Ginkgo biloba Extract EGb 761 and Its Specific Components Elicit Protective Protein Clearance Through the Autophagy-Lysosomal Pathway in Tau-Transgenic Mice and Cultured Neurons.

Alzheimer's disease (AD) is a neurodegenerative disease pathologically characterized by extracellular amyloid-ß (Aß) deposits and intracellular neurofibrillary tangles (NFT) in many brain regions. NFT are primarily composed of hyperphosphorylated tau protein (p-Tau). Aß and p-Tau are two major pathogenic molecules with tau acting downstream to Aß to induce neuronal degeneration. In this study, we investigated whether Ginkgo biloba extract EGb 761 reduces cerebral p-Tau level and prevents AD pathogenesis. Human P301S tau mutant-transgenic mice were fed with EGb 761, added to the regular diet for 2 or 5 months. We observed that treatment with EGb 761 for 5 months significantly improved the cognitive function of mice, attenuated the loss of synaptophysin and recovered the phosphorylation of CREB in the mouse brain. Treatment with EGb 761 for 5 but not 2 months also decreased p-Tau protein amount and shifted microglial pro-inflammatory to anti-inflammatory activation in the brain. As potential therapeutic mechanisms, we demonstrated that treatment with EGb 761, especially the components of ginkgolide A, bilobalide, and flavonoids, but not with purified ginkgolide B or C, increased autophagic activity and degradation of p-Tau in lysosomes of neurons. Inhibiting ATG5 function or treating cells with Bafilomycin B1 abolished EGb 761-enhanced degradation of p-Tau in cultured neurons. Additionally, we observed that 5- instead of 2-month-treatment with EGb 761 inhibited the activity of p38-MAPK and GSK-3ß. Therefore, long-term treatment with Ginkgo biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology through mechanisms against multiple AD pathogenic processes.

Concise Review: Patient-Derived Stem Cell Research for Monogenic Disorders.

Monogenic disorders (MGDs) are caused by a single gene mutation and have a serious impact on human health. At present, there are no effective therapeutic methods for MGDs. Stem cell techniques provide insights into potential treatments for MGDs. With the development of patient-derived stem cells, we can begin to progressively understand the molecular mechanism of MGDs and identify new drugs for MGD treatment. Using powerful genome editing tools, such as zinc finger nucleases, transcriptional activator-like effector nucleases, and the clustered regulatory interspaced short palindromic repeat/Cas9 system, MGD-associated gene mutations can be corrected in MGD stem cells in vitro and then transplanted into MGD animal models to assess their safety and therapeutic effects. Despite the continued challenges surrounding potential pluripotent stem cell tumorigenicity and concerns regarding the genetic modification of stem cells, the extensive clinical application of MGD patient-specific stem cells will be pursued through further advances in basic research in the MGD field. In this review, we will summarize the latest progress in research into the use of patient-derived stem cells for the potential treatment of MGDs and provide predictions regarding the direction of future investigations.

Long-term treatment with Ginkgo biloba extract EGb 761 improves symptoms and pathology in a transgenic mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by extracellular deposits of amyloid ß peptide (Aß) and microglia-dominated neuroinflammation. The therapeutic options for AD are currently limited. In this study, we investigated the antiinflammatory effects and the underlying molecular mechanisms of Ginkgo biloba extract EGb 761 when administered to TgCRND8 AD mice, which overexpress human Alzheimer's amyloid precursor protein (APP) specifically in neurons. We gave APP-transgenic mice EGb 761 as a dietary supplement for 2 or 5months. Plasma concentrations of EGb 761 components in mice were in the same range as such concentrations in humans taking EGb 761 at the recommended dose (240mg daily). Treatment with EGb 761 for 5months significantly improved the cognitive function of the mice as measured by the Barnes Maze test. It also attenuated the loss of synaptic structure proteins, such as PSD-95, Munc18-1, and SNAP25. Treatment with EGb 761 for 5months inhibited microglial inflammatory activation in the brain. The effects of treatment with EGb 761 for 2months were weak and not statistically significant. Moreover, EGb 761 activated autophagy in microglia. Treatment with EGb 761 decreased Aß-induced microglial secretion of TNF-α and IL-1ß and activation of caspase-1, both of which were abolished by the inhibition of autophagy. Treatment with EGb 761 also reduced the concentrations of NLRP3 protein that colocalized with LC3-positive autophagosomes or autolysosomes in microglia. Additionally, long-term treatment with EGb 761 may reduce cerebral Aß pathology by inhibiting ß-secretase activity and Aß aggregation. Therefore, long-term treatment with G. biloba extract EGb 761, a clinically available and well-tolerated herbal medication, ameliorates AD pathology by antiinflammatory and Aß-directed mechanisms.

[Effect of acupuncture serum on the number of osteclast cultured in vitro].

OBJECTIVE: To observe effects of acupuncture serum of ovariectomized rats on the number of in vitro cultural osteoclast of newborn rats. METHODS: Forty 12-month-old SD female rats were randomly divided into 4 groups: sham-operation control group, ovariectomized (model) group, acupuncture prevention group and acupuncture treatment group. Osteoclasts isolated from long bone of the newborn SD rat were cultured on 24-well culture plates with DMEM containing 10% the test serum. Forty-eight hours later, the osteoclasts were stained with tartrate resistant acid phosphatase (TRAP) and the number of TRAP-positive multinucleated cells were counted. RESULTS: The number of TRAP-positive multinucleated cells in the model group significantly increased as compared with the sham-operation control group (P < 0.01), and in the acupuncture prevention group and the acupuncture treatment group significantly declined compared with the model group (P < 0.05). CONCLUSION: Acupuncture serum can equally reduce the number of osteoclasts in the two group.