Inhibitory Effects of Soluble Dietary Fiber from Foxtail Millet on Colorectal Cancer by the Restoration of Gut Microbiota.

Colorectal cancer (CRC) is a common malignant tumor that occurs in the colon. Gut microbiota is a complex ecosystem that plays an important role in the pathogenesis of CRC. Our previous studies showed that the soluble dietary fiber of foxtail millet (FMB-SDF) exhibited significant antitumor activity in vitro. The present study evaluated the anticancer potential of FMB-SDF in the azoxymethane (AOM)- and dextran sodium sulfate (DSS)-induced mouse CRC models. The results showed that FMB-SDF could significantly alleviate colon cancer symptoms in mice. Further, we found that FMB-SDF consumption significantly altered gut microbiota diversity and the overall structure and regulated the abundance of some microorganisms in CRC mice. Meanwhile, KEGG pathway enrichment showed that FMB-SDF can also alleviate the occurrence of colon cancer in mice by regulating certain cancer-related signaling pathways. In conclusion, our findings may provide a novel approach for the prevention and biotherapy of CRC.

Oat ß-D-glucan ameliorates type II diabetes through TLR4/PI3K/AKT mediated metabolic axis.

Diabetes is one of the major global public health problems. Our previous results found that oat ß-D-glucan exhibited ameliorative effects on diabetic mice, but the underlying mechanism is unclear. The present study indicates that oat ß-D-glucan increased glycogen content, decreased glycogen synthase (GS) phosphorylation and increased hepatic glycogen synthase kinase 3ß (GSK3ß) phosphorylation for glycogen synthesis via PI3K/AKT/GSK3-mediated GS activation. Moreover, oat ß-D-glucan inhibited gluconeogenesis through the PI3K/AKT/Foxo1-mediated phosphoenolpyruvate carboxykinase (PEPCK) decrease. In addition, oat ß-D-glucan enhanced glucose catabolism through elevated protein levels of COQ9, UQCRC2, COXIV and ATP5F complexes involved in oxidative phosphorylation, as well as that of TFAM, a key regulator of mitochondrial gene expression. Importantly, our results showed that oat ß-D-glucan maintained hepatic glucose balance via TLR4-mediated intracellular signal. After TLR4 blocking with anti-TLR4 antibody, oat ß-D-glucan had almost no effect on high glucose-induced HepG2 cells. These data revealed that oat ß-D-glucan maintains glucose balance by regulating the TLR4/PI3K/AKT signal pathway.

Millet shell polyphenols ameliorate atherosclerosis development by suppressing foam cell formation.

Polyphenols are bioactive compounds that occur naturally in plants, and they are widely used for disease prevention and health maintenance. In present study, the effects of millet shell polyphenols (MSPs) in thwarting atherosclerosis were explored. The results found that MSPs effectively inhibited the ability of macrophages to phagocytose lipids, and reduced the secretion of inflammatory factors IL-1ß and TNF-α by obstructing the expression of STAT3 and NF-κB in macrophages. Eventually, MSPs hindered the formation of macrophage-derived foam cells. On the other hand, MSPs promoted the transformation of HASMCs from synthesis to contraction by regulating the gene expression levels of smooth muscle myosin heavy chain (SMMHC), desmin (DES), smoothelin (SMTN) and elastin (ELN). Lipid phagocytosis inhibited along with this process, thereby reducing the formation of smooth muscle cell-derived foam cells. In addition, experiments in ApoE-/- mice also showed that MSPs increased high-density lipoprotein cholesterol (HDL-C). Collectively, MSPs play a role in preventing atherosclerosis by impeding foam cell production. This study offers an integrative strategy for thwarting plaque formation in the early stages of atherosclerosis in cardiovascular disease.

Ferulic Acid and P-Coumaric Acid Synergistically Attenuate Non-Alcoholic Fatty Liver Disease through HDAC1/PPARG-Mediated Free Fatty Acid Uptake.

Non-alcoholic fatty liver disease (NAFLD) is the most common liver disease and has become a growing public health concern worldwide. Polyphenols may improve high-fat diet (HFD)-related NAFLD. Our previous study found that ferulic acid (FA) and p-coumaric acid (p-CA) were the polyphenols with the highest content in foxtail millet. In this study, we investigated the mechanism underlying the impact of ferulic acid and p-coumaric acid (FA/p-CA) on non-alcoholic fatty liver (NAFLD). The association of FA and p-CA with fatty liver was first analyzed by network pharmacology. Synergistic ameliorating of NAFLD by FA and p-CA was verified in oleic acid (OA) and palmitic acid (PA) (FFA)-treated hepatocytes. Meanwhile, FA/p-CA suppressed final body weight and TG content and improved liver dysfunction in HFD-induced NAFLD mice. Mechanistically, our data indicated that FA and p-CA bind to histone deacetylase 1 (HDAC1) to inhibit its expression. The results showed that peroxisome proliferator activated receptor gamma (PPARG), which is positively related to HDAC1, was inhibited by FA/p-CA, and further suppressed fatty acid binding protein (FABP) and fatty acid translocase (CD36). It suggests that FA/p-CA ameliorate NAFLD by inhibiting free fatty acid uptake via the HDAC1/PPARG axis, which may provide potential dietary supplements and drugs for prevention of NAFLD.

Polyphenols from foxtail millet bran ameliorate DSS-induced colitis by remodeling gut microbiome.

Introduction: Polyphenols from plants possess the anti-inflammatory and gut microbiota modulated properties. Foxtail millet (Setaria italica L., FM) has potential medical and nutritional functions because of rich phenolic and other phytochemical components. Methods: Here, the study explored the effects of bound polyphenol of inner shell (BPIS) from FM bran on dextran sodium sulfate (DSS)-induced experimental colitis mice. Results: Results showed that BPIS administration effectively relieved the weight loss, decreased disease active index (DAI) scores, restrained the secretion of pro-inflammatory cytokines TNF-α, IL-6 and IL-1ß, increased anti-inflammatory cytokines IL-10, IL-4, IL-5. BPIS prevented gut barrier damage by enhancing tight junction proteins Claudin1, ZO-1 and Occludin, increasing the number of goblet cells and facilitating the gene expressions of mucin family. In addition, BPIS restored the gut microbiota composition and increased the relative abundance of commensal bacteria such as Lachnospiraceae and Rikenellaceae and restrained the growth of S24-7 and Staphylococcaceae. Concentrations of short-chain-fatty acids (SCFAs) generated by gut microbiota were elevated in BPIS treated colitis mice. Conclusion: These data suggest that BPIS effectively ameliorates DSS-induced colitis by preventing intestinal barrier damage and promoting gut microbiota community.

The Mixture of Ferulic Acid and P-Coumaric Acid Suppresses Colorectal Cancer through lncRNA 495810/PKM2 Mediated Aerobic Glycolysis.

Polyphenol-rich foods are gaining popularity due to their potential beneficial effects in the prevention and treatment of cancer. Foxtail millet is one of the important functional foods, riches in a variety of biologically active substance. Our previous study showed that ferulic acid (FA) and p-coumaric acid (p-CA) are the main anticancer components of foxtail millet bran, and the two have a significant synergistic effect. In the present study, the clinical application potential of FA and p-CA (FA + p-CA) were evaluated in vivo and in vitro. The FA and p-CA target gene enrichment analysis discovered that FA + p-CA were associated with aerobic glycolysis. It was further shown that FA + p-CA remodel aerobic glycolysis by inhibiting the glycolysis-associated lncRNA 495810 and the glycolytic rate-limiting enzyme M2 type pyruvate kinase (PKM2). Moreover, PKM2 expression was positively correlated with lncRNA 495810. More interestingly, the exogenous expression of lncRNA 495810 eliminated the inhibitory effects of FA + p-CA on aerobic glycolysis. Collectively, FA + p-CA obstruct the aerobic glycolysis of colorectal cancer cells via the lncRNA 495810/PKM2 axis, which provides a nutrition intervention and treatment candidate for colorectal cancer.

Millet shell polyphenols prevent atherosclerosis by protecting the gut barrier and remodeling the gut microbiota in ApoE-/- mice.

Atherosclerosis, the major cause of cardiovascular disease, is a chronic inflammatory disease. The anti-inflammatory effect of certain polyphenols has been recognized. Active polyphenols were extracted from millet shells (MSPs), and their main components including 3-hydroxybenzylhydrazine, luteolin-3',7-diglucoside, N-acetyltyramine, p-coumaric acid, vanillin, sinapic acid, ferulic acid and isophorone exhibited the anti-atherosclerotic potential in vitro. To explore the anti-atherosclerotic activity of MSPs in vivo, a classic atherosclerosis model was constructed in ApoE-/- mice fed with a high-fat diet. The results showed that MSPs effectively inhibited the development of atherosclerotic plaques in the aorta and reduced the levels of lipopolysaccharide (LPS) and inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß). A further study found that the expression of tight junction proteins (occludin, zona occludens-1 and claudin1) was obviously up-regulated in the MSPs-treated group at the mRNA and protein levels. Interestingly, MSPs significantly changed the structure of gut microbiota in ApoE-/- mice with a high-fat diet, which is characterized by the enriched Oscillospira and Ruminococcus, and the abridged Allobaculum at the genus level. Collectively, these results suggest that MSPs regulate the integrity of the gut barrier and the structure of the gut microbiota, ultimately inhibiting the development of atherosclerotic plaques. This study provides new insights into the potential cardiovascular protective effects induced by millet shell polyphenols.

Inhibitory Effects of Bound Polyphenol from Foxtail Millet Bran on Colitis-Associated Carcinogenesis by the Restoration of Gut Microbiota in a Mice Model.

Colorectal cancer (CRC) is a common malignant tumor occurring in the colon. It has been known that the gut microbiota is a complex ecosystem and plays an important role in the pathogenesis of colorectal cancer. Our previous study showed that bound polyphenol of the inner shell (BPIS) from foxtail millet bran exhibited significant antitumor activities in cancer cells and nude mice models. In the present study, the anticancer potential of BPIS is evaluated in the azoxymethane (AOM) and dextran sodium sulfate (DSS)-induced mouse CRC model. Results showed that BPIS could decrease the number and volume of tumors and protect the epithelial architecture from damage. Certain biomarkers associated with CRC formation, such as COX-2, EMR1, PCNA, and caspase-3, were strongly changed by BPIS. Moreover, by 16S rRNA gene sequence analysis, it was found that BPIS could remodel the overall structure of the gut microbiota from tumor-bearing mice toward that of the normal counterparts, including two phyla and eight genera, together with regulations on several genes that are responsible for 17 signaling pathways.