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Abstract Background Nonalcoholic fatty liver disease (NAFLD) has developed as a leading public wellness challenge as a result of changes in dietary patterns. Unfortunately, there is still a lack of effective pharmacotherapy methods for NAFLD. Wang’s empirical formula (WSF) has demonstrated considerable clinical efficacy in treating metabolic disorders for years. Nevertheless, the protective effect of WSF against NAFLD and its underlying mechanism remains poorly understood. Methods The NAFLD model was established using a 17-week high-sucrose and high-fat (HSHF) diet with 32 ICR mice. In assessing the therapeutic efficacy of WSF on NAFLD, we detected changes in body weight, viscera weight, biomarkers of glycolipid metabolism in serum and liver, transaminase levels and histopathology of liver with H&E and Oil Red O staining after oral administration. The chemical components in WSF were extensively identified and gathered utilizing the HPLC-Q-TOF/MS system, database mining from HMDB, MassBank, and TCMSP databases, alongside literature searches from CNKI, Wanfang and VIP databases. The forecast of network pharmacology approach was then utilized to investigate the probable mechanisms by which WSF improves NAFLD based on the performance of prospective target identification and pathway enrichment analysis. Besides, molecular docking was also conducted for the verification of combination activities between active components of WSF and core proteins related to NAFLD. In final, validation experiments of obtained pathways were conducted through ELISA, immunohistochemistry (IHC), and western blot (WB) analysis. Results Pharmacodynamic outcomes indicated that WSF intervention effectively mitigated obesity, fat accumulation in organs, lipid metabolism disorders, abnormal transaminase levels and liver pathology injury in NAFLD mice (P

Objective: To evaluate the anti-inflammatory effect of black cumin seed oil (BCSO) and its nanoemulsion on lipopolysaccharide (LPS)-induced liver injury in mice. Methods: LPS-induced acute liver injury mouse model was used to evaluate the effects of BCSO and its nanoemulsion formulation on liver function. Hepatic inflammatory markers including Toll-like receptor 4 (TLR4), interleukin(IL)-1β, heme-oxygenase 1, BAX, and BCL-2 were assessed using real-time PCR. Additionally, protein levels of reduced glutathione, tumor necrosis factor-α, and IL-6 were measured using ELISA, and histological analysis was performed. Indomethacin was used as a standard positive control for comparison. Results: BCSO reduced LPS-induced liver injury and exhibited strong anti-inflammatory effects by downregulating the expression of TLR4, IL-1β, IL-6, tumor necrosis factor-α, and heme-oxygenase 1. Additionally, BCSO demonstrated antioxidant properties by increasing reduced glutathione protein levels and decreasing key apoptotic markers BAX and BCL-2 in hepatocytes. The nanoemulsion formulation further enhanced these anti-inflammatory, antioxidant, and anti-apoptotic effects, and histological examination confirmed this effect. Combining BCSO with indomethacin at a lower dose improved efficacy, thereby reducing its potential side effects. Conclusions: The investigation reveals the anti-inflammatory impact of BCSO and its nanoemulsion formulation on LPS-induced liver oxidative stress, inflammation, and apoptosis.

Abstract Background Chronic hepatitis B virus (HBV) infection remains a serious health issue, and determining the optimal time for antiviral therapy is challenging. We aimed to assess liver histological changes in patients with HBeAg-positive chronic hepatitis B (CHB) and those with HBeAg-negative CHB who had persistently normal alanine aminotransferase and to determine the association between significant liver injury and various clinical parameters. Methods We retrospectively included, in this study, 339 treatment-naïve patients with chronic HBV infections who had persistently normal alanine aminotransferase and underwent liver biopsy from 2013 to 2023. Histologic assessment was based on the Metavir scoring system to evaluate the association between clinical characteristics and the severity of liver inflammation and fibrosis. Results Among the included participants, 138 were HBeAg-positive and 201 were HBeAg-negative. Lower hepatitis B surface antigen (HBsAg) (P = 0.003) and higher aspartate aminotransferase (AST) (P = 0.002) levels were associated with significant necroinflammation, whereas increasing age (P = 0.004) and lower HBV DNA (P

Background: Routine liver function tests capture information about the metabolic and inflammatory condition of the liver, but we lack sensitive biomarkers of early hepatocyte stress. In humans, soluble CD46 (sCD46) levels in blood were recently identified as an accurate biomarker of hepatic steatosis. Here, we explore the diagnostic utility of sCD46 in other liver diseases. Methods: We developed, optimised and validated an ELISA that facilitates measurements of human sCD46 in plasma, serum and culture supernatants. Then, we analysed mechanisms that lead to the release of sCD46 and identified its role in various hepatic stress conditions. Results: We discovered that prostaglandin E2 (PGE2) drives upregulation of matrix metalloproteinase (MMP)-1 in fat-loaded hepatocytes, leading to proteolytic shedding of CD46. We further found that sCD46 release was increased by viral, toxic and hypoxic stresses. Conclusions: sCD46 appears to be a promising biomarker with potential applications in the detection of early liver diseases or monitoring therapeutic responses, which could complement established diagnostic algorithms because sCD46 release is uniquely responsive to hepatocyte stress.

Inflammation responses have identified as a key mediator of in various liver diseases with high morbidity and mortality. cGAS-STING signalling is essential in innate immunity since it triggers release of type I interferons and various of proinflammatory cytokines. The potential connection between cGAS-STING pathway and liver inflammatory diseases has recently been reported widely. In our review, the impact of cGAS-STING on liver inflammation and regulatory mechanism are summarized. Furthermore, many inhibitors of cGAS-STING signalling as promising agents to cure liver inflammation are also explored in detail. A comprehensive knowledge of molecular mechanisms of cGAS-STING signalling in liver inflammation is vital for exploring novel treatments and providing recommendations and perspectives for future utilization.

IntroductionMitochondrial membrane potential (MMP) and mitochondrial mass (MM) affect mitochondrial function and lymphocyte activation, but few studies on HBV infection exist. This study aimed to investigate the regulatory mechanism of mitochondrial dysfunction during HBV infection and its clinical significance by analyzing the alterations of MM and MMPlow in peripheral blood immune cells.MethodsThe study enrolled 90 participants, including healthy volunteers(HC) and patients with HBV infection, HBV patients were divided into chronic hepatitis B patients (CHB) and liver cirrhosis (LC) according to the study, and CHB was also divided into an inflammation group and a non-inflammation group. Flow cytometry was used to analyze the changes of MM and MMPlow in peripheral blood immune cells. These analyses were correlated with the presence of CHB and LC and indexes related to liver inflammation.ResultsThe study revealed significant variations in the percentage of MMPlow and MM of CD8+T cells associated with the progression of the disease. The MMPlow percentage of CD8+T cells in the LC group exhibited a notable decrease compared to the HC group and CHB groups. Moreover, MMPlow of CD8+T cells demonstrated potential in distinguishing CHB and LC (AUC=0.7341, P=0.0032). Furthermore, in exploring the link between mitochondrial function of immune cells and liver inflammation, the study found a negative correlation between the MMPlow ratio of CD4+T and CD8+T cells and AST (p=0.0039 and P=0.0070, r=-0.4405 and r=-0.4146), while the MM of CD8+T cells displayed a positive correlation with AST (p=0.0013, r=0.4865). In CHB patients with normal ALT but liver inflammation detected on B-scan ultrasonography, a significant decrease was observed in the MMPlow percentage of CD8+T (66.13 ± 14.27), CD56+NK(57.77 ± 17.40) and CD4-CD8-T (61.98 ± 15.98) cells. Furthermore, it was also found that the percentage of MMPlow in CD4-CD8-T cells could serve as an indicator for early liver inflammation and injury (AUC=0.8408, P=0.0052).DiscussionIn this study, we conducted a systematic analysis of the percentage of lymphocyte MMPlow and MM in various stages of HBV infection. Our findings revealed a correlation between MMPlow and MM and early liver inflammation, as well as the progression of the infection. This study marked the first demonstration of the clinical diagnostic value of MMPlow and MM in HBV infection. Furthermore, this was the first study to discuss the mitochondria of lymphocytes and liver inflammation in HBV infection. It enhanced the understanding of the role of T cells in liver inflammation, and elucidated potential markers for the early detection of liver injury and clinical cirrhosis.

Epidemiological studies have demonstrated exposure to cadmium ion (Cd2+) is significantly associated with the incidence and aggravation of nonalcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). Cd2+ exposure could alter lipid metabolism, and changed lipid metabolites are significantly associated with NASH. Arachidonic acid (ArA) is an omega-6 polyunsaturated fatty acid. Promotion of ArA synthesis and profile changes by Cd2+ exposure potentially to cause NAFLD. ArA metabolism pathway has been identified to enrich in Cd2+ exposure-facilitated NASH. ArA could be generation an impressive metabolic profile through mainly three pathways, including Cyclooxygenases (COX), Lipoxygenases (LOX) and Cytochrome P450 (CYP450) pathway. However, the functions of these metabolites and underlying mechanism in hepatic inflammation are still not clear. In present study, by integrative transcriptomics and metabolomics analysis, we identified that the fatty acid metabolic process and the pro-inflammatory NF-κB signaling pathway were enriched in Cd2+-regulated differentially expressed genes (DEGs) and Cd2+-altered differential metabolites, such as, fatty acid biosynthesis, degradation, and ArA metabolism. The metabolites levels of LOX pathway products 5-HETE and leukotriene C4 (LTC4), and COX catalytic product prostaglandin D2 (PGD2) were significantly elevated in Cd2+ exposed mouse livers. 5-HETE, LTC4, and PGD2 were significantly positive correlated with NF-κB signaling. In addition, the synthase of 20-Hydroxyeicosatetraenoic acid (20-HETE), CYP450 gene 4 family (CYP4A32), was also involved in NF-κB signaling network. Results from both in vitro and in vivo proved that Cd2+ exposure increased ArA metabolite to PGD2 and 20-HETE, and upregulated the mRNA level of their catalytic enzyme PGDS and CYP4A32. Cd2+-induced ArA metabolite to PGD2 and 20-HETE promoted activation of TLR4/IκBα/NF-κB signaling and pro-inflammatory of hepatocytes. Our study explores novel molecular mechanism of Cd2+ exposure-aggravated liver diseases and provides potential novel targets for in hepatic inflammatory treatments and prevention.

Abstract The chemokine (CCL)-chemokine receptor (CCR2) interaction, importantly CCL2-CCR2, involved in the intrahepatic recruitment of monocytes upon liver injury promotes liver fibrosis. CCL2-CCR2 antagonism using Cenicriviroc (CVC) showed promising results in several preclinical studies. Unfortunately, CVC failed in phase III clinical trials due to lack of efficacy to treat liver fibrosis. Lack of efficacy could be attributed to the fact that macrophages are also involved in disease resolution by secreting matrix metalloproteinases (MMPs) to degrade extracellular matrix (ECM), thereby inhibiting hepatic stellate cells (HSCs) activation. HSCs are the key pathogenic cell types in liver fibrosis that secrete excessive amounts of ECM causing liver stiffening and liver dysfunction. Knowing the detrimental role of intrahepatic monocyte recruitment, ECM, and HSCs activation during liver injury, we hypothesize that combining CVC and MMP (MMP1) could reverse liver fibrosis. We evaluated the effects of CVC, MMP1 and CVC + MMP1 in vitro and in vivo in CCl4-induced liver injury mouse model. We observed that CVC + MMP1 inhibited macrophage migration, and TGF-β induced collagen-I expression in fibroblasts in vitro. In vivo, MMP1 + CVC significantly inhibited normalized liver weights, and improved liver function without any adverse effects. Moreover, MMP1 + CVC inhibited monocyte infiltration and liver inflammation as confirmed by F4/80 and CD11b staining, and TNFα gene expression. MMP1 + CVC also ameliorated liver fibrogenesis via inhibiting HSCs activation as assessed by collagen-I staining and collagen-I and α-SMA mRNA expression. In conclusion, we demonstrated that a combination therapeutic approach by combining CVC and MMP1 to inhibit intrahepatic monocyte recruitment and increasing collagen degradation respectively ameliorate liver inflammation and fibrosis.

Abstract Background Changes in plasma protein glycosylation are known to functionally affect proteins and to associate with liver diseases, including cirrhosis and hepatocellular carcinoma. Autoimmune hepatitis (AIH) is a liver disease characterized by liver inflammation and raised serum levels of IgG, and is difficult to distinguish from other liver diseases. The aim of this study was to examine plasma and IgG-specific N-glycosylation in AIH and compare it with healthy controls and other liver diseases. Methods In this cross-sectional cohort study, total plasma N-glycosylation and IgG Fc glycosylation analysis was performed by mass spectrometry for 66 AIH patients, 60 age- and sex-matched healthy controls, 31 primary biliary cholangitis patients, 10 primary sclerosing cholangitis patients, 30 non-alcoholic fatty liver disease patients and 74 patients with viral or alcoholic hepatitis. A total of 121 glycans were quantified per individual. Associations between glycosylation traits and AIH were investigated as compared to healthy controls and other liver diseases. Results Glycan traits bisection (OR: 3.78 [1.88–9.35], p-value: 5.88 × 10− 3), tetraantennary sialylation per galactose (A4GS) (OR: 2.88 [1.75–5.16], p-value: 1.63 × 10− 3), IgG1 galactosylation (OR: 0.35 [0.2–0.58], p-value: 3.47 × 10− 5) and hybrid type glycans (OR: 2.73 [1.67–4.89], p-value: 2.31 × 10− 3) were found as discriminators between AIH and healthy controls. High A4GS differentiated AIH from other liver diseases, while bisection associated with cirrhosis severity. Conclusions Compared to other liver diseases, AIH shows distinctively high A4GS levels in plasma, with potential implications on glycoprotein function and clearance. Plasma-derived glycosylation has potential to be used as a diagnostic marker for AIH in the future. This may alleviate the need for a liver biopsy at diagnosis. Glycosidic changes should be investigated further in longitudinal studies and may be used for diagnostic and monitoring purposes in the future.

BackgroundThis study aimed to investigate the effects of licorice processing of different Evodiae Fructus (EF) specifications on liver inflammation and oxidative stress associated with the intestinal mucosal microbiota.Materials and methodsThe 25 Kunming mice were divided into control (MCN), raw small-flowered Evodiae Fructus (MRSEF), raw medium-flowered EF (MRMEF), licorice-processed small-flowered EF (MLSEF), and licorice-processed medium-flowered EF (MLSEF) groups. The EF intervention groups were given different specifications of EF extract solutions by gavage. After 21 days, indices of liver inflammation and oxidative stress and intestinal mucosal microbiota were measured in mice.ResultsCompared with the MCN, malondialdehyde (MDA), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) levels were significantly increased in the MRMEF. Although the trends of oxidative stress and inflammatory indexes in the MLSEF and MLMEF were consistent with those in the raw EF groups, the changes were smaller than those in the raw EF groups. Compared to the raw EF groups, the MLSEF and MLMEF showed closer approximations of metabolic function to the MCN. The abundance of Corynebacterium in MRMEF was significantly lower than that in the MCN, and it was not significantly different from the MCN after licorice processing. The probiotic Candidatus Arthromitus was enriched in the MLSEF. The probiotic Lactobacillus was enriched in the MLMEF. Correlation analysis revealed significant negative correlations between IL-1β, some metabolic functions and Corynebacterium.ConclusionThe effects of medium-flowered EF on oxidative stress and inflammatory factors in the liver of mice were stronger than those of small-flowered EF. The licorice processing can reduce this difference by modulating the abundance of Corynebacterium and intestinal mucosal metabolic function.

Background: Dihydroartemisinin (DHA), a derivative of Artemisia annua, has been shown to possess anti-inflammatory properties. Besides, Yes-associated protein 1 (YAP1) plays a crucial role in maintaining liver homeostasis. Methods: This study used Yap1Flox/Flox, Albumin-Cre mice with hepatocyte-specific Yap1 knockout (referred to as Yap1LKO) and their control mice (Yap1Flox/Flox, referred to as Yap1Flox). The effect of Yap1 on lipid metabolism homeostasis was investigated through non-targeted metabolomic analysis of mouse liver. Subsequently, DHA was administered to Yap1LKO mice to assess its potential as a treatment. Liver pathology was evaluated via H&E staining, and the levels of AST, ALT, and TG were quantified using biochemical assays. The contents of arachidonic acid (AA), prostaglandin E1 (PGE1), and leukotrienes (LT) in the liver were measured using ELISA, while the protein expressions of PLIN2, 5-lipoxygenase (5-LOX), and cyclooxygenase-2 (COX-2) were analyzed through IHC staining. Results: Hepatocyte-specific Yap1 knockout activated the AA metabolic pathway, resulting in increased elevated levels of AA, PGE1, and LT levels, along with inflammatory cytokine infiltration. DHA mitigated the elevation of metabolites such as PGE1 and LT caused by the AA metabolic pathway activation by down-regulating the levels of COX-2 and 5-LOX in the liver of Yap1LKO mice. Moreover, it alleviated the accumulation of lipid vacuoles and reduced triglyceride (TG) and perilipin-2 (PLIN2) levels in the liver of Yap1LKO mice. Conclusions: Excessively low YAP1 expression induces liver inflammation and disturbances in lipid metabolism, whereas DHA modulated AA metabolism and mitigated liver inflammation by inhibiting the activation of 5-LOX and COX-2.

Hepatitis B Virus (HBV) is a stealthy and insidious pathogen capable of inducing chronic necro-inflammatory liver disease and hepatocellular carcinoma (HCC), resulting in over one million deaths worldwide per year. The traditional understanding of Chronic Hepatitis B (CHB) progression has focused on the complex interplay among ongoing virus replication, aberrant immune responses, and liver pathogenesis. However, the dynamic progression and crucial factors involved in the transition from HBV infection to immune activation and intrahepatic inflammation remain elusive. Recent insights have illuminated HBV’s exploitation of the sodium taurocholate co-transporting polypeptide (NTCP) and manipulation of the cholesterol transport system shared between macrophages and hepatocytes for viral entry. These discoveries deepen our understanding of HBV as a virus that hijacks hepatocyte metabolism. Moreover, hepatic niche macrophages exhibit significant phenotypic and functional diversity, zonal characteristics, and play essential roles, either in maintaining liver homeostasis or contributing to the pathogenesis of chronic liver diseases. Therefore, we underscore recent revelations concerning the importance of hepatic niche macrophages in the context of viral hepatitis. This review particularly emphasizes the significant role of HBV-induced metabolic changes in hepatic macrophages as a key factor in the transition from viral infection to immune activation, ultimately culminating in liver inflammation. These metabolic alterations in hepatic macrophages offer promising targets for therapeutic interventions and serve as valuable early warning indicators, shedding light on the disease progression.

Copper (Cu) serves as an essential cofactor in all organisms, yet excessive Cu exposure is widely recognized for its role in inducing liver inflammation. However, the precise mechanism by which Cu triggers liver inflammation in ducks, particularly in relation to the interplay in gut microbiota regulation, has remained elusive. In this investigation, we sought to elucidate the impact of Cu exposure on liver inflammation through gut-liver axis in ducks. Our findings revealed that Cu exposure markedly elevated liver AST and ALT levels and induced liver inflammation through upregulating pro-inflammatory cytokines (IL-1β, IL-6 and TNF-α) and triggering the LPS/TLR4/NF-κB signaling pathway. Simultaneously, Cu exposure induced alterations in the composition of intestinal flora communities, notably increasing the relative abundance of Sphingobacterium, Campylobacter, Acinetobacter and reducing the relative abundance of Lactobacillus. Cu exposure significantly decreased the protein expression related to intestinal barrier (Occludin, Claudin-1 and ZO-1) and promoted the secretion of intestinal pro-inflammatory cytokines. Furthermore, correlation analysis was observed that intestinal microbiome and gut barrier induced by Cu were closely related to liver inflammation. Fecal microbiota transplantation (FMT) experiments further demonstrated the microbiota-depleted ducks transplanting fecal samples from Cu-exposed ducks disturbed the intestinal dysfunction, which lead to impaire liver function and activate the liver inflammation. Our study provided insights into the mechanism by which Cu exposure induced liver inflammation in ducks through the regulation of gut-liver axis. These results enhanced our comprehension of the potential mechanisms driving Cu-induced hepatotoxicity in avian species.

This work aims to study the effects of oral gavage (0.2 mg/g body weight) of elaidic acid (C18:1–9 t, EA) and linoelaidic acid (C18:2–9 t,12 t, LEA) on lipid metabolism, inflammation and gut homeostasis of mice. Results showed that both EA and LEA gavage significantly increased LDL-c, TC and oxidative stress levels in the liver and serum and may stimulate liver inflammation via NF-κB and MAPK signaling pathway. Compared with EA, LEA gavage significantly promoted TAG accumulation and inflammatory signaling. Serum lipidomics revealed that LEA intake significantly increased the concentration of ∼50 TAGs, while EA gavage primarily caused significant decreases in several SMs. 16S rRNA demonstrated that LEA ingestion markedly changed fecal microbiota by enriching Lactobacillus (phylum Firmicutes), however, EA treatment did not affect it. Overall, LEA gavage has more severe consequences on TAG accumulation, inflammation and microbial structure than EA, highlighting that the number of trans double bonds affects these processes.

Background and aims: Normal serum transaminases and immunoglobulin G (IgG) levels are surrogate markers for hepatic histologic disease activity in autoimmune hepatitis (AIH). This study aimed to evaluate liver inflammation in patients with AIH with normal serum alanine aminotransferase (ALT) and IgG levels. Methods: Two hundred and five AIH patients who underwent liver biopsy in four medical centers were included. Logistic regression analysis was used to identify risk factors associated with advanced inflammation. Results: One hundred and thirty-one (63.9 %) AIH patients had advanced liver inflammation, and 108 (52.7 %) patients had advanced liver fibrosis. 60.0 % of patients with normal ALT and 51.7 % of patients with normal ALT and IgG had advanced inflammation. However, 76.7 % and 35.0 % of patients with or without advanced fibrosis with normal ALT had advanced inflammation, while the corresponding proportions of advanced inflammation were 78.6 % and 26.7 % in patients with normal ALT and IgG, respectively. Moreover, 81.0 % and 44.8 % of patients with and without cirrhosis with normal ALT had advanced inflammation, while the corresponding proportions were 83.3 % and 29.4 % in patients with normal ALT and IgG, respectively. Red cell distribution width (OR = 1.325, 95%CI 1.045–1.681, P = 0.020) and PT (OR = 1.514, 95%CI 1.138–2.014, P = 0.004) were independent factors associated with advanced inflammation. Conclusions: High proportion of advanced inflammation was found in AIH patients with normal ALT and IgG levels despite without advanced fibrosis. Although using non-invasive methods may contribute to rule out liver fibrosis in AIH patients with normal ALT and IgG levels, liver biopsy is encouraged to assess liver inflammation.

Non-alcoholic fatty liver disease (NAFLD) is increasingly prevalent, but treatment options are limited. Previous studies have demonstrated the hepatoprotective effects of Polysaccharide of Atractylodes macrocephala Koidz (PAMK) against liver injury induced by various causes, but its potential in alleviating NAFLD remains unknown. This study aimed to investigate the potential of PAMK in improving NAFLD and its regulatory effects on gene transcription during the process. The results indicated that Highfatdiet (HFD) could induce NAFLD in mice, and PAMK was found to alleviate symptoms of NAFLD and mitigate liver injury caused by HFD. Transcriptome analysis revealed that PAMK affects both metabolic and inflammatory pathways, suggesting its dual impact on maintaining metabolic homeostasis and suppressing inflammation during NAFLD progression. The results of liver biochemical markers, key genes of the cholesterol pathway, glucose (GLU), and inflammatory factors further demonstrated the dual role of PAMK in metabolism and inflammation.

Background & Aims: Acetaminophen (APAP) overdose is the most common cause of drug-induced liver injury worldwide. Uric acid (UA) is involved in sterile inflammation in many organs, but its role in APAP-induced liver injury remains elusive. Methods: We quantified the concentration of UA in the serum and liver tissues of APAP-overdosed mice and explored the changes in proteins involved in UA synthesis, absorption, and degeneration on APAP stimulation. We also examined the effects of inhibiting hepatocyte UA synthesis or reabsorption on APAP-induced liver injury in mice. Furthermore, we explored the process of UA clearance by peripheral macrophages. Results: APAP overdose significantly increased intrahepatic UA contents, which occurred earlier than apparent hepatocyte injury in APAP-overdosed mice. APAP overdose induced significant DNA leakage and may thereby increase the substrate of UA synthesis. APAP overdose also significantly increased the enzymatic activity of xanthine oxidase and urate oxidase and decreased the expression of the UA reabsorption transporter GLUT9 in hepatocytes. Inhibiting hepatocyte UA synthesis by febuxostat or reabsorption by hepatic-specific knockout of GLUT9 alleviated APAP-induced liver injury. Further experiments showed that monosodium urate but not soluble UA may be a major form of UA mediating hepatocyte injury. Additionally, monosodium urate further recruited circulating macrophages into the liver and then aggravated inflammation by increasing the levels of inflammatory factors and reactive oxygen species. Deletion of macrophages significantly ameliorated APAP-induced liver injury in mice. Conclusions: APAP overdose induces excessive UA production and leads to local high concentrations in the liver, which further injures cells and induces liver inflammation. Inhibiting the production of UA may be a potential therapeutic option for treating APAP-induced liver injury.

Background and Aims: The large global population of patients with metabolic dysfunction-associated steatotic liver disease (MASLD) has recently been shown to have an association with chronic kidney disease (CKD) due to a host of proposed mechanisms, one of which being lipoprotein dysmetabolism. Furthermore, metabolic comorbidities have been concurrently prevalent in MASLD and CKD independently. This study aimed at analyzing risk and predictive traits among an obese population for both MASLD and CKD. Methods: A retrospective chart review of 546 obese patients with a diagnosis of either MASLD or metabolic dysfunction-associated steatohepatitis between January 2020 and June 2021 was performed. Markers of liver and kidney function in addition to demographic data and renoprotective medications were recorded. Both univariable and multivariable linear regression analyses were performed to understand possible associations between MASLD markers, renal function, and markers of metabolic derangements. Results: Univariate analysis revealed that increased age (P < .001), elevated alanine aminotransferase (defined as alanine aminotransferase ≥ 30 IU/L, P = .01), low albumin (P = .011), and increasing fibrosis-4 (FIB-4) (P = .005) were statistically associated with a reduced renal function. A reduction in glomerular filtration was associated with an increase in FIB-4 (effect size [beta] of a one-unit increase in glomerular filtration on FIB-4 = −0.013, P < .001) in univariate linear regression. In multivariate linear regression, type 2 diabetes (T2D) was independently associated with increased liver fibrosis (effect size of T2D on FIB-4 = 0.387925, P < .02). Conclusion: Our study shows that in a patient population with obesity and a diagnosis of MASLD, advanced fibrosis is independently associated with reduced renal function.

Background and Aims: Recent studies showed that patients suffering from lysosomal acid lipase deficiency (LAL-D) benefit from enzyme replacement therapy; however, liver histopathology improved in some but not all patients. We hypothesized that the pan-peroxisome proliferator-activated receptor agonist lanifibranor may have beneficial effects on liver inflammation in LAL knockout (Lal−/−) mice based on its promising results in alleviating liver inflammation in patients with metabolic dysfunction-associated steatohepatitis. Methods: Female Lal−/− mice were daily gavaged with lanifibranor or vehicle for 21 days. The effects of the treatment were assessed by measuring body and organ weights, plasma lipids and lipoproteins, as well as hematological parameters, followed by liver proteomics and metabolomics. Results: Lanifibranor treatment slightly altered organ weights without affecting the total body weight of Lal−/− mice. We observed major changes in the proteome, with multiple proteins related to lipid metabolism, peroxisomal, and mitochondrial activities being upregulated and inflammation-related proteins being downregulated in the livers of treated mice. Hepatic lipid levels and histology remained unaltered, whereas plasma triacylglycerol and total cholesterol levels were decreased and the lipoprotein profile of lanifibranor-treated Lal−/− mice improved. Conclusion: Lanifibranor treatment positively affected liver inflammation and dyslipidemia in Lal−/− mice. These findings suggest the necessity of a further combined study of lanifibranor with enzyme replacement therapy in Lal−/− mice to improve the phenotype. Moreover, there is a compelling rationale for conducting clinical trials to assess the efficacy of lanifibranor as a potential treatment option for LAL-D in humans.

The objective of this study was to reveal the effect of rumen degradable starch (RDS) on bile acid metabolism and liver transcription in dairy goats using metabolomics and transcriptomics. Eighteen Guanzhong dairy goats of a similar weight and production level (body weight = 45.8 ± 1.54 kg, milk yield = 1.75 ± 0.08 kg, and second parity) were randomly assigned to 3 treatment groups where they were fed a low RDS (LRDS, RDS = 20.52% DM) diet, medium RDS (MRDS, RDS = 22.15% DM) diet, or high RDS (HRDS, RDS = 24.88% DM) diet, respectively. The goats were fed with the experimental diets for 5 weeks. On the last day of the experiment, all goats were anesthetized, and peripheral blood and liver tissue samples were collected. The peripheral blood samples were used in metabolomic analysis and white blood cell (WBC) count, whereas the liver tissue samples were used in transcriptomic analysis. Based on the metabolomics results, the relative abundances of primary bile acids in the peripheral blood were significantly reduced in the group that was fed the HRDS diet (P

Suling Jiang,1,&ast; Jian Wang,2,3,&ast; Zhiyi Zhang,4,&ast; Jie Zhan,1 Ruifei Xue,1 Yuanwang Qiu,5 Li Zhu,6 Shaoqiu Zhang,2 Yifan Pan,1 Xiaomin Yan,2 Yuxin Chen,3,7 Jie Li,1– 4 Xingxiang Liu,8 Chuanwu Zhu,6 Rui Huang,1– 4 Chao Wu1– 4 1Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China; 2Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China; 3Institute of Viruses and Infectious Diseases, Nanjing University, Nanjing, Jiangsu, People’s Republic of China; 4Department of Infectious Diseases, Nanjing Drum Tower Hospital Clinical College of Nanjing University of Chinese Medicine, Nanjing, Jiangsu, People’s Republic of China; 5Department of Infectious Diseases, The Fifth People’s Hospital of Wuxi, Wuxi, Jiangsu, People’s Republic of China; 6Department of Infectious Diseases, The Affiliated Infectious Diseases Hospital of Soochow University, Suzhou, Jiangsu, People’s Republic of China; 7Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China; 8Department of Clinical Laboratory, Huai’an No. 4 People’s Hospital, Huai’an, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chao Wu, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Tel +86-25-83105890, Fax +86-25-83307115, Email dr.wu@nju.edu.cn Rui Huang, Department of Infectious Diseases, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, No. 321 Zhongshan Road, Nanjing, Jiangsu, 210008, People’s Republic of China, Email doctor_hr@126.comBackground: Noninvasive diagnosis of liver inflammation is important for patients with chronic hepatitis B (CHB). This study aimed to develop a nomogram to predict significant liver inflammation for CHB patients.Methods: CHB patients who underwent liver biopsy were retrospectively collected and randomly divided into a development set and a validation set. The least absolute shrinkage and selection operator regression and logistic regression analysis were used to select independent predictors of significant liver inflammation, and a nomogram was developed. The performance of nomogram was assessed by receiver operating characteristic (ROC) curves, calibration curves and decision curve analysis (DCA).Results: A total of 1019 CHB patients with a median age of 39.0 years were included. Alanine aminotransaminase (ALT, P = 0.018), gamma-glutamyl transpeptidase (P = 0.013), prothrombin time (P < 0.001), and HBV DNA level (P = 0.030) were identified as independent predictors of significant liver inflammation in the development set. A model namely AGPD-nomogram was developed based on the above parameters. The area under the ROC curve in predicting significant inflammation was 0.765 (95% CI: 0.727– 0.803) and 0.766 (95% CI: 0.711– 0.821) in the development and validation sets, which were significantly higher than other indexes. The AGPD-nomogram had a high predictive value in patients with normal ALT. Moreover, the nomogram was proven to be clinically useful by DCA.Conclusion: A visualized AGPD-nomogram which incorporated routine clinical parameters was proposed to facilitate the prediction of significant liver inflammation in CHB patients. This nomogram had high accuracy in the identification of significant liver inflammation and would be a useful tool for the better management of CHB patients, especially for those with normal ALT.Keywords: chronic hepatitis B, liver inflammation, prediction, nomogram, alanine aminotransferase

ABSTRACTThe chronic carrier state of the hepatitis B virus (HBV) often leads to the development of liver inflammation as carriers age. However, the exact mechanisms that trigger this hepatic inflammation remain poorly defined. We analyzed the sequential processes during the onset of liver inflammation based on time-course transcriptome and transcriptional regulatory networks in an HBV transgenic (HBV-Tg) mice model and chronic HBV-infected (CHB) patients (data from GSE83148). The key transcriptional factor (TF) responsible for hepatic inflammation occurrence was identified and then validated both in HBV-Tg mice and liver specimens from young CHB patients. By time-course analysis, an early stage of hepatic inflammation was demonstrated in 3-month-old HBV-Tg mice: a marked upregulation of genes related to inflammation (Saa1/2, S100a8/9/11, or Il1β), innate immunity (Tlr2, Tlr7, or Tlr8), and cells chemotaxis (Ccr2, Cxcl1, Cxcl13, or Cxcl14). Within CHB samples, a unique early stage of inflammation activation was discriminated from immune tolerance and immune activation groups based on distinct gene expression patterns. Enhanced activation of TF Stat3 was strongly associated with increased inflammatory gene expression in this early stage of inflammation. Expression of phosphorylated Stat3 was higher in liver specimens from young CHB patients with relatively higher alanine aminotransferase levels. Specific inhibition of Stat3 activation significantly attenuated the degree of liver inflammation, the expression of inflammation-related genes, and the inflammatory monocytes and macrophages in 3-month-old HBV-Tg mice. Stat3 activation is essential for hepatic inflammation occurrence and is a novel indicator of early-stage immune activation in chronic HBV carriers.IMPORTANCEUntil now, it remains a mystery that chronic hepatitis B virus (HBV)-infected patients in the “immune tolerance phase” will transition to the “immune activation phase” as they age. In this study, we reveal that Stat3 activation-triggered hepatic transcriptional alterations are distinctive characteristics of the early stage of immune/inflammation activation in chronic HBV infection. For the first time, we discover a mechanism that might trigger the transition from immune tolerance to immune activation in chronic HBV carriers.

This study aimed to evaluate the protective role and potential mechanisms of Xie Zhuo Tiao Zhi decoction (XZTZ) on alcohol-associated liver disease (ALD). XZTZ significantly alleviated alcohol-induced liver dysfunction, based on histological examinations and biochemical parameters after 4-week administration. Mechanically, alcohol-stimulated hepatic oxidative stress was ameliorated by XZTZ, accompanied by the improvement of Nrf2/Keap1 expression and alcohol-activated phosphorylation of pro-inflammatory transcription factors, including JNK, P38, P65, and IκBα, were rescued by XZTZ. In conclusion, XZTZ demonstrates potential in alleviating alcohol-induced liver injury, oxidative stress, and inflammation possibly through modulation of Nrf2/Keap1 and MAPKs/NF-κB signaling pathways, suggesting its potential as a therapeutic option for patients with alcoholic liver disease.

IntroductionThe alarmin IL-33 has been implicated in the pathology of immune-mediated liver diseases. IL-33 activates regulatory T cells (Tregs) and type 2 innate lymphoid cells (ILC2s) expressing the IL-33 receptor ST2. We have previously shown that endogenous IL-33/ST2 signaling activates ILC2s that aggravate liver injury in murine immune-mediated hepatitis. However, treatment of mice with exogenous IL-33 before induction of hepatitis ameliorated disease severity. Since IL-33 induces expression of amphiregulin (AREG) crucial for Treg function, we investigated the immunoregulatory role of the ST2+ Treg/AREG axis in immune-mediated hepatitis.MethodsC57BL/6, ST2-deficient (Il1rl1-/-) and Areg-/- mice received concanavalin A to induce immune-mediated hepatitis. Foxp3Cre+ x ST2fl/fl mice were pre-treated with IL-33 before induction of immune-mediated hepatitis. Treg function was assessed by adoptive transfer experiments and suppression assays. The effects of AREG and IL-33 on ST2+ Tregs and ILC2s were investigated in vitro. Immune cell phenotype was analyzed by flow cytometry. Results and discussionWe identified IL-33-responsive ST2+ Tregs as an effector Treg subset in the murine liver, which was highly activated in immune-mediated hepatitis. Lack of endogenous IL-33 signaling in Il1rl1-/- mice aggravated disease pathology. This was associated with reduced Treg activation. Adoptive transfer of exogenous IL-33-activated ST2+ Tregs before induction of hepatitis suppressed inflammatory T-cell responses and ameliorated disease pathology. We further showed increased expression of AREG by hepatic ST2+ Tregs and ILC2s in immune-mediated hepatitis. Areg-/- mice developed more severe liver injury, which was associated with enhanced ILC2 activation and less ST2+ Tregs in the inflamed liver. Exogenous AREG suppressed ILC2 cytokine expression and enhanced ST2+ Treg activation in vitro. In addition, Tregs from Areg-/- mice were impaired in their capacity to suppress CD4+ T-cell activation in vitro. Moreover, application of exogenous IL-33 before disease induction did not protect Foxp3Cre+ x ST2fl/fl mice lacking ST2+ Tregs from immune-mediated hepatitis. In summary, we describe an immunoregulatory role of the ST2+ Treg/AREG axis in immune-mediated hepatitis, in which AREG suppresses the activation of hepatic ILC2s while maintaining ST2+ Tregs and reinforcing their immunosuppressive capacity in liver inflammation.

Non-alcoholic fatty liver disease (NAFLD) is a prevalent chronic liver condition observed globally, with the potential to progress to non-alcoholic steatohepatitis (NASH), cirrhosis, and even hepatocellular carcinoma. Currently, the US Food and Drug Administration (FDA) has not approved any drugs for the treatment of NAFLD. NAFLD is characterized by histopathological abnormalities in the liver, such as lipid accumulation, steatosis, hepatic balloon degeneration, and inflammation. Dysbiosis of the gut microbiota and its metabolites significantly contribute to the initiation and advancement of NAFLD. Bacteroides, a potential probiotic, has shown strong potential in preventing the onset and progression of NAFLD. However, the precise mechanism by which Bacteroides treats NAFLD remains uncertain. In this review, we explore the current understanding of the role of Bacteroides and its metabolites in the treatment of NAFLD, focusing on their ability to reduce liver inflammation, mitigate hepatic steatosis, and enhance intestinal barrier function. Additionally, we summarize how Bacteroides alleviates pathological changes by restoring the metabolism, improving insulin resistance, regulating cytokines, and promoting tight-junctions. A deeper comprehension of the mechanisms through which Bacteroides is involved in the pathogenesis of NAFLD should aid the development of innovative drugs targeting NAFLD.

Abstract Background Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) signaling has been known to play a critical role in maintaining cellular and tissue homeostasis, which also has an essential role in the inflammatory response. However, it remains unidentified whether and how the macrophage PTEN may govern the innate immune signaling stimulator of interferon genes (STING) mediated inflammation and hepatocyte necroptosis in APAP-induced liver injury (AILI). Methods Myeloid-specific PTEN knockout (PTENM−KO) and floxed PTEN (PTENFL/FL) mice were treated with APAP (400 mg/kg) or PBS. In a parallel in vitro study, bone marrow-derived macrophages (BMMs) were isolated from these conditional knockout mice and transfected with CRISPR/Cas9-mediated Notch1 knockout (KO) or CRISPR/Cas9-mediated STING activation vector followed by LPS (100 ng/ml) stimulation. Results Here, we report that myeloid-specific PTEN knockout (PTENM−KO) mice were resistant to oxidative stress-induced hepatocellular injury with reduced macrophage/neutrophil accumulation and proinflammatory mediators in AILI. PTENM−KO increased the interaction of nuclear Notch intracellular domain (NICD) and nuclear factor (erythroid-derived 2)-like 2 (NRF2) in the macrophage nucleus, reducing reactive oxygen species (ROS) generation. Mechanistically, it is worth noting that macrophage NICD and NRF2 co-localize within the nucleus under inflammatory conditions. Additionally, Notch1 promotes the interaction of immunoglobulin kappa J region (RBPjκ) with NRF2. Disruption of the Notch1 signal in PTEN deletion macrophages, reduced RBPjκ and NRF2 binding, and activated STING signaling. Moreover, PTENM−KO macrophages with STING activated led to ROS generation and TNF-α release, resulting in hepatocyte necroptosis upon co-culture with primary hepatocytes. Conclusions Our findings demonstrate that the macrophage PTEN-NICD/NRF2-STING axis is critical to regulating oxidative stress-induced liver inflammation and necroptosis in AILI and implies the therapeutic potential for managing sterile liver inflammation. Video Abstract Graphical Abstract

Summary: The process of dead cell clearance by phagocytic cells, called efferocytosis, prevents inflammatory cell necrosis and promotes resolution and repair. Defective efferocytosis contributes to the progression of numerous diseases in which cell death is prominent, including liver disease. Many gaps remain in our understanding of how hepatic macrophages carry out efferocytosis and how this process goes awry in various types of liver diseases. Thus far, studies have suggested that, upon liver injury, liver-resident Kupffer cells and infiltrating monocyte-derived macrophages clear dead cells, limit inflammation, and, through macrophage reprogramming, repair liver damage. However, in unusual settings, efferocytosis can promote liver disease. In this review, we will focus on efferocytosis in various types of acute and chronic liver diseases, including metabolic dysfunction-associated steatohepatitis. Understanding the mechanisms and consequences of efferocytosis by hepatic macrophages has the potential to shed new light on liver disease pathophysiology and to guide new treatment strategies to prevent disease progression.

ABSTRACTThe purpose of this study was to develop an effective and non-invasive nomogram for evaluating liver obvious inflammation in untreated HBeAg positive patients with chronic hepatitis B virus (HBV) infection. A nomogram was established on a model cohort of 292 treatment-naïve HBeAg positive patients with normal alanine aminotransferase (ALT ≤40 U/L) at Beijing Ditan Hospital from January 2008 to March 2018. Then the nomogram was prospectively validated in a cohort of 88 patients from July 2019 to May 2021. Calibration curves and Concordance index were used to evaluate the accuracy of prediction and identification performance of the model. In untreated HBeAg positive chronic hepatitis B virus infection patients with normal ALT, the formula for predicting liver inflammation was Logit (P) =-0.91-0.41×log10 (qHBeAg)+0.11×AST-0.01×PLT. The nomogram had C-index of 0.751 (95% CI, 0.688–0.815), indicating a good consistency between prediction and real observation on the model cohort. The validation cohort confirmed its good performance. In this study, liver inflammation nomograms based on HBeAg, AST, and PLT were established and verified in treatment-naïve HBeAg positive chronic HBV patients with normal ALT.

Introduction and Objectives: Assessment of liver inflammation plays a vital role in the management of patients with autoimmune hepatitis (AIH). We aimed to establish and validate a nomogram to predict severe liver inflammation in AIH patients. Patients and Methods: AIH patients who underwent liver biopsy were included and randomly divided into a training set and a validation set. Independent predictors of severe liver inflammation were selected by the least absolute shrinkage and selection operator regression from the training set and used to conduct a nomogram. Receiver characteristic curves (ROC), calibration curves, and decision curve analysis (DCA) were adopted to evaluate the performance of nomogram. Results: Of the 213 patients, female patients accounted for 83.1% and the median age was 53.0 years. The albumin, gamma-glutamyl transpeptidase, total bilirubin, red cell distribution width, prothrombin time, and platelets were independent predictors of severe inflammation. An online AIHI-nomogram was established and was available at https://ndth-zzy.shinyapps.io/AIHI-nomogram/. The calibration curve revealed that the AIHI-nomogram had a good agreement with actual observation in the training and validation sets. The area under the ROCs of AIHI-nomogram were 0.795 in the training set and 0.759 in the validation set, showing significantly better performance than alanine aminotransferase and immunoglobulin G in the training and validation sets, as well in AIH patients with normal ALT in the training set. DCA indicated that the AIHI-nomogram was clinically useful. Conclusions: This novel AIHI-nomogram provided an excellent prediction of severe liver inflammation in AIH patients and could be used for the better management of AIH.

Nonalcoholic fatty liver disease (NAFLD) is an expanding worldwide health concern, and the underlying mechanisms contributing to its progression still need further exploration. Neutrophil extracellular traps (NETs) are intricate formations comprised of nuclear constituents and diverse antimicrobial granules that are released into the extracellular milieu by activated neutrophils upon various triggers, which play a pivotal part in the onset and advancement of NAFLD. NETs actively participate in the genesis of NAFLD by fostering oxidative stress and inflammation, ultimately resulting in hepatic fat accumulation and the escalation of liver injury. Recent insights into the interaction with other hepatic immune populations and mediators, such as macrophages and T regulatory cells, have revealed several important mechanisms that can trigger further liver injury. In conclusion, the formation of NETs emerged as an important factor in the development of NAFLD, offering a promising target for innovative therapeutic approaches against this debilitating condition. This comprehensive review seeks to compile existing studies exploring the involvement of NETs in the genesis of NAFLD and their influence on the immune response throughout the progression of NAFLD.

Primary liver cancers rank among the deadliest cancers worldwide and often develop in patients with chronic liver diseases in an inflammatory context. This review highlights recent reports on the mechanisms of inflammatory-mediated hepatic cell transformation that trigger the tumorigenic process (initiation steps) and the impact of the immune response favoring tumor cell expansion (progression steps). Several cytokines, namely interleukin (IL)-6, IL-17, IL-1beta, and tumor necrosis factor-alpha, have been described to play a prominent role in the initiation of liver cancers. Additionally, inflammation contributes to cancer progression by favoring tumor escape from anti-tumor immune response, angiogenesis, and metastasis through tumor growth factor-beta and matrix metalloprotease upregulation. These recent studies allowed the development of novel therapeutic strategies aiming at regulating liver inflammation. These strategies are based on the use of anti-inflammatory agents, antibodies targeting immune checkpoint molecules such as programmed death ligand 1 and molecules targeting angiogenic factors, metastasis key factors, and microRNAs involved in tumor development. This review aims at summarizing the recent studies reporting different mechanisms by which the liver inflammatory responses could contribute to liver cancer development.

Background & Aims: Hepatic immune system disorder plays a critical role in the pathogenesis of acute liver injury. The intrinsic signaling mechanisms responsible for dampening excessive activation of liver macrophages are not completely understood. The Notch and Hippo-YAP signaling pathways have been implicated in immune homeostasis. In this study, we investigated the interactive cell signaling networks of Notch1/YAP pathway during acute liver injury. Methods: Myeloid-specific Notch1 knockout (Notch1M-KO) mice and the floxed Notch1 (Notch1FL/FL) mice were subjected to lipopolysaccharide/D-galactosamine toxicity. Some mice were injected via the tail vein with bone marrow–derived macrophages transfected with lentivirus-expressing YAP. Some mice were injected with YAP siRNA using an in vivo mannose-mediated delivery system. Results: We found that the activated Notch1 and YAP signaling in liver macrophages were closely related to lipopolysaccharide/D-galactosamine-induced acute liver injury. Macrophage/neutrophil infiltration, proinflammatory mediators, and hepatocellular apoptosis were markedly ameliorated in Notch1M-KO mice. Importantly, myeloid Notch1 deficiency depressed YAP signaling and facilitated M2 macrophage polarization in the injured liver. Furthermore, YAP overexpression in Notch1M-KO livers exacerbated liver damage and shifted macrophage polarization toward the M1 phenotype. Mechanistically, macrophage Notch1 signaling could transcriptionally activate YAP gene expression. Reciprocally, YAP transcriptionally upregulated the Notch ligand Jagged1 gene expression and was essential for Notch1-mediated macrophage polarization. Finally, dual inhibition of Notch1 and YAP in macrophages further promoted M2 polarization and alleviated liver damage. Conclusions: Our findings underscore a novel molecular insight into the Notch1-YAP circuit for controlling macrophage polarization in acute liver injury, raising the possibility of targeting macrophage Notch1-YAP circuit as an effective strategy for liver inflammation–related diseases.

Inflammatory bowel disease (IBD) is an immune-mediated gut dysfunction, which might also be associated with an inflammatory phenotype in the liver. It is known that the nutritional intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) is inversely correlated to the severity and occurrence of IBD. In order to investigate whether n-3 PUFA can also reduce liver inflammation and oxidative liver damage due to colon inflammation, we explored the dextran sulfate sodium (DSS)-induced colitis model in wild-type and fat-1 mice with endogenously increased n-3 PUFA tissue content. Besides confirming previous data of alleviated DSS-induced colitis in the fat-1 mouse model, the increase of n-3 PUFA also resulted in a significant reduction of liver inflammation and oxidative damage in colitis-affected fat-1 mice as compared to wild-type littermates. This was accompanied by a remarkable increase of established inflammation-dampening n-3 PUFA oxylipins, namely docosahexaenoic acid-derived 19,20-epoxydocosapentaenoic acid and eicosapentaenoic acid-derived 15-hydroxyeicosapentaenoic acid and 17,18-epoxyeicosatetraenoic acid. Taken together, these observations demonstrate a strong inverse correlation between the anti-inflammatory lipidome derived from n-3 PUFA and the colitis-triggered inflammatory changes in the liver by reducing oxidative liver stress.

Autoimmune hepatitis (AIH) refers to a liver disease in which the immune system abnormally attacks the cells. This study aimed to investigate effects of Longjing extract (LE) rich in polyphenols on intestinal flora of AIH. The S100-triggered AIH mice were intragastrically administrated with low, medium, or high doses of LE, and liver inflammation and pathology, intestinal physical and chemical barrier and flora composition were assessed in the respective group. This study indicated that low and medium doses of LE ameliorated the microflora disorder, intestinal barrier defect, and liver inflammation in AIH mice, whereas high doses exacerbated them. Furthermore, lipopolysaccharide/ toll-like receptor 4 involved in the regulation by LE. The dose-depended disparate effects of LE suggested that drinking tea in moderation are conducive to mitigating autoimmune liver injury, whereas the recommended supplement of polyphenols should be investigated in depth.

The aim of this study is to review and analyze the pleiotropic effects of TGF-β in physiological and pathological conditions of the liver, with particular emphasis on its role in immune suppression, wound healing, regulation of cell growth and differentiation, and liver cell apoptosis. A literature review was conducted, including 52 studies, comprising review articles, in vitro and in vivo studies, and meta-analyses. Only studies published in peer-reviewed scientific journals were included in the analysis. TGF-β is a pleiotropic growth factor that is crucial for the liver, both in physiology and pathophysiology. Although its functions are complex and diverse, TGF-β plays a constant role in immune suppression, wound healing, and the regulation of cell growth and differentiation. In concentrations exceeding the norm, it can induce the apoptosis of liver cells. Increased TGF-β levels are observed in many liver diseases, such as fibrosis, inflammation, and steatosis. TGF-β has been shown to play a key role in many physiological and pathological processes of the liver, and its concentration may be a potential diagnostic and prognostic marker in liver diseases.

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as the most common liver disease worldwide in recent years. MASLD commonly presents as simple hepatic steatosis, but ~25% of patients develop liver inflammation, progressive fibrosis, liver cirrhosis and related hepatocellular carcinoma. Liver inflammation and the degree of fibrosis are key determinants of the prognosis. The pathophysiology of liver inflammation is incompletely understood and involves diverse factors and specifically innate and adaptive immune responses. More specifically, diverse mediators of innate immunity such as proinflammatory cytokines, adipokines, inflammasomes and various cell types like mononuclear cells, macrophages and natural killer cells are involved in directing the inflammatory process in MASLD. The activation of innate immunity is driven by various factors including excess lipids and lipotoxicity, insulin resistance and molecular patterns derived from gut commensals. Targeting pathways of innate immunity might therefore appear as an attractive therapeutic strategy in the future management of MASLD and possibly its complications.

The aim of our present study was to investigate the effects of Gln supplementation on liver inflammatory responses as well as protein synthesis and degradation in the muscle of LPS-challenged broilers. A total of 120 one-day-old male broiler chickens (Arbor Acres Plus) were randomly arranged in a 2 × 2 factorial design with five replicates per treatment and six broilers per replicate, containing two main factors: immune challenge (injected with LPS in a dose of 0 or 500 µg/kg of body weight) and dietary treatments (supplemented with 1.22% alanine or 1% Gln). After feeding with an alanine or Gln diet for 15 days, broilers were administrated an LPS or a saline injection at 16 and 21 days. The results showed that Gln supplementation alleviated the increased mRNA expressions of interleukin-6, interleukin-1β, and tumor necrosis factor-α induced by LPS in liver. Moreover, the increased activity of aspartate aminotransferase combined with the decreased expression of glutaminase in muscle were observed following Gln addition. In addition, in comparison with the saline treatment, LPS challenge altered the signaling molecules’ mRNA expressions associated with protein synthesis and degradation. However, Gln supplementation reversed the negative effects on protein synthesis and degradation in muscle of LPS-challenged broilers. Taken together, Gln supplementation had beneficial effects: alleviating inflammatory responses, promoting protein synthesis, and inhibiting protein degradation of LPS-challenged broilers.

The offspring of super-multiparous sows face problems such as decreased growth performance, poor meat quality and even diseases in animal husbandry. Gama-aminobutyric acid (GABA) has long been known to promote growth and suppress inflammation, but little is known about the mechanisms. A total of 72 growing-finishing pigs from the 8th generation were randomly allotted to 2 groups with 6 replicates per treatment to receive a corn–soybean basal diet or the basal diet supplemented 20 mg/kg GABA for 60 d. After the animal-trial period, samples of serum and liver were collected for further analysis. Additionally, a lipopolysaccharide (LPS)-induced inflammatory model using HepG2 cells was established to explore the role of GABA on regulating hepatic inflammation. The results indicated that inflammatory cell infiltration occurs in the liver of progeny of super-multiparous sows, and dietary supplementation with GABA influenced liver morphology, increased activities of antioxidant enzymes and decreased the expression abundance of pro-inflammatory cytokines, including tumor necrosis factor-α (TNFα) and interleukin (IL)-1β, in the liver of growing-finishing pigs (P

Liver damage caused by various factors results in fibrosis and inflammation, leading to cirrhosis and cancer. Fibrosis results in the accumulation of extracellular matrix components. The role of STAT proteins in mediating liver inflammation and fibrosis has been well documented; however, approved therapies targeting STAT3 inhibition against liver disease are lacking. This study investigated the anti-fibrotic and anti-inflammatory effects of STAT3 decoy oligodeoxynucleotides (ODN) in hepatocytes and liver fibrosis mouse models. STAT3 decoy ODN were delivered into cells using liposomes and hydrodynamic tail vein injection into 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice in which liver injury was induced. STAT3 target gene expression changes were verified using qPCR and Western blotting. Liver tissue fibrosis and bile duct proliferation were assessed in animal experiments using staining techniques, and macrophage and inflammatory cytokine distribution was verified using immunohistochemistry. STAT3 decoy ODN reduced fibrosis and inflammatory factors in liver cancer cell lines and DDC-induced liver injury mouse model. These results suggest that STAT3 decoy ODN may effectively treat liver fibrosis and must be clinically investigated.

Liver disease-related mortality is a major cause of death worldwide. Hepatic innate and adaptive immune cells play diverse roles in liver homeostasis and disease. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immature myeloid cells. MDSCs can be broadly divided into monocytic MDSCs and polymorphonuclear or granulocytic MDSCs, and they functionally interact with both liver parenchymal and nonparenchymal cells, such as hepatocytes and regulatory T cells, to impact liver disease progression. The infiltration and activation of MDSCs in liver disease can be regulated by inflammatory chemokines and cytokines, tumor-associated fibroblasts, epigenetic regulation factors, and gut microbiota during liver injury and cancer. Given the pivotal roles of MDSCs in advanced liver diseases, they can be targeted to treat primary and metastatic liver cancer, liver generation, alcoholic and nonalcoholic liver disease, and autoimmune hepatitis. Currently, several treatments such as the antioxidant and anti-inflammatory agent berberine are under preclinical and clinical investigation to evaluate their therapeutic efficacy on liver disease and their effect on MDSC infiltration and function. Phenotypic alteration of MDSCs in different liver diseases that are in a model-dependent manner and lack special markers for distinct MDSCs are challenges for targeting MDSCs to treat liver disease. Multi-omics study is an option to uncover the features of disease-specific MDSCs and potential gene or protein targets for liver disease treatment. In summary, MDSCs play important roles in the pathogenesis and progression of liver disease by regulating both intrahepatic innate and adaptive immune responses.

Decabromodiphenyl ether (BDE-209) is an environmental toxin. Increasing evidence showed that BDE-209 exposure induced liver injury, but the mechanism still remains unknown. The present study explored the effect and mechanism of ferroptosis on hepatotoxicity triggered by BDE-209 in vivo and in vitro. In vivo experiment, ICR mice were exposed to BDE-209 for 50 days, and then recovered for 50 days; HepG2 and L02 cells were treated with BDE-209 or/and ferrostatin-1 (Fer-1) for establishing in vitro model. In vivo, the results showed that BDE-209 accumulated in liver and induced liver damage, increased Fe2+ and MDA contents, and blocked the activation of SLC7A11/GSH/GPX4 pathway in liver; BDE-209 also activated IKK/IκB/NF-κB pathway and elevated inflammatory cytokines levels in liver after exposure for 50 days. After BDE-209 stopping exposure 50 days, the severity of liver damage, ferroptosis and inflammatory response were still higher than the corresponding control group. In vitro, ferroptosis inhibitor Fer-1 rescued ferroptotic damage and attenuated cell death in BDE-209-treated HepG2 and L02 cells. In addition, Fer-1 reversed the activation of IKK/IκB/NF-κB pathway and the increase of pro-inflammatory cytokines levels in BDE-209-treated HepG2 and L02 cells. Together, the above results suggested that BDE-209 induced tissue damage and inflammatory response by activating ferroptosis through increasing iron-dependent lipid peroxidation and blocking the activation of SLC7A11/GSH/GPX4 pathway in liver, indicating that ferroptosis is a potential mechanism for BDE-209-induced hepatotoxicity.

IntroductionThe gut microbiota plays an important role in the development of nonalcoholic steatohepatitis (NASH). This study investigated the preventive effect of Dendrobium officinale (DO), including whether its effect was related to the gut microbiota, intestinal permeability and liver inflammation.MethodsA NASH model was established in rats using a high-fat diet (HFD) and gavage with different doses of DO or Atorvastatin Calcium (AT) for 10 weeks. Body weight and body mass index along with liver appearance, weight, index, pathology, and biochemistry were measured to assess the preventive effects of DO on NASH rats. Changes in the gut microbiota were analyzed by 16S rRNA sequencing, and intestinal permeability and liver inflammation were determined to explore the mechanism by which DO treatment prevented NASH.ResultsPathological and biochemical indexes showed that DO was able to protect rats against HFD-induced hepatic steatosis and inflammation. Results of 16S rRNA sequencing showed that Proteobacteria, Romboutsia, Turicibacter, Lachnoclostridium, Blautia, Ruminococcus_torques_group, Sutterella, Escherichia-Shigella, Prevotella, Alistipes, and Lactobacillus_acidophilus differed significantly at the phylum, genus, and species levels. DO treatment modulated the diversity, richness, and evenness of gut microbiota, downregulated the abundance of the Gram-negative bacteria Proteobacteria, Sutterella, and Escherichia-Shigella, and reduced gut-derived lipopolysaccharide (LPS) levels. DO also restored expression of the tight junction proteins, zona occludens-1 (ZO-1), claudin-1, and occludin in the intestine and ameliorated the increased intestinal permeability caused by HFD, gut microbiota such as Turicibacter, Ruminococcus, Escherichia-Shigella, and Sutterella, and LPS. Lower intestinal permeability reduced LPS delivery to the liver, thus inhibiting TLR4 expression and nuclear factor-kappaB (NF-κB) nuclear translocation, improving liver inflammation.DiscussionThese results suggest that DO may alleviate NASH by regulating the gut microbiota, intestinal permeability, and liver inflammation.

Abstract Background Noninvasive diagnostic technologies that can dynamically monitor changes in liver inflammation are highly important for the management of chronic hepatitis B (CHB) patients and thus warrant further exploration. This study assessed the diagnostic efficacy of FibroScan for liver inflammation in CHB patients. Methods A total of 1185 patients were selected, and ultrasound-guided liver biopsy was performed within 1 month after the FibroScan test. The liver stiffness measurement (LSM), the reliability criteria (IQR/M) of LSM, the quality of liver biopsy (complete portal area, PA), and the liver inflammation grades were the main observation items of this study. With liver biopsy as the control, the diagnostic efficacy of FibroScan for liver inflammation in CHB patients was evaluated by receiver operating characteristic (ROC) curve analysis. Results The grade of liver inflammation was positively correlated with the stage of fibrosis (rho = 0.829, P 10) served as the control, and the cutoff point and the area under ROC curves (AUCs) of the LSMs for different inflammation grades were as follows: G2, 8.6 kPa, 0.775; G3 9.8 kPa, 0.818; and G4, 11.0 kPa; 0.832. With LSM cutoff values of 8.6 kPa, 9.8 kPa and 11.0 kPa, FibroScan showed certain diagnostic value for CHB patients with G2, G3 and G4 liver inflammation, especially those with G4 inflammation. Conclusions The grade of liver inflammation was positively correlated with the stage of fibrosis, different grades of inflammation will have significant rise in LSM values within the same fibrosis stage. In addition to liver fibrosis, FibroScan could evaluate liver inflammation in CHB patients in a noninvasive manner.

TAM receptors (Tyro3, Axl and MerTK) are a family of tyrosine kinase receptors that are expressed in a variety of cell populations, including liver parenchymal and non-parenchymal cells. These receptors are vital for immune homeostasis, as they regulate the innate immune response by suppressing inflammation via toll-like receptor inhibition and by promoting tissue resolution through efferocytosis. However, there is increasing evidence indicating that aberrant TAM receptor signaling may play a role in pathophysiological processes in the context of liver disease. This review will explore the roles of TAM receptors and their ligands in liver homeostasis as well as a variety of disease settings, including acute liver injury, steatosis, fibrosis, cirrhosis-associated immune dysfunction and hepatocellular carcinoma. A better understanding of our current knowledge of TAM receptors in liver disease may identify new opportunities for disease monitoring as well as novel therapeutic targets. Nonetheless, this review also aims to highlight areas where further research on TAM receptor biology in liver disease is required.

This study aimed to explore whether dietary rumen-protected L-arginine (RP-Arg) or N-carbamylglutamate (NCG) supplementation to feed-restricted pregnant ewes counteracts fetal hepatic inflammation and innate immune dysfunction associated with intrauterine growth retardation (IUGR) in ovine fetuses. On d 35 of pregnancy, twin-bearing Hu ewes (n = 32) were randomly assigned to 4 treatment groups (8 ewes and 16 fetuses per group) and fed diets containing 100% of the NRC requirements (CON), 50% of the NRC requirements (RES), RES + RP-Arg (20 g/d) (RESA), or RES + NCG (5 g/d) (RESN). At 08:00 on d 110 of gestation, fetal blood and liver tissue samples were collected. The levels of triglyceride, free fatty acid, cholesterol and β-hydroxybutyrate in the fetal blood of RESA and RESN groups were lower (P

Background and aims: Effective hepatic blood flow (EHBF) decreases with liver disease progression, and identifying liver pathology is critical for patients with liver disease. This study was designed to elucidate the correlation between EHBF and liver pathology and explore the potential of EHBF for predicting the degree of liver pathology. Methods: In this study, 207 patients with hepatitis B virus (HBV) who underwent liver biopsy and indocyanine green (ICG) clearance tests were enrolled. EHBF was measured using the ICG clearance test, and liver tissue was histologically analyzed to determine the pathological stage according to the Scheuer scoring system. Demographic data, biochemical indexes, and FibroScan data were collected for statistical analysis. Results: EHBF levels decreased as the liver histological stages of inflammation and fibrosis increased (P

Abstract Background A recent study has reported that patients with nonalcoholic fatty liver disease (NAFLD) are more susceptible to coronary microvascular dysfunction (CMD), which may predict major adverse cardiac events. However, little is known regarding the causes of CMD during NAFLD. In this study, we aimed to explore the role of hepatic small extracellular vesicles (sEVs) in regulating the endothelial dysfunction of coronary microvessels during NAFLD. Results We established two murine NAFLD models by feeding mice a methionine-choline-deficient (MCD) diet for 4 weeks or a high-fat diet (HFD) for 16 weeks. We found that the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent endothelial hyperpermeability occurred in coronary microvessels during both MCD diet and HFD-induced NAFLD. The in vivo and in vitro experiments proved that novel-microRNA(miR)-7-abundant hepatic sEVs were responsible for NLRP3 inflammasome-dependent endothelial barrier dysfunction. Mechanistically, novel-miR-7 directly targeted lysosomal associated membrane protein 1 (LAMP1) and promotes lysosomal membrane permeability (LMP), which in turn induced Cathepsin B-dependent NLRP3 inflammasome activation and microvascular endothelial hyperpermeability. Conversely, a specific novel-miR-7 inhibitor markedly improved endothelial barrier integrity. Finally, we proved that steatotic hepatocyte was a significant source of novel-miR-7-contained hepatic sEVs, and steatotic hepatocyte-derived sEVs were able to promote NLRP3 inflammasome-dependent microvascular endothelial hyperpermeability through novel-miR-7. Conclusions Hepatic sEVs contribute to endothelial hyperpermeability in coronary microvessels by delivering novel-miR-7 and targeting the LAMP1/Cathepsin B/NLRP3 inflammasome axis during NAFLD. Our study brings new insights into the liver-to-microvessel cross-talk and may provide a new diagnostic biomarker and treatment target for microvascular complications of NAFLD. Graphical Abstract

ABSTRACT: Lipopolysaccharide (LPS) infection could cause severe liver inflammation and lead to liver damage, even death. Previous studies have shown that polysaccharide of Atractylodes macrocephala Koidz (PAMK) could protect liver from inflammation caused by LPS in mice. However, whether PAMK could alleviate liver inflammatory injury in other animals with LPS is still unknown. For evaluating whether PAMK could alleviate liver inflammatory injury in goslings with LPS, a total of 80 healthy 1-day old Magang goslings were randomly divided into 4 groups (control group, PAMK group, LPS group, and PAMK+LPS group). Goslings in control group and LPS group were fed with basal diet, and goslings in PAMK group and PAMK+LPS group were fed basal diet supplemented with 400 mg/kg PAMK to the end of trial. On 24 d of age, goslings in the control group and PAMK group were intraperitoneal injected 0.5 mL normal saline, and goslings in LPS and PAMK+LPS groups were intraperitoneal injected with LPS at 5 mg/kg BW. The serum and liver samples were collected for further analysis after treatment of LPS at 6, 12, 24, and 48 h. Furthermore, the hepatocytes were extracted from goose embryo to measure the expression of the key genes of miR-223/NLRP3 axis. The results showed that PAMK pretreatment could maintain normal cell morphology of liver, alleviate the enhanced levels of biochemical indexes ALT and AST, decrease the levels of IL-1β and IL-18, increase the relative mRNA expression of miR-223, and decrease the expression of NLRP3, Caspase-1, and cleaved Caspase-1 in liver and hepatocytes of goslings induced by LPS. These results indicated that PAMK could relieve inflammatory liver tissue damage after LPS treatment and downregulate the level of inflammation factors via miR-223/NLRP3 axis, thus playing a liver protective role in liver inflammation injury in goslings.

ObjectivePrecise assessment of liver inflammation in untreated hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B virus (HBV) infection can determine when to initiate antiviral therapy. The aim of this study was to develop and validate a nomogram model for the prediction of non-minimal liver inflammation based on liver pathological injuries combined with age and alanine aminotransferase (ALT), aspartate aminotransferase (AST), hepatitis B surface antigen (HBsAg), HBeAg, and HBV DNA quantification.MethodsWe retrospectively included 735 HBeAg-positive chronic hepatitis B (CHB) patients with ALT

Selenium-containing polysaccharide from Spirulina platensis (Se-SPP) has been demonstrated to help in inhibiting cadmium-induced injury in mice, but the underlying mechanism has not been determined. This study aimed to investigate the beneficial effects of Se-SPP on alleviating Cd-induced toxicity in mice by targeting liver inflammatory and gut microbiota. Se-SPP supplementation for 28 days in Cd-induced toxic mice significantly mitigated liver pathological damage and inflammation, which was correlated to the upregulation of antioxidant enzyme activity. Furthermore, Se-SPP effectively restored Cd-induced disruption of the intestinal barrier compared to model group, as indicated by the depletion of Muribaculaceae and the enrichment of Ruminococcaceae. Spearman's correlation analysis revealed that the Se-SPP-altered microbes were highly correlated with inflammation-related indexes in Cd-induced toxic mice. Noteworthily, the modulation of Se-SPP on the Ruminococcaceae population contributed to the improvement of Cd-induced inflammation-related diseases by downregulating the tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ) in the liver. These findings suggested that Se-SPP may act as prebiotics for ameliorating Cd-induced toxicity in mice by inhibiting liver inflammation mediated by gut microbiota, and target-specific microbiota of Cd-induced inflammation-related diseases deserve further attention.