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Gaudichaudione H (GH) is a natural small molecular compound isolated from Garcinia oligantha Merr. (Clusiaceae). Being an uncommon rare caged polyprenylated xanthone, the potential pharmacological functions of GH remain to be fully elucidated currently. In this study, we primarily focused on identifying potential bioavailable targets and elucidating related therapeutic actions. Herein, the network pharmacology analysis, metabolomics analysis and genome-wide mRNA transcription assay were performed firstly to predict the major pharmacological action and potential targets of GH. To confirm the hypothesis, gene knockout model was created using CRISPR/Cas9 method. The pharmacological action of GH was evaluated in vitro and in vivo. Firstly, our results of network pharmacology analysis and omics assay indicated that GH significantly activated NRF2 signaling pathway, and the function could be associated with liver disease treatment. Then, the pharmacological action of GH was evaluated in vitro and in vivo. The treatment with GH significantly increased the protein levels of NRF2 and promoted the transcription of NRF2 downstream genes. Further analysis suggested that GH regulated NRF2 through an autophagy-mediated non-canonical mechanism. Additionally, the administration of GH effectively protected the liver from carbon tetrachloride (CCl 4)-induced liver fibrosis and inflammation, which depended on the activation of NRF2 in hepatic stellate cells and inflammatory cells respectively. Collectively, our findings underscore the potential therapeutic effect of GH on alleviating hepatic fibrosis and inflammation through the augmentation of NRF2 signaling pathway, providing a promising avenue for the treatment of liver fibrosis and inflammation in clinical settings. [Display omitted] • GH is identified as a functional NRF2 activator in vitro and in vivo. • GH enhances NRF2 signaling via autophagy-mediated non-canonical pathway. • GH alleviates hepatic fibrosis and inflammation in a NRF2-depedent manner. [ABSTRACT FROM AUTHOR]

Magnetic resonance elastography (MRE) is recognized as the most precise imaging technology for assessing liver fibrosis in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD). We aimed to investigate the clinical factors and pathological characteristics that may impact LSM in MASLD patients. This cross-sectional study recruited 124 patients who concurrently performed MRE, MRI-PDFF, and biopsy-proven MASLD. Linear regression models, Spearman's correlation, and subgroup analysis were employed to identify the variables affecting LSM. The AUROC (95 % CI) of MRE for diagnosing fibrosis stage ≥ 1, 2, 3, and 4 was 0.80 (0.70–0.90), 0.76 (0.66–0.85), 0.92 (0.86–0.99), and 0.99 (0.99–1.00), with corresponding cutoffs of 2.56, 2.88, 3.35, and 4.76 kPa, respectively. Multivariate analyses revealed that AST was the only independent clinical variable significantly correlated with LSM. Furthermore, LSM exhibited a notable association with the grade of lobular inflammation and hepatocellular ballooning. Subgroup analysis showed that when AST ≥ 2 ULN or inflammation grade ≥ 2, LSM of patients with early fibrosis stages showed a slight but significant increase. MRE demonstrates significant diagnostic accuracy in predicting liver fibrosis stages for MASLD patients, especially for advanced liver fibrosis and cirrhosis. However, elevated AST and the severity of liver inflammation may impact its accuracy in staging early liver fibrosis. [ABSTRACT FROM AUTHOR]

Cystic fibrosis-related liver disease (CFLD) is a chronic cholangiopathy that increases morbidity and mortality in patients with CF. Current treatments are unsatisfactory, and incomplete understanding of CFLD pathogenesis hampers therapeutic development. We have previously shown that mouse CF cholangiocytes respond to lipopolysaccharide with excessive inflammation. Thus, we investigated the role of the gut-liver axis in the pathogenesis of CFLD. Wild-type (WT), whole-body Cftr knockout (CFTR-KO) and gut-corrected (CFTR-KO-GC) mice were studied. Liver changes were assessed by immunohistochemistry and single-cell transcriptomics (single-cell RNA sequencing), inflammatory mediators were analysed by proteome array, faecal microbiota by 16S ribosomal RNA sequencing and gut permeability by FITC-dextran assay. The livers of CFTR-KO mice showed ductular proliferation and periportal inflammation, whereas livers of CFTR-KO-GC mice had no evident pathology. Single-cell RNA sequencing analysis of periportal cells showed increased presence of neutrophils, macrophages and T cells, and activation of pro-inflammatory and pathogen-mediated immune pathways in CFTR-KO livers, consistent with a response to gut-derived stimuli. CFTR-KO mice exhibited gut dysbiosis with enrichment of Enterobacteriaceae and Enterococcus spp., which was associated with increased intestinal permeability and mucosal inflammation, whereas gut dysbiosis and inflammation were absent in CFTR-KO-GC mice. Treatment with nonabsorbable antibiotics ameliorated intestinal permeability and liver inflammation in CFTR-KO mice. Faecal microbiota transfer from CFTR-KO to germ-free WT mice did not result in dysbiosis nor liver pathology, indicating that defective intestinal CFTR is required to maintain dysbiosis. Defective CFTR in the gut sustains a pathogenic microbiota, creates an inflammatory milieu, and alters intestinal permeability. These changes are necessary for the development of cholangiopathy. Restoring CFTR in the intestine or modulating the microbiota could be a promising strategy to prevent or attenuate liver disease. Severe cystic fibrosis-related liver disease (CFLD) affects 10% of patients with cystic fibrosis (CF) and contributes to increased morbidity and mortality. Treatment options remain limited due to a lack of understanding of disease pathophysiology. The cystic fibrosis transmembrane conductance regulator (CFTR) mediates Cl− and HCO 3 − secretion in the biliary epithelium and its defective function is thought to cause cholestasis and excessive inflammatory responses in CF. However, our study in Cftr -knockout mice demonstrates that microbial dysbiosis, combined with increased intestinal permeability caused by defective CFTR in the intestinal mucosa, acts as a necessary co-factor for the development of CFLD-like liver pathology in mice. These findings uncover a major role for the gut microbiota in CFLD pathogenesis and call for further investigation and clinical validation to develop targeted therapeutic strategies acting on the gut-liver axis in CF. [Display omitted] • The CF gut microbiota features reduced diversity and increased Enterobacteriales. • Gut dysbiosis in CF is associated with gut inflammation and increased permeability. • Intestinal CFTR deficiency is key to the development of liver disease in CF mice. • Restoring intestinal CFTR or modulating microbiota may improve liver disease in CF. [ABSTRACT FROM AUTHOR]

The molecular mediators responsible for the progression of metabolic dysfunction-associated steatotic liver disease (MASLD) to steatohepatitis (MASH) have not yet been completely disentangled. We sought to analyze whether FNDC4, an hepatokine and adipokine with anti-inflammatory properties, is involved in TNF-α-induced inflammatory cell death in patients with MASLD. Plasma FNDC4 (n = 168) and hepatic FNDC4 and inflammatory cell death (n = 65) were measured in samples from patients with severe obesity with available liver biopsy-proven MASLD diagnosis. The effect of FNDC4 on TNF-α-induced pyroptosis, apoptosis and necroptosis (PANoptosis) and mitochondrial dysfunction was studied in vitro using human HepG2 hepatocytes. Compared with individuals with normal liver, patients with type 2 diabetes and MASLD exhibited decreased hepatic FNDC4 mRNA and protein levels, which were related to liver inflammation. An overexpression of TNF-α, its receptor TNF-R1 and factors involved in inflammatory cell death was also found in the liver of these patients. FNDC4 -knockdown in HepG2 hepatocytes increased apoptotic cell death, while FNDC4 treatment blunted NLRP3 inflammasome-induced pyroptosis, apoptosis and necroptosis in TNF-α-stimulated hepatocytes. Moreover, FNDC4 improved TNF-α-induced hepatocyte mitochondrial dysfunction by enhancing mitochondrial DNA (mtDNA) copy number and OXPHOS complex subunits I, II, III and V protein expression. Mechanistically, AMP-activated protein kinase α (AMPKα) was required for the FNDC4-mediated inhibition of cell death and increase in mtDNA content. FNDC4 acts as a hepatocyte survival factor favouring mitochondrial homeostasis and decreasing inflammatory cell death via AMPKα. Collectively, our study identifies FNDC4 as an attractive target to prevent hepatocellular damage in patients with MASLD. [Display omitted] • Hepatic FNDC4 expression is decreased in patients with MASLD. • FNDC4 gene silencing promotes hepatocyte apoptosis. • FNDC4 treatment prevents TNF-α-induced hepatocyte inflammatory cell death via AMPKα. • FNDC4 reduces hepatocyte mitochondrial damage improving mitochondrial biogenesis, dynamics and OXPHOS protein expression. [ABSTRACT FROM AUTHOR]

Biliary atresia (BA) is characterized by a progressive fibroinflammatory cholangiopathy in early infants with unknown etiology. Although innate immune disorder is involved in its mechanism, role of NLRP3 inflammasome in BA remains largely undefined. To explore the role of NLRP3 inflammasome in BA. The expressions of NLRP3 inflammasome-related genes were determined in BA patients. Role of NLRP3 inflammasome was evaluated using MCC950 in experimental BA. Furthermore, gadolinium chloride, a macrophage scavenger, was applied to validate the inflammasome's cellular localization. Finally, the effects of NLRP3 inflammasome activation on liver fibrosis were explored in vivo and vitro in experimental BA. The components of NLRP3 inflammasome were up-regulated in BA patients. Inflammasome-related genes showed positively correlated with liver inflammation and fibrosis in BA patients. In experimental BA, inflammasome-related genes were up-regulated, and their expressions were inhibited by MCC950, which promoted mice growth, protected liver function, alleviated obstructive jaundice, inhibited liver inflammation, and reduced serum IL-1β level. NLRP3 inflammasome was expressed in macrophages, and macrophage elimination exerted the same protective roles as MCC950 did in BA. Additionally, NLRP3 inflammasome activation promoted liver fibrosis in experimental BA. NLRP3 inflammasome activation in macrophages promoted liver inflammation and fibrosis in experimental BA. [ABSTRACT FROM AUTHOR]

During chronic liver injury, inflammation leads to liver fibrosis, particularly due to the activation of hepatic stellate cells (HSCs). The involvement of inflammatory cytokines in HSC activation and the interplay among different liver cells are elaborated. To examine their interactions in vitro, many cultured liver tissue models are performed in organoid or spheroid culture with random 3D structure. Herein, we demonstrated the hierarchical coculture of primary rat hepatocytes with non-parenchymal cells such as the human-derived HSC line (LX-2) and liver sinusoidal endothelial cell line (TMNK-1). The cocultured tissue had high usability with simple operation of separating solid and liquid phases with improved liver functions such as albumin production and hepatic cytochrome P450 3A4 activity. We also studied the effects of stimulation by both oxygen tension and the key pro-fibrogenic cytokine, transforming growth factor beta (TGF-β), on HSC activation. Gene expression of collagen type I and alpha-smooth muscle actin were enhanced in the hierarchical coculture under lower oxygen tension and TGF-β1 stimulation. Therefore, this hierarchical in vitro cocultured liver tissue could provide a useful platform as a disease model for elucidating the interactions of various liver cell types and biochemical signals in future liver fibrogenesis studies. [ABSTRACT FROM AUTHOR]

Nowadays potential preclinical drugs for the treatment of nonalcoholic steatohepatitis (NASH) have failed to achieve expected therapeutic efficacy because the pathogenic mechanisms are underestimated. Inactive rhomboid protein 2 (IRHOM2), a promising target for treatment of inflammation-related diseases, contributes to deregulated hepatocyte metabolism-associated nonalcoholic steatohepatitis (NASH) progression. However, the molecular mechanism underlying Irhom2 regulation is still not completely understood. In this work, we identify the ubiquitin-specific protease 13 (USP13) as a critical and novel endogenous blocker of IRHOM2, and we also indicate that USP13 is an IRHOM2-interacting protein that catalyzes deubiquitination of Irhom2 in hepatocytes. Hepatocyte-specific loss of the Usp13 disrupts liver metabolic homeostasis, followed by glycometabolic disorder, lipid deposition, increased inflammation, and markedly promotes NASH development. Conversely, transgenic mice with Usp13 overexpression, lentivirus (LV)- or adeno-associated virus (AAV)-driven Usp13 gene therapeutics mitigates NASH in 3 models of rodent. Mechanistically, in response to metabolic stresses, USP13 directly interacts with IRHOM2 and removes its K63-linked ubiquitination induced by ubiquitin-conjugating enzyme E2N (UBC13), a ubiquitin E2 conjugating enzyme, and thus prevents its activation of downstream cascade pathway. USP13 is a potential treatment target for NASH therapy by targeting the Irhom2 signaling pathway. USP13 is a novel eliminator of non-alcoholic steatohepatitis (NASH). Liver USP13 interacts with IRHOM2 and restrains its ubiquitination by UBC13 and subsequent downstream signaling cascade activation, resulting in mitigation of NASH pathologies. [Display omitted] [ABSTRACT FROM AUTHOR]

Sterile inflammation contributes to the development of many liver diseases including non-alcoholic fatty liver disease. Tumor necrosis factor alpha (TNFα) is a key cytokine driving liver inflammation primarily through pro-inflammatory activation of liver sinusoidal endothelial cells (LSEC). The knowledge of whether modulating LSEC activation can alleviate liver inflammation is scarce. This study aims to establish and validate an animal model mimicking LSEC dysfunction observed in obese patients with elevated plasma levels of TNFα, and explore whether vasoactive flavonoid diosmetin could serve as a therapeutic agent for liver inflammation by modulation of LSEC dysfunction. Obese patients with elevated plasma levels of TNFα, LSEC dysfunction and liver inflammation had also reduced Mcpip1 expression in peripheral blood mononuclear cells. Mcpip1 is a protein that negatively regulates the levels of pro-inflammatory cytokines. To model this, we generated mice with Mcpip1 knock-out in myeloid cells (Mcpip1fl/flLysMCre), which displayed systemic and liver inflammation like that observed in patients. Diosmetin treatment efficiently reduced TNFα-dependent LSEC activation in vitro and in vivo , and reduced liver inflammation in Mcpip1fl/flLysMCre mice without affecting systemic inflammation. Diosmetin's effects may stem from inhibiting NF-κB pathway in TNFα-activated endothelial cells. Our findings demonstrate that the Mcpip1fl/flLysMCre mouse model is useful for studying new anti-inflammatory therapies for the liver. We show that diosmetin, a vasoactive flavonoid used in the clinic to treat chronic venous insufficiency, also has strong anti-inflammatory properties in the liver. These results indicate that diosmetin has the potential to be further investigated as a supportive therapy for liver inflammation in humans. [Display omitted] • Patients with elevated TNFα levels exhibit LSEC dysfunction and liver inflammation. • Mcpip1fl/flLysMCre mice replicate the inflammatory phenotype observed in patients with high TNFα levels. • Diosmetin treatment prevents liver inflammation by improving LSEC function in mice. • Diosmetin reduces the pro-inflammatory activation of LSEC by inhibiting the NF-κB signaling. [ABSTRACT FROM AUTHOR]

• Whereas STING disruption alleviates the severities of obesity and MASLD phenotype in mice upon HFD feeding for a period of 3 months, STING disruption-based protection is abolished in mice upon HFD feeding for a period of 7 months. • Liver RNAseq analysis indicates that HFD feeding for 7 months reprograms the proinflammatory activation of multiple types of liver cells including hepatocytes, T lymphocytes, neutrophils, and cholangiocytes. • estrogen accounts for female sex-based protect of diet-induced MASLD in a manner independent of STING. Stimulator of interferon genes (STING) is positively correlated with the degrees of liver inflammation in human metabolic dysfunction-associated steatotic liver disease (MASLD). In addition, STING disruption alleviates MASLD in mice fed a high-fat diet (HFD) for 3 months (3-m-HFD). Here we investigated the role of the duration of dietary feeding in regulating MASLD in mice and explored the involvement of STING in sex differences in MASLD. Both male and female STING-disrupted (STINGgt) and wild-type C57BL/6J mice were fed an HFD for 3 or 7 months (7-m-HFD). Additionally, female STINGgt mice upon ovariectomy (OVX) and 3-m-HFD were analyzed for MASLD. Upon 3-m-HFD, STINGgt mice exhibited decreased severity of MASLD compared to control. However, upon 7-m-HFD, STINGgt mice were comparable with wild-type mice in body weight, fat mass, and MASLD. Regarding regulating the liver RNA transcriptome, 7-m-HFD increased the expression of genes indicating proinflammatory activation of various liver cells. Interestingly, the severity of MASLD in female mice was much lighter than in male mice, regardless of STING disruption. Upon OVX, female STINGgt mice showed significantly increased severity of MASLD relative to sham control but were comparable with male STINGgt mice. Upon treatment with 17-beta estradiol (E2), hepatocytes revealed decreased fat deposition while macrophages displayed decreases in lipopolysaccharide-induced phosphorylation of Nfkb p65 and Jnk p46 independent of STING. These results suggest that 7-m-HFD, without altering female sex-based protection, abolishes STING disruption-driven protection of MASLD, likely through causing proinflammatory activation of multiple types of liver cells to offset the effect of STING disruption. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • AC is protective against LPS/D-GalN-induced mice acute liver injury. • AC is also protective against mice acute alcoholic liver injury. • AC inhibits LPS-induced inflammatory response in RAW264.7 cells. • AC exerts anti-hepatic injury effect by inhibiting the TLR4/JNK/NF-ĸB pathway. Acute liver injury is characterized by massive inflammatory cell infiltration, destruction of liver structure and abnormalities in liver function. Acetylcorynoline (AC) is one of the main chemical components of Corydalis bungeana Turcz. which has been shown to have a protective effect against acute liver injury. However, Whether AC is protective against acute liver injury remains unclear. This study aimed to explore the protective mechanism of AC against acute liver injury from in vivo as well as experiments in vitro. In experimental in vivo studies, AC pretreatment reduced the serum levels of ALT and AST and inhibited the expression of inflammatory factors in the liver of LPS/D-GalN-induced mice and alcohol liver disease mice. RNA-sequencing and molecular docking were used to predict that AC exerts its anti-inflammatory effects through the Toll-like receptor signaling pathway. Using RT-qPCR and Western blotting to detect expression levels of key genes and nodal proteins of the Toll-like receptor signaling pathway, AC was found to inhibit the phosphorylation of nuclear factor-kappaB (NF-ĸB) and c-Jun amino-terminal kinase (JNK). This finding was validated in cellular experiments. In conclusion, AC exerts its anti-hepatic injury effect by suppressing inflammation through inhibition of the TLR4/JNK/NF-ĸB pathway. [ABSTRACT FROM AUTHOR]

Gut microbiome dysbiosis is involved in non-alcoholic fatty liver disease (NAFLD) development. Hepatic transmembrane 4 L six family member 5 (TM4SF5) overexpression promotes NAFLD. However, how gut microbiota are associated with TM4SF5-mediated NAFLD remains unexplored. We analyzed the gut microbiome using feces from hepatocyte-specific TM4SF5-overexpressing transgenic (Alb -TGTm4sf5-Flag, TG) or Tm4sf5 −/− knock-out (KO) mice fed a normal chow diet (NCD), high-fat diet (HFD) for 2 weeks (HFD 2W), or methionine-choline-deficient diet (MCD) for 4 weeks to investigate associations among Tm4sf5 expression, diet, and the gut microbiome. TG-NCD mice showed a higher Firmicutes -to- Bacteroidetes (F/B) ratio, with less enrichment of Akkermansia muciniphila and Lactobacillus reuteri. NASH-related microbiomes in feces were more abundant in TG-HFD 2w mice than in KO-HFD 2w mice. Further, TG-MCD showed a higher F/B ratio than TG-NCD or KO mice, with decreases or increases in microbiomes beneficial or detrimental to the liver, respectively. Such effects in TG-MCD animals were correlated with functional pathways producing short-chain fatty acids (SCFAs). Furthermore, potential functional pathways of the gut microbiome were metabolically parallel to NAFLD features in TG-MCD mice. These results suggest that hepatocyte Tm4sf5 supports gut microbiome dysbiosis and metabolic activity, leading to SCFA production and hepatic inflammation during NAFLD development. [Display omitted] • The impact of hepatocyte TM4SF5 in gut microbiome for NAFLD is not documented. • Knockout of TM4SF5 was linked to anti-obesity and anti-NASH-related microbiomes. • Hepatocyte TM4SF5 led to gut microbiota dysbiosis and SCFA synthesis by MCD diet. • TM4SF5 affects diversity and metabolic activity of gut microbiome for early NAFLD. [ABSTRACT FROM AUTHOR]

Chronic infection with Hepatitis B Virus (HBV) often results in a dysfunctional virus-specific T cell response hampering viral clearance. Paradoxically, intrahepatic inflammatory responses that contribute more to liver histopathology than to viral suppression are commonly observed, which are widely believed to be cell mediated. The involvement of humoral immunity in this process however is not well documented. To investigate the possible roles of HBV Capsid-Antibody Complexes (CACs) in eliciting chronic liver inflammation, we developed a novel microplate-based assay for the quantification of CACs in serum. The CACs assay showed high sensitivity and specificity with its readout closely correlating with the molecular features of CACs. A cross-sectional study on untreated chronic hepatitis B (CHB) patients showed a 77% positive rate for CACs with significant association with alanine transaminase (ALT), intrahepatic inflammation, and complement deposition, suggestive of its functional role in hepatic injury. Multiple staining of complement activation fragment C4d with major leukocyte and myofibroblast markers revealed an intertwined picture in periportal area with a morphology reminiscent of "piecemeal necrosis". In a pooled cohort with ALT levels lower than 40 IU/ml, CACs alone revealed subclinical liver inflammation. We provide definitive evidence for a causative role for CACs in complement-mediated intrahepatic immunopathology, an additional mechanism contributing to liver damage in CHB. Assessment of CACs in serum complements current clinical markers for assessing CHB associated inflammation. • Development of a simple microplate-based assay measuring the level of HBV Capsid-Antibody-Complexes (CACs) in patient serum. • CACs are highly prevalent in HBV-infected individuals and close associate with intrahepatic inflammation and complement deposition. • The CACs assay showed diagnostic value in revealing subclinical liver inflammation when the ALT level is below the upper-limit-of-normal. [ABSTRACT FROM AUTHOR]

Acetaminophen (APAP) overdose causes liver injury in animals and humans. Although well-studied in animals, limited longitudinal data exist on cytokine release after APAP overdose in patients. The purpose of this study was to quantify concentrations of cytokines in APAP overdose patients to determine if early cytokine or complement measurements can distinguish between surviving and non-surviving patients. Plasma was obtained from healthy controls, APAP overdose patients with no increase in liver transaminases, and surviving and non-surviving APAP overdose patients with severe liver injury. Interleukin-10 (IL-10), and CC chemokine ligand-2 (CCL2, MCP-1) were substantially elevated in surviving and non-surviving patients, whereas IL-6 and CXC chemokine ligand-8 (CXCL8, IL-8) had early elevations in a subset of patients only with liver injury. Day 1 IL-10 and IL-6 levels, and Day 2 CCL2, levels correlated positively with survival. There was no significant increase in IL-1α, IL-1β or TNF-α in any patient during the first week after APAP. Monitoring cytokines such as CCL2 may be a good indicator of patient prognosis; furthermore, these data indicate the inflammatory response after APAP overdose in patients is not mediated by a second phase of inflammation driven by the inflammasome. • Multiple cytokines were measured in plasma of acetaminophen overdose patients. • TNF-α, IL-1α, and IL-1β levels were not elevated over 5 days after an overdose. • MCP-1 was drastically elevated in overdose patients with liver injury. • Day 1 IL-10 and IL-6 and Day 2 MCP-1 levels correlated positively with survival. • Complement C3 was depleted in all overdose patients but recovered only in survivors. [ABSTRACT FROM AUTHOR]

Although Ikaros (IKZF1) is a well-established transcriptional regulator in leukocyte lymphopoiesis and differentiation, its role in myeloid innate immune responses remains unclear. Sirtuin 1 (SIRT1) is a histone/protein deacetylase involved in cellular senescence, inflammation, and stress resistance. Whether SIRT1 signaling is essential in myeloid cell activation remains uncertain, while the molecular communication between Ikaros and SIRT1, two major transcriptional regulators, has not been studied. We undertook molecular and functional studies to interrogate the significance of the myeloid Ikaros–SIRT1 axis in innate immune activation and whether it may serve as a homeostatic sentinel in human liver transplant recipients (hepatic biopsies) and murine models of sterile hepatic inflammation (liver warm ischemia-reperfusion injury in wild-type, myeloid-specific Sirt1 -knockout, and CD11b-DTR mice) as well as primary bone marrow-derived macrophage (BMM) cultures (Ikaros silencing vs. overexpression). In our clinical study, we identified increased post-reperfusion hepatic Ikaros levels, accompanied by augmented inflammasome signaling yet depressed SIRT1, as a mechanism of hepatocellular damage in liver transplant recipients. In our experimental studies, we identified infiltrating macrophages as the major source of Ikaros in IR-stressed mouse livers. Then, we demonstrated that Ikaros-regulated pyroptosis – induced by canonical inflammasome signaling in BMM cultures – was SIRT1 dependent. Consistent with the latter, myeloid-specific Ikaros signaling augmented hepatic pyroptosis to aggravate pro-inflammatory responses in vivo by negatively regulating SIRT1 in an AMPK-dependent manner. Finally, myeloid-specific SIRT1 was required to suppress pyroptosis, pro-inflammatory phenotype, and ultimately mitigate hepatocellular injury in ischemia-stressed murine livers. These findings identify the Ikaros–SIRT1 axis as a novel mechanistic biomarker of pyroptosis and a putative checkpoint regulator of homeostasis in response to acute hepatic stress/injury in mouse and human livers. This report describes how crosstalk between Ikaros and SIRT1, two major transcriptional regulators, influence acute hepatic inflammation in murine models of liver ischemia-reperfusion injury and liver transplant recipients. We show that the myeloid Ikaros–SIRT1 axis regulates inflammasome-pyroptotic cell death and hepatocellular damage in stressed livers. Thus, the Ikaros-SIRT1 axis may serve as a novel checkpoint regulator that is required for homeostasis in response to acute liver injury in mice and humans. [Display omitted] • Ikaros transcription factor is expressed by host macrophages recruited into ischemia-stressed mouse and human livers. • Ikaros regulates macrophage inflammasome activation and sterile liver inflammation via AMPK-SIRT1 signaling. • Ikaros regulates the inflammasome-pyroptosis response in stressed macrophages in a SIRT1-dependent manner. • Increased Ikaros levels accompanied by inflammasome signaling correlate with worse human liver transplant function. • Ikaros-SIRT1 axis may serve as pyroptosis biomarker and homeostasis checkpoint against liver injury in mice and humans. [ABSTRACT FROM AUTHOR]

Codonopsis pilosula polysaccharides (CPP), the main active ingredient of Codonopsis pilosula , has gained significant attention as a liver-protective agent. Previous studies have demonstrated that CPP could alleviate gut microbiota dysbiosis in colitis or obese mice. However, the effects of CPP on mycotoxin-induced liver injury and gut microbiota dysbiosis are still poorly understood. In this study, we aimed to investigate the protective effects of CPP on sterigmatocystin (STC)-induced liver injury, as well as its regulatory effects on gut microbiota. Our results revealed that CPP intervention significantly alleviated STC-induced liver injury, as evidenced by decreased liver index, reduced liver histopathological changes, and modulation of related molecular markers. Additionally, we found that CPP could alleviate liver injury by reducing liver inflammation and oxidative stress, inhibiting hepatocyte apoptosis, and regulating lipid metabolism. Notably, we also observed that CPP could alleviate STC-induced gut microbiota dysbiosis by modulating the diversity and richness of gut microbiota, suggesting that gut microbiota modulation may also serve as a mechanism for CPP-mediated remission of liver injury. In summary, our study not only provided a new theoretical basis for understanding the hepatotoxicity of STC and the protective effects of CPP against STC-induced liver injury, but also provided new perspectives for the application of CPP in the fields of food, healthcare products, and medicine. [Display omitted] [ABSTRACT FROM AUTHOR]

ADAR1-mediated RNA editing establishes immune tolerance to endogenous double-stranded RNA (dsRNA) by preventing its sensing, primarily by MDA5. Although deleting Ifih1 (encoding MDA5) rescues embryonic lethality in ADAR1-deficient mice, they still experience early postnatal death, and removing other MDA5 signaling proteins does not yield the same rescue. Here, we show that ablation of MDA5 in a liver-specific Adar knockout (KO) murine model fails to rescue hepatic abnormalities caused by ADAR1 loss. Ifih1 ; Adar double KO (dKO) hepatocytes accumulate endogenous dsRNAs, leading to aberrant transition to a highly inflammatory state and recruitment of macrophages into dKO livers. Mechanistically, progranulin (PGRN) appears to mediate ADAR1 deficiency-induced liver pathology, promoting interferon signaling and attracting epidermal growth factor receptor (EGFR)+ macrophages into dKO liver, exacerbating hepatic inflammation. Notably, the PGRN-EGFR crosstalk communication and consequent immune responses are significantly repressed in ADAR1high tumors, revealing that pre-neoplastic or neoplastic cells can exploit ADAR1-dependent immune tolerance to facilitate immune evasion. [Display omitted] • MDA5 loss does not rescue inflammation and dysfunction in ADAR1-deficient liver • Tissue-specific pathways for self-dsRNA response in ADAR1-deficient liver • PGRN mediates IFN responses and macrophage recruitment in ADAR1-deficient liver • ADAR1 represses PGRN-EGFR signaling, promoting tumor immune evasion In this study, Gan et al. use multi-omics approaches to reveal that MDA5 loss in ADAR1-deficient livers does not alleviate inflammation and dysfunction. Hepatocyte-macrophage crosstalk via the PGRN-EGFR axis manages self-dsRNA responses, with PGRN mediating interferon responses and macrophage recruitment. ADAR1 suppression of PGRN-EGFR signaling aids tumor immune evasion. [ABSTRACT FROM AUTHOR]

Yinyanghuo, a famous herb, includes the folium of Epimedium brevicornu Maxim. and Epimedium sagittatum Maxim. It is believed that their processed products, the prepared slices of the folium of Epimedium brevicornu Maxim. (PFEB) and Epimedium sagittatum Maxim. (PFES) have greater efficacy in tonifying kidney Yang to treat kidney-Yang deficiency syndrome (KDS). However, there are few studies comparing the pharmacological effects of PFEB and PFES, and the underlying mechanisms. This study compared their effects on improving hypothalamic-pituitary-adrenal (HPA) axis, immune system and sexual characteristic, as well as repairing liver injury complications in the KDS model mice. Additionally, the mechanisms of the effects relevance to their main components were explored. It was found that PFEB was more effective than PFES in increasing cAMP/cGMP ratio, SOD activity, CRH and ACTH levels, eNOS and testosterone levels, splenic lymphocytes proliferation, while in decreasing MDA content, atrophy of spleen and thymus, splenic lymphocytes apoptosis, and PDE5 level. PFES showed stronger protection than PFEB in decreasing triglyceride and hepatic lipid. The contents of baohuoside I and epimedin A, B were much higher in PFEB, while Epimedin C, Icariin, 2-O″-rhamnosylicaridide II were higher in PFES. Consequently, PFEB exhibits superior efficacy over PFES in tonifying the kidney-Yang by improving the neuroendocrine-immune network, including HPA axis, immune systems, and corpus cavernosum. However, PFES has better recovery effect on mild hepatic lipid caused by KDS. The efficacy difference between PFEB and PFES in kidney-Yang and liver may be attributed to the content variations of baohuoside I. [Display omitted] [ABSTRACT FROM AUTHOR]

The study was to investigate the anti-inflammatory effect of Cyclocarya paliurus polysaccharides (CP) on carbon tetrachloride (CCl 4) induced mice and explore its underlying mechanism. Based on a mouse model of CCl 4 induced liver inflammation and pretreatment with CP. Results showed that CP significantly decreased the levels of the proinflammatory cytokines (NO, TNF-α, IL-1β) as well as the proteins expression levels of COX-2 and iNOS in the liver. TLR4 and MAPK pathways were down-regulated after CP administration. Furthermore, 16S rDNA showed that CP increased the Firmicutes / Bacteroidetes ratio and the abundance of probiotics (Unclassified Clostridiales) as well as decreased abundances of pathogenic bacteria (Proteobacteria , Helicobacter and Aerococcus) compared to model group. Moreover, CP treatment increased the SCFAs levels in CCl 4 induced mice. These findings suggested that CP act as prebiotics in ameliorating the liver inflammation in mice caused by CCl 4 through regulating the gut microbiota composition and increasing the concentration of SCFAs. • Cyclocarya paliurus polysaccharide (CP) improved lipid metabolism disorders. • CP suppressed inflammatory cytokines production, iNOS and COX-2 expression. • CP protects liver inflammation via down-regulating TLR4/MAPK signaling pathways. • CP has effect on SCFAs produced by gut microbiota metabolism. • CP can change the diversity and composition of gut microbiota. [ABSTRACT FROM AUTHOR]

Gut inflammation caused by various factors including microbial infection leads to disorder of absorption of dietary nutrients and decrease in egg production in laying hens. We hypothesized that intestinal inflammation may affect egg production in laying hens through its impact on liver function. Dextran sodium sulphate (DSS) is known to induce intestinal inflammation in mammals, but whether it also induces inflammation in laying hens is not known. The goal of this study was to assess whether oral administration of DSS is a useful model of intestinal inflammation in laying hens and to characterize the effects of intestinal inflammation on egg production using this model. White Leghorn hens (350-day old) were administrated with or without 0.9 g of DSS/kg BW in drinking water for 5 D (n = 8, each). All laid eggs were collected, and their whole and eggshell weights were recorded. Blood was collected every day and used for biochemical analysis. Liver and intestinal tissues (duodenum, jejunum, ileum, cecum, cecal-tonsil, and colon) were collected 1 D after the final treatment. These tissue samples were used for histological analysis and PCR analysis. Oral administration of DSS in laying hens caused 1) histological disintegration of the cecal mucosal epithelium and increased monocyte/macrophage infiltration and IL-1β, IL-6, CXCLi2, IL-10, and TGFβ-4 gene expression; 2) decreased egg production; 3) increased leukocyte infiltration and IL-1β, CXCLi2, and IL-10 expression in association with a high frequency of lipopolysaccharide-positive cells in the liver; and 4) decreased expression of genes related to lipid synthesis, lipoprotein uptake, and yolk precursor production. These results suggested that oral administration of DSS is a useful method for inducing intestinal inflammation in laying hens, and intestinal inflammation may reduce egg production by disrupting egg yolk precursor production in association with liver inflammation. [ABSTRACT FROM AUTHOR]

[Display omitted] • PAMK have potential in alleviating HFD-induced NAFLD. • PAMK alleviates hepatocellular steatosis & liver injury caused by HFD. • Transcriptome analysis suggests dual effects of PAMK on metabolic & inflammatory pathways. 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. [ABSTRACT FROM AUTHOR]

Maximizing the potential of human liver organoids (LOs) for modeling human septic liver requires the integration of innate immune cells, particularly resident macrophage Kupffer cells. In this study, we present a strategy to generate LOs containing Kupffer cells (KuLOs) by recapitulating fetal liver hematopoiesis using human induced pluripotent stem cell (hiPSC)-derived erythro-myeloid progenitors (EMPs), the origin of tissue-resident macrophages, and hiPSC-derived LOs. Remarkably, LOs actively promote EMP hematopoiesis toward myeloid and erythroid lineages. Moreover, supplementing with macrophage colony-stimulating factor (M-CSF) proves crucial in sustaining the hematopoietic population during the establishment of KuLOs. Exposing KuLOs to sepsis-like endotoxins leads to significant organoid dysfunction that closely resembles the pathological characteristics of the human septic liver. Furthermore, we observe a notable functional recovery in KuLOs upon endotoxin elimination, which is accelerated by using Toll-like receptor-4-directed endotoxin antagonist. Our study represents a comprehensive framework for integrating hematopoietic cells into organoids, facilitating in-depth investigations into inflammation-mediated liver pathologies. [Display omitted] • hiPSC-derived EMPs undergo hematopoiesis in a liver organoid environment • M-CSF is essential to establish liver organoids containing Kupffer cells (KuLOs) • LPS/IFN-γ-stimulated KuLOs resemble sepsis-associated liver dysfunction • Septic KuLOs have self-recovery ability Li et al. report the generation of liver organoids containing Kupffer cells (KuLOs) by recapitulating erythro-myeloid progenitor (EMP) hematopoiesis during liver development. LPS/IFN-γ-treated KuLOs can mimic the pathological events of the human septic liver. The impaired organoid functions can recover under stimulus-free conditions. [ABSTRACT FROM AUTHOR]

Polymorphisms of group VIA calcium-independent phospholipase A2 (PLA2G6) are associated with blood C-reactive protein suggesting its role in inflammation. We showed that myeloid-specific Pla2g6-deficiency in Pla2g6M−/− mice led to exaggerated inflammation and fibrosis in a lean fatty liver model. We here investigated whether these mutants display alteration in immune response after treatment with E. coli lipopolysaccharides (LPS) under acute (a single dose) and persistent (four doses) conditions. Without LPS treatment, male Pla2g6M−/− (but not Flox) mice at 12 months of age exhibited splenomegaly and hepatic necrosis, and ~ 30 % of them exhibited autoimmune hepatitis showing lymphoplasma cells with CD3(+) and CD45R(+) staining. Under acute LPS, male mutants showed an elevation of plasma MIP-1α and immunoglobulinA as well as upregulation of hepatic apoptosis and fibrosis PARP-1, Bax, MCP-1, α-SMA, and collagen I proteins. Their bone-marrow-derived macrophages also showed an elevation of MIP-1α release upon LPS stimulation in vitro. Female mutants under acute LPS showed a moderate increase in plasma KC/CXCL1, MCP-1, and IL10, and they showed no remarkable increase in hepatic fibrosis under acute or persistent LPS. Male mutants under persistent LPS displayed an elevation of aspartate aminotransferase, blood eosinophils, and hepatic apoptosis. Moreover, ~30 % of these mutants exhibited eosinophilic sclerosing portal hepatitis associated with an upregulated protein expression of hepatic CD8α, CD68, eosinophilic cationic protein, and Ly6G. Thus, myeloid-PLA2G6 deficiency led to an autoimmune and LPS-induced inflammatory liver disease via MIP-1α in a male-predominant manner. Our results may be applicable to patients with PLA2G6 mutations who undergo bacterial infection and sepsis. [Display omitted] • We studied myeloid-PLA2G6 deficient mice under acute and tolerant/persistent LPS. • Without LPS, 30 % of male mutants show autoimmune hepatitis greater than females. • Male mutants show increased hepatic necrosis, MIP-1α release in plasma and BMDMs. • Under persistent LPS, male mutants show eosinophilic sclerosing portal hepatitis. • Mutants of both sexes show increased hepatic myeloperoxidase and leukotriene B4. [ABSTRACT FROM AUTHOR]

Abstract Interleukin (IL)-35 is a responsive anti-inflammatory cytokine implicated in different diseases processes. It has been reported that elevated IL-35 contributed to immunosuppression in chronic hepatitis by modulation of T helper 17 (Th17) and regulatory T cells. However, the role of IL-35 in acute hepatitis B (AHB) was still not completely elucidated. Thus, in the present study, we analyzed the expression and regulatory activity of IL-35 to Th17 cells and inflammatory response during acute hepatitis B virus (HBV) infection in both peripheral blood cells isolated from AHB patients and in hydrodynamic induced HBV-infected mouse model. Plasma IL-35 level and circulating HBV peptides-induced Th17 frequency was significantly elevated in AHB patients, and IL-35 expression negatively correlated with liver inflammation. In vitro IL-35 stimulation to CD4+ T cells purified from AHB patients down-regulated HBV peptides-induced Th17-phenotype, which presented as reduced IL-17 and IL-22 production. In vivo IL-35 administration dampened liver inflammation in HBV plasmid injected mice, however, did not affect HBV antigens production. This process was accompanied by suppression of natural killer cells and down-regulation of HBV peptides-induced Th17 cells in the liver, but did not affect total intrahepatic lymphocytes and other cell subsets numbers or chemokines expression in the liver. In conclusion, the current data indicated that IL-35 might be a novel mediator associated with hepatocytes damage and liver inflammation by regulating HBV peptides-induced Th17 cells during acute HBV infection. The potential anti-inflammatory property of IL-35 might be pivotal for developing new therapeutic approaches for hepatitis B. Highlights • IL-35 and HBV peptides-induced Th17 cells was elevated in AHB patients. • In vitro IL-35 stimulation to CD4+ T cells down-regulated Th17-phenotype. • In vivo IL-35 administration dampened liver inflammation in acute HBV infected mouse model. • In vivo IL-35 administration suppressed recruitment of Th17 cells into the liver. [ABSTRACT FROM AUTHOR]

• CUR was encapsulated in PLA-PEG nanoparticles. • Nanoemulsification evaporation technique was used. • CUR was loaded into the core of nanrtopaicles. • CUR nanoparticles was administered to STZ- induced diabetic rats. This report focused on loading curcumin (CUR) drug into biodegradable Polylactide-poly(ethylene glycol) (PLA-PEG) copolymer nanoparticles as an effective anti-inflammatory agent in vivo to overcome the limitations resulted from the free CUR. By a simple nano-emulsification technique, hydrophobic CUR was loaded into hydrophobic polymer's segments and stabilized by cationic surfactant. They were then characterized by DLS, TEM, and SEM techniques providing monodispersed and spherical nanoparticles with an average diameter of 117 nm and high surface charge of +35 mV. Thereafter, they were orally administrated into five groups of rats, typically, control (healthy rats), streptozotocin (STZ)-induced diabetic rats, diabetics treated with free CUR, diabetics treated with PLA-PEG NPs, and diabetics treated with CUR-encapsulated PLA-PEG NPs. Next, complete blood analyses were assessed including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and nuclear factor kappa B (NF-ҡB), reduced glutathione (GSH), malondialdehyde (MDA), nitric oxide (NO), cyclooxygenase (COX-2), Peroxisome proliferator-activated receptors (PPAR-γ) and transforming growth factor-β1 (TGF-β1). The obtained results demonstrated that diabetes initially produced liver inflammation in rats manifested by leveraging the mean levels of serum AST, ALT inducing oxidative stress resulting in a clear increase in the levels of hepatic MDA and NO concomitant with a remarkable decrease in GSH. Moreover, diabetes significantly increased serum NF-ҡB, hepatic COX-2 and TGF-β1, while highly reduced hepatic PPAR-γ. In contrast, both CUR free and CUR-encapsulated NPs ameliorated the negative changes in diabetes but CUR-encapsulated NPs showed more pronounced treated effect than free CUR. In addition, histopathological investigations were performed on the liver tissues of all groups, showing a mitigation in inflammation while treating with CUR-NPs. [ABSTRACT FROM AUTHOR]

In this study, highland barley (HB), HB bran (HBB) and whole grain HB (WGHB) alleviating hyperlipemia and liver inflammation in high fat and cholesterol diet (HFCD) mice was investigated. All 50 ICR mice were randomly allocated to 5 treatment groups: Normal control group, HFCD group, HB group, HBB group and WGHB group. The serum lipid profiles, liver and epididymal adipocyte histology, gut microbiota and untargeted metabolomics were adopted. The results suggested that HB especially HBB supplement could obviously decrease BW and BWG. Serum lipid profiles showed that HB especially HBB decreased TG, TC, LDL-C, ALT and AST levels while increased HDL-C level. Liver and epididymal adipocyte H&E staining also confirmed that hepatic injury and adipose accumulation were alleviated by HB especially HBB. Gut microbiota analysis indicated that HBB increased Bacteroidetes/ Firmicutes ratio, Lactobacillus and Akkermansia muciniphila abundances while decreased Proteobacteria and Shigella abundances. Untargeted metabolomics results showed that HBB significantly increased deoxycholic acid levels compared with HFCD mice and HBB regulated arachidonic acid metabolism pathway. The obtained results provided important information about the processing of highland barley to retain its hypolipidemic effect and improve its acceptability and biosafety, and had a guiding effect on the development of HB products. [Display omitted] • Highland barley ameliorated lipid metabolism and liver injury. • Highland barley modulated gut microbiota. • Highland barley regulated metabolites and metabolic pathway based on LC-MS. [ABSTRACT FROM AUTHOR]

Accumulating evidence has suggested a strong link between exposure to air pollution and public health. In particular, inhaled airborne particulate matter <2.5 μm in aerodynamic diameter (PM 2.5 ) can rapidly diffuse from the lungs to the systemic blood circulation and accumulate in the liver. In this study, we used a Balb/c mouse model to investigate liver injury caused by PM 2.5 inhalation and the anti-inflammatory and antioxidant effects of compound essential oils (CEOs) in alleviating the extent of this injury. The results of serum biochemical and histopathological analyses showed that PM 2.5 exposure induced inflammatory liver injury, meantime CEOs pretreatment attenuated PM 2.5 -induced liver inflammatory injury. Western blot and q RT-PCR assays showed that PM 2.5 increased secretion of cytokines, however CEOs suppressed the production of IL-6 and TNF-α. Furthermore, heme oxygenase-1(HO-1) and superoxide dismutase-1(SOD-1) expression levels showed that PM 2.5 could trigger oxidative stress-mediated liver injury, whereas CEOs pretreatment might protect against PM 2.5 -induced liver injury through regulation of the antioxidant system. Molecular analysis showed that the expression of TLR4, a protein which plays a key role in liver health and injury. Results showed that TLR4 was promoted by PM 2.5 but inhibited by CEOs pretreatment in PM 2.5 -induced inflammatory liver injury. In addition, PM 2.5 -promoted secretion of cytokines by activating TLR4/MyD88 pathway, whereas CEOs might alleviate this type of liver inflammation inhibiting the activation of TLR4/MyD88 signaling pathway. [ABSTRACT FROM AUTHOR]

Recent evidence implicates adaptive immunity as a key player in the mechanisms supporting hepatic inflammation during the progression of nonalcoholic fatty liver disease (NAFLD). In these settings, patients with NAFLD often show an increase in the circulating levels of antibodies against oxidative stress-derived epitopes (OSE). Nonetheless, the actual role of humoral immunity in NAFLD is still unclear. This study investigates the contribution of B-lymphocytes to NAFLD evolution. B-lymphocyte immunostaining of liver biopsies from NAFLD patients showed that B-cells were evident within cell aggregates rich in T-lymphocytes. In these subjects, B/T-lymphocyte infiltration positively correlated with both circulating IgG targeting oxidative stress-derived epitopes (OSE) and interferon-γ (IFN-γ) levels. Furthermore, high prevalence of lymphocyte aggregates identified patients with more severe lobular inflammation and fibrosis. In mouse models of NAFLD, the onset of steatohepatitis was characterized by hepatic B2-lymphocytes maturation to plasma cells and by an elevation in circulating anti-OSE IgG titers. B-cell responses preceded T-cell activation and were accompanied by the up-regulation in the hepatic expression of B-cell Activating Factor (BAFF). Selective B2-cell depletion in mice over-expressing a soluble form of the BAFF/APRIL receptor Transmembrane Activator and Cyclophilin Ligand Interactor (TACI-Ig) prevented plasma cell maturation and Th-1 activation of liver CD4 + T-lymphocytes. Furthermore, TACI-Ig mice showed milder steatohepatitis and a decreased progression to fibrosis. Similarly, mice treatment with the BAFF-neutralizing monoclonal antibody Sandy-2 prevented hepatic B2-cell responses and ameliorated steatohepatitis. From these data we conclude that B2-lymphocyte activation is an early event in NAFLD evolution and contributes to the disease progression through the interaction with T-cells. Furthermore, combined clinical and experimental data suggest that elevated circulating anti-OSE IgG can identify a subset of NAFLD patients in whom adaptive immunity has a relevant role in the disease evolution toward fibrosis. [ABSTRACT FROM AUTHOR]

Background and aims We recently showed that plasma cholesteryl ester transfer protein (CETP) is mainly derived from VSIG4-positive Kupffer cells. Activation of these cells by the bacterial endotoxin lipopolysaccharide (LPS) strongly decreases CETP expression. As Kupffer cell activation plays a detrimental role in the progression of non-alcoholic fatty liver disease (NAFLD), we aimed to study if metabolic liver inflammation is also associated with a decrease in hepatic and circulating CETP. Methods We collected plasma and liver biopsy samples at various stages of NAFLD from 93 obese individuals who underwent bariatric surgery. Liver lobular inflammation was histologically determined, and liver CETP expression, CETP positive cells, circulating CETP concentrations, and liver VSIG4 expression were quantified. Results Mean (SD) plasma CETP concentration was 2.68 (0.89) μg/mL. In the presence of liver inflammation, compared to the absence of pathology, the difference in hepatic CETP expression was −0.03 arbitrary units (95% CI -0.26, 0.20), the difference in number of hepatic CETP positive cells (range 11–140 per mm 2 ) was −20.0 per mm 2 (95% CI -41.6, 1.9), and the difference in plasma CETP was −0.35 μg/mL (95% CI -0.80, 0.10). Hepatic VSIG4 expression was not associated with liver inflammation (0.00; 95% CI -0.15, 0.15). Conclusions We found no strong evidence for a strong negative association between metabolic liver inflammation and CETP-related outcomes in obese individuals, although we observed consistent trends. These data indicate that metabolic liver inflammation does not mimic the strong effects of LPS on the hepatic expression and production of CETP by Kupffer cells. [ABSTRACT FROM AUTHOR]

Background & Aim Virus-induced fulminant hepatitis is a major cause of acute liver failure. During acute viral hepatitis the impact of type I interferon (IFN-I) on myeloid cells, including liver-resident Kupffer cells (KC), is only partially understood. Herein, we dissected the impact of locally induced IFN-I responses on myeloid cell function and hepatocytes during acute liver inflammation. Methods Two different DNA-encoded viruses, vaccinia virus (VACV) and murine cytomegalovirus (MCMV), were studied. In vivo imaging was applied to visualize local IFN-β induction and IFN-I receptor (IFNAR) triggering in VACV-infected reporter mice. Furthermore, mice with a cell type-selective IFNAR ablation were analyzed to dissect the role of IFNAR signaling in myeloid cells and hepatocytes. Experiments with Cx3cr1 +/gfp mice revealed the origin of reconstituted KC. Finally, mixed bone marrow chimeric mice were studied to specifically analyze the effect of IFNAR triggering on liver infiltrating monocytes. Results VACV infection induced local IFN-β responses, which lead to IFNAR signaling primarily within the liver. IFNAR triggering was needed to control the infection and prevent fulminant hepatitis. The severity of liver inflammation was independent of IFNAR triggering of hepatocytes, whereas IFNAR triggering of myeloid cells protected from excessive inflammation. Upon VACV or MCMV infection KC disappeared, whereas infiltrating monocytes differentiated to KC afterwards. During IFNAR triggering such replenished monocyte-derived KC comprised more IFNAR-deficient than -competent cells in mixed bone marrow chimeric mice, whereas after the decline of IFNAR triggering both subsets showed an even distribution. Conclusion Upon VACV infection IFNAR triggering of myeloid cells, but not of hepatocytes, critically modulates acute viral hepatitis. During infection with DNA-encoded viruses IFNAR triggering of liver-infiltrating blood monocytes delays the development of monocyte-derived KC, pointing towards new therapeutic strategies for acute viral hepatitis. Lay summary Viral infection can cause fulminant hepatitis, which in turn is a major cause of acute liver failure. Herein, we aimed to study the role of type 1 interferon responses in acute viral hepatitis. We identified that during infection with DNA-encoded viruses, type 1 interferon receptor triggering of blood monocytes delays the development of monocyte-derived Kupffer cells. This points to new therapeutic strategies for acute viral hepatitis. [ABSTRACT FROM AUTHOR]

• Orchatoxin A is the most toxic of ochratoxins commonly present in food and feedstuffs. • Low doses of OTA can be harmful to animals especially young ducks. • Orchatoxin A and curcumin altered the function of intestinal microbiota, such as inflammation and oxidative stress in ducks. • Curcumin could relieve OTA-induced the upregulation of liver inflammatory cytokine interleukin-6, possibly by inhibiting toll like receptor 4 signaling pathway. Curcumin (CUR) has been well known for its anti-inflammatory effects, and could regulate the intestinal microbial composition, and alleviate mycotoxin toxicity. The present study was conducted to explore whether curcumin could alleviate ochratoxin A (OTA)-induced liver inflammation. A total of 720 mixed-sex 1- d -old White Pekin ducklings were randomly assigned to 4 groups: CON (control group, without OTA), OTA (fed 2mg/kg OTA-contaminated diet), CUR (ducks fed a diet with 400mg/kg curcumin), and OTA + CUR (fed the same OTA-contaminated diet plus 400mg/kg curcumin). Each treatment consisted of 6 replicates, each containing 30 ducklings, and treatment lasted for 21 d The results demonstrated that OTA treatment increased the liver interleukin-1beta (P < 0.001) and interleukin-6 (IL-6) contents (P =0.047). Curcumin supplementation alleviated OTA-induced the liver IL-6 content (P < 0.001). Metagenomic sequencing analysis indicated that a clear separation between the cecum microbiota of ducks in CON and OTA treatment. Compared with CON treatment, ochratoxin A increased the relative abundance of Bacteroides (P < 0.05). The OTA treatment increased pathway expression associated with inflammation and exposure to oxidative stress, including lipopolysaccharide (LPS) biosynthesis (P =0.002) and tricarboxylic acid cycle (P =0.006). Curcumin could alleviate the upregulation of inflammation and oxidative stress pathways induced by OTA (P < 0.01). Compared with CON, OTA treatment increased serum LPS content (P < 0.001). Compared with OTA treatment, OTA + CUR treatment decreased serum LPS content (P < 0.001). Compared with the CON treatment, OTA treatment upregulated the relative mRNA expression of toll like receptor 4 (TLR4) (P =0.05) and tumor necrosis factor-alpha (P =0.028) and upregulated the expression of myeloid differentiation factor 88 (P =0.001) and IL-6 (P =0.002). Compared with the OTA treatment, OTA + CUR treatment decreased the expression of TLR4 (P =0.05). The curcumin treatment had the lowest expression rate of TLR4 mRNA (P < 0.05). The results indicated that curcumin could alleviate OTA-induced inflammation by regulating the intestinal microbiota. Furthermore, the protective role of curcumin in OTA-exposed ducks possibly inhibited TLR4 signaling pathway. [ABSTRACT FROM AUTHOR]

In previous studies, 6:2 chlorinated polyfluorinated ether sulfonic acid (6:2 Cl-PFESA), a perfluorooctanesulfonate alternative, has been demonstrated to be toxic to mammals. However, the toxic mechanism of 6:2 Cl-PFESA in mammals is unknown. Herein, adolescent male rats were administered 50 μg/kg/Day 6:2 Cl-PFESA for 28 days (oral gavage) to estimate the toxicity of 6:2 Cl-PFESA and investigate its toxic mechanism. Significant changes in some hematological indicators (e.g., aspartate transaminase and neutrophils) and liver sections (inflammatory cell infiltration) indicated that 6:2 Cl-PFESA exposure caused rat hepatotoxicity. Six steroid hormones (e.g., testosterone, progesterone, and cortisol) in serum and thirteen genes in testicles (related to the pathway of steroid hormone biosynthesis) were significantly regulated in 6:2 Cl-PFESA-treated rats. This suggested that 6:2 Cl-PFESA induced rat endocrine disorders. Compared to the controls, the mean relative abundance of Ruminococcaceae , Pasteurellaceae , Micrococcaceae , and Desulfovibrionaceae was significantly regulated by 1.3-, 0.40-, 0.32-, and 3.2-fold in the 6:2 Cl-PFESA rats, respectively. The 6:2 Cl-PFESA treatment also significantly disturbed 47 gut metabolites (29 upregulated and 18 downregulated), mainly bile acids, short-chain fatty acids, and amino acids. In summary, 6:2 Cl-PFESA induced endocrine disorders and liver inflammation in rats by altering the gut microbiota-gut-testis/liver axis. This study first reveals the toxic mechanism of 6:2 Cl-PFESA in mammals through a multiomics approach and provides comprehensive insight into the toxic mechanism of 6:2 Cl-PFESA. [Display omitted] • 6:2 Cl-PFESA disordered gut microbes, gut metabolites, and serum hormones in rats. • 6:2 Cl-PFESA caused liver inflammation and endocrine disorders in rats. • 6:2 Cl-PFESA might change the rat gut-serum metabolome via altering gut microbiome. • Multiomics technology deeply revealed the toxic mechanism of 6:2 Cl-PFESA in rats. [ABSTRACT FROM AUTHOR]

Background & Aim Natural killer T (NKT) cells are CD1d-restricted innate-like T cells that modulate innate and adaptive immune responses. Unlike the well-characterized invariant/type I NKT cells, type II NKT cells with a diverse T cell receptor repertoire are poorly understood. This study defines the pathogenic role of type II NKT cells in the etiology of chronic liver inflammation. Methods Transgenic mice with the Lck promoter directing CD1d overexpression on T cells in Jα18 wild-type ( Lck-CD1dTgJα18 + ; type I NKT cell sufficient) and Jα18 -deficient ( Lck-CD1dTgJα18 o , type I NKT cell deficient) mice were analyzed for liver pathology and crosstalk between type II NKT cells and conventional T cells. CD1d expression on T cells in peripheral blood samples and liver sections from autoimmune hepatitis patients and healthy individuals were also examined. Results Lck-CD1dTgJα18 o and Lck-CD1dTgJα18 + mice developed similar degrees of liver pathology resembling chronic autoimmune hepatitis in humans. Increased CD1d expression on T cells promoted the activation of type II NKT cells and other T cells. This resulted in T h 1-skewing and impaired T h 2 cytokine production in type II NKT cells. Dysfunction of type II NKT cells was accompanied by conventional T cell activation and pro-inflammatory cytokine production, leading to a hepatic T/B lymphocyte infiltration, elevated autoantibodies and hepatic injury in Lck-CD1dTg mice. A similar mechanism could be extended to humans as CD1d expression is upregulated on activated human T cells and increased presence of CD1d-expressing T cells was observed in autoimmune hepatitis patients. Conclusions Our data reveals enhanced crosstalk between type II NKT cells and conventional T cells, leading to a T h 1-skewed inflammatory milieu, and consequently, to the development of chronic autoimmune liver disease. Lay summary: CD1d overexpression on T cells enhances crosstalk between type II NKT cells and T cells, resulting in their aberrant activation and leading to the development of chronic autoimmune liver disease. [ABSTRACT FROM AUTHOR]

Background & Aims Liver inflammation is key in the progression of chronic viral hepatitis to cirrhosis and hepatocellular carcinoma. The magnitude of viral replication and the specific anti-viral immune responses should govern the degree of inflammation, but a direct correlation is not consistently found in chronic viral hepatitis patients. We aim to better define the mechanisms that contribute to chronic liver inflammation. Methods Intrahepatic CD14 + myeloid cells from healthy donors (n = 19) and patients with viral-related liver cirrhosis (HBV, HBV/HDV or HCV; n = 15) were subjected to detailed phenotypic, molecular and functional characterisation. Results Unsupervised analysis of multi-parametric data showed that liver disease was associated with the intrahepatic expansion of activated myeloid cells mainly composed of pro-inflammatory CD14 + HLA-DR hi CD206 + cells, which spontaneously produced TNFα and GM-CSF. These cells only showed heightened pro-inflammatory responses to bacterial TLR agonists and were more refractory to endotoxin-induced tolerance. A liver-specific enrichment of CD14 + HLA-DR hi CD206 + cells was also detected in a humanised mouse model of liver inflammation. This accumulation was abrogated following oral antibiotic treatment, suggesting a direct involvement of translocated gut-derived microbial products in liver injury. Conclusions Viral-related chronic liver inflammation is driven by the interplay between non-endotoxin-tolerant pro-inflammatory CD14 + HLA-DR hi CD206 + myeloid cells and translocated bacterial products. Deciphering this mechanism paves the way for the development of therapeutic strategies specifically targeting CD206 + myeloid cells in viral-related liver disease patients. Lay summary: Viral-related chronic liver disease is driven by intrahepatic pro-inflammatory myeloid cells accumulating in a gut-derived bacterial product-dependent manner. Our findings support the use of oral antibiotics to ameliorate liver inflammation in these patients. [ABSTRACT FROM AUTHOR]

The sterile inflammatory response is an eminent contributor to acetaminophen (APAP)-hepatotoxicity in humans. Recent advances unraveled an axial role of the NLRP3-inflammasome in APAP-post injury inflammation. Nevertheless, the role of signaling events preceded the NLRP3-inflammasome activation, like the transcription factor NF-κB and the purinergic receptor P2X7, is still unclear and needs further elucidation. Here, we investigated the pharmacological inhibition of these upstream signaling molecules by celastrol and brilliant blue G (BBG) (separately or simultaneously) in APAP-hepatotoxicity in mice. The results indicated that both celastrol and BBG pretreatments, especially when combined together, curbed APAP-induced hepatocellular injury (ALT, AST and LDH) and death (necrosis and apoptosis). The underlying mechanisms of protection of such combination against APAP-challenge were attributed to their efficient cooperation in: i) preventing the consumption of hepatic antioxidants (reduced glutathione and superoxide dismutase); ii) limiting the overproduction of lipid peroxidation aldehydes (malondialdehyde and 4-hydroxynonenal) and total nitrate/nitrite products; iii) attenuating the inflammatory cells accumulation in the liver, as evidenced by reducing the number of F4/80 positive cells/field in immunostaining and myeloperoxidase activity; iv) reversing the dysregulation in production of pro-inflammatory (TNF-α, IL-17A and IL-23) and anti-inflammatory (IL-10) cytokines; and v) enhancing the reparative capacity of injured hepatocytes, as demonstrated by increasing the percentage of PCNA positive hepatocytes per field of immunostaining. In conclusion, this murine study elicits a potential clinical applicability and therapeutic utility of celastrol and BBG combination in human cases of APAP-overdose hepatotoxicity. [ABSTRACT FROM AUTHOR]

Hepatitis C is one of the most widespread infectious diseases worldwide and hepatitis C virus (HCV)-induced chronic inflammation is highly associated with progredient liver damage. It was shown that HCV infection increases levels of pro-inflammatory cytokines via activation of NOD-like receptor (NLRP3) inflammasomes, yet the underlying mechanism is still under question. We propose modulation of intracellular pH by p7, a 63 residue ion channel produced by the hepatitis C virus as a possible pathomechanism for hepatitis C-associated inflammation. Recombinant constructs corresponding to HCV genotypes 1–4 were expressed in HEK 293 and RAW 264.7 cells and changes of intracellular pH were monitored using pH-sensitive fluorescent probes as well as production of inflammatory cytokines. Presence of p7 induced general loss of vesicular acidity as well as producing a significant increase in the levels of interleukin-1β (IL-1β). Effects showed a genotype-dependent pattern of IL-1β production, in agreement with the pH-response profile of p7 channels corresponding to hepatitis C genotypes. Lowering the pH of the extracellular medium increased activity of p7 channels as well as production of IL-1β for genotypes 1, 3, and 4, but less for genotype 2. Our data are in agreement with the hypothesis that p7 activity can trigger intracellular signaling cascades that are involved in HCV-associated cytopathy. [ABSTRACT FROM AUTHOR]

Liver sinusoidal endothelial cells (LSECs) rapidly clear lipopolysaccharide (LPS) from the bloodstream and establish intimate contact with immune cells. However, their role in regulating liver inflammation remains poorly understood. We show that LSECs modify their chemokine expression profile driven by LPS or interferon-γ (IFN-γ), resulting in the production of the myeloid- or lymphoid-attracting chemokines CCL2 and CXCL10, respectively, which accumulate in the serum of LPS-challenged animals. Natural killer (NK) cell exposure to LSECs in vitro primes NK cells for higher production of IFN-γ in response to interleukin-12 (IL-12) and IL-18. In livers of LPS-injected mice, NK cells are the major producers of this cytokine. In turn, LSECs require exposure to IFN-γ for CXCL10 expression, and endothelial-specific Cxcl10 gene deletion curtails NK cell accumulation in the inflamed livers. Thus, LSECs respond to both LPS and immune-derived signals and fuel a positive feedback loop of immune cell attraction and activation in the inflamed liver tissue. [Display omitted] • LPS-induced endotoxemia leads to LSEC activation and chemokine production • LSECs prime NK cells for enhanced IFN-γ production in response to IL-12 and IL-18 • NK cells are the major cellular source of IFN-γ in LPS-challenged mice • LSECs produce CXCL10 in the response to IFN-γ and support NK cell recruitment to the liver Papaioannou et al. show that, during acute endotoxicosis, LSECs respond to both LPS and immune-derived IFN-γ by modifying chemokine and adhesion molecule expression. LSECs prime NK cells for enhanced IFN-γ production, while in response to IFN-γ, they secrete CXCL10 and support NK cell recruitment to the liver. [ABSTRACT FROM AUTHOR]

[Display omitted] • Epigallocatechin gallate with contents of 746.3 mg/L was the most component of green tea polyphenols in ethanol-extracted Longjin. • 200 mg/kg Longjin extract aggravated S100-induced autoimmune hepatitis while the dose of 100 mg/kg relieved it. • Longjin extract influenced intestinal barriers in a dose-dependent manner, thus altering the amount of lipopolysaccharides entering the hepatic portal vein. • TLR4/MyD88/NF-κb signaling pathway was involved in hepatic inflammatory responses of Longjin extract-treated experimental autoimmune hepatitis. 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. [ABSTRACT FROM AUTHOR]

Microplastics (MPs), a new and increasing environmental pollutant, can cause ongoing damage to organisms. Although recent studies have revealed mechanisms of action for some of the hepatotoxicity caused by MPs, the role-played by cellular interactions, particularly immune cells, in the process of liver injury has not been elucidated. In the present study, 5-μm polystyrene microplastics (PS-MPs) induced liver inflammation as well as the formation of Macrophage extracellular traps (METs). Macrophage and LMH cell co-culture systems confirmed that PS-MPs-induced METs promote inflammation in hepatocytes. Mechanistically, macrophages actively phagocytose particles after 4 h of exposure to PS-MPs. Subsequently PS-MPs elevated ROS levels and disrupt mitochondrial kinetic homeostasis. Further activation of mitochondrial autophagy and lysosomes. After phagocytosis of PS-MPs by macrophages for 12 h, continued autophagy and lysosome activation eventually lead to lysosome rupture and release of calcium ions to induce the formation of METs. Blocking ROS (NAC) and autophagy (3MA) partially alleviated mitochondrial and lysosomal damage and thus inhibited the formation of METs induced by PS-MPs. NAC also delayed the onset of respiratory burst to alleviate METs formation. In conclusion, our study reveals the mechanism of METs formation in liver inflammation induced by PS-MPs exposure and suggests that lysosomal damage may be one of the key players in the formation of METs induced by PS-MPs. [Display omitted] • MPs causes mitochondrial damage, autophagy and lysosome activation in macrophages. • MPs trigger sustained mitophagy and lysosomal activation. • Macrophage lysosomal hyperactivation by MPs is involved in the formation of METs. • MPs induce macrophages to produce METs and promote liver inflammation. [ABSTRACT FROM AUTHOR]

With the development of the social economy, unhealthy living habits and eating styles are gradually affecting people's health in recent years. As a chronic liver disease, NAFLD is deeply affected by unhealthy living habits and eating styles and has gradually become an increasingly serious public health problem. As a protein complex in clinical research, the inflammasomes play a crucial role in the development of NAFLD, atherosclerosis, and other diseases. This paper reviews the types, composition, characteristics of inflammasomes, and molecular mechanism of the inflammasome in NAFLD. Meanwhile, the paper reviews the drugs and non-drugs that target NLRP3 inflammasome in the treatment of NAFLD in the past decades. we also analyzed and summarized the related experimental models, mechanisms, and results of NAFLD. Although current therapeutic strategies for NAFLD are not effective, we expect that we will be able to find an appropriate treatment to address this problem in the future with further research on inflammasome. [ABSTRACT FROM AUTHOR]

The earth's natural environmental factors and man-made industrial pollution often lead to the co-occurrence of environmental pathogenic factors and malnutrition. Bisphenol A (BPA) is a serious environmental endocrine disruptor, and its exposure can cause liver tissue damage. Selenium (Se) deficiency is a worldwide problem that afflicts thousands of people, and Se deficiency can cause M1/M2 imbalance. In addition, the crosstalk between hepatocyte and immune cell is closely related to the occurrence of hepatitis. Therefore, this study found for the first time that the combined exposure of BPA and Se deficiency caused liver pyroptosis and M1 polarization through ROS, and the crosstalk between pyroptosis and M1 polarization aggravated liver inflammation in chicken. In this study, the BPA or/and Se deficiency chicken liver, single and co-culture model of LMH and HD11 cells were established. The results displayed that BPA or Se deficiency induced liver inflammation accompanied by pyroptosis and M1 polarization through oxidative stress, and increased expressions of chemokines (CCL4, CCL17, CCL19, and MIF) and inflammatory factors (IL-1β and TNF-α). The vitro experiments further verified the above changes and showed that LMH pyroptosis promoted M1 polarization of HD11 cells, and vice versa. NAC counteracted pyroptosis and M1 polarization caused by BPA and low-Se, reducing the release of inflammatory factors. In brief, BPA and Se deficiency treatment can exacerbate liver inflammation by increasing oxidative stress to induce pyroptosis and M1 polarization. [Display omitted] • BPA or Se deficiency leads to liver pyroptosis and M1 polarization through oxidative stress. • Combined exposure of BPA and Se deficiency has stronger liver injury than single treatment. • ROS mediated pyroptosis-M1 polarization crosstalk amplifies liver inflammation. [ABSTRACT FROM AUTHOR]

Increased biomedical applications of quantum dots (QDs) have raised considerable concern regarding their toxicological impact. However, the toxicity of QDs is largely unknown and the underlying mechanism is still undefined. This study was conducted to examine the hepatotoxicity of CdSe/ZnS core/shell QDs and the underlying mechanism. In hepatic L02 cells, the QDs caused cytotoxicity in a dose-dependent manner. The QDs were then shown to activate the NLR pyrin domain containing 3 (NLRP3) inflammasome in hepatocytes, leading to a novel pro-inflammatory form of cell death named pyroptosis. Further experiments demonstrated that the QDs induced mitochondrial reactive oxygen species (mtROS) production, and that both a mtROS and a total ROS scavenger attenuated QDs-induced NLRP3 activation and pyroptosis. In addition, QDs increased cytoplasmic calcium (Ca 2+ ) levels, while a Ca 2+ release antagonist and chelator alleviated QDs-induced mtROS, NLRP3 activation and subsequent pyroptosis in hepatocytes. In vivo , QDs administration induced liver inflammation and dysfunction. Moreover, the QDs also resulted in NLRP3 activation in liver tissue. However, QDs-induced liver inflammation and dysfunction were abolished in NLRP3 knockout mice. Also, an elevation in mtROS was observed in liver after QDs administration, and the mtROS scavenger suppressed liver NLRP3 activation, inflammation and dysfunction induced by QDs. Our data suggest that QDs induced hepatocyte pyroptosis, liver inflammation and dysfunction via NLRP3 activation, which was caused by QDs-triggered mtROS production and Ca 2+ mobilization. Our results provide novel insights into QDs-induced hepatotoxicity and the underlying mechanism, facilitating control of the side effects of QDs. [ABSTRACT FROM AUTHOR]

The potential mechanisms of action of polyphenols in nonalcoholic fatty liver disease (NAFLD) are overlooked. Here, we evaluate the beneficial therapeutic effects of hydroxytyrosol (HT), the major metabolite of the oleuropein, in a nutritional model of insulin resistance (IR) and NAFLD by high-fat diet. Young male rats were divided into three groups receiving (1) standard diet (STD; 10.5% fat), (2) high-fat diet (HFD; 58.0% fat) and (3) HFD+HT (10 mg/kg/day by gavage). After 5 weeks, the oral glucose tolerance test was performed, and at 6th week, blood sample and tissues (liver and duodenum) were collected for following determinations. The HT-treated rats showed a marked reduction in serum AST, ALT and cholesterol and improved glucose tolerance and insulin sensitivity, reducing homeostasis model assessment index. HT significantly corrected the metabolic impairment induced by HFD, increasing hepatic peroxisome proliferator activated receptor PPAR-α and its downstream-regulated gene fibroblast growth factor 21, the phosphorylation of acetyl-CoA carboxylase and the mRNA carnitine palmitoyltransferase 1a. HT also reduced liver inflammation and nitrosative/oxidative stress decreasing the nitrosylation of proteins, reactive oxygen species production and lipid peroxidation. Moreover, HT restored intestinal barrier integrity and functions (fluorescein isothiocyanate-dextran permeability and mRNA zona occludens ZO-1). Our data demonstrate the beneficial effect of HT in the prevention of early inflammatory events responsible for the onset of IR and steatosis, reducing hepatic inflammation and nitrosative/oxidative stress and restoring glucose homeostasis and intestinal barrier integrity. [ABSTRACT FROM AUTHOR]

We had previously shown that microcystin-LR (MCLR) could induce lung and liver inflammation after acute exposure. The biological outcomes following prolonged exposure to MCLR, although more frequent, are still poorly understood. Thus, we aimed to verify whether repeated doses of MCLR could damage lung and liver and evaluate the dose-dependence of the results. Male Swiss mice received 10 intraperitoneal injections ( i . p .) of distilled water (60 μL, CTRL) or different doses of MCLR (5 μg/kg, TOX5), 10 μg/kg (TOX10), 15 μg/kg (TOX15) and 20 μg/kg (TOX20) every other day. On the tenth injection respiratory mechanics (lung resistive and viscoelastic/inhomogeneous pressures, static elastance, and viscoelastic component of elastance) was measured. Lungs and liver were prepared for histology (morphometry and cellularity) and inflammatory mediators (KC and MIP-2) determination. All mechanical parameters and alveolar collapse were significantly higher in TOX5, 10, 15 and 20 than CTRL, but did not differ among them. Lung inflammatory cell content increased dose-dependently in all TOX groups in relation to CTRL, being TOX20 the largest. The production of KC was increased in lung and liver homogenates. MIP-2 increased in the liver of all TOX groups, but in lung homogenates it was significantly higher only in TOX20 group. All TOX mice livers showed steatosis, necrosis, inflammatory foci and a high degree of binucleated hepatocytes. In conclusion, sub-chronic exposure to MCLR damaged lung and liver in all doses, with a more important lung inflammation in TOX20 group. [ABSTRACT FROM AUTHOR]

Background & Aims Liver fibrosis is the most worrisome feature of non-alcoholic steatohepatitis (NASH). Growing evidence supports a link between hepatocyte apoptosis and liver fibrogenesis. Our aim was to determine the therapeutic efficacy and safety of liver Bid , a key pro-apoptotic molecule, suppression using RNA interference (RNAi) for the treatment of fibrosis. Methods First, we optimized the delivery system for Bid siRNA in mice using ten different stealth RNAi siRNAs and two lipid formulations -Invivofectamine2.0 and a newly developed Invivofectamine3.0 – that have been designed for high efficacy accumulation in the liver, assessed via real-time PCR of Bid mRNA. Next, C57BL/6 mice were placed on a choline-deficient L-amino acid defined (CDAA) diet. After 19 weeks of the CDAA diet, a time point that results in severe fibrotic NASH, mice were injected with the selected Bid siRNA-Invivofectamine3.0 biweekly for three weeks. Additionally hepatocyte-specific Bid deficient ( Bid Δhep ) mice were placed on CDAA diet for 20 weeks. Results A maximum Bid knockdown was achieved at 1.5 mg/kg siRNA with Invivofectamine3.0, whereas it was at 7 mg/kg with Invivofectamine2.0. In NASH mice, after 3 weeks of treatment, BID protein was reduced to 10% and this was associated with an improvement in liver fibrosis and inflammation associated with a marked reduction in TUNEL positive cells, caspase 3 activation, and a reduction in mitochondrial BAX and BAK. Bid Δhep mice showed similar protection from fibrotic changes. Conclusion Our data demonstrate that liver Bid suppression by RNAi technology, as well as hepatocyte-specific Bid deficiency, improves liver fibrosis coupled with a reduction of inflammation in experimental NASH. These findings are consistent with existing evidence that hepatocyte apoptosis triggers hepatic stellate cell activation and liver fibrosis and suggest that Bid inhibition may be useful as an antifibrotic NASH therapy. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to investigate the effects of dietary silicon-enriched spirulina (SES) on atherosclerosis. Methods: Hamsters (six per group) on a high-fat (HF) diet received SES or non-enriched spirulina (both at 57 mg/kg body weight) daily. This corresponded to 0.57 mg silicon/kg body weight daily. Results: The HF diet induced dyslipidemia, insulin resistance, oxidative stress, and vascular dysfunction. Compared with the HF group, SES attenuated increases of lipemia and prevented insulin resistance (IR) (P = 0.001). SES protected against oxidative stress through a reduction of heart (P = 0.006) and liver (P < 0.0001) nicotinamide adenine dinucleotide phosphate-oxidase activity and by sparing the activity of superoxide dismutase (P = 0.0017) and glutathione peroxidase (P = 0.01861). SES decreased inflammation, lowering tumor necrosis factor-a (P = 0.0006) and interleukin-6 levels (P = 0.0112), decreasing polymorphonuclear cells and preventing nuclear factor-xB activity (P = 0.0259). SES corrected plasma level of monocyte chemoattractant protein-1 (P = 0.0380), which was increased by the HF diet. Finally, SES supplementation prevented vascular and endothelial functions assessed respectively by the contractile response to the agonist phenylephrine and the relaxation induced by acetylcholine. Conclusion: SES protects against metabolic imbalance, inflammation, oxidative stress, and vascular dysfunction induced by an HF diet, and could prevent the atherogenic processes. Synergistic effects between spirulina and silicon were observed. [ABSTRACT FROM AUTHOR]

The widespread use of plastics and the rapid development of nanotechnology bring convenience to our lives while also increasing the environmental burden and increasing the risk of exposure of organisms to nanoparticles (NPs). While recent studies have revealed an association between nanoparticles and liver injury, the intrinsic mechanism of NP exposure-induced liver damage remains to be explored. Here, we found that polystyrene nanoparticle (PSNP) exposure resulted in a significant increase in local neutrophil infiltration and neutrophil extracellular trap (NET) formation in the liver. Analysis of a coculture system of PBNs and AML12 cells revealed that PSNP-induced NET formation positively correlates with the reactive oxygen species (ROS)-NLRP3 axis. Inhibition of ROS and genetic and pharmacological inhibition of NLRP3 in AML12 can both alleviate PSNP-induced NET formation. In turn, exposure of mice to deoxyribonuclease I (DNase Ⅰ)-coated PSNPs disassembled NET in vivo , neutrophil infiltration in the liver was reduced, the ROS-NLRP3 axis was inhibited, and the expression of cytokines was markedly decreased. Collectively, our work reveals a mechanism of NET formation in PSNP exposure-induced liver inflammation and highlights the possible role of DNase Ⅰ as a key enzyme in degrading NET and alleviating liver inflammation. [Display omitted] • PS-NPs exposure aggravates LPS-induced liver inflammation in mice. • PS-NPs exposure-induced liver inflammation relies on NET formation. • NET formation induced by PS-NPs exposure is regulated by ROS-NLRP3 axis. • DNase Ⅰ-coated PS-NPs alleviates liver inflammation by blocking NETs. [ABSTRACT FROM AUTHOR]

Summary Objectives MicroRNA-122 has been shown to be crucial for efficient HCV RNA replication in vitro. Pretreatment intrahepatic microRNA-122 levels in chronic hepatitis C (CHC) patients have been associated with the outcomes of interferon therapy. Here, we determined microRNA-122 serum levels in CHC patients and healthy donors using an absolute quantification approach and evaluated the correlation with liver inflammation grades and serum alanine aminotransferase (ALT) levels. Methods Serum samples were collected from 105 treatment-naive CHC patients, 11 acute hepatitis patients, and 33 healthy donors. Serum microRNA-122 was measured using the TaqMan RT-qPCR. The cycle threshold values were converted to copy numbers by drawing a standard curve using a chemical synthetic standard. For accurate quantification, copy numbers were further normalized according to the recovery ratios of spiked-in cel-miR-39. Results Serum levels of microRNA-122 were significantly higher in acute hepatitis and CHC patients than in healthy donors ( p < 0.001). However, there was no significant association between microRNA-122 and ALT serum levels or liver inflammation grades. Conclusions The present study showed that serum microRNA-122 was elevated in acute and chronic hepatitis patients. However, this biomarker for acute liver injury did not reflect the liver inflammation activity in CHC patients. [ABSTRACT FROM AUTHOR]