Hepatoprotective effects of olive leaf extract against carbon tetrachloride-induced oxidative stress: in vivo and in-silico insights into the Nrf2-NFκB pathway.

Olive Leaves Extract (OLE) holds therapeutic potential, traditionally used to treat hepatic ailments, though its molecular mechanisms remain unclear. This study evaluated the efficacy of ethanolic OLE against Carbon Tetrachloride (CCl4)-induced oxidative stress in a rat model. Phytochemical analysis was performed using High Performance Liquid Chromatography (HPLC). For this porous, thirty rats were divided into six groups (n = 5): Group 1 (negative control) received a standard diet, while Groups 2-6 were subjected to CCl4-induced toxicity. Group 2 served as the disease control, and Group 3 was treated with silymarin (100 mg/kg). Groups 4, 5, and 6 received OLE at 100 mg/kg, 200 mg/kg, and 300 mg/kg, respectively, for 21 days. OLE significantly modulated hepatic biomarkers (ALT, AST, ALP), increased Total Antioxidant Capacity (TAC), decreased Total Oxidation Capacity (TOC), and restored levels of SOD, GSH, and CAT compared to the CCl4 group. Malondialdehyde (MDA) levels, elevated in the disease group, however downregulated by OLE, particularly at 300 mg/kg. Histological examination revealed normal liver integrity in the OLE-treated groups. Additionally, OLE modulated the mRNA expression of IL-1β, IL-6, TNF-α, NF-kB, Bcl2, and p-53. Apoptotic markers such as Nrf2, HO-1, Cytochrome c, caspase 3, caspase 7, and Bax were normalized with OLE treatment. The inhibition of KEAP1-NRF2 protein-protein interaction showed OLE's superior efficacy compared to silymarin, with a better docking score. These findings suggest that OLE exerts significant hepatoprotective effects against CCl4-induced oxidative stress and inflammation via the Nrf2-NFκB pathway.

Buzdar JA ，Shah QA ，Khan MZ ，Zaheer A ，Shah T ，Ataya FS ，Fouad D ... -  《-》

Hepatoprotective efficacy of Argemone mexicana L. root in paracetamol-induced hepatotoxicity in a rat model.

Argemone mexicana L. (Papaveraceae), a weed that thrives in the tropical and subtropical areas of South and Central America, Mexico, Caribbean Islands and India. In India, it has been used traditionally to treat vesicular calculus, inflammatory conditions, and hepatobiliary disorders. The present study was aimed to investigate the hepatoprotective efficacy of A. Mexicana roots in paracetamol (PCM)-induced toxicity rat. The methanol extract of A. mexicana (MEAM) root was analyzed using Gas Chromatography-Mass Spectrometry (GC-MS) analysis to identify its compounds. Molecular docking analysis of the compounds was conducted against TGF-β and PPAR-α. The hepatoprotective activity of MEAM (200, 400 mg/kg) was evaluated in PCM (3000 mg/kg) intoxicated rats by measuring serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), lactate dehydrogenase (LDH), total bilirubin (TB), total protein (TP), albumin (ALB), globulin (GLB), total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C). Silymarin (100 mg/kg) was used as reference drug. Oxidative stress biomarkers such as superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH), and lipid peroxidation (LPO) were investigated using liver homogenate. Additionally, the levels of pro-inflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and anti-inflammatory cytokines interleukin-4 (IL-4) and interleukin-10 (IL-10) were studied. The results of the study were supported by histopathological examination. GC-MS analysis revealed 163 compounds, from which eleven compounds were selected based on their docking scores against TGF-β and PPAR-α. MEAM (400 mg/kg) demonstrated a remarkable reduction in ALT, AST, ALP, GGT, and LDH in contrast to the PCM intoxicated group. A remarkable decline in TB and GLB, along with an increase in TP and ALB, was observed in the MEAM (400 mg/kg) group compared to the untreated PCM group. Rats receiving MEAM (400 mg/kg) exhibited a noticeable decrease in TC, TG, and LDL-C, along with an increase in HDL-C levels compared to PCM-induced untreated rats. The higher dose of MEAM also resulted in a significant decrease in TNF-α, IL-1β, and IL-6, and an increase in IL-4 and IL-10. Similarly, a notable elevation in SOD, CAT, and GSH, along with a decrease in MDA content, was observed in the group receiving MEAM (400 mg/kg). The histopathological result showed reduction of sinusoidal space and vesicular nuclei, with improvement of hepatocytes at the dose of MEAM (400 mg/kg). In molecular docking study, Eupatilin exhibited the highest docking scores of -10.4 kcal/mol and -9.1 kcal/mol against TGF-β and PPAR-α, respectively. MEAM root at dose of 400 mg/kg exhibited hepatoprotective effect against PCM-induced toxicity rat. Eupatilin might be considered as a potential candidate for the hepatoprotective effect of A. mexicana root.

Bagchi A ，Raha A ，Das C ，Dash P ，Pradhan D ，Rai VK ，Rajwar TK ，Halder J ，Das D ，Manoharadas S ，Kar B ，Ghosh G ，Rath G ... -  《-》

Unveiling the hepatoprotective mechanisms of Desmodium heterocarpon (L.) DC: Novel flavonoid identification and Keap1/Nrf2 pathway activation.

The pathophysiology of liver diseases is significantly influenced by oxidative stress, making its alleviation a key strategy for treatment. The Keap1/Nrf2 signaling pathway is the body's most crucial antioxidant defense mechanism. Traditional Chinese medicine, Desmodium heterocarpon (L.) DC, has shown promising hepatoprotective effects, however, the specific active components and underlying mechanisms of its liver-protective properties remain inadequately understood. Further investigation into the bioactive constituents and mechanisms of its hepatoprotective action is therefore essential. This study aims to identify the active ingredients in D. heterocarpon and to explore its hepatoprotective properties and underlying mechanisms. The hepatoprotective activity of the ethyl acetate fraction (JEAE) from D. heterocarpon was first evaluated utilizing a mouse model of acute liver damage (ALI) caused by CCl4. Molecular and histological analyses, including H&E staining, ELISA, and Western blot, were used to assess liver protection. The chemical constituents of JEAE were further identified using UPLC-MS/MS, and the molecular network of the JEAE fraction was analyzed. Compounds were isolated through column chromatography, and their antioxidant and hepatoprotective effects were assessed in an H₂O₂-induced HepG2 cell model using molecular assays. Additionally, binding interactions between active compounds and Keap1 were evaluated using molecular docking, molecular dynamics simulations, and surface plasmon resonance. The ethyl acetate fraction of Desmodium heterocarpon (JEAE) showed remarkable antioxidant activity, with the highest flavonoid contents among extract fractions. In CCl₄-induced liver injury models, JEAE improved liver function, reduced ALT and AST levels, and enhanced antioxidant enzyme activities, suggesting hepatoprotective effects via the Keap1/Nrf2 pathway. 47 compounds were identified in JEAE, and fourteen flavonoids, including two novel compounds (1 and 2), were isolated from the JEAE fraction. Compounds 1, 3, 5, 8, and 14 notably protected HepG2 cells from oxidative damage, reduced ROS levels, and maintained mitochondrial function. These compounds also showed strong binding affinities to Keap1 and other antioxidant receptors, with molecular dynamics simulations confirming their stability and binding potential as effective hepatoprotective agents. This study demonstrates that the ethyl acetate fraction of Desmodium heterocarpon (JEAE) exhibits significant hepatoprotective effects, largely attributed to its flavonoid-rich composition. The protective effects are mediated through antioxidant pathways, particularly the Keap1/Nrf2 signaling pathway. Newly identified isoflavanes and other flavonoids in JEAE show strong potential as bioactive compounds, with stability and binding affinities supporting their role in reducing oxidative stress. These findings suggest D. heterocarpon as a promising source of hepatoprotective agents and provide a foundation for further exploration of its therapeutic applications.

Pu X ，Lu C ，Yang X ，He H ，Chen X ，Wang R ，Li B ，Chen S ，Zhang Y ，Wang W ，Li Y ... -  《-》

[Sulforaphane alleviates acute liver injury induced by diquat in mice by activating Keap1/Nrf2 signaling pathway].

Wang J ，Peng L ，Wu L ，Huang S ，He G ，Shen P ，Liang J ，Huang T ，Huang J ，Zhong H ，Zhou M ... -  《-》

The administration of Glycyrrhiza polysaccharides mitigates liver injury in mice caused by mancozeb via the Keap1-Nrf2/NF-κB pathway.

The extensive utilization of mancozeb (MCZ) poses environmental pollution risks, threatens human health, particularly hepatotoxicity. Glycyrrhiza polysaccharides (GP) exhibit antioxidant, anti-inflammatory and other biological activities. The aim of this study is to explore the mechanism of liver injury in mice exposed to MCZ and the protective effect of GP on alleviating MCZ induced liver injury. Initially, 70 female mice were divided into 7 groups, and the optimal dose of MCZ induced liver injury in mice was screened by oral administration different doses of MCZ (0, 50, 100, 150, 200, 250 and 300 mg/kg MCZ). The results demonstrated that, compared to the blank control group, as the concentration of MCZ increased, several physiological and biochemical parameters were significantly affected. Specifically, body weight and liver index significantly decreased, while the activities of SOD and CAT also decreased. Additionally, the content of ROS increased, the levels of Keap1 and Nrf2 proteins increased, the mRNA levels of Gpx2 and HO-1decreased, and the mRNA levels of Gstt2, GcLc and NQO1 were upregulated. Based on the test data, select 100 mg/kg MCZ as the optimal modeling dose for experimental animals. Sixty female mice were divided into six groups and orally administered: control group A (0.2 mL deionized water), model group B (100 mg/kg MCZ), positive control group F (100 mg/kg MCZ+100 mg/kg VC), the high-dose GP group C (100mg/kgMCZ+200mg/kgGP), the medium-dose GP group D (100 mg/kg MCZ+150mg/kgGP) and the low-dose GP group E (100 mg/kg MCZ+100mg/kgGP). The results showed that compared to the model group, adding GP alleviated the effects of MCZ on body weight, liver index, CAT and SOD activity, MDA content, HO-1, TNF-α, and IL-1β. Additionally, the addition of GP decreased the expression of Keap1, Nrf2, NF-kB, and NQO1, GcLc, and Gstt2 mRNA. GP ameliorated liver vacuolar degeneration, steatosis and nuclear pyknosis ameliorate by MCZ. The results show that MCZ triggers hepatotoxicity via the activation of the Keap1/Nrf2 signaling pathway, whereas GP has the potential to mitigate liver damage caused by MCZ exposure by inhibiting this pathway.

Gao N ，Li Y ，Zhang L ，Zhang Y ，Wang X ... -  《-》