Mechanisms underlying large-leaf yellow tea mediated inhibition of cognitive impairment in the 5xFAD model of Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia and is characterized by amyloid-ß (Aß) peptides and hyperphosphorylated Tau proteins. Evidence indicates that AD and type 2 diabetes mellitus (T2DM) share pathophysiological characteristics, including impaired insulin sensitivity. Large-leaf yellow tea (LYT) has been widely recognized for its health benefits, and we previously found that LYT can improve peripheral insulin resistance. PURPOSE: This study aimed to investigate the protective effects and underlying mechanisms of LYT in the 5xFAD mouse model of AD. METHODS: HPLC and spectrophotometric methods determined the chemical composition of the LYT extract. 5xFAD mice were treated with LYT supplementation (2 and 4 mg/ml) in drinking water for six months. Barnes and Y mazes were used to evaluate cognitive function, and the open field test assessed anxiety-like behavior. Immunofluorescence, silver, and Nissl staining were used to evaluate the pathological effects of LYT extract. A FRET-based assay assessed ß-site APP cleavage enzyme 1 (BACE1) activity, ELISA measured Aß levels in the brain, and Western blot analyses explored protein expression levels. RESULTS: Our results revealed that LYT significantly attenuated memory impairment and anxiety levels and alleviated cerebral neural damage. A reduction of senile plaques was also observed in both the cortex and hippocampus. LYT significantly inhibited the activity of BACE1, which resulted in a lower Aß protein level. In addition, LYT enhanced insulin receptor substrate 1 (IRS-1)-mediated phosphorylation of phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT), further suppressed glycogen synthase kinase-3ß (GSK3ß), and ultimately inhibited hyperphosphorylation of the protein Tau. The inhibitory effect of the LYT extract on the phosphorylation of Tau and BACE1 activity was dose-dependent. CONCLUSION: LYT improves cognitive ability and reduces Aß production by inhibiting BACE1 activity. Decreases of Tau protein hyperphosphorylation upon LYT treatment appear to be associated with the regulation of the IRS-1/PI3K/AKT/GSK3ß axis. Thus, the findings of this study also provide new evidence that LYT regulates insulin signaling pathways within the central nervous system.

Green Tea Suppresses Amyloid ß Levels and Alleviates Cognitive Impairment by Inhibiting APP Cleavage and Preventing Neurotoxicity in 5XFAD Mice.

SCOPE: The consumption of green tea is considered to be associated with a lower incidence of neurodegenerative diseases. In the present study, it is investigated the role of amyloid precursor protein cleavage, glial cell activation, neuroinflammation, and synaptic alterations in the protective effects of green tea against the amyloid ß (Aß) accumulation and cognitive impairment. METHODS AND RESULTS: 5XFAD mice are treated with green tea extract (GTE) for 8 or 16 weeks. Barnes maze and Y maze testing demonstrated that spatial learning and memory ability are markedly improved by GTE treatment. Immunofluorescence staining, ELISA, and western blot showed GTE significantly alleviate the formation of Aß and reduce the levels of sAPPß and C99, as well as sAPPα and C83. Meanwhile, GTE suppressed GFAP and Iba1 levels in the glial cells, increased PSD95 and synaptophysin levels in synaptic cells. Further, the IL-1ß level is decreased, RNA sequencing reveals the genes annotated in response to stimulus and immune response are regulated. CONCLUSION: Our findings indicate GTE suppresses Aß levels and alleviate cognitive impairment in 5XFAD mice. These beneficial effects are accompanied by inhibition of APP cleavage pathways, suppression of glial cell activation and pro-inflammatory responses, and a reduction of synapse loss.

Green tea polyphenol epigallocatechin-3-gallate alleviates nonalcoholic fatty liver disease and ameliorates intestinal immunity in mice fed a high-fat diet.

Green tea polyphenol epigallocatechin-3-gallate (EGCG) may help prevent metabolic syndrome and nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanisms of its protective effects are complicated and remain unclear. With the gut-liver axis theory as a foundation, the present study investigated the effects of EGCG on intestinal mucosal immunity in male C57BL/6 mice fed a high-fat Western diet or the diet supplemented with 0.4% dietary EGCG (w/w) for 14 weeks. Dietary EGCG supplementation effectively prevented changes-including excessive accumulation of visceral and hepatic fat, abnormal liver function, and elevated concentrations of serum and liver inflammatory cytokines-known to be caused by high-fat diets. In addition, serum lipopolysaccharide concentrations decreased by 94.3%. RNA sequencing data of differentially expressed genes in ileal samples among three groups indicated that most of the pathways in the Kyoto Encyclopedia of Genes and Genomes in the first 20 enrichment levels were related to immunity and inflammatory reactions. Real-time reverse transcription quantitative polymerase chain reaction was used to determine alterations in expression levels of key genes related to intestinal immune function and inflammatory responses from ileal and colonic samples. Changes in secretory immunoglobulin A in the small intestine, serum, and feces further demonstrated improved intestinal mucosal immunity in the EGCG-treated mice. In conclusion, dietary EGCG effectively prevented the development of NAFLD and significantly improved intestinal mucosal immunity in mice with obesity induced by a high-fat diet. However, whether improved intestinal immune function is the key mechanism underlying the health benefits of dietary EGCG warrants further research.

Effects and Mechanisms of Tea Regulating Blood Pressure: Evidences and Promises.

Cardiovascular diseases have overtaken cancers as the number one cause of death. Hypertension is the most dangerous factor linked to deaths caused by cardiovascular diseases. Many researchers have reported that tea has anti-hypertensive effects in animals and humans. The aim of this review is to update the information on the anti-hypertensive effects of tea in human interventions and animal studies, and to summarize the underlying mechanisms, based on ex-vivo tissue and cell culture data. During recent years, an increasing number of human population studies have confirmed the beneficial effects of tea on hypertension. However, the optimal dose has not yet been established owing to differences in the extent of hypertension, and complicated social and genetic backgrounds of populations. Therefore, further large-scale investigations with longer terms of observation and tighter controls are needed to define optimal doses in subjects with varying degrees of hypertensive risk factors, and to determine differences in beneficial effects amongst diverse populations. Moreover, data from laboratory studies have shown that tea and its secondary metabolites have important roles in relaxing smooth muscle contraction, enhancing endothelial nitric oxide synthase activity, reducing vascular inflammation, inhibiting rennin activity, and anti-vascular oxidative stress. However, the exact molecular mechanisms of these activities remain to be elucidated.

Green Tea Polyphenol EGCG Alleviates Metabolic Abnormality and Fatty Liver by Decreasing Bile Acid and Lipid Absorption in Mice.

SCOPE: The tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been shown to ameliorate metabolic abnormalities and fatty liver. The present study investigates the mechanisms of actions of EGCG on bile acid homeostasis and lipid metabolism. METHODS: Male C57BL/6J mice are fed a low-fat diet, a high-fat western-style diet, or a high-fat western-style diet containing 0.32% EGCG. The effects of the treatments on biochemical parameters, gene expression, and lipidomics are analyzed. RESULTS: EGCG treatment significantly reduces body weight gain, mesenteric fat mass, fasting blood glucose, insulin resistance, serum cholesterol, and severity of fatty liver after treatment for 17 weeks, but most of these effects were less apparent at week 33. At week 17, EGCG treatment significantly elevates the mRNA levels of cholesterol 7α-hydroxylase, HMG-CoA reductase, low-density lipoprotein receptor, and scavenger receptor B1, and partially normalizes the high-fat diet induced lipidomic profile. The intestinal bile acid content is significantly decreased by EGCG, while fecal excretion of bile acids, cholesterol, and total lipids are increased. CONCLUSION: EGCG decreases bile acid reabsorption, results in lower intestinal bile acid levels, which further decreases the absorption of lipids. These actions contribute to the alleviation of metabolic abnormalities and fatty liver disease caused by the high-fat diet.

Green tea polyphenols alter lipid metabolism in the livers of broiler chickens through increased phosphorylation of AMP-activated protein kinase.

Our previous results showed that green tea polyphenols (GTPs) significantly altered the expression of lipid-metabolizing genes in the liver of chickens. However, the underlying mechanism was not elucidated. In this study, we further characterized how GTPs influence AMP-activated protein kinase (AMPK) in the regulation of hepatic fat metabolism. Thirty-six male chickens were fed GTPs at a daily dose of 0, 80 or 160 mg/kg of body weight for 4 weeks. The results demonstrated that oral administration of GTPs significantly reduced hepatic lipid content and abdominal fat mass, enhanced the phosphorylation levels of AMPKα and ACACA, and altered the mRNA levels and enzymatic activities of lipid-metabolizing enzymes in the liver. These results suggested that the activation of AMPK is a potential mechanism by which GTPs regulate hepatic lipid metabolism in such a way that lipid synthesis is reduced and fat oxidation is stimulated.

Green tea infusion protects against alcoholic liver injury by attenuating inflammation and regulating the PI3K/Akt/eNOS pathway in C57BL/6 mice.

Alcohol intake is a major risk factor for the pathogenesis of alcoholic liver diseases. Accumulating evidence suggests that green tea protects against alcoholic liver injury; however, the underlying mechanisms remain unclear. The present study investigated the role of endothelial nitric oxide synthase (eNOS) in the protective effects of green tea against alcohol-induced liver injury and inflammation. Ethanol was intragastrically administered to male C57BL/6 mice once a day, and the mice were allowed free access to green tea infusion or water for two weeks. We assessed the plasma levels of alanine aminotransferase and aspartate aminotransferase, hepatic contents of thiobarbituric acid reactive substances, malondialdehyde and triglyceride and hepatic mRNA expression of pro-inflammatory cytokines (interleukin-1ß, tumor necrosis factor-α, and interleukin-6). Our results showed that compared with water alone, green tea infusion markedly reduced liver damage, hepatic oxidative stress, hepatic lipid accumulation and inflammatory response. Green tea infusion also significantly reduced hepatic nuclear factor-κB expression and its downstream inflammatory mediators (inducible nitric oxide synthase and cyclooxygenase-2) mRNA levels in ethanol-treated mice. Additionally, green tea infusion significantly activated hepatic phosphorylated phosphatidylinositol 3-kinase (PI3K) and phosphorylated protein kinase B (Akt), which are associated with the upregulation of phosphorylated eNOS expression and the increase of plasma nitric oxide levels in ethanol-treated mice. Furthermore, the protective effects of green tea infusion were considerably inhibited by the eNOS inhibitor NG-nitro-l-arginine methyl ester in ethanol-treated mice. In conclusion, our study demonstrated that the protective effects of green tea infusion on alcohol-induced liver injury and inflammation involve the modulation of the PI3K/AKT/eNOS pathway.

Mechanisms of body weight reduction and metabolic syndrome alleviation by tea.

Tea, a popular beverage made from leaves of the plant Camellia sinensis, has been shown to reduce body weight, alleviate metabolic syndrome, and prevent diabetes and cardiovascular diseases in animal models and humans. Such beneficial effects have generally been observed in most human studies when the level of tea consumption was three to four cups (600-900 mg tea catechins) or more per day. Green tea is more effective than black tea. In spite of numerous studies, the fundamental mechanisms for these actions still remain unclear. From a review of the literature, we propose that the two major mechanisms are: (i) decreasing absorption of lipids and proteins by tea constituents in the intestine, thus reducing calorie intake; and (ii) activating AMP-activated protein kinase by tea polyphenols that are bioavailable in the liver, skeletal muscle, and adipose tissues. The relative importance of these two mechanisms depends on the types of tea and diet consumed by individuals. The activated AMP-activated protein kinase would decrease gluconeogenesis and fatty acid synthesis and increase catabolism, leading to body weight reduction and metabolic syndrome alleviation. Other mechanisms and the health relevance of these beneficial effects of tea consumption remain to be further investigated.

Green tea polyphenols alleviate obesity in broiler chickens through the regulation of lipid-metabolism-related genes and transcription factor expression.

The current study investigated the effects of green tea polyphenols (GTPs) on lipid metabolism and its mechanisms using broiler chickens (Gallus gallus domesticus). A total of 36 male chickens (35 days old) had been subjected to an oral administration of GTPs at a dosage of 0, 50 (low), and 100 (high) mg/kg of body weight for 20 days. Our results showed that GTPs significantly decreased the abdominal and subcutaneous fat masses of broilers and reduced the serum triglyceride, total cholesterol, and low-density lipoprotein cholesterol levels compared to those of the control. Furthermore, the expression levels for lipid anabolism genes were significantly downregulated, while the expression levels of fat transportation and catabolism-related genes, carnitine palmitoyl transferase I (CPT-I), acyl-CoA oxidase 1 (ACOX1), and peroxisome proliferator-activated receptor-α (PPARα) in liver, adipose triglyceride lipase (ATGL) in abdominal fat, and lipoprotein lipase (LPL) in skeletal muscles, were notably upregulated. Our data have revealed that GTPs alleviate obesity and serum lipid levels in broiler chickens by suppressing fatty acid synthesis and stimulating lipolysis.

Preclinical evaluation of S18886 in an experimental model of coronary arterial thrombosis.

The specific thromboxane receptor antagonist, S18886, was evaluated for prevention of coronary arterial thrombosis and myocardial ischemia-reperfusion in anesthetized canines. For the primary thrombosis study in left circumflex (LCX) coronary artery, 26 dogs were randomized to receive either vehicle (n = 7) or intravenous S18886 (0.3 mg/kg, n = 6; 1.0 mg/kg, n = 6; and 3.0 mg/kg, n = 7). The respective times to occlusion after S18886 were as follows: 56.8 +/- 9.3, 83.5 +/- 14.9, and 92.4 +/- 15.7 minutes compared to 43.3 +/- 8.2 minutes after vehicle. S18886 caused a minimal increase in tongue bleeding time and a significant decrease in ex vivo platelet aggregation to arachidonic acid or U46619. Another 37 dogs were randomized to receive placebo (n = 12), clopidogrel 1.0 mg/kg p.o. QDX3 (n = 9), clopidogrel + S18886 0.3 (n = 9) or 1.0 (n = 7) mg/kg intravenous. Clopidogrel produced a 50% reduction in adenosine diphosphate-induced platelet aggregation and a slight increase in the time to occlusion. However, clopidogrel + S18886 1.0 mg/kg prevented occlusive thrombus formation in most of the coronary vessels over 6 hours. S18886 did not alter myocardial infarct size in the ischemia-reperfusion model. In conclusion, S18886 alone caused a dose-dependent prolongation in the time to primary occlusive coronary artery thrombosis, whereas S18886 + clopidogrel displayed effective in preventing occlusive thrombus formation with only a moderate increase of tongue-bleeding time.