RESUMEN
Alcoholic liver disease (ALD) is a chronic toxic liver injury caused by long-term heavy drinking. Due to the increasing incidence, ALD is becoming one of important medical tasks. Many studies have shown that the main mechanism of liver damage caused by large amounts of alcohol may be related to antioxidant stress. As an important antioxidant, cysteine (Cys) is involved in maintaining the normal redox balance and detoxifying metabolic function of the liver, which may be closely related to the pathogenesis of ALD. Therefore, it is necessary to develop a simple non-invasive method for rapid monitoring of Cys in liver. Thus, a near-infrared (NIR) fluorescent probe DCI-Ac-Cys which undergoes Cys triggered cascade reaction to form coumarin fluorophore is developed. Using the DCI-Ac-Cys, decreased Cys was observed in the liver of ALD mice. Importantly, different levels of Cys were monitored in the livers of ALD mice taking silybin and curcumin with the antioxidant effects, indicating the excellent therapeutic effect on ALD. This study provides the important references for the accurate diagnosis of ALD and the pharmacodynamic evaluation of silybin and curcumin in the treatment of ALD, and support new ideas for the pathogenesis of ALD.
Asunto(s)
Cumarinas , Cisteína , Colorantes Fluorescentes , Hepatopatías Alcohólicas , Animales , Cisteína/análisis , Cisteína/metabolismo , Cumarinas/química , Colorantes Fluorescentes/química , Hepatopatías Alcohólicas/metabolismo , Hepatopatías Alcohólicas/patología , Masculino , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Espectroscopía Infrarroja Corta/métodos , Curcumina/farmacología , Espectrometría de Fluorescencia , Silibina/farmacología , Silibina/químicaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver-related morbidity and mortality, with hepatic steatosis being the hallmark symptom. Salvia miltiorrhiza Bunge (Smil, Dan-Shen) and Ligusticum striatum DC (Lstr, Chuan-Xiong) are commonly used to treat cardiovascular diseases and have the potential to regulate lipid metabolism. However, whether Smil/Lstr combo can be used to treat NAFLD and the mechanisms underlying its lipid-regulating properties remain unclear. PURPOSE: To assess the feasibility and reliability of a short-term high-fat diet (HFD) induced zebrafish model for evaluating hepatic steatosis phenotype and to investigate the liver lipid-lowering effects of Smil/Lstr, as well as its active components. METHODS: The phenotypic alterations of liver and multiple other organ systems were examined in the HFD zebrafish model using fluorescence imaging and histochemistry. The liver-specific lipid-lowering effects of Smil/Lstr combo were evaluated endogenously. The active molecules and functional mechanisms were further explored in zebrafish, human hepatocytes, and hamster models. RESULTS: In 5-day HFD zebrafish, significant lipid accumulation was detected in the blood vessels and the liver, as evidenced by increased staining with Oil Red O and fluorescent lipid probes. Hepatic hypertrophy was observed in the model, along with macrovesicular steatosis. Smil/Lstr combo administration effectively restored the lipid profile and alleviated hepatic hypertrophy in the HFD zebrafish. In oleic-acid stimulated hepatocytes, Smil/Lstr combo markedly reduced lipid accumulation and cell damage. Subsequently, based on zebrafish phenotypic screening, the natural phthalide senkyunolide I (SEI) was identified as a major molecule mediating the lipid-lowering activities of Smil/Lstr combo in the liver. Moreover, SEI upregulated the expression of the lipid metabolism regulator PPARα and downregulated fatty acid translocase CD36, while a PPARα antagonist sufficiently blocked the regulatory effect of SEI on hepatic steatosis. Finally, the roles of SEI on hepatic lipid accumulation and PPARα signaling were further verified in the hamster model. CONCLUSIONS: We proposed a zebrafish-based screening strategy for modulators of hepatic steatosis and discovered the regulatory roles of Smil/Lstr combo and its component SEI on liver lipid accumulation and PPARα signaling, suggesting their potential value as novel candidates for NAFLD treatment.
Asunto(s)
Modelos Animales de Enfermedad , PPAR alfa , Transducción de Señal , Pez Cebra , Animales , Transducción de Señal/efectos de los fármacos , PPAR alfa/metabolismo , Humanos , Masculino , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Dieta Alta en Grasa , Metabolismo de los Lípidos/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Cricetinae , Hepatocitos/efectos de los fármacos , Hepatocitos/metabolismo , Mesocricetus , Células Hep G2 , Benzofuranos/farmacología , Hígado Graso/tratamiento farmacológicoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Hypercholesterolemia (HLC) was a key risk factor for cardiovascular disease (CVD) characterized by elevated cholesterol levels, particularly LDL. While traditional Chinese medicine preparations Compound Danshen Pills(CDP) has been clinically used for hypercholesterolemia and coronary heart disease, its specific therapeutic effect on HLC remains understudied, necessitating further investigation into its mechanisms. AIM OF THE STUDY: The aim of this study was to explore the potential of CDP in treating HLC and elucidate its underlying mechanisms and active components. MATERIALS AND METHODS: A hypercholesterolemic lipemia rat model induced by a high-fat diet was employed. Network pharmacology combined with UHPLC-Q exactive orbitrap HRMS technique was used to predict the active components, targets and mechanisms of CDP for HLC. Histological analysis and serum biochemical assays were used to assess the therapeutic effect of CDP and its main active ingredient Sa B on hypercholesterolemic lipemia rat model. Immunofluorescence assays and western blotting were used to verify the mechanism of CDP and Sa B in the treatment of HLC. Metabolomics approach was used to demonstrate that CDP and Sa B affected the metabolic profile of HLC. RESULTS: Our findings demonstrated that both CDP and its main active ingredient Sa B significantly ameliorated hypercholesterolemic lipemic lesions, reducing levels of TC, LDL, AST, ALT, and ALP. Histological analysis revealed a decrease in lipid droplet accumulation and collagen fiber deposition in the liver, as well as reduced collagen fiber deposition in the aorta. Network pharmacology predicted potential targets such as PPARα and CYP27A1. Immunofluorescence assays and western blotting confirmed that CDP and Sa B upregulated the expression of Adipor1, PPARα and CYP27A1. Metabolomics analyses further indicated improvements in ABC transporters metabolic pathways, with differential metabolites such as riboflavin, taurine, and choline showed regression in levels after CDP treatment and riboflavin, L-Threonine, Thiamine, L-Leucine, and Adenosine showed improved expression after Sa B treatment. CONCLUSION: CDP and Sa B have been shown to alleviate high-fat diet-induced hypercholesterolemia by activating the PPAR pathway and improving hepatic lipid metabolism. Our study demonstrated, for the first time, the complex mechanism of CDP, Sa B in the treatment of hypercholesterolemia at the protein and metabolic levels and provided a new reference that could elucidate the pharmacological effects of traditional Chinese medicine on hypercholesterolemia from multiple perspectives.
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Dieta Alta en Grasa , Medicamentos Herbarios Chinos , Hipercolesterolemia , Metabolómica , Farmacología en Red , Ratas Sprague-Dawley , Salvia miltiorrhiza , Animales , Hipercolesterolemia/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Masculino , Cromatografía Líquida de Alta Presión , Salvia miltiorrhiza/química , Ratas , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Canfanos , Panax notoginsengRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Si-Ni-San (SNS), a traditional Chinese medicinal formula derived from Treatise on Febrile Diseases, is considered effective in the treatment of inflammatory bowel diseases based upon thousands of years of clinical practice. However, the bioactive ingredients and underlying mechanisms are still unclear and need further investigation. AIM OF THE STUDY: This study aimed to evaluate the effect, explore the bioactive ingredients and the underlying mechanisms of SNS in ameliorating ulcerative colitis (UC) and associated liver injury in dextran sodium sulphate (DSS)-induced mouse colitis models. MATERIALS AND METHODS: The effect of SNS (1.5, 3, 6 g/kg) on 3% DSS-induced acute murine colitis was evaluated by disease activity index (DAI), colon length, inflammatory cytokines, hematoxylin-eosin (H&E) staining, tight junction proteins expression, ALT, AST, and oxidative stress indicators. HPLC-ESI-IT/TOF MS was used to analyze the chemical components of SNS and the main xenobiotics in the colon of UC mice after oral administration of SNS. Network pharmacological study was then conducted based on the main xenobiotics. Flow cytometry and immunohistochemistry techniques were used to demonstrate the inhibitory effect of SNS on Th17 cells differentiation and the amelioration of Th17/Treg cell imbalance. LC-MS/MS, Real-time quantitative polymerase chain reaction (RT-qPCR), and western blotting techniques were performed to investigate the oxysterol-Liver X receptor (LXRs) signaling activity in colon. Targeted bile acids metabolomics was conducted to reveal the change of the two major pathways of bile acid synthesis in the liver, and the expression of key metabolic enzymes of bile acids synthesis was characterized by RT-qPCR and western blotting techniques. RESULTS: SNS (1.5, 3, 6 g/kg) decreased the DAI scores, protected intestinal mucosa barrier, suppressed the production of pro-inflammatory cytokines, improved hepatic and splenic enlargement and alleviated liver injury in a dose-dependent manner. A total of 22 components were identified in the colon of SNS (6 g/kg) treated colitis mice, and the top 10 components ranked by relative content were regarded as the potential effective chemical components of SNS, and used to conduct network pharmacology research. The efficacy of SNS was mediated by a reduction of Th17 cell differentiation, restoration of Th17/Treg cell homeostasis in the colon and spleen, and the experimental results were consistent with our hypothesis and the biological mechanism predicted by network pharmacology. Mechanistically, SNS regulated the concentration of 25-OHC and 27-OHC by up-regulated CH25H, CYP27A1 protein expression in colon, thus affected the expression and activity of LXR, ultimately impacted Th17 differentiation and Th17/Treg balance. It was also found that SNS repressed the increase of hepatic cholesterol and reversed the shift of BA synthesis to the acidic pathway in UC mice, which decreased the proportion of non-12-OH BAs in total bile acids (TBAs) and further ameliorated colitis and concomitant liver injury. CONCLUSIONS: This study set the stage for considering SNS as a multi-organ benefited anti-colitis prescription based on the significant effect of ameliorating intestinal and liver damage, and revealed that derivatives of cholesterol, namely oxysterols and bile acids, were closely involved in the mechanism of SNS anti-colitis effect.
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Colesterol , Colitis Ulcerosa , Sulfato de Dextran , Medicamentos Herbarios Chinos , Animales , Medicamentos Herbarios Chinos/farmacología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/patología , Colitis Ulcerosa/metabolismo , Ratones , Masculino , Colesterol/sangre , Células Th17/efectos de los fármacos , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Colon/efectos de los fármacos , Colon/patología , Colon/metabolismo , Farmacología en Red , Citocinas/metabolismo , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Triptolide is a major bioactive and toxic ingredient isolated from the traditional Chinese herb Tripterygium wilfordii (T. wilfordii) Hook F. It exhibits potent antitumor, immunosuppressive, and anti-inflammatory biological activities; however, its clinical application is hindered by severe systemic toxicity. Two preparations of T. wilfordii, including T. wilfordii glycoside tablets and T. wilfordii tablets, containing triptolide, are commonly used in clinical practice. However, their adverse side effects, particularly hepatotoxicity, limit their safe use. Therefore, it is crucial to discover potent and specific detoxification medicines for triptolide. AIM OF THE STUDY: This study aimed to investigate the detoxification effects and potential mechanism of action of spironolactone on triptolide-induced hepatotoxicity to provide a potential detoxifying strategy for triptolide, thereby promoting the safe applications of T. wilfordii preparations in clinical settings. MATERIALS AND METHODS: Cell viability was assessed using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and crystal violet staining. Nuclear fragmentation was visualized using 4',6-diamidino-2-phenylindole (DAPI) staining, and protein expression was analyzed by Western blotting. The inhibitory effect of spironolactone on triptolide-induced hepatotoxicity was evaluated by examining the effects of spironolactone on serum alanine aminotransferase and aspartate aminotransferase levels, as well as liver pathology in a mouse model of triptolide-induced acute hepatotoxicity. Furthermore, a survival assay was performed to investigate the effects of spironolactone on the survival rate of mice exposed to a lethal dose of triptolide. The effect of spironolactone on triptolide-induced global transcriptional repression was assessed through 5-ethynyl uridine staining. RESULTS: Triptolide treatment decreased the cell viability, increased the nuclear fragmentation and the cleaved caspase-3 levels in both hepatoma cells and hepatocytes. It also increased the alanine aminotransferase and aspartate aminotransferase levels, induced the hepatocyte swelling and necrosis, and led to seven deaths out of 11 mice. The above effects could be mitigated by pretreatment with spironolactone. Additionally, molecular mechanism exploration unveiled that spironolactone inhibited triptolide-induced DNA-directed RNA polymerase II subunit RPB1 degradation, consequently increased the fluorescence intensity of 5-ethynyl uridine staining for nascent RNA. CONCLUSIONS: This study shows that spironolactone exhibits a potent detoxification role against triptolide hepatotoxicity, through inhibition of RPB1 degradation induced by triptolide and, in turn, retardation of global transcriptional inhibition in affected cells. These findings suggest a potential detoxification strategy for triptolide that may contribute to the safe use of T. wilfordii preparations.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Diterpenos , Compuestos Epoxi , Fenantrenos , Espironolactona , Compuestos Epoxi/toxicidad , Fenantrenos/toxicidad , Fenantrenos/farmacología , Diterpenos/farmacología , Diterpenos/toxicidad , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Ratones , Espironolactona/farmacología , Masculino , Humanos , Supervivencia Celular/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Células Hep G2RESUMEN
OBJECTIVE: Liver derangement underlies the development of metabolic syndrome in perimenopause. Previously, we have observed that durva swaras (DS) improved metabolic-associated fatty liver disease (MAFLD) and abnormal liver enzymes (aspartate aminotransferase and alanine aminotransferase) along with other complications of menopause in ovariectomized rats. We aimed to decipher the hepatoprotective mechanisms of DS in acetaminophen (APAP)-induced liver injury model, which is analogous to the pathophysiology of MAFLD. MATERIALS AND METHODS: Male Swiss albino mice were distributed into three groups at random. Group I (Control) was administered with vehicle (distilled water) for 7 days. Group II (APAP) received vehicle for the first 6 days and APAP (350 mg/kg - single dose) on the 7th day. Group III (APAP + D) received test compound DS (quality complied) at a dose of 133 mg/kg for 6 days and APAP (350 mg/kg - single dose) on the 7th day. Subsequently, blood and liver tissues were subjected to biochemical, ultrastructural, and gene expression analysis. RESULTS: DS pretreatment protected the liver from APAP-induced disruption of sinusoids and necrosis. DS prevented the elevation of liver enzymes - AST and ALT induced by APAP. Importantly, DS inhibited the APAP-elicited increase in messenger ribonucleic acid levels of hepatic nuclear factor-kappa beta (NF-κB) and pro-inflammatory cytokines, namely interleukin-1 beta, interleukin 6, and tumor necrosis factor-alpha. Moreover, DS activated gene expression of nuclear factor erythroid 2-related factor 2 and liver-X-receptor-alpha (LXR-α) to combat the liver damage. CONCLUSION: DS hinders APAP-induced liver damage by activating LXR-α and inhibiting the NF-κB-associated pro-inflammatory cytokine gene expression. These observations confirm the protective role of DS in metabolic dysfunction-associated liver conditions.
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Acetaminofén , Enfermedad Hepática Inducida por Sustancias y Drogas , Animales , Masculino , Ratones , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Acetaminofén/toxicidad , Extractos Vegetales/farmacología , Extractos Vegetales/administración & dosificación , Extractos Vegetales/uso terapéutico , Modelos Animales de Enfermedad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Biomarcadores/sangre , Alanina Transaminasa/sangre , FN-kappa B/metabolismo , Citocinas/metabolismo , Aspartato Aminotransferasas/sangre , Inflamación/tratamiento farmacológicoRESUMEN
Liver disease is a major worldwide health and economic problem. Allograft liver transplant is the only effective therapy for end-stage liver disease. The shortage of donors, the high costs, postoperative complications, and lifelong immunosuppression are rate-limiting factors for this established line of treatment. Hence, searching for therapeutic alternatives is mandatory. Stem cells are attractive candidates for cell-based therapy for their potential to support liver regeneration with few complications. They can differentiate into specialized cells, including hepatocytes to restore liver structure and function. Stem cells originating from different sources have been investigated for the treatment of liver diseases. In this review, we highlight the role of stem cells as an appropriate source for liver cell replacement in different liver diseases.
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Hepatopatías , Regeneración Hepática , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Humanos , Hepatopatías/terapia , Hepatopatías/cirugía , Resultado del Tratamiento , Animales , Hepatocitos/trasplante , Medicina Regenerativa/tendencias , Hígado/patología , Diferenciación Celular , Recuperación de la Función , FenotipoRESUMEN
The purpose of this study was to investigate the protective effect of echinacoside (Ech) on carbon tetrachloride (CCL4)-induced chronic liver injury in rats and its potential mechanisms. Thirty Sprague-Dawley (SD) rats were randomly divided into five groups: the Control group, the CCL4 group, the CCL4 + Ech 25 mg/kg group, the CCL4 + Ech 50 mg/kg group, and the CCL4 + Ech 100 mg/kg group. The rats were injected intraperitoneally with CCL4 solution twice a week to induce chronic liver injury, and Ech intervention lasted for 4 weeks. After the intervention, the liver and blood samples from rats were collected for subsequent analysis. Ech effectively reduced the levels of serum liver injury markers (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, alkaline phosphatase, and total bilirubin), attenuated the hepatocyte degeneration and necrosis, improved the severity of liver fibrosis, and inhibited the local inflammatory response of the liver in a dose-dependent manner. Ech effectively mitigated CCL4-induced chronic liver injury in rats by downregulating the NF-κB/NLRP3 inflammasome pathway.
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Tetracloruro de Carbono , Glicósidos , Inflamasomas , FN-kappa B , Proteína con Dominio Pirina 3 de la Familia NLR , Ratas Sprague-Dawley , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , FN-kappa B/metabolismo , Glicósidos/farmacología , Glicósidos/química , Glicósidos/uso terapéutico , Ratas , Inflamasomas/metabolismo , Masculino , Transducción de Señal/efectos de los fármacos , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patologíaRESUMEN
The function of hydroxysteroid dehydrogenase 12 (HSD17B12) in lipid metabolism is poorly understood. To study this further, we created mice with hepatocyte-specific knockout of HSD17B12 (LiB12cKO). From 2 months on, these mice showed significant fat accumulation in their liver. As they aged, they also had a reduced whole-body fat percentage. Interestingly, the liver fat accumulation did not result in the typical formation of large lipid droplets (LD); instead, small droplets were more prevalent. Thus, LiB12KO liver did not show increased macrovesicular steatosis with the increasing fat content, while microvesicular steatosis was the predominant feature in the liver. This indicates a failure in the LD expansion. This was associated with liver damage, presumably due to lipotoxicity. Notably, the lipidomics data did not support an essential role of HSD17B12 in fatty acid (FA) elongation. However, we did observe a decrease in the quantity of specific lipid species that contain FAs with carbon chain lengths of 18 and 20 atoms, including oleic acid. Of these, phosphatidylcholine and phosphatidylethanolamine have been shown to play a key role in LD formation, and a limited amount of these lipids could be part of the mechanism leading to the dysfunction in LD expansion. The increase in the Cidec expression further supported the deficiency in LD expansion in the LiB12cKO liver. This protein is crucial for the fusion and growth of LDs, along with the downregulation of several members of the major urinary protein family of proteins, which have recently been shown to be altered during endoplasmic reticulum stress.
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Hígado Graso , Hepatocitos , Gotas Lipídicas , Ratones Noqueados , Animales , Ratones , Gotas Lipídicas/metabolismo , Hepatocitos/metabolismo , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/genética , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , 17-Hidroxiesteroide Deshidrogenasas/genética , Metabolismo de los Lípidos , Peso Corporal , Hígado/metabolismo , Hígado/patología , Masculino , Ratones Endogámicos C57BL , Ácidos Grasos/metabolismoRESUMEN
Sarcoidosis is an inflammatory disease characterised by non-caseating granulomas that can affect any organ, although lung involvement is the most common. It is rare to find sarcoidosis isolated to extrapulmonary organs. We describe a case of extrapulmonary sarcoidosis with involvement of the liver in a man in his late 40s. His initial clinical history and investigations were more consistent with a diagnosis of lymphoma until a liver biopsy was performed revealing non-caseating granulomas more suggestive of a diagnosis of sarcoidosis. This patient had a history of young-onset ischaemic heart disease (IHD). We discuss the possible links between sarcoidosis, an inflammatory condition, and IHD, as well as the challenges to treating such patients with concurrent metabolic syndrome. This case also highlights the heterogeneous nature of sarcoidosis, with the diagnosis being important as prompt treatment can prevent complications of end-stage liver disease, including portal hypertension and cirrhosis.
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Hepatopatías , Linfoma , Sarcoidosis , Humanos , Masculino , Sarcoidosis/diagnóstico , Sarcoidosis/patología , Diagnóstico Diferencial , Hepatopatías/diagnóstico , Hepatopatías/patología , Linfoma/diagnóstico , Linfoma/patología , Hígado/patología , Hígado/diagnóstico por imagen , Adulto , Biopsia , Persona de Mediana EdadRESUMEN
Gold nanoparticles (AuNPs) have unique features which could be beneficial to various aspects of clinics and industry. Long-term exposure to AuNPs damages the physiologic functions and tissue structure of organs. Gingerol has anti-inflammatory and antioxidant properties. This study explored the effect of 6-gingerol on alleviation of AuNPs exposure effects in rats' liver. Thirty-two male Wistar rats were randomly assigned to four groups of negative control (received no AuNPs or treatment), positive control (received AuNPs but not treatment), and two study arms (both received AuNPs and one group 50 and the other 100 mg/Kg body weight 6-gingerol). All injections were performed intraperitoneally. After 30 days, serum levels of ALP, AST, ALT were assessed through ELISA method by an autoanalyzer while GGT, SOD, GPx, CAT, IL-6, IL-1ß, TNF-α, CRP, 8-OHdG, MDA, and Bax/Bcl2 were measured using an ELISA reader. Paraffin-embedded tissue sections of the livers from all groups were also prepared and H&E staining was performed on them for investigation of tissue changes. Statistical analyses were performed using SPSS version 26 and p = 0.05 was considered as the level of significancy. AuNPs exposure significantly increased the levels of ALP, AST, ALT, GGT, CRP, IL-6, IL-1ß, TNF-α, Bax/Bcl2, 8-OHdG, MDA (p < 0.001) in positive control groups compared to negative controls, while treatment with 6-gingerol significantly decreased the mentioned enzyme levels (p < 0.001). The level of antioxidant enzymes of SOD, GPx, and CAT, on the other hand, was found to be highest and lowest in negative and positive controls, respectively (p < 0.001). Treatment with 6-gingerol significantly decreased the mentioned enzyme levels (p < 0.001). Histology results showed no signs of degeneration, necrosis, or immune cell infiltration in negative controls, while positive controls showed dilated central veins and hyperemia along with infiltration of mononuclear immune cells to the portal area, tissue degeneration, and necrosis. The study arms showed improved signs as they showed normal trabecular structures with no clear portal space. Treatment with 6-gingerol seems to significantly and efficiently reduce the hepatic side effects of AuNPs exposure in Wistar rats.
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Biomarcadores , Catecoles , Alcoholes Grasos , Oro , Hígado , Nanopartículas del Metal , Estrés Oxidativo , Ratas Wistar , Animales , Alcoholes Grasos/farmacología , Catecoles/farmacología , Masculino , Estrés Oxidativo/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Nanopartículas del Metal/toxicidad , Ratas , Oro/farmacología , Biomarcadores/metabolismo , Biomarcadores/sangre , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/patología , Inflamación/inducido químicamente , Antioxidantes/farmacología , Antioxidantes/metabolismoRESUMEN
Rationale: Dysregulated T-cell immune response-mediated inflammation plays critical roles in the pathology of diverse liver diseases, but the underlying mechanism of liver immune homeostasis control and the specific therapies for limiting T-cell overactivation remain unclear. Methods: The metabolic changes in concanavalin A (ConA) mice and autoimmune hepatitis (AIH) patients and their associations with liver injury were analyzed. The expression of purine catabolism nucleases (e.g., CD39 and CD73) on liver cells and immune cells was assessed. The effects of MCregs and their extracellular vesicles (EVs) on CD4+ T-cell overactivation and the underlying mechanism were also explored. Results: Our findings revealed significant alterations in purine metabolism in ConA mice and AIH patients, which correlated with liver injury severity and therapeutic response. CD39 and CD73 were markedly upregulated on CD11b+Gr-1+ MCs under liver injury conditions. The naturally expanded CD39+CD73+Gr-1highCD11b+ MCreg subset during early liver injury effectively suppressed CD4+ T-cell hyperactivation and liver injury both in vitro and in vivo. Mechanistically, MCregs released CD73high EVs, which converted extracellular AMP to immunosuppressive metabolites (e.g., adenosine and inosine), activating the cAMP pathway and inhibiting glycolysis and cytokine secretion in activated CD4+ T cells. Conclusions: This study provides insights into the mechanism controlling immune homeostasis during the early liver injury phase and highlights that MCreg or MCreg-EV therapy may be a specific strategy for preventing diverse liver diseases induced by T-cell overactivation.
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Vesículas Extracelulares , Hepatitis Autoinmune , Ratones Endogámicos C57BL , Purinas , Animales , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/inmunología , Ratones , Purinas/metabolismo , Hepatitis Autoinmune/inmunología , Hepatitis Autoinmune/metabolismo , Hepatitis Autoinmune/patología , Humanos , Apirasa/metabolismo , Hígado/metabolismo , Hígado/inmunología , Hígado/patología , Células Mieloides/metabolismo , Células Mieloides/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Masculino , 5'-Nucleotidasa/metabolismo , Activación de Linfocitos/inmunología , Concanavalina A , Femenino , Modelos Animales de Enfermedad , Inflamación/metabolismo , Inflamación/inmunología , Antígenos CDRESUMEN
The histological changes in the liver, kidney, spleen, and gills of Syacium papillosum from the continental shelf of the Yucatan Peninsula, Gulf of Mexico, and their statistical associations with environmental conditions and pollutants were assessed in 2010, 2011, and 2012. We evaluated the extension and severity of the lesions through a degree of tissue change (DTC), and, with the sum of the number of lesion types within each of their DTC stages, we determined the histological alteration index (HAI). The liver and kidney were the most affected organs, with HAI values > 100. Fish with the most severe damage were observed on the Campeche Bank and the Caribbean Sea, contrasting with those collected from the northern Yucatan continental shelf. The presence of foci cellular alteration and abundant melanomacrophage centers indicated that these flatfishes were chronically exposed to environmental stress factors. Redundancy analyses showed strong associations between HAI values and hydrocarbon and heavy metal concentrations in muscle. Our results provide evidence for the first time of a differential health condition of the Yucatan shelf through the histopathology shown in S. papillosum, establishing the baseline for future monitoring programs in the region.
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Monitoreo del Ambiente , Lenguado , Branquias , Riñón , Hígado , Contaminantes Químicos del Agua , Animales , Contaminantes Químicos del Agua/análisis , Riñón/patología , Branquias/patología , Hígado/patología , Estrés Fisiológico , Golfo de México , Bazo/patología , Metales Pesados/análisisRESUMEN
Arsenic is a toxic metal-like element widely used in the pesticide, preservative and semiconductor industries. However, accumulation of arsenic through the food chain can cause serious damage to animal and human health. However, the toxic mechanism of arsenic-induced hepatotoxicity in chickens is not clear, and the present study aimed to investigate the potential role of cGAS-STING and NF-κB pathways on inflammatory injury in chicken liver. In this study, 75 white-feathered broilers were divided into a control group, a low-dose arsenic group (4 mg/kg) and a high-dose arsenic group (8 mg/kg) to investigate the toxic effects of arsenic on chicken liver. In this study, we found that pathological changes such as inflammatory cell infiltration and vesicular degeneration occurred in the liver when exposed to ATO. Crucially, exposure to ATO triggered the cGAS-STING pathway and markedly raised the levels of mRNA and protein expression of cGAS, STING, TBK1, and IRF7. The type I interferon response was also triggered. Simultaneously, STING induced the activation of the conventional NF-κB signaling pathway and stimulated the expression of genes associated with inflammation, such as IL-6, TNF-α and IL-1ß. In summary, the induction of inflammatory responses via cGAS-STING and NF-κB signaling pathways under high ATO exposure provides new ideas for further studies on the toxicological mechanisms of arsenic.
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Trióxido de Arsénico , Pollos , Inmunidad Innata , Hígado , FN-kappa B , Nucleotidiltransferasas , Transducción de Señal , Animales , Trióxido de Arsénico/toxicidad , FN-kappa B/metabolismo , Inmunidad Innata/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hígado/inmunología , Transducción de Señal/efectos de los fármacos , Nucleotidiltransferasas/metabolismo , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Inflamación/inducido químicamente , Enfermedad Hepática Inducida por Sustancias y Drogas , Proteínas Aviares/metabolismo , Proteínas Aviares/genéticaRESUMEN
OBJECTIVE: 28-55% of chronic hepatitis B (CHB) patients belong to the grey zone (GZ). By analyzing the pathological characteristics of the liver of patients in the GZ, this study clarified whether the patients in the GZ need anti-hepatitis B virus treatment. METHOD: We reviewed 324 cases of liver pathology that underwent liver biopsy between 2011 and 2022. According to the total score of inflammation G, 0-6 points are classified as mild, 7-12 points are classified as moderate, and 13-18 points are classified as severe. According to the total score of fibrosis F, 0-2 is mild, 3-4 is moderate, and 5-6 is severe. Significant histological diseases (SHD) are defined as the presence of inflammation G ≥ 6 and/or fibrosis F ≥ 2 in liver biopsy specimens. RESULT: 324 GZ patients were scored using the Ishak method, with G7-18 accounting for 9%, F3-6 accounting for 19.2%, and SHD accounting for 37%. The inflammation, fibrosis, and SHD in the HBeAg (+) group were more pronounced than those in the HBeAg (-) group. Among the GZ-A â¼ GZ-D subgroups, the highest proportion of SHD in the GZ-B group was 58.35%. CONCLUSION: More than 1/3 of the patients in GZ need anti-hepatitis B virus treatment. More than half of GZ-B patients need anti-hepatitis B virus treatment. It is very necessary to carry out rescue anti-hepatitis B virus treatment for patients in GZ as soon as possible.
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Antivirales , Antígenos e de la Hepatitis B , Hepatitis B Crónica , Cirrosis Hepática , Hígado , Humanos , Hepatitis B Crónica/tratamiento farmacológico , Hepatitis B Crónica/patología , Hepatitis B Crónica/virología , Antivirales/uso terapéutico , Masculino , Femenino , Adulto , Hígado/patología , Persona de Mediana Edad , Cirrosis Hepática/virología , Cirrosis Hepática/patología , Cirrosis Hepática/tratamiento farmacológico , Antígenos e de la Hepatitis B/sangre , Biopsia , Virus de la Hepatitis B/efectos de los fármacos , Estudios Retrospectivos , Índice de Severidad de la EnfermedadRESUMEN
Recent evidence indicates that liver cirrhosis (LC) is a reversible condition, but there is no established intervention against liver fibrosis. Although the gut microbiota is considered involved in the pathogenesis of LC, the underlying mechanisms remain unclear. Although the antibiotic, rifaximin (RFX), is effective for hepatic encephalopathy (HE) with LC, the impact of RFX on intestinal bacteria is unknown. We investigated the bacterial compositions along the GI tract under RFX treatment using a murine LC model. RFX improved liver fibrosis and hyperammonemia and altered the bacterial composition in the small intestine. The efficacy of RFX was associated with increases in specific bacterial genera, including Akkermansia. Administration of a commensal strain of Akkermansia muciniphila improved liver fibrosis and hyperammonemia with changing bacterial composition in the small intestine. This study proposed a new concept "small intestine-liver axis" in the pathophysiology of LC and oral A. muciniphila administration is a promising microbial intervention.
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Akkermansia , Modelos Animales de Enfermedad , Microbioma Gastrointestinal , Intestino Delgado , Cirrosis Hepática , Rifaximina , Animales , Ratones , Intestino Delgado/microbiología , Intestino Delgado/patología , Cirrosis Hepática/microbiología , Rifaximina/uso terapéutico , Rifaximina/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Masculino , Verrucomicrobia , Ratones Endogámicos C57BL , Hígado/patología , Hígado/microbiología , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , ARN Ribosómico 16S/genéticaRESUMEN
BACKGROUND: Abnormal lipid deposition is an important driver of the progression of metabolic dysfunction-associated steatotic liver disease (MASLD). MicroRNA-411-5p (miR-411-5p) and eukaryotic translation initiation factor 4γ2 (EIF4G2) are related to abnormal lipid deposition, but the specific mechanism is unknown. METHODS: A high-fat, high-cholesterol diet (HFHCD) and a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) and a high-fructose diet (HFrD) were used to establish MASLD rat and mouse models, respectively. MiR-411-5p agomir and mimic were used to upregulate the miR-411-5p in vivo and in vitro, respectively. Adeno-associated virus type 8 (AAV8) carrying EIF4G2 short hairpin RNA (shRNA) and small interfering RNA (siRNA) were used to downregulate the EIF4G2 expression in vivo and in vitro, respectively. Liver histopathological analysis, Biochemical analysis and other experiments were used to explore the functions of miR-411-5p and EIF4G2. RESULTS: MiR-411-5p was decreased in both MASLD rats and mice, and was negatively correlated with liver triglycerides and serum alanine transaminase (ALT) and aspartate transaminase (AST) levels. Upregulation of miR-411-5p alleviated liver lipid deposition and hepatocellular steatosis. Moreover, miR-411-5p targeted and downregulated EIF4G2. Downregulation of EIF4G2 not only reduced liver triglycerides and serum ALT and AST levels in MASLD model, but also alleviated lipid deposition. Notably, upregulation of miR-411-5p and downregulation of EIF4G2 led to the reduction of forkhead box class O3 (FOXO3) and inhibited the expression of sterol regulatory-element binding protein 1 (SREBP1), acetyl-CoA carboxylase 1 (ACC1) and fatty acid synthase (FASN), thereby reducing fatty acid synthesis. CONCLUSIONS: Upregulation of miR-411-5p inhibits EIF4G2 to reduce the FOXO3 expression, thereby reducing fatty acid synthesis and alleviating abnormal lipid deposition in MASLD.
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Proteína Forkhead Box O3 , Metabolismo de los Lípidos , MicroARNs , Animales , MicroARNs/genética , MicroARNs/metabolismo , Ratones , Masculino , Ratas , Metabolismo de los Lípidos/genética , Proteína Forkhead Box O3/metabolismo , Proteína Forkhead Box O3/genética , Factor 4G Eucariótico de Iniciación/metabolismo , Factor 4G Eucariótico de Iniciación/genética , Ratones Endogámicos C57BL , Humanos , Hígado Graso/metabolismo , Hígado Graso/patología , Hígado Graso/genética , Dieta Alta en Grasa/efectos adversos , Modelos Animales de Enfermedad , Ratas Sprague-Dawley , Hígado/metabolismo , Hígado/patologíaRESUMEN
BACKGROUND: At present, hepatic ischemia-reperfusion injury (IRI) is an important complication of partial hepatectomy and liver transplantation, and it is an important cause of poor prognosis. Spleen tyrosine kinase(SYK) plays an important role in a variety of signaling pathways in the liver, but its role in hepatic IRI is still unclear. This study aims to investigate the role and mechanism of SYK in hepatic IRI and tumor recurrence. METHODS: We first observed the activation of SYK in the liver of mice in response to hepatic IRI. Subsequently, Pharmacological inhibitions of SYK were used to evaluated the effect of SYK on neutrophil recruitment and NETosis, and further explored the effect of SYK on IRI and tumor recurrence. RESULTS: Our study shows that SYK is activated in response to hepatic IRI and aggravates liver injury. On the one hand, neutrophils SYK during the early stage of liver reperfusion increases neutrophil extracellular traps (NETs) production by promoting Pyruvate kinase M2(PKM2) nuclear translocation leading to upregulation of phosphorylated STAT3, thereby exacerbating liver inflammation and tumor recurrence. On the other hand, macrophages SYK can promote the recruitment of neutrophils and increase the activation of NLRP3 inflammasome and IL1ß, which further promotes the formation of NETs. CONCLUSIONS: Our study demonstrates that neutrophil and macrophage SYK synergistically promote hepatic IRI and tumor recurrence, and SYK may be a potential target to improve postoperative hepatic IRI and tumor recurrence.
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Trampas Extracelulares , Proteínas de la Membrana , Neutrófilos , Daño por Reperfusión , Factor de Transcripción STAT3 , Quinasa Syk , Quinasa Syk/metabolismo , Animales , Factor de Transcripción STAT3/metabolismo , Trampas Extracelulares/metabolismo , Daño por Reperfusión/metabolismo , Daño por Reperfusión/patología , Fosforilación , Ratones , Proteínas de la Membrana/metabolismo , Masculino , Neutrófilos/metabolismo , Proteínas Portadoras/metabolismo , Piruvato Quinasa/metabolismo , Hígado/metabolismo , Hígado/patología , Proteínas de Unión a Hormona Tiroide , Recurrencia Local de Neoplasia/metabolismo , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Humanos , Transducción de SeñalRESUMEN
The diagnosis of liver antibody-mediated rejection (AMR) is challenging and likely under-recognized. The association of AMR with donor-specific antibodies (DSA), and its clinical course in relation to pathologic findings and treatment are ill defined. We identified cases of liver AMR by following the criteria outlined by the 2016 Banff Working Group. Patient demographics, native liver disease, histopathologic findings, treatment type, clinical outcome, and transaminase levels during AMR diagnosis, treatment, and resolution were determined. Patients (n = 8) with AMR average age was 55.2 years (range: 19-68). Seven of eight cases met the Banff criteria for AMR. Personalized treatment regimens consisted of optimization of immunosuppression, intravenous pulse steroids, plasmapheresis, IVIG, rituximab, and bortezomib. Five patients experienced complete resolution of AMR, return of transaminases to baseline, and decreased DSA at long-term follow-up. One patient developed chronic AMR and two patients required re-transplantation. Follow-up after AMR diagnosis ranged from one to 11 years. Because AMR can present at any time, crossmatch, early biopsy, and routine monitoring of DSA levels should be implemented following transaminase elevation to recognize AMR. Furthermore, treatment should be immediately implemented to reverse AMR and prevent graft failure, chronic damage, re-transplantation, and possibly mortality.
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Rechazo de Injerto , Trasplante de Hígado , Humanos , Rechazo de Injerto/inmunología , Persona de Mediana Edad , Adulto , Masculino , Femenino , Anciano , Estudios de Seguimiento , Adulto Joven , Isoanticuerpos/inmunología , Inmunosupresores/uso terapéutico , Hígado/patología , Rituximab/uso terapéutico , Plasmaféresis , Bortezomib/uso terapéutico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
Toxoplasmosis is a globally significant disease that poses a severe threat to immunocompromised individuals, especially in Brazil, where a high prevalence of virulent and atypical strains of Toxoplasma gondii is observed. In 1998, the EGS strain, exhibiting a unique infection phenotype, was isolated in Brazil, adding to the complexity of strain diversity. The P2X7 receptor is critical in inflammation and controlling intracellular microorganisms such as T. gondii. However, its genetic variability can result in receptor dysfunction, potentially worsening susceptibility. This study investigates the role of the P2X7 receptor during acute infection induced by the EGS atypical strain, offering insight into the mechanisms of T. gondii infection in this context. We infected the female C57BL/6 (WT) or P2X7 knockout (P2X7-/-) by gavage. The EGS infection causes intestinal inflammation. The P2X7-/- mice presented higher parasite load in the intestine, spleen, and liver. The absence of the P2X7 receptor disrupts inflammatory cell balance by reducing NLRP3, IL-1ß, and Foxp3 expression while increasing IFN-γ expression and production in the intestine. In the liver, P2X7-/- animals demonstrate diminished inflammatory infiltrate within the portal and lobular regions concurrent with an enlargement of the spleen. In conclusion, the infection of mice with the EGS strain elicited immune alterations, leading to acute inflammation and cytokine dysregulation, while the P2X7 receptor conferred protection against parasitic proliferation across multiple organs.