RESUMEN
Alcoholic liver disease (ALD) remains to be a worldwide health problem. It is generally accepted that oxidative stress plays critical roles in the pathogenesis of ALD, and antioxidant therapy represents a logical strategy for the prevention and treatment of ALD. Nuclear factor erythroid-derived 2-like 2 (NFE2L2 or Nrf-2) is essential for the antioxidant responsive element (ARE)-mediated induction of endogenous antioxidant enzymes such as heme oxygenase 1 (HO-1) and glutamate-cysteine ligase [GCL, the rate-limiting enzyme in the synthesis of glutathione (GSH)]. Activation of Nrf-2 pathway by genetic manipulation or pharmacological agents has been demonstrated to provide protection against ALD, which suggests that targeting Nrf-2 may be a promising approach for the prevention and treatment of ALD. Herein, we review the relevant literature about the potential hepatoprotective roles of Nrf-2 activation against ALD.
Asunto(s)
Antioxidantes/metabolismo , Glutatión/biosíntesis , Hepatopatías Alcohólicas/prevención & control , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Glutamato-Cisteína Ligasa/metabolismo , Hemo-Oxigenasa 1/metabolismo , Humanos , Hepatopatías Alcohólicas/enzimología , Hepatopatías Alcohólicas/metabolismo , Modelos BiológicosRESUMEN
Alcoholic liver disease (ALD) is a progressively aggravated liver disease with a diverse spectrum from steatosis to hepatitis, fibrosis, and cirrhosis. Epidemiological studies reveal that alcohol is one of the major causes of advanced liver disease in Europe, United States, and China. Despite the considerable harm, progression in ALD research is slow and the current therapies for ALD have less efficient. Garlic (Allium sativum) has been used as a flavoring agent and also a folk medicine since ancient time. Along with the prosperity in the use of herbal medicines for the treatment of human diseases in recent decades, a series of studies have focused on the beneficial effects of garlic against ALD. This mini-review highlighted the protective roles of garlic against ALD and the potential mechanisms.
Asunto(s)
Etanol/toxicidad , Ajo , Hepatopatías Alcohólicas/prevención & control , Animales , Antioxidantes/farmacología , Humanos , Hígado/efectos de los fármacosRESUMEN
Protein kinase B (PKB/Akt) plays important roles in the regulation of lipid homeostasis, and impairment of Akt activity has been demonstrated to be involved in the development of non-alcoholic fatty liver disease (NAFLD). Previous studies suggest that cytochrome P4502E1 (CYP2E1) plays causal roles in the pathogenesis of alcoholic fatty liver (AFL). We hypothesized that Akt activity might be impaired due to CYP2E1-induced oxidative stress in chronic ethanol-induced hepatic steatosis. In this study, we found that chronic ethanol-induced hepatic steatosis was accompanied with reduced phosphorylation of Akt at Thr308 in mice liver. Chronic ethanol exposure had no effects on the protein levels of phosphatidylinositol 3 kinase (PI3K) and phosphatase and tensin homologue deleted on chromosome ten (PTEN), and led to a slight decrease of phosphoinositide-dependent protein kinase 1 (PDK-1) protein level. Ethanol exposure resulted in increased levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE)-Akt adducts, which was significantly inhibited by chlormethiazole (CMZ), an efficient CYP2E1 inhibitor. Interestingly, N-acetyl-L-cysteine (NAC) significantly attenuated chronic ethanol-induced hepatic fat accumulation and the decline of Akt phosphorylation at Thr308. In the in vitro studies, Akt phosphorylation was suppressed in CYP2E1-expressing HepG2 (CYP2E1-HepG2) cells compared with the negative control HepG2 (NC-HepG2) cells, and 4-HNE treatment led to significant decrease of Akt phosphorylation at Thr308 in wild type HepG2 cells. Lastly, pharmacological activation of Akt by insulin-like growth factor-1 (IGF-1) significantly alleviated chronic ethanol-induced fatty liver in mice. Collectively, these results indicate that CYP2E1-induced oxidative stress may be responsible for ethanol-induced suppression of Akt phosphorylation and pharmacological modulation of Akt in liver may be an effective strategy for the treatment of ethanol-induced fatty liver.
Asunto(s)
Citocromo P-450 CYP2E1/metabolismo , Hígado Graso Alcohólico/metabolismo , Estrés Oxidativo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Animales , Enfermedad Crónica , Hígado Graso Alcohólico/patología , Células Hep G2 , Humanos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , FosforilaciónRESUMEN
Alcoholic liver disease (ALD) encompasses a spectrum of liver injury ranging from steatosis to steatohepatitis, fibrosis, and finally cirrhosis. Accumulating evidences have demonstrated that Kupffer cells (KCs) play critical roles in the pathogenesis of both chronic and acute ALD. It has become clear that alcohol exposure can result in increased hepatic translocation of gut-sourced endotoxin/lipopolysaccharide, which is a strong M1 polarization inducer of KCs. The activated KCs then produce a large amount of reactive oxygen species (ROS), pro-inflammatory cytokines, and chemokines, which finally lead to liver injury. The critical roles of KCs and related inflammatory cascade in the pathogenesis of ALD make it a promising target in pharmaceutical drug developments for ALD treatment. Several drugs (such as rifaximin, pentoxifylline, and infliximab) have been evaluated or are under evaluation for ALD treatment in randomized clinical trials. Furthermore, screening pharmacological regulators for KCs toward M2 polarization may provide additional therapeutic agents. The combination of these potentially therapeutic drugs with hepatoprotective agents (such as zinc, melatonin, and silymarin) may bring encouraging results.
Asunto(s)
Consumo Excesivo de Bebidas Alcohólicas/fisiopatología , Microbioma Gastrointestinal/fisiología , Hepatopatías Alcohólicas/prevención & control , Hepatopatías Alcohólicas/fisiopatología , Animales , Consumo Excesivo de Bebidas Alcohólicas/tendencias , Etanol/toxicidad , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Ratones Endogámicos C57BLRESUMEN
BACKGROUND: The critical roles of tumor necrosis factor-α (TNF-α) and interleukin-10 (IL-10) in the pathogenesis of alcoholic liver diseases (ALD) suggest that functional variations in the TNF-α (TNFA) and IL-10 genes may be related to individual susceptibility to ALD. As available studies examining the associations between TNFA or IL-10 polymorphisms and ALD risk have yielded conflicting results, a meta-analysis was conducted to clarify the potential relation between TNFA and IL-10 polymorphisms and the risk of ALD. METHODS: A comprehensive literature search was conducted to identify relevant studies. Pooled odds ratios and 95% confidence intervals were calculated using a random-effects model. The heterogeneity between studies was assessed using the Cochran's Q statistic and the I(2) statistic. Publication bias was assessed using funnel plots and the Egger's regression test. RESULTS: A total of 17studies and 12studies were identified and included in the meta-analysis of the associations between TNFA polymorphisms and ALD risk, and IL-10 polymorphisms and ALD risk, respectively. The pooled results showed that the "A" allele of the TNFA-238G>A polymorphism was significantly associated with an increased risk of ALD. Significant differences in the allele and genotype distributions of the IL-10-1082A>G polymorphism were detected in the comparison between ALD patients and healthy controls, but not when comparing ALD patients and alcohol dependent individuals without ALD. No significant associations between other polymorphic loci and ALD risks were detected. CONCLUSIONS: The TNFA-238G>A polymorphism was significantly associated with ALD risk, while the TNFA-308G>A polymorphism and IL-10 polymorphisms (-1082A>G and -592C>A) may not be associated with the individual susceptibility to ALD. The impact of combined TNFA and IL-10 polymorphisms on individual susceptibility to ALD needs to be investigated in future studies.
Asunto(s)
Predisposición Genética a la Enfermedad , Interleucina-10/genética , Hepatopatías Alcohólicas/genética , Polimorfismo Genético , Factor de Necrosis Tumoral alfa/genética , HumanosRESUMEN
To explore the underlying mechanisms for the protective effects of garlic oil (GO) against nitrosodiethylamine (NDEA)-induced hepatocarcinoma, 60 male Wistar rats were randomized into 4 groups (n=15): control group, NDEA group, and two GO plus NDEA groups. The rats in GO plus NDEA groups were pretreated with GO (20 or 40 mg/kg) for 7 days. Then, all rats except those in control group were gavaged with NDEA for 20 weeks, and the rats in GO plus NDEA groups were continuously administered with GO. The results showed that GO co-treatment significantly suppressed the NDEA-induced increases of alpha fetal protein (AFP) level in serum, nuclear atypia in H&E staining, sirius red-positive areas and proliferating cell nuclear antigen (PCNA) expression. The molecular mechanisms exploration revealed that the protein levels of phosphatidylinositol 3 kinase (PI3K)-p85, PI3K-p110, total AKT, p-AKT (Ser473) and p-AKT (Thr308) in the liver of NDEA group rats were higher than those in control group rats. In addition, NDEA treatment induced IκB degradation and NF-κB p65 phosphorylation, and up-regulated the protein levels of downstream pro-inflammatory mediators. GO co-treatment significantly reversed all the above adverse effects induced by NDEA. These results suggested that the protective effects of GO against NDEA-induced hepatocarcinoma might be associated with the suppression of PI3K- AKT-NF-κB pathway.
Asunto(s)
Compuestos Alílicos/farmacología , Carcinoma/inducido químicamente , Dietilnitrosamina/toxicidad , Neoplasias Hepáticas/inducido químicamente , Sustancias Protectoras/farmacología , Sulfuros/farmacología , alfa-Fetoproteínas/metabolismo , Animales , Ciclooxigenasa 2/metabolismo , Proteínas I-kappa B/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , FN-kappa B/metabolismo , Proteínas de Neoplasias/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Fosforilación/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Cytochrome P4502E1 (CYP2E1) has been demonstrated to play crucial roles in chronic ethanol-induced fatty liver, while its role in acute ethanol-induced fatty liver remains unclear. The current study was designed to evaluate the effects of chlormethiazole (CMZ), a specific inhibitor of CYP2E1, on acute ethanol-induced fatty liver, and to explore the mechanisms. Mice were pretreated with single dose of CMZ (50mg/kg body weight) by intraperitoneal injection or equal volume of saline, and then exposed to three doses of ethanol (5g/kg body weight, 25%, w/v) by gavage with 12h intervals. The mice were sacrificed at 4h after the last ethanol dosing. It was found that CMZ significantly attenuated acute ethanol-induced increase of the hepatic and serum triglyceride levels, and reduced fat droplets accumulation in mice liver. Acute ethanol-induced increase of the hepatic malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE) levels (two biomarkers for oxidative stress) and decrease of glutathione (GSH) level was significantly suppressed by CMZ. CMZ also suppressed ethanol-induced decline of serum adiponectin level, but did not significantly affect the serum tumor necrosis factor-α (TNF-α) and ethanol levels. Furthermore, a significant decline of p62 protein level was observed in CMZ/ethanol group mice liver compared with that of the ethanol group mice. However, acute ethanol-induced increase of peroxisome proliferator-activated receptor α (PPAR-α) protein level was suppressed by CMZ, while the protein levels of sterol regulatory element-binding protein-1c (SREBP-1) and diacylglycerol acyltransferase 2 (DGAT2) were not significantly affected by ethanol or CMZ. Collectively, the results of the current study demonstrated that CMZ could effectively attenuate acute ethanol-induced fatty liver possibly by suppressing oxidative stress and adiponectin decline, and activating autophagy, which suggest that CYP2E1 might also play important roles in acute ethanol-induced fatty liver.
Asunto(s)
Clormetiazol/farmacología , Inhibidores del Citocromo P-450 CYP2E1/farmacología , Hígado Graso Alcohólico/prevención & control , Proteínas Quinasas Activadas por AMP/metabolismo , Adiponectina/sangre , Animales , Autofagia/efectos de los fármacos , Ligasas de Carbono-Carbono/metabolismo , Diacilglicerol O-Acetiltransferasa/metabolismo , Modelos Animales de Enfermedad , Ácido Graso Sintasas/metabolismo , Hígado Graso Alcohólico/metabolismo , Hígado Graso Alcohólico/patología , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , PPAR alfa/genética , PPAR alfa/metabolismo , Fosforilación , ARN Mensajero/genética , ARN Mensajero/metabolismo , Proteína 1 de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
BACKGROUND: Cytochrome P4502E1 (CYP2E1) has been suggested to play critical roles in the pathogenesis of alcoholic fatty liver (AFL), but the underlying mechanisms remains unclear. The current study was designed to evaluate whether CYP2E1 suppression by chlormethiazole (CMZ) could suppress AFL in mice, and to explore the underlying mechanisms. METHODS: Mice were treated with or without CMZ (50 mg/kg bw, i.p.) and subjected to liquid diet with or without ethanol (5%, w/v) for 4 weeks. Biochemical parameters were measured using commercial kits. The protein and mRNA levels were detected by western blot and qPCR, respectively. Histopathology and immunohistochemical assay were performed with routine methods. RESULTS: CYP2E1 inhibition by CMZ completely blocked AFL in mice, shown as the decline of the hepatic and serum triglyceride levels, and the fewer fat droplets in the liver sections. Chronic ethanol exposure led to significant decrease of the mRNA and protein levels of peroxisome proliferator-activated receptor α (PPAR-α), which was blocked by CMZ co-treatment. CMZ co-treatment suppressed ethanol-induced oxidative stress, overproduction of tumor necrosis α (TNF-α), and decrease of protein levels of the PPAR-α co-activators including p300 and deacetylated PGC1-α. Furthermore, CMZ co-treatment led to the activation of AMP-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK), and PI3K/Akt/GSK3ß pathway. However, chronic ethanol-induced decline of acyl-CoA carboxylase (ACC) and fatty acid synthase (FAS) protein levels was partially restored by CMZ, while the activation of autophagy appeared to be suppressed by CMZ. CONCLUSION: These results suggested that CMZ suppressed chronic ethanol-induced oxidative stress, TNF-α overproduction, decline of p300 protein level and deacetylation of PGC1-α, and activated AMPK, MAPK, and PI3K/Akt/GSK3ß pathway, which might contribute to the activation of PPAR-α and account for the protection of CMZ against AFL.
Asunto(s)
Etanol/toxicidad , Glucógeno Sintasa Quinasa 3/metabolismo , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Estrés Oxidativo/efectos de los fármacos , PPAR alfa/metabolismo , Factores de Transcripción/metabolismo , Acetilación/efectos de los fármacos , Animales , Clormetiazol/uso terapéutico , Hígado Graso/inducido químicamente , Hígado Graso/tratamiento farmacológico , Glucógeno Sintasa Quinasa 3 beta , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma , Transducción de Señal/efectos de los fármacosRESUMEN
AIMS: Pentoxifylline has been used to treat nonalcoholic fatty liver diseases (NAFLDs) due to its anti-tumor necrosis factor-α effects. We conducted a meta-analysis of randomized, double-blinded, placebo-controlled trials to investigate the effect of pentoxifylline on the biochemical and histological parameters of NAFLD patients. MATERIALS AND METHODS: A comprehensive literature search was conducted in the database including PubMed, Embase, ISI web of knowledge, the Cochrane Library, and Google Scholar to identify randomized, double-blind, placebo-controlled clinical trials about the effects of pentoxifylline on NAFLD. The pooled weighted mean difference (WMD) with 95% confidence interval (CI) was calculated to compare the effects of pentoxifylline and placebo. RESULTS: Five well-designed studies were retrieved. Pooled results showed that pentoxifylline significantly reduced the serum alanine transaminase activity (WMD=-27.97; 95% CI: -42.59, -13.34) and aspartate transaminase activity (WMD=-13.97; 95% CI: -23.31, -4.63) in NAFLD patients compared with placebo. In addition, pentoxifylline significantly improved steatosis (WMD=-0.68; 95% CI: -1.01, -0.34), lobular inflammation (WMD=-0.49; 95% CI: -0.86, -0.12), and fibrosis (WMD=-0.60; 95% CI: -0.99, -0.21). Furthermore, pentoxifylline also led to significant reduction in BMI (WMD=-0.51; 95% CI: -0.96, -0.06) and fasting glucose (WMD=-8.97; 95% CI: -14.52, -3.42), but did not significantly affect the serum tumor necrosis factor α and adiponectin levels when compared with placebo. CONCLUSION: Pentoxifylline could reduce the aminotransferase activities and improve the histological parameters in NAFLD patients. Large well-designed, randomized, placebo-controlled studies are needed to confirm these results.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Pentoxifilina/uso terapéutico , Antiinflamatorios no Esteroideos/efectos adversos , Método Doble Ciego , Humanos , Pentoxifilina/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Transaminasas/sangre , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
PURPOSE: The formation of pyrrole adducts might be responsible for peripheral nerve injury caused by n-hexane, but there is not an effective biomarker for monitoring occupational exposure of n-hexane. The current study was designed to investigate the changes of pyrrole adducts in serum and urine of rats exposed to 2,5-hexanedione (2,5-HD) and analyze the correlation between pyrrole adducts and 2,5-HD. METHODS: Two groups of male Wistar rats (n = 8) were administered a single dose of 200 and 400 mg/kg 2,5-HD (i.p.), and another two groups (n = 8) were given daily dose of 200 and 400 mg/kg 2,5-HD (i.p.) for 5 days. Pyrrole adducts and 2,5-HD in serum and urine were determined, at different time points after dosing, using Ehrlich's reagent and gas chromatography, respectively. RESULTS: The levels of pyrrole adducts in serum accumulated in a time-dependant manner after repeated exposure to 2,5-HD, while pyrrole adducts in urine, and 2,5-HD in serum and urine were kept stable. The half-life times (t1/2) of 2,5-HD and pyrrole adducts in serum were 2.27 ± 0.28 and 25.3 ± 3.34 h, respectively. Furthermore, the levels of pyrrole adducts in urine were significantly correlated with the levels of 2,5-HD in serum (r = 0.736, P < 0.001) and urine (r = 0.730, P < 0.001), and the levels of pyrrole adducts in serum were correlated with the cumulative dosage of 2,5-HD (r = 0.965, P < 0.001). CONCLUSION: The results suggested that pyrrole adducts in serum and urine might be markers of chronic exposure to n-hexane or 2,5-HD.
Asunto(s)
Monitoreo del Ambiente , Hexanonas/metabolismo , Neurotoxinas/metabolismo , Pirroles/metabolismo , Animales , Área Bajo la Curva , Biomarcadores/sangre , Biomarcadores/orina , Hexanos/metabolismo , Hexanos/toxicidad , Hexanonas/toxicidad , Masculino , Neurotoxinas/toxicidad , Pirroles/toxicidad , Ratas , Ratas Wistar , Espectrofotometría , ToxicocinéticaRESUMEN
OBJECTIVE: To investigate the protective effects of docosahexaenoic acid (DHA) and nervonic acid (NA) on the learning and memory abilities in rats exposed to 1-bromopropane (1-BP) and their action mechanisms. METHODS: Forty male Wistar rats (specific pathogen-free) were randomly divided into 4 groups (n = 10 for each), i.e., solvent control group, 1-BP (800 mg/kg) group, NA (150 mg/kg) + 1-BP (800 mg/kg) group, and DHA (500 mg/kg) + 1-BP (800 mg/kg) group. The rats were given respective test substances by gavage for 7 d. The Morris water maze (MWM) test was performed from days 8 to 12 to evaluate the rats' learning and memory abilities. After MWM test, rats were sacrificed in the next day, and cerebral cortex was quickly dissected and homogenized in an ice bath. The supernatant of the obtained homogenate was collected to measure the content of glutathione (GSH) and malondialdehyde (MDA) and the activities of glutathione reductase (GR) and γ-glutamate cysteine ligase (γ-GCL). RESULTS: The MWM spatial navigation test showed that the 1-BP group had significantly longer escape latency and significantly longer total swimming distance compared with the control group (P<0.05), while the DHA+1-BP group had significant decreases in escape latency and total swimming distance compared with the 1-BP group (P<0.05). The spatial probe test showed that the number of platform crossings was significantly greater in the DHA+1-BP group and NA+1-BP group than in the 1-BP group (P<0.05); compared with the control group, the 1-BP group had a significantly lower ratio of time spent in the zone around the platform to total time (P < 0.05), and the ratio was significantly higher in the DHA+1-BP group than in the 1-BP group (P < 0.05). Compared with the control group, the 1-BP group had a 18.1% decrease in GSH content, and DHA could significantly reverse 1-BP-induced decrease in GSH content (P < 0.05). Compared with the 1-BP group, the DHA+1-BP group and NA+1-BP group had significantly decreased MDA content (P < 0.05), the DHA+1-BP group had significantly increased GR activity (P < 0.05), and the NA+1-BP group had significantly increased γ-GCL activity (P < 0.05). CONCLUSION: The rats exposed to 1-BP have oxidative stress in the brain and impaired cognitive function. DHA and NA can reduce 1-BP-induced cognitive function impairment in rats, possibly by increasing the activities of GR and γ-GCL and the content of GSH in the brain.
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Ácidos Docosahexaenoicos/farmacología , Ácidos Grasos Monoinsaturados/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Memoria/efectos de los fármacos , Animales , Conducta Animal , Encéfalo/efectos de los fármacos , Glutamato-Cisteína Ligasa/metabolismo , Glutatión/metabolismo , Glutatión Reductasa/metabolismo , Hidrocarburos Bromados/toxicidad , Masculino , Malondialdehído/metabolismo , Estrés Oxidativo , Ratas , Ratas WistarAsunto(s)
Acrilamida/toxicidad , Proteínas del Citoesqueleto/sangre , Síndromes de Neurotoxicidad/sangre , Animales , Conducta Animal/efectos de los fármacos , Western Blotting , Relación Dosis-Respuesta a Droga , Electroforesis en Gel de Poliacrilamida , Ataxia de la Marcha/sangre , Ataxia de la Marcha/inducido químicamente , Masculino , Actividad Motora/efectos de los fármacos , Síndromes de Neurotoxicidad/etiología , Ratas , Ratas WistarRESUMEN
OBJECTIVE: To investigate the relationship between formation of pyrrole adducts and concentration of 2, 5-hexanedione (2, 5-HD) and to provide an experimental basis for the study on toxicity of n-hexane. METHODS: Serum samples were collected from normal persons and were then filtered and sterilized. They were mixed with 2,5-HD to obtain sera with final 2, 5-HD concentrations of 10, 25, 50, 100, and 200 mg/L, and blank serum was also prepared. The sera were cultured at 37°C and taken at different time points. Colorimetry was used to quantify the pyrrole adducts formed in sera, and gas chromatography was used to measure the remaining 2, 5-HD levels in sera. RESULTS: The content of pyrrole adducts increased as the culture proceeded and was dependent on the dose of 2, 5-HD; at the end of the experiment, the content of pyrrole adducts differed significantly across all concentration groups (P < 0.5). The concentrations of 2,5-HD decreased as the culture proceeded; at the end of the experiment, the concentrations of 2, 5-HD, from the highest to the lowest, decreased by 29%, 55%, 22%, 44%, and 40%, respectively. The decrease in 2, 5-HD had a positive correlation with the increase in pyrrole adducts, and the correlation coefficients for 200â¼10 mg/L 2, 5-HD were 0.865, 0.697, 0.835, 0.823, and 0.814, respectively. CONCLUSION: The content of formed pyrrole adducts increases as the concentration of 2,5-HD rises; there is a positive correlation between the decrease in 2, 5-HD and the increase in pyrrole adducts in human serum.
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Hexanonas/química , Pirroles/química , Suero/química , Humanos , Oxidación-ReducciónRESUMEN
BACKGROUND: Diallyl disulfide (DADS) is a garlic-derived organosulfur compound. The current study is designed to evaluate the protective effects of DADS against ethanol-induced oxidative stress, and to explore the underlying mechanisms by examining the HO-1/Nrf-2 pathway. METHODS: We investigated whether or not DADS could activate the HO-1 in normal human liver cell LO2, and then evaluated the protective effects of DADS against ethanol-induced damage in LO2 cells and in acute ethanol-intoxicated mice. The biochemical parameters were measured using commercial kits. HO-1 mRNA level was determined by RT-PCR. Histopathology and immunofluorescence assay were performed with routine methods. Protein levels were measured by western blot. RESULTS: DADS significantly increased the mRNA and protein levels of HO-1, stimulated the nuclear translocation of Nrf-2 and increased the phosphorylation of MAPK in LO2 cells. The nuclear translocation of Nrf-2 was abrogated by MAPK inhibitors. DADS significantly suppressed ethanol-induced elevation of lactate dehydrogenase (LDH) and aspartate transaminase (AST) activities, decrease of glutathione (GSH) level, increase of malondialdehyde (MDA) levels, and apoptosis of LO2 cells, which were all blocked by ZnPPIX. In mice, DADS effectively suppressed acute ethanol-induced elevation of aminotransferase activities, and improved liver histopathological changes, which might be associated with HO-1 activation. CONCLUSION: These results demonstrate that DADS could induce the activation of HO-1/Nrf-2 pathway, which may contribute to the protective effects of DADS against ethanol-induced liver injury. GENERAL SIGNIFICANCE: DADS may be beneficial for the prevention and treatment of ALD due to significant activation of HO-1/Nrf-2 pathway.
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Compuestos Alílicos/farmacología , Disulfuros/farmacología , Etanol/toxicidad , Hemo-Oxigenasa 1/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Animales , Secuencia de Bases , Línea Celular , Cartilla de ADN , Humanos , Sistema de Señalización de MAP Quinasas , Masculino , Ratones , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Although the anticancer effects of garlic and its products have been demonstrated by a variety of studies; however, few studies were conducted to investigate the effects of garlic on the adverse effects of chemo/radiotherapy. In order to clarify the above question and make a more comprehensive understanding of the anticancer effects of garlic, tumor xenograft mice model was established by subcutaneous injection of H22 tumor cells, and was used for the investigation of effects of garlic oil (GO) on the chemo/radiotherapy. In the chemotherapy test, tumor-bearing mice were treated with cyclophosphamide (CTX) or CTX plus GO (25 or 50 mg/kg bw) for 14 d, while the mice received a single 5 Gy total body radiation or radiation plus GO (25 or 50 mg/kg bw) in radiotherapy test. The results showed that GO did not increase the tumor inhibitory rate of CTX/radiation, which indicated that GO could not enhance the chemo/radiosensitivity of cancer cells. However, the decrease of the peripheral total white blood cells (WBCs) count induced by CTX/radiation was significantly suppressed by GO cotreatment. Furthermore, GO cotreatment significantly inhibited the decrease of the DNA contents and the micronuclei ratio of the bone marrow. Lastly, the reduction of the endogenous spleen colonies induced by CTX/radiation was significantly suppressed by GO cotreatment. These findings support the idea that GO consumption may benefit for the cancer patients receiving chemotherapy or radiotherapy.
Asunto(s)
Compuestos Alílicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ajo/química , Enfermedades Hematológicas/tratamiento farmacológico , Aceites de Plantas/farmacología , Sulfuros/farmacología , Animales , Antineoplásicos , Línea Celular Tumoral , Ensayo de Unidades Formadoras de Colonias , Ciclofosfamida/efectos adversos , Modelos Animales de Enfermedad , Enfermedades Hematológicas/etiología , Masculino , Ratones , Pruebas de Micronúcleos , Neoplasias/tratamiento farmacológico , Neoplasias/radioterapia , Bazo/citología , Bazo/metabolismoRESUMEN
AIMS: The association between CD14-159C>T polymorphisms and alcoholic liver disease (ALD) risk has been investigated in many studies, but the results were inconsistent. Therefore, we performed a meta-analysis to investigate the association between the CD14-159C>T polymorphisms and the risk for ALD. METHODS: A comprehensive literature search was conducted to identify the relevant studies from PubMed, ISI Web of Science, and Embase. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using either the fixed-effects model or random-effects model on the basis of the heterogeneity test. RESULTS: A total of eight eligible studies were included in the meta-analyses. The combined results showed no significant association between CD14-159C>T polymorphisms and ALD risk when ALD patients were compared with alcoholics without ALD (T vs. C, OR=1.22, 95% CI 0.84-1.77; TT/TC vs. CC, OR=1.43, 95% CI 0.86-2.37) and when ALD patients were compared with nonalcoholics (T vs. C, OR=1.13, 95% CI 0.90-1.43; TT/TC vs. CC, OR=1.05, 95% CI 0.76-1.46). However, a significant association was observed in the heterozygous comparison (TC vs. CC, OR=3.47, 95% CI 1.93-6.22), whereas a marginal association was observed in the dominant model (TT/CT vs. CC, OR=2.43, 95% CI 1.00-5.91) when alcoholic cirrhosis patients were compared with alcoholics without ALD. CONCLUSION: This meta-analysis suggests that the CD14-159C>T polymorphism may not be significantly associated with the risk for ALD. Although a significant association was observed between the -159C>T polymorphism and the risk for alcoholic cirrhosis, well-designed studies with large sample sizes are warranted to confirm these results.
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Receptores de Lipopolisacáridos/genética , Hepatopatías Alcohólicas/genética , Polimorfismo de Nucleótido Simple , Predisposición Genética a la Enfermedad , Humanos , Hepatopatías Alcohólicas/inmunología , Selección de Paciente , Sesgo de Publicación , Medición de Riesgo/métodos , Sensibilidad y EspecificidadRESUMEN
Nitrosodiethylamine (NDEA) is a potent carcinogen widely existing in the environment. Our previous study has demonstrated that garlic oil (GO) could prevent NDEA-induced hepatocarcinogenesis in rats, but the underlying mechanisms are not fully understood. It has been well documented that the metabolic activation may play important roles in NDEA-induced hepatocarcinogenesis. Therefore, we designed the current study to explore the potential mechanisms by investigating the changes of hepatic phase â enzymes (including cytochrome P450 enzyme (CYP) 2E1, CYP1A2 and CYP1A1) and phase â ¡ enzymes (including glutathione S transferases (GSTs) and UDP- Glucuronosyltransferases (UGTs)) by using enzymatic methods, real-time PCR, and western blotting analysis. We found that NDEA treatment resulted in significant decreases of the activities of CYP2E1, CYP1A2, GST alpha, GST mu, UGTs and increases of the activities of CYP1A1 and GST pi. Furthermore, the mRNA and protein levels of CYP2E1, CYP1A2, GST alpha, GST mu and UGT1A6 in the liver of NDEA-treated rats were significantly decreased compared with those of the control group rats, while the mRNA and protein levels of CYP1A1 and GST pi were dramatically increased. Interestingly, all these adverse effects induced by NDEA were simultaneously and significantly suppressed by GO co-treatment. These data suggest that the protective effects of GO against NDEA-induced hepatocarcinogenesis might be, at least partially, attributed to the modulation of phase I and phase II enzymes.
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Compuestos Alílicos/farmacología , Biotransformación/efectos de los fármacos , Carcinógenos Ambientales/toxicidad , Dietilnitrosamina/toxicidad , Neoplasias Hepáticas Experimentales/prevención & control , Sulfuros/farmacología , Animales , Carcinógenos Ambientales/farmacocinética , Transformación Celular Neoplásica/inducido químicamente , Sistema Enzimático del Citocromo P-450/metabolismo , Dietilnitrosamina/farmacocinética , Glutatión Transferasa/metabolismo , Inactivación Metabólica , Hígado/metabolismo , Masculino , ARN Mensajero/metabolismo , Ratas , Ratas WistarRESUMEN
BACKGROUND: Previous studies investigating the association between cytochrome P4502E1 (CYP2E1) polymorphisms and the risk of alcoholic liver diseases (ALD) have yielded conflicting results. Thus, a meta-analysis was performed to clarify the association between CYP2E1 polymorphisms and the risks of ALD. METHODS: A comprehensive literature search was conducted to identify the relevant studies. The fixed or random effect model was selected based on the heterogeneity test among studies. Publication bias was estimated using Begg's funnel plots and Egger's regression test. RESULTS: A total of 27 and 9 studies were finally included for the association between the CYP2E1 Pst I/Rsa I or Dra I polymorphisms and the risks of ALD, respectively. Overall, the combined results showed that homozygous genotype c2c2 was significantly associated with increase risk of ALD in worldwide populations (c2c2 vs. c1c1: OR = 3.12, 95%CI 1.91-5.11) when ALD patients were compared with alcoholics without ALD. Significant associations between CYP2E1 Pst I/Rsa I polymorphism and ALD risk were also observed in Asians (c2c2 vs. c1c1: OR = 4.11, 95%CI 2.32-7.29) and in Caucasians (c2c2/c1c2 vs. c1c1: OR = 1.58, 95%CI 1.04-2.42) when ALD patients were compared with alcoholics without ALD. However, subgroup analysis stratified by ALD types showed that CYP2E1 Pst I/Rsa I polymorphism was not significantly associated with the risks of alcoholic cirrhosis (ALC). No significant association was observed between CYP2E1 Dra I polymorphism and ALD risks. CONCLUSION: This meta-analysis suggested that CYP2E1 Pst I/Rsa I polymorphism might be not significantly associated with advanced form of ALD (ALC), but might be significantly associated with other form of ALD such as steatosis, hepatisis, fibrosis. Furthermore, CYP2E1 Dra I polymorphism might be not significantly associated with the ALD risks. Since potential confounders could not be ruled out completely, further studies were needed to confirm these results.