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Background: An important feature of aging cells is the gradual loss of physiological integrity. As aging progresses, MSCs change preferring to differentiate toward adipocytes rather than osteoblasts. Oxidative stress accumulation is an important factor in age-related bone loss. Many experiments have demonstrated the good therapeutic effect of Ginsenoside (Rg1) on oxidative stress injury. In this study, we investigated the effect of Rg1 on the osteogenic-adipogenic differentiation balance of bone marrow mesenchymal stem cells (BMMSC). Objective: To analyze the potential application value of Rg1 in the treatment of senile osteoporosis. Methods: BMMSCs were isolated from healthy donors of different ages and identified based on isotype and by multi-differentiation induction. Rg1 was used to treat BMMSCs, The differentiation propensity was analyzed by induction of differentiation assay. Antioxidant capacity of BMMSCs as measured by oxidative stress product assay Related mechanism studies were confirmed by quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR), immunofluorescence, western blotting, and inhibitor treatment. Moreover, Observation of the effects of Rg1 on aging BMMSCs under in vivo conditions by treatment of aged mice with Rg1 injections. Results: Rg1 treatment rescued age-induced switch of BMMSCs differentiation fate in vitro. In elderly people, Rg1 markedly increased osteogenic differentiation of BMMSCs by decreasing oxidative stress, while inhibiting adipogenic differentiation. However, this effect was abolished in BMMSCs by an Nrf2-inhibitor. Notably, aging mice showed a reduction in adipocyte distribution in the bone marrow and a decrease in oxidative stress products after a 3-month period of Rg1 treatment. Conclusion: We have uncovered a novel function for Rg1 that involves attenuating bone loss via Nrf2 antioxidant signaling, which in turn may potentially be utilized as a therapeutic agent for improving osteogenic differentiation in aging BMMSCs.
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AIMS: Rg1 is the most active component of traditional Chinese medicine ginseng, having anti-aging and anti-oxidative stress features in multiple organs. Cellular senescence of hepatocytes is involved in the progression of a wide spectrum of chronic liver diseases. In this study, we investigated the potential benefits and mechanism of action of Rg1 on aging-driven chronic liver diseases. MATERIALS AND METHODS: A total of 40 male C57BL/6 mice were randomly divided into four groups: control group; Rg1 group; Rg1+d-gal group; and d-gal group. Blood and liver tissue samples were collected for determination of liver function, biochemical and molecular markers, as well as histopathological investigation. KEY FINDINGS: Rg1 played an anti-aging role in reversing d-galactose induced increase in senescence-associated SA-ß-gal staining and p53, p21 protein in hepatocytes of mice and sustained mitochondria homeostasis. Meanwhile, Rg1 protected livers from d-galactose caused abnormal elevation of ALT and AST in serum, hepatic steatosis, reduction in hepatic glucose production, hydrogenic degeneration, inflammatory phenomena including senescence-associated secretory phenotype (SASP) IL-1ß, IL-6, MCP-1 elevation and lymphocyte infiltration. Furthermore, Rg1 suppressed drastic elevation in FOXO1 phosphorylation resulting in maintaining FOXO1 protein level in the liver after d-galactose treatment, followed by FOXO1 targeted antioxidase SOD and CAT significant up-regulation concurrent with marked decrease in lipid peroxidation marker MDA. SIGNIFICANCE: Rg1 exerts pharmaceutic effects of maintaining FOXO1 activity in liver, which enhances anti-oxidation potential of Rg1 to ameliorate SASP and to inhibit inflammation, also promotes metabolic homeostasis, and thus protects livers from senescence induced fatty liver disease. The study provides a potential therapeutic strategy for alleviating chronic liver pathology.
Assuntos
Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Proteína Forkhead Box O1/metabolismo , Ginsenosídeos/farmacologia , Animais , Antioxidantes/farmacologia , Senescência Celular/efeitos dos fármacos , Modelos Animais de Doenças , Galactose/farmacologia , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Fatores de Transcrição/metabolismoRESUMO
The incidence of neurodegenerative diseases is severely increasing with the aging. It has been proposed that NSCs (neural stem cells) help to control aging, but the mechanisms responsible remain unclear. Angelica polysaccharide is an active ingredient of Angelica sinensis in traditional Chinese medicine, which possesses versatile pharmacological activities including anti-oxidative and anti-aging effects. In this study, D-gal (D-galactose) was used to construct an aging model of Nestin-GFP transgenic mice brain tissues and NSCs. Mouse model was subcutaneously injected with D-gal, as we observed that mice consistently displayed acceleration of aging-like behavior change, energy metabolism decreased, the expression of aging-related genes was up-regulated. Conversely, aging retardation was achieved in Nestin-GFP mice Induced by D-gal that was locally injected with ASP (Angelica polysaccharide). Mechanistically, we isolated and cultured NSCs in vitro. ASP protected NSCs by increasing the cell proliferation; decreasing the number of SA-ß-gal stained neurons; increasing the activity of SOD(superoxide dismutase) and T-AOC(total antioxidant capacity), decreasing the content of MDA(malondialdehyde); decreasing the levels of IL-1b,IL-6,TNF-a and ROS; and down-regulated the expression of cellular senescence associated genes p53, p21 in the aging NSCs. In conclusion, ASP can delay aging speed by protecting NSCs and promote neurogenesis by enhancing the antioxidant and anti-inflammatory capacity, up-regulation of p53/p21 signaling pathway. As to provide theoretical basis for treatment for brain aging related diseases, add new scientific connotation for "qi and blood theory" and "supplement blood and delay aging" of Traditional Chinese Medicine.
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Encéfalo/efeitos dos fármacos , Galactose/farmacologia , Nestina/metabolismo , Polissacarídeos/farmacologia , Angelica sinensis/efeitos dos fármacos , Animais , Antioxidantes/farmacologia , Encéfalo/metabolismo , Encéfalo/patologia , Modelos Animais de Doenças , Masculino , Malondialdeído/metabolismo , Camundongos Transgênicos , Células-Tronco Neurais/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacosRESUMO
Myelosuppression is the most common complication of chemotherapy. Decline of self-renewal capacity and stress-induced premature senescence (SIPS) of hematopoietic stem cells (HSCs) induced by chemotherapeutic agents may be the cause of long-term myelosuppression after chemotherapy. Whether the mechanism of SIPS of hematopoietic cells relates to chemotherapeutic injury occurred in hematopoietic microenvironment (HM) is still not well elucidated. This study explored the protective effect of Angelica sinensis polysaccharide (ASP), an acetone extract polysaccharide found as the major effective ingredients of a traditional Chinese medicinal herb named Chinese Angelica (Dong Quai), on oxidative damage of homo sapiens bone marrow/stroma cell line (HS-5) caused by 5-fluorouracil (5-FU), and the effect of ASP relieving oxidative stress in HM on SIPS of hematopoietic cells. Tumor-suppressive doses of 5-FU inhibited the growth of HS-5 in a dose-dependent and time-dependent manner. 5-FU induced HS-5 apoptosis and also accumulated cellular hallmarks of senescence including cell cycle arrest and typical senescence-associated ß-galactosidase positive staining. The intracellular reactive oxygen species (ROS) was increased in 5-FU treated HS-5 cells and coinstantaneous with attenuated antioxidant capacity marked by superoxide dismutase and glutathione peroxidase. Oxidative stress initiated DNA damage indicated by increased γH2AX and 8-OHdG. Oxidative damage of HS-5 cells resulted in declined hematopoietic stimulating factors including stem cell factor (SCF), stromal cell-derived factor (SDF), and granulocyte-macrophage colony-stimulating factor (GM-CSF), however, elevated inflammatory chemokines such as RANTES. In addition, gap junction channel protein expression and mediated intercellular communications were attenuated after 5-FU treatment. Significantly, co-culture on 5-FU treated HS-5 feeder layer resulted in less quantity of human umbilical cord blood-derived hematopoietic cells and CD34⺠hematopoietic stem/progenitor cells (HSPCs), and SIPS of hematopoietic cells. However, it is noteworthy that ASP ameliorated SIPS of hematopoietic cells by the mechanism of protecting bone marrow stromal cells from chemotherapeutic injury via mitigating oxidative damage of stromal cells and improving their hematopoietic function. This study provides a new strategy to alleviate the complication of conventional cancer therapy using chemotherapeutic agents.