Date (Phoenix dactylifera L.) seed oil is an agro-industrial waste with biopreservative effects and antimicrobial activity.

Antimicrobial resistant (AMR) infections are a leading health threat globally. Previous literature has underscored the farm-to-fork continuum as a potential focal point for the emergence and spread of AMR. In the present study, date (Phoenix dactylifera L.) seed oil was investigated for its chemical composition and antimicrobial activity against common foodborne pathogens including Escherichia coli O157:H7, Salmonella enteritidis, Salmonella typhimurium, Listeria monocytogenes, and Staphylococcus aureus in vitro, and in ultra-high-temperature (UHT) milk as a food model at storage temperatures of 37 °C (24 h) and 10 °C (7 days). GC-MS analysis of the seed oil revealed 20 compounds, with octadecane (52.2-55.4%) as the major constituent, and the fatty acid analysis revealed 17 fatty acids, with oleic acid (42.3-43.1%) as the main constituent, followed by lauric acid (19.8-20.3%). The antimicrobial activity of date seed oil was determined using the microdilution method. A significant inhibition against gram-negative bacteria was noted in microbiological media and UHT milk, with a log reduction ranging from 4.3 to 6.7 (at 37 °C/24 h) and 5.7 to 7.2 (at 10 °C/7 days), respectively, at oil concentrations ranging between 10 and 15 µl/ml. The oil showed a similar significant inhibitory effect against St. aureus in the microbiological media (2.0-6.0 log reduction), whereas the inhibitory effect against L. monocytogenes was not statistically significant, with a maximum log reduction of 0.64 achieved at a concentration of 10 µl/ml. AFM imaging of the bacteria showed that oil treatment led to morphological changes in the bacteria including the formation of distorted shapes, surface blebs, indentations, stiffness, and swelling. Present findings suggest that date seed oil can be a promising by-product with potential antimicrobial activity and a food preservative.

Efficacy and Interpretability Analysis of Noninvasive Imaging Based on Computed Tomography in Patients with Hepatocellular Carcinoma After Initial Transarterial Chemoembolization.

RATIONALE AND OBJECTIVES: The objective of this study is to accurately and timely assess the efficacy of patients with hepatocellular carcinoma (HCC) after the initial transarterial chemoembolization (TACE). MATERIALS AND METHODS: This retrospective study consisted of 279 patients with HCC in Center 1, who were split into training and validation cohorts in the ratio of 4:1, and 72 patients in Center 2 as an external testing cohort. Radiomics signatures both in the arterial phase and venous phase of contrast-enhanced computed tomography images were selected by univariate analysis, correlation analysis, and least absolute shrinkage and selection operator regression to build the predicting models. The clinical model and combined model were constructed by independent risk factors after univariate and multivariate logistic regression analysis. The biological interpretability of radiomics signatures correlating transcriptome sequencing data was explored using publicly available data sets. RESULTS: A total of 31 radiomics signatures in the arterial phase and 13 radiomics signatures in the venous phase were selected to construct Radscore_arterial and Radscore_venous, respectively, which were independent risk factors. After constructing the combined model, the area under the receiver operating characteristic curve in three cohorts was 0.865, 0.800, and 0.745, respectively. Through correlation analysis, 11 radiomics signatures in the arterial phase and 4 radiomics signatures in the venous phase were associated with 8 and 5 gene modules, respectively (All P < .05), which enriched some pathways closely related to tumor development and proliferation. CONCLUSION: Noninvasive imaging has considerable value in predicting the efficacy of patients with HCC after initial TACE. The biological interpretability of the radiological signatures can be mapped at the micro level.

Research Hotspots and Trends Analysis of TFEB: A Bibliometric and Scientometric Analysis.

Objective: To explore the development context, research hotspots and frontiers of Transcription factor EB (TFEB) from 1991 to 2021 by bibliometric analysis. Methods: Publications about TFEB research from 1991 to 2021 were retrieved from the Web of Science Core Collection (WoSCC). Excel 2007 was used to collect basic information, including publications, research areas. VOSviewer 1.6.17 was used to analyze co-authorship of countries, institutes and authors. Co-citation of cited authors, cited references were analyzed by CiteSpace V.5.8.R3. In addition, CiteSpace was used to analyze keywords cluster and forecast research frontiers. Results: A total of 1,059 literatures were retrieved, including 1,340 research institutes and 393 academic journals. The main area of research related to TFEB is biology (340), the most published country and institutes were the United States (487) and Baylor College of Medicine (70). Settembre C owned the highest co-citations (663). Trending keywords may indicate frontier topics, including "Alzheimer's disease," "Parkinson's disease," "(p21; q12)," "melanoma," "pancreatic cancer," "breast cancer," "calcineurin," "TFE3," "trehalose," and "curcumin." Conclusion: This research provides valuable information for the study of TFEB. Disease research focuses more on neurodegenerative diseases (NDs) and tumors. Trehalose and curcumin are novel agents acting on TFEB. Rap-TRPML1-Calcineurin-TFEB and TFE3 are increasing signal pathway researches, similarly, the molecular biological mechanism of TFEB needs further exploration.

Dietary Flavonoids as Modulators of Lipid Metabolism in Poultry.

Flavonoids, naturally-occurring compounds with multiple phenolic structures, are the most widely distributed phytochemicals in the plant kingdom, and are mainly found in vegetables, fruits, grains, roots, herbs, and tea and red wine products. Flavonoids have health-promoting effects and are indispensable compounds in nutritional and pharmaceutical (i.e., nutraceutical) applications. Among the demonstrated bioactive effects of flavonoids are anti-oxidant, anti-inflammatory, and anti-microbial in a range of research models. Through dietary formulation strategies, numerous flavonoids provide the ability to support bird health while improving the nutritional quality of poultry meat and eggs by changing the profile of fatty acids and reducing cholesterol content. A number of such compounds have been shown to inhibit adipogenesis, and promote lipolysis and apoptosis in adipose tissue cells, and thereby have the potential to affect fat accretion in poultry at various ages and stages of production. Antioxidant and anti-inflammatory properties contribute to animal health by preventing free radical damage in tissues and ameliorating inflammation in adipose tissue, which are concerns in broiler breeders and laying hens. In this review, we summarize the progress in understanding the effects of dietary flavonoids on lipid metabolism and fat deposition in poultry, and discuss the associated physiological mechanisms.

Deletion of GPR30 Drives the Activation of Mitochondrial Uncoupling Respiration to Induce Adipose Thermogenesis in Female Mice.

Thermogenic adipocytes possess a promising approach to combat obesity with its capability promoting energy metabolism. We previously discovered that deletion of GPR30 (GPRKO), a presumably membrane-associated estrogen receptor, protected female mice from developing obesity, glucose intolerance, and insulin resistance when challenged with a high-fat diet (HFD). In vivo, the metabolic phenotype of wild type (WT) and GPRKO female mice were measured weekly. Acute cold tolerance test was performed. Ex vivo, mitochondrial respiration of brown adipose tissue (BAT) was analyzed from diet-induced obese female mice of both genotypes. In vitro, stromal vascular fractions (SVF) were isolated for beige adipocyte differentiation to investigate the role of GPR30 in thermogenic adipocyte. Deletion of GPR30 protects female mice from hypothermia and the mitochondria in BAT are highly energetic in GPRKO animals while the WT mitochondria remain in a relatively quiescent stage. Consistently, GPR30 deficiency enhances beige adipocyte differentiation in white adipose tissue (WAT) and activates the thermogenic browning of subcutaneous WAT due to up-regulation of UCP-1, which thereby protects female mice from HFD-induced obesity. GPR30 is a negative regulator of thermogenesis, which at least partially contributes to the reduced adiposity in the GPRKO female mice. Our findings provide insight into the mechanism by which GPR30 regulates fat metabolism and adiposity in female mice exposed to excess calories, which may be instrumental in the development of new therapeutic strategies for obesity.

Noninvasive Imaging Evaluation Based on Computed Tomography of the Efficacy of Initial Transarterial Chemoembolization to Predict Outcome in Patients with Hepatocellular Carcinoma.

Purpose: This study aims to develop a new model to more comprehensively and accurately predict the survival of patients with HCC after initial TACE. Patients and Methods: The whole cohort (n = 102) was randomly divided into a training cohort and a validation cohort in the ratio of 8:2. The optimal radiomics signatures were screened using the least absolute shrinkage and selection operator algorithm (LASSO) regression for constructing the radscore to predict overall survival (OS). The C-index (95% confidence interval, CI), calibration curve, and decision curve analysis (DCA) were used to evaluate the performance of the models. The independent risk factors (hazard ratio, HR) for predicting OS were stratified by Kaplan-Meier (K-M) analysis and the Log rank test. Results: The median OS was 439 days (95% CI: 215.795-662.205) in whole cohort, and in the training cohort and validation cohort, the median OS was 552 days (95% CI: 171.172-932.828), 395 days (95% CI: 309.415-480.585), respectively (P = 0.889). After multivariate cox regression, the combined radscore-clinical model was consisted of radscore (HR: 2.065, 95% CI: 1.285-3.316; P = 0.0029) and post-response (HR: 1.880, 95% CI: 1.310-2.697; P = 0.0007), both of which were independent risk factors for the OS. In the validation cohort, the efficacy of both the radscore (C-index: 0.769, 95% CI: 0.496-1.000) and combined model (C-index: 0.770, 95% CI: 0.581-0.806) were higher than that of the clinical model (C-index: 0.655, 95% CI: 0.508-0.802). The calibration curve of the combined model for predicting OS presented good consistency between observations and predictions in both the training cohort and validation cohort. Conclusion: Noninvasive imaging has a good prediction performance of survival after initial TACE in patients with HCC. The combined model consisting of post-response and radscore may be able to better predict outcome.

Natural Compound Resveratrol Attenuates TNF-Alpha-Induced Vascular Dysfunction in Mice and Human Endothelial Cells: The Involvement of the NF-κB Signaling Pathway.

Resveratrol, a natural compound in grapes and red wine, has drawn attention due to potential cardiovascular-related health benefits. However, its effect on vascular inflammation at physiologically achievable concentrations is largely unknown. In this study, resveratrol in concentrations as low as 1 µm suppressed TNF-α-induced monocyte adhesion to human EA.hy926 endothelial cells (ECs), a key event in the initiation and development of atherosclerosis. Low concentrations of resveratrol (0.25-2 µm) also significantly attenuated TNF-α-stimulated mRNA expressions of MCP-1/CCL2 and ICAM-1, which are vital mediators of EC-monocyte adhesion molecules and cytokines for cardiovascular plaque formation. Additionally, resveratrol diminished TNF-α-induced IκB-α degradation and subsequent nuclear translocation of NF-κB p65 in ECs. In the animal study, resveratrol supplementation in diet significantly diminished TNF-α-induced increases in circulating levels of adhesion molecules and cytokines, monocyte adhesion to mouse aortic ECs, F4/80-positive macrophages and VCAM-1 expression in mice aortas and restored the disruption in aortic elastin fiber caused by TNF-α treatment. The animal study also confirmed that resveratrol blocks the activation of NF-κB In Vivo. In conclusion, resveratrol at physiologically achievable concentrations displayed protective effects against TNF-α-induced vascular endothelial inflammation in vitro and In Vivo. The ability of resveratrol in reducing inflammation may be associated with its role as a down-regulator of the NF-κB pathway.

A monoclonal antibody neutralizes pesudorabies virus by blocking gD binding to the receptor nectin-1.

Pseudorabies virus (PRV) was isolated from some human cases recently and the infected patients manifested respiratory dysfunction and acute neurological symptoms. However, no effective drug or vaccine, preventing the progression of PRV infection, is available. Nectin-1 was the only reported receptor for PRV cell entry both swine and human origin, representing an excellent target to block PRV infection, and especially its transmission from pigs to humans. A PRV-gD specific mAbs (10B6) was isolated from hybridomas and its neutralizing activities in vitro and in vivo were determined. 10B6 exhibited effective neutralizing activities in vitro with IC50 = 2.514 µg/ml and 4.297 µg/ml in the presence and absence of complement. And in vivo, 10B6 provided 100% protection against PRV lethal challenge with a dose of 15 mg/kg. Further, 10B6 could bind to a conserved epitope, 316QPAEPFP322, locating in gD pro-fusion domain, and finally blocks the binding of PRV-gD to nectin-1. Moreover, 10B6 showed an effective inhibition on PRV cell-attachment in a cell type-independent manner and could also block the virus spreading among cells. 10B6 exhibited effectively neutralizing activities to Chinese PRV variant strain in vitro and in vivo by blocking gD binding to nectin-1, implied both prophylactic and therapeutic interventions against PRV infections.

Sirt1 coordinates with ERα to regulate autophagy and adiposity.

Sex difference in adiposity has long been recognized but the mechanism remains incompletely understood. Previous studies suggested that adiposity was regulated by autophagy in response to energy status change. Here, we show that the energy sensor Sirt1 mediates sex difference in adiposity by regulating autophagy and adipogenesis in partnership with estrogen receptor α (ERα). Autophagy and adipogenesis were suppressed by Sirt1 activation or overexpression, which was associated with reduced sex difference in adiposity. Mechanistically, Sirt1 deacetylated and activated AKT and STAT3, resulting in suppression of autophagy and adipogenesis via mTOR-ULK1 and p55 cascades. ERα induced Sirt1 expression and inhibited autophagy in adipocytes, while silencing Sirt1 reversed the effects of ERα on autophagy and promoted adipogenesis. Moreover, Sirt1 deacetylated ERα, which constituted a positive feedback loop in the regulation of autophagy and adiposity. Our results revealed a new mechanism of Sirt1 regulating autophagy in adipocytes and shed light on sex difference in adiposity.

Dietary Anti-Aging Polyphenols and Potential Mechanisms.

For years, the consumption of a diet rich in fruits and vegetables has been considered healthy, increasing longevity, and decreasing morbidities. With the assistance of basic research investigating the potential mechanisms, it has become clear that the beneficial effects of plant-based foods are mainly due to the large amount of bioactive phenolic compounds contained. Indeed, substantial dietary intervention studies in humans have supported that the supplementation of polyphenols have various health-promoting effects, especially in the elderly population. In vitro examinations on the anti-aging mechanisms of polyphenols have been widely performed, using different types of natural and synthetic phenolic compounds. The aim of this review is to critically evaluate the experimental evidence demonstrating the beneficial effects of polyphenols on aging-related diseases. We highlight the potential anti-aging mechanisms of polyphenols, including antioxidant signaling, preventing cellular senescence, targeting microRNA, influencing NO bioavailability, and promoting mitochondrial function. While the trends on utilizing polyphenols in preventing aging-related disorders are getting growing attention, we suggest the exploration of the beneficial effects of the combination of multiple polyphenols or polyphenol-rich foods, as this would be more physiologically relevant to daily life.

The Emerging Role of Polyphenols in the Management of Type 2 Diabetes.

Type 2 diabetes (T2D) is a fast-increasing health problem globally, and it results from insulin resistance and pancreatic ß-cell dysfunction. The gastrointestinal (GI) tract is recognized as one of the major regulatory organs of glucose homeostasis that involves multiple gut hormones and microbiota. Notably, the incretin hormone glucagon-like peptide-1 (GLP-1) secreted from enteroendocrine L-cells plays a pivotal role in maintaining glucose homeostasis via eliciting pleiotropic effects, which are largely mediated via its receptor. Thus, targeting the GLP-1 signaling system is a highly attractive therapeutic strategy to treatment T2D. Polyphenols, the secondary metabolites from plants, have drawn considerable attention because of their numerous health benefits, including potential anti-diabetic effects. Although the major targets and locations for the polyphenolic compounds to exert the anti-diabetic action are still unclear, the first organ that is exposed to these compounds is the GI tract in which polyphenols could modulate enzymes and hormones. Indeed, emerging evidence has shown that polyphenols can stimulate GLP-1 secretion, indicating that these natural compounds might exert metabolic action at least partially mediated by GLP-1. This review provides an overview of nutritional regulation of GLP-1 secretion and summarizes recent studies on the roles of polyphenols in GLP-1 secretion and degradation as it relates to metabolic homeostasis. In addition, the effects of polyphenols on microbiota and microbial metabolites that could indirectly modulate GLP-1 secretion are also discussed.

The R2R3-MYB transcription factor CsMYB73 negatively regulates l-Theanine biosynthesis in tea plants (Camellia sinensis L.).

l-Theanine, a non-proteinaceous amino acid abundantly present in tea (Camellia sinensis), contributes to the umami flavor of tea and has beneficial effects on human health. While key l-theanine biosynthetic genes have been well documented, their transcriptional regulation remains poorly understood. In this study, we determined the l-theanine contents in tea leaves of two cultivars at three developmental stages and investigated the expression patterns of the l-theanine biosynthetic genes CsGS1 and CsGS2. Additionally, we identified an R2R3-MYB transcription factor, CsMYB73, belonging to subgroup 22 of the R2R3-MYB family. CsMYB73 expression negatively correlated with l-theanine accumulation during leaf maturation. We found that CsMYB73, as a nuclear protein, binds to the promoter regions of CsGS1 and CsGS2 via MYB recognition sequences and represses the transcription of CsGS1 and CsGS2 in tobacco leaves. Collectively, our results demonstrate that CsMYB73 is a transcriptional repressor involved in l-theanine biosynthesis in tea plants. Our findings might contribute to future tea plant breeding strategies.

Does GPER Really Function as a G Protein-Coupled Estrogen Receptor in vivo?

Estrogen can elicit pleiotropic cellular responses via a diversity of estrogen receptors (ERs)-mediated genomic and rapid non-genomic mechanisms. Unlike the genomic responses, where the classical nuclear ERα and ERß act as transcriptional factors following estrogen binding to regulate gene transcription in estrogen target tissues, the non-genomic cellular responses to estrogen are believed to start at the plasma membrane, leading to rapid activation of second messengers-triggered cytoplasmic signal transduction cascades. The recently acknowledged ER, GPR30 or GPER, was discovered in human breast cancer cells two decades ago and subsequently in many other cells. Since its discovery, it has been claimed that estrogen, ER antagonist fulvestrant, as well as some estrogenic compounds can directly bind to GPER, and therefore initiate the non-genomic cellular responses. Various recently developed genetic tools as well as chemical ligands greatly facilitated research aimed at determining the physiological roles of GPER in different tissues. However, there is still lack of evidence that GPER plays a significant role in mediating endogenous estrogen action in vivo. This review summarizes current knowledge about GPER, including its tissue expression and cellular localization, with emphasis on the research findings elucidating its role in health and disease. Understanding the role of GPER in estrogen signaling will provide opportunities for the development of new therapeutic strategies to strengthen the benefits of estrogen while limiting the potential side effects.

Flavone Hispidulin Stimulates Glucagon-Like Peptide-1 Secretion and Ameliorates Hyperglycemia in Streptozotocin-Induced Diabetic Mice.

SCOPE: Loss of functional ß-cell mass is central for the deterioration of glycemic control in diabetes. The incretin hormone glucagon-like peptide-1 (GLP-1) plays a critical role in maintaining glycemic homeostasis via potentiating glucose-stimulated insulin secretion and promoting ß-cell mass. Agents that can directly promote GLP-1 secretion, thereby increasing insulin secretion and preserving ß-cell mass, hold great potential for the treatment of T2D. METHODS AND RESULTS: GluTag L-cells, INS832/13 cells, and mouse ileum crypts and islets are cultured for examining the effects of flavone hispidulin on GLP-1 and insulin secretion. Mouse livers and isolated hepatocytes are used for gluconeogenesis. Streptozotocin-induced diabetic mice are treated with hispidulin (20 mg kg-1 day-1 , oral gavage) for 6 weeks to evaluate its anti-diabetic potential. Hispidulin stimulates GLP-1 secretion from the L-cell line, ileum crypts, and in vivo. This hispidulin action is mediated via activation of cyclic adenosine monophosphate/protein kinase A signaling. Hispidulin significantly improves glycemic control in diabetic mice, concomitant with improved insulin release, and ß-cell survival. Additionally, hispidulin decreases hepatic pyruvate carboxylase expression in diabetic mice and suppresses gluconeogenesis in hepatocytes. Furthermore, hispidulin stimulates insulin secretion from ß-cells. CONCLUSION: These findings suggest that Hispidulin may be a novel dual-action anti-diabetic compound via stimulating GLP-1 secretion and suppressing hepatic glucose production.

Synergetic Sensing Effect of Sodium Carboxymethyl Cellulose and Bismuth on Cadmium Detection by Differential Pulse Anodic Stripping Voltammetry.

In the present work, a novel electrochemical sensor was developed for the detection of trace cadmium with high sensitivity and selectivity in an easy and eco-friendly way. Firstly, a glassy carbon electrode (GCE) was modified with nontoxic sodium carboxymethyl cellulose (CMC) by a simple drop-casting method, which was applied to detect cadmium by differential pulse anodic stripping voltammetry (DPASV) in a solution containing both target cadmium and eco-friendly bismuth ions, based on a quick electro-codeposition of these two metal ions on the surface of the modified electrode (CMC-GCE). Investigated by scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS), and Fourier transform infrared spectroscopy (FT-IR), both CMC (with good film-forming ability) and bismuth (with well-defined stripping signal) were found to be well complexed with target cadmium, leading to vital signal amplification for cadmium detection at a sub-nanomolar level. Under the optimal conditions, the proposed sensor exhibited a good linear stripping signal response to cadmium (Ⅱ) ion, in a concentration range of 0.001 µmol/L-1 µmol/L with a limit of detection of 0.75 nmol/L (S/N = 3). Meanwhile, the results demonstrate that this novel electrochemical sensor has excellent sensitivity and reproducibility, which can be used as a promising detection technique for testing natural samples such as tap water.

Mapping the B cell epitopes within the major capsid protein L1 of human papillomavirus type 16.

Persistent infection with human papillomavirus type16 (HPV16) has much association with the development of cervical cancer. L1 is the major capsid protein of HPV, it has been well investigated as a potential vaccine candidate. However, B cell epitopes present on L1 have not been well characterized. To identify the potential B-cell antigenic epitopes within HPV16 L1 protein, sixteen serial overlapping truncations (H1-H16) covering the whole region were expressed in E. coli and used in mice immunization. The mice antisera were tested in ELISA binding, IFA and HI assays. Finally, four fragments (H2, H4, H11, H12) were found to contain B cell epitopes of HPV16 L1 protein in ELISA and IFA assays, three fragments (H2, H3, H9) might contain neutralizing epitopes of HPV16 L1 protein in HI assay. Among them, H11 and H12 fragments contain B cell epitopes have never been reported before, and H3 was found as hemagglutination inhibition epitope for the first time. This work provides new insights to B cell epitopes on HPV16 L1 protein. Several new epitopes were identified and may provide some guidance for HPV16 subunit vaccine design. The results of this study might open new perspectives on the antibody-antigen reaction and have important implications for the development of epitopes-based protective HPV16 vaccines.

Phytonutrient genistein is a survival factor for pancreatic ß-cells via GPR30-mediated mechanism.

We previously discovered that phytonutrient genistein rapidly activates cAMP signaling in ß-cells and improves islet mass in diabetic mice. However, the mechanism underlying these actions of genistein is still unclear. Here, we show that pharmacological or molecular inhibition of Gαs blocked genistein-stimulated adenylate cyclase activity in plasma membrane and intracellular cAMP production in INS1 cells and islets. Further, genistein stimulation of cAMP generation was abolished in islets exposed to a specific GPR30 inhibitor G15 or islets from GPR30 deficient (GPR30-/-) mice. In vivo, dietary provision of genistein (0.5 g/kg diet) significantly mitigated streptozotocin-induced hyperglycemia in male WT mice, which was associated with improved blood insulin levels and pancreatic islet mass and survival, whereas these effects were absent in Gpr30-/- mice. Genistein treatment promoted survival of INS1 cells and human islets chronically exposed to palmitate and high glucose. At molecular level, genistein activated CREB phosphorylation and subsequently induced Bcl-2 expression, and knockdown of CREB diminished the protective effect of genistein on ß-cells induced by lipoglucotoxicity. Finally, deletion of GPR30 in ß-cells or islets ablated genistein-induced CREB phosphorylation and its cytoprotective effect. These findings demonstrate that genistein is a survival factor for ß-cells via GPR30-initiated, Gαs-mediated activation of CREB.

Kaempferol ameliorates hyperglycemia through suppressing hepatic gluconeogenesis and enhancing hepatic insulin sensitivity in diet-induced obese mice.

Obesity-associated insulin resistance (IR) is a major risk factor for developing type 2 diabetes and an array of other metabolic disorders. In particular, hepatic IR contributes to the increase in hepatic glucose production and consequently the development of fasting hyperglycemia. In this study, we explored whether kaempferol, a flavonoid isolated from Gink go biloba, is able to regulate hepatic gluconeogenesis and blood glucose homeostasis in high-fat diet-fed obese mice and further explored the underlying mechanism by which it elicits such effects. Oral administration of kaempferol (50 mg/kg/day), which is the human equivalent dose of 240 mg/day for an average 60 kg human, significantly improved blood glucose control in obese mice, which was associated with reduced hepatic glucose production and improved whole-body insulin sensitivity without altering body weight gain, food consumption or adiposity. In addition, kaempferol treatment increased Akt and hexokinase activity, but decreased pyruvate carboxylase (PC) and glucose-6 phosphatase activity in the liver without altering their protein expression. Consistently, kaempferol decreased PC activity and suppressed gluconeogenesis in HepG2 cells as well as primary hepatocytes isolated from the livers of obese mice. Furthermore, we found that kaempferol is a direct inhibitor of PC. These findings suggest that kaempferol may be a naturally occurring antidiabetic compound that acts by suppressing glucose production and improving insulin sensitivity. Kaempferol suppression of hepatic gluconeogenesis is due to its direct inhibitory action on the enzymatic activity of PC.

Dietary Flavonoids in the Prevention of T2D: An Overview.

Type 2 diabetes (T2D) is a progressive metabolic disease that is increasing in prevalence globally. It is well established that insulin resistance (IR) and a progressive decline in functional ß-cell mass are hallmarks of developing T2D. Obesity is a leading pathogenic factor for developing IR. Constant IR will progress to T2D when ß-cells are unable to secret adequate amounts of insulin to compensate for decreased insulin sensitivity. Recently, a considerable amount of research has been devoted to identifying naturally occurring anti-diabetic compounds that are abundant in certain types of foods. Flavonoids are a group of polyphenols that have drawn great interest for their various health benefits. Results from many clinical and animal studies demonstrate that dietary intake of flavonoids might be helpful in preventing T2D, although cellular and molecular mechanisms underlying these effects are still not completely understood. This review discusses our current understanding of the pathophysiology of T2D and highlights the potential anti-diabetic effects of flavonoids and mechanisms of their actions.

Estradiol signaling mediates gender difference in visceral adiposity via autophagy.

Excessive adiposity (particularly visceral fat mass) increases the risks of developing metabolic syndrome. Women have lower deposit of visceral fat than men, and this pattern becomes diminished postmenopausally, but the underlying mechanism remains largely unknown. Here, we show that the gender difference in visceral fat distribution is controlled by an estradiol-autophagy axis. In C57BL/6J and wild-type control mice, a higher visceral fat mass was detected in the males than in the females, which was associated with lower expression of estrogen receptor α (ERα) and more active autophagy in males vs. females. However, deletion of ERα normalized autophagy activity and abolished the gender difference in visceral adiposity. In line with the adiposity-reducing effect of the ERα-autophagy axis, we found that downregulation of ERα and increased autophagy activity were required for adipogenesis, while induction of estradiol signaling dampened autophagy and drastically prevented adipogenesis. Mechanistically, the estradiol-ERα signaling activated mTOR, which phosphorylated and inhibited ULK1, thereby suppressing autophagy and adipogenesis. Together, our study suggests that the lower visceral adiposity in the females (vs. the males) arises from a more active estradiol-ERα signaling, which tunes down autophagy and adipogenesis.