Integrated network analysis identifying potential novel drug candidates and targets for Parkinson's disease.

This study aimed to identify potential novel drug candidates and targets for Parkinson's disease. First, 970 genes that have been reported to be related to PD were collected from five databases, and functional enrichment analysis of these genes was conducted to investigate their potential mechanisms. Then, we collected drugs and related targets from DrugBank, narrowed the list by proximity scores and Inverted Gene Set Enrichment analysis of drug targets, and identified potential drug candidates for PD treatment. Finally, we compared the expression distribution of the candidate drug-target genes between the PD group and the control group in the public dataset with the largest sample size (GSE99039) in Gene Expression Omnibus. Ten drugs with an FDR < 0.1 and their corresponding targets were identified. Some target genes of the ten drugs significantly overlapped with PD-related genes or already known therapeutic targets for PD. Nine differentially expressed drug-target genes with p < 0.05 were screened. This work will facilitate further research into the possible efficacy of new drugs for PD and will provide valuable clues for drug design.

Inverse associations of outdoor activity and vitamin D intake with the risk of Parkinson's disease.

Early studies had suggested that vitamin D intake was inversely associated with neurodegenerative diseases, such as Alzheimer's disease and multiple sclerosis. However, the associations of vitamin D intake and outdoor activities with Parkinson's disease (PD) are still unclear, so this study is to evaluate these relationships from a case-control study in elderly Chinese. The study population involved 209 cases with new onsets of PD and 210 controls without neurodegenerative diseases. The data on dietary vitamin D and outdoor activities were collected using a food-frequency questionnaire and self-report questionnaire. Multivariable logistic regressions were used to examine the associations between dietary outdoor activities, vitamin D intake and PD. Adjustment was made for sex, age, smoking, alcohol use, education, and body mass index (BMI). Adjusted odds ratios (ORs) for PD in quartiles for outdoor physical activity were 1 (reference), 0.739 (0.413, 1.321), 0.501 (0.282, 0.891), and 0.437 (0.241, 0.795), respectively (P=0.002 for trend). Adjusted ORs for PD in quartiles for total vitamin D intake were 1 (reference), 0.647 (0.357, 1.170), 0.571 (0.318, 1.022), and 0.538 (0.301, 0.960), respectively (P=0.011 for trend). Our study suggested that outdoor activity and total vitamin D intake were inversely associated with PD, and outdoor activity seems to be more significantly associated with decreased risk for PD.

WITHDRAWN: Effects of traditional Chinese medicine Fuzhisan on PP1 expression in the hippocampus of SAMP8 mice.

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Effects of Chinese herbal medicine Fuzhisan on autologous neural stem cells in the brain of SAMP-8 mice.

Fuzhisan (FZS), a Chinese herbal complex prescription, has been used in the treatment of Alzheimer's disease (AD) for more than 16 years. However the underlying mechanism remains to be explored. The effects of the aqueous extract of FZS on the cognitive functions of the aged mice and the pharmacological basis for its therapeutic efficacy were investigated. The results showed that FZS improved impaired cognitive ability of aged SAMP-8 mice. FZS (2.4, 4.8 g/kg/d) increased hippocampal neurogenesis and the long-term survival of BrdU-labeled cells without affecting the proportion of BrdU-positive neurons and glial cells. FZS also increased the number of BrdU-positive cells in the subventricular zone (SVZ) of the lateral ventricles of 8-month-old SAMP-8 mice. These studies suggest that FZS upregulates neurogenesis by increasing proliferation of neural progenitor cells and prolonging survival of the newborn cells in the hippocampal DG. FZS may be beneficial for the treatment of senile dementia, especially Alzheimer's disease.

Fuzhisan, a Chinese herbal medicine, inhibits beta-amyloid-induced neurotoxicity and tau phosphorylation through calpain/Cdk5 pathway in cultured cortical neurons.

It has been shown that ß-amyloid (Aß) induced hyperphosphorylation of tau is implicated in the pathogenesis of Alzheimer's disease (AD), and deregulation of cyclin-dependent kinase 5 (Cdk5) activity is involved in the abnormal tau phosphorylation. The cleavage of neuron-specific Cdk5 activator, p35, to p25, mediated by calpain and calcium, deregulates Cdk5 activity and promotes neurodegeneration. Fuzhisan (FZS), a Chinese herbal complex prescription that has been used for the treatment of AD for over 15 years, is known to enhance the cognitive ability in AD patients. In this study, we investigated the neuroprotective effects and potential molecular mechanisms of FZS against Aß(25-35)-induced toxicity in cultured cortical neurons. We revealed that FZS attenuated Aß(25-35)-induced neurotoxicity in a dose-dependent manner. FZS inhibited Aß(25-35)-induced activation of Cdk5 and decreased tau hyperphosphorylation although it did not directly inhibit Cdk5. In addition, FZS also blocked Aß(25-35)-induced calcium influx, calpain activation and decreased cleavage of p35 to p25.

Inhibition of glycogen synthase kinase-3ß by Angelica sinensis extract decreases ß-amyloid-induced neurotoxicity and tau phosphorylation in cultured cortical neurons.

Increasing evidence has shown that ß-amyloid (Aß) induces hyperphosphorylation of tau and contributes to Aß toxicity. Recently, tau hyperphosphorylation by glycogen synthase kinase-3ß (GSK-3ß) activation has been emphasized as one of the pathogenic mechanisms of Alzheimer's disease (AD). The phosphoinositide 3 kinase (PI3K)/Akt pathway is known as an upstream element of GSK-3ß. The inhibitory control of GSK-3ß, via the PI3K/Akt pathway, is an important mechanism of cell survival. In the present study, we investigated the neuroprotective effects of Angelica sinensis (AS), a traditional Chinese herbal medicine, against Aß(1-42) toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK-3ß signal pathway. We revealed that AS extract significantly attenuated Aß(1-42) -induced neurotoxicity and tau hyperphosphorylation at multiple AD-related sites in a dose-dependent manner. Simultaneously, it increased the levels of phospho-Ser(473) -Akt and down-regulated GSK-3ß activity by PI3K activation. The neuroprotective effects of AS extract against Aß(1-42) -induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 µM), a PI3K inhibitor. In addition, AS extract reversed the Aß(1-42) -induced decrease in phosphorylation cyclic AMP response element binding protein (CREB), which could be blocked by the PI3K inhibitor. These results suggest that AS-mediated neuroprotection against Aß toxicity is likely mediated by the PI3K/Akt/GSK-3ß signal pathway.

Implication of phosphatidylinositol-3 kinase/Akt/glycogen synthase kinase-3ß pathway in ginsenoside Rb1's attenuation of beta-amyloid-induced neurotoxicity and tau phosphorylation.

Ginseng has long been used to alleviate many ailments, particularly those associated with aging and memory deterioration. In the present study we aimed to investigate the neuroprotective effects of ginsenoside Rb1, against Aß(1-42) toxicity in cultured cortical neurons and also the potential involvement of PI3K/Akt/GSK-3ß signal pathway. Cortical neurons were pre-treated with ginsenoside Rb1 (20, 40, 100 µM) or LiCl (1, 5, 10 mM) for 24 h, and then were co-treated with 20 µM Aß(1-42) for 12 h. In some experiments to evaluate the mechanism of Rb1 action, a PI3K inhibitor (LY294002 10 µM) was co-administered with Rb1 for the 24-h pretreatment. We revealed that Rb1 significantly attenuated Aß(1-42)-induced neurotoxicity and tau hyperphosphorylation at multiple AD-related sites in a dose-dependent manner. Simultaneously, it increased the levels of phospho-Ser(473)-Akt and down-regulated GSK-3ß activity by PI3K activation. The neuroprotective effects of Rb1 against Aß(1-42)-induced neurotoxicity and tau hyperphosphorylation were blocked by LY294002 (10 µM), a PI3K inhibitor. In addition, Rb1 reversed the Aß(1-42)-induced decrease in phosphorylation cyclic AMP response element binding (CREB) protein, which could also be blocked by the PI3K inhibitor. All these findings suggest that Rb1 may represent a potential treatment strategy for Alzheimer's disease.