RESUMO
BACKGROUND & AIMS: NOTCH signaling in liver sinusoidal endothelial cells (LSECs) regulates liver fibrosis, a pathological feature of chronic liver diseases. POFUT1 is an essential regulator of NOTCH signaling. Here, we investigated the role of LSEC-expressed POFUT1 in liver fibrosis. METHODS: Endothelial-specific Pofut1 knockout mice were generated and experimental liver fibrosis was induced by chronic carbon tetrachloride exposure or common bile duct ligation. Liver samples were assessed by ELISA, histology, electron microscopy, immunostaining and RNA in situ hybridization. LSECs and hepatic stellate cells (HSCs) were isolated for gene expression analysis by RNA sequencing, qPCR, and western blotting. Signaling crosstalk between LSECs and HSCs was investigated by treating HSCs with supernatant from LSEC cultures. Liver single-cell RNA sequencing datasets from patients with cirrhosis and healthy individuals were analyzed to evaluate the clinical relevance of gene expression changes observed in mouse studies. RESULTS: POFUT1 loss promoted injury-induced LSEC capillarization and HSC activation, leading to aggravated liver fibrosis. RNA sequencing analysis revealed that POFUT1 deficiency upregulated fibrinogen expression in LSECs. Consistently, fibrinogen was elevated in LSECs of patients with cirrhosis. HSCs treated with supernatant from LSECs of Pofut1 null mice showed exacerbated activation compared to those treated with supernatant from control LSECs, and this effect was attenuated by knockdown of fibrinogen or by pharmacological inhibition of fibrinogen receptor signaling, altogether suggesting that LSEC-derived fibrinogen induced the activation of HSCs. Mechanistically, POFUT1 loss augmented fibrinogen expression by enhancing NOTCH/HES1/STAT3 signaling. CONCLUSIONS: Endothelial POFUT1 prevents injury-induced liver fibrosis by repressing the expression of fibrinogen, which functions as a profibrotic paracrine signal to activate HSCs. Therapies targeting the POFUT1/fibrinogen axis offer a promising strategy for the prevention and treatment of fibrotic liver diseases. IMPACT AND IMPLICATIONS: Paracrine signals produced by liver vasculature play a major role in the development of liver fibrosis, which is a pathological hallmark of most liver diseases. Identifying those paracrine signals is clinically relevant in that they may serve as therapeutic targets. In this study, we discovered that genetic deletion of Pofut1 aggravated experimental liver fibrosis in mouse models. Moreover, fibrinogen was identified as a downstream target repressed by Pofut1 in liver endothelial cells and functioned as a novel paracrine signal that drove liver fibrosis. In addition, fibrinogen was found to be relevant to cirrhosis and may serve as a potential therapeutic target for this devastating human disease.
Assuntos
Células Endoteliais , Fibrinogênio , Células Estreladas do Fígado , Cirrose Hepática , Camundongos Knockout , Animais , Humanos , Masculino , Camundongos , Tetracloreto de Carbono/toxicidade , Tetracloreto de Carbono/efeitos adversos , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Fibrinogênio/metabolismo , Fibrinogênio/biossíntese , Fibrinogênio/genética , Células Estreladas do Fígado/metabolismo , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/genética , Receptores Notch/metabolismo , Receptores Notch/fisiologia , Transdução de SinaisRESUMO
BACKGROUND & AIMS: Men are more prone to develop and die from liver fibrosis than women. In this study, we aim to investigate how sex-determining region Y gene (SRY) in hepatocytes promotes liver fibrosis. METHODS: Hepatocyte-specific Sry knock-in (KI), Sry knockout (KO), and Sry KI with platelet-derived growth factor receptor α (Pdgfrα) KO mice were generated. Liver fibrosis was induced in mice by bile duct ligation for 2 weeks or carbon tetrachloride treatment for 6 weeks. In addition, primary hepatocytes, hepatic stellate cells (HSCs), and immortalized cell lines were used for in vitro studies and mechanistic investigation. RESULTS: Compared to females, the severity of toxin- or cholestasis-induced liver fibrosis is similarly increased in castrated and uncastrated male mice. Among all Y chromosome-encoded genes, SRY was the most significantly upregulated and consistently increased gene in fibrotic/cirrhotic livers in male patients and in mouse models. Sry KI mice developed exacerbated liver fibrosis, whereas Sry KO mice had alleviated liver fibrosis, compared to age- and sex-matched control mice after bile duct ligation or administration of carbon tetrachloride. Mechanistically, both our in vivo and in vitro studies illustrated that SRY in hepatocytes can transcriptionally regulate Pdgfrα expression, and promote HMGB1 (high mobility group box 1) release and subsequent HSC activation. Pdgfrα KO or treatment with the SRY inhibitor DAX1 in Sry KI mice abolished SRY-induced HMGB1 secretion and liver fibrosis. CONCLUSIONS: SRY is a strong pro-fibrotic factor and accounts for the sex disparity observed in liver fibrosis, suggesting its critical role as a potentially sex-specific therapeutic target for prevention and treatment of the disease. IMPACT AND IMPLICATION: We identified that a male-specific gene, sex-determining region Y gene (SRY), is a strong pro-fibrotic gene that accounts for the sex disparity observed in liver fibrosis. As such, SRY might be an appropriate target for surveillance and treatment of liver fibrosis in a sex-specific manner. Additionally, SRY might be a key player in the sexual dimorphism observed in hepatic pathophysiology more generally.
Assuntos
Células Estreladas do Fígado , Hepatócitos , Cirrose Hepática , Camundongos Knockout , Proteína da Região Y Determinante do Sexo , Animais , Masculino , Feminino , Camundongos , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Cirrose Hepática/fisiopatologia , Humanos , Hepatócitos/metabolismo , Proteína da Região Y Determinante do Sexo/genética , Proteína da Região Y Determinante do Sexo/metabolismo , Células Estreladas do Fígado/metabolismo , Caracteres Sexuais , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/genética , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Tetracloreto de Carbono/toxicidade , Tetracloreto de Carbono/efeitos adversos , Colestase/genética , Colestase/metabolismo , Colestase/fisiopatologia , Modelos Animais de DoençasRESUMO
Mesenchymal stem cells (MSCs) have shown great potential for the treatment of liver injuries, and the therapeutic efficacy greatly depends on their homing to the site of injury. In the present study, we detected significant upregulation of hepatocyte growth factor (HGF) in the serum and liver in mice with acute or chronic liver injury. In vitro study revealed that upregulation of miR-9-5p or miR-221-3p promoted the migration of human MSCs (hMSCs) toward HGF. Moreover, overexpression of miR-9-5p or miR-221-3p promoted hMSC homing to the injured liver and resulted in significantly higher engraftment upon peripheral infusion. hMSCs reduced hepatic necrosis and inflammatory infiltration but showed little effect on extracellular matrix (ECM) deposition. By contrast, hMSCs overexpressing miR-9-5p or miR-221-3p resulted in not only less centrilobular necrosis and venous congestion but also a significant reduction of ECM deposition, leading to obvious improvement of hepatocyte morphology and alleviation of fibrosis around central vein and portal triads. Further studies showed that hMSCs inhibited the activation of hepatic stellate cells (HSCs) but could not decrease the expression of TIMP-1 upon acute injury and the expression of MCP-1 and TIMP-1 upon chronic injury, while hMSCs overexpressing miR-9-5p or miR-221-3p led to further inactivation of HSCs and downregulation of all three fibrogenic and proinflammatory factors TGF-ß, MCP-1, and TIMP-1 upon both acute and chronic injuries. Overexpression of miR-9-5p or miR-221-3p significantly downregulated the expression of α-SMA and Col-1α1 in activated human hepatic stellate cell line LX-2, suggesting that miR-9-5p and miR-221-3p may partially contribute to the alleviation of liver injury by preventing HSC activation and collagen expression, shedding light on improving the therapeutic efficacy of hMSCs via microRNA modification.
Assuntos
Células Estreladas do Fígado , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais , MicroRNAs , MicroRNAs/genética , MicroRNAs/metabolismo , Humanos , Células-Tronco Mesenquimais/metabolismo , Células Estreladas do Fígado/metabolismo , Animais , Camundongos , Transplante de Células-Tronco Mesenquimais/métodos , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/terapia , Doença Hepática Induzida por Substâncias e Drogas/genética , Masculino , Tetracloreto de Carbono/efeitos adversos , Fator de Crescimento de Hepatócito/metabolismo , Fator de Crescimento de Hepatócito/genética , Camundongos Endogâmicos C57BL , Movimento CelularRESUMO
This study aims to investigate the mitigating effect and mechanism of Cichorium glandulosum n-butanol extraction site(CGE) on the disease in carbon tetrachloride(CCl_4)-induced chronic liver injury model in rats. A chronic liver injury model was constructed by subcutaneous injection of CCl_4 olive oil solution, and after four weeks of CGE treatment, serum levels of aspartate aminotransferase(AST), alanine aminotransferase(ALT), alkaline phosphatase(AKP), hydroxyproline(HYP), interleukin-4(IL-4), interleukin-6(IL-6), malondialdehyde(MDA), superoxide dismutase(SOD), and tumor necrosis factor-α(TNF-α) were detected. Liver tissue was processed by hematoxylin-eosin(HE) staining and Masson staining to observe the structure of the rat liver. qPCR and Western blot were used to examine the expression of transforming growth factor-ß1(TGF-ß1)/small mothers against decapentaplegic(Smad), Toll-like receptor 4(TLR4), α-smooth muscle actin(α-SMA), and fibronectin(Fn) in rat liver tissue and hepatic stellate-T6(HSC-T6) and evaluate the inhibitory effect of CGE on HSC activation. The results showed that CGE could significantly reduce the serum levels of AST, ALT, AKP, HYP, and affect the levels of related inflammatory indexes including IL-4, IL-6, and TNF-α, and MDA in CCl_4-induced chronic liver injury in rats and had no effect on SOD activity, which could delay the process of liver injury, alleviate the hepatic collagen deposition and inflammatory infiltration, and had significant efficacy in mitigating chronic liver injury in rats. CGE could inhibit α-SMA and TLR4 protein expression in the liver tissue and reverse the increased TGF-ß1/Smad, Fn, and TLR4-related expression in HSC-T6 in vitro. The above results indicated that CGE exerted hepatoprotective effects in rats by inhibiting HSC activation and alleviated CCl_4-induced chronic liver injury in rats and could ameliorate inflammatory response and slight liver fibrosis in rat liver tissue. Its pharmacodynamic mechanism might be related to TGF-ß1/Smad and TLR4-related expression.
Assuntos
Tetracloreto de Carbono , Fígado , Ratos Sprague-Dawley , Animais , Ratos , Tetracloreto de Carbono/efeitos adversos , Masculino , Fígado/metabolismo , Fígado/efeitos dos fármacos , Fígado/lesões , 1-Butanol/química , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/administração & dosagem , Humanos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Superóxido Dismutase/metabolismo , Superóxido Dismutase/genética , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/genética , Interleucina-6/genética , Interleucina-6/metabolismo , Malondialdeído/metabolismo , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo , Interleucina-4/genética , Doença Hepática Crônica Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Crônica Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/genéticaRESUMO
OBJECTIVE: To investigate the protective effect of NDUFA13 protein against acute liver injury and liver fibrosis in mice and explore the possible mechanisms. METHODS: BALB/C mice (7 to 8 weeks old) were divided into normal group, CCl4 group, CCl4+AAV-NC group and CCl4+AAV-NDU13 group (n=18). Mouse models of liver fibrosis were established by intraperitoneal injection of CCl4 twice a week for 3, 5 or 7 weeks, and the recombinant virus AAV8-TBG-NC or AAV8-TBG-NDUFA13 was injected via the tail vein 7-10 days prior to CCl4 injection. After the treatments, pathological changes in the liver of the mice were observed using HE and Masson staining. Hepatic expression levels of NDUFA13 and α-SMA were detected with Western blotting, and the coexpression of NDUFA13 and NLRP3, TNF-α and IL-1ß, and α-SMA and collagen â ¢ was analyzed with immunofluorescence assay. RESULTS: HE and Masson staining showed deranged liver architecture, necrotic hepatocytes and obvious inflammatory infiltration and collagen fiber deposition in mice with CCl4 injection (P < 0.001). NDUFA13 expression markedly decreased in CCl4-treated mice (P < 0.001), while a significant reduction in inflammatory aggregation and fibrosis was observed in mice with AAV-mediated NDUFA13 overexpression (P < 0.001). In CCl4+AAV-NDU13 group, immunofluorescence assay revealed markedly weakened activation of NLRP3 inflammasomes (P < 0.001), significantly decreased TNF-α and IL-1ß secretion (P < 0.001), and inhibited hepatic stellate cell activation (P < 0.05) and collagen formation in the liver (P < 0.001). CONCLUSION: Mitochondrial NDUFA13 overexpression in hepatocytes protects against CCl4- induced liver fibrosis in mice by inhibiting activation of NLRP3 signaling.
Assuntos
Dependovirus , Fator de Necrose Tumoral alfa , Camundongos , Animais , Fator de Necrose Tumoral alfa/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Camundongos Endogâmicos BALB C , Fígado/metabolismo , Cirrose Hepática , Hepatócitos , Colágeno/metabolismo , Células Estreladas do Fígado/metabolismo , Tetracloreto de Carbono/efeitos adversosRESUMO
BACKGROUND: Mesenchymal cells, including hepatic stellate cells (HSCs), fibroblasts (FBs), myofibroblasts (MFBs), and vascular smooth muscle cells (VSMCs), are the main cells that affect liver fibrosis and play crucial roles in maintaining tissue homeostasis. The dynamic evolution of mesenchymal cells is very important but remains to be explored for researching the reversible mechanism of hepatic fibrosis and its evolution mechanism of hepatic fibrosis to cirrhosis. METHODS: Here, we analysed the transcriptomes of more than 50,000 human single cells from three cirrhotic and three healthy liver tissue samples and the mouse hepatic mesenchymal cells of two healthy and two fibrotic livers to reconstruct the evolutionary trajectory of hepatic mesenchymal cells from a healthy to a cirrhotic state, and a subsequent integrative analysis of bulk RNA sequencing (RNA-seq) data of HSCs from quiescent to active (using transforming growth factor ß1 (TGF-ß1) to stimulate LX-2) to inactive states. RESULTS: We identified core genes and transcription factors (TFs) involved in mesenchymal cell differentiation. In healthy human and mouse livers, the expression of NR1H4 and members of the ZEB families (ZEB1 and ZEB2) changed significantly with the differentiation of FB into HSC and VSMC. In cirrhotic human livers, VSMCs transformed into HSCs with downregulation of MYH11, ACTA2, and JUNB and upregulation of PDGFRB, RGS5, IGFBP5, CD36, A2M, SOX5, and MEF2C. Following HSCs differentiation into MFBs with the upregulation of COL1A1, TIMP1, and NR1H4, a small number of MFBs reverted to inactivated HSCs (iHSCs). The differentiation trajectory of mouse hepatic mesenchymal cells was similar to that in humans; however, the evolution trajectory and proportion of cell subpopulations that reverted from MFBs to iHSCs suggest that the mouse model may not accurately reflect disease progression and outcome in humans. CONCLUSIONS: Our analysis elucidates primary genes and TFs involved in mesenchymal cell differentiation during liver fibrosis using scRNA-seq data, and demonstrated the core genes and TFs in process of HSC activation to MFB and MFB reversal to iHSC using bulk RNA-seq data of human fibrosis induced by TGF-ß1. Furthermore, our findings suggest promising targets for the treatment of liver fibrosis and provide valuable insights into the molecular mechanisms underlying its onset and progression.
Assuntos
Análise da Expressão Gênica de Célula Única , Fatores de Transcrição , Camundongos , Animais , Humanos , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Tetracloreto de Carbono/efeitos adversos , Tetracloreto de Carbono/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Fígado/metabolismo , Diferenciação Celular/genética , Células Estreladas do Fígado/metabolismoRESUMO
BACKGROUND: Hepatic fibrosis is the pivotal determinant in the progression of chronic liver diseases towards cirrhosis or advanced stages. Studies have shown that Schisantherin A (Sin A), the primary active compound from Schizandra chinensis (Turcz.) Baill., exhibits anti-hepatic fibrosis effects. However, the mechanism of Sin A in liver fibrosis remain unclear. PURPOSE: To examine the effects and underlying mechanism of Sin A on hepatic fibrosis. STUDY DESIGN AND METHODS: The effects and mechanism of Sin A were investigated using liver fibrosis mouse models induced by carbon tetrachloride (CCl4) or dimethylnitrosamine (DMN), as well as H2O2-induced hepatocyte injury in vitro. RESULTS: Sin A treatment ameliorated hepatocyte injury, inflammation, hepatic sinusoidal capillarization, and hepatic fibrosis in both CCl4-induced and DMN-induced mice. Sin A effectively reversed the reduction of DDAH1 expression, the p-eNOS/eNOS ratio and NO generation and attenuated the elevation of hepatic ADMA level induced by CCl4 and DMN. Knockdown of DDAH1 in hepatocytes not only triggered hepatocyte damage, but it also counteracted the effect of Sin A on protecting hepatocytes in vitro. CONCLUSION: Our findings indicate that Sin A ameliorates liver fibrosis by upregulating DDAH1 to protect against hepatocyte injury. These results provide compelling evidence for Sin A treatment in liver fibrosis.
Assuntos
Ciclo-Octanos , Dioxóis , Peróxido de Hidrogênio , Lignanas , Hepatopatias , Camundongos , Animais , Peróxido de Hidrogênio/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Hepatócitos , Fígado , Hepatopatias/metabolismo , Tetracloreto de Carbono/efeitos adversosRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Ganoderma lucidum, a traditional edible medicinal mushroom, has been widely reported to improve liver diseases as a dietary intervention for people. Ganoderma lucidum extracts, primarily total triterpenoids (GLTTs), are one of the bioactive ingredients that have excellent beneficial effects on hepatic fibrosis. Therefore, its prevention and reversal are particularly critical due to the increasing number of patients with chronic liver diseases worldwide. AIM OF THE STUDY: The study aimed to evaluate whether GLTTs had a hepatoprotective effect against hepatic fibrosis through metabolic perturbations and gut microbiota changes and its underlying mechanisms. MATERIALS AND METHODS: The compound compositions of GLTTs were quantified, and carbon tetrachloride (CCl4)-induced hepatic fibrosis rats were used to investigate the cause of the improvement in various physiological states with GLTTs treatment, and to determine whether its consequent effect was associated with endogenous metabolites and gut microbiota using UPLC-Q-TOF-MSE metabolomics and 16S rRNA gene sequencing technology. RESULTS: GLTTs alleviated physical status, reduced liver pathological indicators, proinflammatory cytokines, and deposition of hepatic collagen fibers via regulating the NF-κB and TGF-ß1/Smads pathways. The untargeted metabolomics analysis identified 16 potential metabolites that may be the most relevant metabolites for gut microbiota dysbiosis and the therapeutic effects of GLTTs in hepatic fibrosis. Besides, although GLTTs did not significantly affect the α-diversity indexes, significant changes were observed in the composition of microflora structure. In addition, Spearman analysis revealed strong correlations between endogenous metabolites and gut microbiota g_Ruminococcus with hepatic fibrosis. CONCLUSION: GLTTs could provide a potential target for the practical design and application of novel functional food ingredients or drugs in the therapy of hepatic fibrosis.
Assuntos
Microbioma Gastrointestinal , Reishi , Humanos , Ratos , Animais , NF-kappa B/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Reishi/metabolismo , Ruminococcus/metabolismo , RNA Ribossômico 16S , Cirrose Hepática/metabolismo , Comunicação , Tetracloreto de Carbono/efeitos adversosRESUMO
Albumin infusions improve circulatory and renal function in patients with decompensated cirrhosis. However, there is no convincing evidence that hypoalbuminemia contributes to ascites formation in liver cirrhosis. The aim of our study is to determine the exact role of hypoalbuminemia in the formation of ascites caused by liver cirrhosis and its underlying mechanism. Clinical profiles of patients with liver cirrhosis retrospectively analyzed. The details of albumin involved in ascites formation were investigated in rat model and murine model. Statistical analysis demonstrated hypoalbuminemia was an independent risk factor for ascites formation in patients with liver cirrhosis (OR = 0.722, P < 0.001). In carbon tetrachloride (CCl4)-induced rat model of liver cirrhosis, a significant reduction in serum albumin was observed in rats with ascites (13.37 g/L) compared with rats without ascites (21.43 g/L, P < 0.001). In thioacetamide (TAA)-treated mice, ascites amount of heterozygous albumin (Alb+/-) mice (112.0 mg) was larger than that of wild-type (Alb+/+) mice (58.46 mg, P < 0.001). In CCl4-induced chronic liver injury, ascites amounts of Alb+/- or Alb+/+ mice were 80.00 mg or 48.46 mg (P = 0.001). Further study demonstrated 24-h urinary sodium excretion in Alb+/- mice was lower than that of Alb+/+ mice in TAA/CCl4-induce murine models of liver cirrhosis. Additionally, serum sodium concentration of Alb+/- mice was lower than that of Alb+/+ mice. In cirrhotic mice, higher level of antidiuretic hormone was observed in Alb+/- mice compared with the control; and renal aquaporin (AQP2) expression in Alb+/- mice was significantly higher than that of WT mice. These revealed hypoalbuminemia contributed to the occurrence of ascites in liver cirrhosis through sodium and water retention.
Assuntos
Ascite , Hipoalbuminemia , Cirrose Hepática , Sódio , Animais , Hipoalbuminemia/metabolismo , Hipoalbuminemia/patologia , Ascite/metabolismo , Ascite/patologia , Sódio/metabolismo , Sódio/urina , Camundongos , Masculino , Humanos , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Cirrose Hepática/complicações , Cirrose Hepática/genética , Feminino , Ratos , Tetracloreto de Carbono/toxicidade , Tetracloreto de Carbono/efeitos adversos , Pessoa de Meia-Idade , Aquaporina 2/metabolismo , Aquaporina 2/genética , Modelos Animais de Doenças , Estudos Retrospectivos , Albumina Sérica/metabolismo , Tioacetamida , Água/metabolismo , IdosoRESUMO
Background: Over the years, Alisma Shugan Decoction (ASD), because of its potent anti-inflammation activity, has been used in traditional Chinese medicine (TCM) for treatment of many inflammation-associated disorders including those of the heart, blood vessel and brain. Methods: Herein, we examined the probable therapeutic effect of ASD in carbon tetrachloride (CCl4)-induced liver injury and fibrosis mice models. Results: Our results demonstrate that ASD dose-dependently reduced the fibrosis-related increased collagen deposition secondary to liver tissue exposure to CCl4. Data from our biochemical analyses showed significantly less liver damage biomarkers including ALT, AST and hydroxyproline in the ASD-treated samples, suggesting hepato-protective effect of ASD. Furthermore, we demonstrated that treatment with ASD significantly reversed CCl4-induced elevation of TNF-α, IL-6, IL-1ß and MP-1. Interestingly, NF-κB signalling, a principal regulator of inflammation was markedly suppressed by ASD treatment. In addition, treatment with ASD deregulated stress signalling pathways by suppressing the expression of markers of unfolded protein response, such as ATF6, IRE and GRP78. Conclusion: In conclusion, the present study provides preclinical evidence for the use of ASD as an efficacious therapeutic option in cases of chemical-induced liver damage and/or fibrosis. Further large-cohort validation of these findings is warranted.
Assuntos
Alisma , Tetracloreto de Carbono , Humanos , Ratos , Camundongos , Animais , Tetracloreto de Carbono/efeitos adversos , Tetracloreto de Carbono/metabolismo , Ratos Sprague-Dawley , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Fígado/patologia , Fibrose , Inflamação/metabolismo , Estresse do Retículo EndoplasmáticoAssuntos
Antioxidantes , Tetracloreto de Carbono , Doença Hepática Induzida por Substâncias e Drogas , Fígado , Óleos de Plantas , Rosa , Sementes , Animais , Antioxidantes/farmacologia , Camundongos , Rosa/química , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Sementes/química , Tetracloreto de Carbono/efeitos adversos , Masculino , Óleos de Plantas/farmacologia , Óleos de Plantas/química , Fígado/efeitos dos fármacos , Fígado/metabolismo , Substâncias Protetoras/farmacologia , Humanos , Extratos Vegetais/farmacologiaRESUMO
Abstract Carbon tetrachloride (CCl4) represents an organic chemical that causes reactive oxygen species derived organ disturbances including male infertility. Melatonin (MLT) is a neurohormone with strong antioxidant capacity, involved in numerous physiological processes. In this study we evaluated the capability of MLT, administered in a single dose of 50 mg/kg, to preserve the testicular tissue function after an acute administration of CCl4 to rats. The disturbance in testicular tissue and the effects of MLT after CCl4 exposure were estimated using biochemical parameters that enabled us to determine the tissue (anti)oxidant status and the intensity of arginine/nitric oxide metabolism. Also, the serum levels of testosterone and the histopathological analysis of tissue gave us a better insight into the occurring changes. A significant diminution in tissue antioxidant defences, arginase activity and serum testosterone levels, followed by the increased production of nitric oxide and extensive lipid and protein oxidative damage, was observed in the CCl4-treated group. The application of MLT after the CCl4 caused changes, clearly visible at both biochemical and histological level, which could be interpreted mainly as a consequence of general antioxidant system stimulation and a radical scavenger. On the other hand, the application of MLT exerted a limited action on the nitric oxide signalling pathway.
Assuntos
Animais , Masculino , Ratos , Arginina/metabolismo , Tetracloreto de Carbono/efeitos adversos , Melatonina/análise , Dose Única/classificação , Infertilidade Masculina , AntioxidantesRESUMO
Introducción: las enfermedades hepáticas son un serio problema de salud. El estudio de agentes de origen natural que disminuyan el daño hepático inducido por sustancias químicas ha despertado un interés especial. Objetivo: evaluar el efecto del Noni C sobre el daño hepático inducido por tetracloruro de carbono, en modelo experimental desarrollado en ratas Wistar machos. Métodos: se realizó estudio experimental y se usó como control positivo el tetracloruro de carbono a dosis de 0,3 mL/kg de peso, intraperitoneal, durante 3 días; y como control negativo solución salina. Se utilizaron 4 dosis (85, 130, 170 y 215 mg/kg de peso) de Noni C durante 6 días, postratamiento con tetracloruro de carbono. Se determinaron niveles de transaminasa glutámico pirúvica y glutámico oxalacética; también lesión hepática como tumefacción celular, hepatitis reactiva, esteatosis y necrosis. Resultados: se obtuvo reducción significativa de las transaminasas glutámico pirúvica y glutámico oxalacética a las dosis de 85 y 170 mg/kg de Noni C, y ausencia de necrosis y esteatosis en los grupos tratados con las dosis de 170 y 215 mg/kg de peso. Conclusiones: en los grupos tratados con Noni C disminuyó el daño hepático inducido por el tetracloruro de carbono
Introduction: liver diseases are a serious health problem. The study of natural agents that can reduce the chemical substance-induced hepatic damage has aroused a particular interest. Objective: to evaluate the effect of Noni C on the carbon tetrachloride-induced hepatic damage in an experimental model developed in male Wistar rats. Methods: An experimental study was conducted in which the positive control was carbon tetrachloride at a dose of 0.3 mL/kg of weight, intraperitoneally administered for 3 days, and the negative control was saline solution. Four doses of Noni C(85, 130, 170 and 215 mg/kg of weight) were administered for 6 days, after treatment with the carbon tetrachloride. glutamic piruvic and glutamic oxaloacetic transaminase levels were determined, as well as hepatic lesions such as cell tumors, reactive hepatitis, steatosis and necrosis. Results: glutamic piruvic and glutamic oxaloacetic transaminases levels significantly decreased at doses of 85 and 170 mg/kg of Noni C, and no necrosis or steatosis was observed in the groups treated with 170 and 215 mg/kg doses. Conclusions: the carbon tetrachloride-induced hepatic damage diminished in the groups treated with Noni C
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/terapia , Morinda , Tetracloreto de Carbono/efeitos adversosRESUMO
Os autores apresentam um modelo de vídeolaparoscopia experimental para avaliar a hepatotoxicidade induzida pelo tetracloreto de carbono (CCl4) em ratos. Nódulos sobre a superfície hepática e aumento significativo das provas de função hepatobiliar (alanina aminotransferase, aspartato aminotransferase, fosfatase alcalina e g -glutamiltranspeptidase) foram observados nos ratos tratados com CCl4. Além disso, cirrose hepática foi diagnosticada por estudo histopatológico em todos os ratos submetidos à administração de CC1(4). Desta maneira, a vídeolaparoscopia experimental em ratos parece ser um método diagnóstico excelente que merece mais investigação para explorar as conseqüências fisiológicas da cirurgia laparoscópica.
Assuntos
Animais , Ratos , Tetracloreto de Carbono/efeitos adversos , Cirrose Hepática/induzido quimicamente , Modelos Animais de Doenças , Laparoscopia , Cirurgia Vídeoassistida , Cirrose Hepática/diagnóstico , Fígado/patologia , Ratos WistarRESUMO
Se comprobó experimentalmente en ratas la utilidad del Polypodium polypodiodes en la atenuación del efecto hepatotóxico provocado por el tetracloruro de carbono, que origina un incremento del nivel de los peróxidos lipídicos y las transaminasas sanguíneas. Se logró una disminución de la transaminasa glutamicopirúvica por debajo de los niveles normales con la administración del extracto de la planta a una dosis de 300 mg/kg de peso corporal. Los peróxidos lipídicos y la transaminasa glutamicooxalacética reducen su actividad, pero no notablemente, lo cual evidencia que el daño hepático persiste a pesar de la recuperación parcial. Los resultados fueron confirmados por un estudio anatomopatológico. Se determinó la toxicidad aguda por vía oral del extracto de la planta y se observó que la DL50 se encuentra por encima de 1 g/kg, por lo que puede considerarse esta preparación como relativamente inocua en los animales de experimentación
Assuntos
Alanina Transaminase/análise , Aspartato Aminotransferases/análise , Tetracloreto de Carbono/efeitos adversos , Peroxidação de Lipídeos , Hepatopatias/induzido quimicamente , Plantas MedicinaisRESUMO
Os autores estudaram os efeitos do verapamil sobre a necrose hepática induzida pelo tetracloreto de carbono no camundongo. O tratamento de camundongos com verapamil, antes e após o C Cl4, protege o hepatócito da necrose: a necrose centrolobular foi menor nos camundongos tratados com verapamil. Um discreto efeito protetor foi observado quando os animais receberam uma só dose de verapamil, três horas antes ou três horas depois do C Cl4. É possível que o efeito protetor seja maior quando os níveis plasmáticos da droga säo mantidos por período maiores após a injeçäo de C Cl4
Assuntos
Camundongos , Animais , Masculino , Feminino , Tetracloreto de Carbono/efeitos adversos , Fígado , Verapamil/uso terapêutico , Fígado/patologia , NecroseRESUMO
Kupffer cells have been implicated in the pathogenesis of liver injury, but there is controversy about the effects of activation of these cells on the hepatotoxicity of chemicals and endotoxin. It has been shown that injection of Corynebacterium parvum in rats induces macrophage activation that protects against toxic effects of carbon tetrachloride and acetaminophen, five days after injection, and this protection is due to inhibition of microsomal oxidizing enzimes and increased production of glutathion. To verify if the protective effect occurs soon after Kupffer cell activation, with different activators, male albino rats were treated with intravenous injection of BCG (0.5 ml with 7.5 10(8) bacilli), Corynebacterium parvum (30 mg/kg) or zymosan (7.5.10(6) yeast cells). Fourty-eight hours after the injection of one of the macrophage activators, the animals and rats treated with intravenous injection of saline (controls) received carbon tetrachloride by subcutaneous route (1 ml/kg of CCl(4), 3:1 in soybean oil). Fourty-eight hours after the animals were killed after ether anesthesia and fragments of the liver were fixed, paraffin embedded and the sections stained with hematoxylin and eosin. A Weibel grid with 168 points was used to estimate the percent volume of necrosis and severe hydropic degeneration. The results showed that the volume density of necrosis and severe hydropic degeneration were significatively lesser in rats treated with the three Kupffer cells activators. The protection was greater with BCG and Corynebacterium parvum than with zymosan. These results confirm that activation of Kupffer cell with three different activators can induce protection against liver cell injury produced by carbon tetrachloride in rats soon as 48 h after injection of activators.
Assuntos
Animais , Ratos , Masculino , Tetracloreto de Carbono/efeitos adversos , Citoproteção , Células de Kupffer , Hepatopatias/induzido quimicamente , Fígado/patologia , Ativação de Macrófagos , Mycobacterium bovis , Propionibacterium acnes , Zimosan , Necrose , Ratos EndogâmicosRESUMO
É objetivo dos autores avaliar se ocorre maior produçäo de radicais livres no tecido hepático cirrótico. Foram usados ratos Wistar divididos em três grupos: grupo I (controle), o qual recebeu óleo mineral; grupo II (cirrose), no qual foi induzida cirrose com tetracloreto de carbono (Ccl4)l e grupo III (Ccl4), o qual recebeu dose única de tetracloreto de carbono. A produçäo de radicais livres no tecido hepático cirrótico foi avaliada pela lipoperoxidaçäo através dos métodos de substâncias reativas ao ácido tiobarbitúrico (TBARS) e quimiluminescência iniciada por hidroperóxido de tert-butil (CL). O tecido hepático foi submetido a avaliaçäo histológica para evidenciar a presença de cirrose. Demonstrou-se maior lipoperoxidaçao no grupo II quando comparado com os grupos I e III, com diferença estatística significativa (p £ 0,05). Todos os animais tratados com Ccl4 apresentaram alteraçöes compatíveis com cirrose hepática. Observando os resultados deste estudo, podemos concluir que ocorre maior atividade metabólica de radicais livres no tecido hepático cirrótico, criando novas perspectivas no desenvolvimento de substâncias que visem diminuir o efeito deletério deste tipo de afecçäo sobre o fígado.
Assuntos
Animais , Ratos , Tetracloreto de Carbono/efeitos adversos , Cirrose Hepática Experimental/metabolismo , Radicais Livres/metabolismo , Estresse Oxidativo/fisiologia , Fígado/patologia , Ratos WistarRESUMO
En un estudio previo se sugirió que la dieta suplementada con semilla de nabo evita el desarrollo de cirrosis experimental en la rata. En el presente trabajo se demostró por morfometría que la semilla de nabo produce hipertrofia de los hepatocitos. Este crecimiento, a juzgar por los hallazgos con microscopía electrónica, dependió fundamentalmente de la superficie citoplásmica, y en menor grado, del núcleo del hepatocito. La combinación de semilla de nabo con tetracloruro de carbono (CC14) produjo igualmente hipertrofia; sin embargo, aquélla no modificó el cuadro histológico de cirrosis inducida por CC14. El hecho de que la hipertrofia provocada por la semilla de nabo sea básicamente a expensas de organelos membranosos sustenta la idea de que algún ingrediente de ésta modifica la actividad de síntesis o degradación proteínica del hepatocito.
Assuntos
Animais , Masculino , Ratos , Fígado/patologia , Hipertrofia/etiologia , Hipertrofia/patologia , Plantas Comestíveis , Sementes , Tetracloreto de Carbono/efeitos adversos , Cirrose Hepática Experimental/induzido quimicamente , MéxicoRESUMO
Se revisaron 2671 biopsias hepáticas entre los años 1972 y 1985 en el Hospital A. Posadas. Hubo 26 pacientes con daño hepático producido por drogas, habiéndose incluido aquellos enfermos con los siguientes criterios: contacto con un fármaco capaz de producir efecto hepatotóxico; cuadro clínico, biológico e histológico compatible con la droga examinada; remisión completa del cuadro al interrumpir la droga; ausencia de otros tóxicos hepáticos. Catorce pacientes mostraron colestasis intrahepática inducida por estrógenos; 5 tuvieron lesiones hepatitis-like debido a: alfametildopa (3), ketoconazol (1) e indometacina (1). Dos presentaron cambios inflamatorios y cambios grasos por tetracloruro de carbono mientras que la fenibutazona produjo una granulomatosis hepática y una hepatitis colestática. Los últimos tres casos fueron lesiones colestáticas después de la administración de clorpromazina allopurinol y penicilina respectivamente. La evolución en 24 pacientes fue excelente después que se retiró la droga. Dos pacientes murieron por complicaciones quirúrgicas ya que fueron operados con el diagnóstico erróneo de colestasis extrahepática