Maternal Brown Rice Diet during Pregnancy Promotes Adipose Tissue Browning in Offspring via Reprogramming PKA Signaling and DNA Methylation.

SCOPE: Brown rice, the most consumed food worldwide, has been shown to possess beneficial effects on the prevention of metabolic diseases. However, the way in which maternal brown rice diet improves metabolism in offspring and the regulatory mechanisms remains unclear. The study explores the epigenetic regulation of offspring energy metabolic homeostasis by maternal brown rice diet during pregnancy. METHODS AND RESULTS: Female mice are fed brown rice during pregnancy, and then body phenotypes, the histopathological analysis, and adipose tissues biochemistry assay of offspring mice are detected. It is found that maternal brown rice diet significantly reduces body weight and fat mass, increases energy expenditure and heat production in offspring. Maternal brown rice diet increases uncoupling protein 1 (UCP1) protein level and upregulates the mRNA expression of thermogenic genes in adipose tissues. Mechanistically, protein kinase A (PKA) signaling is likely responsible in the induced thermogenic program in offspring adipocytes, and the progeny adipocytes browning program is altered due to decreased level of DNA methyltransferase 1 protein and hypomethylation of the transcriptional coregulator positive regulatory domain containing 16 (PRDM16). CONCLUSIONS: These findings demonstrate that maternal brown rice during pregnancy improves offspring mice metabolic homeostasis via promoting adipose browning, and its mechanisms may be mediated by DNA methylation reprogramming.

Quercetin Enhances the Availability of 5-Heptadecylresorcinol by Inhibiting the Expression of P-gp.

5-Heptadecylresorcinol (AR-C17), as the most important active monomer, is found in large quantities in wheat and triticale and plays a variety of health benefits, such as antidiabetic, anti-inflammatory, and antitumor. However, the low bioavailability of AR-C17 due to its low water solubility restricts its application. Moreover, the transport mechanism of AR-C17 is not fully understood. Here, we showed that the transport of AR-C17 in vitro was time- and concentration-dependent, and relatively higher temperature and lower pH obviously promoted the transport of AR-C17. Besides, transporters, especially P-glycoprotein (P-gp), markedly affected the transport of AR-C17 as well. Quercetin, a natural synergist in triticale bran (TB), was confirmed as an inhibitor of P-gp to promote the transport of AR-C17 in this study, and the bioavailability of AR-C17 reached the highest when the concentration ratio of quercetin to AR-C17 was 1:1.

Ferulic acid ameliorates hyperuricemia by regulating xanthine oxidase.

Hyperuricemia is characterized by elevated uric acid (UA) level in the body. The xanthine oxidase (XO) inhibitory ability is an important way to evaluate the anti-hyperuricemia effect of natural products. Ferulic acid (FA) is a phenolic acid compound, and it is a free radical scavenger with many physiological functions. The aim of this study was to investigate the structure-activity relationship, potential mechanism and interaction of FA as XO's inhibitor. In the cell experiment, using 1.25 mM adenosine to incubate for 24 h under the optimal conditions (37 °C, pH = 7.2) can increase the UA production by 1.34 folds. PCR analysis showed that FA could reduce the mRNA expression level of XO. FA inhibited XO in a mixed mode (IC50 = 13.25 µM). The fluorescence quenching of XO by FA occurs through a static mechanism, with an inhibition constant of Ki = 9.527 × 10-5 mol L-1 and an apparent coefficient of α = 1.768. The enthalpy and entropy changes were found as -267.79 KJ mol-1 and - 860.85 KJ mol-1, indicating that both hydrogen binding and hydrophobic are involved in the interaction of this polyphenolic natural compound with XO. Thus, FA supplementation may be a potential therapeutic strategy to improve hyperuricemia by reducing UA production.

MRTCM: A comprehensive dataset for probabilistic risk assessment of metals and metalloids in traditional Chinese medicine.

Traditional Chinese medicine (TCM) is still considered a global complementary or alternative medical system, but exogenous hazardous contaminants remain in TCM even after decocting. Besides, it is time-consuming to conduct a risk assessment of trace elements in TCMs with a non-automatic approach due to the wide variety of TCMs. Here, we present MRTCM, a cloud-computing infrastructure for automating the probabilistic risk assessment of metals and metalloids in TCM. MRTCM includes a consumption database and a pollutant database involving forty million rows of consumption data and fourteen types of TCM potentially toxic elements concentrations. The algorithm of probabilistic risk assessment was also packaged in MRTCM to assess the risks of eight elements with Monte Carlo simulation. The results demonstrated that 96.64% and 99.46% had no non-carcinogenic risk (hazard indices (HI) were < 1.0) for animal and herbal medicines consumers, respectively. After twenty years of exposure, less than 1% of the total carcinogenic risk (CRt) was > 10-4 for TCM consumers, indicating that they are at potential risk for carcinogenicity. Sensitivity analysis revealed that annual consumption and concentration were the main variables affecting the assessment results. Ultimately, a priority management list of TCMs was also generated, indicating that more attention should be paid to the non-carcinogenic risks of As, Mn, and Hg and the carcinogenic risks of As and Cr in Pheretima and Cr in Arcae Conch. In general, MRTCM could significantly enhance the efficiency of risk assessment in TCM and provide reasonable guidance for policymakers to optimize risk management.

Highland Barley Tea Polyphenols Extract Alleviates Skeletal Muscle Fibrosis in Mice by Reducing Oxidative Stress, Inflammation, and Cell Senescence.

The tea of roasted Highland barley is a cereal-based drink rich in polyphenols. A model of skeletal muscle senescence and fibrosis was constructed using d-galactose-induced C2C12 myotubes, and Highland barley tea Polyphenols (HBP) were extracted for the intervention. We found that HBP effectively alleviated oxidative stress, inflammation, and fibrosis induced by d-galactose-induced skeletal muscle senescence. Also, HBP treatment significantly down-regulated pro-fibrotic genes, inflammation, and oxidative stress levels in a contusion model of senescent mice. Reduced levels of SIRT3 protein was found to be an essential factor in skeletal muscle senescence and fibrosis in both cellular and animal models, while HBP treatment significantly increased SIRT3 protein levels and viability in skeletal muscle. The ability of HBP to mitigate skeletal muscle fibrosis and oxidative stress was significantly reduced after SIRT3 silencing. Together, these results suggest that HBP intervention can significantly alleviate aging-induced oxidative stress, inflammation, and skeletal muscle fibrosis, with the activation of SIRT3 as the underlying mechanism of action.

5-Heptadecylresorcinol Regulates the Metabolism of Thermogenic Fat and Improves the Thermogenic Capacity of Aging Mice via a Sirtuin 3-Adenosine Monophosphate-Activated Protein Kinase Pathway.

5-Heptadecylresorcinol (AR-C17), a well-known biomarker for whole grain rye consumption, is a primary homolog of alkylresorcinols. In this study, the effects of AR-C17 on the thermogenesis of brown adipocytes and 3T3-L1 adipocytes were investigated. The results showed that AR-C17 increased sirtuin 3 (Sirt3) expression, and the expressions of specific thermogenic genes in adipocytes were increased. Furthermore, AR-C17 increased the mitochondrial functions during the thermogenic activation of adipocytes. In in vivo study, AR-C17 increased the cold tolerance and thermogenic capacity of adipose tissues in aging mice. In addition, Sirt3 activity was required for AR-C17-induced thermogenesis. Meanwhile, AR-C17 increased adenosine monophosphate-activated protein kinase (AMPK) phosphorylation, and AMPK was involved in the regulation of AR-C17 on thermogenic adipocytes. Mechanically, AR-C17 upregulated a Sirt3-AMPK positive-feedback loop in adipocytes and further increased the expression of uncoupling protein 1 to activate thermogenesis. This study indicated that AR-C17 could be a promising thermogenic activator of adipocytes to alleviate obesity and aging-associated metabolic diseases.

Effect of boiling and roasting on phenolic components and their bioaccessibilities of highland barley.

This study investigated the effects of two thermal treatments (boiling and roasting) on highland barley (HB) phenolics and their bioaccessibilities (in-vitro). The UPLC Q-TOF-MS system was utilized to identify the individual phenolic compounds in HB. Twenty-one phenolics and two non-phenolic compounds were identified in HB, and the fundamental phenolics in HB were flavanols and phenolic acids. Both boiling and roasting improved free and bound phenolics' extractability and antioxidant activity by loosening the grain matrix. In-vitro simulated digestion showed that thermal-treated HB had higher bioaccessibility of phenolics than raw samples, and the boiled samples had higher bioaccessibility (36.3%) of phenolics than those of roasted samples (22.75%). Therefore, boiling and roasting could be used as non-chemical treatments to improve whole grain's phenolic content and their bioaccessibility.

Polyphenols in Highland Barley Tea Inhibit the Production of Advanced Glycosylation End-Products and Alleviate the Skeletal Muscle Damage.

SCOPE: Highland barley tea is a kind of caffeine-free cereal tea. Previous studies have shown that it is rich in polyphenol flavonoids. Here, the effect of Highland barley tea polyphenols (HBP) on the production of advanced glycosylation end-products and alleviate the skeletal muscle damage is systematically investigated. METHODS AND RESULTS: HBP effectively inhibits the formation of AGEs in vitro, and 12 phenolic compounds are identified. In addition, d-galactose is used to construct a mouse senescence model and intervenes with different doses of HBP. It is found that high doses of HBP effectively inhibit AGEs in serum and flounder muscle species and increased muscle mass in flounder muscle; also, high doses of HBP increase the expression of the mitochondrial functional protein SIRT3 and decrease the expression of myasthenia-related proteins. Furthermore, cellular experiments show that AGEs can significantly increase oxidative stress in skeletal muscle. CONCLUSION: These data indicate that the relationship between the biological activity and HBP properties is relevant since Highland barley can be a potential functional food to prevent AGEs-mediated skeletal muscle damage.

Geniposide suppresses thermogenesis via regulating PKA catalytic subunit in adipocytes.

Geniposide has been widely found to ameliorate many metabolic diseases. The recruitment and activation of brown/beige adipocytes are effective and promising methods for counteracting obesity and related diseases. However, the effect of geniposide on thermogenesis of adipocytes and its underlying mechanism have not yet been investigated. Here, we demonstrate that geniposide (25 mg/kg) reduces body temperature and cold tolerance of mice via suppressing thermogenic genes in interscapular brown adipose tissue (iBAT) and inguinal white adipose tissue (iWAT). Consistently, geniposide (20 mg/mL) suppresses thermogenic capacity of adipocytes (brown adipocytes and 3T3L1 preadipocyte cells) in vitro. Mechanistically, geniposide reduces the level of protein kinase A (PKA) catalytic subunit and further suppresses transcription activity and protein stability of uncoupling protein 1 (UCP1), leading to reduction of thermogenic capacity in adipocytes. Moreover, pharmacological PKA activation reverses geniposide-induced UCP1 inhibition, which indicated that geniposide suppresses thermogenesis of adipocytes via regulating PKA signaling. Together, our findings suggest that geniposide is an inhibitor of fat thermogenesis, establishing a novel function characteristic of geniposide.

Growth hormone receptor disrupts glucose homeostasis via promoting and stabilizing retinol binding protein 4.

Rationale: The molecular mechanisms underlying the pathogenesis of systemic insulin resistance in type 2 diabetes remain elusive. Growth hormone receptor (GHR) deficiency has long been known to improved insulin sensitivity. However, whether hepatic GHR overexpression or activation is a cause of insulin resistance is still unknown. The aim of this study was to identify the new role of GHR in systemic insulin resistance and explore the underlying mechanism. Method: Different samples obtained from obese humans, ob/ob mice, db/db mice, high-fat diet (HFD)-fed mice and primary mouse hepatocytes were used to evaluate the correlations between GHR and metabolic disorders. Recombinant adeno-associated viruses encoding GHR and STAT5 and GHR knockout mice were used to investigate the roles of hepatic GHR in glucose homeostasis. Tissue H&E, Oil Red O and PAS staining were performed for histomorphological analysis. Gel filtration chromatography was employed for the separation of serum RBP4-TTR complexes. Plasmids (related to GHR, STAT5 and HIF1α), siRNA oligos (siGHR and siSTAT5), luciferase activity and ChIP assays were used to explore the potential mechanism of hepatic GHR. Results: Here, we found that hepatic GHR expression was elevated during metabolic disorder. Accordingly, hepatic GHR overexpression disrupted systemic glucose homeostasis by promoting gluconeogenesis and disturbing insulin responsiveness in the liver. Meanwhile, hepatic GHR overexpression promoted lipolysis in white adipose tissue and repressed glucose utilization in skeletal muscle by promoting the circulating level of RBP4, which contributed to impaired systemic insulin action. A mechanistic study revealed that hepatic GHR disrupted systemic insulin sensitivity by increasing RBP4 transcription by activating STAT5. Additionally, overexpression of hepatic GHR promoted TTR transcriptional levels by enhancing the expression of HIF1α, which not only increased the protein stability of RBP4 but also inhibited renal clearance of RBP4 in serum. Conclusions: Hepatic GHR overexpression and activation accelerated systemic insulin resistance by increasing hepatic RBP4 production and maintaining circulating RBP4 homeostasis. Our current study provides novel insights into the pathogenesis of type 2 diabetes and its associated metabolic complications.

Novel Metabolic Regulation of Bile Acid Responses to Low Cholesterol in Whole-Grain-Diet-Fed Mice.

Hypercholesterolemia is a major risk factor for chronic metabolic diseases. Nevertheless, a whole-grain diet could ameliorate this issue in a number of ways, including by regulating bile acid metabolism. However, the potential mechanism is unclear. The aim of the current study is to explore the effects of whole-grain diets (brown rice diet and whole wheat diet) on bile acid homeostasis. After intervention for 8 weeks in mouse model, whole-grain diets showed reduced feed conversion ratio, and the lipid levels (total cholesterol (TC) and triglycerides (TG)) were also meliorated in the serum and liver of mice. Moreover, whole-grain diets reduced the expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) (cholesterol synthesis) in the liver of mice. Interestingly, whole-grain diets not only promoted the mRNA expressions of low-density lipoprotein receptor (LDLR), ATP binding cassette transporter G1 (ABCG1), and scavenger receptor class B type I (SR-BI) (reverse cholesterol transport) but also facilitated the expressions of cytochrome P450, family 7, subfamily a, polypeptide 1 (CYP7a1) and cytochrome P450, family 27, subfamily a, polypeptide 1 (CYP27a1) (bile acid synthesis). Further study found that whole-grain diets promoted intestinal bile acid reabsorption and reduced bile acid excretion. Our study provided a novel metabolic regulation of bile acids in response to reduced cholesterol levels induced by whole-grain diets.

Geniposide reduces cholesterol accumulation and increases its excretion by regulating the FXR-mediated liver-gut crosstalk of bile acids.

Hypercholesterolemia is the main risk factor to threaten human health and geniposide has been found to have hypolipidemic functions. However, its underlying mechanism is not clear. In this study, we firstly confirmed the hypolipidemic functions of geniposide in C57BL/6 and ApoE-/- mice (i.p, 50 mg/kg/d). Then hepatic or arterial lipid accumulation was analyzed through histomorphology. Moreover, the effects of geniposide on the bile acid metabolism were analyzed by the hepatic RNA-seq and biological molecular analysis. Mechanistically, GW4064, an FXR agonist, was carried out to verify the mechanisms of geniposide in human HepG2 and Caco2 cells. As expected, geniposide decreased the lipid accumulations both in plasma and liver. Morever, the atherosclerotic plaque shrank in HCD-fed ApoE-/- mice with geniposide treatment. The molecular analysis revealed that geniposide accelerated the hepatic synthesis of bile acids through inactivating the negative feedback regulation of bile acids mediated by FXR, led to the enhancive reverse cholesterol transport and cholesterol catabolism. What's more, geniposide reduced ileal FXR-mediated reabsorption of bile acids, resulting in the increasing excretion of bile acids. Our study pointed out the regulatory functions of geniposide on FXR-mediated liver-gut crosstalk of bile acids and geniposide might be a novel strategy for maintaining cholesterol homeostasis.

l-Arabinose Inhibits Colitis by Modulating Gut Microbiota in Mice.

l-Arabinose is a monosaccharide extracted from plants or fibers, which is known to have a variety of functional properties. In this study, we aim to investigate whether l-arabinose could inhibit colitis by modulating gut microbiota. l-Arabinose was administered in mice daily in a dextran sodium sulfate (DSS)-induced colitis model. The histological analysis, disease index, and the expression of inflammatory genes were measured. 16S-rRNA sequence analysis was performed to investigate gut microbiota. Intriguingly, we found that l-arabinose could repress DSS-induced colitis and inhibit p38-/p65-dependent inflammation activation. Besides that, our data revealed that l-arabinose-modulated DSS-induced gut microbiota were disturbed. Additionally, the perturbed gut microbiota was responsible for the suppressive effects of l-arabinose on DSS-induced colitis treated with antibiotics. Lastly, Caco-2 cells were used to confirm the protective effects of l-arabinose in colitis or inflammatory bowel disease. As expected, the protein expression levels in Caco-2 cells of pro-inflammatory genes, which were treated with l-arabinose and incubated with or without tumor necrosis factor alpha. Our work suggested that l-arabinose exerts anti-inflammation effects in DSS-induced colitis. These beneficial effects have correlations with the composition, diversity, and abundance of the gut microbiota regulated by l-arabinose. l-Arabinose could be a remarkable candidate as a functional food or novel therapeutic strategy for intestinal health.