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1.
Biomed Pharmacother ; 173: 116340, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38428308

RESUMO

The current study investigated the ameliorating impact of GA water extract (GAE) on CCl4-induced nephrotoxicity in renal cells and tissue by comparing its effectiveness with the Ketosteril (Ks) drug in restoring oxidative stress and necroinflammation. The cell morphology, necrosis, and redox state were evaluated in Vero cells. The influence of GAE on CCl4-induced oxidative stress, inflammation, and necrosis was examined in rats. The predicted inhibitory mechanism of GAE phenolic constituents against COX-2 and iNOS was also studied. The results revealed that GAE contains crucial types of phenolic acids, which are associated with its antiradical activities. GAE improved CCl4-induced Vero cell damage and restored renal architecture damage, total antioxidant capacity, ROS, TBARS, NO, GSH, GPX, SOD, and MPO in rats. GAE downregulated the gene expression of renal NF-κB, TNF-α, iNOS, and COX-2, as well as kidney injury molecule-1 (KIM-1) in rats. The GAE improved blood urea, creatinine, cholesterol, and reducing power. The computational analysis revealed the competitive inhibitory mechanism of selected phenolic composites of GAE on COX-2 and iNOS activities. The GAE exhibited higher potency than Ks in most of the studied parameters, as observed by the heatmap plots. Thus, GAE is a promising extract for the treatment of kidney toxicity.


Assuntos
NF-kappa B , Insuficiência Renal , Chlorocebus aethiops , Ratos , Animais , NF-kappa B/metabolismo , Tetracloreto de Carbono/toxicidade , Goma Arábica , Células Vero , Ciclo-Oxigenase 2/metabolismo , Antioxidantes/farmacologia , Estresse Oxidativo , Insuficiência Renal/metabolismo , Oxirredução , Rim/metabolismo , Necrose/metabolismo
2.
Eur Rev Med Pharmacol Sci ; 28(4): 1259-1271, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38436159

RESUMO

OBJECTIVE: This study aimed to assess the hepatoprotective role of oleuropein (Olp), a phenolic compound found in olive, against carbon tetrachloride (CCl4)-induced liver damage in rats. MATERIALS AND METHODS: The research involved male albino rats, which received intraperitoneal injections of 100 mg/kg b.w. of oleuropein for 8 consecutive weeks before being subjected to carbon tetrachloride (CCl4) at a dosage of 1.0 ml/kg b.w. Changes induced by CCl4 in antioxidant and inflammatory marker levels were assessed using ELISA assay kits. Moreover, CCl4-induced liver tissue architecture alteration, fibrosis, and expression pattern of protein were evaluated by performing H&E, Sirius red, Masson trichrome, and immunohistochemistry staining. RESULTS: Increased serum transaminases and massive hepatic damage were observed by this liver toxicant. The hepatic injury was further evidenced by a significant decrease in antioxidant enzyme activity [superoxide dismutase (SOD), glutathione peroxidase (GPx), Glutathione (GSH) and Total Antioxidant Capacity (T-AOC)]. The administration of CCl4 resulted in an increased inflammatory response, which was measured by C-reactive protein, interleukin-6, as well as tumor necrosis factor-alpha. Olp as a curative regimen led to significant attenuation in the inflammatory response and oxidative/nitrosative stress. This polyphenol treatment improved the hepatic tissue architecture and decreased fibrosis. In the CCl4 treatment group, the expression pattern of IL-6 protein was high, whereas expression was decreased after Olp, as evidenced by immunohistochemistry staining. CONCLUSIONS: The study suggests that oleuropein treatment has the potential to reduce liver damage caused by CCl4 induction by inhibiting oxidative stress and inflammation and maintaining liver tissue architecture. This could make it a promising treatment option for liver pathogenesis.


Assuntos
Doença Hepática Crônica Induzida por Substâncias e Drogas , Glucosídeos Iridoides , Olea , Masculino , Animais , Ratos , Antioxidantes/farmacologia , Tetracloreto de Carbono/toxicidade , Inflamação/tratamento farmacológico , Estresse Oxidativo , Fenóis/farmacologia , Glutationa , Fibrose
3.
J Biochem Mol Toxicol ; 38(4): e23691, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38500399

RESUMO

Sustained liver injuries predominantly promote oxidative stress and inflammation that lead to the progression of chronic liver disease (CLD), including fibrosis, cirrhosis, and hepatocellular carcinoma. Boldine, an alkaloid isolated from Peumus boldus, has been shown to have antioxidant and anti-inflammatory effects. Currently, there is no definitive treatment option available for CLD. Therefore, we investigated the hepatoprotective effect of boldine against carbon tetrachloride (CCl4 )-induced chronic liver injury in rats. CCl4 (2 mL/kg., b.w., i.p.) was administered twice weekly for 5 weeks to induce chronic liver injury in rats. Separate groups of rats were given boldine (20 mg/kg b.w., and 40 mg/kg b.w.) and silymarin (100 mg/kg b.w.) orally, daily. Serum transaminases, lipid peroxidation, and antioxidant levels were measured, and nuclear factor-κB (NF-κB), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (cox-2), interleukin-1 ß (IL-1ß), and α-smooth muscle actin (α-SMA) gene and protein expressions were evaluated. CCl4 administration increased liver marker enzymes of hepatotoxicity in serum and oxidative stress markers, inflammatory genes and α-smooth muscle actin expression in liver tissue. Boldine concurrent treatment suppressed CCl4 -induced elevation of transaminase levels in serum, restored enzymic and non-enzymic antioxidants, and downregulated NF-κB, TNF-α, Cox-2 and IL-1ß expressions, thereby suppressing hepatic inflammation. Boldine administration also repressed α-SMA expression. The results of this study demonstrate the antioxidant, anti-inflammatory, and antifibrotic properties of boldine, and it can be a potential therapeutic candidate in the treatment of CLD.


Assuntos
Aporfinas , Doença Hepática Induzida por Substâncias e Drogas , NF-kappa B , Ratos , Animais , NF-kappa B/metabolismo , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Tetracloreto de Carbono/toxicidade , Actinas/metabolismo , Actinas/farmacologia , Fator de Necrose Tumoral alfa/metabolismo , Ciclo-Oxigenase 2/metabolismo , Fígado/metabolismo , Transdução de Sinais , Estresse Oxidativo , Inflamação/metabolismo , Anti-Inflamatórios/farmacologia , Doença Hepática Induzida por Substâncias e Drogas/metabolismo
4.
Nan Fang Yi Ke Da Xue Xue Bao ; 44(2): 201-209, 2024 Feb 20.
Artigo em Chinês | MEDLINE | ID: mdl-38501404

RESUMO

OBJECTIVE: To investigate the protective effect of NDUFA13 protein against acute liver injury and liver fibrosis in mice and explore the possible mechanisms. METHODS: BALB/C mice (7 to 8 weeks old) were divided into normal group, CCl4 group, CCl4+AAV-NC group and CCl4+AAV-NDU13 group (n=18). Mouse models of liver fibrosis were established by intraperitoneal injection of CCl4 twice a week for 3, 5 or 7 weeks, and the recombinant virus AAV8-TBG-NC or AAV8-TBG-NDUFA13 was injected via the tail vein 7-10 days prior to CCl4 injection. After the treatments, pathological changes in the liver of the mice were observed using HE and Masson staining. Hepatic expression levels of NDUFA13 and α-SMA were detected with Western blotting, and the coexpression of NDUFA13 and NLRP3, TNF-α and IL-1ß, and α-SMA and collagen Ⅲ was analyzed with immunofluorescence assay. RESULTS: HE and Masson staining showed deranged liver architecture, necrotic hepatocytes and obvious inflammatory infiltration and collagen fiber deposition in mice with CCl4 injection (P < 0.001). NDUFA13 expression markedly decreased in CCl4-treated mice (P < 0.001), while a significant reduction in inflammatory aggregation and fibrosis was observed in mice with AAV-mediated NDUFA13 overexpression (P < 0.001). In CCl4+AAV-NDU13 group, immunofluorescence assay revealed markedly weakened activation of NLRP3 inflammasomes (P < 0.001), significantly decreased TNF-α and IL-1ß secretion (P < 0.001), and inhibited hepatic stellate cell activation (P < 0.05) and collagen formation in the liver (P < 0.001). CONCLUSION: Mitochondrial NDUFA13 overexpression in hepatocytes protects against CCl4- induced liver fibrosis in mice by inhibiting activation of NLRP3 signaling.


Assuntos
Dependovirus , Fator de Necrose Tumoral alfa , Camundongos , Animais , Fator de Necrose Tumoral alfa/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Camundongos Endogâmicos BALB C , Fígado/metabolismo , Cirrose Hepática , Hepatócitos , Colágeno/metabolismo , Células Estreladas do Fígado/metabolismo , Tetracloreto de Carbono/efeitos adversos
5.
Hepatol Commun ; 8(4)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38466882

RESUMO

BACKGROUND: Lysyl oxidase (LOX) family members (LOX and LOXL1 to 4) are crucial copper-dependent enzymes responsible for cross-linking collagen and elastin. Previous studies have revealed that LOX and LOXL1 are the most dramatically dysregulated LOX isoforms during liver fibrosis. However, the crosstalk between them and the underlying mechanisms involved in the profibrotic behaviors of HSCs, as well as the progression of liver fibrosis, remain unclear. METHODS: pCol9GFP-HS4,5Tg mice, Loxl1fl/flGfapCre mice, human HSC line, and primary HSCs were enrolled to study the dysregulation pattern, profibrotic roles, and the potential mechanisms of LOX and LOXL1 interaction involved in the myofibroblast-like transition of HSCs and liver fibrogenesis. RESULTS: LOX and LOXL1 were synergistically upregulated during liver fibrogenesis, irrespective of etiology, together orchestrating the profibrotic behaviors of HSCs. LOX and LOXL1 coregulated in HSCs, whereas LOXL1 dominated in the coregulation loop. Interestingly, the interaction between LOXL1 and LOX prolonged their half-lives, specifically enhancing the Notch signal-mediated myofibroblast-like transition of HSCs. Selective disruption of Loxl1 in Gfap+ HSCs deactivated the Notch signal, inhibited HSC activation, and relieved carbon tetrachloride-induced liver fibrosis. CONCLUSIONS: Our current study confirmed the synergistic roles and the underlying mechanisms of LOXL1 and LOX crosstalk in the profibrotic behaviors of HSCs and liver fibrosis progression, providing experimental evidence for further clear mechanism-based anti-LOXL1 strategy development in the therapy of liver fibrosis.


Assuntos
Aminoácido Oxirredutases , Proteína-Lisina 6-Oxidase , Animais , Humanos , Camundongos , Aminoácido Oxirredutases/genética , Tetracloreto de Carbono , Colágeno , Cirrose Hepática , Proteína-Lisina 6-Oxidase/genética
6.
Math Biosci Eng ; 21(1): 237-252, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-38303421

RESUMO

In this work, we propose a mathematical model that describes liver evolution and concentrations of alanine aminotransferase and aspartate aminotransferase in a group of rats damaged with carbon tetrachloride. Carbon tetrachloride was employed to induce cirrhosis. A second groups damaged with carbon tetrachloride was exposed simultaneously a plant extract as hepatoprotective agent. The model reproduces the data obtained in the experiment reported in [Rev. Cub. Plant. Med. 22(1), 2017], and predicts that using the plants extract helps to get a better natural recovery after the treatment. Computer simulations show that the extract reduces the damage velocity but does not avoid it entirely. The present paper is the first report in the literature in which a mathematical model reliably predicts the protective effect of a plant extract mixture in rats with cirrhosis disease. The results reported in this manuscript could be used in the future to help in fighting cirrhotic conditions in humans, though more experimental and mathematical work is required in that case.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Extratos Vegetais , Humanos , Ratos , Animais , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/patologia , Fígado/patologia , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/patologia , Modelos Teóricos
7.
Life Sci ; 340: 122480, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38301876

RESUMO

AIM: The liver plays a crucial role in biotransformation but it is susceptible to chemical-induced damage, known as hepatotoxicity. Traditional therapies for protecting the liver face significant challenges, including poor bioavailability, off-target effects, adverse reactions, drug breakdown, and inadequate uptake. These issues emphasize the need for precise, targeted therapeutic approaches against hepatotoxicity. MATERIALS AND METHODS: The objective of our research was to develop a customized, biocompatible, and biodegradable nanodrug delivery system for hepatoprotection. We chose collagen hydrolyzed protein, or gelatin, as the base material and utilized solvent evaporation and nanoprecipitation methods to create nanoparticles with size ranging from 130 to 155 nm. The resulting nanoparticles exhibited a spherical and smooth surface, as confirmed by scanning and transmission electron microscopy. KEY FINDINGS: Bioactive aescin (AES), into these gelatin nanoparticles (AES-loaded gel NPs), we tested these nanoparticles using a hepatotoxicity model. The results were indicating a significant reduction in the levels of key biomolecules, including NF-κB, iNOS, BAX, and COX-2 and decreased serum levels of enzymes ALT and AST. This reduction correlated with a notable alleviation in the severity of hepatotoxicity. Furthermore, the treatment with AES-loaded gel NPs resulted in the downregulation of several inflammatory and liver-specific biomarkers, including nitrite, MPO, TNF-α, and IL-6. SIGNIFICANCE: In summary, our study demonstrates that the AES-loaded gel NPs were markedly more effective in mitigating experimental hepatotoxicity when compared to the free aescin. The nanoparticles exhibited a propensity for suppressing liver damage, showcasing the potential of this targeted therapeutic approach for safeguarding the liver from harmful chemical insults.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Nanopartículas , Ratos , Animais , Ratos Wistar , Escina/metabolismo , Gelatina/farmacologia , Tetracloreto de Carbono/toxicidade , Fígado/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Nanopartículas/química
8.
Front Biosci (Landmark Ed) ; 29(2): 62, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38420807

RESUMO

BACKGROUND: Mesenchymal cells, including hepatic stellate cells (HSCs), fibroblasts (FBs), myofibroblasts (MFBs), and vascular smooth muscle cells (VSMCs), are the main cells that affect liver fibrosis and play crucial roles in maintaining tissue homeostasis. The dynamic evolution of mesenchymal cells is very important but remains to be explored for researching the reversible mechanism of hepatic fibrosis and its evolution mechanism of hepatic fibrosis to cirrhosis. METHODS: Here, we analysed the transcriptomes of more than 50,000 human single cells from three cirrhotic and three healthy liver tissue samples and the mouse hepatic mesenchymal cells of two healthy and two fibrotic livers to reconstruct the evolutionary trajectory of hepatic mesenchymal cells from a healthy to a cirrhotic state, and a subsequent integrative analysis of bulk RNA sequencing (RNA-seq) data of HSCs from quiescent to active (using transforming growth factor ß1 (TGF-ß1) to stimulate LX-2) to inactive states. RESULTS: We identified core genes and transcription factors (TFs) involved in mesenchymal cell differentiation. In healthy human and mouse livers, the expression of NR1H4 and members of the ZEB families (ZEB1 and ZEB2) changed significantly with the differentiation of FB into HSC and VSMC. In cirrhotic human livers, VSMCs transformed into HSCs with downregulation of MYH11, ACTA2, and JUNB and upregulation of PDGFRB, RGS5, IGFBP5, CD36, A2M, SOX5, and MEF2C. Following HSCs differentiation into MFBs with the upregulation of COL1A1, TIMP1, and NR1H4, a small number of MFBs reverted to inactivated HSCs (iHSCs). The differentiation trajectory of mouse hepatic mesenchymal cells was similar to that in humans; however, the evolution trajectory and proportion of cell subpopulations that reverted from MFBs to iHSCs suggest that the mouse model may not accurately reflect disease progression and outcome in humans. CONCLUSIONS: Our analysis elucidates primary genes and TFs involved in mesenchymal cell differentiation during liver fibrosis using scRNA-seq data, and demonstrated the core genes and TFs in process of HSC activation to MFB and MFB reversal to iHSC using bulk RNA-seq data of human fibrosis induced by TGF-ß1. Furthermore, our findings suggest promising targets for the treatment of liver fibrosis and provide valuable insights into the molecular mechanisms underlying its onset and progression.


Assuntos
Análise da Expressão Gênica de Célula Única , Fatores de Transcrição , Camundongos , Animais , Humanos , Fatores de Transcrição/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Tetracloreto de Carbono/efeitos adversos , Tetracloreto de Carbono/metabolismo , Cirrose Hepática/genética , Cirrose Hepática/metabolismo , Fígado/metabolismo , Diferenciação Celular/genética , Células Estreladas do Fígado/metabolismo
9.
Gut Microbes ; 16(1): 2323236, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38416424

RESUMO

Deoxycholic acid (DCA) serves essential functions in both physiological and pathological liver processes; nevertheless, the relationship among DCA, gut microbiota, and metabolism in chronic liver injury remain insufficiently understood. The primary objective of this study is to elucidate the potential of DCA in ameliorating chronic liver injury and evaluate its regulatory effect on gut microbiota and metabolism via a comprehensive multi-omics approach. Our study found that DCA supplementation caused significant changes in the composition of gut microbiota, which were essential for its antagonistic effect against CCl4-induced chronic liver injury. When gut microbiota was depleted with antibiotics, the observed protective efficacy of DCA against chronic liver injury became noticeably attenuated. Mechanistically, we discovered that DCA regulates the metabolism of bile acids (BAs), including 3-epi DCA, Apo-CA, and its isomers 12-KLCA and 7-KLCA, IHDCA, and DCA, by promoting the growth of A.muciniphila in gut microbiota. This might lead to the inhibition of the IL-17 and TNF inflammatory signaling pathway, thereby effectively countering CCl4-induced chronic liver injury. This study illustrates that the enrichment of A. muciniphila in the gut microbiota, mediated by DCA, enhances the production of secondary bile acids, thereby mitigating chronic liver injury induced by CCl4. The underlying mechanism may involve the inhibition of hepatic IL-17 and TNF signaling pathways. These findings propose a promising approach to alleviate chronic liver injury by modulating both the gut microbiota and bile acids metabolism.


Assuntos
Tetracloreto de Carbono , Microbioma Gastrointestinal , Tetracloreto de Carbono/toxicidade , Interleucina-17 , Multiômica , Fígado , Ácidos e Sais Biliares , Ácido Desoxicólico
10.
Biochem Pharmacol ; 221: 116033, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38301964

RESUMO

Purinergic P2X4 receptor (P2X4R) has been shown to have immunomodulatory properties in infection, inflammation, and organ damage including liver regeneration and fibrosis. However, the mechanisms and pathophysiology associated with P2X4R during acute liver injury remain unknown. We used P2X4R-/- mice to explore the role of P2X4R in three different models of acute liver injury caused by concanavalin A (ConA), carbon tetrachloride, and acetaminophen. ConA treatment results in an increased expression of P2X4R in the liver of mice, which was positively correlated with higher levels of aspartate aminotransferase and alanine aminotransferase in the serum. However, P2X4R gene ablation significantly reduced the severity of acute hepatitis in mice caused by ConA, but not by carbon tetrachloride or acetaminophen. The protective benefits against immune-mediated acute hepatitis were achieved via modulating inflammation (Interleukin (IL)-1ß, IL-6, IL-17A, interferon-γ, tumor necrosis factor-α), oxidative stress (malondialdehyde, superoxide dismutase, glutathione peroxidase, and catalase), apoptosis markers (Bax, Bcl-2, and Caspase-3), autophagy biomarkers (LC3, Beclin-1, and p62), and nucleotide oligomerization domain-likereceptorprotein 3(NLRP3) inflammasome-activated pyroptosis markers (NLRP3, Gasdermin D, Caspase-1, ASC, IL-1ß). Additionally, administration of P2X4R antagonist (5-BDBD) or agonist (cytidine 5'-triphosphate) either improved or worsened ConA-induced autoimmune hepatitis, respectively. This study is the first to reveal that the absence of the P2X4 receptor may mitigate immune-mediated liver damage, potentially by restraining inflammation, oxidation, and programmed cell death mechanisms. And highlight P2X4 receptor is essential for ConA-induced acute hepatitis.


Assuntos
Hepatite Autoimune , Animais , Camundongos , Hepatite Autoimune/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR , Receptores Purinérgicos P2X4/genética , Acetaminofen/toxicidade , Tetracloreto de Carbono , Inflamação
11.
J Pak Med Assoc ; 74(1 (Supple-2)): S63-S67, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38385474

RESUMO

OBJECTIVE: To examine the therapeutic effects of Olea europaea L. leaves extract on carbon tetrachloride-induced liver injury in rats. Methods: The experimental study was conducted at the Department of Physiology, University of Karachi, Karachi, in July 2021, and comprised Albino Wistar male rats weighing 180-220gm. The animals were divided into control group I, carbon tetrachloride group II, Olea europaea L. + carbon tetrachloride group III and Olea europaea L. group IV. In Vitro model of hepatic toxicity was developed by carbon tetrachloride. A daily dose of 50mg/kg of aqueous extract of olive leaves was administered orally and 0.8ml/kg of carbon tetrachloride was administered twice a week subcutaneously for 28 days. On the 29th day, the animals were sacrificed, and tested for hepatic enzymes, lipid peroxidation markers and histopathology. Data was analysed using SPSS 20. RESULTS: Of the 24 rats, 6(25%) were in each of the 4 groups. Alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase and total bilirubin levels were significantly reduced (p<0.05) in group II whereas, 4- hydroxynonenal, isoprostane and malondialdehyde levels were significantly increased (p<0.05). However, total antioxidant level increased significantly (p<0.05) in group III compared to group II. Histopathology showed severe liver damage in group II and mild damage in group III. Conclusion: Olea europaea L. leaves extract was found to have profound hepatoprotective effects.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Olea , Ratos , Masculino , Animais , Tetracloreto de Carbono/toxicidade , Tetracloreto de Carbono/metabolismo , Olea/metabolismo , Fitoterapia , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle , Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Antioxidantes/farmacologia , Antioxidantes/metabolismo , Fígado/patologia , Ratos Wistar , Aspartato Aminotransferases , Alanina Transaminase/metabolismo , Peroxidação de Lipídeos
12.
Methods Mol Biol ; 2769: 57-65, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38315388

RESUMO

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD). Obesity is a known risk factor of NASH, which, in turn, increases the risk of developing cirrhosis (liver scarring) and hepatocellular carcinoma (HCC). In addition to being a potentially life-threatening condition, public health concerns surrounding NASH are amplified by the lack of FDA-approved treatments. Although various preclinical models reflecting both the histopathology and the pathophysiological progression of human NASH exist, most of these models are diet-based and require 6-13 months for NASH symptom manifestation. Here, we describe a simple and rapid-progression model of NASH and NASH-driven HCC in mice. Mice received a western diet equivalent (WD; i.e., a high-fat, high-fructose, and high-cholesterol diet), high-sugar water (23.1 g/L fructose and 18.9 g/L glucose), and weekly intraperitoneal injections of carbon tetrachloride (CCl4) at a dose of 0.2 µL/g of body weight. The resulting phenotype, consisting in liver fibrosis and HCC, appeared within 24 weeks of diet/treatment initiation and presented similar histological and transcriptomic features as human NASH and NASH-driven HCC, thereby supporting the adequacy of this preclinical model for the development and evaluation of drugs that can prevent or reverse these diseases.


Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Hepatopatia Gordurosa não Alcoólica , Humanos , Camundongos , Animais , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/patologia , Carcinoma Hepatocelular/genética , Tetracloreto de Carbono/toxicidade , Neoplasias Hepáticas/patologia , Dieta Ocidental/efeitos adversos , Modelos Animais de Doenças , Cirrose Hepática/patologia , Frutose , Dieta Hiperlipídica/efeitos adversos , Fígado/patologia , Camundongos Endogâmicos C57BL
13.
J Ethnopharmacol ; 326: 117963, 2024 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-38387680

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Liver fibrosis is a serious complication of liver disease characterized by excessive collagen deposition, without effective therapeutic agents in the clinic. Fu-Gan-Wan (FGW) is an empirical formula used for the clinical treatment of hepatitis and cirrhosis. It has been shown to reverse experimental liver fibrosis. However, its corresponding mechanisms remain unclear. AIM OF THE REVIEW: This study aimed to elucidate the key pathways and target genes of FGW in attenuating liver fibrosis. MATERIALS AND METHODS: The therapeutic effects of different doses of FGW on liver fibrosis were investigated using a 2 mL/kg 15% CCl4-induced mouse model. Then, RNA-seq combined with network pharmacology was used to analyze the key biological processes and signaling pathways underlying the anti-liver fibrosis exertion of FGW. These findings were validated in a TGF-ß1-induced model of activation and proliferation of mouse hepatic stellate cell line JS-1. Finally, the key signaling pathways and molecular targets were validated using animal tissues, and the effect of FGW on tissue lipid peroxidation was additionally observed. RESULTS: We found that 19.5 g/kg FGW significantly down-regulated CCl4-induced elevation of hepatic ALT and AST, decreased collagen deposition, and inhibited the expression of pro-fibrotic factors α-SMA, COL1α1, CTGF, TIMP-1, as well as pro-inflammatory factor TGF-ß1. Additionally, FGW at doses of 62.5, 125, and 250 µg/mL dose-dependently blocked JS-1 proliferation, migration, and activation. Furthermore, RNA-seq identified the NF-κB signaling pathway as a key target molecular pathway for FGW against liver fibrosis, and network pharmacology combined with RNA-seq focused on 11 key genes. Significant changes were identified in CCL2 and HMOX1 by tissue RT-PCR, Western blot, and immunohistochemistry. We further demonstrated that FGW significantly attenuated CCl4-induced increases in p-p65, CCL2, CCR2, and HMOX1, while significantly elevating Nrf2. Finally, FGW significantly suppressed the accumulation of lipid peroxidation products MDA and 4-HNE and reconfigured the oxidation-reduction balance, including promoting the increase of antioxidants GPx, GSH, and SOD, and the decrease of peroxidation products ROS and GSSG. CONCLUSIONS: This study demonstrated that FGW exhibits potential in mitigating CCl4-induced hepatic fibrosis, lipid peroxidation, and iron metabolism disorders in mice. This effect may be mediated through the NF-κB/CCL2/CCR2 and Nrf2/HMOX1 pathways.


Assuntos
NF-kappa B , Fator de Crescimento Transformador beta1 , Camundongos , Animais , NF-kappa B/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Peroxidação de Lipídeos , Farmacologia em Rede , RNA-Seq , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Transdução de Sinais , Fígado , Colágeno/metabolismo , Tetracloreto de Carbono/farmacologia , Células Estreladas do Fígado
14.
J Nutr Biochem ; 125: 109565, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38176621

RESUMO

Various endogenous and exogenous stimuli can result in an inflammatory response and collagen deposition in the liver, which affect liver function and increase the risk of developing liver cirrhosis and cancer. Rice bran, the main by-product of rice milling, contains various nutrients which possess hepatoprotective activities. In this study, we investigated the effects of rice bran on carbon tetrachloride (CCl4)-induced liver fibrosis in mice. Mice were fed a rice-bran-containing diet (10% rice bran w/w) or a standard diet with or without an injection of 20% CCl4 to induce liver fibrosis. Our results showed that feeding a rice-bran-containing diet could alleviate CCl4-induced liver damage, collagen deposition, and expressions of fibrosis-related genes, including α-smooth muscle actin (α-SMA), collagen 1a2 (COL1A2), and transforming growth factor-ß (TGF-ß) in liver tissues. Moreover, consumption of rice bran enhanced phase II detoxification and antioxidant gene expressions, including Gsta3, Gstp1, Catalase, SOD1, SOD2, and SOD3. Treatment with γ-oryzanol, the major bioactive compound in rice bran, decreased the sensitivity of hepatic stellate cells (HSCs) to TGF-ß1-induced α-SMA, COL1A2, and phosphorylated smad2 expressions. In conclusion, a rice-bran-containing diet may have beneficial effects on liver fibrogenesis through increased antioxidant and detoxification activities. γ-Oryzanol, the major bioactive compound of rice bran, can inhibit activation of HSCs.


Assuntos
Antioxidantes , Oryza , Fenilpropionatos , Animais , Camundongos , Antioxidantes/metabolismo , Oryza/metabolismo , Células Estreladas do Fígado/metabolismo , Transdução de Sinais , Cirrose Hepática/metabolismo , Fígado/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Dieta , Tetracloreto de Carbono/toxicidade
15.
Carbohydr Res ; 536: 109042, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38244321

RESUMO

Two selenized chitooligosaccharide (O-Se-COS and N,O-Se-COS) with different sites modification were synthesized to alleviate liver injury in vivo. Comparing to traditional COS, both selenized COS exhibited enhanced reducibility as well as antioxidant capacity in vitro. Furthermore, O-Se-COS demonstrated superior efficacy in reducing intracellular reactive oxygen species (ROS) and mitochondrial damage compared to N,O-Se-COS as its enhanced cellular uptake by the positive/negative charge interactions. Two mechanisms were proposed to explained these results: one is to enhance the enzymatic activity of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px), which effectively scavenge free radicals; the other is to down-regulate intracellular cytochrome P450 (CYP2E1) levels, inhibiting carbon tetrachloride (CCl4)-induced peroxidation damage. In vivo studies further demonstrated the effective alleviation of CCl4-induced liver injury by selenized COS, with therapeutic efficacy observed in the following order: O-Se-COS > N,O-Se-COS > COS. Finally, hemolysis and histological tests confirmed the biosafety of both selenized COS. Taken together, these finding demonstrated that selenium has the potential to improve the biological activity of COS, and precise selenylation was more conducive to achieving the synergistic effect where 1 + 1>2.


Assuntos
Quitosana , Fígado , Oligossacarídeos , Selênio , Antioxidantes/farmacologia , Tetracloreto de Carbono/toxicidade , Tetracloreto de Carbono/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Quitina/farmacologia , Quitina/uso terapêutico , Quitina/metabolismo , Estresse Oxidativo , Selênio/farmacologia , Selênio/metabolismo
16.
Eur J Pharmacol ; 966: 176337, 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38246330

RESUMO

Hepatic fibrosis, when left untreated, causes serious health problems that progress to cirrhosis and, in some cases, liver cancer. Activation of hepatic stellate cells may be a key characteristic in the development of hepatic fibrosis. Melatonin, a pineal hormone, exerts anti-fibrotic effects; however, the exact mechanisms remain unclear. In this study, the beneficial effects of melatonin against hepatic fibrosis and the underlying mechanisms were investigated using the human hepatic stellate cell line, LX-2, and in vivo murine animal models. The results showed that melatonin suppressed the expression of transforming growth factor (TGF)-ß1-induced fibrosis markers and production of reactive oxygen species in LX-2 cells. Either 4-phenyl-2-propionamidotetralin, a melatonin receptor 2 selective antagonist, or melatonin receptor 2 small interfering RNA abolished the suppressive effects of melatonin, suggesting the involvement of melatonin receptor 2 in melatonin-induced anti-fibrotic and anti-oxidative actions. Melatonin increased the expression of the brain and muscle aryl hydrocarbon receptor nuclear translocator-like 1 (BMAL1), a positive circadian clock gene. BMAL1 knockdown reduced the anti-fibrotic and anti-oxidative effects of melatonin, demonstrating the protective effects of melatonin against TGF-ß1-induced hepatic stellate cell activation by exhibiting melatonin receptor 2-BMAL1-anti-oxidative effects. In high-fat diet-induced and carbon tetrachloride-induced hepatic fibrosis models, oral melatonin administration decreased the expression of hepatic fibrosis markers and increased the expression of messenger RNA and levels of proteins of BMAL1 and melatonin receptor 2. Thus, melatonin exerted protective effects against hepatic fibrosis through melatonin receptor 2 activation, followed by an upregulation of the BMAL1-anti-oxidative enzyme pathways.


Assuntos
Melatonina , Animais , Humanos , Camundongos , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Tetracloreto de Carbono , Células Estreladas do Fígado , Fígado , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/genética , Melatonina/farmacologia , Melatonina/uso terapêutico , Receptores de Melatonina/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta1/metabolismo , Regulação para Cima
17.
Biomed Res Int ; 2024: 6673550, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38204757

RESUMO

Background: Traditional herbal medicine practitioners in the Ashanti region of Ghana use the fruit peels of Citrus limon (L.) Osbeck (C. limon) in preventive and curative treatment of many cancers including liver cancer. This ethnobotanical claim remains to be verified scientifically. Aim of the Study. This study investigated prophylactic hepatoprotective and anti-HCC effects of C. limon peel extract (LPE) in CCl4/olive oil-induced HCC-like rats. Materials and Methods: After preparation of LPE, it was subjected to phytochemical screening using standard phytochemical methods. A total of 30 healthy adult male Sprague-Dawley rats (weighing 150-200 g) were randomly assigned into six groups of 5 rats each. Rats in the control group received olive oil (5 mL/kg ip) twice weekly for 16 weeks. Rats in the model group received CCl4/olive oil (2 mL/kg, ip) twice weekly for 16 weeks. Rats in capecitabine (10 mg/kg po) and LPE (50, 100, and 200 mg/kg po) groups received CCl4/olive oil (2 mL/kg, i.p) in the morning and their respective treatments in the afternoon twice a week for 16 weeks. Rats in all groups had free access to food and water ad libitum. Body weight and survival rates were monitored. Rats were sacrificed under deep anesthesia, blood was collected, and liver and other organs were isolated. Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyltransferase (GGT), prothrombin time, bilirubin, C-reactive protein (CRP), alpha- (α-) fetoprotein (AFP), and liver histology were assessed. Results: Alkaloids, tannins, flavonoids, terpenoids, and saponins were detected in LPE. Model rats demonstrated increased serum levels of AFP, CRP, ALP, GGT, ALT, and AST, prothrombin time, total bilirubin, direct bilirubin, blood lymphocyte, and monocyte counts, but decreased serum albumin and total protein compared to control rats. Unlike the control, model rats demonstrated fat accumulation in periportal and centrilobular hepatocytes and neoplastic transformation. Semiquantitation of periodic acid Schiff- (PAS-) stained liver sections showed decreased glycogen storage in hepatocytes of model rats compared to control rats. Compared to the model, LPE treatment protected against CCl4-induced hepatocarcinogenesis, which was evidenced by decreased AFP, CRP, liver enzymes, total and direct bilirubin, prothrombin time, and blood lymphocyte and monocyte counts; attenuation of fat accumulation; and increased glycogen storage, albumin, and total protein. Conclusion: LPE abates CCl4-induced hepatocarcinogenesis by attenuating liver inflammation and improving metabolic, biosynthetic, and detoxification functions of the liver. The prophylactic hepatoprotective and anti-hepatocarcinogenic effects of LPE are attributable to its phytochemical composition raising hopes of finding potential anticancer bioactive compounds from C. limon fruit peels.


Assuntos
Carcinoma Hepatocelular , Citrus , Neoplasias Hepáticas , Masculino , Ratos , Animais , Ratos Sprague-Dawley , Tetracloreto de Carbono , alfa-Fetoproteínas , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/tratamento farmacológico , Frutas , Azeite de Oliva , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/tratamento farmacológico , Carcinogênese , Alanina Transaminase , Fosfatase Alcalina , Aspartato Aminotransferases , Bilirrubina , Compostos Fitoquímicos , Glicogênio , Extratos Vegetais/farmacologia
18.
Sci Rep ; 14(1): 1434, 2024 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-38228668

RESUMO

Early and sensitive biomarkers of liver dysfunction and drug-induced liver injury (DILI) are still needed, both for patient care and drug development. We developed the Serum Enhanced Binding (SEB) test to reveal post-transcriptional modifications (PTMs) of human serum albumin resulting from hepatocyte dysfunctions and further evaluated its performance in an animal model. The SEB test consists in spiking serum ex-vivo with ligands having specific binding sites related to the most relevant albumin PTMs and measuring their unbound fraction. To explore the hypothesis that albumin PTMs occur early during liver injury and can also be detected by the SEB test, we induced hepatotoxicity in male albino Wistar rats by administering high daily doses of ethanol and CCl4 over several days. Blood was collected for characterization and quantification of albumin isoforms by high-resolution mass spectrometry, for classical biochemical analyses as well as to apply the SEB test. In the exposed rats, the appearance of albumin isoforms paralleled the positivity of the SEB test ligands and histological injuries. These were observed as early as D3 in the Ethanol and CCl4 groups, whereas the classical liver tests (ALT, AST, PAL) significantly increased only at D7. The behavior of several ligands was supported by structural and molecular simulation analysis. The SEB test and albumin isoforms revealed hepatocyte damage early, before the current biochemical biomarkers. The SEB test should be easier to implement in the clinics than albumin isoform profiling.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Fígado , Ratos , Masculino , Humanos , Animais , Fígado/metabolismo , Ratos Wistar , Doença Hepática Induzida por Substâncias e Drogas/patologia , Albuminas/metabolismo , Etanol/metabolismo , Biomarcadores/metabolismo , Isoformas de Proteínas/metabolismo , Tetracloreto de Carbono/toxicidade
19.
Phytomedicine ; 124: 155330, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38185067

RESUMO

BACKGROUND: Hepatic fibrosis is the pivotal determinant in the progression of chronic liver diseases towards cirrhosis or advanced stages. Studies have shown that Schisantherin A (Sin A), the primary active compound from Schizandra chinensis (Turcz.) Baill., exhibits anti-hepatic fibrosis effects. However, the mechanism of Sin A in liver fibrosis remain unclear. PURPOSE: To examine the effects and underlying mechanism of Sin A on hepatic fibrosis. STUDY DESIGN AND METHODS: The effects and mechanism of Sin A were investigated using liver fibrosis mouse models induced by carbon tetrachloride (CCl4) or dimethylnitrosamine (DMN), as well as H2O2-induced hepatocyte injury in vitro. RESULTS: Sin A treatment ameliorated hepatocyte injury, inflammation, hepatic sinusoidal capillarization, and hepatic fibrosis in both CCl4-induced and DMN-induced mice. Sin A effectively reversed the reduction of DDAH1 expression, the p-eNOS/eNOS ratio and NO generation and attenuated the elevation of hepatic ADMA level induced by CCl4 and DMN. Knockdown of DDAH1 in hepatocytes not only triggered hepatocyte damage, but it also counteracted the effect of Sin A on protecting hepatocytes in vitro. CONCLUSION: Our findings indicate that Sin A ameliorates liver fibrosis by upregulating DDAH1 to protect against hepatocyte injury. These results provide compelling evidence for Sin A treatment in liver fibrosis.


Assuntos
Ciclo-Octanos , Dioxóis , Peróxido de Hidrogênio , Lignanas , Hepatopatias , Camundongos , Animais , Peróxido de Hidrogênio/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Hepatócitos , Fígado , Hepatopatias/metabolismo , Tetracloreto de Carbono/efeitos adversos
20.
J Ethnopharmacol ; 321: 117516, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38042390

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: In the progression of chronic liver diseases, liver fibrosis is a reversible pathophysiologic event for liver diseases prognosis and risk of cirrhosis. Liver injury factors of different etiologies mediate this process. There is still a lack of effective medications for treating liver fibrosis. Additionally, the ameliorative effects of traditional herbs on liver fibrosis have been commonly reported. Tianhuang formula (THF) is a drug combination consisting of 2 traditional Chinese herbs, which has been showing significant improvement in metabolic liver diseases. However, the hepatoprotective effect and mechanism of THF in ameliorating liver fibrosis are still unclear. AIM OF THE STUDY: This study aimed to investigate the effects of THF on carbon tetrachloride (CCl4)-induced and methionine-choline-deficient (MCD) diet-induced liver fibrosis model and to reveal the potential mechanisms. It can provide experimental evidence for THF as a therapeutic candidate for liver fibrosis. MATERIALS AND METHODS: In this study, CCl4-induced mice were treated with THF (80 mg/kg, 160 mg/kg) or Fuzheng Huayu (FZHY) capsules (4.8 g/kg) for 6 weeks. MCD-induced mice received the same doses of THF or FZHY for 4 weeks. FZHY is used as a comparative study in these two models. Following that, using kit reagents detected changes in relevant serum and liver biochemical indicators. Histological changes in mouse liver were measured by staining of H&E and Sirius Red. The markers expression of liver fibrosis and inflammation were detected using qRT-PCR, western blotting and immunohistochemical staining analysis. The potential regulatory mechanism of THF to ameliorate liver fibrosis was performed by RNA-sequencing analysis. Finally, the analysis results were verified by immunofluorescence co-staining, qRT-PCR and western blotting. RESULTS: Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), and hepatic triglyceride (TG) levels in CCl4 and MCD-induced liver fibrosis mice were significantly improved after THF treatment. Meanwhile, the expression of fibrosis and inflammation markers were significantly suppressed. Furthermore, THF downregulated the expression of the macrophage marker CD68. According to RNA-sequencing analysis, we found the CCL2-CCR2 axis and MAPK/NF-κB as the potential signaling pathway for THF against liver fibrosis. CONCLUSION: This study revealed that THF ameliorated liver injury, inflammation and fibrotic process by inhibiting CCL2-CCR2 axis and its downstream MAPK/NF-κB signaling pathway.


Assuntos
Cirrose Hepática , NF-kappa B , Camundongos , Animais , NF-kappa B/metabolismo , Cirrose Hepática/induzido quimicamente , Cirrose Hepática/tratamento farmacológico , Cirrose Hepática/metabolismo , Fígado , Fibrose , Transdução de Sinais , Tetracloreto de Carbono/farmacologia , Inflamação/patologia , RNA/metabolismo , RNA/farmacologia , RNA/uso terapêutico
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