RESUMEN
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.
Asunto(s)
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
BACKGROUND: Drug-induced liver injury (DILI) is gradually becoming a common global problem that causes acute liver failure, especially in acute hepatic damage caused by acetaminophen (APAP). Paeoniflorin (PF) has a wide range of therapeutic effects to alleviate a variety of hepatic diseases. However, the relationship between them is still poorly investigated in current studies. PURPOSE: This work aimed to explore the protective effects of PF on APAP-induced hepatic damage and researched the potential molecular mechanisms. METHODS: C57BL/6J male mice were injected with APAP to establish DILI model and were given PF for five consecutive days for treatment. Aiming to clarify the pharmacological effects, the molecular mechanisms of PF in APAP-induced DILI was elucidated by high-throughput and other techniques. RESULTS: The results demonstrated that serum levels of ALP, γ-GT, AST, TBIL, and ALT were decreased in APAP mice by the preventive effects of PF. Moreover, PF notably alleviated hepatic tissue inflammation and edema. Meanwhile, the results of TUNEL staining and related apoptotic factors coincided with the results of transcriptomics, suggesting that PF inhibited hepatocyte apoptosis by regulated MAPK signaling. Besides, PF also acted on reactive oxygen species (ROS) to regulate the oxidative stress for recovery the damaged mitochondria. More importantly, transmission electron microscopy showed the generation of autophagosomes after PF treatment, and PF was also downregulated mTOR and upregulated the expression of autophagy markers such as ATG5, ATG7, and BECN1 at the mRNA level and LC3, p62, ATG5, and ATG7 at the protein level, implying that the process by which PF exerted its effects was accompanied by the occurrence of autophagy. In addition, combinined with molecular dynamics simulations and western blotting of MAPK, the results suggested p38 as a direct target for PF on APAP. Specifically, PF-activated autophagy through the downregulation of MAPK/mTOR signaling, which in turn reduced APAP injury. CONCLUSIONS: Paeoniflorin mitigated liver injury by activating autophagy to suppress oxidative stress and apoptosis via the MAPK/mTOR signaling pathway. Taken together, our findings elucidate the role and mechanism of paeoniflorin in DILI, which is expected to provide a new therapeutic strategy for the development of paeoniflorin.
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Acetaminofén , Autofagia , Enfermedad Hepática Inducida por Sustancias y Drogas , Glucósidos , Hepatocitos , Ratones Endogámicos C57BL , Monoterpenos , Serina-Treonina Quinasas TOR , Animales , Autofagia/efectos de los fármacos , Glucósidos/farmacología , Serina-Treonina Quinasas TOR/metabolismo , Monoterpenos/farmacología , Masculino , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Ratones , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Acetaminofén/efectos adversos , Transducción de Señal/efectos de los fármacos , Apoptosis/efectos de los fármacos , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Sustancias Protectoras/farmacología , Especies Reactivas de Oxígeno/metabolismo , Estrés Oxidativo/efectos de los fármacosRESUMEN
Monosodium glutamate (MSG) is commonly used as a flavor-enhancing agent in foods, and studies have demonstrated its toxic effects in animal models. Black garlic is known for its antioxidant and anti-inflammatory properties; however, there is a lack of studies on the potential hepatoprotective effect of black garlic ethanol extract (BGE) against MSG-induced hepatotoxicity in rats. The aim of this study was to investigate the hepatoprotective effects of ethanol extract of black garlic against MSG-induced liver damage in animal model. Twenty-five male Wistar rats were randomly assigned to five groups (n=5): negative control, MSG only, and MSG with three different doses of BGE. The MSG only and MSG with BGE groups were orally administered with 8 mg/kg MSG daily. After MSG treatment, the MSG with BGE groups received BGE orally at daily doses of 200, 400, or 600 mg/kg body weight for 16 consecutive days. Subsequently, the levels of serum liver enzymes aspartate aminotransferase (AST), alanine aminotransferase (ALT), interferon-gamma (IFN-γ), and cyclooxygenase-2 (COX-2) were measured. Our data indicated that the group treated with 200 mg/kg BGE had significant lower levels of AST and ALT significantly compared to the MSG-only group. The MSG-treated group had higher levels of the inflammatory markers COX-2 and IFN-γ, which were lowered by administration of 200 mg/kg BGE. In contrast, higher doses of BGE led to greater levels of COX-2 and IFN-γ compared to those in the MSG-only group. This study suggested that BGE might have hepatoprotective effects at low dose, potentially mitigating MSG-induced liver damage. However, the higher dose of black garlic extract did not alleviate inflammation, as shown by the higher levels of COX-2 and IFN-γ.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Ajo , Extractos Vegetales , Ratas Wistar , Glutamato de Sodio , Animales , Ajo/química , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Ratas , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Masculino , Modelos Animales de Enfermedad , Alanina Transaminasa/sangre , Alanina Transaminasa/metabolismo , Aspartato Aminotransferasas/sangre , Aspartato Aminotransferasas/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Interferón gamma/metabolismo , Ciclooxigenasa 2/metabolismoRESUMEN
Hepatic microvascular disruption caused by injury to liver sinusoidal endothelial cells (LSECs) is an aggravating factor for drug-induced liver injury (DILI). It is suggested that prostaglandin E2 (PGE2) may be able to attenuate LSEC injury. However, it is also known that 15-keto PGE2, a metabolite of PGE2 produced by 15-prostaglandin dehydrogenase (15-PGDH) that is not a ligand of PGE2 receptors, suppresses inflammatory acute liver injury as a ligand of peroxisome proliferator-activated receptor γ. In this study, we aimed to understand whether 15-PGDH activity is essential for preventing DILI by suppressing hepatic microvascular disruption in a mouse model of acetaminophen (APAP)-induced liver injury. To inhibit 15-PGDH activity prior to APAP-induced LSEC injury, we administered the 15-PGDH inhibitor, SW033291, 1 h before and 3 h after APAP treatment. We observed that LSEC injury preceded hepatocellular injury in APAP administered mice. Hepatic endogenous PGE2 levels did not increase up till the initiation of LSEC injury but rather increased after hepatocellular injury. Moreover, hepatic 15-PGDH activity was downregulated in APAP-induced liver injury. The inhibition of 15-PGDH attenuated LSEC injury and subsequently hepatic injury by inhibiting apoptosis in APAP administered mice. Our in vitro studies also suggested that PGE2 inhibited APAP-induced apoptosis via the EP4/PI3K pathway in endothelial cells. Therefore, a decrease in 15-PGDH activity would be beneficial for preventing APAP-induced liver injury by attenuating LSEC injury.
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Acetaminofén , Apoptosis , Enfermedad Hepática Inducida por Sustancias y Drogas , Dinoprostona , Células Endoteliales , Hidroxiprostaglandina Deshidrogenasas , Hígado , Animales , Acetaminofén/efectos adversos , Acetaminofén/toxicidad , Apoptosis/efectos de los fármacos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/metabolismo , Ratones , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hidroxiprostaglandina Deshidrogenasas/metabolismo , Hidroxiprostaglandina Deshidrogenasas/antagonistas & inhibidores , Dinoprostona/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Masculino , Ratones Endogámicos C57BL , Piridinas , TiofenosRESUMEN
OBJECTIVE: To explore the mechanism underlying the protective effect of Lonicerae japonicae flos (LJF) extract against doxorubicin (DOX) -induced liver injury in mice. METHODS: Network pharmacology methods were used to obtain the intersection genes between LJF targets and disease targets, based on which the protein-protein interaction (PPI) network was constructed using STRING database for screening the core targets using Cytoscape software. DAVID database was used for bioinformatics analysis, and the core components and core targets were verified using molecular docking study. In a mouse model of DOX-induced liver injury, the effect of LJF extract on liver pathologies, serum levels of ALT and AST, and hepatic expressions of HYP, ROS, TNF-α, IL-6, COL-â £ and P53 proteins were evaluated using HE and Masson staining, ELISA, and Western blotting. RESULTS: We identified 12 core targets from 43 intersection genes involving cancer pathway, IL-17 signaling pathway, and TNF signaling pathways. Molecular docking study suggested that 10 core components of LJF could bind to different core targets. The mice with DOX-induced liver injury showed elevated serum AST and ALT levels with obvious liver injury and fibrosis, increased ROS content, and enhanced expressions of TNF-α, IL-6, HYP, COL-â £ and P53 proteins in the liver tissue. All these changes in the mouse models were significantly alleviated by treatment with LJF extract, suggesting obviously lowered levels of oxidative stress, inflammation and fibrosis in the liver tissues. CONCLUSION: LJF extract is capable of alleviating DOX-induced liver injury in mice by downregulating Trp53, TNF and IL-6 to reduce liver oxidative stress, inflammation and fibrosis.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Doxorrubicina , Interleucina-6 , Lonicera , Simulación del Acoplamiento Molecular , Factor de Necrosis Tumoral alfa , Animales , Doxorrubicina/efectos adversos , Ratones , Lonicera/química , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Interleucina-6/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo , Extractos Vegetales/farmacología , Hígado/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Proteína p53 Supresora de Tumor/metabolismo , Sustancias Protectoras/farmacología , Mapas de Interacción de Proteínas , Transducción de Señal/efectos de los fármacos , Farmacología en RedRESUMEN
Lindane (LDN) is a well-known herbicidal drug that exerts deleterious impacts on vital body organs including the liver. Catechin (CTN) is a plant-based flavonoid that demonstrates various pharmacological abilities. This trial was executed to evaluate the ameliorative efficacy of CTN to combat LDN instigated hepatotoxicity in male albino rats (Rattus norvegicus). Thirty-two rats were categorized into four groups including control, LDN (30 mg/kg), LDN (30 mg/kg) + CTN (40 mg/kg) and CTN (40 mg/kg) alone treated group. It was observed that LDN dysregulated the expressions of PI3K/PIP3/Akt and Nrf-2/Keap-1 pathway. Moreover, the activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), hemeoxygenase-1 (HO-1) and glutathione reductase (GSR) were subsided after LDN intoxication. Besides, the levels of reactive oxygen species (ROS), malondialdehyde (MDA), ALT (Alanine aminotransferase), AST (Aspartate transaminase), Gamma-glutamyl transferase (GGT) and ALP (Alkaline phosphatase) were increased whereas reduced the levels of albumin and total proteins in response to LDN exposure. Additionally, LDN administration escalated the levels of Interleukin-6 (IL-6), Nuclear factor kappa-B (NF-κB), Interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and the activity of cyclooxygenase-2 (COX-2). Furthermore, the gene expressions of Bcl-2-associated X protein (Bax) and Cysteinyl aspartate-acid proteases-3 (Caspase-3) were enhanced whereas the expression of B-cell lymphoma-2 (Bcl-2) was lowered following the LDN treatment. LDN instigated various histological impairments in hepatic tissues. Nonetheless, concurrent administration of CTN remarkably ameliorated liver impairments via regulating aforementioned disruptions owing to its antioxidant, anti-apoptotic and histo-protective potentials.
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Catequina , Hexaclorociclohexano , Hígado , Factor 2 Relacionado con NF-E2 , FN-kappa B , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Animales , Masculino , Ratas , Hígado/efectos de los fármacos , Hígado/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Catequina/farmacología , Hexaclorociclohexano/toxicidad , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Transducción de Señal/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Herbicidas/toxicidadAsunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Ingredientes Alimentarios , Enfermedades Transmitidas por los Alimentos , Sustitutos de la Carne , United States Food and Drug Administration , Humanos , Ingredientes Alimentarios/análisis , Ingredientes Alimentarios/envenenamiento , Ingredientes Alimentarios/normas , Regulación Gubernamental , Riesgo , Estados Unidos , United States Food and Drug Administration/normas , Sustitutos de la Carne/análisis , Sustitutos de la Carne/envenenamiento , Sustitutos de la Carne/normas , Enfermedades Transmitidas por los Alimentos/etiología , Enfermedades Transmitidas por los Alimentos/prevención & control , Inocuidad de los Alimentos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & controlRESUMEN
The effects of alpha-pinene (AP), a monoterpenoid, known for its antioxidant, anti-inflammatory, and anti-apoptotic properties, on methotrexate (MTX)-induced cardiac and hepatic damage were investigated in this study. Male Sprague-Dawley rats were divided into Control, Vehicle, AP, MTX, and AP+MTX groups (n=7). AP (50 mg/kg/day, 14 days) was applied subcutaneously in the AP and AP+MTX groups. MTX (20 mg/kg) was injected three days before sacrification. Serum CK-MB, troponin T, ALT, and AST levels, as well as cardiac and hepatic MDA, GSH, caspase-3, and p53 levels, were measured by ELISA. Histological changes in tissues were evaluated by scoring in terms of tissue damage and cellular degeneration parameters after hematoxylin-eosin staining. MTX caused significant increase in serum CK-MB, troponin T, ALT, and AST levels, hepatic and cardiac lipid peroxidation, GSH depletion, and caspase-3 level. However, tissue levels of p53 did not change significantly. MTX-induced histological deterioration was observed in both tissues. These MTX-induced changes were significantly reduced in the AP+MTX group. Present results show that MTX-induced cardiac and hepatic damage is prevented by AP pretreatment. This protection can be attributed to the antioxidant and anti-apoptotic properties of AP. Considering the importance of MTX in cancer treatment, AP appears to have highly promising potential as a cardioprotective and hepatoprotective agent in anti-tumoral therapy. Key words: MDA, GSH, Caspase-3, p53, Oxidative stress, Apoptosis.
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Monoterpenos Bicíclicos , Metotrexato , Ratas Sprague-Dawley , Animales , Masculino , Metotrexato/toxicidad , Ratas , Monoterpenos Bicíclicos/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacología , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Miocardio/patología , Miocardio/metabolismo , Monoterpenos/farmacología , Monoterpenos/uso terapéuticoRESUMEN
The liver is a highly metabolically active organ, and one of the causes of its dysfunction is the damage caused by drugs and their metabolites as well as dietary supplements and herbal preparations. A common feature of such damage is drugs, which allows it to be defined as drug-induced liver injury (DILI). In this review, we analysed available research findings in the global literature regarding the effects of green tea and/or its phenolic compounds on liver function in the context of protective action during prolonged exposure to xenobiotics. We focused on the direct detoxifying action of epigallocatechin gallate (EGCG) in the liver, the impact of EGCG on gut microbiota, and the influence of microbiota on liver health. We used 127 scientific research publications published between 2014 and 2024. Improving the effectiveness of DILI detection is essential to enhance the safety of patients at risk of liver damage and to develop methods for assessing the potential hepatotoxicity of a drug during the research phase. Often, drugs cannot be eliminated, but appropriate nutrition can strengthen the body and liver, which may mitigate adverse changes resulting from DILI. Polyphenols are promising owing to their strong antioxidant and anti-inflammatory properties as well as their prebiotic effects. Notably, EGCG is found in green tea. The results of the studies presented by various authors are very promising, although not without uncertainties. Therefore, future research should focus on elucidating the therapeutic and preventive mechanisms of polyphenols in the context of liver health through the functioning of gut microbiota affecting overall health, with particular emphasis on epigenetic pathways.
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Catequina , Enfermedad Hepática Inducida por Sustancias y Drogas , Microbioma Gastrointestinal , Té , Humanos , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Catequina/análogos & derivados , Microbioma Gastrointestinal/efectos de los fármacos , Hígado/efectos de los fármacos , Hígado/metabolismo , Antioxidantes , Polifenoles/farmacología , AnimalesRESUMEN
Anoectochilus roxburghii polysaccharides exhibit notable hepatoprotective effects, but the underlying substance basis and mechanisms remain unknown. In this study, four new polysaccharides named ARP-1a, ARP-1b, ARP-2a and ARP-2b, were isolated from A. roxburghii. Their structural characteristics were systematically analyzed using HPGPC, HPLC, GC-MS, IR and NMR analysis. ARP-1a, the leading polysaccharide isolated from A. roxburghii, was further evaluated for its hepatoprotective effects on acute liver injury mice induced by CCl4. ARP-1a significantly reduced the serum ALT, AST, TNF-α, IL-1ß and IL-6 levels, liver MDA content, and increased the SOD and CAT activities and GSH level in liver. H&E staining revealed that ARP-1a pretreatment could markedly relieve liver injury. Further mechanism exploration indicated that ARP-1a could relieve CCl4-induced oxidative damage through activating the Nrf2 signaling. In addition, metabolomics, lipidomics and 16S rRNA amplicon sequencing were used to elucidate the underlying mechanisms of ARP-1a. Multi-omics analysis indicated that ARP-1a exerted hepatoprotective effect against CCl4-induced acute liver injury by regulating lipid metabolism and modulating the gut microbiota. In conclusion, the above results suggest that ARP-1a can be considered a promising and safe candidate for hepatoprotective drug, as well as a potential prebiotic for maintaining intestinal homeostasis and promoting human intestinal health.
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Tetracloruro de Carbono , Enfermedad Hepática Inducida por Sustancias y Drogas , Microbioma Gastrointestinal , Metabolismo de los Lípidos , Orchidaceae , Polisacáridos , Animales , Polisacáridos/farmacología , Polisacáridos/química , Polisacáridos/aislamiento & purificación , Microbioma Gastrointestinal/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Ratones , Metabolismo de los Lípidos/efectos de los fármacos , Orchidaceae/química , Masculino , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Sustancias Protectoras/farmacología , Sustancias Protectoras/química , Estrés Oxidativo/efectos de los fármacosRESUMEN
We investigated the role and mechanism of ginsenoside RD (GRD) in acute liver injury. Network pharmacology was used to analyze the correlations among GRD-liver injury-pyroptosis targets. A mouse model of acute liver injury was established by lipopolysaccharide + d-galactoseï¼LPS + d/Gal). After pretreatment with GRD, the changes in mouse liver function were detected. The histopathological changes were assayed by hematoxylin and eosin and Masson staining, the tissue expressions of inflammatory cytokines were detected by enzyme-linked immunosorbent assay, and the protein expressions were assayed by immunohistochemical staining and Western blotting. Meanwhile, mechanism research was conducted using STAT3-knockout transgenic mice and STAT3-IN13, a STAT3 inhibitor. GRD inhibited liver injury, mitigated tissue inflammation, and suppressed STAT3-mediated pyroptosis in mice. After applying STAT3-knockout mouse model or STAT3-IN13, GRD did not further inhibit the liver injury. GRD can resist liver injury by inhibiting the STAT3-mediated pyroptosis, which is one of the hepatoprotective mechanisms of GRD.
Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas , Ginsenósidos , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR , Factor de Transcripción STAT3 , Animales , Ginsenósidos/farmacología , Factor de Transcripción STAT3/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Ratones , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Masculino , Ratones Endogámicos C57BL , Hígado/metabolismo , Hígado/patología , Hígado/efectos de los fármacos , Piroptosis/efectos de los fármacosRESUMEN
OBJECTIVE: This study explores the therapeutic effects and mechanisms of DHA-enriched phosphatidylserine (DHA-PS) on liver injury induced by cyclophosphamide (CTX) in mice, focusing on the gut-liver axis. METHODS: A mouse model was established by administering CTX (80 mg/kg) intraperitoneally for 5 days. DHA-PS (50 or 100 mg/kg) was administered for the next 7 days to assess its reparative impact on liver damage. RESULTS: The findings revealed significant improvements in liver biochemical indices, inflammatory markers, and oxidative stress levels in the mice treated with DHA-PS. Through non-targeted metabolomics analysis, DHA-PS mitigated CTX-induced metabolic disruptions by modulating lipid, amino acid, and pyrimidine metabolism. Immunofluorescence analysis further confirmed that DHA-PS reduced the expression of liver-associated inflammatory proteins by inhibiting the TLR4/NF-κB pathway. Additionally, DHA-PS restored the intestinal barrier, evidenced by adjustments in the levels of intestinal lipopolysaccharide (LPS), secretory immunoglobulin A (sIgA), and tight junction proteins (Claudin-1, Occludin, and ZO-1). It also improved gut microbiota balance by enhancing microbial diversity, increasing beneficial bacteria, and altering community structures. CONCLUSION: These results suggest that DHA-PS could be a potential therapeutic agent or functional food for CTX-induced liver injury through its regulation of the gut-liver axis.
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Enfermedad Hepática Inducida por Sustancias y Drogas , Ciclofosfamida , Microbioma Gastrointestinal , Hígado , Fosfatidilserinas , Animales , Ciclofosfamida/efectos adversos , Fosfatidilserinas/metabolismo , Microbioma Gastrointestinal/efectos de los fármacos , Ratones , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Masculino , Ácidos Docosahexaenoicos/farmacología , Ácidos Docosahexaenoicos/uso terapéutico , Receptor Toll-Like 4/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Modelos Animales de EnfermedadRESUMEN
Arsenic (As) is a highly toxic metal and one of the main factors in cancer development through oxidative stress and production of reactive oxygen species. Prior research has demonstrated melatonin's potential as a free radical scavenger. Raf kinase inhibitory protein (RKIP) is an important regulator of intracellular signaling pathways that has been linked to various types of cancer. The aim of this research was to explore the influence of melatonin's antioxidant properties on the expression of the protein RKIP and the antioxidant status of liver tissue in rats that were exposed to arsenic. Thirty two male Wistar rats were divided into four groups of eight, including control, melatonin-treated (20 mg/Kg of melatonin), sodium arsenite-treated (5.5 mg/Kg of sodium arsenite), and melatonin + sodium arsenite-treated groups (combination) for 4 weeks. The expression level of protein RKIP was measured by Western blot, and malondialdehyde (MDA) content of the liver as well as the activities of antioxidant enzymes were measured. The data analyzed using one-way ANOVA (significance level of p < 0.05) and GraphPad Prism (9) software. Sodium arsenite treatment led to a significant decrease in RKIP protein expression and antioxidant enzyme activity, and an increase in liver MDA levels (p < 0.001). Conversely, melatonin treatment in the combination group resulted in a significant increase in RKIP protein expression and antioxidant enzyme activity and a decrease in liver MDA levels (p < 0.05). These findings suggest that melatonin can attenuate oxidative damage caused by arsenic in liver cells by enhancing RKIP protein expression and antioxidant enzyme activity.
Asunto(s)
Antioxidantes , Enfermedad Hepática Inducida por Sustancias y Drogas , Hígado , Melatonina , Proteínas de Unión a Fosfatidiletanolamina , Animales , Masculino , Ratas , Antioxidantes/farmacología , Antioxidantes/metabolismo , Arsénico/toxicidad , Arsenitos/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Hígado/metabolismo , Hígado/efectos de los fármacos , Malondialdehído/metabolismo , Melatonina/farmacología , Estrés Oxidativo/efectos de los fármacos , Proteínas de Unión a Fosfatidiletanolamina/metabolismo , Ratas Wistar , Compuestos de Sodio/toxicidadRESUMEN
Fenamiphos (FNP) is an organophospate pesticide that causes many potential toxicities in non-target organisms. Naringenin (NAR) has protective properties against oxidative stress. In this study, FNP (0.76 mg/kg bw) toxicity and the effect of NAR (50 mg/kg bw) on the liver and kidney of rats were investigated via biochemical, oxidative stress, immunohistochemical, cytopathological and histopathologically. As a result of biochemical studies, FNP caused oxidative stress in tissues with a change in total antioxidant/oxidant status. After treatment with FNP, hepatic and renal levels of AChE were significantly reduced while 8-OHdG and IL-17 levels, caspase-3 and TNF-α immunoreactivity increased compared to the control group. It also changed in serum biochemical markers such as ALT, AST, BUN, creatinine. Exposure to FNP significantly induced cytopathological, histopathological and immunohistochemical changes through tissue damage. NAR treatment restored biochemical parameters, renal/hepatic AChE, ultrastructural, histopathological and immunohistochemical changes modulated and blocked the increasing effect of FNP on tissues caspase-3 and TNF-α expressions, 8-OHdG and IL-17 levels. In electron microscopy studies, swelling was observed in the mitochondria of the cells in both tissues of the FNP-treated rats, while less ultrastructural changes in the FNP plus NAR-treated rats.
Asunto(s)
Biomarcadores , Caspasa 3 , Flavanonas , Riñón , Hígado , Compuestos Organofosforados , Estrés Oxidativo , Animales , Flavanonas/farmacología , Estrés Oxidativo/efectos de los fármacos , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/ultraestructura , Riñón/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/ultraestructura , Hígado/patología , Ratas , Masculino , Caspasa 3/metabolismo , Compuestos Organofosforados/toxicidad , Biomarcadores/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Ratas Wistar , Factor de Necrosis Tumoral alfa/metabolismo , Acetilcolinesterasa/metabolismo , Interleucina-17/metabolismo , Inmunohistoquímica , 8-Hidroxi-2'-Desoxicoguanosina/metabolismoRESUMEN
Arsenic is a metalloid found in the environment that causes toxic effects in different organs, mainly the liver. This study aimed to investigate the protective effects of epicatechin (EC), a natural flavonol, on glucose intolerance (GI) and liver toxicity caused by sodium arsenite (SA) in mice. Our findings showed that SA exposure led to the development of GI. Liver tissue damage and decreased pancreatic Langerhans islet size were also observed in this study. Mice exposed to SA exhibited hepatic oxidative damage, indicated by reduced antioxidant markers (such as superoxide dismutase, catalase, glutathione peroxidase, and glutathione), along with elevated levels of thiobarbituric acid reactive substances. SA administration elevated the serum activities of liver enzymes alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. Furthermore, notable increases in the levels of inflammatory and apoptotic markers (Toll-like receptor 4, nuclear factor-kappa B, tumor necrosis factor-α, nitric oxide, B-cell lymphoma-2, and cysteine aspartate-specific protease-3) were observed in the liver. Treatment of SA-exposed mice with EC considerably reversed these biochemical and histological changes. This study demonstrated the beneficial effects of EC in ameliorating SA-induced hyperglycemia and hepatotoxicity due to its ability to enhance the antioxidant system by modulating inflammation and apoptosis.
Asunto(s)
Arsenitos , Catequina , Enfermedad Hepática Inducida por Sustancias y Drogas , Intolerancia a la Glucosa , Hígado , Compuestos de Sodio , Animales , Arsenitos/toxicidad , Compuestos de Sodio/toxicidad , Ratones , Intolerancia a la Glucosa/inducido químicamente , Intolerancia a la Glucosa/tratamiento farmacológico , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Masculino , Catequina/farmacología , Estrés Oxidativo/efectos de los fármacos , Antioxidantes/farmacología , Aspartato Aminotransferasas/sangre , Aspartato Aminotransferasas/metabolismo , Alanina Transaminasa/sangre , Alanina Transaminasa/metabolismo , Apoptosis/efectos de los fármacosRESUMEN
Numerous factors, including exposure to harmful substances, drinking too much alcohol, contracting certain hepatitis serotypes, and using specific medicines, contribute to the development of liver illnesses. Lipid peroxidation and other forms of oxidative stress are the main mechanisms by which hepatotoxic substances harm liver cells. Pathological changes in the liver include a rise in the levels of blood serum, a decrease in antioxidant enzymes, as well as the formation of free radical radicals. It is necessary to find pharmaceutical alternatives to treat liver diseases to increase their efficacy and decrease their toxicity. For the development of new therapeutic medications, a greater knowledge of primary mechanisms is required. In order to mimic human liver diseases, animal models are developed. Animal models have been used for several decades to study the pathogenesis of liver disorders and related toxicities. For many years, animal models have been utilized to investigate the pathophysiology of liver illness and associated toxicity. The animal models are created to imitate human hepatic disorders. This review enlisted numerous hepatic damage in vitro and in vivo models using various toxicants, their probable biochemical pathways and numerous metabolic pathways via oxidative stressors, different serum biomarkers enzymes are discussed, which will help to identify the most accurate and suitable model to test any plant preparations to check and evaluate their hepatoprotective properties.
Asunto(s)
Modelos Animales de Enfermedad , Estrés Oxidativo , Animales , Humanos , Estrés Oxidativo/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Sustancias Protectoras/farmacología , Sustancias Protectoras/uso terapéutico , Hepatopatías/tratamiento farmacológico , Hepatopatías/metabolismo , Hepatopatías/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patologíaRESUMEN
Doxorubicin (DOX), which is frequently used in cancer treatment, has limited clinical use due to adverse effects on healthy tissues, especially the liver. Therefore, it is necessary to research the molecular basis of DOX-induced organ and tissue damage and protective agents. In this study, we aimed to examine the protective effects of tannic acid (TA) against DOX-induced hepatoxicity in experimental rat models. Rats were randomly divided into four experimental groups: the untreated control, DOX, TA, and cotreatment (DOX + TA) groups. We investigated the antioxidant system's main components and oxidative stress indicators. Moreover, we examined alterations in the mRNA expression of critical regulators that modulate apoptosis, inflammation, and cell metabolism to better understand the underlying factors of DOX-induced liver toxicity. The results showed that DOX exposure caused an increase in MDA levels and a significant depletion of GSH content in rat liver tissues. Consistent with oxidative stress-related metabolites, DOX was found to significantly suppress both mRNA expression and enzyme activities of antioxidant system components. Moreover, DOX exposure had significant adverse effects on regulating the other regulatory genes studied. However, it was determined that TA could alleviate many of the negative changes caused by DOX. The results of the present study indicated that TA might be considered a versatile candidate that could prevent DOX-induced hepatotoxicity, possibly by preserving cell physiology, viability, and especially redox balance.
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Antiinflamatorios , Antioxidantes , Apoptosis , Enfermedad Hepática Inducida por Sustancias y Drogas , Doxorrubicina , Hígado , Polifenoles , Animales , Masculino , Ratas , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Doxorrubicina/efectos adversos , Doxorrubicina/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Estrés Oxidativo/efectos de los fármacos , Polifenoles/farmacología , Ratas Sprague-DawleyRESUMEN
This study reports a novel, eco-friendly; fast and cost-effective microwave method for synthesizing carboxymethylated graphene oxide (CMGO) from sugarcane residues. Fourier-transform infrared spectroscopy (FTIR) confirmed successful CMGO synthesis through the presence of characteristic peaks at 1567.93 and 1639.29 cm-1 (COONa vibrations) and increased CH2 intensity compared to unmodified graphene oxide (GO). Furthermore, CMGO derived from sugarcane residues demonstrated potential in mitigating the side effects of toxic materials like carbon tetrachloride (CCl4). Treatment with CMGO partially reduced elevated levels of liver enzymes (ALT and AST) and nitrogenous waste products (urea and uric acid) in CCl4-induced liver damage models, suggesting an improvement in liver function despite ongoing cellular damage.This work paves the way for a sustainable and economical approach to produce functionalized graphene oxide with promising biomedical applications in alleviating toxin-induced liver injury.
Asunto(s)
Tetracloruro de Carbono , Enfermedad Hepática Inducida por Sustancias y Drogas , Grafito , Hígado , Microondas , Grafito/química , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Tetracloruro de Carbono/toxicidad , Masculino , Sustancias Protectoras/farmacología , Sustancias Protectoras/química , Sustancias Protectoras/uso terapéutico , Ácido Úrico , Alanina Transaminasa/sangre , Aspartato Aminotransferasas/sangre , Urea/análogos & derivados , Urea/farmacología , RatonesRESUMEN
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
ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia stechmanniana Besser, one of the most prevalent botanical medicines in Chinese, has been traditionally used for hepatitis treatment. However, the bioactive components and pharmacological mechanism on alcohol-induced liver injury remains unclear. AIM OF THE STUDY: To investigate the effect of A. stechmanniana on alcohol-induced liver damage, and further explore its mechanism. MATERIALS AND METHODS: Phytochemical isolation and structural identification were used to determine the chemical constituents of A. stechmanniana. Then, the alcohol-induced liver damage animal and cell model were established to evaluate its hepato-protective potential. Network pharmacology, molecular docking and bioinformatics were integrated to explore the mechanism and then the prediction was further supported by experiments. Moreover, both compounds were subjected to ADMET prediction through relevant databases. RESULTS: 28 compounds were isolated from the most bioactive fraction, ethyl acetate extract A. stechmanniana, in which five compounds (abietic acid, oplopanone, oplodiol, hydroxydavanone, linoleic acid) could attenuate mice livers damage caused by alcohol intragastration, reduce the degree of oxidative stress, and serum AST and ALT, respectively. Furthermore, abietic acid and hydroxydavanone exhibited best protective effect against alcohol-stimulated L-O2 cells injury among five bioactive compounds. Network pharmacology and bioinformatics analysis suggested that abietic acid and hydroxydavanone exhibiting drug likeliness characteristics, were the principal active compounds acting on liver injury treatment, primarily impacting to cell proliferation, oxidative stress and inflammation-related PI3K-AKT signaling pathways. Both of them displayed strong binding energies with five target proteins (HRAS, HSP90AA1, AKT1, CDK2, NF-κB p65) via molecular docking. Western blotting results further supported the predication with up-regulation of protein expressions of CDK2, and down-regulation of HRAS, HSP90AA1, AKT1, NF-κB p65 by abietic acid and hydroxydavanone. CONCLUSION: Alcohol-induced liver injury protection by A. stechmanniana was verified in vivo and in vitro expanded its traditional use, and its two major bioactive compounds, abietic acid and hydroxydavanone exerted hepatoprotective effect through the regulation of PI3K-AKT signaling pathway.