Isoflavone-Enriched Soybean Leaves (Glycine Max) Alleviate Cognitive Impairment Induced by Ovariectomy and Modulate PI3K/Akt Signaling in the Hippocampus of C57BL6 Mice.

(1) Background: The estrogen decline during perimenopause can induce various disorders, including cognitive impairment. Phytoestrogens, such as isoflavones, lignans, and coumestans, have been tried as a popular alternative to avoid the side effects of conventional hormone replacement therapy, but their exact mechanisms and risk are not fully elucidated. In this study, we investigated the effects of isoflavone-enriched soybean leaves (IESLs) on the cognitive impairment induced by ovariectomy in female mice. (2) Methods: Ovariectomy was performed at 9 weeks of age to mimic menopausal women, and the behavior tests for cognition were conducted 15 weeks after the first administration. IESLs were administered for 18 weeks. (3) Results: The present study showed the effects of IESLs on the cognitive function in the OVX (ovariectomized) mice. Ovariectomy markedly increased the body weight and fat accumulation in the liver and perirenal fat, but IESL treatment significantly inhibited them. In the behavioral tests, ovariectomy impaired cognitive functions, but administration of IESLs restored it. In addition, in the OVX mice, administration of IESLs restored decreased estrogen receptor (ER) ß and PI3K/Akt expression in the hippocampus. (4) Conclusions: The positive effects of IESLs on cognitive functions may be closely related to the ER-mediated PI3/Akt signaling pathway in the hippocampus.

The Root of Polygonum multiflorum Thunb. Alleviates Non-Alcoholic Steatosis and Insulin Resistance in High Fat Diet-Fed Mice.

Non-alcoholic steatosis and insulin resistance are critical health problems and cause metabolic complications worldwide. In this study, we investigated the molecular mechanism of Polygonum multiflorum Thunb. (PM) against hepatic lipid accumulation and insulin resistance by using in vitro and in vivo models. PM extract significantly attenuated the accumulation of lipid droplets and hepatic triglyceride in free fatty acid (FFA)-exposed HepG2 cells. PM extract increased the AMPK and ACC phosphorylation and GLUT4 expression, whose levels were downregulated in FFA-exposed cells. PM extract also decreased precursor and mature forms of SREBP-1 in FFA-exposed cells. C57BL/6 mice fed with normal diet (ND) or high-fat diet (HFD) were administered PM extract (100 mg/kg) or vehicle orally for 16 weeks. PM extract attenuated the increases of the epididymal and perirenal fats on HFD feeding. PM extract markedly reduced hepatic lipid accumulation and fasting glucose levels, and improved glucose and insulin sensitivity in HFD-fed mice. HFD-fed mice decreased the AMPK and ACC phosphorylation and GLUT4 expression, and increased precursor and mature forms of SREBP-1; these changes were significantly restored by PM extract. In conclusion, PM extract alleviates non-alcoholic steatosis and insulin resistance through modulating the expression of proteins on lipid metabolism and glucose transport in the liver.

Glutamine Supplementation Prevents Chronic Stress-Induced Mild Cognitive Impairment.

We recently reported that glutamine (Gln) supplementation protected glutamatergic neurotransmission from the harmful effects of chronic stress. Altered glutamatergic neurotransmission is one of the main causes of cognitive disorders. However, the cognitive enhancer function of Gln has not been clearly demonstrated thus far. Here, we evaluated whether and how Gln supplementation actually affects chronic stress-induced cognitive impairment. Using a chronic immobilization stress (CIS) mouse model, we confirmed that chronic stress induced mild cognitive impairment (MCI) and neuronal damage in the hippocampus. In contrast, Gln-supplemented mice did not show evidence of MCI. To investigate possible underlying mechanisms, we confirmed that CIS increased plasma corticosterone levels as well as brain and plasma levels of reactive oxygen/nitrogen species. CIS also increased levels of inducible nitric oxide synthase and NADPH oxidase subunits (p47phox and p67phox) in both the prefrontal cortex and CA1 region of the hippocampus. CIS decreased the number of synaptic puncta in the prefrontal cortex and hippocampus, but these effects were inhibited by Gln supplementation. Taken together, the present results suggest that Gln is an effective agent against chronic stress-induced MCI.

Anti-Stress and Anti-Depressive Effects of Spinach Extracts on a Chronic Stress-Induced Depression Mouse Model through Lowering Blood Corticosterone and Increasing Brain Glutamate and Glutamine Levels.

Spinach is one of the most widely consumed vegetables, and is known as for both physical and mental health maintenance. However, there is little information about how spinach protects one from stress. In the present study, we created three extracts from Spinach oleracea L., (frozen powder (FP), water extract (WE), and ethanol extract (EE)), and examined their anti-stress and anti-depressive effects on mouse using a chronic immobilization stress (CIS) regimen. FP, WE, and EE showed different free amino acid constituents. Calorie-balanced diets derived from each extract were tested for their ability to reduce blood corticosterone (CORT) levels in naïve mice. Diets supplemented with FP or EE induced lower blood CORT levels than a normal diet, but the WE diet did not. Mobility duration and sucrose preference were increased by FP and EE supplementation in the CIS-induced depression animal models. Moreover, FP and EE increased glutamate and glutamine levels in the medial prefrontal cortex (mPFC) compared with CIS-induced depressed group. These results suggest that spinach has anti-stress and anti-depressive properties by lowering CORT and increasing glutamate and glutamine levels in the mPFC.

The GABAB receptor associates with regulators of G-protein signaling 4 protein in the mouse prefrontal cortex and hypothalamus.

Regulators of G-protein signaling (RGS) proteins regulate certain G-protein-coupled receptor (GPCR)-mediated signaling pathways. The GABA(B) receptor (GABA(B)R) is a GPCR that plays a role in the stress response. Previous studies indicate that acute immobilization stress (AIS) decreases RGS4 in the prefrontal cortex (PFC) and hypothalamus (HY) and suggest the possibility of a signal complex composed of RGS4 and GABA(B)R. Therefore, in the present study, we tested whether RGS4 associates with GABA(B)R in these brain regions. We found the co-localization of RGS4 and GABA(B)R subtypes in the PFC and HY using double immunohistochemistry and confirmed a direct association between GABA(B2)R and RGS4 proteins using co-immunoprecipitation. Furthermore, we found that AIS decreased the amount of RGS4 bound to GABA(B2)R and the number of double-positive cells. These results indicate that GABA(B)R forms a signal complex with RGS4 and suggests that RGS4 is a regulator of GABA(B)R.