The development of compounds that selectively modulate thyroid hormone action by serving as subtype-selective ligands of the thyroid hormone receptors (TRs) would be useful for clinical therapy. In the present work, quantitative structure-activity relationship (QSAR) models by adopting molecular descriptors to predict the TR binding activity were established based on a data set of TR ligands. The linear (multiple linear regression (MLR) and partial least squares regression (PLSR)) and nonlinear (support vector machine regression (SVR)) methods were employed to investigate the relationship between structural properties and binding activities. The proposed PLSR model was slightly superior to the MLR model and SVR model, as indicated by the reasonable statistical properties (TRβ: Rtr2 = 0.9594, Qte2 = 0.8091. TRα: Rtr2 = 0.9705, Qte2 = 0.8057). Additionally, molecular docking simulations were also performed to study the probable binding modes of the ligands and the TR subtype selectivity. The results indicate that substituents located in region A, region B, and region C and the orientation of these groups might result in the subtype selectivity based on the hydrogen bonding and electrostatic interactions. The derived QSAR models together with the molecular docking results have good potential in facilitating the discovery of novel TR ligands with improved activity and subtype selectivity.

Oxidized tyrosine products (OTPs) have been detected in commercial food and have been demonstrated to induce oxidative damage in vivo. The pancreas plays an important role in glucose metabolism, but its antioxidant capacity is low. The present study investigates the potential impact of dietary OTPs on the pancreatic function. Sprague Dawley (SD) rats (8 rats per group) were fed a diet containing OTPs for 24 weeks, and the blood glucose and plasma insulin levels were then measured. Elevated fasting blood glucose and decreased plasma insulin levels indicated dysfunction of the pancreatic islets. The rats fed the OTPs-containing diet also exhibited pancreatic oxidative stress, accompanied by inflammation. Furthermore, the expression of genes involved in the Nrf2/ARE pathway was down-regulated in the OTPs-treated groups. In addition, supplementation with lipoic acid (LA) significantly remitted the OTPs induced oxidative stress of the pancreas, and mitigated the effects of OTPs on the blood glucose and insulin synthesis. A gavage experiment was performed to explore whether dityrosine (Dityr), a major component of OTPs, was responsible for the injury induced by OTP. The OTPs, including Dityr, induced mitochondrial defects in cultured mice insulinoma MIN-6 cells and mice pancreas, as evidenced by less ATP production, loss of mitochondrial membrane potential, mitochondrial DNA (mtDNA) depletion, and alteration of the mRNA levels of genes involved in mitochondrial function. Moreover, the apoptosis of pancreatic islets and MIN-6 cells increased after exposure to OTPs/Dityr. The findings suggest that decreased insulin secretion triggered by OTPs may be mediated by oxidative stress and mitochondrial damage in pancreatic β cells.

Oxidized tyrosine products (OTPs) have been detected in commercial foods with high protein content. Dityrosine (Dityr) is a typical oxidized tyrosine product. The previous studies in our lab demonstrated that dityrosine administration impaired glucose tolerance and suppressed the bio-function of thyroid hormone T3 of mice. The T3-activated Akt–mTOR signaling pathway plays important roles in insulin synthesis in pancreatic β cells. Due to the structural homology between dityrosine and T3, the molecular binding domain for these two compounds in TRβ1 might be the same site. Therefore, the present study investigates the potential impact of dietary OTPs on the pancreatic function. Sprague Dawley (SD) rats were fed a diet containing OTPs for 12 weeks. In addition, a 10 week gavage experiment using C57BL/J mice was performed to explore whether dityrosine was responsible for the injury induced by OTPs. The blood glucose, plasma insulin levels, and plasma free thyroid hormones (THs) were then measured. After 12 week dietary OTPs or 10 week OTPs/dityrosine gavage, elevated fasting blood glucose and decreased plasma insulin levels were detected both in rats and mice in the presence of enhanced plasma free THs content, which indicated dysfunction of the pancreatic islets and that the regulation of T3 to insulin synthesis was suppressed by OTPs and dityrosine. A cell experiment using mouse MIN-6 cells was performed to explore the mechanism of the diminished T3 bio-function in pancreatic islets induced by dityrosine. Dityrosine incubation attenuated the T3-mediated insulin synthesis via an indirect way of regulating the mRNA expression of genes related to insulin synthesis and decreasing the protein level of TRβ1. In addition, dityrosine inhibited the Akt phosphorylation activated by T3 in MIN-6 cells. Dityrosine treatment altered the T3-activated translation factors involved in the Akt–mTOR signaling pathway. These findings indicate that decreased insulin secretion triggered by dietary OTPs may be mediated by suggested T3-stimulated protein synthesis in pancreatic β cells.

Oxidized tyrosine (O-Tyr) has attracted more interest in recent years because many researchers have discovered that it and its product (dityrosine) are associated with pathological conditions and metabolic disorders, especially various age-related disorders in biological systems. However, biochemical responses of an organism to short-term O-Tyr and dityrosine (Dityr) administration are unclear. Therefore, our objective is to provide insight into the effects of O-Tyr and Dityr administration on internal metabolic processes. In this study, three groups of Kunming mice were respectively given O-Tyr (320 μg kg−1 body weight), Dityr (320 μg kg−1 body weight) and sterile saline (control group) via gavage once daily for 7 consecutive days. We systematically analysed the O-Tyr and Dityr-induced metabonomic changes in mice serum and urine using proton nuclear magnetic resonance-based metabonomics approaches in conjunction with body weight, indices of oxidative damage, antioxidant capacity assessments, and antioxidant enzymes mRNA expressions. Compared with mice in the control group, O-Tyr and Dityr administration elevated oxidative damage to proteins and lipids, reduced antioxidant capacity, and suppressed antioxidant enzymes mRNA expression in mice. What's more, O-Tyr and DT administration can alter certain systemic metabolic processes in common, including enhanced fatty acid oxidation, glycolysis, glucose–alanine cycle, tricarboxylic acid (TCA) cycle metabolism, induced oxidative stress responses, elevated metabolism of vitamin-B3, and altered gut microbiota functions. Our work provides a comprehensive view of the effects of O-Tyr and Dityr administration, implies an excess intake of oxidative proteins may result in deficiency of vitamin-B3 in body, and reveals it is absolutely essential to avoid overly processed foods. These findings are very important for animal and human food safety.

A series of sulfonylnitrophenylthiazoles derivatives were identified as effective targeting agents that block the interaction of the thyroid hormone receptor with its coactivators. In this work, in order to analyze the structure-activity relationship of these inhibitors and investigate the structural requirements for thyroid hormone receptor inhibitory activity, new statistically validated in silico models adopting different molecular descriptors were established. The two-dimensional quantitative structure-activity relationship models were developed using multiple linear regression method, which show both significant statistical quality and predictive ability (R2 = 0.939, Q2 = 0.622 for thyroid hormone receptor β; R2 = 0.862, Q2 = 0.763 for thyroid hormone receptor α), and different molecular descriptors were included, namely R2e, H5U, EEigo4r and Ram for thyroid hormone receptor β, MATS1P, IC2 and R5e+ for thyroid hormone receptor α. The optimum comparative molecular field analysis models were established using the template ligand-based alignment, which show satisfactory linear correlations (thyroid hormone receptor β: R2cv = 0.577, R2pred = 0.8013; thyroid hormone receptor α: R2cv = 0.549, R2pred = 0.8639). In addition, the R2cv of 0.543, R2pred of 0.8523 for thyroid hormone receptor β and R2cv of 0.560, R2pred of 0.8695 for thyroid hormone receptor α have been observed when comparative molecular similarity analysis fields were applied. All the developed statistical models give satisfactory results with accurate fitting and strong predictive abilities. Moreover, the contour maps provide an intuitive understanding of the structural requirements for the inhibitors. In conclusion, these data can provide some meaningful theoretical references to understand the factors influencing the inhibitory activity and direct the molecular design of novel inhibitors with increased activity.

Oxidized tyrosine products are commonly found in food with high protein content and have been demonstrated to cause damage of liver and kidney in our previous studies. Dityrosine (Dityr) is a typical oxidized tyrosine product. Due to its structural homology with thyroid hormones T3, we assumed that one of the endocrine systems most likely considered in connection with its disruption by Dityr may be the T3 action. T3 plays important roles in insulin synthesis, and thyroid hormone resistance (RTH) is associated with the impairment of glucose metabolism. Therefore, this study determined whether Dityr exposure impaired T3 function in pancreas leading to glucose metabolism disruption. After 10-week gavage with Dityr, mice exhibited impaired glucose tolerance and disturbed energy metabolism. The elevated free THs content in plasma, the up-regulation of THs synthesis-specific genes expressions in thyroid glands, and the increased thyroid follicles histology shapes and areas indicated that Dityr enhanced the THs synthesis in thyroid glands. In addition, Dityr-induced RTH, which reflected as elevated plasma free THs in the presence of unsuppressed thyroid stimulating hormone. The mRNA downregulation of membrane transporter of T3 (MCT8) and co-activator factors (RXRα, Src-1), together with the decreased protein level of thyroid hormone receptor β1 (TRβ1) in pancreas illustrated that the activation ability of T3 to downstream gene involved in insulin synthesis was suppressed by Dityr. In MIN-6 cell experiment, T3 improved glucose-stimulated insulin secretion by upregulating mRNA levels of insulin synthesis-related genes (Ins2, MafA, Pdx1) and T3 action-related genes, as well as increasing protein level of TRβ1. These data suggest that Dityr suppress T3-regulated insulin synthesis stimulated by glucose via an indirect way of decreasing sensibility to T3 in pancreas. All these findings indicate that Dityr can disrupt THs function in pancreas leading to glucose metabolism disorder.

•Poly-mannose was rapidly synthesized under microwave irradiation for the first time.•The structural features were studied upon methylation analysis.•The structural features were studied upon NMR spectroscopy analysis.•The main chain was (1 → 3)-linked β-d-Manp, (1 → 3)-linked and (1 → 6)-linked α-d-Manp.•Poly-mannose was branched at the O-2, O-3, O-4, O-6 position.Poly-mannose with molecular weight of 2.457 kDa was synthesized using d-mannose as substrate and phosphoric acid as catalyst under the condition of microwave irradiation for the first time. The optimum reaction conditions were microwave output power of 900 W, temperature 115 °C, proton concentration 2.5 mol/L, and microwave irradiation time 5 min. The actual maximum yield was 91.46%. After purified by Sepherdex G-25 column chromatography, the structural features of poly-mannose were investigated by high-performance anion-exchange chromatography (HPAEC), high-performance gel-permeation chromatography (HPGPC), infrared (IR) spectroscopy, methylation analysis and NMR spectroscopy analysis (1H, 13C, COSY, TOCSY, HMQC, and HMBC). HPAEC analysis showed that the composition of synthetic polysaccharides was d-mannose, its purity was demonstrated by HPGPC as a single symmetrical sharp peak, and additionally IR spectra demonstrated the polymerization of d-mannose. Methylation analysis and NMR spectroscopy revealed that the backbone of poly-mannose consisting of (1 → 3)-linked β-d-Manp, (1 → 3)-linked α-d-Manp, and (1 → 6)-linked α-d-Manp residues, and the main chain were branched at the O-2, O-3, O-4, O-6 position.

•P7 shows antibacterial activities against five food-borne pathogenic microorganisms with MIC values between 4 and 32 μM.•P7 does not cause significant E. coli cell membranes destroy but induces pore-forming on the E. coli cell surface.•P7 can penetrate the E. coli cell membranes and accumulate in the cytoplasm.•P7 interferes with the normal cell cycle and DNA replication by binding to E. coli genomic DNA.•P7 induces the decreases expression of DNA replication genes but increases expression of DNA damage repair genes.The antibacterial activities and mechanism of a new P7 were investigated in this study. P7 showed antimicrobial activities against five harmful microorganisms which contaminate and spoil food (MIC = 4–32 μM). Flow cytometry and scanning electron microscopy analyses demonstrated that P7 induced pore-formation on the cell surface and led to morphological changes but did not lyse cell. Confocal fluorescence microscopic observations and flow cytometry analysis expressed that P7 could penetrate the Escherichia coli cell membrane and accumulate in the cytoplasm. Moreover, P7 possessed a strong DNA binding affinity. Further cell cycle analysis and change in gene expression analysis suggested that P7 induced a decreased expression in the genes involved in DNA replication. Up-regulated expression genes encoding DNA damage repair. This study suggests that P7 could be applied as a candidate for the development of new food preservatives as it exerts its antibacterial activities by penetrating cell membranes and targets intracellular DNA.

•Polydextrose and galactoglucomannan were synthesized by microwave-assisted.•The synthetic polysaccharides exert obesity prevention capacity.•The synthetic polysaccharides showed antioxidant activity.•The synthetic polysaccharides improved gut microbiota dysbiosis induced by high-fat diet.•The synthetic polysaccharides increased the production of short chain fatty acids.The effect of novel synthetic polysaccharides such as polydextrose and galactoglucomannan to host physiology has not been well studied. This study was conducted to test the impact of synthetic polysaccharides on lipid metabolism, antioxidant activity, and the composition of gut microbiota of mice fed with high-fat diet (HFD). The results showed that HFD supplemented with polysaccharides induced positive effects in relation to serum endotoxin, blood glucose, serum and liver lipids, decreased fat accumulation and Lee obesity index, and reduced liver adipose steatosis. Fifteen week treatment with polysaccharides significantly decreased the levels of reactive oxygen species (ROS) and thiobarbituric acid reactive substances (TBARS), and increased total antioxidant capacity and the activity of superoxide dismutase and glutathione peroxidase. The polysaccharides improved gut microbiota dysbiosis induced by HFD, including increasing the Bacteroidetes-to-Firmicutes ratios, significantly inhibiting the growth of Enterococcus faecalis, and promoting proliferation of Bifidobacteria and Lactobacilli. Furthermore, polysaccharides significantly increased the production of short chain fatty acids (SCFAs) in vitro. Thus, synthetic polysaccharides can be used as potential functional foods. Moreover, it can sufficiently decrease the risk of obesity and restore liver redox status under oxidative stress conditions mediated by HFD possibly by regulating gut microbes and increasing acetate, propionate, and butyrate.

•Assumption that hypothyroidism by oxidative stress contributed to obesity occurrence was raised.•Oxidative injury and declined functions of thyroid and thyroid hormones (THs) were responsible for high-fat diet-induced obesity.•GABA improves oxidative stress and functions of thyroid and THs explaining lowered weight gains.Redox status and thyroid functions of diet-induced obesity (DIO) and DIO-resistant (DIO-R) mice from 20-week high-fat diet-fed (HFD) mice were studied (study I). Whether antiobesity action of gamma-aminobutyric acid (GABA) in HFD mice was related to its antioxidative action or improvement in thyroid function was also examined (study II) by GABA in drinking water (0.2, 0.12 and 0.06%). In DIO mice, thyroid stimulating hormone (TSH) remarkably increased, free thyroid hormones (THs) decreased, thyroid structures deformed and expressions of THs synthesis-specific and thyroid antioxidative markers, THs receptors β and deiodinases in hypothalamus and liver decreased. DIO-R mice showed normalized TSH, increased THs and its functions. Three GABA treatments normalized TSH, while 0.2% and 0.12% GABA treatments restored redox status, raised THs excretions and functions. Consequently, Down-regulated thyroid and THs functions in DIO mice accounted for obesity. GABA could prevent obesity by ameliorating oxidative stress and HFD-disrupted functions of thyroid and THs.

•Short-term high-fat diets induced brain oxidative damage, impaired cognition.•Oxidative stress might be the initial factor that triggered cognitive decline.•Short-term high-fat diets feeding did not induce insulin resistance, inflammation.•Salvianolic acid B could improve cognitive deficit induced by high-fat diets.•Altering antioxidant capacity and long-term potentiation could affect cognition.The present study was designed to find out the initial factor that triggered cognitive deficits induced by high-fat diets (HFD) and whether salvianolic acid B (Sal B) had beneficial role on cognition. Seven weeks' consumption of HFD resulted in higher food intake, dyslipidaemia, cognitive impairment and increasing hippocampal and frontal cortex oxidative stress (OS) without significant change in blood glucose and hippocampal inflammation. Microarray analysis data demonstrated that long-term potentiation (LTP) pathway was altered with down-regulation of genes against OS. Correlation analysis showed that hippocampal OS biomarkers had strong relations to Morris water maze performance. Sal B in drinking water (0.07 mg/ml) normalised the cognitive deficits through attenuating hippocampal redox status, altering LTP pathway and other biological pathways, up-regulating antioxidative genes expression. Thus, OS induced by HFD might be the initial factor that triggers cognitive impairment. Sal B was an efficient agent that exerted neuroprotective effects.

•Polydextrose was rapidly synthesized by microwave-assisted.•Polydextrose yield was 99%.•Polydextrose free of glucose was obtained by ethanol elution.•The structural features were studied upon IR spectrum.•The biological functions were studied upon in vitro fermentation.Microwave irradiation is a rapid and efficient method to synthesize oligomers and can be employed in polysaccharides production. As an artificial polysaccharide, polydextrose is known for its solid performance in food processing and its additional health benefits. This study was aimed at producing polydextrose by microwave irradiation using glucose and sorbitol as substrates; water and phosphoric acid as initiator and catalyst. The actual maximum yield was 99%. Synthetic polydextrose were purified by ethanol elution and Sepherdex G-25 column chromatography. Its purity was demonstrated by the high-performance gel-permeation chromatography as a single symmetrical sharp peak, additionally the average molecular weight was calculated to be 2.131 kDa. FT-IR spectra showed that the synthesized polydextrose has the structural feature similar to Polydextrose-Litesse®. In vitro fermentation revealed that polydextrose possesses the biological function similar to Polydextrose-Litesse® in increasing the concentration of short chain fatty acid and decreasing pH. This research demonstrated the feasibility of a rapid and efficient microwave mediated method to synthesize polydextrose and potentially other value added carbohydrate polymers

High-fat diet (HFD)-induced obesity is often associated with immune dysfunction. Resveratrol (trans-3,5,4′-trihydroxystilbene), which has well-founded immunity-related beneficial properties, was used to elucidate the regulatory effect on glucose metabolism and T-lymphocyte subsets in the development of HFD-induced obesity. Resveratrol, being associated with decreases of plasma leptin and plasma lipids and the release of oxidative stress, significantly decreased the body weight and fat masses in HF mice after 26 weeks of feeding. Furthermore, resveratrol decreased the fasting blood glucose and fasting plasma insulin and increased the CD3+CD4+/CD3+CD8+ subsets percentages and the regulatory T cells (Tregs) production after 13 and 26 weeks of feeding. The results indicate that resveratrol, as an effective supplement for HFD, maintained glucose homeostasis by activating the PI3K and SIRT1 signaling pathways. Moreover, resveratrol activated the Nrf2 signaling pathway-mediated antioxidant enzyme expression to alleviate inflammation by protecting against oxidative damage and T-lymphocyte subset-related chronic inflammatory response in the development of HFD-induced obesity.

Recent studies have investigated the anti-obesity effect of resveratrol, but the pathways through which resveratrol resists obesity are not clear. In the present study, we hypothesize that resveratrol exerts anti-obesity effects that are likely mediated by mechanisms of regulating gut microbes, and in turn, improving fat storage and metabolism. Gut microbes, glucose and lipid metabolism in high-fat diet (HF) mice in vivo are investigated after resveratrol treatment. Several biochemical markers are measured. Fluorescence in situ hybridization and flow cytometry are used to monitor and quantify the changes in gut microbiota. The key genes related to fat storage and metabolism in the liver and visceral adipose tissues are measured by real-time PCR. The results show that resveratrol (200 mg per kg per day) significantly lowers both body and visceral adipose weights, and reduces blood glucose and lipid levels in HF mice. Resveratrol improves the gut microbiota dysbiosis induced by the HF diet, including increasing the Bacteroidetes-to-Firmicutes ratios, significantly inhibiting the growth of Enterococcus faecalis, and increasing the growth of Lactobacillus and Bifidobacterium. Furthermore, resveratrol significantly increases the fasting-induced adipose factor (Fiaf, a key gene negatively regulated by intestinal microbes) expression in the intestine. Resveratrol significantly decreases mRNA expression of Lpl, Scd1, Ppar-γ, Acc1, and Fas related to fatty acids synthesis, adipogenesis and lipogenesis, which may be driven by increased Fiaf expression. The Pearson's correlation coefficient shows that there is a negative correlation between the body weight and the ratios of Bacteroidetes-to-Firmicutes. Therefore, resveratrol mediates the composition of gut microbes, and in turn, through the Fiaf signaling pathway, accelerates the development of obesity.

Both hyperthyroidism and overt hypothyroidism are associated with increased prevalence of metabolic syndrome and its components, while data on subclinical hypothyroidism is currently limited especially in working populations. The aim of this study was to examine the association between subclinical hypothyroidism and metabolic syndrome components in workers; and to evaluate whether there are differences by sex and occupation.A total of 1150 university employees (male — 792, female — 358) aged 30–60 years who came for an annual medical check-up were studied. Anthropometric measurements were taken, and blood pressure, fasting plasma glucose (FPG), lipid profiles, thyroid stimulating hormone (TSH), free thyroxin (FT4) and free triiodothyronine (FT3) levels were measured.After adjustment for age and body mass index (BMI), TSH was positively associated with increased triglyceride (TG) levels (β = 0.108, p = 0.020) and FPG (β = 0.130, p = 0.006) in subclinical hypothyroid male workers. However, TSH was not associated (p > 0.05) with any component of metabolic syndrome (MS) in the euthyroid group. In females, TSH was not correlated with MS components in both euthyroid and subclinical hypothyroid groups. Furthermore, comparison by occupation showed higher TSH in subclinical hypothyroid male workers employed in administration (5.23±0.52 mU/l) than those working as academics (5.12±0.52 mU/l), which resulted in elevated systolic and diastolic blood pressure, FPG, total cholesterol, TG and high density lipoprotein cholesterol. In females, BMI, systolic and diastolic blood pressure, TG and FPG were significantly (p < 0.05) higher in subclinical hypothyroid administrators than those in academics.Subclinical hypothyroidism was associated with metabolic syndrome components in male workers and not in females. Administration workers showed increased metabolic risks compared to academics. The findings suggest that the assessment of thyroid function in individuals with metabolic syndrome in the workplace may be favorable especially among men.

In the present study, the antimicrobial peptides BF2-A and BF2-C, two analogues of Buforin 2, were chemically synthesized and the activities were assayed. To elucidate the bactericidal mechanism of BF2-A/C and their different antimicrobial activities, the influence of peptides to E. coli cell membrane and targets of intracellular action were researched. Obviously, BF2-A and BF2-C did not induce the influx of PI into the E. coli cells, indicating nonmemebrane permeabilizing killing action. The FITC-labeled BF2-A/C could penetrate the E. coli cell membrane and BF2-C penetrated the cells more efficiently. Furthermore, BF2-A/C could bind to DNA and RNA respectively, and the affinity of BF2-C to DNA was powerful at least over 4 times than that of BF2-A. The present results implied that BF2-A and BF2-C inhibited the cellular functions by binding to DNA and RNA of cells after penetrating the cell membranes, resulting in the rapid cell death. The structure-activity relationship analysis of BF2-A/C revealed that the cell-penetrating efficiency and the affinity ability to DNA were critical factors for determining the antimicrobial potency of both peptides. The more efficient cell-penetrating and stronger affinity to DNA caused that BF2-C displayed more excellent antimicrobial activity and rapid killing kinetics than BF2-A.

The mechanisms of some gastrointestinal disease related to high-GI (glycemic index) diet are unknown. Oxidative stress is a well-recognized mechanism in many pathological conditions. Some study reported dietary GI was positively associated with oxidative stress. Whether high-GI diet can induce oxidative stress in digestive tract, whether higher GI diet can induce higher oxidative stress, to explore these two questions, we examined the effect of diet with different GI on redox status of duodenum of mice. In a 2-week study, male Kunming mice were randomized to six groups. Six groups were separately fed using diet with different GI that was obtained by adjusting ratio of cornstarch and glucose. The ratios of cornstarch and glucose in diets for group 1, 2, 3, 4, 5 and 6 were separately as follows: 40%, 0; 30%, 10%; 25%, 15%; 20%, 20%; 10%, 30%; 0%, 40%. The diet for group 4 induced the optional redox status in duodenum compared with other groups. The diet for group 6 induced the complete destruction on redox balance in duodenums of mice. We also detected the underlying mechanism using quantitative real-time reverse transcription polymerase chain reaction (qRT–PCR). We found the expression of Prdx4 was very high in group 4, which might explain why diet for group 4 induced the optional redox status. These findings indicate that (1) higher GI diet inducing higher oxidative stress was not justified; (2) oxidative stress may be the cause of digestive disease induced by high-GI diet.

A high-fat diet (HFD) leads to an increased risk of osteoporosis-related fractures, but the molecular mechanisms for its effects on bone metabolism have rarely been addressed. The present study investigated the possible molecular mechanisms for the dyslipidemic HFD-induced bone loss through comparing femoral gene expression profiles in HFD-fed mice versus the normal diet-fed mice during the growth stage. We used Affymetrix 430A Gene Chips to identify the significant changes in expression of the genes involved in bone metabolism, lipid metabolism, and the related signal transduction pathways. Quantitative RT-PCR was carried out on some significant genes for corroboration of the microarray results. At the conclusion of the 12-week feeding, the down-regulation of most of the genes related to bone formation and the up-regulation of most of the genes related to bone resorption were observed in the HFD-fed mice, consistent with the changes in plasma bone metabolic biomarkers. Together, the HFD induced a decrease in the majority of the adipogenesis-, lipid biosynthesis-, and fatty acid oxidation-related gene expression, such as PPARg and APOE. Furthermore, some genes engaged in the related signal transduction pathway were strongly regulated at the transcript level, including IGFBP4, TGFbR1, IL-17a, IL-4, and P53. These results indicate that an HFD may induce inhibitory bone formation and enhanced bone resorption, thus causing adverse bone status.

Antimicrobial peptides from edible insects may serve as a potentially significant group of food preservatives. In the present work, the mode of action of a novel antimicrobial peptide MDpep9 from Chinese traditional edible housefly larvae was investigated. MDpep9 was shown to bind to bacterial DNA from the results of gel retardation and fluorescence quenching experiments. Further investigations confirmed that MDpep9 could bind with the phosphate group of DNA and intercalate into the base pairs in a helix of DNA or locate in hydrophobic environment of DNA. The previous and present results demonstrated that MDpep9 has dual mechanisms of bactericidal activity: disrupting bacterial cell membranes and binding to bacterial genomic DNA to inhibit cellular functions, ultimately leading to cell death. The results of DNA-binding mode may be contributive in designing new and promising antimicrobial peptides for food preservatives.

P7, an analogue of the cell-penetrating peptide (CPP) ppTG20, was derived by replacing Phe and Trp with Arg based on the structure–activity relationships of CPPs and antimicrobial peptides (AMPs). P7 showed antimicrobial activity against Salmonella typhimurium at 4 μM and possessed broad antimicrobial activity greater than its parent peptide. P7 displayed good selectivity, with low haemolysis below its minimum inhibitory concentration range, but displayed cytotoxic activity against the HT29 and MDA-MB231 mammalian cell lines. Studies of calcein leakage from egg yolk l-α-phosphatidylcholine/egg yolk l-α-phosphatidyl-dl-glycerol (EYPC/EYPG) (bacterial membrane mimic) and EYPC/cholesterol (eukaryotic membrane mimic) vesicles also demonstrated that P7 exhibited high selectivity and caused pore formation in the bacterial membrane. Circular dichroism experiments suggested that the conformation of P7 underwent transitions from a random coil in sodium phosphate buffer to an α-helical conformation in bacterial model membranes. P7 induced influx of the membrane fluorescent probe 1-N-phenylnaphthylamine (NPN) and the nucleic acid fluorescent probe SYTOX® Green by increasing live S. typhimurium cell outer membrane and plasma membrane permeability, respectively. P7 also induced ion channel formation in the cell plasma membrane causing leakage of potassium ions. Flow cytometric analysis demonstrated that S. typhimurium cell membrane integrity was destroyed following incubation with P7. These results indicated that P7 exhibited good bacterial selectivity and exerted its antibacterial activity by a membrane damage mechanism. Furthermore, these results suggested that CPPs may represent a source of templates for AMP design.

Consumption of a high-fat diet (HFD) is correlated with increased oxidative stress and chronic inflammation in many organs. Regulatory T cells (Tregs) are essential negative regulators of inflammation. We hypothesized that resveratrol (trans-3,5,4′-trihydroxystilbene) could protect against HFD-induced oxidative stress and inflammation. Therefore, we examined the effect of resveratrol on oxidative stress and the relevant peripheral immune-regulating mechanisms in HFD-induced obese (DIO) and diet-resistant mice. C57BL/6 mice were fed a normal diet and an HFD for 13 weeks. Then the experimental group was subdivided into DIO and diet-resistant groups according to their body weights, which were further supplemented with 0.03% resveratrol and 0.06% resveratrol, respectively, for an additional 13 weeks. Resveratrol prevented the accumulation of chronic oxidative stress and suppression of Tregs production in HFD mice, modulated changes of cytokines in the plasma and spleen, and decreased expressions of inflammatory mediators compared with those of the DIO group. Our results indicate that resveratrol, as a feasible effective supplement for HFD, can relieve oxidative stress, inhibit inflammatory genes expression, and increase Tregs number via aryl hydrocarbon receptor activation inhibited by HFD, especially in DIO mice.

BackgroundThe exact mechanism for different propensities to obesity when consuming a high-fat diet (HFD) is largely unknown. Thyroid hormone (TH) is an important modulator of energy homeostasis and body weight.ObjectiveThe present study aimed to find the potential mechanisms of TH in the development of obesity-prone (OP) and obesity-resistant (OR) mice after short-term and long-term HFD feeding.MethodsC57Bl/6 male mice were randomly divided into two groups: a low-fat diet (LFD) group and an HFD group. In the 7th week, HFD-fed mice were classified as OP or OR according to upper and lower tertiles of body weight. Half of the mice were sacrificed at this time point and the remaining mice were kept on feeding and sacrificed in the 27th week. Indirect calorimetry was performed. At harvest, serum was used for ELISA assays and oxidative stress biomarkers determination. Tissues were dissected for deiodinases activity and relative mRNA expression determination, as well as antioxidant capacity evaluation.ResultsIn the 7th week, OP mice showed a significant body weight gain, decreased energy expenditure (EE), normal circulating TH levels, and activated HPT axis, whereas OR mice had normal body weight and maintained T3 levels only through enhancing hepatic D1 activity. In the 27th week, OR mice gained more body weight than LFD mice accompanied by an activation of HPT axis and decreased hepatic deiodination. Genes involved in TH production were down-regulated in OP mice and up-regulated in OR mice. Changes in deiodinases activity and thyroid function were related with redox status in specific tissues. Furthermore, OP mice had more serious hepatic steatosis than OR mice, with up-regulation of T3 target genes (e.g. Srebp1c, Acc1, Fasn) involved in lipid synthesis and down-regulation of Pgc1α, Cyp7a1 and Cpt1α.ConclusionsHPT axis function and deiodinases activity might be involved in different propensities to obesity and the ability of OR mice to resist obesity was limited.

This study investigated possible mechanisms for cardioprotective effects of lipoic acid (LA), quercetin (Q) and resveratrol (R) on oxidative stress related to thyroid hormone alterations in long-term obesity. Female C57BL/6 mice were fed on high-fat diet (HFD), HFD + LA, HFD + R, HFD + Q and normal diet for 26 weeks. Body weight, blood pressure, thyroid hormones, oxidative stress markers, angiotensin converting enzyme (ACE), nitric oxide synthase (NOS) and ion pump activities were measured, and expression of cardiac genes was analyzed by real-time polymerase chain reaction. HFD induced marked increase (P < .05) in body weight, blood pressure and oxidative stress, while plasma triidothyronine levels reduced. ACE activity increased (P < .05) in HFD mice (0.69 ± 0.225 U/mg protein) compared with controls (0.28 ± 0.114 U/mg protein), HFD + LA (0.231 ± 0.02 U/mg protein) and HFD + Q (0.182 ± 0.096 U/mg protein) at 26 weeks. Moreover, Na+/K+-ATPase and Ca2 +-ATPase activities increased in HFD mice whereas NOS reduced. A 1.5-fold increase in TRα1 and reduction in expression of the deiodinase iodothyronine DIO1, threonine protein kinase and NOS3 as well as up-regulation of AT1α, ACE, ATP1B1, GSK3β and Cja1 genes also occurred in HFD mice. Conversely, LA, Q and R inhibited weight gain; reduced TRα1 expression as well as increased DIO1; reduced ACE activity and AT1α, ATP1B1 and Cja1 gene expression as well as inhibited GSK3β; increased total antioxidant capacity, GSH and catalase activity; and reduced blood pressure. In conclusion, LA, resveratrol and quercetin supplementation reduces obesity thereby restoring plasma thyroid hormone levels and attenuating oxidative stress in the heart and thus may have therapeutic potential in heart diseases.

•Foxtail millet is gluten free cereal popular in East Asia and consume as porridge in northern China.•Fermented foxtail millet meal is a good way to add the nutritional values.•Fermented and heat moisture treatment are effective means to improve physicochemical properties of foxtail millet flour.This research intends to verify the effect of Lactobacillus paracasei Fn032 fermentation and heat-moisture treatment (HMT) on the physicochemical properties of foxtail millet (Setaria italica) flour. The results obtained showed a significant (P < 0.05) increase in protein content (12.02–20.54%), total starch (15.78–51.01%) and starch fractions after fermentation and HMT. Differential scanning calorimetry (DSC) analysis showed high decomposition temperature (Td) trend of 180.59 and 189.82 °C after HMT. However, there was significant (P < 0.05) enthalpy (ΔH) decrease. Flour digestion resulted in variation of slow digestible starch (SDS) and resistant starch (RS) count from 6.83 to 18.42% and 7.61 to 22.68% respectively, after fermentation and HTM. Following this observation, it was ascertained that in X-ray diffraction; pasting viscosity and fluorescence spectrophotometry show greater HMT influenced on the flour components. Findings from the scanning electron microscopy (SEM) analysis showed microstructure differences of the flours samples. Fermentation and heat moisture treatment methods present a possible way of changing or improving the physicochemical properties and add nutritional value to foxtail millet meal.

Oxidative stress plays an important role in overnutrition-induced metabolic syndrome. Somatostatin (SST) inhibits a wide variety of physiologic functions in the gastrointestinal tract, which may in turn control the levels of reactive oxygen species (ROS) derived from ingestion of macronutrients. In this study, the involvement of SST in the progression of metabolic syndrome in response to a high-fat diet (HFD) was investigated. Male C57BL/6 mice were fed either a normal diet (4.89% fat) or a high-fat diet (21.45% fat) for 4 weeks. The SST analog octreotide (20 μg/kg/day) was then administered intraperitoneally to half of the HFD mice throughout the 10-day experimental period. Body weight, adipose tissue weight, gastric acidity, total bile acid, and lipase activity were measured. Plasma lipid, glucose, insulin, SST, the levels of ROS and GSH/GSSG, and lipid peroxidation in the stomach, small intestine, pancreas, and liver were also evaluated. Following HFD intake for 38 days, a decrease in the plasma levels of SST and GSH/GSSG ratio was observed, while there was an increase in body weight, adipose tissue weight, plasma glucose, triglyceride, and levels of ROS and lipid peroxidation of the stomach, small intestine, pancreas, and liver. However, simultaneous administration of SST analog octreotide to HFD-fed mice significantly reduced ROS production of the digestive system and resulted in the improvement of all the aforesaid adverse changes, suggesting the involvement of SST in the progression of HFD-induced metabolic syndrome.

The objective of this investigation was to explore possible molecular changes for role of a high-fat diet (HFD)-induced oxidative stress in splenic lymphocytes, and whether a dietary lipoic acid (LA) supplement could attenuate these changes. Male C57BL/6 mice were fed one of three diets 10 weeks and outcome measures centered on parameters of oxidative stress and lymphocytes apoptosis in spleen. Two-dimensional gel electrophoresis was used to compare the proteomes of splenic lymphocytes with three dietary groups. Differentially expressed spots whose expression altered over three fold were identified by MALDI-TOF MS. In this study, HFD resulted in oxidative stress in mice spleen, and significantly increased apoptotic percentage of splenic lymphocytes. Bioinformatic evaluation results of MALDI-TOF MS showed that 20 differentially expressed protein spots were known to be involved in many processes associated with cell function, such as cytoskeleton, energy metabolism and oxidative stress, signal transduction and cell defense. In conclusion, these results indicate that HFD-induced oxidative stress could lead to the functional decline of splenic lymphocytes, and LA supplement attenuates the alterations of protein expression to maintain the basic biological processes.

Jejunal Peyer’s patches contain specialized epithelial M cells that take up ingested microorganisms from the lumen of the gut by transcytosis. Using DNA-micro array, we analyzed the gene expression patterns of jejunal Peyer’s patches in order to gain insight into the molecular mechanism by which Lp6 interacted with the host organism in a gnotobiotic environment v. in the gut normal microflora. The micro array data revealed that, among approximately 14,000 genes, 420 were expressed in Lp6 administration group at twofold or higher levels compared to the control group. These included genes involved in immune response, and cell differentiation, cell–cell signaling, cell adhesion, signal transcription, and transduction. Real-time PCR confirmed the reliability of the analysis. These data indicated that administration of Lactobacillus Lp6 was associated with a complex genetic response in the jejunal Peyer’s patches.

A high fat diet (HFD) has long been linked to immune dysfunction, including diminished numbers or reactivity of lymphocytes, increased susceptibility to infection, inhibited lymphocytes function during antigen-specific responses and developed oxidative stress. Whereas the molecular mechanistic events associated with immune deficiency remain to be fully determined. Using the DNA microarray system, we analyzed the gene expression patterns of lymphocyte related signal transduction proteins in jejunum of C57BL/6 mice in order to gain insight on the possible molecular mechanism by which HFD induced oxidative stress effects on signal transduction of lymphocytes. Results of present study showed that HFD induced oxidative stress and immunosuppression in jejunum. Antioxidant lipoic acid (LA) supplement ameliorated that HFD induced oxidative stress and immunosuppression by recovering transcriptional levels of the gene involved in B cell receptor, T cell differentiation signaling pathway, and free radical scavengers. The present study indicates that a HFD can induce chronic oxidative stress, suppress signal transduction of gut-associated lymphocytes, and lead to an inhibition of mucosal immunity.

•Intragastric administration of dityrosine impairs mice memory in novel object recognition task.•Dityrosine administration does not impair the spatial learning and memory of mice in Morris water maze.•Neurobehavioral function such as locomotor activity, anxiety and social interaction are not affected by dityrosine.•Dityrosine administration declines hippocampal relative mRNA expression of NMDA receptor subunits Nr1, Nr2a, Nr2b; Bdnf, Trkb.Dietary modifications have been shown to contribute to the physical and mental diseases. Oxidative modifications of protein can be easily found in protein-rich food such as meat and milk products. Previous studies mainly focus on the consequences of lipid oxidation products intake in vivo, but the effects of protein oxidation products consumption have been largely neglected. Oxidants have been shown to play an important role in aging and neurodegenerative diseases. Dityrosine is the oxidated product of tyrosine residues in protein which is considered as a biomarker for oxidative stress, but the potential deleterious effects of dityrosine are unknown. In the present study, we explored the effects of dityrosine administration on the behavioral aspect. We found that dityrosine-ingested mice displayed impaired memory during novel object recognition test, but no influence to the spatial memory in Morris water maze compared with the saline group. Other aspects of neurobehavioral function such as locomotor activity, anxiety and social behavior were not affected by dityrosine ingestion. Furthermore, we found that dityrosine-ingested mice showed decreased expression level of NMDA receptor subunits Nr1, Nr2a, Nr2b as well as Bdnf, Trkb. Our study suggests that dityrosine exposure impairs hippocampus-dependent nonspatial memory accompanied by modulation of NMDA receptor subunits and Bdnf expression.