Effect of Catechins on Upper Respiratory Tract Infections in Winter: A Randomized, Placebo-Controlled, Double-Blinded Trial.

Tea catechins are plant-derived compounds that improve immune functions. Previous randomized control trials have demonstrated the efficacy of primarily epi-type catechins against upper respiratory tract infections (URTIs). Green tea can be consumed in several ways, including popular bottled beverages. These beverages, however, require sterilization during manufacturing, which results in catechin isomerization. We conducted a randomized, double-blinded, placebo-controlled trial involving healthy Japanese participants to evaluate whether catechin consumption via bottled beverages has an alleviating effect on the duration and severity of URTIs in winter. The catechin group (490 mg catechin, 0.14%, containing 59% epi-type catechin, n = 55) showed reduced durations of running nose, nasal congestion, and headache, compared with the placebo group (0 mg catechin, n = 54; p = 0.013, 0.018, and <0.001, respectively). Furthermore, when considering physical symptoms, the duration of nasopharyngeal symptoms improved significantly in the catechin group (p < 0.001) compared with that in the control group. The daily consumption of catechin thus reduced the duration and severity of URTIs in healthy men and women. Humans are regularly exposed to several potential infectious threats, and the oral administration of heat-epimerized tea catechins might help prevent and reduce the severity of URTIs.

Preventive effects of tea and tea catechins against influenza and acute upper respiratory tract infections: a systematic review and meta-analysis.

PURPOSE: Gargling with tea has protective effects against influenza infection and upper respiratory tract infection (URTI). To evaluate if tea and tea catechin consumption has the same protective effects as gargling with tea, we performed a systematic review and meta-analysis. METHODS: We performed a comprehensive literature search using the PubMed, Cochrane Library, Web of Science, and Ichu-shi Web databases. The search provided six randomized controlled trials (RCTs) and four prospective cohort studies (n = 3748). The quality of each trial or study was evaluated according to the Cochrane risk-of-bias tool or Newcastle-Ottawa Scale. We collected data from publications meeting the search criteria and conducted a meta-analysis of the effect of tea gargling and tea catechin consumption for preventing URTI using a random effects model. RESULTS: Tea gargling and tea catechin consumption had significant preventive effects against URTI (risk ratio [RR] = 0.74, 95% confidence interval [CI] 0.64-0.87). In sub-analyses, a significant preventive effect was observed by study type (prospective cohort study: RR = 0.67, 95% CI 0.50-0.91; RCT: RR = 0.79, 95% CI 0.66-0.94) and disease type (influenza: RR = 0.69, 95% CI 0.58-0.84; acute URTI: RR = 0.78, 95% CI 0.62-0.98). Both gargling with tea and consuming tea catechins effectively protected against URTI (tea and tea catechins consumption: RR = 0.68, 95% CI 0.52-0.87; tea gargling: RR = 0.83, 95% CI 0.72-0.96). CONCLUSION: Our findings suggest that tea gargling and tea catechin consumption may have preventive effects against influenza infection and URTI. The potential effectiveness of these actions as non-pharmaceutical interventions, however, requires further investigation.

Identification of the Catechin Uptake Transporter Responsible for Intestinal Absorption of Epigallocatechin Gallate in Mice.

Many studies have shown that epigallocatechin gallate (EGCg) contribute to the health benefits of green tea, although its bioavailability is usually low. However, the mechanism underlying its intestinal absorption remains unclear. In human subjects, it has been reported that the bioavailability of EGCg increases after repeated oral catechin intake. We hypothesized that a certain uptake transporter was involved in this increase, and investigated a novel EGCg transporter. We first confirmed the increase in EGCg bioavailability in mice fed the catechin diet for two weeks. Then, in situ intestinal catechin infusion exhibited that the absorption of EGCg in the ileum was selectively increased in mice fed the catechin diet. A comprehensive analysis of plasma membrane proteins revealed 10 candidates for EGCg transporter, which were selectively increased in the ileum. EGCg uptake by a Xenopus laevis oocyte expressed with respective transporter revealed that oocytes microinjected with DTDST cRNA exhibited significantly higher EGCg uptake. Furthermore, uptake of EGCg by CHO-K1 cells stably expressing DTDST was significantly higher than that by mock cells, which was nullified by treating with a DTDST inhibitor. In conclusion, this study identified DTDST as a novel intestinal EGCg transporter that is upregulated after repeated oral catechin intake.

Green Tea Extracts Attenuate Brain Dysfunction in High-Fat-Diet-Fed SAMP8 Mice.

Unhealthy diet promotes progression of metabolic disorders and brain dysfunction with aging. Green tea extracts (GTEs) have various beneficial effects and alleviate metabolic disorders. GTEs have neuroprotective effects in rodent models, but their effects against brain dysfunction in models of aging fed unhealthy diets are still unclear. Here, we showed that GTEs attenuate high-fat (HF) diet-induced brain dysfunction in senescence-accelerated mouse prone-8 (SAMP8), a murine model of senescence. SAMP8 mice were fed a control diet, HF diet, or HF diet with 0.5% GTEs (HFGT) for four months. The HF diet reduced memory retention and induced amyloid ß1-42 accumulation, whereas GTEs attenuated these changes. In HF diet-fed mice, lipid oxidative stress, assessed by malondialdehyde levels, was increased. The levels of proteins that promote synaptic plasticity, such as brain-derived neurotrophic factor (BDNF) and postsynaptic density protein 95 (PSD95), were reduced. These alterations related to brain dysfunction were not observed in HFGT diet-fed mice. Overall, our data suggest that GTEs intake might attenuate brain dysfunction in HF diet-fed SAMP8 mice by protecting synaptic plasticity as well as via anti-oxidative effects. In conclusion, GTEs might ameliorate unhealthy diet-induced brain dysfunction that develops with aging.

Green tea extracts reduce leukocyte cell-Derived chemotaxin 2 and selenoprotein P levels in the livers of C57BL/6J mice fed a high-fat diet.

Epidemiological studies suggest that green tea extracts (GTEs), including catechins such as epigallocatechin gallate and epicatechin gallate, have a beneficial effect on obesity, hyperglycemia, insulin resistance, endothelial dysfunction, and inflammation. Although several studies have shown that catechins directly modulate the cellular and molecular alterations in the liver tissue, the contributions of indirect mechanisms underlying these systemic effects of catechins remain unclear. In this study, we report that, in the C57BL/6J mouse liver, GTEs reduce high-fat diet-induced increases in the levels of hepatokines, liver-derived secretary proteins such as leukocyte cell-derived chemotaxin 2 and selenoprotein P production, which have been shown to induce systemic adverse effects, including several metabolic diseases. These findings suggest that the systemic effects of GTEs involve the regulation of hepatokine production as an indirect mechanism.

Green tea extracts ameliorate high-fat diet-induced muscle atrophy in senescence-accelerated mouse prone-8 mice.

Muscle atrophy (loss of skeletal muscle mass) causes progressive deterioration of skeletal function. Recently, excessive intake of fats was suggested to induce insulin resistance, followed by muscle atrophy. Green tea extracts (GTEs), which contain polyphenols such as epigallocatechin gallate, have beneficial effects on obesity, hyperglycemia, and insulin resistance, but their effects against muscle atrophy are still unclear. Here, we found that GTEs prevented high-fat (HF) diet-induced muscle weight loss in senescence-accelerated mouse prone-8 (SAMP8), a murine model of senescence. SAMP8 mice were fed a control diet, an HF diet, or HF with 0.5% GTEs (HFGT) diet for 4 months. The HF diet induced muscle weight loss with aging (measured as quadriceps muscle weight), whereas GTEs prevented this loss. In HF diet-fed mice, blood glucose and plasma insulin concentrations increased in comparison with the control group, and these mice had insulin resistance as determined by homeostasis model assessment of insulin resistance (HOMA-IR). In these mice, serum concentrations of leukocyte cell-derived chemotaxin 2 (LECT2), which is known to induce insulin resistance in skeletal muscle, were elevated, and insulin signaling in muscle, as determined by the phosphorylation levels of Akt and p70 S6 kinases, tended to be decreased. In HFGT diet-fed mice, these signs of insulin resistance and elevation of serum LECT2 were not observed. Although our study did not directly show the effect of serum LECT2 on muscle weight, insulin resistance examined using HOMA-IR indicated an intervention effect of serum LECT2 on muscle weight, as revealed by partial correlation analysis. Accordingly, GTEs might have beneficial effects on age-related and HF diet-induced muscle weight loss, which correlates with insulin resistance and is accompanied by a change in serum LECT2.

Discovery and characterization of a novel potent, selective and orally active inhibitor for mammalian ELOVL6.

The elongase of long chain fatty acids family 6 (ELOVL6) is a rate-limiting enzyme for the elongation of saturated and monounsaturated long chain fatty acids. ELOVL6 is abundantly expressed in lipogenic tissues such as liver, and its mRNA expression is up-regulated in obese model animals. ELOVL6 deficient mice are protected from high-fat-diet-induced insulin resistance, suggesting that ELOVL6 might be a new therapeutic target for diabetes. We previously identified an indoledione compound, Compound A, as the first inhibitor for mammalian ELOVL6. In this study, we discovered a novel compound, Compound B, and characterized its biochemical and pharmacological properties. Compound B has a more appropriate profile for use as a pharmacological tool compared to Compound A. Chronic treatment with Compound B in model animals, diet-induced obesity (DIO) and KKAy mice, showed significant reduction in hepatic fatty acid composition, suggesting that it effectively inhibits ELOVL6 activity in the liver. However, no improvement in insulin resistance by ELOVL6 inhibition was found in these model animals. Further studies need to address the impact of ELOVL6 inhibition on pharmacological abnormalities in several model animals. This is the first report on pharmacology data from chronic studies using a selective ELOVL6 inhibitor. Compound B appears to be a useful tool to further understand the physiological roles of ELOVL6 and to evaluate the therapeutic potential of ELOVL6 inhibitors.

Identification and characterization of a selective radioligand for ELOVL6.

ELOVL6, a member of the elongation of very long-chain fatty acids (ELOVL) family, has recently been identified as the rate-limiting enzyme for the elongation of palmitoyl-CoA. ELOVL6 deficient mice are protected from high-fat diet induced insulin resistance, suggesting that ELOVL6 might be a promising target for the treatment of metabolic disorders. Despite the increasing interest in Elovl6 as a therapeutic target, the lack of chemical tools for this enzyme has limited further elucidation of the biochemical and pharmacological properties of ELOVL6. We have identified Compound-A, a potent inhibitor for ELOVL6, by screening our company library and subsequently optimizing hit compounds. Compound-A potently inhibited human and mouse ELOVL6 and displayed >100-fold greater selectivity for ELOVL6 over other ELOVL family members. Consistent with its potent and selective inhibitory activity toward ELOVL6, [(3)H]Compound-A bound to ELOVL6 with high affinity while showing no specific binding to other ELOVL enzymes. The observation that [(3)H]Compound-A bound to ELOVL6 in a palmitoyl-CoA-dependent manner in the absence of malonyl-CoA and NADPH suggests that Compound-A might recognize an enzyme-substrate complex, e.g. an acyl-enzyme intermediate. Collectively, these observations demonstrate that Compound-A and its tritiated form are useful tools for biochemical and pharmacological characterization of ELOVL6.

Intectin, a novel small intestine-specific glycosylphosphatidylinositol-anchored protein, accelerates apoptosis of intestinal epithelial cells.

Intestinal epithelial cells undergo rapid turnover and exfoliation especially at the villus tips. This process is modulated by various nutrients especially fat. Apoptosis is one of the important regulatory mechanisms of this turnover. Therefore, identification of the factors that control epithelial cell apoptosis should help us understand the mechanism of intestinal mucosal turnover. Here, we report the identification of a novel small intestine-specific member of the Ly-6 family, intectin, by signal sequence trap method. Intectin mRNA expression was exclusively identified in the intestine and localized at the villus tips of intestinal mucosa, which is known to undergo apoptosis. Intectin mRNA expression was modulated by nutrition. Intestinal epithelial cells expressing intectin were more sensitive to palmitate-induced apoptosis, compared with control intestinal epithelial cells, and such effect was accompanied by increased activity of caspase-3. Intectin expression also reduced cell-cell adhesion of intestinal epithelial cells.