Involution of the bursa of Fabricius (BF) with increasing age in avian species leads to decreases in lymphocyte counts and pathogen recognition, thereby compromising immune function and increasing susceptibility to infections. Polysaccharides of Atractylodes macrocephala Koidz (PAMK), a major component of the traditional Chinese medicine Atractylodes macrocephala, increase immunity. This study aimed to explore the impact of PAMK on the BF during involution in Magang geese. Following the prefeeding period, 54 four-month-old Magang geese were selected for the experiment. These geese were evenly divided into three groups. Each group consisted of three replicates, with six geese per replicate. One group was immediately euthanized to collect serum and BF samples. The remaining 36 geese were further divided into two groups: one group was maintained on a standard diet, and the other group was provided a diet supplemented with 400 mg/kg PAMK. One month later, serum and BF samples were collected for analysis. Morphological, organ index and histological observations indicate that PAMK can alleviate the significant reduction in the organ index of the BF during the involution process in Magang geese and mitigate the disorder of follicular arrangement and the decrease in the ratio of the cortical area to the medullary area in the BF. Immunoglobulin and oxidative stress results revealed that PAMK can increase the levels of immunoglobulins and reduce oxidative stress in involuting Magang geese. Functional enrichment analysis revealed that the Wnt signaling pathway plays a significant role in alleviating the involution of the BF in Magang geese. Further cellular studies revealed that the addition of PAMK inhibited apoptosis and promoted cell cycle progression into the S and G2 phases. In summary, PAMK effectively mitigates the involution of the BF in Magang geese by inhibiting the Wnt signaling pathway, thereby enhancing humoral immunity and improving antioxidant status.

Astragaloside IV (C41H68O14, AS-IV) is a naturally occurring saponin isolated from the root of Astragalus membranaceus, a widely used traditional Chinese botanical drug in medicine. In recent years, AS-IV has attracted considerable attention for its hepatoprotective properties, which are attributed to its low toxicity as well as its anti-inflammatory, antioxidant and antitumour effects. Numerous preclinical studies have demonstrated its potential in the prevention and treatment of various liver diseases, including multifactorial liver injury, metabolic-associated fatty liver disease, liver fibrosis and liver cancer. Given the promising hepatoprotective potential of AS-IV and the growing interest in its research, this review provides a comprehensive summary of the current state of research on the hepatoprotective effects of AS-IV, based on literature available in databases such as CNKI, PubMed, ScienceDirect, Google Scholar and Web of Science. The hepatoprotective mechanisms of AS-IV are multifaceted, encompassing the inhibition of inflammatory responses, reduction of oxidative stress, improvement of insulin and leptin resistance, modulation of the gut microbiota, suppression of hepatocellular carcinoma cell proliferation and induction of tumour cell apoptosis. Notably, key molecular pathways involved in these effects include Nrf2/HO-1, NF-κB, NLRP3/Caspase-1, JNK/c-Jun/AP-1, PPARα/FSP1 and Akt/GSK-3β/β-catenin. Toxicity studies indicate that AS-IV has a high level of safety. In addition, this review discusses the sources, physicochemical properties, and current challenges in the development and clinical application of AS-IV, providing valuable insights into its potential as a hepatoprotective agent in the pharmaceutical and nutraceutical industries.

The integration of integrin-binding peptides within self-assembling building blocks is crucial for the development of targeted nanoarchitectonics. However, such constructs typically incorporate only a single integrin-binding peptide, limiting their multifunctionality. Herein, a rationally designed self-assembling peptide with dual integrin-binding motifs for α5β1 and αvβ3 is presented. This peptide forms highly ordered nanofibers or nanoparticles (VH-NPs) with tailored secondary structures. In vitro and in vivo studies demonstrate that VH-NPs target activated hepatic stellate cells via dual-integrin interactions, enabling selective targeting to fibrotic livers and suppressing α5β1 and αvβ3. Notably, VH-NPs can encapsulate rhein through noncovalent interactions, resulting in peptide-rhein nanoarchitectonics that display augmented antifibrotic effects. These findings highlight the potential of self-assembling peptides that leverage multiple targets and therapeutic modules as a promising strategy for constructing multifunctional nanoarchitectonics.

Liver fibrosis is a key pathological process in chronic liver diseases, regulated by various cytokines and signaling pathways. Among these, the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway plays a significant role in the initiation and progression of liver fibrosis. Recently, natural products have garnered attention as potential anti-fibrotic agents. This review highlights recent studies on how natural products, including flavonoids, terpenoids, polysaccharides, phenols, alkaloids, quinones, phenylpropanoids, steroids, and nitrogen compounds, mitigate liver fibrosis by modulating the NF-κB signaling pathway. Specifically, it examines how these natural products influence NF-κB activation, nuclear translocation, and downstream signaling, thereby inhibiting inflammatory responses, reducing apoptosis, and regulating hepatic stellate cell (HSC) activity, ultimately achieving therapeutic effects against liver fibrosis. A deeper understanding of the mechanisms by which natural products regulate the NF-κB signaling pathway can provide crucial theoretical foundations and valuable insights for the development of novel anti-fibrotic drugs.

Antagonistic peptide Leu-Ser-Lys-Leu (LSKL) is capable of blocking the transforming growth factor-β1 (TGF-β1) signaling pathway and exhibits anti-fibrotic effects. Herein, we constructed LSKL nanoparticles (NPs) in situ based on an alkaline phosphatase (ALP)-instructed self-assembly strategy for improving its specific therapeutic effect against liver fibrosis.

Reactive oxygen species (ROS) are widely considered key to pathogenesis in chronic metabolic disease. Consequently, much attention is rightly focused on minimising oxidative damage. However, for ROS production to be most effectively modulated, it is crucial to first appreciate that ROS do not solely function as pathological mediators. There are >90 gene products specifically evolved to generate, handle, and tightly buffer the cellular concentration of ROS. Therefore, it is likely that ROS plays a role as integral homeostatic signalling components and only become toxic in extremis. This review explores these commonly overlooked normal physiological functions, including how ROS are generated in response to environmental or hormonal stimuli, the mechanisms by which the signals are propagated and regulated, and how the cell effectively brings the signal to an end after an appropriate duration. In the course of this, several specific and better-characterised signalling mechanisms that rely upon ROS are explored, and the threshold at which ROS cross from beneficial signalling molecules to pathology mediators is discussed.

(1) Background: Cystic echinococcosis (CE) is an Echinococcus granulosus-induced worldwide parasitic zoonosis and is a recognized public health and socio-economic concern. The liver is the major target organ for CE's infective form protoscolex (PSCs), which causes serious liver damage and endangers the host's life. Reports show that PSC infection causes liver cell Fe2+ metabolism disorder and abnormal deposition of Fe2+ in liver cells and results in liver cell death. However, whether PSC-induced liver cell death is associated with ferroptosis remains to be clarified. (2) Methods: Using both an in vivo rat model and an in vitro co-culture of PSCs and the cell system, we studied the histopathological progress of PSCs infection and the cytopathogenesis of PSC-induced cell death in the liver. Hepatic-injury-related ferroptosis signaling pathways were identified by proteomics analysis at various stages of PSCs infection, and physiological and the biochemical indexes and expression of pathway proteins related to hepatic ferroptosis were studied. Ferrostatin-1, a ferroptosis inhibitor, was employed for in vivo interference with early protoscolices infection in rats, and the effects of the inhibition of hepatocyte ferroptosis on hepatocyte injury and the generation of fibrotic cysts were investigated. Additionally, PSCs were exposed to in vitro co-culture with BRL, a rat hepatocyte line, to clarify the direct influences of PSCs on BRL ferroptosis. (3) Results: The results of our in vivo studies revealed that PSCs infection induced Fe2+ enrichment in liver cells surrounding the PSCs cysts, cellular oxidation, and liver tissue damage along with the prolongation of PSCs parasitism. The results of our in vitro studies verified the ability of PSCs to directly induce ferroptosis, the formation of fibrotic cysts, and alteration of the iron metabolism of liver cells. The analysis of KEGG signaling pathways revealed that ferroptosis- and ROS-related pathways were significantly induced with PSCs infection. Using Ferrostatin-1 effectively blocked ferroptosis, reversed Fe2+ content, reduced liver cell oxidation, and reduced PSC-induced fibrosis cysts. (4) Conclusions: Our study reveals the histopathological progress of PSC infection and the cytopathogenesis of PSC-induced ferroptosis. Ferrostatin-1 effectively blocked PSCs infection and PSC-induced cell death in vivo and in vitro. Accordingly, the inhibition of PSC-induced hepatocyte ferroptosis may be an effective method in the control of Echinococcus granulosus infection and should be seriously considered in clinical studies.

There is growing evidence that NADPH oxidase 4 (Nox4) in hepatocytes contributes to liver inflammation and fibrosis during the development of metabolic dysfunction-associated steatohepatitis (MASH). However, how Nox4 is regulated and leads to liver pathogenesis is unclear. Our previous studies showed that the cytosolic protein SH3 domain-containing Ysc84-like 1 (SH3YL1) regulates Nox4 activity. Here, we asked whether SH3YL1 also participates in liver inflammation and fibrosis during MASH development. We generated that whole body SH3YL1 knockout (SH3YL1-/-), Nox4 knockout (Nox4-/-) mice, and the hepatocyte-specific SH3YL1 conditional knockout (Alb-Cre/SH3YL1fl/fl) mice were fed a methionine/choline-deficient (MCD) diet to induce liver inflammation and fibrosis in pathogenesis of MASH. Palmitate-stimulated primary SH3YL1-and Nox4-deficient hepatocytes and hepatic stellate cells (HSCs) did not generate H2O2. While the liver of MCD diet-fed wild type (WT) mice demonstrated elevated 3-nitrotyrosine as a protein oxidation and 4-hydroxynonenal adducts as a lipid oxidation and increased liver inflammation, hepatocyte apoptosis, and liver fibrosis, these events were markedly reduced in SH3YL1-/-, Nox4-/-, and Alb-Cre/SH3YL1fl/fl mice. The MCD diet-fed WT mice also showed elevated hepatocyte expression of SH3YL1 protein. Similarly, liver biopsies from MASH patients demonstrated strong hepatocyte SH3YL1 protein expression, whereas hepatocytes from patients with steatosis weakly expressed SH3YL1 and histologically normal patient hepatocytes exhibited very little SH3YL1 expression. The Nox4-SH3YL1 complex in murine hepatocytes elevates their H2O2 production, which promotes the liver inflammation, hepatocyte apoptosis, and liver fibrosis that characterize MASH. This axis may also participate in MASH in humans.

Liver fibrosis is a significant contributor to global morbidity and mortality, making the identification of non-toxic natural therapies to slow its progression essential. This study evaluated the anti-fibrotic potential of a nutraceutical blend comprising extra virgin olive oil, linseed oil, and ginger extract, formulated in both emulsion and nanoemulsion forms, using a rat model of liver fibrosis. Nanoemulsions were prepared using the ultrasonication technique, and their particle size and stability were analyzed via the DLS method. Twenty-four male albino rats were divided into four groups: normal control, CCl4-treated, oil emulsion-treated, and nanoemulsion-treated. Liver fibrosis was induced by oral administration of carbon tetrachloride (CCl4), while the emulsions were administered daily alongside CCl4 for four weeks. Liver function indices, oxidative stress biomarkers, and gene expressions were assessed, along with histopathological and immunohistochemical analyses. The results revealed that both emulsions significantly improved liver function, enhanced antioxidant capacity, and reduced lipid peroxidation. They downregulated pro-fibrogenic markers (TGF-β1, TIMP-1) and upregulated anti-fibrogenic markers (MMP9, HGF), leading to a reduction in liver fibrosis. The nanoemulsion exhibited superior efficacy compared to the emulsion. These findings demonstrate that the nutraceutical blend, particularly in nanoemulsion form, effectively attenuated liver fibrosis and improved hepatic health markers. This underscores its potential as a natural therapy for liver fibrosis and related conditions, emphasizing its nutritional value in supporting liver health.

Oxidative stress plays a crucial role in the pathogenesis of HBV. This study aimed to investigate the value of fibroblast growth factor 21 (FGF21) promoter methylation in the occurrence and development of chronic hepatitis B (CHB) oxidative stress.

A total of 241 participants including 221 patients with CHB and 20 healthy controls (HCs) were recruited. Methylation level of FGF21 promoter in peripheral blood mononuclear cells was quantitatively determined. Enzyme-linked immunosorbent assay was used to assess oxidative stress in CHB patients.

Our study shows that the FGF21 methylation level was significantly lower in HBeAg-positive CHB patients compared to HBeAg-negative CHB patients and HCs (P < 0.0001). The oxidative stress of HBeAg-positive CHB patients was more severe. Further correlation analysis showed that there was a significant correlation between the methylation level of FGF21 promoter and the occurrence of oxidative stress in CHB patients. In addition, assessment based on FGF21 promoter methylation level proved effective for predicting oxidative stress occurrence and disease progression among CHB patients.

FGF21 promoter methylation level is an important marker for predicting oxidative stress and disease progression in patients with CHB.

Cyclophosphamide (CP)-induced hepatotoxicity is a significant problem in clinical settings. This study aimed to evaluate the protective effect of levocabastine (LEV) on CP-induced hepatotoxicity in Swiss albino mice.

Mice were given CP (toxic drug) 200 mg/kg, i.p., once on the 7th day, and LEV 50 and 100 µg/kg, i.p., and fenofibrate (FF) 80 mg/kg, p.o., daily for 14 days. On the 15th day, blood and liver samples were collected to assess biological parameters. CP 200 mg/kg caused hepatotoxicity due to oxidative stress, inflammation, apoptosis, and fibrosis as manifested by a reduction in catalase, reduced glutathione (GSH), superoxide dismutase (SOD), and an increase in thiobarbituric acid reactive substance (TBARS), nitrite, tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), transforming growth factor-beta 1 (TGF-β1), interleukin-1β (IL-1β), alkaline phosphatase (ALP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) levels. Cleaved caspase-3 and nuclear factor kappa-B (NF-κB) expression was also increased and nuclear factor erythroid 2-related factor (Nrf2) expression was decreased as confirmed by Immunohistochemical analysis. It also caused histopathological abnormalities and fibrosis as manifested by Hematoxylin-Eosin (H&E) and Masson's trichrome (MT) staining. These alterations were returned to almost normal when treated with LEV 100 µg/kg and FF 80 mg/kg. Thus, LEV protected CP-induced hepatotoxicity by reversing inflammation, apoptosis, fibrosis, oxidative stress, hepatic injury, and histopathological damages.

LEV can be helpful as an adjuvant in cancer patients who are on CP treatment, to minimize toxicity. However, its role in in-vivo cancer model is further needed to be confirmed.

The liver is vitally metabolic for a multitude of biochemical reactions. Consequently, it generates many free radicals and reactive oxygen species, rendering it more susceptible to oxidative stress-induced damage. Oxidative stress represents a pivotal factor in the pathogenesis of liver diseases. We screened some antioxidant peptides previously. Here we investigated whether the peptides could attenuate oxidative damage with APPH in L02 cells. The results showed that one of the peptides, sequence FETLMPLWGNK, could decrease the excessive reactive oxygen species, increase antioxidant enzyme activity and protect mitochondrial function, reduce the ratio of apoptosis and S phase cycle arrest, and improve the survival rate of L02 cells damaged by APPH compared to cells of the control group. Then the peptide was evaluated in mice that CCl4 injured. We found that CCl4-injured mice had significantly increased serum inflammatory factors and liver injury markers, a large number of inflammatory cell infiltration, and local necrosis in the liver. The peptide could reduce inflammation, and improve liver pathological changes. This phenomenon may be associated with the activation of the Nrf2 signaling pathway. Concurrently, the peptide protects the liver by regulating the expression of proteins related to the mitochondrial apoptosis pathway (p53, Bax, Bcl-2, and Caspase3) and mitophagy-related proteins (PINK1, Parkin, and AMPKα). Therefore, the results indicated that the peptide is an active substance with antioxidant activity and anti-inflammatory effects.

Pyroptosis, a newly identified form of programmed cell death intertwined with inflammatory responses, is facilitated by the Gasdermin family's pore-forming activity, leading to cell lysis and the release of pro-inflammatory cytokines. This process is a double-edged sword in innate immunity, offering protection against pathogens while risking excessive inflammation and tissue damage when dysregulated. Specifically, pyroptosis operates through two distinct signaling pathways, namely the Caspase-1 pathway and the Caspase-4/5/11 pathway. In the context of chronic liver diseases like fibrosis and cirrhosis, inflammation emerges as a central contributing factor to their pathogenesis. The identification of inflammation is characterized by the activation of innate immune cells and the secretion of pro-inflammatory cytokines such as IL-1α, IL-1β, and TNF-α. This review explores the interrelationship between pyroptosis and the inflammasome, a protein complex located in liver cells that recognizes danger signals and initiates Caspase-1 activation, resulting in the secretion of IL-1β and IL-18. The article delves into the influence of the inflammasome and pyroptosis on various liver disorders, with a specific focus on their molecular and pathophysiological mechanisms. Additionally, the potential therapeutic implications of targeting pyroptosis for liver diseases are highlighted for future consideration.

Hepatic fibrosis is becoming an increasingly serious public health issue worldwide. Although liver transplantation is the only and definitive treatment for end-stage liver fibrosis, traditional Chinese medicine offers certain benefits in the treatment of advanced hepatic fibrosis.

This study aims to explore the protective effect of lithospermic acid (LA), an extraction from Salvia miltiorrhiza (the roots of S. miltiorrhiza Bunge, known as Danshen in Chinese), on liver fibrosis and investigate its potential mechanisms.

Mice were treated with carbon tetrachloride (CCl4) via intraperitoneal injection for 4 weeks. LA was orally administered or colchicine (COL) was injected intraperitoneally for 3 weeks starting one week after the initial CCl4 injection. After the LA treatment, we observed a decrease in the fibrosis index and an improvement in liver function. Molecular docking results revealed that Piezo1 may be a potential pharmacological target of LA. The further experimental results showed that LA inhibited Piezo1 activation and expression in macrophages. Mechanistically, both Piezo1/Notch-mediated inflammation and oxidative stress regulated by the Piezo1/Ca2+ pathway were alleviated in fibrotic livers following LA treatment. Moreover, less oxidative stress and Notch activation were observed in the deficiency of macrophage Piezo1 (Piezo1ΔLysM) mice. In addition, Piezo1ΔLysM partially counteracted the pharmacological effects of LA on liver fibrosis.

In conclusion, our present study corroborated LA limits the progression of liver fibrosis by regulating Piezo1-mediated oxidative stress and inflammation. These results indicate that LA could be a potential medication for hepatic fibrosis treatment.

In this study, the liquid culture system of Pleurotus nebrodensis mycelium with high yield were established by using orthogonal experiments. Results indicated a 58.08 % increase in mycelium biomass and a 2.22 % increase in polysaccharide content after condition optimization. Experiments showed that the extracted polysaccharides have significant antioxidant and anti-exercise fatigue activities. They could effectively scavenge DPPH, ABTS, hydroxyl free radicals and superoxide anaion, prolong weight-loaded swimming time in mice, reduce levels of MDA, LD, and LDH in serum, enhance SOD activity, as well as increase hepatic and muscle glycogen reserves. The mechanism may be attributed to the activation of the Nrf2/Keap1 signaling pathway, inhibition of oxidative stress, and subsequent exerting anti-fatigue effects. The results in this work provides new avenue for easily accessible natural polysaccharide resources with a very convenient approach, which is beneficial for the development of anti-fatigue functional foods for public consumption.

Liver fibrosis is a common complication of chronic liver disease, significantly affecting patients' quality of life and potentially leading to cirrhosis and hepatocellular carcinoma. Despite advancements in modern medicine, the treatment of liver fibrosis remains limited and challenging. Thus, identifying new therapeutic strategies is of great clinical importance. Signaling pathways related to liver fibrosis play a crucial regulatory role in immune response and inflammation. Aberrant activation of specific pathways, such as the NF-κB signaling pathway, results in the overexpression of genes associated with liver inflammation and fibrosis, thereby promoting the progression of liver fibrosis. Chinese medicine offers unique potential advantages as a therapeutic approach. Recent studies have increasingly demonstrated that certain Chinese medicines can effectively treat liver fibrosis by regulating relevant signaling pathways. The active ingredients in these medicines can inhibit hepatic inflammatory responses and fibrotic processes by interfering with these pathways, thus reducing the severity of liver fibrosis. This paper aims to investigate the mechanisms of Chinese medicine in treating liver fibrosis and its modulation of related signaling pathways. Additionally, it discusses the prospects of the clinical application of these treatments and provides valuable references for further research and clinical practice.

Fibrosis is the tissue scarring characterized by excess deposition of extracellular matrix (ECM) proteins, mainly collagens. A fibrotic response can take place in any tissue of the body and is the result of an imbalanced reaction to inflammation and wound healing. Metabolism has emerged as a major driver of fibrotic diseases. While glycolytic shifts appear to be a key metabolic switch in activated stromal ECM-producing cells, several other cell types such as immune cells, whose functions are intricately connected to their metabolic characteristics, form a complex network of pro-fibrotic cellular crosstalk. This review purports to clarify shared and particular cellular responses and mechanisms across organs and etiologies. We discuss the impact of the cell-type specific metabolic reprogramming in fibrotic diseases in both experimental and human pathology settings, providing a rationale for new therapeutic interventions based on metabolism-targeted antifibrotic agents.

Liver fibrosis is a key and reversible stage in the progression of many chronic liver diseases to cirrhosis or hepatocellular carcinoma. Forsythiaside-A (FTA), a main compound isolated from Forsythiae Fructus, has an excellent liver protective activity. This study aims to investigate the efficacy of FTA in improving cholestatic liver fibrosis. Bile-duct-ligation (BDL) was conducted to induce liver fibrosis in mice. Hepatic collagen deposition was evaluated by Masson and Sirus red staining. The bile acid spectrum in the liver and serum was analyzed by mass spectrometry. Liver oxidative stress injury and mitochondria damage were observed by using Mito-Tracker Red fluorescence staining, transmission electron microscopy, etc. The level of ferrous iron (Fe2+) and the expression of ferroptosis-associated molecules were detected. The binding between FTA and its target protein was confirmed by Co-immunoprecipitation (Co-IP), cellular thermal shift assay (CETSA), drug affinity responsive target stability (DARTS) and surface plasmon resonance (SPR). Our results demonstrated that FTA alleviated BDL-induced liver fibrosis in mice. FTA did not decrease the elevated amount of bile acids in BDL-treated mice, but reduced the bile acid-induced mitochondrial damage, oxidative stress and ferroptosis in hepatocytes, and also induced nuclear factor erythroid 2-related factor-2 (Nrf2) activation. In Nrf2 knock-out mice, the FTA-provided protection against BDL-induced liver fibrosis was disappeared, and FTA's inhibition on mitochondrial damage, oxidative stress and ferroptosis were lowered. Further results displayed that FTA could directly bind to Kelch-like ECH-associated protein-1 (Keap1), thereby activating Nrf2. Moreover, the BDL-induced liver fibrosis was markedly weakened in liver-specific Keap1 knockout mice. Hence, this study suggests that FTA alleviated the BDL-induced liver fibrosis through attenuating mitochondrial damage and ferroptosis in hepatocytes by activating Nrf2 via directly binding to Keap1.

Fufang Muji granules (FMGs) are a prominent modern prescription Chinese patent formulation derived from the Muji decoction. Utilized in clinical practice for nearly four decades, FMGs have demonstrated efficacy in treating liver diseases. However, the precise mechanism of action remains unclear. This study investigates the hepatoprotective effects of FMGs against liver fibrosis in rats based on untargeted metabolomics and elucidates their underlying mechanisms. A comprehensive model of liver fibrosis was established with 30% CCl4 (2 mL/kg) injected intraperitoneally, and a fat and sugar diet combined with high temperatures and humidity. Rats were orally administered FMGs (3.12 g/kg/d) once daily for six weeks. FMG administration resulted in improved liver fibrosis and attenuated hepatic oxidative stress and apoptosis. Furthermore, FMGs inhibited hepatic stellate cell activation and modulated transforming growth factor β1/Smad signaling. Additionally, FMG treatment influenced the expression levels of interleukin-6, interleukin-1β, and tumour necrosis factor alpha in the injured liver. Metabolic pathways involving taurine and hypotaurine metabolism, as well as primary bile acid biosynthesis, were identified as mechanisms of action for FMGs. Immunohistochemistry, quantitative reverse transcription polymerase chain reaction (RT-qPCR), and quantitative analysis also revealed that FMGs regulated taurine and hypotaurine metabolism and bile acid metabolism. These findings provide a valuable understanding of the role of FMGs in liver fibrosis management.

Tazobactam/piperacillin and meropenem are commonly used as an empiric treatment in patients with severe bacterial infections. However, few studies have investigated the cause of tazobactam/piperacillin- or meropenem-induced liver injury in them. Our objective was to evaluate the association between tazobactam/piperacillin or meropenem and liver injury in the intensive care unit patients. We evaluated the expression profiles of antibiotics-induced liver injury using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database. Further, in the retrospective observational study, data of patients who initiated tazobactam/piperacillin or meropenem in the intensive care unit were extracted. In FAERS database, male, age, the fourth-generation cephalosporin, carbapenem, β-lactam and β-lactamase inhibitor combination, and complication of sepsis were associated with liver injury (p < 0.001). In the retrospective observational study, multivariate logistic regression analyses indicated that the risk factors for liver injury included male (p = 0.046), administration period ≥ 7 days (p < 0.001), and alanine aminotransferase (p = 0.031). Not only administration period but also sex and alanine aminotransferase should be considered when clinicians conduct the monitoring of liver function in the patients receiving tazobactam/piperacillin or meropenem.

Previous studies, including our own, have demonstrated that arsenic exposure can induce liver fibrosis, while the underlying mechanism remains unclear and there is currently no effective pharmacological intervention available. Recent research has demonstrated that vitamin D supplementation can ameliorate liver fibrosis caused by various etiologies, potentially through modulation of the Nrf2 signaling pathways. However, it remains unclear whether vitamin D intervention can mitigate arsenic-caused liver fibrosis. As is known hepatic stellate cells (HSCs) activation and extracellular matrix (ECM) deposition are pivotal in the pathogenesis of liver fibrosis. In this study, we investigated the intervention effect of calcitriol (a form of active vitamin D) on arsenite-triggered Lx-2 cells (a human hepatic stellate cell line) activation and ECM oversecretion. Additionally, we also elucidated the role and mechanism of Nrf2 antioxidant signaling pathway. Our results demonstrated that calcitriol intervention significantly inhibits Lx-2 cell activation and ECM oversecretion induced by arsenite exposure. Additionally, calcitriol activates Nrf2 and its downstream antioxidant enzyme expression in Lx-2 cells, thereby reducing ROS overproduction caused by arsenite exposure. Further investigation reveals that calcitriol activates the Nrf2 signaling pathway and inhibits arsenite-triggered Lx-2 cell activation and ECM oversecretion by targeting vitamin D receptor (VDR). In conclusion, this study has demonstrated that vitamin D intervention can effectively inhibit HSC activation and ECM oversecretion triggered by arsenite exposure through its antioxidant activity. This provides a novel strategy for targeted nutritional intervention in the treatment of arsenic-induced liver fibrosis.

Leptin has important roles in numerous physiological functions, including those in the regulation of energy balance, and in immune and reproductive systems. However, in the recent years, evidence has implicated it in a number of obesity-related diseases, where its concentrations in serum are significantly elevated. Elevated serum leptin concentrations and increased placental leptin secretion have been reported in women with hypertensive disorders of pregnancy. Whether leptin is responsible for this disorder remains to be established. Leptin injections in healthy rats and mice during pregnancy result in endothelial activation, increased blood pressure and proteinuria. A potential role for leptin in the pathogenesis of pre-eclampsia is hypothesised, particularly in women who are overweight or obese where serum leptin concentrations are often elevated. This review summarises pertinent information in the literature on the role of leptin in puberty, pregnancy, and hypertensive disorders of pregnancy. In particular, the possible mechanism that may be involved in leptin-induced increase in blood pressure and proteinuria during pregnancy and the potential role of marinobufagenin in this disease entity. We hypothesise a significant role for oxidative stress in this, and propose a conceptual framework on the events that lead to endothelial activation, raised blood pressure and proteinuria following leptin administration.

Hepatic fibrosis (HF) is a critical step in the progression of hepatocellular carcinoma (HCC). Gene associated with retinoid-IFN-induced mortality 19 (GRIM19), an essential component of mitochondrial respiratory chain complex I, is frequently attenuated in various human cancers, including HCC. Here, we aimed to investigate the potential relationship and underlying mechanism between GRIM19 loss and HF pathogenesis.

GRIM19 expression was evaluated in normal liver tissues, hepatitis, hepatic cirrhosis, and HCC using human liver disease spectrum tissue microarrays. We studied hepatocyte-specific GRIM19 knockout mice and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein-9 (Cas9) lentivirus-mediated GRIM19 gene-editing in murine hepatocyte AML12 cells in vitro and in vivo. We performed flow cytometry, immunofluorescence, immunohistochemistry, western blotting, and pharmacological intervention to uncover the potential mechanisms underlying GRIM19 loss-induced HF.

Mitochondrial GRIM19 was progressively downregulated in chronic liver disease tissues, including hepatitis, cirrhosis, and HCC tissues. Hepatocyte-specific GRIM19 heterozygous deletion induced spontaneous hepatitis and subsequent liver fibrogenesis in mice. In addition, GRIM19 loss caused chronic liver injury through reactive oxygen species (ROS)-mediated oxidative stress, resulting in aberrant NF-кB activation via an IKK/IкB partner in hepatocytes. Furthermore, GRIM19 loss activated NLRP3-mediated IL33 signaling via the ROS/NF-кB pathway in hepatocytes. Intraperitoneal administration of the NLRP3 inhibitor MCC950 dramatically alleviated GRIM19 loss-driven HF in vivo.

The mitochondrial GRIM19 loss facilitates liver fibrosis through NLRP3/IL33 activation via ROS/NF-кB signaling, providing potential therapeutic approaches for earlier HF prevention.

Macrophage inhibitory factor (MIF) is a multipotent cytokine, involved in the inflammatory response to infections or injuries. This study investigates the role of MIF in liver fibrosis and the modulating effect of betaine on MIF in thioacetamide (TAA)-induced liver fibrosis. The wild-type and knockout MIF-/- C57BL/6 mice were divided into the following groups: control; Bet group, which received betaine; MIF-/-; MIF-/-+Bet; TAA group, which received TAA; TAA+Bet; MIF-/-+TAA; and MIF-/-+TAA+Bet group. After eight weeks of treatment, liver tissue was collected for further analysis. The results revealed that TAA-treated MIF-deficient mice had elevated levels of hepatic TGF-β1 and PDGF-BB, as well as MMP-2, MMP-9, and TIMP-1 compared to TAA-treated wild-type mice. However, the administration of betaine to TAA-treated MIF-deficient mice reduced hepatic TGF-β1 and PDGF-BB levels and also the relative activities of MMP-2, MMP-9 and TIMP-1, albeit less effectively than in TAA-treated mice without MIF deficiency. Furthermore, the antifibrogenic effect of MIF was demonstrated by an increase in MMP2/TIMP1 and MMP9/TIMP1 ratios. The changes in the hepatic levels of fibrogenic factors were confirmed by a histological examination of liver tissue. Overall, the dual nature of MIF highlights its involvement in the progression of liver fibrosis. Its prooxidant and proinflammatory effects may exacerbate tissue damage and inflammation initially, but its antifibrogenic activity suggests a potential protective role against fibrosis development. The study showed that betaine modulates the antifibrogenic effects of MIF in TAA-induced liver fibrosis, by decreasing TGF-β1, PDGF-BB, MMP-2, MMP-9, TIMP-1, and the deposition of ECM (Coll1 and Coll3) in the liver.

Liver fibrosis significantly impacts public health globally. Untreated liver fibrosis eventually results in cirrhosis. Cigarette smoking is the main etiologic factor for various diseases. However, the causal effects of cigarette smoking on liver fibrosis and cirrhosis have yet to be fully elucidated.

In this study, Mendelian randomization (MR) analysis was performed to assess the association between cigarette smoking, liver fibrosis, and cirrhosis. Single-nucleotide polymorphisms (SNPs) were selected as instrumental variables from a genome-wide association study (GWAS) of European ancestry. Patients were divided into six exposure categories as follows: "ever smoked," "pack years of smoking," "age of smoking initiation," "smoking status: never," "smoking status: current," and "smoking status: previous." The outcomes of this study included liver fibrosis and cirrhosis. MR-Egger, weighted median, inverse variance weighted, simple mode, and weighted mode were selected as the analysis methods. Cochran's Q and the MR-PRESSO tests were conducted to measure heterogeneity. The MR-Egger method was performed to evaluate horizontal pleiotropy, while the "leave-one-out" analysis was performed for sensitivity testing.

The results of this study showed that having a smoking history increases the risk of liver fibrosis and cirrhosis ["ever smoked": odds ratio (OR) = 5.704, 95% CI: 1.166-27.910, p = 0.032; "smoking status: previous": OR = 99.783, 95% CI: 2.969-3.353e+03, p = 0.010]. A negative correlation was observed between patients who never smoked and liver fibrosis and cirrhosis ("smoking status: never": OR = 0.171, 95% CI: 0.041-0.719, p = 0.016). However, there were no significant associations between "smoking status: current," "pack years of smoking," and "age of smoking initiation" and liver fibrosis and cirrhosis. Cigarette smoking did not have a significant horizontal pleiotropic effect on liver fibrosis and cirrhosis. The "Leave-one-out" sensitivity analysis indicated that the results were stable.

The study confirmed the causal effects of cigarette smoking on liver fibrosis and cirrhosis.

Cucurbitacins, natural compounds highly abundant in the Cucurbitaceae plant family, are characterized by their anticancer, anti-inflammatory, and hepatoprotective properties. These compounds have potential as therapeutic agents in the treatment of liver cancer. This study investigated the association of cucurbitacin D, I, and E (CuD, CuI, and CuE) with the caspase cascade, Bcl-2 family, and oxidative stress modulators in the HepG2 cell line. We evaluated the antiproliferative effects of CuD, CuI, and CuE using the MTT assay. We analyzed Annexin V/PI double staining, cell cycle, mitochondrial membrane potential, and wound healing assays at different doses of the three compounds. To examine the modulation of the caspase cascade, we determined the protein and gene expression levels of Bax, Bcl-xL, caspase-3, and caspase-9. We evaluated the total antioxidant status (TAS), total oxidant status (TOS), superoxide dismutase (SOD), glutathione (GSH), Total, and Native Thiol levels to measure cellular redox status. CuD, CuI, and CuE suppressed the proliferation of HepG2 cells in a dose-dependent manner. The cucurbitacins induced apoptosis by increasing caspase-3, caspase-9, and Bax activity, inhibiting Bcl-xL activation, causing loss of ΔΨm, and suppressing cell migration. Furthermore, cucurbitacins modulated oxidative stress by increasing TOS levels and decreasing SOD, GSH, TAS, and total and native Thiol levels. Our findings suggest that CuD, CuI, and CuE exert apoptotic effects on the hepatocellular carcinoma cell line by regulating Bax/Bcl-xL, caspase-3/9 signaling, and causing intracellular ROS increase in HepG2 cells.

Recent research has generated awareness of the existence of various pathophysiological pathways that contribute to the development of chronic diseases; thus, pro-oxidative factors have been accepted as significant contributors to the emergence of a wide range of diseases, from inflammatory to malignant. Redox homeostasis is especially crucial in liver pathology, as disturbances at this level have been linked to a variety of chronic diseases. Hepatitis is an umbrella term used to describe liver inflammation, which is the foundation of this disease regardless of its cause. Chronic hepatitis produces both oxidative stress generated by hepatocyte inflammation and viral inoculation. The majority of hepatitis in children is caused by a virus, and current studies reveal that 60-80% of cases become chronic, with many young patients still at risk of advancing liver damage. This review intends to emphasize the relevance of understanding these pathological redox pathways, as well as the need to update therapeutic strategies in chronic liver pathology, considering the beneficial effects of antioxidants.

The gut-liver axis has emerged as a focal point in chronic liver disorders, prompting more research into the role of the gut microbiota in liver cirrhosis. In individuals with liver cirrhosis, changes in the structure and function of the gut microbiota are closely tied to clinical prognosis. However, there is a scarcity of bibliometric evaluations conducted in this particular field.

This study is aiming to conduct a complete analysis of the knowledge structure and centers pertaining to gut microbiota in liver cirrhosis using bibliometric methods. Publications on gut microbiota and liver cirrhosis from 2001 to 2023 are sourced from the Web of Science Core Collection. For the bibliometric analysis, we employ VOSviewer, CiteSpace, and the R package "bibliometrix".

Our study encompasses a comprehensive collection of 3109 articles originating from 96 countries, with notable contributions from leading nations such as the United States and China. The quantity of publications concerning the gut microbiota of liver cirrhosis rises annually. The University of California San Diego, Virginia Commonwealth University, Zhejiang University are the primary research institutions. World Journal of Gastroenterology publishes the most papers in this field, while hepatology is the most frequently co-cited journal. These publications come from a total of 15,965 authors, and the most prolific authors are Bajaj Jasmohan S., Schnabl Bernd and Gillevet Patrick M., while the most co-cited authors are Bajaj Jasmohan S., Younossi Zobair M., and Reiner Wiest. In addition, "dysbiosis", "gut microbiota", "intestinal barrier", "fecal microbiota transplantation", and "complement-system" are the primary keywords of research trends in recent years.

This study offering a comprehensive insight into the research dynamics surrounding gut microbiota in patients with liver cirrhosis. It delineates the current research frontiers and hotspots, serving as a valuable guide for scholars.

Liver fibrosis is a formidable global medical challenge, with no effective clinical treatment currently available. Yinhuang granule (YHG) is a proprietary Chinese medicine comprising Scutellariae Radix and Lonicerae Japonicae Flos. It is frequently used for upper respiratory tract infections, pharyngitis, as well as acute and chronic tonsillitis.

To investigate the potential of YHG in alleviating carbon tetrachloride (CCl4)-induced liver fibrosis in mice.

To induce a hepatic fibrosis model in mice, this study involved intraperitoneal injections of 2 mL/kg of CCl4 twice a week for 4 wk. Meanwhile, liver fibrosis mice in the low dose of YHG (0.4 g/kg) and high dose of YHG (0.8 g/kg) groups were orally administered YHG once a day for 4 wk. Serum alanine/aspartate aminotransferase (ALT/AST) activity and liver hydroxyproline content were detected. Sirius red and Masson's trichrome staining assay were conducted. Real-time polymerase chain reaction, western-blot and enzyme-linked immunosorbent assay were conducted. Liver glutathione content, superoxide dismutase activity level, reactive oxygen species and protein carbonylation amount were detected.

The administration of YHG ameliorated hepatocellular injury in CCl4-treated mice, as reflected by decreased serum ALT/AST activity and improved liver histological evaluation. YHG also attenuated liver fibrosis, evident through reduced liver hydroxyproline content, improvements in Sirius red and Masson's trichrome staining, and lowered serum hyaluronic acid levels. Furthermore, YHG hindered the activation of hepatic stellate cells (HSCs) and ameliorated oxidative stress injury and inflammation in liver from CCl4-treated mice. YHG prompted the nuclear accumulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the expression of Nrf2-dependent downstream antioxidant genes. In addition, YHG promoted mitochondrial biogenesis in liver from CCl4-treated mice, as demonstrated by increased liver adenosine triphosphate content, mitochondrial DNA levels, and the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha and nuclear respiratory factor 1.

YHG effectively attenuates CCl4-induced liver fibrosis in mice by inhibiting the activation of HSCs, reducing inflammation, alleviating liver oxidative stress damage through Nrf2 activation, and promoting liver mitochondrial biogenesis.

Cannabidiol (CBD) is an extract of natural cannabinoids that has therapeutic implications for a variety of ailments, such as neurological diseases, cardiomyopathy, and diabetes, due to its strong anti-inflammatory and oxidative stress properties. Our purpose was to reveal the possible underlying mechanisms and effect of CBD on the glucose oxidase (GO)-induced activation of HSC-T6 and LX-2 cells. The results showed that CBD effectively inhibited the proliferation and activation of HSC-T6 and LX-2 cells, and reduced the production of profibrotic factors to different degrees. CBD disrupted the NOX4 signalling pathway in activated HSC-T6 and LX-2 cells, reduced ROS and MDA levels, and increased SOD and GSH levels, thereby stabilizing the oxidative imbalance. CBD significantly inhibited the phosphorylation and degradation of NF-κB and IκBα, and decreased the release of TNF-α, IL-1β and IL-6. Moreover, CBD and an NF-κB-specific inhibitor (CAPE) effectively inhibited the expression of α-SMA, COL I, TNF-α and IL-1β to promote collagen metabolism and inhibit the inflammatory response. Overall, CBD inhibited HSCs activation through a and the mechanism involving the inhibition of NOX4 and NF-κB-dependent ROS regulation, thereby reducing inflammation and ameliorating oxidative imbalances.

Yangyinghuoxue decoction (YYHXD) is a Traditional Chinese medicine (TCM) compound with satisfactory clinical efficacy in the treatment of hepatic fibrosis (HF). However, the pharmacological molecular mechanisms of YYHXD in the treatment of hepatic fibrosis have not yet been clarified.

To determine the pharmacological mechanisms of YYHXD for the treatment of hepatic fibrosis via network pharmacology analysis combined with experimental verification.

First, the bioactive ingredients and potential targets of YYHXD and HF-related targets were retrieved from the online databases and literatures. Next, the "herb-ingredient-target-disease" network and PPI network were constructed for topological analyses and key active compounds and targets screening. Enrichment analyses were performed to identify the critical biological processes and signaling pathways. Then, the molecular docking experiment was performed to initially validate the network pharmacology prediction results. Finally, the antifibrotic effect and pharmacological mechanisms of YYHXD were investigated in CCl4 induced liver fibrosis in rats.

In total, 141 active compounds in YYHXD, 637 YYHXD-related targets and 1598 liver fibrosis-related targets were identified. Among them, 69 overlapped targets were finally obtained. Network analysis screened 5 critical bioactive components and 34 key targets. Functional enrichment analysis indicated that YYHXD obviously influenced biological processes such as oxidative stress, cellular inflammation and hepatocyte apoptosis and signaling pathways such as PI3K-Akt, Apoptosis, and JAK-STAT in the treatment of HF. The molecular docking results suggested that the YYHXD may have a direct impact on the PI3K-Akt signaling pathway. Further, in vivo experiment indicated that YYHXD treatment not only reduced liver injury and protected liver function, but also decrease the apoptosis of hepatic parenchyma cells, reducing inflammatory and attenuating oxidative stress. Moreover, YYHXD significantly attenuated the upregulation of target proteins enriched in PI3K signaling pathway, including P-PI3K, P-Akt1, HSP90, MYC, p53.

The mechanisms of YYHXD against liver fibrosis were involved in multiple ingredients, multiple targets and multiple signaling pathways. The PI3K/Akt pathway could be the most important pharmacological mechanism of YYHXD therapy for liver fibrosis.

The incidence of autoimmune hepatitis (AIH) has increased significantly worldwide. The present study aims to explore the protective effect of L-lysine supplementation against AIH and to investigate its potential underlying mechanisms. A chronic experimental AIH mouse model was established by repeated tail vein injection of human cytochrome P450 2D6 (CYP2D6) plasmid. Starting from day 14 of the modeling, mice in the CYP2D6-AIH +L-lysine group were given 200 µl of purified water containing 10 mg/kg L-lysine by gavage until day27, once a day, and mice in the healthy control group and model group were given an equal volume of purified water by gavage. Our results showed that L-lysine supplementation partially reversed the liver injury mediated by CYP2D6 overexpression. These effects were consistent with the restraining impacts of L-lysine supplementation on decreasing pro-inflammatory cytokines expression level and CD4+ and CD8+ T lymphocytes infiltration, as well as curbing hepatic oxidative stress. Furthermore, L-lysine supplement relieved liver fibrosis in the context of AIH. In conclusion, L-lysine supplementation attenuates CYP2D6-induced immune liver injury in mice, which may serve as a novel nutrition support approach for AIH.

The purpose of this study was to investigate the antioxidant activity of Armillaria gallica polysaccharides. It explored whether Armillaria gallica polysaccharides (AgP) could prevent HepG2 cells from H2O2-induced oxidative damage. The results demonstrated that HepG2 cells were significantly protected by AgP, and efficiently suppressed the production of reactive oxygen species (ROS) in HepG2 cells. Additionally, AgP significantly decreased the abnormal leakage of alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) caused by H2O2, protecting cell membrane integrity. It was discovered that AgP was also found to regulate the activities of antioxidant enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-PX), while reducing malondialdehyde (MDA), thus protecting cells from oxidative damage. According to the flow cytometry analysis and measurement of caspase-3, caspase-8, and caspase-9 activities, AgP could modulate apoptosis-related proteins and attenuate ROS-mediated cell apoptosis.

Liver fibrosis is a life-threatening and irreversible disease. The fibrosis process is largely driven by hepatic stellate cells (HSCs), which undergo transdifferentiation from an inactivated state to an activated one during persistent liver damage. This activated state is responsible for collagen deposition in liver tissue and is accompanied by increased CD44 expression on the surfaces of HSCs and amplified intracellular oxidative stress, which contributes to the fibrosis process. To address this problem, we have developed a strategy that combines CD44-targeting of activated HSCs with an antioxidative approach. We developed hyaluronic acid-bilirubin nanoparticles (HABNs), composed of endogenous bilirubin, an antioxidant and anti-inflammatory bile acid, and hyaluronic acid, an endogenous CD44-targeting glycosaminoglycan biopolymer. Our findings demonstrate that intravenously administered HABNs effectively targeted the liver, particularly activated HSCs, in fibrotic mice with choline-deficient l-amino acid-defined high-fat diet (CD-HFD)-induced nonalcoholic steatohepatitis (NASH). HABNs were able to inhibit HSC activation and proliferation and collagen production. Furthermore, in a murine CD-HFD-induced NASH fibrosis model, intravenously administered HABNs showed potent fibrotic modulation activity. Our study suggests that HABNs have the potential to serve as a targeted anti-hepatic-fibrosis therapy by modulating activated HSCs via CD44-targeting and antioxidant strategies. This strategy could also be applied to various ROS-related diseases in which CD44-overexpressing cells play a pivotal role.

Chronic Liver fibrosis may progress to liver cirrhosis and hepatocellular carcinoma (HCC), hence cause a substantial global burden. However, effective therapies for blocking fibrosis are still lacking. Although mesenchymal stem cells (MSCs) have been proven beneficial to liver regeneration after damage, the underlying mechanism of their therapeutic effects are not fully understood. Oxidative stress and mitochondrial functionality alteration directly contributes to the hepatocyte apoptosis and development of liver fibrosis. This study aims to elucidate the mechanism by which hUC-MSC alleviates liver fibrosis and mitochondrial dysfunction. RNA-sequencing was performed to characterize the transcriptomic changes after implantation of hUC-MSCs in mice with liver fibrosis. Next, western blot, RT-PCR, immunohistochemical and immunofluorescence staining were used to evaluate the expression of different genes in vitro and in vivo. Additionally, mitochondrial morphological and dynamic changes, ROS content, and ATP production were examined. Slc25a47, a newly identified liver-specific mitochondrial NAD+ transporter, was notably reduced in CCl4-treated mice and H2O2-stimulated hepatocytes. Conversely, hUC-MSCs increased the Slc25a47 expression and NAD+ level within mitochondria, thereby enhanced Sirt3 protein activity and alleviated mitochondrial dysfunction in the liver. Furthermore, Slc25a47 knockdown could partially abrogate the protective effects of hUC-MSCs on H2O2-induced mitochondrial fission and oxidative stress in hepatocytes. Our study illustrates that Slc25a47 is a key molecular for hUC-MSCs to improve liver fibrosis and regulates mitochondrial function through Sirt3 for the first time, and providing a theoretical basis for the clinical translation of hUC-MSCs transplantation in the treatment of patients with liver fibrosis/cirrhosis.

Liver fibrosis contributes to significant morbidity and mortality in Western nations, primarily attributed to chronic hepatitis C virus (HCV) infection. Hypoxia and immune status have been reported to be significantly correlated with the progression of liver fibrosis. The current research aimed to investigate the gene signature related to the hypoxia-immune-related microenvironment and identify potential targets for liver fibrosis.

Sequencing data obtained from GEO were employed to assess the hypoxia and immune status of the discovery set utilizing UMAP and ESTIMATE methods. The prognostic genes were screened utilizing the LASSO model. The infiltration level of 22 types of immune cells was quantified utilizing CIBERSORT, and a prognosis-predictive model was established based on the selected genes. The model was also verified using qRT-PCR with surgical resection samples and liver failure samples RNA-sequencing data.

Elevated hypoxia and immune status were linked to an unfavorable prognosis in HCV-induced early-stage liver fibrosis. Increased plasma and resting NK cell infiltration were identified as a risk factor for liver fibrosis progression. Additionally, CYP1A2, CBS, GSTZ1, FOXA1, WDR72 and UHMK1 were determined as hypoxia-immune-related protective genes. The combined model effectively predicted patient prognosis. Furthermore, the preliminary validation of clinical samples supported most of the conclusions drawn from this study.

The prognosis-predictive model developed using six hypoxia-immune-related genes effectively predicts the prognosis and progression of liver fibrosis. The current study opens new avenues for the future prediction and treatment of liver fibrosis.

Effective approaches for prevention of hepatocellular carcinoma (HCC) will have a significant impact on HCC-related mortality. There are strong preclinical data and rationale to support targeting epidermal growth factor receptor (EGFR) for HCC chemoprevention. Small molecule inhibitors of EGFR have been Food and Drug Administration-approved for cancer therapy, which provides an opportunity to repurpose one of these drugs for chemoprevention of HCC. Unfortunately, the frequency of side effects associated with administration of these drugs at oncology doses renders them ineffective for chemoprevention. This clinical trial assesses whether lower doses of one of these inhibitors, erlotinib, still engages EGFR in the liver to block signaling (eg, EGFR phosphorylation). The objective of this clinical trial was determination of a safe and minimum effective dose of erlorinib for which ≥ 50% reduction phospho-EGFR immunohistochemical staining in the liver was observed.

Forty six participants were preregistered and 25 participants were registered in this multicenter trial. By dose de-escalation trial design, cohorts of participants received a 7-day course of erlotinib 75 mg/day, 50 mg/day or 25 mg/day with liver tissue acquisition prior to and after erlotinib.

A ≥50% reduction phospho-EGFR immunohistochemical staining in the liver was observed in a minimum of 40% of participants (predetermined threshhold) at each of the dose levels. Erlotinib was very well tolerated with few side effects observed, particularly at the dose of 25 mg/day. Favorable modulation of the Prognostic Liver Signature was observed in participants who received erlotinib.

These data support the selection of erlotinib doses as low as 25 mg/day of for a longer intervention to assess for evidence of efficacy as an HCC chemoprevention drug (ClinicalTrials.govNCT02273362).

This review provides an update on recent findings from basic, translational, and clinical studies on the molecular mechanisms of mitochondrial dysfunction and apoptosis of hepatocytes in multiple liver diseases, including but not limited to alcohol-associated liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and drug-induced liver injury (DILI). While the ethanol-inducible cytochrome P450-2E1 (CYP2E1) is mainly responsible for oxidizing binge alcohol via the microsomal ethanol oxidizing system, it is also responsible for metabolizing many xenobiotics, including pollutants, chemicals, drugs, and specific diets abundant in n-6 fatty acids, into toxic metabolites in many organs, including the liver, causing pathological insults through organelles such as mitochondria and endoplasmic reticula. Oxidative imbalances (oxidative stress) in mitochondria promote the covalent modifications of lipids, proteins, and nucleic acids through enzymatic and non-enzymatic mechanisms. Excessive changes stimulate various post-translational modifications (PTMs) of mitochondrial proteins, transcription factors, and histones. Increased PTMs of mitochondrial proteins inactivate many enzymes involved in the reduction of oxidative species, fatty acid metabolism, and mitophagy pathways, leading to mitochondrial dysfunction, energy depletion, and apoptosis. Unique from other organelles, mitochondria control many signaling cascades involved in bioenergetics (fat metabolism), inflammation, and apoptosis/necrosis of hepatocytes. When mitochondrial homeostasis is shifted, these pathways become altered or shut down, likely contributing to the death of hepatocytes with activation of inflammation and hepatic stellate cells, causing liver fibrosis and cirrhosis. This review will encapsulate how mitochondrial dysfunction contributes to hepatocyte apoptosis in several types of liver diseases in order to provide recommendations for targeted therapeutics.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder caused by insulin resistance and dysfunctional beta (β)-cells in the pancreas. Hyperglycaemia is a characteristic of uncontrolled diabetes which eventually leads to fatal organ system damage. In T2DM, free radicals are continuously produced, causing extensive tissue damage and subsequent macro-and microvascular complications. The standard approach to managing T2DM is pharmacological treatment with anti-diabetic medications. However, patients' adherence to treatment is frequently decreased by the side effects and expense of medications, which has a detrimental impact on their health outcomes. Quercetin, a flavonoid, is a one of the most potent anti-oxidants which ameliorates T2DM. Thus, there is an increased demand to investigate quercetin and its derivatives, as it is hypothesised that similar structured compounds may exhibit similar biological activity. Gossypetin is a hexahydroxylated flavonoid found in the calyx of Hibiscus sabdariffa. Gossypetin has a similar chemical structure to quercetin with an extra hydroxyl group. Furthermore, previous literature has elucidated that gossypetin exhibits neuroprotective, hepatoprotective, reproprotective and nephroprotective properties. The mechanisms underlying gossypetin's therapeutic potential have been linked to its anti-oxidant, anti-inflammatory and immunomodulatory properties. Hence, this review highlights the potential role of gossypetin in the treatment of diabetes and its associated complications.

Fine particulate matter (PM2.5) is a source of pollution worldwide, that causes inflammation and liver fibrosis. Melatonin, as the predominant hormone secreted by the pineal gland, can inhibit PM2.5-induced lung injury by activating nuclear factor erythroid 2-related factor 2 (Nrf2) to inhibit ferroptosis. However, the possible role of melatonin in PM2.5-induced liver damage remains unclear.

In vitro, the effects of melatonin on PM2.5-induced oxidative stress and LX-2 cell activation were examined. In vivo, a PM2.5-induced inflammation and liver fibrosis mouse model was used to evaluate the hepatoprotective effect of melatonin.

In vitro, melatonin induced the expression of Nrf2 and its downstream genes and inhibited PM2.5-induced reactive oxygen species (ROS) production and mitochondrial damage. Melatonin also ameliorated the PM2.5-induced oxidative stress and fibrogenic marker upregulation. However, the antifibrotic effect of melatonin was abolished in siNrf2-treated LX-2 cells. In vivo, we observed mitochondrial abnormalities and mitochondrial fragmentation, which were accompanied by increased PTEN-induced kinase 1 (PINK1) and Parkin expression, in PM2.5-treated mouse hepatocytes. These changes were partially reversed by melatonin. In addition, melatonin activated the Nrf2 signaling pathway and protected against PM2.5-induced oxidative stress. Furthermore, melatonin alleviated inflammation and liver fibrosis. Moreover, Nrf2-KO mice exhibited more severe inflammation and liver fibrosis after PM2.5 exposure than wild-type mice, and the protective effect of melatonin on PM2.5- treated Nrf2-KO mice was greatly compromised.

These data suggest that melatonin effectively inhibits PM2.5-induced liver fibrosis by activating Nrf2 and inhibiting ROS-mediated mitophagy and inflammation.