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1.
Ren Fail ; 41(1): 987-994, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31662023

RESUMO

To evaluate the relationship between the aryl hydrocarbon receptor (AHR) rs2066853 gene polymorphism and the risk of male infertility. PubMed, Embase, Web of Science, and Chinese National Knowledge Infrastructure (CNKI) were searched for relevant case-control studies up to 31 July 2019. Odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the strength of associations. Finally, seven case-control studies involving 1247 cases and 1762 controls were included in this meta-analysis. The pooled results showed that there was no significant association between AHR rs2066853 gene polymorphism and male infertility risk (A vs. G: OR = 1.08, 95% CI = 0.83-1.39; AA vs. GG: OR = 1.16, 95% CI = 0.65-2.04; AA vs. GA + GG: OR = 1.17, 95% CI = 0.66-2.07; AA + GA vs. GG: OR = 0.99, 95% CI = 0.85-1.15). Subgroup analysis by ethnicity showed the same result. However, significant association was found between AHR rs2066853 gene polymorphism and male infertility risk in oligoasthenotspermia (A vs. G: OR = 2.52, 95% CI = 1.72-3.70). In conclusion, our meta-analysis indicated that AHR rs2066853 gene polymorphism might be associated with an increased susceptibility to oligoasthenotspermia.

2.
Front Physiol ; 10: 1077, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31496957

RESUMO

Lipophagy degrades lipid droplets (LDs) through the lysosomal degradative pathway, thus plays important roles in regulating lipid metabolism in mammals. However, information on the existence and functions of lipophagy in fish lipid metabolism is still limited. In the present study, we confirmed the existence of lipophagy by observing the structures of LDs sequestered in autophagic vacuoles in the zebrafish liver cell line (ZFL) via electronic microscopy. Moreover, starved cells increased the mRNA expression of the microtubule-associated protein 1A/1B light chain 3 beta (LC3), which is a marker protein for autophagy and protein conversion from LC3-I to LC3-II. Inhibiting autophagy with chloroquine increased significantly the LDs content and decreased fatty acid ß-oxidation and esterification activities in the ZFL cells cultured in the fed state. Furthermore, inhibiting autophagy function downregulated the mRNA expression of the genes and their proteins related to lipid metabolism. Altogether, the present study verified the existence of lipophagy and its essential regulatory roles in lipid metabolism in fish cells.

3.
Medicine (Baltimore) ; 98(31): e16543, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31374016

RESUMO

BACKGROUND: Number of studies have been performed to investigate the relationship between the CYP1A1 rs4646903 polymorphism and male infertility risk, but the sample size was small and the results were conflicting. A meta-analysis was performed to assess these associations. METHODS: A systematic search was conducted to identify all relevant studies from Medline, Web of science, Embase, China biology medical literature database (CBM), China National Knowledge Infrastructure (CNKI), WanFang and Weipu (VIP) databases up to June 30, 2018. The odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of associations. All of the statistical analyses were conducted using Revman 5.3 and Stata 14.0. RESULTS: Ten studies involved 3028 cases and 3258 controls. Overall, significant association was observed between the CYP1A1 rs4646903 polymorphism and male infertility (C vs T: OR = 1.42, 95%CI = 1.14-1.76; CC vs TT: OR = 2.13, 95%CI = 1.36-3.34; CC vs CT+TT: OR = 1.96, 95%CI = 1.30-2.95; CC+CT vs TT: OR = 1.51, 95%CI = 1.16-1.97). In subgroup analysis by ethnic group, a statistically significant association was observed in Asians (C vs T: OR = 1.59, 95%CI = 1.22-2.08), but not in Non-Asians (C vs T: OR = 1.01, 95%CI = 0.79-1.30). Additionally, none of the individual studies significantly affected the association between CYP1A1 rs4646903 polymorphism and male infertility, according to sensitivity analysis. CONCLUSION: Our meta-analysis supports that the CYP1A1 rs4646903 polymorphism might contribute to individual susceptibility to male infertility in Asians.


Assuntos
Citocromo P-450 CYP1A1/genética , Infertilidade Masculina/etiologia , Infertilidade Masculina/genética , Predisposição Genética para Doença , Humanos , Masculino , Razão de Chances
4.
Chemosphere ; 237: 124422, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31352104

RESUMO

Environmental estrogenic compounds are important pollutants, which are widely distributed in natural water bodies. They produce various adverse effects on fish, but their concentration-dependent toxicities in fish metabolism and health are not fully understood. This study investigated the effects of 17ß-estradiol (E2) and bisphenol A (BPA) at low and high concentrations on lipid deposition, inflammation and antioxidant response in male zebrafish. We measured fish growth parameters, gonad development, lipid contents and the activities of inflammatory and antioxidant enzymes, as well as their mRNA expressions. All E2 and BPA concentrations used increased body weight, damaged gonad structure and induced feminization in male zebrafish. The exposure of zebrafish to E2 and BPA promoted lipid accumulation by increasing total fat, liver triglycerides and free fatty acid contents, and also upregulated lipogenic genes expression, although they decreased total cholesterol content. Notably, zebrafish exposed to low concentrations of E2 (200 ng/L) and BPA (100 µg/L) had higher lipid synthesis and deposition compared to high concentrations (2000 ng/L and 2000 µg/L, respectively). However, the high concentrations of E2 and BPA increased inflammation and antioxidant response. Furthermore, BPA caused greater damage to fish gonad development and more severe lipid peroxidation compared to E2. Overall, the results suggest that the toxic effects of E2 and BPA on zebrafish are concentration-dependent such that, the relative low concentrations used induced lipid deposition, whereas the high ones caused adverse effects on inflammation and antioxidant response.


Assuntos
Antioxidantes/metabolismo , Compostos Benzidrílicos/farmacologia , Estradiol/farmacologia , Inflamação/induzido quimicamente , Metabolismo dos Lipídeos/efeitos dos fármacos , Fenóis/farmacologia , Poluentes Químicos da Água/toxicidade , Animais , Compostos Benzidrílicos/metabolismo , Relação Dose-Resposta a Droga , Estradiol/metabolismo , Estrogênios/farmacologia , Gônadas/efeitos dos fármacos , Inflamação/metabolismo , Masculino , Fenóis/metabolismo , Diferenciação Sexual , Peixe-Zebra/metabolismo
5.
Org Lett ; 21(15): 6000-6004, 2019 Aug 02.
Artigo em Inglês | MEDLINE | ID: mdl-31334666

RESUMO

Structurally novel atropisomeric arylindole frameworks have been successfully constructed through chiral phosphoric acid-catalyzed asymmetric cross-coupling of indoles and quinone derivatives in a precise regioselective manner. This approach features high convergence and functional group tolerance to efficiently deliver diverse heteroaryl atropisomers with excellent enantiocontrol. The dominant formation of axial chirality but not central chirality, as the major unmet challenge for this type of reactions, was conquered by the rational and accurate modulation of the electronic and steric effects on both coupling partners. Preliminary investigation demonstrated the practicality of such axially chiral arylindoles as chiral ligands in asymmetric catalysis.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31220619

RESUMO

Cold stress is a major threat to fish in both nature and aquaculture, and can induce oxidative stress in various fish. While the exact role of oxidative stress in cold-caused mortality is still unknown. The purpose of the present study was to evaluate the effects of oxidative stress on cold tolerance in fish and verify whether changing oxidative status could affect cold tolerance. We firstly demonstrated that acute cold exposure induced high oxidative stress in zebrafish liver, which may lead to mortality. Then we performed in vivo and in vitro experiments to determine the effects of the altered oxidative status on cold tolerance in zebrafish and zebrafish liver cell line (ZFL), respectively. In the in vivo study, the zebrafish which were fed with α-lipoic acid or reduced glutathione had lower cold-caused oxidative stress and tissues damage, and showed higher cold tolerance. In the experiment using zebrafish cells, increasing oxidative stress by H2O2 decreased the cellular cold tolerance, and the cold tolerance was partly recovered when oxidative stress was reduced by the addition of Vitamin C (VC). Taken together, we conclude that the reduction of oxidative stress increases cold tolerance in fish.

7.
Mar Pollut Bull ; 141: 61-69, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30955774

RESUMO

This study presents the distribution, seasonal variations and factors influencing phosphorus (P) forms in surface sediments from the Maowei Sea. P forms were measured using the sequential extraction (SEDEX) procedures. Inorganic P (IP) was the predominant chemical form of total P (TP). Fe-bound P (FeP) was the main IP form. Sediment particle sizes, organic matter distribution, terrestrial input and aquaculture activity were responsible for the seasonal variations of different forms of P in sediment. In summer, the average proportions of P fractions in TP followed the order of organic P (OP) > Fe-P > authigenic P (CaP) > detrital P (De-P) > exchangeable P (Ex-P); in winter, the corresponding order was OP > Fe-P > De-P > Ca-P > Ex-P. The potential bio-available P accounted for 71.1 ±â€¯4.9% and 70.6 ±â€¯6.3% of TP in summer and winter, respectively. Sedimentary organic matter mainly came from land-based sources in winter.


Assuntos
Sedimentos Geológicos/análise , Fósforo/análise , Aquicultura , Disponibilidade Biológica , China , Monitoramento Ambiental , Sedimentos Geológicos/química , Ferro/análise , Ferro/química , Tamanho da Partícula , Fósforo/química , Fósforo/farmacocinética , Estações do Ano
8.
Medicine (Baltimore) ; 98(6): e14166, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30732132

RESUMO

BACKGROUND: A meta-analysis was applied to evaluate the associations between the glutathione-S-transferases (GSTs) M1/T1 gene polymorphisms and male infertility in Chinese populations. METHODS: A comprehensive search for articles was conducted from PubMed, Web of Science, Embase, China biology medical literature database (CBM), China National Knowledge Infrastructure (CNKI), VIP, and Chinese literature database(Wang fang) up to April 30, 2018. All of the statistical analyses were performed using Review Manager 5.3 and Stata 14.0. RESULTS: Ten studies on GSTM1 gene polymorphism involving 3302 cases and 1959 controls, and ten studies on GSTT1 gene polymorphism involving 3048 cases and 1861 controls were included in this meta-analysis. Overall, the null genotype of GSTM1/GSTT1 was significantly related to male infertility risk in Chinese populations (GSTM1, OR = 1.35, 95% CI: 1.02-1.78; GSTT1, OR = 1.40, 95% CI: 1.15-1.70). In subgroup analyses stratified by infertility type, significant association was observed between GSTT1 null genotype and male infertility in both nonobstructive azoospermia (NOA) and oligoasthenozoospermia (OAT). However, the GSTM1 null genotype was associated with OAT, but not NOA in Chinese populations. The sensitivity analysis confirmed the reliability and stability of the meta-analysis. CONCLUSION: Our meta-analysis supports that the GSTM1/GSTT1 null genotype might contribute to individual susceptibility to male infertility in Chinese populations.


Assuntos
Glutationa Transferase/genética , Infertilidade Masculina/genética , Grupo com Ancestrais do Continente Asiático/genética , Azoospermia/genética , Estudos de Casos e Controles , China/epidemiologia , Predisposição Genética para Doença , Genótipo , Humanos , Infertilidade Masculina/etnologia , Masculino , Razão de Chances , Oligospermia/genética , Polimorfismo Genético , Reprodutibilidade dos Testes
9.
J Physiol ; 597(6): 1585-1603, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30615194

RESUMO

KEY POINTS: In a cold environment, mammals increase their food intake while fish decrease or stop feeding. However, the physiological value of fasting during cold resistance in fish is currently unknown. Fasting for more than 48 h enhanced acute cold resistance in zebrafish, which correlated with lipid catabolism and cell damage attenuation. Lipid catabolism and autophagy were necessary for cold resistance in fish and the inhibition of mitochondrial fatty acid ß-oxidation or autophagy weakened the fasting-induced cold resistance. Repression of mechanistic target of rapamycin (mTOR) signalling pathway by rapamycin largely mimicked the beneficial effects of fasting in promoting cold resistance, suggesting mTOR signalling may be involved in the fasting-induced cold resistance in fish. Our study demonstrates that fasting may be a protective strategy for fish to survive under cold stress. ABSTRACT: In cold environments, most homeothermic animals increase their food intake to supply more energy to maintain body temperature, whereas most poikilothermic animals such as fishes decrease or even stop feeding under cold stress. However, the physiological value of fasting during cold resistance in poikilotherms has not been explained. Here, we show that moderate fasting largely enhanced cold resistance in fish. By using pharmacological (fenofibrate, mildronate, chloroquine and rapamycin) and nutritional approaches (fatty acids diets and amino acids diets) in wild-type or specific gene knock-out zebrafish models (carnitine palmitoyltransferase-1b-deficient strain, CPT1b-/- , or autophagy-related protein 12-deficient strain, ATG12-/- ), we verified that fasting-stimulated lipid catabolism and autophagy played essential roles in the improved cold resistance. Moreover, suppression of the mechanistic target of rapamycin (mTOR) pathway by using rapamycin mostly mimicked the beneficial effects of fasting in promoting cold resistance as either the physiological phenotype or transcriptomic pattern. However, these beneficial effects were largely reduced when the mTOR pathway was activated through high dietary leucine supplementation. We conclude that fasting helps fish to resist cold stress by modulating lipid catabolism and autophagy, which correlates with the mTOR signalling pathway. Therefore, fasting can act as a protective strategy of fish in resisting coldness.

10.
Fish Shellfish Immunol ; 86: 785-793, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30553889

RESUMO

Dietary α-lipoic acid (LA), ß-glucan (Gluc) and l-carnitine (L-Ca) are commonly used additives to promote fish growth and stress resistance in aquaculture production. However their mechanisms and efficiencies in helping fish to resist diseases have not been compared before. In this study, we fed Nile tilapia (Oreochromis niloticus) with diets containing appropriate doses of LA, Gluc and L-Ca for five weeks and further intraperitoneally injected the fish with Aeromonas hydrophila. After dietary treatment, none of the additives affected the fish growth, but dietary Gluc and L-Ca reduced protein and lipid body contents in fish, respectively. After A. hydrophila challenge, all fish treated with the three dietary additives showed higher survival rate, but those fed on dietary L-Ca had lower survival than those fed on LA and Gluc diets, indicating high protection efficiency of LA and Gluc. The protective mechanisms of the three feed additives were quite different under A. hydrophila infection. Dietary LA induced higher total antioxidant capacity and higher mRNA expression of anti-oxidative genes than other additives in liver and also activated partly the immune function in serum and spleen. Gluc largely increased the immune function by activating the immunity enzymes in serum, inducing inflammation in liver and increasing the expression of immune genes in spleen and head kidney. Gluc also increased partly the antioxidant capacity in serum and liver and lipid catabolism in liver. L-Ca largely increased lipid catabolism in liver while it increased partly the antioxidant capacities in serum and liver. Taken together, these results indicate that, dietary LA, Gluc and L-Ca have various protective mechanisms and differ in their efficiencies on resisting A. hydrophila infection in Nile tilapia.


Assuntos
Carnitina/farmacologia , Ciclídeos/imunologia , Doenças dos Peixes/imunologia , Substâncias Protetoras/farmacologia , Ácido Tióctico/farmacologia , beta-Glucanas/farmacologia , Aeromonas hydrophila/fisiologia , Ração Animal/análise , Animais , Carnitina/administração & dosagem , Dieta/veterinária , Suplementos Nutricionais/análise , Infecções por Bactérias Gram-Negativas/imunologia , Infecções por Bactérias Gram-Negativas/veterinária , Substâncias Protetoras/administração & dosagem , Ácido Tióctico/administração & dosagem , beta-Glucanas/administração & dosagem
11.
PLoS One ; 13(10): e0204845, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30273380

RESUMO

BACKGROUND: The inflammatory potential of diet has been shown to have an association with the risk of several cancer types, but the evidence is inconsistent regarding the related risk of urologic cancer (UC). Therefore, we conducted the present meta-analysis to investigate the association between the inflammatory potential of diet and UC. METHODS: PubMed, Embase and Web of Science were searched up to July 31, 2018. Two reviewers independently selected the studies and extracted the data. The pooled risk ratio (RR) and its 95% confidence interval (CI) were calculated using the Stata12.0 software package. RESULTS: Nine case-control studies and three cohort studies including 83,197 subjects met the inclusion criteria. The overall meta-analysis results showed that individuals with the highest category of DII (dietary inflammatory index) were associated with an increased risk of prostate cancer (RR = 1.62, 95% CI: 1.30-2.02); subgroup analysis showed consistent results. For kidney and bladder cancer, significant positive associations were found in individuals with the highest category of DII score; however, no significant association was found between DII and the risk of urothelial cell carcinoma (UCC). CONCLUSION: Available data suggest that more pro-inflammatory diets are associated with an increased risk of prostate cancer, kidney cancer and bladder cancer. However, further well designed large-scaled cohort studies are warranted to provide more conclusive evidence.


Assuntos
Dieta/efeitos adversos , Inflamação/induzido quimicamente , Neoplasias Urogenitais/epidemiologia , Estudos de Casos e Controles , Humanos , Inflamação/complicações , Neoplasias Renais/epidemiologia , Neoplasias Renais/etiologia , Masculino , Razão de Chances , Neoplasias da Próstata/epidemiologia , Neoplasias da Próstata/etiologia , Medição de Risco , Neoplasias da Bexiga Urinária/epidemiologia , Neoplasias da Bexiga Urinária/etiologia , Neoplasias Urogenitais/etiologia
12.
Andrologia ; 50(10): e13122, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30155914

RESUMO

To evaluate the association between TP53 codon72 polymorphism and male infertility risk. We conducted a search on Medline, Embase, Web of Science and CNKI up to April 30, 2017. Odds ratio (OR) and 95% confidence interval (95% CI) were used to assess the strength of the association. Seven studies including 1,818 cases and 2,278 controls met the inclusion criteria. The pooled results indicated that no significant association was observed between TP53 codon72 polymorphism and male infertility risk (G versus C: OR = 1.11, 95%CI = 0.94-1.32; GG versus CC: OR = 1.26, 95%CI = 0.90-1.78; GG versus GC+CC: OR = 1.16, 95%CI = 0.90-1.49; GG+GC versus CC: OR = 1.15, 95%CI = 0.88-1.49). In the subgroup analysis by ethnicity, significant association was observed between TP53 codon72 polymorphism and male infertility risk in non-Chinese (G versus C: OR = 1.47, 95%CI = 1.14-1.89), but not in Chinese population (G versus C: OR = 1.03, 95%CI = 0.87-1.22). In conclusion, this study suggested that TP53 codon72 polymorphism might be associated with an increased susceptibility to male infertility in non-Chinese population, but not in Chinese population. Studies with larger sample sizes and representative population-based cases and well-matched controls are needed to validate our results.


Assuntos
Predisposição Genética para Doença , Infertilidade Masculina/genética , Proteína Supressora de Tumor p53/genética , Arginina/genética , Grupo com Ancestrais do Continente Asiático/genética , Humanos , Infertilidade Masculina/epidemiologia , Masculino , Polimorfismo de Nucleotídeo Único , Prolina/genética
14.
Sci Rep ; 7: 41706, 2017 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-28139735

RESUMO

Peroxisome proliferation activated receptor α (PPARα) is an important transcriptional regulator of lipid metabolism and is activated by high-fat diet (HFD) and fibrates in mammals. However, whether nutritional background affects PPARα activation and the hypolipidemic effects of PPARα ligands have not been investigated in fish. In the present two-phase study of Nile tilapia (Oreochromis niloticus), fish were first fed a HFD (13% fat) or low-fat diet (LFD; 1% fat) diet for 10 weeks, and then fish from the first phase were fed the HFD or LFD supplemented with 200 mg/kg body weight fenofibrate for 4 weeks. The results indicated that the HFD did not activate PPARα or other lipid catabolism-related genes. Hepatic fatty acid ß-oxidation increased significantly in the HFD and LFD groups after the fenofibrate treatment, when exogenous substrates were sufficiently provided. Only in the HFD group, fenofibrate significantly increased hepatic PPARα mRNA and protein expression, and decreased liver and plasma triglyceride concentrations. This is the first study to show that body fat deposition and dietary lipid content affects PPARα activation and the hypolipidemic effects of fenofibrate in fish, and this could be due to differences in substrate availability for lipid catabolism in fish fed with different diets.


Assuntos
Ciclídeos/fisiologia , Fenofibrato/farmacologia , Hipolipemiantes/farmacologia , Fenômenos Fisiológicos da Nutrição , Animais , Dieta Hiperlipídica , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Metabolismo dos Lipídeos/efeitos dos fármacos , Especificidade de Órgãos/genética , Oxirredução , PPAR alfa/genética , PPAR alfa/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
15.
Sci Rep ; 7: 40815, 2017 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-28102299

RESUMO

Excess fat accumulation has been observed widely in farmed fish; therefore, efficient lipid-lowering factors have obtained high attention in the current fish nutrition studies. Dietary L-carnitine can increase fatty acid ß-oxidation in mammals, but has produced contradictory results in different fish species. To date, the mechanisms of metabolic regulation of L-carnitine in fish have not been fully determined. The present study used zebrafish to investigate the systemic regulation of nutrient metabolism by dietary L-carnitine supplementation. L-carnitine significantly decreased the lipid content in liver and muscle, accompanied by increased concentrations of total and free carnitine in tissues. Meanwhile, L-carnitine enhanced mitochondrial ß-oxidation activities and the expression of carnitine palmitoyltransferase 1 mRNA significantly, whereas it depressed the mRNA expression of adipogenesis-related genes. In addition, L-carnitine caused higher glycogen deposition in the fasting state, and increased and decreased the mRNA expressions of gluconeogenesis-related and glycolysis-related genes, respectively. L-carnitine also increased the hepatic expression of mTOR in the feeding state. Taken together, dietary L-carnitine supplementation decreased lipid deposition by increasing mitochondrial fatty acid ß-oxidation, and is likely to promote protein synthesis. However, the L-carnitine-enhanced lipid catabolism would cause a decrease in glucose utilization. Therefore, L-carnitine has comprehensive effects on nutrient metabolism in fish.


Assuntos
Carnitina/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Peixe-Zebra/metabolismo , Animais , Carnitina/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Suplementos Nutricionais , Gluconeogênese/genética , Glicogênio/metabolismo , Glicólise/genética , Peroxidação de Lipídeos/efeitos dos fármacos , Fígado/metabolismo , Mitocôndrias/metabolismo , Músculos/metabolismo , Serina-Treonina Quinases TOR/metabolismo
16.
Biochim Biophys Acta ; 1861(9 Pt A): 1036-1048, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27320014

RESUMO

Although the key metabolic regulatory functions of mammalian peroxisome proliferator-activated receptor α (PPARα) have been thoroughly studied, the molecular mechanisms and metabolic regulation of PPARα activation in fish are less known. In the first part of the present study, Nile tilapia (Nt)PPARα was cloned and identified, and high mRNA expression levels were detected in the brain, liver, and heart. NtPPARα was activated by an agonist (fenofibrate) and by fasting and was verified in primary hepatocytes and living fish by decreased phosphorylation of NtPPARα and/or increased NtPPARα mRNA and protein expression. In the second part of the present work, fenofibrate was fed to fish or fish were fasted for 4weeks to investigate the metabolic regulatory effects of NtPPARα. A transcriptomic study was also performed. The results indicated that fenofibrate decreased hepatic triglyceride and 18C-series fatty acid contents but increased the catabolic rate of intraperitoneally injected [1-(14)C] palmitate in vivo, hepatic mitochondrial ß-oxidation efficiency, the quantity of cytochrome b DNA, and carnitine palmitoyltransferase-1a mRNA expression. Fenofibrate also increased serum glucose, insulin, and lactate concentrations. Fasting had stronger hypolipidemic and gene regulatory effects than those of fenofibrate. Taken together, we conclude that: 1) liver is one of the main target tissues of the metabolic regulation of NtPPARα activation; 2) dephosphorylation is the basal NtPPARα activation mechanism rather than enhanced mRNA and protein expression; 3) activated NtPPARα has a hypolipidemic effect by increasing activity and the number of hepatic mitochondria; and 4) PPARα activation affects carbohydrate metabolism by altering energy homeostasis among nutrients.


Assuntos
Hepatócitos/metabolismo , Fígado/metabolismo , PPAR alfa/biossíntese , Tilápia/genética , Animais , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , PPAR alfa/metabolismo , RNA Mensageiro/biossíntese , Triglicerídeos/metabolismo
17.
Free Radic Biol Med ; 85: 127-37, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25912482

RESUMO

Developing anticancer agents by a prooxidant strategy has attracted increasing attention in recent years, although it is not conventional in medicinal chemistry and is completely opposite to antioxidant therapy. In this work, a panel of diarylpentanoids as the curcumin mono-carbonyl analogs were designed and synthesized, and their cytotoxic and proapoptotic mechanisms against human lung cancer A549 cells were investigated at the frontiers of chemistry and biology. It was found that compared with curcumin, the compounds (A1, B1, and C1) bearing two ortho substituents on the aromatic rings, especially A1, exhibit significantly increased cytotoxic and proapoptotic activities through a Michael acceptor unit-dependent prooxidant-mediated mechanism. The prooxidative ability is governed not only by their electrophilicity but also by their geometry, cellular uptake and metabolic stability, and TrxR-inhibitory activity. Mechanistic investigation reveals that the compound A1 could effectively and irreversibly modify the TrxR by virtue of the above optimal biochemical parameters, and convert this antioxidant enzyme into a reactive oxygen species (ROS) promoter, resulting in a burst of the intracellular ROS including H2O2 and O2(-)•. The ROS generation is associated with falling apart in the redox buffering system, and subsequently induces increases in Ca(2+) influx and oxidative stress, collapse of mitochondrial membrane potential, and activation of caspase-9 and caspase-3, ultimately leading to cell apoptosis. This work highlights the feasibility in designing curcumin-inspired anticancer agents by a prooxidant strategy, and gives us useful information on how to design them.


Assuntos
Antineoplásicos/química , Curcumina/química , Espécies Reativas de Oxigênio/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Curcumina/farmacologia , Desenho de Drogas , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Ácidos Pentanoicos/química , Espécies Reativas de Oxigênio/metabolismo , Espécies Reativas de Oxigênio/farmacologia , Relação Estrutura-Atividade
18.
Food Chem ; 165: 191-7, 2014 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-25038666

RESUMO

[6]-Gingerol and [6]-shogaol are the major pungent components in ginger with a variety of biological activities including antioxidant activity. To explore their structure determinants for antioxidant activity, we synthesized eight compounds differentiated by their side chains which are characteristic of the C1-C2 double bond, the C4-C5 double bond or the 5-OH, and the six- or twelve-carbon unbranched alkyl chain. Our results show that their antioxidant activity depends significantly on the side chain structure, the reaction mediums and substrates. Noticeably, existence of the 5-OH decreases their formal hydrogen-transfer and electron-donating abilities, but increases their DNA damage- and lipid peroxidation-protecting abilities. Additionally, despite significantly reducing their DNA strand breakage-inhibiting activity, extension of the chain length from six to twelve carbons enhances their anti-haemolysis activity.


Assuntos
Antioxidantes/química , Catecóis/química , Álcoois Graxos/química , Extratos Vegetais/química , Dano ao DNA , Peroxidação de Lipídeos
19.
Food Chem ; 141(2): 1259-66, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-23790911

RESUMO

The activity and chemical mechanisms of ortho-dihydroxychalcones as cupric ion-dependent prooxidants were investigated under aerobic conditions. This work confirms that 3,4,3',4'-tetrahydroxychalcone and cupric ions could synergistically advance strand breakage of plasmid DNA, but also effectively induce DNA damage and apoptosis of human hepatoma HepG2 cells under low concentrations by promoting ROS production. Interestingly, ortho-dihydroxy groups on the aromatic B ring, connected by a double bond, possess higher DNA-cleaving activity than those on the aromatic A ring directly attached to a carbonyl group. Further mechanistic investigation on the cupric ion-mediated oxidation of 3,4,3',4'-tetrahydroxychalcone, by UV/vis spectral changes, reveals that at neutral pH, electron transfer is facilitated by means of sequential proton loss from the 4'-OH on the aromatic A ring and the subsequent formation of phenolate anion-Cu(II) complexes; the resulting phenoxyl radical could undergo the second deprotonation and electron transfer to give an ortho-quinone on the aromatic B ring.


Assuntos
Chalconas/química , Cobre/química , Oxidantes/química , Apoptose/efeitos dos fármacos , Chalconas/farmacologia , Dano ao DNA/efeitos dos fármacos , Células Hep G2 , Humanos , Estrutura Molecular , Oxidantes/farmacologia , Oxirredução , Plasmídeos/química , Plasmídeos/genética
20.
Chembiochem ; 14(9): 1094-104, 2013 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-23703900

RESUMO

Resveratrol (3,5,4'-trihydroxystilbene, RES), a star among dietary polyphenols, shows a wide range of biological activities, but it is rapidly and extensively metabolized into its glucuronide and sulfate conjugates as well as to the corresponding reduced products. This begs the question of whether the metabolites of RES contribute to its in vivo biological activity. To explore this possibility, we synthesized its glucuronidation (3-GR and 4'-GR) and reduction (DHR) metabolites, and evaluated the effect of these structure modifications on biological activities, including binding ability with human serum albumin (HSA), antioxidant activity in homogeneous solutions and heterogeneous media, anti-inflammatory activity, and cytotoxicity against various cancer cell lines. We found that 1) 4'-GR, DHR and RES show nearly equal binding to HSA, mainly through hydrogen bonding, whereas 3-GR adopts a quite different orientation mode upon binding, thereby resulting in reduced ability; 2) 3-GR shows comparable (even equal) ability to RES in FRAP- and AAPH-induced DNA strand breakage assays; DHR, 3-GR, and 4'-GR exhibit anti-hemolysis activity comparable to that of RES; additionally, 3-GR and DHR retain some degree activity of the parent molecule in DPPH.-scavenging and cupric ion-initiated oxidation of LDL assays, respectively; 3) compared to RES, 4'-GR displays equipotent ability in the inhibition of COX-2, and DHR presents comparable activity in inhibiting NO production and growth of SMMC-7721 cells. Relative to RES, its glucuronidation and reduction metabolites showed equal, comparable, or some degree of activity in the above assays, depending on the specific compound and test model, which probably supports their roles in contributing to the in vivo biological activities of the parent molecule.


Assuntos
Glucuronídeos/química , Estilbenos/metabolismo , Animais , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/toxicidade , Antioxidantes/síntese química , Antioxidantes/química , Antioxidantes/farmacologia , Sítios de Ligação , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Glucuronídeos/síntese química , Hemólise/efeitos dos fármacos , Humanos , Cinética , Camundongos , Simulação de Acoplamento Molecular , Oxirredução , Ligação Proteica , Estrutura Terciária de Proteína , Resveratrol , Albumina Sérica/química , Albumina Sérica/metabolismo , Estilbenos/química
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