism may be involved in the total homocysteine-lowering effect of folic acid in patients who have cardiovascular disease.

Antioxidant and anticonvulsant effect of a modified formula of chaihu-longu-muli-tang.

Antiepileptic drug therapy in individuals with epilepsy can induce free radical generation and profound lipid peroxidation. Some Chinese herbs with antiepileptic potential show antioxidant effects. We performed an open add-on study of TW970, a modified formula of the Chinese medicine "chaihu-longu-muli-tang", on 20 patients with refractory epilepsy and a seizure frequency of at least four fits per month, and another 20 patients with benign epilepsy and a seizure frequency of less than four fits per month. The control group consisted of 20 age-matched healthy adults. Seizure frequency, serum malondialdehyde (MDA), glutathione (GSH) and copper-zinc superoxide dismutase (Cu,Zn-SOD) were investigated in patients with refractory and benign epilepsy before and after four months add-on treatment of TW970. There was a decrease in seizure frequency in refractory epileptics from 13.4 +/- 3.4 to 10.7 +/- 2.5/per month, although the p value was 0.084. Before TW970 add-on treatment, a significant enhancement of lipid peroxidation with increased MDA and Cu,Zn-SOD activities together with decreased GSH were seen in refractory epileptics compared with normal controls. After TW970 add-on treatment of refractory epileptics for four months, normalization of MDA and Cu,Zn-SOD levels was achieved. Before and after TW970 add-on treatment, there were no statistically significant changes of the above-mentioned parameters in the patients with benign epilepsy. These results suggest that TW970 can reduce the seizure frequency in patients with refractory epilepsy and this may be due to the antioxidant effects of the modified formula of chaihu-longu-muli-tang.