Oxidative stress is caused by an imbalance between the antioxidant and the reactive oxygen species, which results in damage to cells or tissues. Recent studies have reported that oxidative stress is involved in obesity, in addition to many other human diseases and aging. A prospective, randomized, double-blind study was performed to investigate the effect of astaxanthin (ASX), which is known to be a potent antioxidant, on oxidative stress in overweight and obese adults in Korea. Twenty-three adults with BMI > 25.0 kg/m(2) enrolled in this study and were randomly assigned to two dose groups: ASX 5 mg and 20 mg once daily for 3 weeks. Malondialdehyde (MDA), isoprostane (ISP), superoxide dismutase (SOD) and total antioxidant capacity (TAC), as oxidative stress biomarkers, were measured at baseline and 1, 2 and 3 weeks after ASX administration. Compared with baseline, the MDA (by 34.6% and 35.2%) and ISP (by 64.9% and 64.7%) levels were significantly lowered, whereas SOD (by 193% and 194%) and TAC (by 121% and 125%) levels were significantly increased in two dose groups after the 3 week intervention. This study revealed that supplemental ASX for 3 weeks improved oxidative stress biomarkers by suppressing lipid peroxidation and stimulating the activity of the antioxidant defense system.
Background: Previously we demonstrated that metformin stimulates GLUT4 through AMPK in skeletal muscle system. However, it was not clear how GLUT4 translocation is affected by metformin in adipocyte system. Results: Metformin stimulates AMPK to phosphorylate Cbl and induce CAP expression, thus modulating GLUT4 translocation. Conclusion: Cbl and CAP are involved in metformin-induced AMPK-mediated GLUT4 translocation. Significance: Cbl and CAP are downstream effectors of metformin on GLUT4 translocation.
Background: Chemotherapy is a standard therapeutic regimen to treat triple-negative breast cancer (TNBC); however, chemotherapy alone does not result in significant improvement and often leads to drug resistance in patients. In contrast, combination therapy has proven to be an effective strategy for TNBC treatment. Whether metformin enhances the anticancer effects of cisplatin and prevents cisplatin resistance in TNBC cells has not been reported. Methods: Cell viability, wounding healing, and invasion assays were performed on Hs 578T and MDA-MB-231 human TNBC cell lines to demonstrate the anticancer effects of combined cisplatin and metformin treatment compared to treatment with cisplatin alone. Western blotting and immunofluorescence were used to determine the expression of RAD51 and gamma-H2AX. In an in vivo 4T1 murine breast cancer model, a synergistic anticancer effect of metformin and cisplatin was observed. Results: Cisplatin combined with metformin decreased cell viability and metastatic effect more than cisplatin alone. Metformin suppressed cisplatin-mediated RAD51 upregulation by decreasing RAD51 protein stability and increasing its ubiquitination. In contrast, cisplatin increased RAD51 expression in an ERK-dependent manner. In addition, metformin also increased cisplatin-induced phosphorylation of γ-H2AX. Overexpression of RAD51 blocked the metformin-induced inhibition of cell migration and invasion, while RAD51 knockdown enhanced cisplatin activity. Moreover, the combination of metformin and cisplatin exhibited a synergistic anticancer effect in an orthotopic murine model of 4T1 breast cancer in vivo. Conclusions: Metformin enhances anticancer effect of cisplatin by downregulating RAD51 expression, which represents a novel therapeutic target in TNBC management.
Retinoic acid (RA) is one of the major components of vitamin A.In the present study, we found that retinoic acid activated AMPactivated protein kinase (AMPK). RA induced Rac1-GTP formation and phosphorylation of its downstream target, p21-activated kinase (PAK), whereas the inhibition of AMPK blocked RA-induced Rac1 activation. Moreover, cofilin, an actin polymerization regulator, was activated when incubated with RA. We then showed that inhibition of AMPK by compound C, a selective inhibitor of AMPK, or small interfering RNA of AMPK ␣1 blocked RA-induced cofilin phosphorylation. Additionally, we found that retinoic acid-stimulated glucose uptake in differentiated C2C12 myoblast cells and activated p38 mitogen-activated protein kinase (MAPK). Finally, the inhibition of AMPK and p38 MAPK blocked retinoic acid-induced glucose uptake. In summary, our results suggest that retinoic acid may have cytoskeletal roles in skeletal muscle cells via stimulation of the AMPK-Rac1-PAK-cofillin pathway and may also have beneficial roles in glucose metabolism via stimulation of the AMPK-p38 MAPK pathway.Retinoids are important regulators of differentiation and cell proliferation. Induction of differentiation by retinoic acid has been observed in various cell systems, such as endothelial, neuronal, and lung cancers (1). Retinoic acid has been shown to inhibit the growth of breast cancer cells and to reduce the number of tumors in animal models (2, 3). The anti-tumor potential of retinoids has been demonstrated by their ability to inhibit the growth of several human cancers, including colon cancer, prostate cancer, and melanoma (4, 5). Retinoic acid mediates its effects by binding to its receptors, retinoid acid receptor, or retinoid X receptor, followed by heterodimerization of the receptors and their recognition of binding to retinoid acid receptor element-containing promoters.AMP-activated protein kinase (AMPK) 2 is a phylogenetically conserved intracellular energy sensor that plays a central role in the regulation of glucose and lipid metabolism. AMPK, a heterotrimeric complex comprised of a catalytic subunit and two regulatory subunits, is activated when cellular energy is depleted (6). Upon activation by allosteric binding of AMP or phosphorylation at Thr 172 of the catalytic subunit by AMPK kinase, AMPK accelerates ATP-generating catabolic pathways, including glucose and fatty acid oxidation (7-9) while simultaneously reducing ATP-consuming anabolic pathways including cholesterol, fatty acid, and triacylglycerol synthesis (10). In addition to its roles in energy homeostasis, AMPK also has been shown to regulate the endothelial nitric-oxide synthase pathway through Rac1 (11). The involvement of interaction of Rac1 with AMPK has been implicated in many of the biological effects of AMPK in cytoskeletal remodeling.Small GTPases of the Rho family have diverse effects on cellular structure and function. Depending on the cell type, specific Rho GTPases induce particular surface protrusions generated by actin-remodeling reactions t...
ObjectiveThis study was conducted to examine the following: whether patients with mild cognitive impairment (MCI) show impairments in instrumental activities of daily living (IADL) as compared to controls; to identify the functional sub-domains of instrumental activities of daily living (IADL) that are affected in MCI and, finally, to identify the Seoul-Instrumental Activities of Daily Living (S-IADL) scale cut-off score that best differentiated between MCI and controls.MethodsThis study was carried out at the geropsychiatry clinic, university hospital. The study participants included 66 patients with MCI and 61 normal elderly. The S-IADL and Seoul-Activities of Daily Living (S-ADL) scales were administered to the main caregivers of all participants in order to assess everyday functioning.ResultsThe total S-IADL score was significantly higher in the patients with MCI [mean (SD) score=4.47 (2.06)] than in the controls [mean (SD) score=1.44 (1.65)] (p<0.001). The patients with MCI performed significantly worse on IADLs, such as the ability to use the telephone, prepare meals, take medication, manage belongings, keep appointments, talk about recent events, and perform leisure activities/hobbies (p<0.05). The S-IADL scale discriminated well between patients with MCI and controls (Area Under Curve=87%).ConclusionThe patients with MCI showed impairments in the ability to perform complex ADL in comparison to healthy controls. IADLs related to memory and frontal/executive functioning were particularly affected in MCI.
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