RESUMEN
Liver disease is a global health problem that affects the well-being of tens of thousands of people. Dihydroquercetin (DHQ) is a flavonoid compound derived from various plants. Furthermore, DHQ has shown excellent activity in the prevention and treatment of liver injury, such as the inhibition of hepatocellular carcinoma cell proliferation after administration, the normalization of oxidative indices (like SOD, GSH) in this tissue, and the down-regulation of pro-inflammatory molecules (such as IL-6 and TNF-α). DHQ also exerts its therapeutic effects by affecting molecular pathways such as NF-κB and Nrf2. This paper discusses the latest research progress of DHQ in the treatment of various liver diseases (including viral liver injury, drug liver injury, alcoholic liver injury, non-alcoholic liver injury, fatty liver injury, and immune liver injury). It explores how to optimize the application of DHQ to improve its effectiveness in treating liver diseases, which is valuable for preparing potential therapeutic drugs for human liver diseases in conjunction with DHQ.
Asunto(s)
Quercetina , Quercetina/análogos & derivados , Quercetina/farmacología , Quercetina/uso terapéutico , Quercetina/química , Humanos , Animales , Hepatopatías/tratamiento farmacológico , Hepatopatías/metabolismo , Hepatopatías/prevención & control , Hepatopatías/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hígado/lesiones , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antioxidantes/químicaRESUMEN
Diabetic liver injury (DLI) has raised attention in recent years. Liver injury results from type 2 diabetes mellitus (T2DM), and in turn accelerates T2DM development by exacerbating insulin resistance. However, effective approaches for mitigating DLI are surprisingly rare. Krill oil (KO) is an alternative source of omega-3 polyunsaturated fatty acids, possessing antioxidant and anti-inflammatory capacities. Here we investigated the effect of KO supplementation on DLI in a mouse model of T2DM induced by streptozotocin and high-fat diet. The diabetic mice developed glucose intolerance, elevated serum alanine aminotransferase and aspartate aminotransferase, and hepatic pathological injuries such as vacuolation, lipid accumulation and fibrosis deposition, the effects of which were mitigated by KO. Further investigation showed that KO ameliorated the DM-induced expression of fibrotic and inflammatory genes. Notably, KO dramatically reduced hepatic oxidative gene expression, lipid peroxidation and ROS production, all of which are hallmarks of ferroptosis. The inhibitory effect of KO on ferroptosis was confirmed by the KO-decreased hepatic expression of GPX4, COX2 and ACSL4, as well as the KO-reduced hepatic iron deposition. Further, KO restored hepatic NRF2 antioxidant signaling which combats ferroptosis. The present study may provide KO supplementation as a viable approach for the intervention of DLI.
Asunto(s)
Antioxidantes , Diabetes Mellitus Experimental , Euphausiacea , Ferroptosis , Factor 2 Relacionado con NF-E2 , Aceites , Animales , Euphausiacea/química , Antioxidantes/farmacología , Ferroptosis/efectos de los fármacos , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Masculino , Aceites/farmacología , Factor 2 Relacionado con NF-E2/metabolismo , Factor 2 Relacionado con NF-E2/genética , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hígado/efectos de los fármacos , Ratones , Ácidos Grasos Omega-3/farmacología , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Expresión Génica/efectos de los fármacos , Hepatopatías/etiología , Hepatopatías/prevención & control , Hepatopatías/metabolismo , Hepatopatías/tratamiento farmacológico , Hepatopatías/patologíaRESUMEN
Aim Hepatic ischemia reperfusion injury (HIRI) is a leading cause of mortality post liver transplantation, hypovolemic shock and trauma. In this study, we tested, on molecular bases, the possible protective role of two different derivatives of 2-oxindole in a preclinical model of HIRI in rats. MAIN METHODS: HIRI was operated in male Wistar albino rats and prophylactic treatment with oxindole-curcumin (Coxi) or oxindole-vanillin (Voxi) was carried out before the operation. The biochemical and histopathological investigations, in addition to the mechanistic characterizations of the effect of the tested drugs were performed. KEY FINDINGS: HIRI was assured with elevated liver enzymes and marked changes in histopathological features, inflammatory response and oxidative stress. Pretreatment with Coxi and Voxi improved the hepatic histopathological alterations, reduced the elevated serum liver enzymes level and hepatic Malondialdehyde (MDA) content, increased the hepatic Superoxide Dismutase (SOD) activity and reduced Glutathione (GSH) content, downregulated the expression of TNF-α, IL-6, Nod-Like Receptor p3 (NLRP3), Cleaved caspase1, Cleaved caspase 3 proteins, alongside the expression level of IL-1ß, ICAM-1, VCAM-1 and BAX genes, attenuated NF-кB p-P65 Ser536 and Myeloperoxidase (MPO)-positive neutrophils, and activated the PI3K/AKT pathway. SIGNIFICANCE: Coxi and Voxi have promising hepatoprotective activity against HIRI in rats through ameliorating the biochemical and histopathological alterations, attenuating inflammatory and oxidative stress status by modulating the inflammatory TNF-α/ICAM-1, the pyroptosis NLRP3/Caspase-1, and the antioxidant PI3K/AKT pathways.
Asunto(s)
Caspasa 1 , Modelos Animales de Enfermedad , Hígado , Proteína con Dominio Pirina 3 de la Familia NLR , Estrés Oxidativo , Oxindoles , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Ratas Wistar , Daño por Reperfusión , Transducción de Señal , Animales , Daño por Reperfusión/metabolismo , Daño por Reperfusión/prevención & control , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/patología , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratas , Oxindoles/farmacología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Transducción de Señal/efectos de los fármacos , Caspasa 1/metabolismo , Estrés Oxidativo/efectos de los fármacos , Hepatopatías/metabolismo , Hepatopatías/prevención & control , Hepatopatías/patología , Hepatopatías/tratamiento farmacológicoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Ginseng (Panax ginseng C. A. Meyer) is a precious traditional Chinese medicine with multiple pharmacological effects. Ginsenoside Rg1 is a main active ingredient extracted from ginseng, which is known for its age-delaying and antioxidant effects. Increasing evidence indicates that Rg1 exhibits anti-inflammatory properties in numerous diseases and may ameliorate oxidative damage and inflammation in many chronic liver diseases. AIM OF THE STUDY: Chronic inflammatory injury in liver cells is an important pathological basis of many liver diseases. However, its mechanism remains unclear and therapeutic strategies to prevent its development need to be further explored. Thus, our study is to delve the protective effect and mechanism of Rg1 against chronic hepatic inflammatory injuries induced by lipopolysaccharide (LPS). MATERIALS AND METHODS: The chronic liver damage model in mice was build up by injecting intraperitoneally with LPS (200 µg/kg) for 21 days. Serum liver function indicators and levels of IL-1ß, IL-6 and TNF-α were examined by using corresponding Kits. Hematoxylin and Eosin (H&E), Periodic acid-Schiff (PAS), and Masson stains were utilized to visualize hepatic histopathological damage, glycogen deposition, and liver fibrosis. The nuclear import of p-Nrf2 and the generation of Col4 in the liver were detected by IF, while IHC was employed to detect the expressions of NLRP3 and AIM2 in the hepatic. The Western blot and q-PCR were used to survey the expressions of proteins and mRNAs of fibrosis and apoptosis, and the expressions of Keap1, p-Nrf2 and NLRP3, NLRP1, AIM2 inflammasome-related proteins in mouse liver. The cell viability of human hepatocellular carcinoma cells (HepG2) was detected by Cell Counting Kit-8 to select the action concentration of LPS, and intracellular ROS generation was detected using a kit. The expressions of Nuclear Nrf2, HO-1, NQO1 and NLRP3, NLRP1, and AIM2 inflammasome-related proteins in HepG2 cells were detected by Western blot. Finally, the feasibility of the molecular interlinking between Rg1 and Nrf2 was demonstrated by molecular docking. RESULTS: Rg1 treatment for 21 days decreased the levels of ALT, AST, and inflammatory factors of serum IL-1ß, IL-6 and TNF-α in mice induced by LPS. Pathological results indicated that Rg1 treatment obviously alleviated hepatocellular injury and apoptosis, inflammatory cell infiltration and liver fibrosis in LPS stimulated mice. Rg1 promoted Keap1 degradation and enhanced the expressions of p-Nrf2, HO-1 and decreased the levels of NLRP1, NLRP3, AIM2, cleaved caspase-1, IL-1ß and IL-6 in livers caused by LPS. Furthermore, Rg1 effectively suppressed the rise of ROS in HepG2 cells induced by LPS, whereas inhibition of Nrf2 reversed the role of Rg1 in reducing the production of ROS and NLRP3, NLRP1, and AIM2 expressions in LPS-stimulated HepG2 cells. Finally, the molecular docking illustrated that Rg1 exhibits a strong affinity towards Nrf2. CONCLUSION: The findings indicate that Rg1 significantly ameliorates chronic liver damage and fibrosis induced by LPS. The mechanism may be mediated through promoting the dissociation of Nrf2 from Keap1 and then activating Nrf2 signaling and further inhibiting NLRP3, NLRP1, and AIM2 inflammasomes in liver cells.
Asunto(s)
Ginsenósidos , Inflamasomas , Hepatopatías , Humanos , Ratones , Animales , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Lipopolisacáridos/farmacología , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Interleucina-6/metabolismo , Simulación del Acoplamiento Molecular , Hígado , Hepatocitos/metabolismo , Hepatopatías/tratamiento farmacológico , Hepatopatías/prevención & control , Hepatopatías/metabolismo , Cirrosis Hepática/metabolismo , FibrosisRESUMEN
Background: Cholestasis is a health problem, both in humans and animals, which in the disease's course involves oxidative stress, inflammation, and liver fibrosis. EA has been proven to have beneficial effects on various diseases. Aim: This study was conducted to determine the effect of EA in protecting liver damage because of cholestasis. In addition, to understand the underlying mechanism of liver damage in rats as a model animal by bile duct ligation (BDL) technique. Methods: In this study, male adult rats were used and randomly divided into three treatment groups. S is the sham-operated group, BDL is the group that is treated with BDL and the BDL-EA group is treated with BDL and given EA by gavage at a dose of 60 mg/kg bw/day, starting on the second day after BDL and given for 21 days. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT) were evaluated using spectrophotometer; tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-ß1) were evaluated using sandwich ELISA and histopathological examination using HE and Massion's Trichrome staining. Results: In this study, BDL significantly increased serum levels of AST, ALT, ALP, and hepatic GGT. In addition, BDL also increased levels of TNF-α, and TGF-ß1 compared to sham-operated controls. Histological studies in the BDL group also showed that the BDL increased the degree of necro-inflammation and collagen deposition area in the liver compared to the sham-operated group. Administration of EA has been shown to significantly improve liver morpho-function of the liver. I attenuated these changes in the BDL-EA group, where all observed study variables appeared to have improved. Conclusion: EA has been shown to reduce cholestasis that causes liver injury and improves liver enzyme profiles, and is suspected to have occurred because of its activities as an antioxidant, anti-inflammatory, and anti-fibrotic.
Asunto(s)
Colestasis , Hepatopatías , Granada (Fruta) , Animales , Masculino , Ratas , Colestasis/complicaciones , Colestasis/tratamiento farmacológico , Colestasis/metabolismo , Colestasis/veterinaria , Ácido Elágico/farmacología , Ácido Elágico/uso terapéutico , Frutas/metabolismo , Inflamación/veterinaria , Hepatopatías/tratamiento farmacológico , Hepatopatías/etiología , Hepatopatías/prevención & control , Hepatopatías/veterinaria , Factor de Crecimiento Transformador beta1/uso terapéutico , Factor de Necrosis Tumoral alfa/uso terapéuticoRESUMEN
Liver problems are a worldwide concern, and conventional medicinal therapies are ineffective. Hence, safeguarding the healthy liver is vital for good health and well-being. Infections due to virus, immune problems, cancer, alcohol abuse, and an overdose of drugs are some of the causes of liver diseases. Antioxidants derived from medicinal plants and conventional dietary sources can protect the liver from damages caused by oxidative stress system and various chemicals. Plants and plant-derived phytochemicals are appealing hepatoprotective agents since they have less side effects and still there is a lot of interest shown in using herbal tonics for treating liver disorders. This review therefore primarily focuses on newly discovered medicinal plants and compounds produced from plants that fall under the classifications of flavonoids, alkaloids, terpenoids, polyphenolics, sterols, anthocyanins, and saponin glycosides, all of which have the potential to be hepatoprotective. Hosta plantaginea, Ligusticum chuanxiong, Daniella oliveri, Garcinia mangostana, Solanum melongena, Vaccinium myrtillus, Picrorhiza kurroa, and Citrus medica are some potential plants having hepatoprotective effects. We conclude that these phytochemicals and the plant extracts listed above are used in the future to treat a variety of liver diseases, additional research is still needed to develop safer and more potent phytochemical drugs.
Asunto(s)
Hepatopatías , Plantas Medicinales , Plantas Medicinales/química , Fitoterapia , Antocianinas/uso terapéutico , Hepatopatías/tratamiento farmacológico , Hepatopatías/prevención & control , Fitoquímicos/farmacología , Fitoquímicos/uso terapéuticoRESUMEN
BACKGROUND: Intestinal failure-associated liver disease (IFALD) occurs in up to 50% of neonates treated with prolonged parenteral nutrition. Preventative strategies for IFALD include soybean oil lipid emulsion (SOLE) minimization and use of mixed-oil intravenous lipid emulsions (ILE). We conducted a pilot study prospectively comparing these two ILE strategies in the prevention of IFALD in neonates who required abdominal surgery. METHODS: We randomized eligible neonates to SOLE at 1 g/kg/day (SOLE Min) or mixed-oil ILE containing fish oil (MOLE) at 3 g/kg/day. These treatment groups were also compared with historic controls who received SOLE at 2-3 g/kg/day (SOLE Historic). We defined IFALD as a direct bilirubin >2 mg/dl on two measurements. Secondary outcomes included laboratory, growth, clinical, and nutrition outcomes. RESULTS: A total of 24 prospective and 24 historic patients were included. There was no difference in the rate of IFALD. However, there was a difference in the weekly change of direct bilirubin levels (SOLE Historic +0.293 mg/dl/week vs MOLE, P < 0.001; SOLE Min +0.242 mg/dl/week vs MOLE, P < 0.001). The MOLE group also had a lower direct bilirubin at study completion (SOLE Historic, 1.7 ± 1.7 mg/dl; SOLE Min, 1.6 ± 1.4 mg/dl; MOLE, 0.4 ± 0.4 mg/dl; P = 0.002) and received greater total calories (P = 0.008). CONCLUSION: The rate of IFALD did not differ when comparing ILE strategies in neonates requiring abdominal surgery. However, the MOLE group maintained significantly lower direct bilirubin levels over time while receiving increased calories. This pilot study highlights the need for further randomized controlled trials comparing these ILE strategies.
Asunto(s)
Enfermedades Intestinales , Insuficiencia Intestinal , Hepatopatías , Fallo Hepático , Humanos , Bilirrubina , Emulsiones Grasas Intravenosas/uso terapéutico , Aceites de Pescado/uso terapéutico , Enfermedades Intestinales/terapia , Hepatopatías/complicaciones , Hepatopatías/prevención & control , Fallo Hepático/complicaciones , Proyectos Piloto , Estudios Prospectivos , Aceite de Soja/uso terapéuticoRESUMEN
BACKGROUND: Exome sequencing in hundreds of thousands of persons may enable the identification of rare protein-coding genetic variants associated with protection from human diseases like liver cirrhosis, providing a strategy for the discovery of new therapeutic targets. METHODS: We performed a multistage exome sequencing and genetic association analysis to identify genes in which rare protein-coding variants were associated with liver phenotypes. We conducted in vitro experiments to further characterize associations. RESULTS: The multistage analysis involved 542,904 persons with available data on liver aminotransferase levels, 24,944 patients with various types of liver disease, and 490,636 controls without liver disease. We found that rare coding variants in APOB, ABCB4, SLC30A10, and TM6SF2 were associated with increased aminotransferase levels and an increased risk of liver disease. We also found that variants in CIDEB, which encodes a structural protein found in hepatic lipid droplets, had a protective effect. The burden of rare predicted loss-of-function variants plus missense variants in CIDEB (combined carrier frequency, 0.7%) was associated with decreased alanine aminotransferase levels (beta per allele, -1.24 U per liter; 95% confidence interval [CI], -1.66 to -0.83; P = 4.8×10-9) and with 33% lower odds of liver disease of any cause (odds ratio per allele, 0.67; 95% CI, 0.57 to 0.79; P = 9.9×10-7). Rare coding variants in CIDEB were associated with a decreased risk of liver disease across different underlying causes and different degrees of severity, including cirrhosis of any cause (odds ratio per allele, 0.50; 95% CI, 0.36 to 0.70). Among 3599 patients who had undergone bariatric surgery, rare coding variants in CIDEB were associated with a decreased nonalcoholic fatty liver disease activity score (beta per allele in score units, -0.98; 95% CI, -1.54 to -0.41 [scores range from 0 to 8, with higher scores indicating more severe disease]). In human hepatoma cell lines challenged with oleate, CIDEB small interfering RNA knockdown prevented the buildup of large lipid droplets. CONCLUSIONS: Rare germline mutations in CIDEB conferred substantial protection from liver disease. (Funded by Regeneron Pharmaceuticals.).
Asunto(s)
Proteínas Reguladoras de la Apoptosis , Mutación de Línea Germinal , Hepatopatías , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Reguladoras de la Apoptosis/metabolismo , Predisposición Genética a la Enfermedad/genética , Predisposición Genética a la Enfermedad/prevención & control , Humanos , Hígado/metabolismo , Hepatopatías/genética , Hepatopatías/metabolismo , Hepatopatías/prevención & control , Transaminasas/genética , Secuenciación del ExomaRESUMEN
The intestinal flora plays an important role in the development of many human and animal diseases. Microbiome association studies revealed the potential regulatory function of intestinal bacteria in many liver diseases, such as autoimmune hepatitis, viral hepatitis and alcoholic hepatitis. However, the key intestinal bacterial strains that affect pathological liver injury and the underlying functional mechanisms remain unclear. We found that the gut microbiota from gentamycin (Gen)-treated mice significantly alleviated concanavalin A (ConA)-induced liver injury compared to vancomycin (Van)-treated mice by inhibiting CD95 expression on the surface of hepatocytes and reducing CD95/CD95L-mediated hepatocyte apoptosis. Through the combination of microbiota sequencing and correlation analysis, we isolated 5 strains with the highest relative abundance, Bacteroides acidifaciens (BA), Parabacteroides distasonis (PD), Bacteroides thetaiotaomicron (BT), Bacteroides dorei (BD) and Bacteroides uniformis (BU), from the feces of Gen-treated mice. Only BA played a protective role against ConA-induced liver injury. Further studies demonstrated that BA-reconstituted mice had reduced CD95/CD95L signaling, which was required for the decrease in the L-glutathione/glutathione (GSSG/GSH) ratio observed in the liver. BA-reconstituted mice were also more resistant to alcoholic liver injury. Our work showed that a specific murine intestinal bacterial strain, BA, ameliorated liver injury by reducing hepatocyte apoptosis in a CD95-dependent manner. Determination of the function of BA may provide an opportunity for its future use as a treatment for liver disease.
Asunto(s)
Bacteroides/fisiología , Microbioma Gastrointestinal , Hepatopatías/prevención & control , Receptor fas/metabolismo , Animales , Apoptosis , Bacterias/clasificación , Bacterias/genética , Bacterias/aislamiento & purificación , Bacteroides/genética , Bacteroides/aislamiento & purificación , Heces/microbiología , Glutatión/metabolismo , Hepatocitos/citología , Hepatocitos/metabolismo , Humanos , Hepatopatías/metabolismo , Hepatopatías/microbiología , Hepatopatías/fisiopatología , Ratones , Ratones Endogámicos C57BL , Receptor fas/genéticaRESUMEN
CONTEXT: Crocin has been reported to have multiple bioactivities. However, the effect of crocin administration on caecal ligation and puncture (CLP)-induced sepsis remains unknown. OBJECTIVE: We investigated the effects of crocin on CLP-induced sepsis in mice and the underlying mechanism of action. MATERIALS AND METHODS: Five experimental groups (n = 10) of BALB/c mice were used: control, CLP (normal saline) and CLP + crocin (50, 100 and 250 mg/kg, 30 min prior to CLP). Mice were sacrificed 24 h after CLP. Liver, kidney and lung histopathology, indicator levels, apoptotic status, pro-inflammatory cytokines and relative protein levels were evaluated. RESULTS: Compared to the CLP group, crocin treatment significantly increased the survival rate (70%, 80%, 90% vs. 30%). Crocin groups exhibited protection against liver, kidney and lung damage with mild-to-moderate morphological changes and lower indicator levels: liver (2.80 ± 0.45, 2.60 ± 0.55, 1.60 ± 0.55 vs. 5.60 ± 0.55), kidney (3.00 ± 0.71, 2.60 ± 0.55, 1.40 ± 0.55 vs. 6.20 ± 0.84) and lungs (8.00 ± 1.59, 6.80 ± 1.64, 2.80 ± 0.84 vs. 14.80 ± 1.79). The proinflammatory cytokines (IL-1ß, TNF-α, IL-6 and IL-10 levels in the crocin groups) were distinctly lower and the apoptotic index showed a significant decrease. Crocin administration significantly suppressed p38 MAPK phosphorylation and inhibited NF-κB/IκBα and Bcl-2/Bax activation. DISCUSSION AND CONCLUSIONS: Pre-treatment with crocin confers protective effects against CLP-induced liver, kidney and lung injury, implying it to be a potential therapeutic agent.
Asunto(s)
Carotenoides/farmacología , FN-kappa B/metabolismo , Sepsis/tratamiento farmacológico , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Animales , Carotenoides/administración & dosificación , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Enfermedades Renales/etiología , Enfermedades Renales/prevención & control , Hepatopatías/etiología , Hepatopatías/prevención & control , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/prevención & control , Ratones , Ratones Endogámicos BALB C , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Sepsis/complicaciones , Proteína X Asociada a bcl-2/efectos de los fármacosRESUMEN
BACKGROUND AND AIMS: p21-activated kinase 4 (PAK4), an oncogenic protein, has emerged as a promising target for anticancer drug development. Its role in oxidative stress conditions, however, remains elusive. We investigated the effects of PAK4 signaling on hepatic ischemia/reperfusion (I/R) injury. APPROACH AND RESULTS: Hepatocyte- and myeloid-specific Pak4 knockout (KO) mice and their littermate controls were subjected to a partial hepatic I/R (HIR) injury. We manipulated the catalytic activity of PAK4, either through genetic engineering (gene knockout, overexpression of wild-type [WT] or dominant-negative kinase) or pharmacological inhibitor, coupled with a readout of nuclear factor erythroid 2-related factor 2 (Nrf2) activity, to test the potential function of PAK4 on HIR injury. PAK4 expression was markedly up-regulated in liver during HIR injury in mice and humans. Deletion of PAK4 in hepatocytes, but not in myeloid cells, ameliorated liver damages, as demonstrated in the decrease in hepatocellular necrosis and inflammatory responses. Conversely, the forced expression of WT PAK4 aggravated the pathological changes. PAK4 directly phosphorylated Nrf2 at T369, and it led to its nuclear export and proteasomal degradation, all of which impaired antioxidant responses in hepatocytes. Nrf2 silencing in liver abolished the protective effects of PAK4 deficiency. A PAK4 inhibitor protected mice from HIR injury. CONCLUSIONS: PAK4 phosphorylates Nrf2 and suppresses its transcriptional activity. Genetic or pharmacological suppression of PAK4 alleviates HIR injury. Thus, PAK4 inhibition may represent a promising intervention against I/R-induced liver injury.
Asunto(s)
Hepatopatías , Daño por Reperfusión , Quinasas p21 Activadas , Animales , Apoptosis , Humanos , Isquemia/metabolismo , Isquemia/patología , Hígado/patología , Hepatopatías/etiología , Hepatopatías/metabolismo , Hepatopatías/prevención & control , Ratones , Ratones Noqueados , Factor 2 Relacionado con NF-E2/metabolismo , Fosforilación , Daño por Reperfusión/metabolismo , Quinasas p21 Activadas/genética , Quinasas p21 Activadas/metabolismoRESUMEN
We investigated whether diallyl disulfide (DADS) has protective effects against 1,3-dichloro-2-propanol (1,3-DCP)-induced hepatotoxicity and oxidative damage in rats and HepG2 cells. DADS was administered to rats once daily for 7 days at doses of 30 and 60 mg/kg/day. One hour after the final DADS treatment, the rats were administered 90 mg/kg 1,3-DCP to induce acute hepatotoxicity. DADS treatment significantly suppressed the increase in serum aminotransferase levels induced by 1,3-DCP administration, and reduced histopathological alterations in the liver. DADS treatment reduced 1-3-DCP-induced apoptotic changes in the liver, as revealed by terminal deoxynucleotidyl transferase dUTP nick end labeling staining and immunohistochemistry for caspase-3. DADS treatment competitively inhibited or reduced cytochrome p450 2E1 (CYP2E1) expression, which is involved in the metabolic activation of 1,3-DCP, and enhanced antioxidant properties. Furthermore, DADS treatment inhibited phosphorylation of mitogen-activated protein kinases (MAPKs) and apoptotic signaling. In in vitro experiments, MAPKs inhibitors reduced the expression of Bax/Bcl-2/Caspase 3 signaling, which effects were more significant in co-treated cells with DADS and MAPKs inhibitors. In conclusion, the protective effect of DADS against 1,3-DCP-induced hepatotoxicity may be related to blocking the metabolic activation of 1,3-DCP by suppressing CYP2E1 expression, inducing antioxidant enzyme activity, and reducing apoptotic activity by inhibiting phosphorylation of MAPKs.
Asunto(s)
Compuestos Alílicos/administración & dosificación , Disulfuros/administración & dosificación , Hepatopatías/prevención & control , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Sustancias Protectoras/farmacología , alfa-Clorhidrina/análogos & derivados , Animales , Apoptosis/efectos de los fármacos , Caspasa 3/genética , Caspasa 3/metabolismo , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Células Hep G2 , Humanos , Hepatopatías/etiología , Hepatopatías/metabolismo , Hepatopatías/fisiopatología , Masculino , Proteínas Quinasas Activadas por Mitógenos/genética , Estrés Oxidativo/efectos de los fármacos , Fosforilación , Ratas , Ratas Sprague-Dawley , Transducción de Señal/efectos de los fármacos , alfa-Clorhidrina/toxicidadRESUMEN
BACKGROUND AND AIMS: Parenteral nutrition (PN)-associated cholestasis (PNAC) complicates the care of patients with intestinal failure. In PNAC, phytosterol containing PN synergizes with intestinal injury and IL-1ß derived from activated hepatic macrophages to suppress hepatocyte farnesoid X receptor (FXR) signaling and promote PNAC. We hypothesized that pharmacological activation of FXR would prevent PNAC in a mouse model. APPROACH AND RESULTS: To induce PNAC, male C57BL/6 mice were subjected to intestinal injury (2% dextran sulfate sodium [DSS] for 4 days) followed by central venous catheterization and 14-day infusion of PN with or without the FXR agonist GW4064. Following sacrifice, hepatocellular injury, inflammation, and biliary and sterol transporter expression were determined. GW4064 (30 mg/kg/day) added to PN on days 4-14 prevented hepatic injury and cholestasis; reversed the suppressed mRNA expression of nuclear receptor subfamily 1, group H, member 4 (Nr1h4)/FXR, ATP-binding cassette subfamily B member 11 (Abcb11)/bile salt export pump, ATP-binding cassette subfamily C member 2 (Abcc2), ATP binding cassette subfamily B member 4(Abcb4), and ATP-binding cassette subfamily G members 5/8(Abcg5/8); and normalized serum bile acids. Chromatin immunoprecipitation of liver showed that GW4064 increased FXR binding to the Abcb11 promoter. Furthermore, GW4064 prevented DSS-PN-induced hepatic macrophage accumulation, hepatic expression of genes associated with macrophage recruitment and activation (ll-1b, C-C motif chemokine receptor 2, integrin subunit alpha M, lymphocyte antigen 6 complex locus C), and hepatic macrophage cytokine transcription in response to lipopolysaccharide in vitro. In primary mouse hepatocytes, GW4064 activated transcription of FXR canonical targets, irrespective of IL-1ß exposure. Intestinal inflammation and ileal mRNAs (Nr1h4, Fgf15, and organic solute transporter alpha) were not different among groups, supporting a liver-specific effect of GW4064 in this model. CONCLUSIONS: GW4064 prevents PNAC in mice through restoration of hepatic FXR signaling, resulting in increased expression of canalicular bile and of sterol and phospholipid transporters and suppression of macrophage recruitment and activation. These data support augmenting FXR activity as a therapeutic strategy to alleviate or prevent PNAC.
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Colestasis/prevención & control , Expresión Génica/efectos de los fármacos , Isoxazoles/farmacología , Nutrición Parenteral/efectos adversos , Receptores Citoplasmáticos y Nucleares/agonistas , Receptores Citoplasmáticos y Nucleares/genética , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP/genética , Miembro 11 de la Subfamilia B de Transportador de Casetes de Unión al ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 5/genética , Transportador de Casete de Unión a ATP, Subfamilia G, Miembro 8/genética , Animales , Ácidos y Sales Biliares/sangre , Colestasis/etiología , Regulación de la Expresión Génica/efectos de los fármacos , Hepatocitos/metabolismo , Interleucina-1beta/farmacología , Enfermedades Intestinales/inducido químicamente , Enfermedades Intestinales/terapia , Isoxazoles/uso terapéutico , Lipoproteínas/genética , Hepatopatías/etiología , Hepatopatías/patología , Hepatopatías/prevención & control , Activación de Macrófagos/efectos de los fármacos , Macrófagos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Proteína 2 Asociada a Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/genética , ARN Mensajero/metabolismo , Receptores Citoplasmáticos y Nucleares/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
OBJECTIVES: This study aimed to investigate the hepatoprotective effects of specnuezhenide against carbon tetrachloride (CCl4)-induced liver injury in mice. METHODS: Male C57BL/6 mice were intraperitoneally injected with 10 ml/kg body weight of CCl4 (0.5% diluted in arachis oil) for acute liver injury after oral administration of specnuezhenide for 7 days. Twenty-four hours after the final CCl4 injection, mice were euthanized and plasma and liver samples were collected. KEY FINDINGS: The results showed that specnuezhenide markedly and dose-dependently reduced serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) activity and relative liver weight, as well as ameliorated histopathological damage caused by CCl4 and decreased malondialdehyde (MDA) levels, and increased the activity of antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). Moreover, specnuezhenide promoted the expression and nuclear translocation of the nuclear factor erythroid 2-related factor 2 (Nrf2) and increased the mRNA and protein expression of Nrf2 signalling-related genes heme oxygenase-1 (HO-1), glutamate-cysteine ligase catalytic subunit (GCLC) and NAD(P)H:quinone oxidoreductase 1 (NQO1). Finally, TUNEL staining and immunohistochemistry indicated that specnuezhenide prevented CCl4-induced hepatocytic apoptosis by up-regulating B-cell lymphoma 2 (Bcl-2) expression and downregulating Bcl-2-associated X (Bax) expression. CONCLUSIONS: Specnuezhenide reduced CCl4-induced liver injury in mice by inhibiting oxidative stress via activation of Nrf2 signalling and decreasing hepatocyte apoptosis.
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Glucósidos/farmacología , Hepatocitos/efectos de los fármacos , Hepatopatías/prevención & control , Estrés Oxidativo/efectos de los fármacos , Piranos/farmacología , Animales , Apoptosis/efectos de los fármacos , Tetracloruro de Carbono , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Glucósidos/administración & dosificación , Hepatocitos/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Factor 2 Relacionado con NF-E2/metabolismo , Piranos/administración & dosificación , Transducción de Señal/efectos de los fármacosRESUMEN
Short-bowel syndrome (SBS) is defined as a state of malabsorption after resection or loss of a major portion of the bowel due to congenital or acquired factors. This article presents an overview on the recent management of pediatric SBS. The pediatric SBS population is very heterogeneous. The incidence of SBS is estimated to be 24.5 per 100,000 live births. The nutritional, medical, and surgical therapies available require a comprehensive evaluation. Thus, multidisciplinary intestinal rehabilitation programs (IRPs) are necessary for the management of these complex patients. The key points of focus in IRP management are hepato-protective strategies to minimize intestinal failure-associated liver disease; the aggressive prevention of catheter-related bloodstream infections; strategic nutritional supply to optimize the absorption of enteral calories; and the management and prevention of small bowel bacterial overgrowth, nephrocalcinosis, and metabolic bone disease. As the survival rate of children with SBS currently exceeds 90%, the application of small bowel transplantation has been evolving. The introduction of innovative treatments, such as combined therapy of intestinotrophic hormones, including glucagon-like peptide-2, may lead to further improvements in patients' quality of life.
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Síndrome del Intestino Corto/rehabilitación , Síndrome del Intestino Corto/terapia , Factores de Edad , Enfermedades Óseas Metabólicas/etiología , Enfermedades Óseas Metabólicas/prevención & control , Preescolar , Femenino , Péptido 2 Similar al Glucagón/uso terapéutico , Humanos , Incidencia , Lactante , Recién Nacido , Insuficiencia Intestinal/etiología , Insuficiencia Intestinal/prevención & control , Intestino Delgado/trasplante , Hepatopatías/etiología , Hepatopatías/prevención & control , Masculino , Nefrocalcinosis/etiología , Nefrocalcinosis/prevención & control , Calidad de Vida , Síndrome del Intestino Corto/epidemiología , Síndrome del Intestino Corto/etiologíaRESUMEN
ABSTRACT: This study aimed to quantify and evaluate the knowledge and awareness toward liver health and diseases as well as explore the attitudes and knowledge toward screening, diagnosis, and treatment of liver disease among the Thai population.This is a cross-sectional, self-reported and web-based questionnaire study. Awareness, perceptions and attitudes toward liver-related health and diseases as well as screening, diagnosis and treatment of liver diseases were assessed among 500 Thai adults.Respondents were mostly ≥35âyears (62.0%) and females (52.0%). While there was an overall awareness regarding viral hepatitis as the main etiology of liver failure/cancer, respondents expressed misperceptions that hint at social stigmatization or discrimination toward infected individuals. A significant proportion lacked knowledge of liver screening tests and relevant diagnostic tests for viral hepatitis-related liver diseases. Screening or treatment costs and perception of being healthy were among reasons for not seeking medical consultation when exposed to risk factors or diagnosed. Treatment practices of hepatitis included prescription medication (59.1%), functional foods (51.8%) and traditional treatment (28.2%). Multivariate analysis identified income, recent health screening status and being diagnosed with liver disease(s) as significant predictors of the knowledge, attitude, and behaviors of the Thai population toward liver diseases.This study highlighted a degree of misperception and lack of in-depth understanding toward hepatitis-related liver diseases including poor attitudes and knowledge toward screening, diagnosis, and treatment of liver diseases. Factors identified suggest an unmet need to encourage proactive health-seeking behaviors to reduce transmission risks of hepatitis-related liver diseases within the community.
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Conocimientos, Actitudes y Práctica en Salud , Hepatitis Viral Humana , Hepatopatías , Adulto , Anciano , Estudios Transversales , Femenino , Hepatitis B/diagnóstico , Hepatitis B/epidemiología , Hepatitis B/prevención & control , Hepatitis C/diagnóstico , Hepatitis C/epidemiología , Hepatitis C/prevención & control , Hepatitis Viral Humana/diagnóstico , Hepatitis Viral Humana/epidemiología , Hepatitis Viral Humana/prevención & control , Humanos , Hepatopatías/diagnóstico , Hepatopatías/epidemiología , Hepatopatías/prevención & control , Persona de Mediana Edad , Encuestas y Cuestionarios , Tailandia/epidemiologíaRESUMEN
ABSTRACT: Vitexin is a natural active ingredient in hawthorn leaves, which has a wide range of anti-tumor effects. This study was conducted to assess the protective effect of hawthorn vitexin on the ethanol-injured DNA of hepatocytes in vitro and to explore its mechanism. The effect of different concentrations of hawthorn vitexin on ethanol-injured hepatocytes was detected via the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method to study the protective effect of hawthorn vitexin on ethanol-injured DNA damage in hepatocytes. Single-cell gel electrophoresis was used to observe the effect of hawthorn vitexin on ethanol-induced DNA damage in hepatocytes, and the Olive tail moment was measured. Cell physiological and biochemical indexes, such as superoxide dismutase activity, malonaldehyde content, and glutathione peroxidase activity, were detected with kits. The mRNA expression of the superoxide dismutase gene was measured via real-time quantitative polymerase chain reaction. It was showed that 0.2, 0.4, and 0.8âmg mL-1 hawthorn vitexin could significantly repair hepatocyte growth and ethanol-induced DNA damage. This effect was closely related to the improvement in superoxide dismutase, malonaldehyde, and glutathione peroxidase. Hawthorn vitexin could be used to repair ethanol-injured hepatocytes through antioxidation effects, and showed potential for the treatment of liver injury.
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Apigenina/química , Crataegus , ADN/efectos de los fármacos , Etanol/toxicidad , Hepatocitos/efectos de los fármacos , Hepatopatías/prevención & control , Extractos Vegetales , Daño del ADN/efectos de los fármacos , Glutatión Peroxidasa , Hepatocitos/patología , Malondialdehído , Estrés Oxidativo/efectos de los fármacos , Superóxido DismutasaRESUMEN
Betaine is a kind of water-soluble quaternary amine-type alkaloid widely existing in food, such as wheat germ, beet, spinach, shrimp and wolfberry. As an important methyl donor and osmotic pressure regulator in human body, betaine plays an important role in a variety of physiological activities. In recent years, a large number of literatures have shown that betaine has good preventive and therapeutic effects on many liver diseases, including chemical or drug-induced liver injury, nonalcoholic fatty liver disease, alcoholic fatty liver disease, liver fibrosis, hepatitis B and hepatitis C. Therefore, by searching the databases of Web of Science, PubMed, SciFinder and CNKI, this paper has summarized the molecular mechanisms of betaine in improving liver diseases. The results show that the improvement of liver diseases by betaine is closely related to a variety of molecular mechanisms, including inhibition of inflammatory response, improvement of insulin resistance, reduction of endoplasmic reticulum stress, alleviation of liver oxidative stress, increase of autophagy, remodeling of intestinal flora and regulation of epigenetic modification. More importantly, nuclear transcription factor kappa (NF-κB), AMP-activated protein kinase (AMPK), peroxisome proliferator-activated receptor α/γ (PPAR-α/γ), liver X receptor α (LXRα), protein kinase B (Akt), toll-like receptor 4 (TLR4) and cysteinyl aspartate specific proteinase-3 (Caspase-3) signaling pathways are considered as important molecular targets for betaine to improve liver diseases. These important findings will provide a direction and basis for further exploring the pathogenesis of various liver diseases and tapping the potential of betaine in the clinical treatment.
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Betaína/farmacología , Hepatopatías/tratamiento farmacológico , Hepatopatías/prevención & control , Sustancias Protectoras/farmacología , Animales , Betaína/uso terapéutico , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Humanos , Hepatopatías/metabolismo , Hepatopatías Alcohólicas/tratamiento farmacológico , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/prevención & control , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Sustancias Protectoras/uso terapéuticoRESUMEN
Transient ischaemia and reperfusion in liver tissue induce hepatic ischaemia/reperfusion (I/R) tissue injury and a profound inflammatory response in vivo. Hepatic I/R can be classified into warm I/R and cold I/R and is characterized by three main types of cell death, apoptosis, necrosis and autophagy, in rodents or patients following I/R. Warm I/R is observed in patients or animal models undergoing liver resection, haemorrhagic shock, trauma, cardiac arrest or hepatic sinusoidal obstruction syndrome when vascular occlusion inhibits normal blood perfusion in liver tissue. Cold I/R is a condition that affects only patients who have undergone liver transplantation (LT) and is caused by donated liver graft preservation in a hypothermic environment prior to entering a warm reperfusion phase. Under stress conditions, autophagy plays a critical role in promoting cell survival and maintaining liver homeostasis by generating new adenosine triphosphate (ATP) and organelle components after the degradation of macromolecules and organelles in liver tissue. This role of autophagy may contribute to the protection of hepatic I/R-induced liver injury; however, a considerable amount of evidence has shown that autophagy inhibition also protects against hepatic I/R injury by inhibiting autophagic cell death under specific circumstances. In this review, we comprehensively discuss current strategies and underlying mechanisms of autophagy regulation that alleviates I/R injury after liver resection and LT. Directed autophagy regulation can maintain liver homeostasis and improve liver function in individuals undergoing warm or cold I/R. In this way, autophagy regulation can contribute to improving the prognosis of patients undergoing liver resection or LT.
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Autofagia , Hepatopatías/etiología , Hepatopatías/metabolismo , Sustancias Protectoras/farmacología , Daño por Reperfusión/etiología , Daño por Reperfusión/metabolismo , Animales , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Biomarcadores , Manejo de la Enfermedad , Susceptibilidad a Enfermedades , Regulación de la Expresión Génica/efectos de los fármacos , Hepatectomía/efectos adversos , Hepatectomía/métodos , Humanos , Precondicionamiento Isquémico/métodos , Hepatopatías/patología , Hepatopatías/prevención & control , Trasplante de Hígado/efectos adversos , Trasplante de Hígado/métodos , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Mitofagia , Sustancias Protectoras/uso terapéutico , Daño por Reperfusión/patología , Daño por Reperfusión/prevención & control , Transducción de Señal/efectos de los fármacosRESUMEN
High L-carnitine ingestion has been shown to cause liver injury, mechanically due to an elevated circulating level of trimethylamine-N-oxide (TMAO), a gut microbiota-derived metabolite from L-carnitine. This study aimed to investigate whether chlorogenic acid (CGA), a health-promoting polyphenol, could inhibit TMAO formation and thereafter might prevent L-carnitine-induced liver injury in mice. Feeding of mice with 3% L-carnitine in drinking water increased the serum and urinary levels of TMAO (p < 0.01 vs. Normal), whereas the serum and urinary TMAO formation was sharply reduced by CGA administration (p < 0.01). At the phylum level, CGA inhibited the L-carnitine-induced increase in the abundance of Firmicutes and Proteobacteria, while it promoted Bacteroidetes. At the genus level, CGA notably increased the abundance of Akkermansia and Bacteroides, but reduced the population of Erysipelatoclostridium, Faecalibaculum and Erysipelotrichaceae in high L-carnitine feeding mice. Meanwhile, CGA caused strong inhibition against the increase of liver injury markers (i.e. AST, ALT and ALP), hepatic inflammatory cytokines (i.e. IL-1, IL-6, TNF-α and TNF-ß) and dyslipidemia (i.e. TC, TG, LDL-C and HDL-C) in L-carnitine-fed mice (p < 0.05). These findings suggest that CGA holds great potential to alleviate liver dysfunction induced by high L-carnitine ingestion. The beneficial effect might be attributed to the protection against TMAO formation and the improvement of the health-promoting gut microbiota, as well as the antioxidant and anti-inflammatory properties of CGA.