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The administration of D-galactose triggers brain aging by poorly understood mechanisms. It is generally recognized that D-galactose induces oxidative stress or affects protein modifications via receptors for advanced glycated end products in a variety of species. In the present study, we aimed to investigate the involvement of astrocytes in D-galactose-induced brain aging in vitro. We found that D-galactose treatment significantly suppressed cell viability and induced cellular senescence. In addition, as of the accumulation of senescent cells, we proposed that the senescence-associated secretory phenotype (SASP) can stimulate age-related pathologies and chemoresistance in brain. Consistently, senescent astrocytic CRT cells induced by D-galactose exhibited increases in the levels of IL-6 and IL-8 via NF-κB activation, which are major SASP components and inflammatory cytokines. Conditioned medium prepared from senescent astrocytic CRT cells significantly promoted the viability of brain tumor cells (U373-MG and N2a). Importantly, conditioned medium greatly suppressed the cytotoxicity of U373-MG cells induced by temozolomide, and reduced the protein expression levels of neuron marker neuron-specific class III β-tubulin, but markedly increased the levels of c-Myc in N2a cells. Thus, our findings demonstrated that D-galactose treatment might mimic brain aging, and that D-galactose could contribute to brain inflammation and tumor progression through inducing the accumulation of senescent-secretory astrocytes.

Ginsenosides, the secondary plant metabolites produced by Panax ginseng are responsible for the enhancing effects on learning observed following treatment with Panax ginseng. A number of studies have provided correlational evidence that cell proliferation and survival are closely associated with hippocampal-dependent learning tasks. In this study, to investigate the beneficial effects of ginsenoside Rh1 on hippocampal cells and learning, mice (6 months old) were administered ginsenoside Rh1 at a dose of 5 and 10 mg/kg/day for a period of 3 months. Saline-treated mice were used as controls. The enhancement of memory and learning in the mice was evaluated by hippocampal-dependent tasks (passive avoidance tests and Morris water maze tests) and the immunohistochemical marker of cell proliferation, bromodeoxyuridine (BrdU). In addition, the levels of brain-derived neurotrophic factor (BDNF) were measured following treatment. Based on our data, the Rh1-treated group (5 and 10 mg/kg) showed a significantly improved learning and memory ability in the passive avoidance tests compared with the control group; however, only treatment with 10 mg/kg ginsenoside Rh1 significantly promoted spatial learning ability in the Morris water maze test. Ginsenoside Rh1 significantly enhanced cell survival in the dentate gyrus of mice, although it did not enhance hippocampal cell proliferation. In addition, ginsenoside Rh1 upregulated the expression of BDNF. These findings address the potential therapeutic significance of ginsenoside Rh1 as a nutritional supplement in memory loss and neurodegenerative diseases.

The acute exposure of trimethyltin (TMT) develops clinical syndrome characterized by amnesia, aggressive behavior, and complex seizures. This neurotoxicant selectively induces hippocampal neuronal injury and glial activation accompanied with resultant neuroinflammation. Here we report two candidates ginsenosides Rg3 and Rh2 as neuroprotection agents using a mouse model of TMT intoxication via a single injection (2 mg/kg) and primary neuronal culture systems. Four-week administration of Rg3 or Rh2 significantly reduced TMT-induced seizures and behavioral changes. Rg3 and Rh2 significantly attenuated the oxidative stress evidenced by improvement on antioxidant enzymes and neuronal loss and astrocytic activation in mouse brain. In primary cultures, TMT induced significant neuronal death after 24-h intoxication and vigorous secretion of inflammatory cytokines (IL-1α/β, IL-6, TNF-α, and MCP-1) in astrocytes. Pretreatment with Rg3 or Rh2 not only reduced cell death but efficiently suppressed above mentioned inflammatory cytokines confirmed by antibody array test. The underlying protective mechanism by Rg3 and Rh2 was delineated through selective upregulation of PI3K/Akt and suppression of ERK activation. Intriguingly, Rg3 and Rh2 protected oligodendrocyte progenitor cells (O-2A) from TMT intoxication via promoting type 2 astrocytic differentiation without further inflammatory activation. Collectively, Rg3 and Rh2 interventions aimed at reducing oxidative stress and neuroinflammation neurotoxicity therefore are of therapeutic benefit in TMT-induced neurodegeneration. KEYWORDS neuroinflammation, oligodendrocyte progenitor cells (O-2A), oxidative stress, Rg3 and Rh2, TMT

Aims: This study examined the biotransformation pathway of ginsenoside Rb 1 by the fungus Esteya vermicola CNU 120806. Methods and Results: Ginsenosides Rb 1 and Rd were extracted from the root of Panax ginseng. Liquid fermentation and purified enzyme hydrolysis were employed to investigate the biotransformation of ginsenoside Rb 1 . The metabolites were identified and confirmed using NMR analysis as gypenoside XVII and gypenoside LXXV. A mole yield of 95Á4% gypenoside LXXV was obtained by enzymatic conversion (pH 5Á0, temperature 50°C). Ginsenoside Rd was used to verify the transformation pathway under the same reaction condition. The product Compound K (mole yield 49Á6%) proved a consecutive hydrolyses occurred at the C-3 position of ginsenoside Rb 1 . Conclusions: Strain CNU 120806 showed a high degree of specific b-glucosidase activity to convert ginsenosides Rb 1 and Rd to gypenoside LXXV and Compound K, respectively. The maximal activity of the purified glucosidase for ginsenosides transformation occurred at 50°C and pH 5Á0. Compared with its activity against pNPG (100%), the b-glucosidase exhibited quite lower level of activity against other aryl-glycosides. Enzymatic hydrolysate, gypenoside LXXV and Compound K were produced by consecutive hydrolyses of the terminal and inner glucopyranosyl moieties at the C-3 carbon of ginsenoside Rb 1 and Rd, giving the pathway: ginsenoside Rb 1 ? gypenoside XVII ? gypenoside LXXV; ginsenoside Rd?F 2 ? Compound K, but did not hydrolyse the 20-C, b-(1-6)-glucoside of ginsenoside Rb 1 and Rd. Significance and Impact of the Study: The results showed an important practical application on the preparation of gypenoside LXXV. Additionally, this study for the first time provided a high efficient preparation method for gypenoside LXXV without further conversion, which also gives rise to a potential commercial enzyme application.