Differential Effects of Astrocyte Manipulations on Learned Motor Behavior and Neuronal Ensembles in the Motor Cortex.

Although motor cortex is crucial for learning precise and reliable movements, whether and how astrocytes contribute to its plasticity and function during motor learning is unknown. Here, we report that astrocyte-specific manipulations in primary motor cortex (M1) during a lever push task alter motor learning and execution, as well as the underlying neuronal population coding. Mice that express decreased levels of the astrocyte glutamate transporter 1 (GLT1) show impaired and variable movement trajectories, whereas mice with increased astrocyte Gq signaling show decreased performance rates, delayed response times, and impaired trajectories. In both groups, which include male and female mice, M1 neurons have altered interneuronal correlations and impaired population representations of task parameters, including response time and movement trajectories. RNA sequencing further supports a role for M1 astrocytes in motor learning and shows changes in astrocytic expression of glutamate transporter genes, GABA transporter genes, and extracellular matrix protein genes in mice that have acquired this learned behavior. Thus, astrocytes coordinate M1 neuronal activity during motor learning, and our results suggest that this contributes to learned movement execution and dexterity through mechanisms that include regulation of neurotransmitter transport and calcium signaling.SIGNIFICANCE STATEMENT We demonstrate for the first time that in the M1 of mice, astrocyte function is critical for coordinating neuronal population activity during motor learning. We demonstrate that knockdown of astrocyte glutamate transporter GLT1 affects specific components of learning, such as smooth trajectory formation. Altering astrocyte calcium signaling by activation of Gq-DREADD upregulates GLT1 and affects other components of learning, such as response rates and reaction times as well as trajectory smoothness. In both manipulations, neuronal activity in motor cortex is dysregulated, but in different ways. Thus, astrocytes have a crucial role in motor learning via their influence on motor cortex neurons, and they do so by mechanisms that include regulation of glutamate transport and calcium signals.

Extract of Cycas revoluta Thunb. enhances the inhibitory effect of 5-fluorouracil on gastric cancer cells through the AKT-mTOR pathway.

BACKGROUND: Gastric cancer is one of the most common and deadly malignancies worldwide. Despite recent medical progress, the 5-year survival rate of gastric cancer is still unsatisfactory. 5-fluorouracil (5-Fu) is one of the first-line antineoplastic treatments for gastric cancer, as it can effectively induce cancer cell apoptosis. However, the effect of 5-Fu is limited due to drug resistance of the malignant tumor. Previous studies have reported that Sotetsuflavone from Cycas revoluta Thunb. can markedly suppress lung cancer cell proliferation by apoptosis, though its effect on gastric cancer remains unknown. AIM: To investigate the inhibitory effect of Cycas revoluta Thunb. and to determine whether it can overcome gastric cancer cell drug resistance to 5-Fu. METHODS: Cell viability was examined to determine whether the natural extract of Cycas revoluta Thunb. induced gastric cancer cell death. The half-maximal effective concentration and the half-maximal lethal concentration were calculatede. Wound-healing and transwell assays were performed to examine gastric cancer cell motility. Clonogenic assays were performed to investigate the synergistic effects of Cycas revoluta Thunb. with 5-Fu, and apoptotic bodies were detected by Hoechst staining. Western blotting was performed to examine the expression of related proteins and to investigate the molecular mechanism of Cycas revoluta Thunb.-induced cancer cell apoptosis. The expressions of proteins, including mammalian target of rapamycin (mTOR) and p-AKT, were detected in different combinations of treatments for 48 h, then analyzed by ECL detection. RESULTS: Gastric cancer cells were more sensitive to the natural extract of Cycas revoluta Thunb. compared to normal gastric epithelial cells, and the extract effectively inhibited gastric cancer cell migration and invasion. The extract improved the anti-cancer effect of 5-Fu by enhancing the chemosensitization of gastric cancer cells. Extract plus 5-Fu further reduced the expression of the drug-resistance-related proteins p-AKT and mTOR after 48 h compared to 5-Fu alone. Compared to 5-Fu treatment alone, mTOR and p-AKT expression was significantly reduced by about 50% and 75%, respectively. We also found that the natural extract of Cycas revoluta Thunb. further increased 5-Fu-induced gastric cancer cell apoptosis. Expression of apoptosis-related protein X-linked inhibitor of apoptosis protein and apoptosis inducing factor were significantly reduced and increased, respectively, in the 5-Fu-resistant gastric cancer line SGC-7901/R treated with extract plus 5-Fu, while the expression of survivin did not change. CONCLUSION: The natural extract of Cycas revoluta Thunb. effectively inhibited gastric cancer cell growth and enhanced the anti-cancer effect of 5-Fu through the AKT-mTOR pathway.

Low Habitual Dietary Calcium and Linear Growth from Adolescence to Young Adulthood: results from the China Health and Nutrition Survey.

Evidences from clinical trials and meta-analyses of calcium supplementation in linear growth have given conflicting results, and few longitudinal studies have investigated the long-term associations between dietary calcium and linear growth, especially in the population with low-calcium plant-based diets. We investigated the prospective associations of low habitual dietary calcium with adult height and height-for-age z-score (HAZ) from adolescence to adulthood among 2019 adolescents from the China Health and Nutrition Survey (CHNS). The average dietary calcium intakes were 426(standard deviation: 158) mg/d in boys and 355(134) mg/d in girls during adolescence. During a median follow-up of 7.0 (interquartile range: 5.9-9.0) years, boys reached an average of 169.0(6.7) cm and girls reached 158.4(5.8) cm in adulthood. After adjusting for other potential confounders, non-linear regression found that boys with dietary calcium intakes below 327 mg/d had shorter adult stature, and those taking over 566 mg/d had faster height growth whether adjusting for physical exercises level or not. No significant associations were found in girls. Our study suggests that in boys with plant-based diets, higher dietary calcium intake during adolescence is associated with faster height growth, but not with adult height; calcium intake below 300 mg/d may result in shorter adult stature.

Plant sterol-enriched milk tea decreases blood cholesterol concentrations in Chinese adults: a randomised controlled trial.

The cholesterol-lowering effects of plant sterols in a format suitable for use in China have not previously been investigated. We conducted the study to quantify in adult Chinese the effects on blood lipid concentrations of a plant sterol-enriched milk tea powder. The study was a double-blind, randomised trial in which 309 participants were randomised to receive daily 2.3 or 1.5 g plant sterol supplementation or placebo for 5 weeks. The milk tea was consumed with the two fattiest meals of the day with half the assigned daily dose taken on each occasion. Fasting venous blood samples were collected before commencement and upon completion of randomised treatment. The mean age of study participants was 44 years, 62% were female and 62% had a history of hypercholesterolaemia. Baseline mean total cholesterol was 5.5 mmol/l and LDL-cholesterol was 3.2 mmol/l. Compared with placebo, the 2.3 g/d plant sterol dose reduced total cholesterol by 0.25 (95% CI 0.07, 0.43) mmol/l (P = 0.01) and the 1.5 g/d dose by 0.23 (95% CI 0.06, 0.41) mmol/l (P = 0.01). For LDL-cholesterol the corresponding reductions were 0.17 (95% CI 0.00, 0.35) mmol/l (P = 0.06) and 0.15 (95% CI -0.02, 0.32) mmol/l (P = 0.08). For neither outcome was there evidence of differences between the effects of the two doses (both P values >0.4). In conclusion, the consumption of plant sterol-enriched milk tea decreased cholesterol concentrations although to a lesser extent than was anticipated. The reason for reduced efficacy is unclear but may be attributable to the novel food format used or the Chinese population studied.

The effects of an instant haw beverage on lipid levels, antioxidant enzyme and immune function in hyperlipidemia patients.

OBJECTIVE: To determine the effectiveness of an instant haw beverage in regulating lipid disturbance, enhancing antioxidant enzyme activity and immune function. METHODS: Data was collected from 60 hyperlipidemic subjects. In this crossover design, each subject randomly received either the instant haw beverage (100 ml corresponding to 3 g of haw powder or 30 g of fresh haw fruit plus the carrier-guar gum plus some starch) or placebo (guar gum 1.5 g plus some starch as the carrier of the beverage) twice daily. Each supplementation lasted 31 days with a 28-day washout period between treatments. RESULTS: The instant haw beverage significantly reduced total serum cholesterol (9.6%), triglyceride (12.1%), LDLC (18%) while significantly increased SOD activities (7.5%). The placebo was shown to have positive results in some of the lipid profiles, though the effects of the instant haw beverage demonstrated greater significance. Serum triglyceride levels were significantly decreased and SOD activity significantly increased only as subjects were supplemented with the instant haw beverage while no significant changes were seen with placebo. CONCLUSION: Supplementation with the instant haw beverage positively affects blood lipid profile, antioxidant status and immune function in individuals with hyperlipidemia.