Dextran sulfate sodium-induced mild chronic colitis induced cognitive impairment accompanied by inhibition of neuronal maturation in adolescent mice.

INTRODUCTION: Epidemiological studies indicated that inflammatory bowel disease (IBD), with Crohn's disease and ulcerative colitis as its two main types, is associated with dementia. However, little is known about how adolescents with IBD will affect their cognitive ability as adults. The hippocampus, which is crucial for memory and adult neurogenesis, is closely associated with modulation of cognitive processes. Using a low kDa dextran sulfate sodium (DSS, 5 kDa)-induced chronic colitis (mild chronic colitis) mice model in adolescent mice, we investigated the effects of mild chronic colitis on cognitive functions and hippocampal neurogenesis from adolescent mice to adult mice. METHODS: We induced DSS-induced mild chronic colitis in C57BL/6J male mice by multiple-cycle administration of 1%-2% DSS in autoclaved drinking water. Mice were subjected to novel-object recognition and Y-maze tests. Neurogenesis markers and neuroinflammation-related proteins in the hippocampus of mice were measured. Tight junction proteins in the colon of mice were measured. RESULTS: Mild chronic colitis induced cognitive impairment and decreased adult neurogenesis. Notably, we found a positive correlation with the protein levels between tight junction protein, ZO-1, in the colon and mature neuron marker, NeuN, in the hippocampus. Moreover, mild chronic colitis leads to hippocampal neuroinflammation in adolescent mice. CONCLUSION: Our findings provide new evidence of the association between IBD and dementia risk.

Circulating miRNA profiles in mice plasma following flavonoid intake.

BACKGROUND: Polyphenols, including flavonoids, have been the focus of numerous studies that have revealed diverse health benefits. MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that function as posttranscriptional regulators of gene expression. miRNAs can be detected in the blood and these so-called circulating miRNAs are potential biomarkers of various diseases. This study aimed to explore circulating miRNAs in plasma as a means to predict the biological effects of functional food ingredients. METHODS AND RESULTS: We used miRNA microarray analysis to compare plasma miRNA levels in mice orally administered three flavonoids (daidzein, quercetin, and delphinidin). Several miRNAs were differentially expressed in plasma from mice in each treatment group compared with the vehicle-treated group. The plasma levels of miR-25-5p, miR-146b-5p, and miR-501-3p were increased in the flavonoid-treated and the plasma levels of miR-148b-3p, miR-669e-5p, and miR-3962 were decreased. CONCLUSIONS: Our findings suggested that flavonoids alter miRNA expression in plasma and identified promising plasma miRNAs for assessing the functionality of flavonoids.

Eriodictyol-Amplified 67-kDa Laminin Receptor Signaling Potentiates the Antiallergic Effect of O-Methylated Catechin.

(-)-Epigallocatechin-3-O-(3-O-methyl) gallate (1, EGCG3″Me), an antiallergic O-methylated catechin, is present in high quantities in the green tea cultivar "Benifuuki" (Camellia sinensis L.). Previous studies have shown that EGCG3″Me inhibited basophil degranulation mediated through the cell-surface 67-kDa laminin receptor (67LR), but the mechanisms are not fully elucidated. This study aimed to investigate the mechanisms underlying the inhibitory effect of EGCG3″Me on IgE/antigen (Ag)-mediated degranulation and the combined effect of EGCG3″Me with eriodictyol (2), a bioactive flavanone. EGCG3″Me inhibited ß-hexosaminidase release from the rat basophilic/mast cell line RBL-2H3 stimulated by IgE/Ag and induced acid sphingomyelinase (ASM) activity. This induction was inhibited by anti-67LR antibody treatment. The ASM-specific inhibitor desipramine inhibited EGCG3″Me-induced suppression of degranulation. The soluble guanylate cyclase (sGC) inhibitor NS2028 weakened the potency of EGCG3″Me, and the sGC activator BAY41-2272 suppressed degranulation. The ability of EGCG3″Me to induce ASM activity and inhibit degranulation was amplified by eriodictyol. Furthermore, oral administration of the lemon-peel-derived eriodyctiol-7-O-glucoside (3) potentiated the suppressive effect of EGCG3″Me-rich "Benifuuki" green tea on the IgE/Ag-induced passive cutaneous anaphylaxis (PCA) reaction in BALB/c mice. These results suggest that EGCG3″Me inhibits IgE/Ag-mediated degranulation by inducing the 67LR/sGC/ASM signaling pathway, and eriodictyol amplifies this signaling.

Regulatory effect of Epigallocatechin-3-O-gallate on circular RNA expression in mouse liver.

There are few studies on the connection between food components and circular RNA (circRNA), a type of noncoding RNA that is significant for living organisms. (-)-Epigallocatechin-3-O-gallate (EGCG) has been reported to have various biological effects, and elucidation of the molecular mechanism is important for clarifying the functionality of EGCG. In the current study, we looked at how EGCG regulates the expression of circRNA in the liver, which expresses a lot of circRNAs. Mice were given EGCG (10 mg/kg b.w.) orally for one week before circRNA microarray testing was done on their livers. The microarray analysis revealed that mice treated with EGCG had altered expression of 35 circRNAs in their livers. To clarify the function of mmu_circRNA_011775, one of the circRNAs upregulated by EGCG, mouse liver cells after the mmu_circRNA_011775 expression vector was transfected into NMuLi cells, next-generation sequencing (NGS) was used to analyze the gene expression. NGS analysis shows that the expression of the genes responsible for liver fibrosis and inflammation. Gene ontology (GO) analysis showed that mmu_circRNA_011775 changed the meaning of GO terms associated with the cardiovascular system. In the microarray, EGCG altered 35 genes expression. Among them, pre-ribosomal RNA-derived circRNA mmu_circRNA_011775 regulated the expression of various genes related to liver fibrosis and cardiovascular system.

Bioactivity-boosting strategy based on combination of anti-allergic O-methylated catechin with a Citrus flavanone, hesperetin.

Many patients with allergies have anxiety about taking anti-allergic medicines due to their side effects and increased medical expenses. Thus, developing functional foods/agricultural products for allergy prevention is strongly desired. In this study, we revealed that a Citrus flavanone, hesperetin, amplified IgE/antigen-mediated degranulation-inhibitory potency of anti-allergic catechin, (-)-epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3''Me), in the rat basophilic/mast cell line RBL-2H3. Hesperetin also significantly elevated the activation of acid sphingomyelinase (ASM), essential for eliciting anti-allergic effect of EGCG3''Me through the cell surficial protein, 67-kDa laminin receptor (67LR). Furthermore, oral administration of the highly absorbent hesperidin, α-glucosyl hesperidin, also enhanced the inhibitory potency of EGCG3''Me-rich 'Benifuuki' green tea (Camellia sinensis L.) on passive cutaneous anaphylaxis (PCA) reaction evoked by IgE/antigen in BALB/c mice. These observations indicate that hesperetin amplifies the ability of EGCG3''Me to inhibit the IgE/antigen-mediated degranulation through activating ASM signaling.

(-)­Epigallocatechin­3­O­gallate upregulates the expression levels of miR­6757­3p, a suppressor of fibrosis­related gene expression, in extracellular vesicles derived from human umbilical vein endothelial cells.

As pulmonary fibrosis (PF), a severe interstitial pulmonary disease, has such a poor prognosis, the development of prevention and treatment methods is imperative. (-)-Epigallocatechin-3-O-gallate (EGCG), one of the major catechins in green tea, exerts an antifibrotic effect, although its mechanism remains unclear. Recently, it has been reported that microRNAs (miRNAs or miRs) transported by extracellular vesicles (EVs) from vascular endothelial cells (VECs) are involved in PF. In the present study, the effects of EGCG on the expression of miRNAs in EVs derived from human umbilical vein endothelial cells (HUVECs) were assessed and miRNAs with antifibrotic activity were identified. miRNA microarray analysis revealed that EGCG modulated the expression levels of 31 miRNAs (a total of 27 miRNAs were upregulated, and 4 miRNAs were downregulated.) in EVs from HUVECs. Furthermore, TargetScan analysis indicated that miR-6757-3p in particular, which exhibited the highest degree of change, may target transforming growth factor-ß (TGF-ß) receptor 1 (TGFBR1). To evaluate the effects of miR-6757-3p on TGFBR1 expression, human fetal lung fibroblasts (HFL-1) were transfected with an miR-6757-3p mimic. The results demonstrated that the miR-6757-3p mimic downregulated the expression of TGFBR1 as well the expression levels of fibrosis-related genes including fibronectin and α-smooth muscle actin in TGF-ß-treated HFL-1 cells. In summary, EGCG upregulated the expression levels of miR-6757-3p, which may target TGFBR1 and downregulate fibrosis-related genes, in EVs derived from VECs.

Sesame lignans upregulate glutathione S-transferase expression and downregulate microRNA-669c-3p.

Oxidative stress is associated with aging and pathologies such as cardiovascular diseases, Alzheimer's disease, and cancer. Glutathione S-transferase (GST), a family of detoxification enzymes, plays a crucial role in countering oxidative stress. Therefore, there is a need for the development of physiologically functional foods and agricultural products, which enhance GST activity. Sesamin and episesamin are major lignans in refined sesame oil that exhibit beneficial properties including antioxidative stress effects. A previous study showed that sesamin upregulated GST activity. This study aimed to elucidate the mechanism underlying the GST activity enhancement elicited by sesame lignans. C57BL/6J mice were orally administered 20 mg/kg body weight sesame lignans (sesamin:episesamin=1:1) for 7 days. Oral administration of sesame lignans increased the GST activity in the mouse liver. Furthermore, the lignans upregulated GSTA1, GSTA4, and GSTM4 protein expression. Microarray analysis revealed that sesame lignans changed the expression of various microRNAs (miRNAs) (84 upregulated, 19 downregulated). We also found 16 miRNAs, including miR-669c-3p, that may negatively regulate GST expression among the 19 miRNAs with reduced expression caused by the sesame lignans. miR-669c is reportedly negatively correlated with GST. Additionally, we transfected NMuLi cells with an miR-669c-3p mimic and evaluated the effect of miR-669c-3p on GST mRNA and protein expressions. The results showed that the miR-669c-3p mimic suppressed the mRNA and protein levels of GSTA4 and GSTM4. In conclusion, sesame lignans increased GST protein expression and activity and downregulated miRNAs, including miR-669c-3p, which is a possible suppressor of GST.

Glucosyl-hesperidin enhances the cyclic guanosine monophosphate-inducing effect of a green tea polyphenol EGCG.

Animal and clinical studies have revealed that (-)-epigallocatechin-3-O-gallate (EGCG), one of the major bioactive polyphenols in green tea, showed several pharmacological effects including anti-obesity effect and anti-inflammatory effect. We previously reported that the second messenger cyclic guanosine monophosphate (cGMP) mediates its anti-inflammatory and anti-cancer properties. Here we demonstrated that glucosyl-hesperidin, enhances the cGMP-inducing effects of green tea extract in vivo. Moreover, glucosyl-hesperidin intake potentiated the green tea-elicited upregulation of the anti-inflammatory factor, toll-interacting protein.

EGCG down-regulates MuRF1 expression through 67-kDa laminin receptor and the receptor signaling is amplified by eriodictyol.

(-)-epigallocatechin-3-O-gallate (EGCG) is a bioactive polyphenol in green tea. Previous studies have demonstrated the beneficial effects of EGCG on muscle mass and muscle atrophy. In the current study, we investigated the mechanisms underlying effect of EGCG on muscle atrophy. It was demonstrated that EGCG suppressed muscle-specific ubiquitin ligase, muscle RING Finger 1 (MuRF1) expression through 67-kDa laminin receptor (67LR). Previous studies have shown that eriodictyol potentiates the anti-tumor activities of EGCG by amplifying 67LR signaling. Therefore, we investigated the effects of EGCG and eriodictyol on the MuRF1 expression in C2C12 myotubes. The combined treatment of EGCG and eriodictyol significantly suppressed MuRF1 expression in dexamethasone-treated C2C12 myotubes. Tail suspension was maintained for 10 consecutive days using C57BL6/J mice, and during this time EGCG and eriodictyol were orally administered. In the gastrocnemius muscle, the muscle mass loss was inhibited by the combination of EGCG and eriodictyol. Therefore, EGCG may prevent muscle atrophy by inducing 67LR signaling and eriodictyol amplifies this pathway.

Plasma Homocysteine Concentration is Associated with the Expression Level of Folate Receptor 3.

Folic acid and folate receptors (FOLRs) play an important role in the downregulation of homocysteine (Hcy), a risk factor of Alzheimer's disease, thrombosis, neuropsychiatric illness and fractures. While several studies have reported that FOLR1 and FOLR2 import folic acid into cells, the role of FOLR3 remains unknown. In this study, we evaluated the impact of FOLR3 on the metabolism of Hcy alongside its protective effect against homocysteine-induced neurotoxicity. To reveal the role of FOLR3, we constructed FOLR3-overexpressed HEK293 cells (FOLR3+ cells) and evaluated cell growth, folic acid intake and Hcy-induced neurotoxicity. Subjects with a high expression of FOLR3 exhibited low levels of plasma homocysteine. The ectopic expression of FOLR3 enhanced cell growth, and the enhanced effect was neutralised by folic acid-deficient media. The Western blot analysis revealed that FOLR3 is secreted into cell supernatant. The folic acid intake of FOLR3+ cells was higher than that of wild-type cells. Supernatant from FOLR3+ cells showed a protective effect on Hcy-induced cytotoxicity. FOLR3 expression in plasma is negatively correlated with plasma homocysteine. Our study emphasizes the role of FOLR3 in the intake of folic acid into cells on the one hand and its protective role in Hcy-induced cytotoxicity on the other.