Xiang-Rong Cheng

Differential effects of quercetin on hippocampus-dependent learning and memory in mice fed with different diets related with oxidative stress.

High fat diets induce oxidative stress which may be involved in neurodegenerative diseases. Quercetin is a kind of antioxidant that has neuroprotective effects and potent7ial pro-oxidant effects as well. In this study, we evaluated cognitive function in mice fed with high fat diets and basic diets with or without quercetin. Male Chinese Kunming (KM) mice were randomly assigned to five groups fed with basic diet (Control), basic diet with 0.005% (w/w) quercetin (CQ1), high fat diet (HFD), HFD with 0.005% (w/w) quercetin (HFDQ1) and 0.01% (w/w) quercetin (HFDQ2) for 13weeks. At the end of the study period, fasting blood glucose (FBG), plasma and hippocampal markers of oxidative stress, plasma lipid status, Morris water maze as well as hippocampal relative mRNA expression of akt, bdnf, camkII, creb, gsk-3β, nrf2 and pi3k were examined. The results suggested that in comparison to the control group, the escape latency was increased and percent time spent in the target quadrant was decreased, with increased reactive carbonyls, malondialdehyde (MDA) and declined expression of pi3k, akt, nrf2, creb and bdnf in the hippocampus of HFD and CQ1 groups. Conversely, higher quercetin supplemented to HFD improved antioxidant capacity and reversed cognitive decline completely. Significant correlations between the redox status and cognition-related gene expression were observed as well (P<0.05). Thus, in the case of oxidative stress, an appropriate dose of quercetin can attenuate oxidative stress to improve hippocampus dependent cognition. But under a balanced situation, quercetin exerts pro-oxidant effects to impair cognition.

Role of thyroid hormone homeostasis in obesity-prone and obesity-resistant mice fed a high-fat diet

BACKGROUNDnThe 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.nnnOBJECTIVEnThe 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.nnnMETHODSnC57Bl/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.nnnRESULTSnIn 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 T(3) 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 T(3) target genes (e.g. Srebp1c, Acc1, Fasn) involved in lipid synthesis and down-regulation of Pgc1α, Cyp7a1 and Cpt1α.nnnCONCLUSIONSnHPT axis function and deiodinases activity might be involved in different propensities to obesity and the ability of OR mice to resist obesity was limited.

Resveratrol restores the circadian rhythmic disorder of lipid metabolism induced by high-fat diet in mice

Circadian rhythmic disorders induced by high-fat diet are associated with metabolic diseases. Resveratrol could improve metabolic disorder, but few reports focused on its effects on circadian rhythm disorders in a variety of studies. The aim of the present study was to analyze the potential effects of resveratrol on high-fat diet-induced disorders about the rhythmic expression of clock genes and clock-controlled lipid metabolism. Male C57BL/6 mice were divided into three groups: a standard diet control group (CON), a high-fat diet (HFD) group and HFD supplemented with 0.1% (w/w) resveratrol (RES). The body weight, fasting blood glucose and insulin, plasma lipids and leptin, whole body metabolic status and the expression of clock genes and clock-controlled lipogenic genes were analyzed at four different time points throughout a 24-h cycle (8:00, 14:00, 20:00, 2:00). Resveratrol, being associated with rhythmic restoration of fasting blood glucose and plasma insulin, significantly decreased the body weight in HFD mice after 11 weeks of feeding, as well as ameliorated the rhythmities of plasma leptin, lipid profiles and whole body metabolic status (respiratory exchange ratio, locomotor activity, and heat production). Meanwhile, resveratrol modified the rhythmic expression of clock genes (Clock, Bmal1 and Per2) and clock-controlled lipid metabolism related genes (Sirt1, Pparα, Srebp-1c, Acc1 and Fas). The response pattern of mRNA expression for Acc1 was similar to the plasma triglyceride. All these results indicated that resveratrol reduced lipogenesis and ultimately normalized rhythmic expression of plasma lipids, possibly via its action on clock machinery.

A cell-penetrating peptide analogue, P7, exerts antimicrobial activity against Escherichia coli ATCC25922 via penetrating cell membrane and targeting intracellular DNA.

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.

Preparation and structural characterization of poly-mannose synthesized by phosphoric acid catalyzation under microwave irradiation

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 ((1)H, (13)C, 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.

Effect of dietary oxidized tyrosine products on insulin secretion via the oxidative stress-induced mitochondria damage in mice pancreas

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.

Role of miR-383 and miR-146b in different propensities to obesity in male mice.

The study was designed to investigate the possible mechanisms of hepatic microRNAs (miRs) in regulating local thyroid hormone (TH) action and ultimately different propensities to high-fat diet (HFD)-induced obesity. When obesity-prone (OP) and obesity-resistant (OR) mice were fed HFD for 7 weeks, OP mice showed apparent hepatic steatosis, with significantly higher body weight and lower hepatic TH receptor b (TRb) expression and type 1 deiodinase (DIO1) activity than OR mice. Next-generation sequencing technology revealed that 13 miRs in liver were dysregulated between the two phenotypes, of which 8 miRs were predicted to target on Dio1 or TRb When mice were fed for 17 weeks, OR mice had mild hepatic steatosis and increased Dio1 and TRb expression than OP mice, with downregulation of T3 target genes (including Srebp1c, Acc1, Scd1 and Fasn) and upregulation of Cpt1α, Atp5c1, Cox7c and Cyp7a1 A stem-loop qRT-PCR analysis confirmed that the levels of miR-383, miR-34a and miR-146b were inversely correlated with those of DIO1 or TRb. Down-regulated expression of miR-383 or miR-146b by miR-383 inhibitor (anti-miR-383) or miR-146b inhibitor (anti-miR-146b) in free fatty acid-treated primary mouse hepatocytes led to increased DIO1 and TRb expressions, respectively, and subsequently decreased cellular lipid accumulation, while miR-34a inhibitor (anti-miR-34a) transfection had on effects on TRb expression. Luciferase reporter assay illustrated that miR-146b could directly target TRb 3untranslated region (3UTR). These findings suggested that miR-383 and miR-146b might play critical roles in different propensities to diet-induced obesity via targeting on Dio1 and TRb, respectively.

Dityrosine administration induces dysfunction of insulin secretion accompanied by diminished thyroid hormones T3 function in pancreas of mice

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 suppressxa0T3-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.

Structure-based approach for the study of thyroid hormone receptor binding affinity and subtype selectivity

Thyroid hormone (TH) possesses the ability to lower cholesterol and improve cardiac performance, which have prompted the efforts to design analogs that can utilize the cholesterol-lowering property without adversely affecting heart function. In order to gain insights into the interaction mechanism for agonists at the active site of thyroid hormone receptor β (TRβ), quantitative structure–activity relationship (QSAR) models have been developed on TRβ agonists, significant statistical coefficients were obtained (CoMFA, R2cv, .732), (CoMSIA, R2cv, .853), indicating the internal consistency of the models, the obtained models were further validated using the test set, the acquired R2pred values .7054 and .7129 were in good agreement with the experimental results. The key amino acids affecting ligand binding were identified by molecular docking, and the detailed binding modes of the compounds with different activities were also determined. Furthermore, molecular dynamics (MD) simulations were conducted to assess the reliability of the derived models and the docking results. Moreover, TH exerts significant physiological effects through modulation of the two human thyroid hormone receptor subtypes. Because TRβ and TRα locate in different target cells, selective TR ligands would target specific tissues regulated by one receptor without affecting the other. Thus, the 3D information was analyzed to reveal the most relevant structural features involved in selectivity. The findings serve as the basis for further investigation into selective TRβ/TRα agonists.

Metabolomic studies on the systemic responses of mice with oxidative stress induced by short-term oxidized tyrosine administration

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. Whats 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.