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P7, a peptide analogue derived from cell-penetrating peptide ppTG20, possesses antibacterial and antitumor activities without significant hemolytic activity. In this study, we investigated the antifungal effect of P7 and its anti-Candida acting mode in Candida albicans. P7 displayed antifungal activity against the reference C. albicans (MIC = 4 µM), Aspergilla niger (MIC = 32 µM), Aspergillus flavus (MIC = 8 µM), and Trichopyton rubrum (MIC = 16 µM). The effect of P7 on the C. albicans cell membrane was examined by investigating the calcein leakage from fungal membrane models made of egg yolk l-phosphatidylcholine/ergosterol (10 : 1, w/w) liposomes. P7 showed potent leakage effects against fungal liposomes similar to Melittin-treated cells. C. albicans protoplast regeneration assay demonstrated that P7 interacted with the C. albicans plasma membrane. Flow cytometry of the plasma membrane potential and integrity of C. albicans showed that P7 caused 60.9 ± 1.8% depolarization of the membrane potential of intact C. albicans cells and caused 58.1 ± 3.2% C. albicans cell membrane damage. Confocal laser scanning microscopy demonstrated that part of FITC-P7 accumulated in the cytoplasm. DNA retardation analysis was also performed, which showed that P7 interacted with C. albicans genomic DNA after penetrating the cell membrane, completely inhibiting the migration of genomic DNA above the weight ratio (peptide : DNA) of 6. Our results indicated that the plasma membrane was the primary target, and DNA was the secondary intracellular target of the mode of action of P7 against C. albicans. Copyright © 2016 European Peptide Society and John Wiley & Sons, Ltd.
Assuntos
Antifúngicos/farmacologia , Candida albicans/efeitos dos fármacos , Membrana Celular/efeitos dos fármacos , Peptídeos Penetradores de Células/farmacologia , DNA Fúngico/efeitos dos fármacos , Ascomicetos/efeitos dos fármacos , Ascomicetos/genética , Aspergillus flavus/efeitos dos fármacos , Aspergillus flavus/genética , Aspergillus niger/efeitos dos fármacos , Aspergillus niger/genética , Candida albicans/genética , Potenciais da Membrana/efeitos dos fármacos , Oligopeptídeos/químicaRESUMO
We investigated the antifungal properties and anti-candidal mechanism of antimicrobial peptide APP. The minimum inhibitory concentration of APP was 8 µM against Candida albicans and Aspeogillus flavus, the concentration against Saccharomyces cerevisiae and Cryptococcus neoformans was 16 µM, while 32 µM inhibited Aspergilla niger and Trichopyton rubrum. APP caused slight depolarization (12.32 ± 0.87%) of the membrane potential of intact C. albicans cells when it exerted its anti-candidal activity and only caused 21.52 ± 0.48% C. albicans cell membrane damage. APP interacted with cell wall membrane, caused potassium efflux and nucleotide leakage. However, confocal fluorescence microscopy experiment and flow cytometry confirmed that FITC-labeled APP penetrated C. albicans cell membrane with 52.31 ± 1.88% cell-penetrating efficiency and accumulated in the cytoplasm. Then, APP interact with C. albicans genomic DNA and completely suppressed DNA migration above weight ratio (peptide/DNA) of 2, and significantly arrested cell cycles during the S-phase (S-phase cell population was 27.09 ± 0.73%, p < 0.05) after penetrating the cell membrane. Results indicated that APP kills C. albicans for efficient cell-penetrating efficiency, strong DNA-binding affinity and significant physiological changes inducing S-phase arrest in intracellular environment.
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Antifúngicos/farmacologia , Peptídeos Catiônicos Antimicrobianos/farmacologia , DNA Fúngico/antagonistas & inibidores , Pontos de Checagem da Fase S do Ciclo Celular/efeitos dos fármacos , Sequência de Aminoácidos , Antifúngicos/síntese química , Peptídeos Catiônicos Antimicrobianos/síntese química , Aspergillus/efeitos dos fármacos , Aspergillus/crescimento & desenvolvimento , Aspergillus/metabolismo , Candida albicans/efeitos dos fármacos , Candida albicans/crescimento & desenvolvimento , Candida albicans/metabolismo , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Permeabilidade da Membrana Celular , Cryptococcus neoformans/efeitos dos fármacos , Cryptococcus neoformans/crescimento & desenvolvimento , Cryptococcus neoformans/metabolismo , DNA Fúngico/metabolismo , Testes de Sensibilidade Microbiana , Saccharomyces cerevisiae/efeitos dos fármacos , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismo , Trichophyton/efeitos dos fármacos , Trichophyton/crescimento & desenvolvimento , Trichophyton/metabolismoRESUMO
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.
Assuntos
Transtornos Cronobiológicos/tratamento farmacológico , Ritmo Circadiano/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Metabolismo dos Lipídeos/efeitos dos fármacos , Estilbenos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Transtornos Cronobiológicos/etiologia , Ritmo Circadiano/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Lipídeos/sangue , Masculino , Camundongos Endogâmicos C57BL , ResveratrolRESUMO
Patients with colorectal cancer (CRC) are at high risk of frailty, leading to reduced quality of life and survival. Diet is associated with frailty in the elderly through regulating inflammation. Thus, we hypothesized that dietary inflammatory potential (as assessed by dietary inflammatory index [DII]) might be associated with frailty in patients with CRC through regulating inflammatory biomarkers. A total of 231 patients with CRC were included in this cross-sectional study. Dietary intake was evaluated by 3-day, 24-hour dietary recalls, and frailty status was assessed in accordance with the Fried frailty criteria. Plasma inflammatory cytokines were determined in 126 blood samples. A total of 67 patients (29.0%) were frail, with significantly higher DII scores than nonfrail patients, accompanied with significantly increased interleukin-6 (IL-6) and decreased interleukin-10 (IL-10) concentrations. Each 1-point increase of DII was related to a 25.0% increased risk of frailty. IL-6 was positively correlated with frailty and DII, whereas IL-10 was negatively correlated. After adjusting for age, sex, body mass index, education level, smoking status, and energy, mediation analysis revealed that the association between DII and frailty was significantly mediated by IL-6 (average causal mediation effect [ACME], 0.052; 95% confidence interval, 0.020-0.087; P = .002) and IL-10 (ACME, 0.025; 95% confidence interval, 0.004-0.063; P = .016). The ρ values for the sensitivity measure at which estimated ACMEs were zero were 0.3 and -0.2 for IL-6 and IL-10, respectively. Therefore, a pro-inflammatory diet was associated with frailty in patients with CRC possibly in part by affecting circulating IL-6 and IL-10 concentrations.
Assuntos
Neoplasias Colorretais , Dieta , Fragilidade , Inflamação , Interleucina-10 , Interleucina-6 , Humanos , Neoplasias Colorretais/sangue , Estudos Transversais , Masculino , Feminino , Fragilidade/sangue , Inflamação/sangue , Idoso , Interleucina-6/sangue , Interleucina-10/sangue , Pessoa de Meia-Idade , Biomarcadores/sangueRESUMO
Increasing evidence indicates that tryptophan (Trp) metabolism disturbance controls hippocampal 5-hydroxytryptamine (5-HT) and thereby affecting depression-like behavior, in which the gut microbiota (GM) might be involved. This study investigated the effect of Trp-rich whey protein isolate (WPI) on depressive-like behavior in 4T1 tumor-bearing mice. Female BALB/c mice were subcutaneously inoculated with murine 4T1 mammary carcinoma cells and received 2 g/kg of WPI by gavage daily for 21 days. The results showed that WPI exerted no significant effects on tumor weight and volume, but abrogated tumor-induced depression-like behavior, as evidenced by remarkably increased time and distance in the center of the open-field test, decreased immobility time in the tail suspension test, increased time and number of entries to the open arms in the elevated plus maze and sucrose preference. Moreover, WPI promoted the hippocampal Trp, 5-hydroxytryptophan (5-HTP), 5-HT, 5-hydroxyindoleacetic acid (5-HIAA) levels and inhibited kynurenine (Kyn) through up-regulating serotonin transporter (SERT) and down-regulating indoleamine 2, 3-dioxygenase (IDO). WPI showed an enriched microbial diversity indicated by increased Shannon index and decreased Simpson index, reduced the abundances of Proteobacteria, Rikenellaceae_RC9_gut_group, Alloprevotella and Prevotellaceae_UCG-001, and increased the abundance of unclassified_k__norank_d__Bacteria in tumor-bearing mice (P < 0.05). At level 3, WPI enhanced the function of microbial gene related to Trp metabolism in the KEGG pathways (P < 0.05). Our results suggest that WPI exhibits a potent antidepressant-like effect via the regulation of hippocampal Trp metabolism and alteration of GM composition and function, and it may be an effective prevention for cancer-related depression.
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Depressão , Triptofano , Animais , Feminino , Camundongos , 5-Hidroxitriptofano , Depressão/induzido quimicamente , Depressão/metabolismo , Cinurenina/metabolismo , Serotonina , Triptofano/metabolismo , Proteínas do Soro do Leite/farmacologiaRESUMO
This study investigated the associations between diet and frailty in lung cancer patients and the potential role of the gut microbiota involved. We assessed dietary intake and frailty status in 231 lung cancer patients by 3-day, 24-h dietary recalls and Fried frailty criteria, respectively, and collected 50 fecal samples for next-generation sequencing. A total of 75 (32.5%) patients were frail, which might be related to significantly lower intake of energy, protein, carbohydrate, dietary fiber, niacin, leucine, some minerals, and a poorer dietary quality as indicated by the Chinese Healthy Eating Index (p < 0.05). Among these, carbohydrate (OR = 0.98; 95% CI 0.96-0.99; p = 0.010), calcium (OR = 0.99; 95% CI 0.99-1.00; p = 0.025), and selenium (OR = 1.03; 95% CI 1.00-1.06; p = 0.022) were all significantly associated with frailty. A multivariate logistic regression analysis showed that the mean risk of frailty was 0.94 times lower (95% CI 0.90-0.99; p = 0.009) among participants with higher CHEI scores. Additionally, the frail patients demonstrated significantly lower gut microbiota ß diversity (p = 0.001) and higher relative abundance of Actinobacteriota (p = 0.033). Frailty in lung cancer patients might be associated with insufficient nutrients intake and a poor dietary quality through gut microbiota regulation.
Assuntos
Fragilidade , Microbioma Gastrointestinal , Neoplasias Pulmonares , Humanos , Dieta , Ingestão de EnergiaRESUMO
This study examined the association between the energy-adjusted Dietary Inflammatory Index (E-DII)-based dietary inflammatory potential and depressive symptoms (DepS) among patients with breast cancer and explores whether systemic inflammation mediates this association. We assessed dietary intake and DepS in 220 breast cancer patients by three 24 h dietary recalls and the Center for Epidemiological Studies Depression Scale (CES-D), respectively, and determined plasma levels of C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), and interleukin (IL)-1ß, IL-4, and IL-6 in 123 blood samples. We found that each one-point increase of E-DII was related to a 53% elevated risk of DepS. Patients with the most pro-inflammatory diets had a 5.13 times higher risk of DepS than those with the most anti-inflammatory diets. Among the E-DII components, vitamin B2, zinc, and iron were inversely associated with DepS risk. Furthermore, E-DII scores were positively associated with CRP and TNF-α. Higher levels of TNF-α and IL-6 were associated with higher DepS risk. A significant mediating effect of TNF-α was revealed between E-DII and DepS. Our findings suggest that a pro-inflammatory diet is positively associated with breast cancer-related DepS, which may be mediated by TNF-α.
Assuntos
Neoplasias da Mama , Fator de Necrose Tumoral alfa , Humanos , Feminino , Depressão/etiologia , Interleucina-6 , Dieta/efeitos adversos , Inflamação , Proteína C-Reativa/metabolismoRESUMO
Little is known about the relationship between diet and depression through the gut microbiota among breast cancer patients. This study aimed to examine the dietary intake differences between depressed breast cancer (DBC) and non-depressed breast cancer (NBC) patients, and whether the differences could lead to gut microbiota changes that affect depressive symptoms. Participants completed the Center for Epidemiological Studies-Depression Scale (CES-D) and 24 h dietary recall. Fecal samples of 18 DBC patients and 37 NBC patients were collected for next-generation sequencing. A total of 60 out of 205 breast cancer patients reported significant depressive symptoms suggested by a CES-D score ≥ 16, which might be related to lower intakes of energy, protein, dietary fiber, vitamin A, vitamin B2, niacin, calcium, phosphorus, potassium, iron, zinc, selenium, manganese and tryptophan, and a poor diet quality indicated by a lower total Chinese Healthy Eating Index (CHEI) score. Additionally, NBC patients demonstrated greater gut microbiota diversity and a healthier composition, in which the relative abundances of Proteobacteria and Escherichia-Shigella were both lower than in the DBC patients (p < 0.05). Alpha diversity was a significant mediator between diet quality and depression, while calcium, phosphorus and selenium significantly regulated depression independent of the gut microbiota. Breast cancer-related depressive symptoms might be associated with a poor diet quality via gut microbiota-dependent pathways and lower micronutrient intake via microbiota-independent pathways.
Assuntos
Neoplasias da Mama , Microbioma Gastrointestinal , Depressão/etiologia , Dieta , Fibras na Dieta , Feminino , HumanosRESUMO
BACKGROUND: China has the largest number of patients with type 2 diabetes mellitus (T2DM) in the world. However, owing to insufficient knowledge of self-management in patients with diabetes, blood glucose (BG) control is poor. Most diabetes-related self-management applications fail to bring significant benefits to patients with T2DM because of the low use rate and difficult operation. OBJECTIVE: This study aims to examine the effectiveness of the combination of the self-designed web-based T2DM management software TangPlan and WeChat on fasting BG (FBG), glycated hemoglobin (HbA1c), body weight, blood pressure (BP), and lipid profiles in patients with T2DM over a 6-month period. METHODS: Participants were recruited and randomized into the TangPlan and WeChat or control groups. Participants in the control group received usual care, whereas the TangPlan and WeChat participants received self-management guidance with the help of TangPlan and WeChat from health care professionals, including BG self-monitoring; healthy eating; active physical exercise; increasing medication compliance; and health education during follow-ups, lectures, or web-based communication. They were also asked to record and send self-management data to the health care professionals via WeChat to obtain timely and effective guidance on diabetes self-management. RESULTS: In this study, 76.9% (120/156) of participants completed the 6-month follow-up visit. After the intervention, FBG (mean 6.51, SD 1.66 mmol/L; P=.048), HbA1c (mean 6.87%, SD 1.11%; P<.001), body weight (mean 66.50, SD 9.51 kg; P=.006), systolic BP (mean 127.03, SD 8.00 mm Hg; P=.005), diastolic BP (mean 75.25, SD 5.88 mm Hg; P=.03), serum low-density lipoprotein cholesterol (mean 2.50, SD 0.61 mmol/L; P=.006), and total cholesterol (mean 4.01, SD 0.83 mmol/L; P=.02) in the TangPlan and WeChat group were all significantly lower, whereas serum high-density lipoprotein cholesterol (mean 1.20, SD 0.25 mmol/L; P=.01) was remarkably higher than in those in the control group. Compared with the baseline data, significance was found in the mean change in FBG (95% CI -0.83 to -0.20; P=.002), HbA1c (95% CI -1.92 to -1.28; P<.001), body weight (95% CI -3.13 to -1.68; P<.001), BMI (95% CI -1.10 to -0.60; P<.001), systolic BP (95% CI -7.37 to -3.94; P<.001), diastolic BP (95% CI -4.52 to -2.33; P<.001), triglycerides (95% CI -0.16 to -0.03; P=.004), serum low-density lipoprotein cholesterol (95% CI -0.54 to -0.30; P<.001), and total cholesterol (95% CI -0.60 to -0.34; P<.001) in the TangPlan and WeChat group but not in the control group (P=.08-.88). CONCLUSIONS: Compared with usual care for patients with T2DM, the combination of TangPlan and WeChat was effective in improving glycemic control (decrease in HbA1c and BG levels) and serum lipid profiles as well as reducing body weight in patients with T2DM after 6 months. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR2000028843; https://tinyurl.com/559kuve6.
Assuntos
Diabetes Mellitus Tipo 2 , Autogestão , Diabetes Mellitus Tipo 2/terapia , Exercício Físico , Hemoglobinas Glicadas/análise , Humanos , InternetRESUMO
PURPOSE: Normal weight obesity (NWO), defined as normal body mass index (BMI) and excessive body fat percentage (BF%), has been shown to be associated with a significantly higher risk of developing metabolic syndrome, cardiometabolic dysfunction and with higher mortality. However, there is limited literature regarding the potential associations between NWO and lifestyles. This study aimed to investigate the associations of lifestyles with NWO in Chinese university students. PARTICIPANTS AND METHODS: A total of 279 university students with normal BMI were recruited and divided into NWO and normal weight non-obesity (NWNO) groups by BF%. Body composition and anthropometrics were measured, and participants were asked to finish the Healthy Lifestyle Scale for University Students (HLSUS) questionnaire. RESULTS: A total of 26 male (25.5%) and 71 female (40.1%) students were identified as NWO. Compared to NWNO students, body weight, BMI, body fat mass, visceral fat area, waist circumference and hip circumference of NWO students were all significantly higher both in male and female students (P < 0.05). The body fat mass, BF% and visceral fat area were significantly negatively correlated with the total HLSUS, physical exercise behavior, and dietary nutrition behavior scores in NWNO males, NWO and NWNO females (P < 0.05). The risk of NWO was lower in those students with higher scores in physical exercise behavior in both males (OR = 0.298, 95% CI = 0.121~0.733) and females (OR = 0.653, 95% CI = 0.505~0.843), while dietary nutrition behavior (OR = 0.759, 95% CI = 0.584~0.986) and stress management behavior (OR = 0.503, 95% CI = 0.335~0.755) decreased the risk of NWO only in females. CONCLUSION: The incidence of NWO was high among university students, especially in females, which might be related with unhealthy lifestyles. NWO university students should pay attention to lifestyle adjustments, especially physical exercise, dietary nutrition and stress management, for preventing the health risk in NWO.
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AIMS: The present study was designed to compare the effects of a low-fat diet (LF), calorie restriction (CR), quercetin (Que) and exercise (Ex) on hepatic steatosis in a high-fat (HF) diet-induced obesity prone (OP) model in the perspective of microRNA (miR)-dependent thyroid hormone (TH) synthesis and action. MAIN METHODS: Male C57BL/6J mice were administered a HF diet for 10 weeks to induce OP phenotype and then divided into 5 groups, HF diet (OP-HF), LF diet (OP-LF), 70% CR (OP-CR), 0.05% Que (OP-Que) and a treadmill exercise regimen (OP-Ex); one additional group fed LF diet served as control (LF). 7 weeks later, serum indexes, metabolic alterations, redox status and histological appearance in the thyroid and liver, and TH related miRs with their targets expressions were determined. KEY FINDINGS: No significance on T3 levels was observed among the six groups. LF, CR, Que and Ex significantly ameliorated HF-induced hepatic steatosis to varying degrees, inhibited T4 production via differentially elevating miR-339, miR-383 and miR-146b to decrease NIS expression and regulating miR-200a/Nrf2 to maintain redox status in the thyroid. Furthermore, these four interventions differentially and significantly decreased miR-383 and miR-146b to elevate TRb and DIO1 expression, and subsequent TH responsive lipid metabolism genes regulation. Among them, the effects of CR on hepatic steatosis were the most prominent. SIGNIFICANCE: Our data indicated that amelioration of hepatic steatosis by LF, CR, Que and Ex resulted in many shared, but also many differential changes in the miR-dependent TH production and action.
Assuntos
Dieta com Restrição de Gorduras , Fígado Gorduroso/terapia , MicroRNAs/fisiologia , Obesidade/complicações , Condicionamento Físico Animal , Hormônios Tireóideos/metabolismo , Animais , Restrição Calórica , Fígado Gorduroso/dietoterapia , Fígado Gorduroso/etiologia , Hipolipemiantes/uso terapêutico , Lipídeos/análise , Fígado/química , Masculino , Camundongos Endogâmicos C57BL , MicroRNAs/metabolismo , Estresse Oxidativo , Quercetina/uso terapêuticoRESUMO
To develop a wound dressing material that conforms to the healing process, we prepared a multilayer composite (MC) membrane consisting of an antibacterial layer (ABL), a reinforcement layer (RFL), and a healing promotion layer (HPL). Biocompatible zein/ethyl cellulose (zein/EC) electrospun nanofibrous membranes with in situ loaded antibacterial photosensitizer protoporphyrin (PPIX) and healing promotion material vaccarin (Vac) were, respectively, chosen as the ABL on the surface and the HPL on the bottom, between which nonwoven incorporated bacterial cellulose (BC/PETN) as the HPL was intercalated to enhance the mechanical property. Photodynamic antibacterial activity against Staphylococcus aureus and Pseudomonas aeruginosa was confirmed by the enlarged inhibition zones; meanwhile, satisfactory biocompatibility of the HPL was verified by scanning electronic microscopy (SEM) of L929 cells cultured on its surface. The potential effects on wound healing in a mice skin defect model of the MC membranes were also evaluated. The animal experiments demonstrated that the wound healing rate in the MC group was significantly increased compared with that in the control group (p < 0.05). Histopathological observation revealed an alleviated inflammatory response, accompanied with vascular proliferation in the MC group. The MC membranes significantly promoted wound healing by creating an antibacterial environment and promoting angiogenesis. Taken together, this MC membrane may act as a promising wound dressing for skin wound healing.
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Taurine is a key functional amino acid with many functions in the nervous system. The effects of taurine on cognitive function have aroused increasing attention. First, the fluctuations of taurine and its transporters are associated with cognitive impairments in physiology and pathology. This may help diagnose and treat cognitive impairment though mechanisms are not fully uncovered in existing studies. Then, taurine supplements in cognitive impairment of different physiologies, pathologies and toxicologies have been demonstrated to significantly improve and restore cognition in most cases. However, elevated taurine level in cerebrospinal fluid (CSF) by exogenous administration causes cognition retardations only in physiologically sensitive period between the perinatal to early postnatal period. In this review, taurine levels are summarized in different types of cognitive impairments. Subsequently, the effects of taurine supplements on cognitions in physiology, different pathologies and toxication of cognitive impairments (e.g. aging, Alzheimer' disease, streptozotocin (STZ)-induced brain damage, ischemia model, mental disorder, genetic diseases and cognitive injuries of pharmaceuticals and toxins) are analyzed. These data suggest that taurine can improve cognition function through multiple potential mechanisms (e.g. restoring functions of taurine transporters and γ-aminobutyric acid (GABA) A receptors subunit; mitigating neuroinflammation; up-regulating Nrf2 expression and antioxidant capacities; activating Akt/CREB/PGC1α pathway, and further enhancing mitochondria biogenesis, synaptic function and reducing oxidative stress; increasing neurogenesis and synaptic function by pERK; activating PKA pathway). However, more mechanisms still need explorations.
Assuntos
Cognição/efeitos dos fármacos , Taurina/metabolismo , Taurina/farmacologia , Doença de Alzheimer/fisiopatologia , Animais , Antioxidantes/farmacologia , Cognição/fisiologia , Disfunção Cognitiva/fisiopatologia , Suplementos Nutricionais , Feminino , Humanos , Masculino , Fator 2 Relacionado a NF-E2/efeitos dos fármacos , Neurogênese/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Gravidez , Receptores de GABA , Receptores de GABA-A/efeitos dos fármacos , Estreptozocina/farmacologia , Taurina/fisiologiaRESUMO
Ischemia-reperfusion (I/R) injury is a common pathological process, which may lead to dysfunctions and failures of multiple organs. A flawless medical way of endogenous therapeutic target can illuminate accurate clinical applications. γ-Aminobutyric acid (GABA) has been known as a marker in I/R injury of the central nervous system (mainly in the brain) for a long time, and it may play a vital role in the occurrence of I/R injury. It has been observed that throughout cerebral I/R, levels, syntheses, releases, metabolisms, receptors, and transmissions of GABA undergo complex pathological variations. Scientists have investigated the GABAergic enhancers for attenuating cerebral I/R injury; however, discussions on existing problems and mechanisms of available drugs were seldom carried out so far. Therefore, this review would summarize the process of pathological variations in the GABA system under cerebral I/R injury and will cover corresponding probable issues and mechanisms in using GABA-related drugs to illuminate the concern about clinical illness for accurately preventing cerebral I/R injury. In addition, the study will summarize the increasing GABA signals that can prevent I/R injuries occurring in peripheral organs, and the roles of GABA were also discussed correspondingly.
Assuntos
Sistema Nervoso Central/efeitos dos fármacos , Traumatismo por Reperfusão/tratamento farmacológico , Ácido gama-Aminobutírico/uso terapêutico , Sistema Nervoso Central/patologia , Humanos , Traumatismo por Reperfusão/patologia , Ácido gama-Aminobutírico/farmacologiaRESUMO
Hepatic microRNAs (miRs) regulate local thyroid hormone (TH) action and TH-related lipid metabolism. We previously found that myricetin effectively ameliorated hepatic steatosis by targeting PPAR signaling pathway, in which the differentially expressed genes were TH-responsive. The present study was designed to explore the mechanism by which myricetin regulated miR-dependent TH action and lipid metabolism on high-fat diet (HFD)-induced hepatic steatosis. C57BL/6J mice were fed a HFD with or without 100 mg kg-1 myricetin by oral gavage for 16 weeks (n = 8 for each group). The results showed that myricetin improved HFD-induced hepatic steatosis, increased serum TH levels and hepatic type 1 deiodinase (DIO1) activities, and elevated energy expenditure in relation to the HFD mice. Meanwhile, myricetin inhibited miR-205 and miR-146b up-regulation induced by HFD, and also up-regulated their targets, Dio1 and thyroid hormone receptor b (TRb) expression, at both the transcriptional and translational levels, accompanied by the regulation of TH responsive lipid metabolism genes. Overexpression or knockdown of miR-205 failed to affect Dio1 mRNA and protein levels in primary mouse hepatocytes. Myricetin directly decreased miR-146b expression in miR-146b mimic-treated hepatocytes to elevate TRb levels. However, the beneficial effects of myricetin on hepatic TH action and lipid metabolism were abolished by TRb siRNA in free fatty acid (FFA)-treated hepatocytes. Our results indicated that myricetin attenuated hepatic steatosis via the miR-146b/TRb pathway and should be considered for the management of NAFLD conditions.
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Dieta Hiperlipídica/efeitos adversos , Fígado Gorduroso/tratamento farmacológico , Flavonoides/farmacologia , MicroRNAs/metabolismo , Receptores beta dos Hormônios Tireóideos/metabolismo , Tecido Adiposo , Animais , Peso Corporal , Regulação da Expressão Gênica/efeitos dos fármacos , Lipídeos/sangue , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Receptores beta dos Hormônios Tireóideos/genéticaRESUMO
Hepatic lipid accumulation and oxidative stress (OS) lead to non-alcoholic fatty liver disease (NAFLD). Thus, we hypothesized that antihyperlipidemic and antioxidant activities of niga-ichigoside F1 (NI) would ameliorate events leading to NAFLD. Lanbuzheng (Geum japonicum Thunb. var. chinense), a type of wild vegetable found in Southwest China, was used to extract NI. Male C57BL/6J mice were fed a standard diet (Con) or a high-fat diet (HFD) (denoted as diet) with or without 40 mg kg-1 NI (defined as treatment) for 12 weeks. Diet-treatment interactions were observed in the final body weight, fat pad mass, respiratory exchange ratio (RER) in the daytime, and energy expenditure during the whole day. Moreover, NI alleviated hepatic steatosis, possibly by significantly interacting with HFD to regulate lipid metabolism genes (including Srebp1c, Acc1, Fasn, Scd1, Cpt1a and Fabp5). We also found significant diet-treatment interactions on superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT) activities, and thiobarbituric acid reactive substance (TBARS) levels, as well as the nuclear and cellular Nrf2 protein levels. Significant free fatty acid (FFA)-treatment interactions on Nrf2 nuclear translocation, antioxidant enzymes activities, genes in lipogenesis (Srebp1c, Acc1, Fasn, and Scd1), and fatty acid oxidation (Pparα) and transport (Fabp5 and Cd36) were also detected in 1 mM FFA-treated HepG2 cells with or without 20 µM NI. These beneficial effects of NI on oxidative stress and lipid accumulation were abolished by Nrf2 siRNA. Our data revealed that dietary NI could prevent HFD-induced hepatic steatosis, possibly via interacting with HFD to activate Nrf2 nuclear translocation to maintain a redox status, thus regulating lipid metabolism genes expressions.
Assuntos
Geum/química , Fator 2 Relacionado a NF-E2/genética , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Extratos Vegetais/administração & dosagem , Saponinas/administração & dosagem , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Animais , Dieta Hiperlipídica/efeitos adversos , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismoRESUMO
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 3'untranslated region (3'UTR). 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.
Assuntos
Regulação da Expressão Gênica/fisiologia , MicroRNAs/metabolismo , Obesidade/genética , Animais , Dieta Hiperlipídica , Metabolismo Energético/genética , Metabolismo Energético/fisiologia , Hepatócitos/metabolismo , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/genética , Atividade Motora/genética , Atividade Motora/fisiologia , Obesidade/metabolismo , Consumo de Oxigênio , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tiroxina/sangue , Tri-Iodotironina/sangueRESUMO
Myricetin is an effective antioxidant in the treatment of obesity and obesity-related metabolic disorders. The objective of this study was to explore the regressive effect of myricetin on pre-existing hepatic steatosis induced by high-fat diet (HFD). C57BL/6 mice were fed either a standard diet or a HFD for 12 weeks and then half of the mice were treated with myricetin (0.12% in the diet, w/w) while on their respective diets for further 12 weeks. Myricetin treatment significantly alleviated HFD-induced steatosis, decreased hepatic lipid accumulation and thiobarbituric acid reactive substance (TBARS) levels, and increased antioxidative enzyme activities, including catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx) activities. Microarray analysis of hepatic gene expression profiles showed that myricetin significantly altered the expression profiles of 177 genes which were involved in 12 biological pathways, including the peroxisome proliferator activated receptor (PPAR) signaling pathway and peroxisome. Further research indicated that myricetin elevated hepatic nuclear Nrf2 translocation, increased the protein expression of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase 1 (NQO1), reduced the protein expression of PPARγ, and normalized the expressions of genes that were involved in peroxisome and the PPAR signaling pathway. Our data indicated that myricetin might represent an effective therapeutic agent to treat HFD-induced hepatic steatosis via activating the Nrf2 pathway and the PPAR signaling pathway.
Assuntos
Antioxidantes/uso terapêutico , Suplementos Nutricionais , Modelos Animais de Doenças , Flavonoides/uso terapêutico , Regulação da Expressão Gênica , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/dietoterapia , Transporte Ativo do Núcleo Celular , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Dieta Hiperlipídica/efeitos adversos , Perfilação da Expressão Gênica , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Fígado/enzimologia , Fígado/patologia , Masculino , Proteínas de Membrana/agonistas , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , NAD(P)H Desidrogenase (Quinona)/química , NAD(P)H Desidrogenase (Quinona)/genética , NAD(P)H Desidrogenase (Quinona)/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Estresse Oxidativo , PPAR gama/antagonistas & inibidores , PPAR gama/genética , PPAR gama/metabolismo , Peroxissomos/metabolismo , Peroxissomos/patologia , Distribuição Aleatória , Transdução de SinaisRESUMO
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.
Assuntos
Anti-Infecciosos/farmacologia , Permeabilidade da Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Peptídeos Penetradores de Células/metabolismo , DNA/química , Escherichia coli/química , Antibacterianos/farmacologia , Conservação de AlimentosRESUMO
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-3ß, 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.