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1.
Int J Mol Sci ; 22(6)2021 Mar 23.
Artículo en Inglés | MEDLINE | ID: mdl-33807047

RESUMEN

Acetaminophen (APAP) is one of the most commonly used analgesic and anti-pyretic drugs, and APAP intoxication is one of the main reasons for liver transplantation following liver failure in the Western world. While APAP poisoning ultimately leads to liver necrosis, various programmed cell death modalities have been implicated, including ER stress-triggered apoptosis. The BCL-2 family member BOK (BCL-2-related ovarian killer) has been described to modulate the unfolded protein response and to promote chemical-induced liver injury. We therefore investigated the impact of the loss of BOK following APAP overdosing in mice. Surprisingly, we observed sex-dependent differences in the activation of the unfolded protein response (UPR) in both wildtype (WT) and Bok-/- mice, with increased activation of JNK in females compared with males. Loss of BOK led to a decrease in JNK activation and a reduced percentage of centrilobular necrosis in both sexes after APAP treatment; however, this protection was more pronounced in Bok-/- females. Nevertheless, serum ALT and AST levels of Bok-/- and WT mice were comparable, indicating that there was no major difference in the overall outcome of liver injury. We conclude that after APAP overdosing, loss of BOK affects initiating signaling steps linked to ER stress, but has a more minor impact on the outcome of liver necrosis. Furthermore, we observed sex-dependent differences that might be worthwhile to investigate.


Asunto(s)
Acetaminofén/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Sobredosis de Droga/complicaciones , Predisposición Genética a la Enfermedad , Proteínas Proto-Oncogénicas c-bcl-2/deficiencia , Acetaminofén/administración & dosificación , Animales , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocromo P-450 CYP2E1/genética , Citocromo P-450 CYP2E1/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Estrés del Retículo Endoplásmico/genética , Femenino , Regulación de la Expresión Génica , Genes p53 , Masculino , Ratones , Ratones Noqueados , Índice de Severidad de la Enfermedad , Factores Sexuales , Respuesta de Proteína Desplegada/efectos de los fármacos
2.
Int J Mol Sci ; 22(5)2021 Mar 08.
Artículo en Inglés | MEDLINE | ID: mdl-33800244

RESUMEN

Hypoxia-induced mitogenic factor (HIMF), which is also known as resistin-like molecule α (RELM-α), found in inflammatory zone 1 (FIZZ1), or resistin-like alpha (retlna), is a cysteine-rich secretory protein and cytokine. HIMF has been investigated in the lung as a mediator of pulmonary fibrosis, inflammation and as a marker for alternatively activated macrophages. Although these macrophages have been found to have a role in acute liver injury and acetaminophen toxicity, few studies have investigated the role of HIMF in acute or immune-mediated liver injury. The aim of this focused review is to analyze the literature and examine the effects of HIMF and its human homolog in organ-specific inflammation in the lung and liver. We followed the guidelines set by PRISMA in constructing this review. The relevant checklist items from PRISMA were included. Items related to meta-analysis were excluded because there were no randomized controlled clinical trials. We found that HIMF was increased in most models of acute liver injury and reduced damage from acetaminophen-induced liver injury. We also found strong evidence for HIMF as a marker for alternatively activated macrophages. Our overall risk of bias assessment of all studies included revealed that 80% of manuscripts demonstrated some concerns in the randomization process. We also demonstrated some concerns (54.1%) and high risk (45.9%) of bias in the selection of the reported results. The need for randomization and reduction of bias in the reported results was similarly detected in the studies that focused on HIMF and the liver. In conclusion, we propose that HIMF could be utilized as a marker for M2 macrophages in immune-mediated liver injury. However, we also detected the need for randomized clinical trials and additional experimental and human prospective studies in order to fully comprehend the role of HIMF in acute or immune-mediated liver injury.


Asunto(s)
Lesión Renal Aguda/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Péptidos y Proteínas de Señalización Intercelular/inmunología , Hígado/inmunología , Pulmón/inmunología , Macrófagos/inmunología , Acetaminofén/efectos adversos , Lesión Renal Aguda/patología , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Pulmón/patología , Macrófagos/patología , Especificidad de Órganos/inmunología
3.
Int J Mol Sci ; 22(6)2021 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-33799477

RESUMEN

Idiosyncratic drug-induced liver injury (IDILI) remains a significant problem for patients and drug development. The idiosyncratic nature of IDILI makes mechanistic studies difficult, and little is known of its pathogenesis for certain. Circumstantial evidence suggests that most, but not all, IDILI is caused by reactive metabolites of drugs that are bioactivated by cytochromes P450 and other enzymes in the liver. Additionally, there is overwhelming evidence that most IDILI is mediated by the adaptive immune system; one example being the association of IDILI caused by specific drugs with specific human leukocyte antigen (HLA) haplotypes, and this may in part explain the idiosyncratic nature of these reactions. The T cell receptor repertoire likely also contributes to the idiosyncratic nature. Although most of the liver injury is likely mediated by the adaptive immune system, specifically cytotoxic CD8+ T cells, adaptive immune activation first requires an innate immune response to activate antigen presenting cells and produce cytokines required for T cell proliferation. This innate response is likely caused by either a reactive metabolite or some form of cell stress that is clinically silent but not idiosyncratic. If this is true it would make it possible to study the early steps in the immune response that in some patients can lead to IDILI. Other hypotheses have been proposed, such as mitochondrial injury, inhibition of the bile salt export pump, unfolded protein response, and oxidative stress although, in most cases, it is likely that they are also involved in the initiation of an immune response rather than representing a completely separate mechanism. Using the clinical manifestations of liver injury from a number of examples of IDILI-associated drugs, this review aims to summarize and illustrate these mechanistic hypotheses.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Inmunidad Innata/inmunología , Hígado/inmunología , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocinas/genética , Humanos , Inmunidad Innata/genética , Hígado/efectos de los fármacos , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología
4.
Life Sci ; 274: 119331, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33716060

RESUMEN

AIMS: Cyclophosphamide (CP) is a common therapeutic drug for cancer, but exposure to CP can cause acute hepatotoxicity. This study aimed to elucidate the protective effects of Ligustrazine (2, 3, 5, 6-tetramethylpyrazine, TMP) on hepatotoxicity induced by CP or its active metabolite 4-hydroperoxycyclophosphamide (4-HC). MAIN METHODS: We presented a comprehensive investigation about the hepatoprotection of TMP on CP-induced mice and 4-HC-treated HSC-LX2 cells. Liver function was detected via enzyme-linked immunosorbent assay (ELISA). Hepatic histopathology analysis was performed via hematoxylin and eosin (H&E) and Masson staining. Survival of hepatocytes was detected by TUNEL assay. Related proteins in the thioredoxin (Trx)-interacting protein (Txnip)/Trx/Nuclear factor-kappa B (NF-κB) pathway were measured by western blotting. KEY FINDINGS: The results indicated that CP or 4-HC could increase the levels of alanine aminotransferase and aspartate aminotransferase, enhance inflammatory factors and oxidative indicators, and suppress the activity of oxidoreductases. Moreover, significant changes in liver histological structure, fibrosis, and cell death were observed through the activation of Txnip/Trx/NF-κB pathway. In contrast, administration of TMP significantly reversed these above changes. Furthermore, TMP intervention participated in the inhibition of NLRP3 inflammasome accompanied with pyroptosis, as well as upregulating Trx expression and downregulating p-NF-κB, while the protective effect of TMP was limited to the involvement of Txnip overexpression. SIGNIFICANCE: TMP treatment could significantly alleviate the hepatotoxicity process as evidenced by improving the structure and function of the liver, inhibiting oxidative stress and inflammation accompanied with pyroptosis, which was positively correlated with the inhibition of Txnip/Trx/NF-κB pathway.


Asunto(s)
Proteínas Portadoras/antagonistas & inhibidores , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Ciclofosfamida/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , FN-kappa B/antagonistas & inhibidores , Pirazinas/farmacología , Tiorredoxinas/antagonistas & inhibidores , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Inflamasomas/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos ICR , Mutágenos/toxicidad , Vasodilatadores/farmacología
5.
Toxicol Lett ; 343: 1-10, 2021 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-33571620

RESUMEN

AIMS: Both gefitinib and afatinib are epidermal growth factor tyrosine kinase inhibitors (EGFR-TKI) in the treatment of non-small cell lung cancer (NSCLC). It has been reported that gefitinib and afatinib could cause hepatotoxicity during the clinic treatment, therefore it is critical to investigate their hepatotoxicity systematically. In this study, zebrafish (Danio rerio) were used as model animals to compare the hepatotoxicity and their toxic mechanism. MAIN METHODS: The zebrafish transgenic line [Tg (fabp10a: dsRed; ela3l:EGFP) was used in this study. After larvae developed at 3 days post fertilization (dpf), they were put into different concentrations of gefitinib and afatinib. At 6 dpf, the viability, liver area, fluorescence intensity, histopathology, apoptosis, transaminase reflecting liver function, the absorption of yolk sac, and the expression of relative genes were observed and analyzed respectively. KEY FINDINGS: Both gefitinib and afatinib could induce the larvae hepatotoxicity dose-dependently. Based on the liver morphology, histopathology, apoptosis and function assessments, gefitinib showed higher toxicity, causing more serious liver damage. Both gefitinib and afatinib caused abnormal expressions of genes related to endoplasmic reticulum stress (ERS) pathway and apoptosis. For example, jnk, perk, bip, chop, ire1, bid, caspase3 and caspase9 were up-regulated, while xbp1s, grp78, bcl-2/bax, and caspase8 were down-regulated. The hepatotoxicity difference of gefitinib and afatinib might be due to the different expression level of related genes.


Asunto(s)
Afatinib/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Embrión no Mamífero/efectos de los fármacos , Gefitinib/toxicidad , Hígado/efectos de los fármacos , Inhibidores de Proteínas Quinasas/toxicidad , Animales , Animales Modificados Genéticamente , Regulación de la Expresión Génica/efectos de los fármacos , Hígado/patología , Pez Cebra/embriología
6.
Science ; 371(6532)2021 02 26.
Artículo en Inglés | MEDLINE | ID: mdl-33632818

RESUMEN

Organ homeostasis is orchestrated by time- and spatially restricted cell proliferation. Studies identifying cells with superior proliferative capacities often rely on the lineage tracing of a subset of cell populations, which introduces a potential selective bias. In this work, we developed a genetic system [proliferation tracer (ProTracer)] by incorporating dual recombinases to seamlessly record the proliferation events of entire cell populations over time in multiple organs. In the mouse liver, ProTracer revealed more hepatocyte proliferation in distinct zones during liver homeostasis, injury repair, and regrowth. Clonal analysis showed that most of the hepatocytes labeled by ProTracer had undergone cell division. By genetically recording proliferation events of entire cell populations, ProTracer enables the unbiased detection of specific cellular compartments with enhanced regenerative capacities.


Asunto(s)
Proliferación Celular , Hepatocitos/fisiología , Regeneración Hepática , Hígado/fisiología , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Ciclina A2/genética , Hepatectomía , Homeostasis , Antígeno Ki-67/análisis , Antígeno Ki-67/genética , Hígado/citología , Ratones
7.
Medicine (Baltimore) ; 100(6): e24723, 2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33578617

RESUMEN

ABSTRACT: This study objected to evaluate the accuracy of the gamma-glutamyl transpeptidase-to-platelet ratio (GPR), aspartate aminotransferase-to-platelet ratio index (APRI), red cell distribution width (RDW), and fibrosis-4 index (FIB4) index, compared with liver biopsy (LB), in predicting the severity of inflammation in drug-induced liver injury (DILI) patients.We evaluated patients with DILI who were followed at the First Hospital of Jilin University and underwent LB. Accuracy of each method was analyzed using ROC analysis. Classifications of liver inflammation included G0-4.One hundred fifty six DILI patients were included with LB and complete medical records. 62.8% (98), 39.1% (61), and 16.7% (26) were classified as ≥G2, ≥G3, or G4, respectively. The AUROCs, by degree of inflammation, were: ≥G2: GPR: 0.654, RDW: 0.635, APRI: 0.728, and FIB4: 0.739; ≥G3: GPR: 0.623, RDW: 0.703, APRI: 0.777, and FIB4: 0.781; and G4: GPR: 0.556, RDW: 0.647, APRI: 0.729, and FIB4: 0.714. To predict ≥G2 inflammation, there were no differences between the AUROCs for GPR, RDW, APRI, and FIB4. To predict ≥G3 inflammation, the AUROCs for FIB4 and APRI were higher than that for GPR (0.781 vs 0.623, P < .01; 0.777 vs 0.623, P < .05). As for G4 inflammation, the AUROCs for FIB4 and APRI were also higher than GPR (0.714 vs 0.556, P < .05, 0.729 vs 0.556, P < .05).When the level of inflammation was higher than G2 in patients with DILI, it could be predicted using APRI and FIB4 as non-invasive markers for this condition.


Asunto(s)
Aspartato Aminotransferasas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Índices de Eritrocitos , Índice de Severidad de la Enfermedad , gamma-Glutamiltransferasa/sangre , Adulto , Biomarcadores/sangre , Biopsia , Enfermedad Hepática Inducida por Sustancias y Drogas/complicaciones , Enfermedad Hepática Inducida por Sustancias y Drogas/enzimología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Femenino , Hepatitis/etiología , Humanos , Hígado/patología , Masculino , Persona de Mediana Edad , Recuento de Plaquetas
8.
Ecotoxicol Environ Saf ; 208: 111610, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-33396130

RESUMEN

Hepatic oxidative stress, as one important mechanism of cadmium (Cd)-induced hepatic toxicity, could, as known, be ameliorated by vitamin E (VE). However, the underlying mechanism remains to be elucidated. To investigate whether the antioxidant vitamin E can protect against Cd-induced sub-chronic liver injury associated with oxidative stress and nuclear factor erythrocyte 2-related factor 2 (Nrf2) pathway, male Sprague-Dawley rats (nine-week-old) were randomly divided into four groups (eight rats/group), namely, control, VE (100 mg/kg VE), Cd (5 mg/kg CdCl2) and VE+Cd (100 mg/kg VE+5 mg/kg CdCl2), and received intragastric administration of Cd and/or VE for four weeks. Cd-exposure alone resulted in reduced liver weight, liver histological alteration and oxidative stress, accumulation of Cd in the liver, elevated ALT and AST concentrations in serum together with decreased mRNA and protein expressions of Nrf2 pathway related molecules (Nrf2, HO-1, NQO-1, GCLC, GCLM and GST). However, the co-treatment of Cd and VE significantly ameliorated the changes mentioned above, and promoted the expression of genes and proteins of Nrf2 pathway related molecules in comparison to the Cd-exposure alone. Our results indicate that the protective effect of VE against Cd-induced sub-chronic hepatic damage in rats is associated with the inhibition of oxidative stress and activation of Nrf2 pathway.


Asunto(s)
Antioxidantes/farmacología , Cadmio/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Contaminantes Ambientales/toxicidad , Factor 2 Relacionado con NF-E2/metabolismo , Estrés Oxidativo/efectos de los fármacos , Vitamina E/farmacología , Animales , Antioxidantes/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Pruebas de Función Hepática , Masculino , Tamaño de los Órganos/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Transducción de Señal
9.
J Ethnopharmacol ; 264: 113277, 2021 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-32810616

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Evodiae Fructus (EF), the traditional Chinese medicine, has been typically used to treat headache, abdominal pain, hernias, and menorrhagia for thousands of years. It is a mild toxicity herb-medicine listed in Sheng Nong's Herbal Classic. Recently, EF was reported to have toxicity or no toxicity in some investigations. Toxicity and approaches to reducing toxicity of EF are of great interest. Limonin (LIM), a major triterpenoid component of EF, also had various pharmacological activities such as anti-inflammatory, anticancer, and antioxidant effects. However, little attention was paid to the role of LIM in EF-induced hepatotoxicity. AIM OF STUDY: The study aimed to address the problem of controversial hepatotoxicity of EF, evaluate the role of CYP3A4 inducer/inhibitor in EF-induced hepatotoxicity and disclose the effect of LIM in EF-induced hepatotoxicity. MATERIALS AND METHODS: The chemical compositions and hepatotoxicity of small flower EF (SEF), medium flower EF (MEF), big flower EF (BEF) and the "organ knock-out" samples (the shell and seed part of BEF) were investigated. Simultaneously, C57BL-6 mice were randomly divided into four groups, which were given orally administered BEF, BEF in combination with dexamethasone (DEX), BEF in combination with ketoconazole (KTC), and BEF in combination with LIM, respectively. RESULTS: In this study, more alkaloids and less LIM were detected in BEF compared with the compounds in SEF and MEF. Furthermore, we found that BEF group induced hepatotoxicity whereas no hepatotoxicity was observed in SEF and MEF groups. In addition, no LIM was detected in the shell part of BEF and five alkaloids were not detected in the seed part of BEF. Correspondingly, the shell part of BEF group induced hepatotoxicity whereas no hepatotoxicity was observed in the seed part of BEF group. It was also found that the BEF-induced hepatotoxicity was remarkably exacerbated when the mice were pretreated with DEX whereas the BEF-induced hepatotoxicity could be reversed by pretreatment with KTC or LIM. CONCLUSIONS: Based on the results in this study, the misuse of BEF but not SEF and MEF could produce hepatotoxicity. The hepatotoxicity difference of different categories of EF might be associated with the relative contents of alkaloids and LIM. In addition, the results demonstrated that CYP3A4 inducer aggravated BEF-induced hepatotoxicity and LIM attenuated its hepatotoxicity.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Inductores del Citocromo P-450 CYP3A/toxicidad , Evodia , Flores , Frutas , Limoninas/uso terapéutico , Extractos Vegetales/toxicidad , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Inductores del Citocromo P-450 CYP3A/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Masculino , Ratones , Ratones Endogámicos C57BL , Extractos Vegetales/aislamiento & purificación , Distribución Aleatoria
10.
Biomed Pharmacother ; 134: 111159, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33370627

RESUMEN

The purpose of this study is to use Dicliptera chinensis (L.) Juss (Acanthaceae) polysaccharide (DCP) to act on the NF-κB inflammatory pathway and Fas/FasL ligand system, in order to find a new method to improve immune liver injury. Lipopolysaccharide (LPS) was used to establish an injury model in vivo (Kunming mice) and in vitro (LO2 cells). In this experiment, hematoxylin-eosin (H&E) staining and related biochemical indicators were used to observe the pathological changes of liver tissues, oxidative stress and inflammatory reactions. Immunohistochemistry, ELISA, RT-PCR and Western blot were used to detect protein or mRNA expressions associated with inflammation response and apoptosis. The experimental results show that the model group has obvious liver cell damage and inflammatory infiltration. After DCP intervention, it could significantly reduce the levels of ALT, AST, ALP, TBIL and MDA in serum, and increase the content of SOD and GSH-Px. In addition, DCP can reduce the expression level of NF-κB in the liver and reduce the release of downstream inflammatory factors TNF-α, IL-6 and IL-1ß, thereby reducing the inflammation. At the same time, DCP can significantly inhibit the expression of Fas/FasL ligand system and apoptosis related-proteins and mRNA, which in turn can reduce cell apoptosis. In conclusion, DCP can alleviate liver injury by inhibiting liver inflammation and apoptosis, which provides a new strategy for clinical treatment of immune liver injury.


Asunto(s)
Acanthaceae , Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Mediadores de Inflamación/metabolismo , Hígado/efectos de los fármacos , Extractos Vegetales/farmacología , Polisacáridos/farmacología , Acanthaceae/química , Animales , Antiinflamatorios/aislamiento & purificación , Línea Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/inmunología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocinas/genética , Citocinas/metabolismo , Modelos Animales de Enfermedad , Proteína Ligando Fas/genética , Proteína Ligando Fas/metabolismo , Lipopolisacáridos , Hígado/inmunología , Hígado/metabolismo , Hígado/patología , Masculino , Ratones , FN-kappa B/genética , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Extractos Vegetales/aislamiento & purificación , Polisacáridos/aislamiento & purificación , Transducción de Señal , Receptor fas/genética , Receptor fas/metabolismo
11.
Phytomedicine ; 81: 153411, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33310307

RESUMEN

BACKGROUND: Nodakenin, a coumarin glucoside isolated from the roots of Angelica biserrata, has been reported to have anti-inflammatory, antibacterial, anticancer effects. However, despite these studies, the potential liver protective effects of nodakenin in inflammatory liver injury models have not been reported. METHODS: A mouse model of inflammatory liver injury was induced by injection of lipopolysaccharide (LPS) (15 mg/kg, intraperitoneally (i.p)). Liver tissue AST, ALT, ROS, T-GSH and T-SOD were analyzed by ELISA. The concentrations of TNF-α, IL-6, and IL-1ß in serum of LPS-induced inflammatory liver injury mice were analyzed. The mRNA expression levels of GPx1, catalase, SOD1, SOD2, TNF-α, IL-6, IL-1ß, iNOS and COX-2 were analyzed using real-time PCR. The expressions of MAPK, IRF3, NF-κB, Nrf2, HO-1, caspase-3 and caspase-7 were analyzed using western blotting. Liver tissue was stained with IHC to confirm NF-κB, Nrf-2, HO-1, caspase-3, Bax, and Bcl2. Tunnel analysis was performed to confirm the fragmented nuclear DNA characteristics of apoptosis. RESULTS: The administration of nodakenin (10 and 30 mg/kg) reduced serum aminotransferase levels compared to LPS-induced liver damage and significantly improved the oxidative state of liver tissue and pathological damage. Moreover, inhibited the phosphorylation of transforming growth factor beta (TGF-ß)-activated kinase (TAK)-1 in LPS-induced inflammatory liver injury model, and significantly inhibited the transcriptional of nuclear factor-kappa B (NF-kB) and the secretion of pro-inflammatory mediators. In addition nodakenin pre-treatment also attenuated hepatocyte death by regulating apoptosis-related mitochondrial proteins, such as cysteinyl aspartate specific proteinase 3 (caspase 3), poly (ADP-ribose) polymerase (PARP), B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X (Bax). CONCLUSION: Our findings suggest that nodakenin has anti-inflammatory, anti-oxidant and anti-apoptotic activity and may be an adjunctive prevention agent for liver injury.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Cumarinas/farmacología , Glucósidos/farmacología , Hepatitis Animal/tratamiento farmacológico , Lipopolisacáridos/toxicidad , Animales , Antiinflamatorios no Esteroideos/farmacología , Antioxidantes/metabolismo , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Citocinas/sangre , Citocinas/genética , Enzimas/metabolismo , Hepatitis Animal/metabolismo , Hepatitis Animal/patología , Masculino , Ratones Endogámicos ICR , Factor 2 Relacionado con NF-E2/metabolismo , FN-kappa B/metabolismo , Estrés Oxidativo/efectos de los fármacos , Sustancias Protectoras/farmacología
12.
Sci Rep ; 10(1): 22265, 2020 12 17.
Artículo en Inglés | MEDLINE | ID: mdl-33335297

RESUMEN

Arachidonic acid (AA) signaling pathway is an important constituent of inflammatory processes. In our previous study, it was found that dihydro-stilbene gigantol relieved hepatic inflammation in mice with CCl4-induced acute liver injury. This study aimed to investigate the involvement of arachidonate metabolic cascade in this process. Our results showed CCl4 activated AA metabolism with the evidence of cPLA2 phosphorylation, which was dependent on the MAPK/JNK activation. Pretreatment with JNK inhibitor SU3327 or gigantol abolished the cPLA2 activation, along with the attenuation of liver damage. Besides, gigantol markedly decreased immune cells activation. Metabolomic analysis revealed that gigantol universally reversed the upregulation of major AA metabolites in injured mouse livers induced by CCl4, especially 12-hydroxyeicosatetraenoic acid (12-HETE). Gigantol also decreased the mRNA and protein expression of platelet-, and leukocyte-type 12-lipoxxygenase (LOX) in the liver. Furthermore, pan-LOX inhibitor nordihydroguaiaretic acid (NDGA) and specific 12-LOX inhibitors baicalein and ML351 attenuated the liver injury to the same extent as gigantol. Overall, our study elucidated a comprehensive profile of AA metabolites during hepatic inflammation caused by CCl4, highlighting the role of 12-LOX-12-HETE pathway in this process. And gigantol alleviated liver inflammation partly through inhibiting the JNK/cPLA2/12-LOX pathway.


Asunto(s)
Araquidonato 12-Lipooxigenasa/genética , Bibencilos/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Fosfolipasas A2 Grupo IV/genética , Guayacol/análogos & derivados , Animales , Ácido Araquidónico/metabolismo , Tetracloruro de Carbono/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Guayacol/farmacología , Humanos , Inflamación/inducido químicamente , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/patología , Hígado/efectos de los fármacos , Hígado/patología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Metabolómica , Ratones
13.
PLoS One ; 15(12): e0243451, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33347443

RESUMEN

Drug induced liver injury (DILI) and cell death can result from oxidative stress in hepatocytes. An initial pattern of centrilobular damage in the APAP model of DILI is amplified by communication from stressed cells and immune system activation. While hepatocyte proliferation counters cell loss, high doses are still lethal to the tissue. To understand the progression of disease from the initial damage to tissue recovery or death, we computationally model the competing biological processes of hepatocyte proliferation, necrosis and injury propagation. We parametrize timescales of proliferation (α), conversion of healthy to stressed cells (ß) and further sensitization of stressed cells towards necrotic pathways (γ) and model them on a Cellular Automaton (CA) based grid of lattice sites. 1D simulations show that a small α/ß (fast proliferation), combined with a large γ/ß (slow death) have the lowest probabilities of tissue survival. At large α/ß, tissue fate can be described by a critical γ/ß* ratio alone; this value is dependent on the initial amount of damage and proportional to the tissue size N. Additionally, the 1D model predicts a minimum healthy population size below which damage is irreversible. Finally, we compare 1D and 2D phase spaces and discuss outcomes of bistability where either survival or death is possible, and of coexistence where simulated tissue never completely recovers or dies but persists as a mixture of healthy, stressed and necrotic cells. In conclusion, our model sheds light on the evolution of tissue damage or recovery and predicts potential for divergent fates given different rates of proliferation, necrosis, and injury propagation.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Hígado/patología , Modelos Animales , Acetaminofén/toxicidad , Alanina Transaminasa/metabolismo , Animales , Apoptosis , Aspartato Aminotransferasas/metabolismo , Proliferación Celular , Hepatocitos/citología , Hepatocitos/metabolismo , Hígado/enzimología , Hígado/metabolismo , Ratones , Necrosis
14.
Nat Commun ; 11(1): 5666, 2020 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-33168815

RESUMEN

Aquaporin 3 (AQP3) is a transporter of water, glycerol and hydrogen peroxide (H2O2) that is expressed in various epithelial cells and in macrophages. Here, we developed an anti-AQP3 monoclonal antibody (mAb) that inhibited AQP3-facilitated H2O2 and glycerol transport, and prevented liver injury in experimental animal models. Using AQP3 knockout mice in a model of liver injury and fibrosis produced by CCl4, we obtained evidence for involvement of AQP3 expression in nuclear factor-κB (NF-κB) cell signaling, hepatic oxidative stress and inflammation in macrophages during liver injury. The activated macrophages caused stellate cell activation, leading to liver injury, by a mechanism involving AQP3-mediated H2O2 transport. Administration of an anti-AQP3 mAb, which targeted an extracellular epitope on AQP3, prevented liver injury by inhibition of AQP3-mediated H2O2 transport and macrophage activation. These findings implicate the involvement of macrophage AQP3 in liver injury, and provide evidence for mAb inhibition of AQP3-mediated H2O2 transport as therapy for macrophage-dependent liver injury.


Asunto(s)
Anticuerpos Monoclonales/farmacología , Acuaporina 3/antagonistas & inhibidores , Acuaporina 3/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Animales , Acuaporina 3/genética , Células CHO , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Quimiocina CCL4/efectos adversos , Cricetulus , Modelos Animales de Enfermedad , Descubrimiento de Drogas , Glicerol/metabolismo , Peróxido de Hidrógeno/metabolismo , Hígado/metabolismo , Hígado/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Medicina Molecular , FN-kappa B/metabolismo , Estrés Oxidativo , Transducción de Señal , Transcriptoma
15.
Signal Transduct Target Ther ; 5(1): 256, 2020 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-33139693

RESUMEN

Coronavirus disease-2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The infection is spreading globally and poses a huge threat to human health. Besides common respiratory symptoms, some patients with COVID-19 experience gastrointestinal symptoms, such as diarrhea, nausea, vomiting, and loss of appetite. SARS-CoV-2 might infect the gastrointestinal tract through its viral receptor angiotensin-converting enzyme 2 (ACE2) and there is increasing evidence of a possible fecal-oral transmission route. In addition, there exist multiple abnormalities in liver enzymes. COVID-19-related liver injury may be due to drug-induced liver injury, systemic inflammatory reaction, and hypoxia-ischemia reperfusion injury. The direct toxic attack of SARS-CoV-2 on the liver is still questionable. This review highlights the manifestations and potential mechanisms of gastrointestinal and hepatic injuries in COVID-19 to raise awareness of digestive system injury in COVID-19.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/epidemiología , Infecciones por Coronavirus/epidemiología , Enfermedades Gastrointestinales/epidemiología , Hepatopatías/epidemiología , Neumonía Viral/epidemiología , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enfermedad Hepática Inducida por Sustancias y Drogas/virología , Infecciones por Coronavirus/genética , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Heces/virología , Enfermedades Gastrointestinales/complicaciones , Enfermedades Gastrointestinales/genética , Enfermedades Gastrointestinales/virología , Tracto Gastrointestinal/lesiones , Tracto Gastrointestinal/patología , Tracto Gastrointestinal/virología , Humanos , Hígado/fisiopatología , Hígado/virología , Hepatopatías/genética , Hepatopatías/patología , Hepatopatías/virología , Pandemias , Peptidil-Dipeptidasa A/genética , Neumonía Viral/genética , Neumonía Viral/patología , Neumonía Viral/virología
16.
Medicine (Baltimore) ; 99(41): e22259, 2020 Oct 09.
Artículo en Inglés | MEDLINE | ID: mdl-33031266

RESUMEN

Drug-induced liver injury (DILI) is difficult in diagnose, criteria used now are mostly based on history review. We tried to evaluate the value of these criteria and histopathology features in DILI to perform a method diagnosing DILI more definitely.We enrolled 458 consecutive hospitalized DILI patients from January 1, 2012 to December 31, 2018, using Roussel-Uclaf Causality Assessment Method (RUCAM), Maria & Victorino scale (M&V), and Digestive Disease Week-Japan criterion (DDW-J) combined with refined pathological scoring system respectively to perform the evaluation.A total of 458 DILI patients were enrolled, the area under receiver operating characteristics (AUROC) of the 3 clinical diagnostic criteria were 0.730 (95% confidence interval [CI]: 0.667-0.793), 0.793 (95% CI: 0.740-0.847), and 0.764 (95% CI: 0.702-0.826) respectively. Three hundred two DILI patients' liver biopsies were included: steatosis in 204 cases (67.5%), cholestasis in 151 cases (50%), cell apoptosis in 139 cases (46%), eosinophil granulocyte infiltration in 131 cases (43.4%), central and/or portal phlebitis in 103 cases (34.1%), iron deposition in 90 cases (29.8%), and pigmented macrophages in 92 cases (30.5%). The AUROC of refined pathological scale combined with 3 criteria were 0.843 (95% CI: 0.747-0.914), 0.907 (95% CI: 0.822-0.960), and 0.881 (95% CI: 0.790-0.942) respectively. In hepatocellular type, the AUROCs were 0.894 (95% CI: 0.787-0.959), 0.960 (95% CI: 0.857-0.994), and 0.940 (95% CI: 0.847-0.985); in cholestatic type, the AUROCs were 0.750 (95% CI: 0.466-0.931), 0.500 (95% CI: 0.239-0.761), and 0.500 (95% CI: 0.239-0.761); in mixed type, the AUROCs were 0.786 (95% CI: 0.524-0.943), 0.869 (95% CI: 0.619-0.981), and 0.762 (95% CI: 0.498 to -0.930).Combined with pathological scale can significantly improve the accuracy of clinical diagnostic criteria, no matter in alone or combined condition, M&V might be more accurate in diagnosing DILI from suspected patients.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/diagnóstico , Biomarcadores/sangre , Biopsia con Aguja , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Diagnóstico Diferencial , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad
17.
Ecotoxicol Environ Saf ; 203: 110928, 2020 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-32888618

RESUMEN

Hexavalent chromium [Cr(VI)] is seriously harmful to ecosystems and living organisms due to its strong toxicity. Role of dynamin-related protein 1 (Drp1) and Drp1-associated mitochondrial fragmentation in mitophagy and cytotoxicity after Cr(VI) exposure has not been clarified so far. We confirmed that Cr(VI) caused mitochondrial fission by up-regulating Drp1 expression and enhancing Drp1 mitochondrial translocation. By applying the intracellular Ca2+ antagonist BAPTA-AM and mitochondrial Ca2+ antagonist Ru360, we demonstrated that Cr(VI)-induced excessive mitochondrial fission was in a Ca2+-Drp1 dependent manner. The administration of Drp1 siRNA significantly suppressed the overactivation of mitophagy in Cr(VI)-induced hepatotoxicity. The specific Drp1 inhibitor mitochondrial division inhibitor-1 (Mdivi-1) blocked the overactive mitophagy and subsequently ameliorated hepatotoxicity caused by Cr(VI) in vivo. We reached the conclusion that Drp1-dependent mitochondrial fission contributes to Cr(VI)-induced mitophagy and hepatotoxicity, which may provide experimental basis for the study of chromium-associated toxicity, especially for the prevention of health damage in chromium-exposed population.


Asunto(s)
Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Cromo/toxicidad , Dinaminas/metabolismo , Contaminantes Ambientales/toxicidad , Hepatocitos/efectos de los fármacos , Dinámicas Mitocondriales/efectos de los fármacos , Mitofagia/efectos de los fármacos , Animales , Línea Celular , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Ecosistema , Hepatocitos/metabolismo , Hepatocitos/patología , Humanos , Ratones , Ratones Endogámicos C57BL , Mitocondrias Hepáticas/efectos de los fármacos , Mitocondrias Hepáticas/metabolismo , Mitocondrias Hepáticas/patología , ARN Interferente Pequeño/metabolismo
18.
Ecotoxicol Environ Saf ; 205: 111342, 2020 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-32971455

RESUMEN

Radix aconiti lateralis (Fuzi) is widely used in China as a traditional Chinese medicine for the treatment of asthenia, pain and inflammation. However, its toxic alkaloids often lead to adverse reactions. Currently, most of the toxicity studies on Fuzi are focused on the heart and nervous system, and more comprehensive toxicity studies are needed. In this study, based on the previous reports of Fuzi hepatotoxicity, serum pharmacochemistry and network toxicology were used to screen the potential toxic components of Heishunpian(HSP), a processed product of Fuzi, and to explore the possible mechanism of HSP-induced hepatotoxicity. The results obtained are expressed based on the toxicological evidence chain (TEC). It was found that 22 potential toxic components screened can affect Th17 cell differentiation, Jak-STAT signaling pathway, glutathione metabolism, and other related pathways by regulating AKT1, IL2, F2, GSR, EGFR and other related targets, which induces oxidative stress, metabolic disorders, cell apoptosis, immune response, and excessive release of inflammatory factors, eventually inducing liver damage in rats. This is the first study on HSP-induced hepatotoxicity based on the TEC concept, providing references for further studies on the toxicity mechanism of Fuzi.


Asunto(s)
Aconitum/química , Alcaloides/toxicidad , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Medicamentos Herbarios Chinos/toxicidad , Modelos Biológicos , Alcaloides/sangre , Alcaloides/aislamiento & purificación , Animales , Apoptosis/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/sangre , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , China , Medicamentos Herbarios Chinos/aislamiento & purificación , Medicamentos Herbarios Chinos/farmacocinética , Masculino , Medicina China Tradicional , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Wistar
19.
Life Sci ; 260: 118426, 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-32937159

RESUMEN

AIMS: Tobacco smoking is a major health problem associated with lung and liver damage. Lung and liver damage secondary to tobacco smoking is mediated through nicotine-induced oxidative stress. Therefore, we hypothesized that antioxidant treatment with tiron may improve nicotine-induced lung and liver damage. MATERIALS AND METHODS: Rats were divided into six groups, a control, nicotine (10 mg/kg/day, i.p.; for 8 weeks) and tiron (100 or 200 mg/kg/day, i.p.; for 8 weeks) with or without nicotine administration. KEY FINDINGS: Tiron improved survival rate and attenuated lung and liver damage as reflected by decreased total and differential cell counts, lactate dehydrogenase (LDH) activity in bronchoalveolar lavage fluid (BALF) and decreased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) in serum; also histopathological examination confirmed the protective effect of tiron in lung and liver tissues of nicotine treated rats. Tiron attenuated dyslipidemia, which is associated with nicotine. These ameliorative effects of tiron may be mainly due to its antioxidant effect as proved by a significant decrease in malondialdehyde (MDA) content, reactive oxygen species (ROS) and total nitrite/nitrate (NOx) levels, and increase in reduced glutathione (GSH) level, catalase (CAT) and superoxide dismutase (SOD) activities. This is likely related to suppression of protein levels of NADPH oxidase enzyme (NOX1), inducible nitric oxide synthase (iNOS), nuclear factor kappa B (NF-κB) and tumor necrosis factor alpha (TNF-α); and up-regulation of protein levels of nuclear factor erythroid-2 (Nrf2). SIGNIFICANCE: This makes tiron (synthetic analogue of vitamin E) good candidate for future use to minimize nicotine's hazards among smokers.


Asunto(s)
Sal Disódica del Ácido 1,2-Dihidroxibenceno-3,5-Disulfónico/farmacología , Antioxidantes/farmacología , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Lesión Pulmonar/prevención & control , Nicotina/toxicidad , Animales , Antiinflamatorios no Esteroideos/farmacología , Peso Corporal/efectos de los fármacos , Líquido del Lavado Bronquioalveolar/química , Recuento de Células , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/mortalidad , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Enzimas/sangre , L-Lactato Deshidrogenasa/metabolismo , Lípidos/sangre , Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/mortalidad , Lesión Pulmonar/patología , Masculino , NADPH Oxidasa 1/sangre , NADPH Oxidasa 1/metabolismo , FN-kappa B/sangre , FN-kappa B/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Sustancias Protectoras/farmacología , Ratas Sprague-Dawley
20.
Environ Health Prev Med ; 25(1): 53, 2020 Sep 11.
Artículo en Inglés | MEDLINE | ID: mdl-32917140

RESUMEN

BACKGROUND: Pilea umbrosa (Urticaceae) is used by local communities (district Abbotabad) for liver disorders, as anticancer, in rheumatism and in skin disorders. METHODS: Methanol extract of P. umbrosa (PUM) was investigated for the presence of polyphenolic constituents by HPLC-DAD analysis. PUM (150 mg/kg and 300 mg/kg) was administered on alternate days for eight weeks in rats exposed with carbon tetrachloride (CCl4). Serum analysis was performed for liver function tests while in liver tissues level of antioxidant enzymes and biochemical markers were also studied. In addition, semi quantitative estimation of antioxidant genes, endoplasmic reticulum (ER) induced stress markers, pro-inflammatory cytokines and fibrosis related genes were carried out on liver tissues by RT-PCR analysis. Liver tissues were also studied for histopathological injuries. RESULTS: Level of antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), peroxidase (POD) and glutathione (GSH) decreased (p < 0.05) whereas level of thiobarbituric acid reactive substance (TBARS), H2O2 and nitrite increased in liver tissues of CCl4 treated rat. Likewise increase in the level of serum markers; alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP) and total bilirubin was observed. Moreover, CCl4 caused many fold increase in expression of ER stress markers; glucose regulated protein (GRP-78), x-box binding protein1-total (XBP-1 t), x-box binding protein1-unspliced (XBP-1 u) and x-box binding protein1-spliced (XBP-1 s). The level of inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) was aggregated whereas suppressed the level of antioxidant enzymes; γ-glutamylcysteine ligase (GCLC), protein disulfide isomerase (PDI) and nuclear erythroid 2 p45-related factor 2 (Nrf-2). Additionally, level of fibrosis markers; transforming growth factor-ß (TGF-ß), Smad-3 and collagen type 1 (Col1-α) increased with CCl4 induced liver toxicity. Histopathological scrutiny depicted damaged liver cells, neutrophils infiltration and dilated sinusoids in CCl4 intoxicated rats. PUM was enriched with rutin, catechin, caffeic acid and apigenin as evidenced by HPLC analysis. Simultaneous administration of PUM and CCl4 in rats retrieved the normal expression of these markers and prevented hepatic injuries. CONCLUSION: Collectively these results suggest that PUM constituted of strong antioxidant chemicals and could be a potential therapeutic agent for stress related liver disorders.


Asunto(s)
Tetracloruro de Carbono/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Estrés del Retículo Endoplásmico/efectos de los fármacos , Fibrosis/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Sustancias Protectoras/farmacología , Urticaceae/química , Animales , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/patología , Fibrosis/genética , Inflamación/genética , Hígado/efectos de los fármacos , Hígado/enzimología , Hígado/metabolismo , Masculino , Ratas , Ratas Sprague-Dawley
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