Search Results (327)

Liver fibrosis, a critical pathological feature of chronic liver injury, is closely associated with macrophage-mediated inflammatory responses and metabolic reprogramming. Blocking the fibrosis process will be beneficial to the treatment and recovery of the disease. Liver macrophages are a remarkably heterogeneous population of immune cells that play multiple functions in homeostasis and are central to liver fibrosis. Glycolysis-mediated macrophage metabolic reprogramming leads to an increase in the proportion of M1 macrophages and the release of pro-inflammatory cytokines. The present study aimed to investigate the therapeutic effect and mechanism of acid B (SAL B) against carbon tetrachloride (CCl₄)-induced liver fibrosis. Here, we demonstrate that SAL B reduced the production of inflammatory factors in CCl₄-induced liver fibrosis. Mechanistically, SAL B increased the expression of migration inhibitor 1 (MIG1) by inhibiting DNMT1-mediated methylation of the MIG1 promoter. Subsequently, MIG1 reduced the transcription of lactate dehydrogenase A (LDHA) and hexokinase 2 (HK2) which blocked glycolysis-mediated macrophage M1 polarization. In summary, our results suggested that SAL B is a promising intervention for ameliorating liver fibrosis. Full article

Retired chemically polluted sites in southern Jiangsu Province, China, are characterized by dense nonaqueous phase liquids (DNAPLs) and extremely thick aquifers (>30 m), which pose substantial challenges for determining investigation and remediation depths during redevelopment and exploitation. This study constructed a 2D groundwater transport model using TMVOC to systematically investigate the migration, diffusion, and natural attenuation processes of two typical DNAPLs—1,2-dichloroethane (DCE) and carbon tetrachloride (CTC)—under three scenarios: individual transport, mixed transport, and heterogeneous aquifer conditions, with a simulation period of 35 years. In individual transport scenarios, DCE and CTC showed distinct migration behaviors. DCE achieved a maximum vertical transport distance of 14.01 m and a downstream migration distance of 459.58 m, while CTC reached 13.57 m vertically and 453.51 m downstream. When transported as a mixture, their migration was inhibited: DCE’s vertical and downstream distances decreased to 13.76 m and 440.46 m, respectively; and CTC’s to 13.23 m and 420.32 m, likely due to mutual solvent effects that altered their physicochemical properties such as viscosity and solubility. Under natural attenuation conditions, both DNAPLs ceased downstream transport by the end of the 6th year. DCE concentrations dropped below its risk control value (0.81 mg/L) by the 14th year, and CTC (with a risk control value of 0.23 mg/L) by the 11th year. By the 10th year, DCE’s downstream plume had retreated to 48.65 m, and CTC’s to 0.95 m. In heterogeneous aquifers, vertical upward transport of DCE and CTC increased to 14.82 m and 14.22 m, respectively, due to the partial absence of low-conductivity silt layers, while their downstream distances decreased to 397.99 m and 354.11 m, constrained by low-permeability lenses in the migration path. These quantitative results clarify the dynamic differences in DNAPL transport under varying conditions, highlighting the impacts of multicomponent interactions, natural attenuation, and aquifer heterogeneity. They provide critical references for risk management, scientific determination of remediation depths, and safe exploitation of retired chemically polluted sites with similar hydrogeological characteristics. Full article

Background: Liver fibrosis, a consequence of various chronic liver diseases, is characterized by excessive accumulation of extracellular matrix (ECM), leading to impaired liver function and potentially progressing to cirrhosis or hepatocellular carcinoma. The molecular mechanisms underlying liver fibrosis are complex and not fully understood. In vivo experiments are essential for studying the molecular mechanisms of the disease. However, the diverse principles behind mouse modeling techniques for liver fibrosis can complicate the elucidation of specific fibrotic mechanisms. Methods: Five distinct liver fibrosis models were utilized: CONTROL, NASH (non-alcoholic steatohepatitis), BDL (bile duct ligation), TAA (thioacetamide), and CCl₄ (carbon tetrachloride). Patents for these drugs were reviewed using Patentscope^® and Worldwide Espacenet^®. ScRNA-seq was performed to analyze and compare the cellular and molecular differences in these models. Results: The analysis revealed that, particularly in the drug-induced fibrosis models, hepatic stellate cells (HSCs), Kupffer cells, and T-cell subsets exhibit distinct regulatory patterns and dynamic remodeling processes across different liver fibrosis models. These findings highlight the heterogeneity of immune responses and extracellular matrix (ECM) remodeling in various models, providing important insights into the complex mechanisms underlying liver fibrosis. Conclusions: The study enhances our understanding of liver fibrosis development and provides valuable insights for selecting the most representative animal models in future research. This comprehensive analysis underscores the importance of model-specific immune responses and ECM remodeling in liver fibrosis. Full article

Liver fibrosis remains a critical health concern with limited therapeutic options. Kaempferol (Kae) is a natural flavonoid widely present in natural plants, yet its role in modulating gut–liver axis interactions during fibrosis is unexplored. This study investigates the hepatoprotective effects of Kae on alleviating carbon tetrachloride (CCl₄)-induced liver fibrosis, and its underlying mechanisms, focusing on oxidative stress, gut microbiota, and short-chain fatty acids (SCFAs), are revealed. A mouse model of hepatic fibrosis was built by the subcutaneous injection of CCl₄. Meanwhile, Kae was administered by gavage at doses of 25, 50, and 100 mg/kg body weight. Serum biomarkers, liver histopathology, oxidative damage markers, and nuclear factor erythroid 2-related factor 2 (Nrf2)/kelch-like ECH-associated protein 1 (Keap1)/heme oxygenase 1 (HO-1) signaling were analyzed. AML12 hepatocytes were pretreated with Kae or SCFAs (acetate, propionate, butyrate) before H₂O₂-induced oxidative injury. The changes in gut microbiota and the levels of SCFAs were assessed via 16S rRNA sequencing and GC-MS, respectively. Kae effectively alleviated the destruction of the liver morphology and tissue structure, reduced the infiltration of inflammatory cells, collagen deposition in the liver, and the expression of fibrotic factors, and downregulated the oxidative stress level in the liver of mice with liver fibrosis by activating the Nrf2/Keap1/HO-1 pathway (p < 0.05 or 0.01). In vitro, Kae significantly mitigated H₂O₂-induced cytotoxicity and oxidative damage (p < 0.05 or 0.01). Furthermore, Kae restored gut microbiota diversity, increased beneficial genera (e.g., Lactobacillus), and elevated both intestinal and hepatic SCFA levels (p < 0.01). The discrepant SCFA pretreatment similarly protected AML12 cells by activating Nrf2 signaling (p < 0.05 or 0.01). Our research suggests that Kae could inhibit CCl₄-induced liver fibrosis by restoring the levels of intestinal metabolite SCFAs to reduce oxidative damage. Full article

Background: Taraxacum officinale (T. officinale), commonly known as dandelion, is a plant with recognized therapeutic properties in both traditional and modern medicine. Historically, it has been used to treat various conditions, particularly liver disorders, owing to its antioxidant and anti-inflammatory activities. This narrative review focuses on its biological activity, with an emphasis on hepatoprotective effects. Methods: We performed a compilation and analysis of published studies on the effects of T. officinale in animal models and its potential application in liver diseases. Results: Preclinical studies have reported that extracts of this plant protect against liver damage induced by toxic agents such as alcohol, carbon tetrachloride, and paracetamol. Among the most relevant and predominant bioactive compounds of T. officinale is taraxasterol, which modulates inflammatory and oxidative stress pathways, helping to prevent liver damage. Conclusions: While preclinical studies are promising, further clinical trials are essential to confirm the safety and efficacy of T. officinale in the treatment of liver diseases. Determining the optimal dosing, evaluating its potential as an adjuvant in pharmacological treatments, as well as evaluating possible interactions with conventional drugs, is necessary for the potential use of T. officinale as an adjuvant agent in the treatment of liver diseases. Full article

Background: Baicalin (BG) has been used in the treatment of many diseases. However, the effect of hepatic insufficiency on its pharmacokinetics has not been reported, and there is a lack of clinical guidance for the use of BG in patients with hepatic impairment. Methods: Carbon tetrachloride (CCl₄)-induced rat models were used to simulate hepatic failure patients to assess the effect of hepatic impairment on the pharmacokinetics and distribution of BG. In vitro metabolism and transporter studies were employed to elucidate the potential mechanisms. Results: After intragastric administration of 10 mg/kg of BG, the peak plasma concentration and exposure (AUC_0–t) of BG decreased by 64.6% and 52.6%, respectively, in CCl₄-induced rats. After intravenous administration, the AUC_0–t decreased by 73.6%, and unlike in the control group, the second absorption peak of BG was not obvious in the concentration–time curve of CCl₄-induced rats. The cumulative excretion of BG in the feces increased, but that in the bile decreased. In vivo data indicated that the absorption and enterohepatic circulation of BG were affected. In vitro studies found that the hydrolysis of BG to the aglycone baicalein decreased significantly in the intestinal tissues and contents of the CCl₄-induced rats. And BG was identified as a substrate for multiple efflux and uptake transporters, such as breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs), organic anion transporting polypeptides (OATP1B1, 1B3, 2B1), and organic anion transporters (OATs). The bile acids accumulated by liver injury inhibited the uptake of BG by OATPs, especially that by OATP2B1. Conclusions: Hepatic impairment reduced BG hydrolysis by intestinal microflora and inhibited its transporter-mediated biliary excretion, which synergistically led to the attenuation of the enterohepatic circulation of BG, which altered its pharmacokinetics. Full article

Bone marrow-derived macrophages (BMMs) exhibit dynamic behavior and functional capabilities in response to specific microenvironmental stimuli. Recent investigations have proved that BMMs play crucial roles in promoting necrotic lesion resolution. Despite substantial advancements in understanding their activation and interaction with injured livers, researchers face challenges to develop effective treatments based on manipulating BMMs function. Caveolin-1 (Cav-1) is the major structural protein on the plasma membrane. We previously reported that Cav-1 knockout (KO) mice exhibited less functional damage and necrosis in carbon tetrachloride (CCl₄)-induced liver injury. We hypothesize that the activation and recruitment of BMMs are involved in the resolution of necrotic lesions in Cav-1 KO mice. Wild-type (WT) and Cav-1 KO mice were injected with CCl₄ (10% v/v) to induce acute liver injury model. Blood samples and hepatic tissues were harvested for serum alanine transaminase (ALT) activity assessment, histopathological examination through hematoxylin–eosin (H&E) staining, and BMMs subpopulation analysis via flow cytometry. Then, primary BMMs were isolated and cultured to investigate the effect of Cav-1 on BMMs polarization, migration, and activation of STAT3 signal pathway. Validation of hepatic macrophage depletion was induced by administrating clodronate liposomes (CLs), and BMMs reconstitution was evaluated by EGFP labelled BMMs. Following this, hepatic macrophages were depleted by CLs, BMMs were isolated from Cav-1 KO, and WT mice were cultured and administrated to evaluate the protective role of Cav-1-deleted BMMs on the resolution of hepatocellular necrosis and apoptosis in acute liver injury. The BMMs ratio significantly increased from 2.12% (1D), 4.38% (1W), and 5.38% (2W) in oil control mice to 7.17%, 14.90%, and 19.30% in CCl₄-treated mice (p < 0.01 or p < 0.001). Concurrently, Cav-1 positive BMMs exhibited a marked elevation from 6.41% at 1D to 24.90% by 2W (p = 0.0228). Cav-1 KO exerted protective effects by reducing serum ALT by 26% (p = 0.0265) and necrotic areas by 28% (p = 0.0220) and enhancing BMMs infiltration by 60% (p = 0.0059). In vitro, Cav-1 KO BMMs showed a decrease in CD206 fluorescence intensity (p < 0.001), a time-dependent upregulation of arginase-1 mRNA (p < 0.05 or p < 0.01), a 1.22-fold increase in phosphorylated STAT3 (p = 0.0036), and impaired wound healing from 12 to 24 h (p < 0.001). The macrophage-depleting action in livers by CL injection persists for a minimum of 48 h. Administrated EGFP⁺ BMMs emerged as the predominant population following CL injection for a duration of 48 h. Following clodronate liposome-mediated hepatic macrophage depletion, the adoptive transfer of Cav-1 KO BMMs demonstrated therapeutic efficacy in CCl₄-induced acute liver injury. In CCl₄-induced acute liver injury, the adoptive transfer of Cav-1 KO BMMs reduced necrosis by 12.8% (p = 0.0105), apoptosis by 25.2% (p = 0.0127), doubled macrophages infiltration (p = 0.0269), and suppressed CXCL9/10 mRNA expression (p = 0.0044 or p = 0.0385). BMMs play a key role in the resolution of liver necrotic lesions in CCl₄-induced acute liver injury. Cav-1 depletion attenuates hepatocellular necrosis and apoptosis by accelerating BMMs recruitment and M2 polarization. Cav-1 in macrophages may represent a potential therapeutic target for acute liver injury. Full article

The aim of the present study was to investigate the alkaloids of Tibetan medicine Corydalis conspersa Maxim. and their hepatoprotective effect against carbon tetrachloride (CCl₄)-induced acute liver injury (ALI). The ethanol extract of this herbal medicine was subjected to a phytochemical study. Network pharmacology (NP) and molecular docking were used to predict the active constituents and mechanism of action against ALI. Seven alkaloid components were isolated and identified from this herb medicine, including acetylcorynoline (1, ACE), corynoline (2), scoulerine (3), protopine (4), bulbocapnine (5, BBC), palmatine (6), and isocorydine (7, ISO), among which compounds 1, 3, and 5 were isolated from this plant for the first time. Pharmacological experiments have shown that compounds 1, 5, 7, and the total alkaloids (TTA) of the plant exhibit good improvement effects on CCl₄-induced ALI in mice. NP and molecular docking predicted that their mechanism of action may be related to targets such as STAT3, SRC, EGFR, PIK3CA, and HSP90AA1. These research findings provide a theoretical basis for the development of the medicinal value of Tibetan medicine Corydalis conspersa Maxim. Full article

Previous studies have demonstrated that underwater low-temperature plasma is effective for synthesizing nanomaterials by generating plasma discharges between metal electrodes submerged in water. This study extends this approach to the one-step synthesis of MXenes containing titanium, molybdenum, and titanium–molybdenum composites through pulsed discharges in carbon tetrachloride, an oxygen-free, non-flammable solvent characterized by a high boiling point and low permittivity. By employing titanium and molybdenum electrodes in various configurations, three MXene samples were synthesized: Ti₂CT_X, Mo₂CT_X, and Mo₂TiC₂T_X. Characterization techniques, including UV-Vis spectroscopy, X-ray diffraction, Raman spectroscopy, scanning electron microscopy, and energy-dispersive X-ray spectroscopy, confirmed the successful synthesis of high-purity MXenes with distinct structural and optical properties. Notably, the bandgap values of the synthesized MXenes were determined as 1.71 eV for Ti₂CT_X, 1.42 eV for Mo₂TiC₂T_X, and 1.07 eV for Mo₂CT_X. The photocatalytic performance of the synthesized MXenes was evaluated, showing a removal efficiency of 65% to 98% for dye mixtures, with methylene blue showing the highest degradation rate. This plasma-assisted method offers a scalable, precursor-free route for the synthesis of MXenes with potential applications in energy storage, environmental remediation, and optoelectronics due to their tunable bandgaps and high catalytic activity. Full article

Background: Liver diseases are a global health issue with an annual mortality of 80,000 patients, mainly due to complications that arise during disease progression, as effective treatments are lacking. Objectives: This study evaluated the hepatoprotective effects of two derivatives of cinnamic acid, LQM717 and LQM755, in a murine model of acute liver damage induced by carbon tetrachloride (CCl_4, 4 g/kg, single dose p.o.). Methods: Male Wistar rats were pretreated with five doses of LQM717 (20 mg/kg i.p.) or LQM755 (equimolar dose), starting 2 days before inducing hepatotoxic damage with CCl₄. Results: The key parameters of hepatocellular function and damage showed significant increases in ALT, ALP, GGT, and total and direct bilirubin in rats intoxicated with CCl₄, with decreased liver glycogen and serum albumin. Macroscopic and microscopic liver examinations revealed reduced inflammation, necrosis, and steatosis in animals pretreated with LQM717 or LQM755. Hepatomegaly was observed only in the LQM717 + CCl₄ group. LQM755 statistically provided partial protection against increases in ALT and ALP and completely prevented elevations in GGT and total and direct bilirubin. LQM755 completely prevented albumin reduction, while LQM717 only partially prevented it. Both compounds partially prevented glycogen depletion. Bioinformatic analysis identified 32 potential liver protein targets for LQM717 and 36 for LQM755. Conclusions: These findings suggest that LQM717 and LQM755 have significant hepatoprotective effects against CCl₄-induced acute liver injury, providing information for future studies in other acute and chronic models, as well as to elucidate their mechanisms of action. Full article

The transformative effect of nanotechnology is revolutionizing medicine by introducing new therapeutic approaches. This study explores the utilization of aqueous extract from mushroom (Cortinarius sp.) used as a reducing agent to prepare zinc oxide myco-nanoparticles (ZnO-MNPs) in an eco-friendly manner. The synthesis of ZnO-MNPs has been confirmed by various characterization studies, including UV-vis spectroscopy, which revealed an absorption peak at 378 nm; X-ray diffraction (XRD) analysis, which revealed a wurtzite hexagonal structure; and Fourier transform infrared spectra (FTIR), which showed stabilizing agents around the ZnO-MNPs. The effectiveness of ZnO-MNPs as an anti-cancer agent was evaluated by monitoring liver biochemical parameters against hepatotoxicity caused by carbon tetrachloride (CCl₄) in Balb C mice. The results showed that the levels of catalase, glutathione (GSH), and total protein were significantly lower, while alanine aminotransferase (ALT), aspartate aminotransferase (ASAT), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), melanin dialdehyde (MDA), and total bilirubin (TB) were significantly higher in each of the CCl₄ treatment groups. ZnO-MNP treatment significantly reduced the toxicological effects of CCl₄ but did not completely restore the accumulation. The antimicrobial efficacy of ZnO-MNPs was investigated and showed potential results against common pathogens, including Bacillus subtilis (29.05 ± 0.76), Bacillus meurellus (27.05 ± 0.5), Acetobacter rhizospherensis (23.36 ± 0.5), and Escherichia coli (25.86 ± 0.80), while antifungal activity was relatively lower. Moreover, the 2,2-diphenyl-1-picrylhydrazyl (DPPH) assay showed that ZnO-MNPs are strong antioxidant agents. Overall, these findings highlight the effectiveness of myco-synthesized ZnO-NPs in combating pathogenic diseases, their promising role in cancer therapy, and their potential as a biomaterial option for future therapeutic applications. Full article

Abroma augustum (L.) L. f. is characterized by its fibrous structure, spiny trichomes, and distinctive leaf formations, which collectively contribute to its unique morphology and potential medicinal applications. This study aims to investigate the phytochemical constituents and elucidate the pharmacognostic and physicochemical characteristics of the stem bark powder, including evaluation of its antioxidant capacity and hepatoprotective effects against carbon tetrachloride (CCl₄)-induced hepatotoxicity in both in vitro and ex vivo experimental models. Comprehensive phytochemical screening identified 50 distinct phytochemicals, including a range of alkaloids, flavonoids, terpenes, phenolics, and coumarins, among others. The extract displayed substantial solubility, with total phenolic and flavonoid content quantified as 12.32 ± 0.01 mg/g and 42.14 ± 3.5 mg/g, respectively. The antioxidant activity revealed IC₅₀ values obtained from 2,2-diphenyl-1-picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), and 2,2′-azinobis-(3-ethylbenzothiazoline-6-sulfonic) acid (ABTS), measured at 214.007 µg/mL, 132.307 µg/mL, and 45.455 µg/mL, respectively. Additionally, the methanolic extract exhibited significant hepatoprotective properties, with observable reductions in lipid peroxidation and decreased concentrations of liver damage biomarkers (ALT, AST, and LDH) in both HepG2 cells and goat liver homogenate. Future investigations are warranted to elucidate the underlying mechanisms of these effects, including histopathological examinations and biochemical assays, followed by the administration of plant methanolic extracts. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem and the discovery of drugs is challenging. In this study, we aimed to investigate the effects of intestinal activation of the liver X receptor (LXR)α on MASH. Methods: An intestinal-specific LXRα activation model in mice was established and subjected to MASH development by combining a Western diet and carbon tetrachloride. Lipid metabolism, reverse cholesterol transport (RCT), steatosis, inflammation, and fibrosis were evaluated. In vitro models of steatosis and fibrosis were used to explore the role of scavenger receptor class B type 1 (SRB1). Results: We found that the intestinal activation of LXRα improved several MASLD features, including levels of triglycerides, RCT, steatosis, systemic and hepatic inflammatory profiles, and liver fibrosis. These effects were associated with increased high-density lipoprotein (HDL) levels and hepatic SRB1 expression. In vitro depletion of SRB1 hampered the beneficial effects of HDL on steatosis and fibrogenesis in liver cells by altering the activation of both peroxisome proliferator-activated receptors γ and small mothers against decapentaplegic homolog protein (SMAD)2/3 proteins. Conclusions: Our findings showed that the intestinal activation of LXRα and a parallel induction of hepatic SRB1 are protective against inflammation, steatosis, and advanced liver fibrosis in MASLD. Full article

Background: Liver regeneration is a critical measure of liver health and plays an essential role in inhibiting the progression of fibrotic lesions and preventing liver failure after hepatocellular carcinoma surgery. However, there are no approved drugs to address this clinical challenge. Methods: The effects of TUDCA on liver regeneration and fibrosis were studied using BRL-3A cells, a partial hepatectomy (PH) rat liver regeneration model, and a carbon tetrachloride (CCl₄)-induced liver fibrosis model. GATA3-knockdown BRL-3A cells were employed to assess the role of GATA3 in TUDCA-induced proliferation. Results: TUDCA promoted the proliferation of BRL-3A cells and enhanced liver regeneration in PH rats while ameliorating liver fibrosis in CCl₄-treated rats. Additionally, the knockdown of GATA3 eliminated the proliferative effect of TUDCA on BRL-3A cells. Conclusions: TUDCA promotes liver regeneration and alleviates liver fibrosis by activating GATA3. Full article

Isoquercitrin, a flavonoid glycoside found in various plants, has demonstrated antioxidant, anti-inflammatory, and anticancer properties. However, its hepatoprotective effects and underlying mechanisms against oxidative liver injury remain unclear. In this study, we evaluated the antioxidant and hepatoprotective effects of isoquercitrin using integrated in silico, in vitro, and in vivo approaches. HepG2 cells exposed to arachidonic acid (AA) and iron exhibited oxidative stress-induced apoptosis, which was significantly attenuated by isoquercitrin treatment, as evidenced by increased cell viability and reduced apoptosis-related protein alterations. Isoquercitrin decreased reactive oxygen species (ROS) generation and preserved mitochondrial function in a dose-dependent manner. Molecular docking and Western blot analyses revealed that isoquercitrin activates the LKB1/AMPK pathway, increasing phosphorylation of AMPK and its downstream target ACC, thereby modulating energy metabolism and reducing oxidative stress. This activation was LKB1 dependent, as confirmed in LKB1-deficient HeLa cells. Additionally, isoquercitrin modulated the YAP signaling pathway in hepatic cells. In vivo, isoquercitrin protected mice against carbon tetrachloride-induced liver injury, reducing serum ALT and AST levels and improving histopathological features. These findings suggest that isoquercitrin exerts hepatoprotective effects by activating the LKB1/AMPK pathway and modulating metabolic enzymes, highlighting its potential as a therapeutic agent against oxidative liver damage. Full article