Kupffer Cell Activation Research Articles

Catechin reduces liver inflammation by regulating Kupffer cell activation in rats

The liver is a defense against infections due to its strategic location between the gastrointestinal and systemic circulations. In dogs and cats, infectious hepatitis encompasses a range of contagious diseases affecting the liver either directly or as part of a broader systemic infection, including bacterial, mycobacterial, viral, fungal, protozoal, parasitic, and rickettsial diseases. Catechins possess well-recognized natural antioxidant properties. This study investigated their therapeutic potential for applications in hepatology, evaluating whether catechins reduce hepatic inflammation in rats repeatedly exposed to carbon tetrachloride (CCl4). Sprague-Dawley rats were given catechin 50 (C50) or 100 (C100) mg/kg body weight orally daily for 3 days. This treatment was given with or without concurrent intraperitoneal injections of CCl4. Phosphate-buffered saline served as the vehicle control, while silymarin administered at 100 mg/kg was used as the positive control.Gross examination revealed significant enlargement, edema, and darker tissue in CCl4-induced livers treated with vehicle. Additionally, spotty discoloration was observed on the surface. Kupffer cell activation suppressed the expression of inflammatory mediators, including inducible nitric oxide synthase (iNOS), in groups co-treated with catechin and CCl4; this effect was reversed when catalase replaced catechin in CCl4-injured rats. Catechin alleviates hepatic inflammation in rats repeatedly exposed to CCl4; it also modulates the activation of Kupffer cells and monocytes. These results should lead to new treatments for liver inflammation in veterinary practice.

Correlation between Kupffer Cell Infiltration and Liver Parenchymal Cell Damages in Immunosuppressed Drugs-Induced Rats

The liver is the largest organ in the body, composed of both parenchymal and non-parenchymal cells. Chemical substances and various drugs can induce liver injury and involve Kupffer cells which are non-parenchymal cells that release biologically active substances, promoting pathological processes. This study aimed to evaluate the correlation between the number of Kupffer cells and liver parenchymal cell damages in immunosuppressed, drug-induced rats. The study was conducted from July to December 2019 at the Oral Biology Laboratory of the Faculty of Dentistry and the Biochemical Laboratory of the Faculty of Medicine at Universitas Hang Tuah Surabaya. Twelve healthy male Wistar rats were divided into two groups: Healthy (H) and Immunosuppressed Drug-Induced (ID) groups. Immunosuppression was induced using dexamethasone (0.5 mg/day/rat), administered orally for 14 days, combined with tetracycline (1%/day/rat). Liver samples from all rats were examined for Kupffer cell count and parenchymal cell damages were assessed using a light microscope with 400x magnification. Results revealed a significant difference in the number of Kupffer cells and liver parenchymal cell damages between the H and ID groups (p<0.05). Pearson correlation analysis indicated a significant correlation between Kupffer cell number and parenchymal cell damages (p=0.000). Continuous administration of immunosuppressive drugs may activate Kupffer cells, leading to damage of liver parenchymal cells. In conclusion, the infiltration of Kupffer cells is associated with liver parenchymal cell damages, mediated by various factors in the immunosuppressed drug-induced rat model.

The role of forkhead box M1-methionine adenosyltransferase 2 A/2B axis in liver inflammation and fibrosis

Methionine adenosyltransferase 2 A (MAT2A) and MAT2B are essential for hepatic stellate cells (HSCs) activation. Forkhead box M1 (FOXM1) transgenic mice develop liver inflammation and fibrosis. Here we examine if they crosstalk in male mice. We found FOXM1/MAT2A/2B are upregulated after bile duct ligation (BDL) and carbon tetrachloride (CCl4) treatment in hepatocytes, HSCs and Kupffer cells (KCs). FDI-6, a FOXM1 inhibitor, attenuates the development and reverses the progression of CCl4-induced fibrosis while lowering the expression of FOXM1/MAT2A/2B, which exert reciprocal positive regulation on each other transcriptionally. Knocking down any of them lowers HSCs and KCs activation. Deletion of FOXM1 in hepatocytes, HSCs, and KCs protects from BDL-mediated inflammation and fibrosis comparably. Interestingly, HSCs from Foxm1Hep−/−, hepatocytes from Foxm1HSC−/−, and HSCs and hepatocytes from Foxm1KC−/− have lower FOXM1/MAT2A/2B after BDL. This may be partly due to transfer of extracellular vesicles between different cell types. Altogether, FOXM1/MAT2A/MAT2B axis drives liver inflammation and fibrosis.

Sphingosine Kinase 1 Aggravates Liver Fibrosis by Mediating Macrophage Recruitment and Polarization

Sphingosine kinase 1 (SphK1) has distinct roles in the activation of Kupffer cells and hepatic stellate cells in liver fibrosis. Here, we aim to investigate the roles of SphK1 on hepatic macrophage recruitment and polarization in liver fibrosis. Liver fibrosis was induced by carbon tetrachloride in wild-type and SphK1-/- mice to study the recruitment and polarization of macrophages. The effects of SphK1 originated from macrophages or other liver cell types on liver fibrosis were further strengthened by bone marrow transplantation. The direct effects of SphK1 on macrophage polarization were also investigated invitro. Expression analysis of SphK1 and macrophage polarization index was conducted with human liver samples. SphK1 deletion attenuated the recruitment of hepatic macrophages along with reduced M1 and M2 polarization in mice induced by carbon tetrachloride. SphK1 deficiency in endogenous liver cells attenuated macrophage recruitment via C-C motif chemokine ligand 2. Macrophage SphK1 activated the ASK1-JNK1/2-p38 signaling pathway to promote M1 polarization. Furthermore, macrophage SphK1 downregulated small ubiquitin-like modifier-specific peptidase1 to decrease de-SUMOylation of Kruppel-like factor 4 to promote M2 polarization. Finally, we confirmed that SphK1 expression was elevated and positively correlated with macrophage M1 and M2 polarization in human fibrosis livers. Our findings demonstrated that SphK1 aggravated liver fibrosis by promoting macrophage recruitment and M1/M2 polarization. SphK1 in macrophages is a potential therapeutic target for the treatment of liver fibrosis.

Hepatoprotective Effect of Corn Silk Extract on Carbonated Alcoholic Herbal Beverages Induced Hepatoxicity in Adult Wistar Rats

Corn silk is the long shiny fibers at the top of an ordinary ear of corn (Zea mays). Corn silk contains phytochemicals of medical benefit such as flavonoids compounds which act as antioxidant agents and has been widely reported possess hepatoprotective effect. The objective of this paper is to evaluate the hepatoprotective effect of corn silk extract on carbonated alcoholic herbal beverages (CAHB) induced hepatoxicity in adult Wistar rats. A total of forty five adult Wistar rats weighing between 200g and 250g were randomly assigned into nine groups of five rats each in a group. Group A was the normal control group (no CAHB administration). Groups B, C, D, E, F, G, H and I were the CAHB intoxicated groups and treated with corn silk extract at different doses. After administering a carbonated alcoholic herbal beverage, there was a substantial increase (p≤0.05) in the mean concentration of liver enzymes (ALP, ALT, ALT), total bilirubin, and direct bilirubin. While those characteristics reversed to values similar to the control after being treated with varying doses of corn silk extract The oxidative stress parameter (SOD, GPX, Catalase, MDA) shown significant increase in group. Histological examination of the liver revealed infiltrate of inflammatory cells, vascular ulceration, periportal infiltration of inflammatory cell, and vascular congestion in a group treated with carbonated alcoholic herbal beverages (CAHB). The only group exhibiting normal hepatocyte morphology and kupffer cell activity was the one administered 200 mg/kg of maize silk extract. Group D showed a similar and more powerful hepatic architecture after receiving only 600 mg/kg of maize silk extract. The hepatoprotective and anti- oxidative effects of corn silk extract were confirmed by the treatment groups (200 mg/kg and 600 mg/kg), which displayed normal hepatocytes with minor vascular congestion, respectively. Corn silk administration lowers a number of the harmful effects of in vivo carbonated alcoholic herbal beverage administration in the liver of Wister rats, according to the findings in this study.

Inhibitor of differentiation 3 confers the robust anti-tumor activity of Kupffer cells.

Inhibitor of differentiation 3 confers the robust anti-tumor activity of Kupffer cells.

Ameliorative Effects of Teucrium polium Leaves Ethanolic Extract on Liver Histopathology Induced by Eimeria papillata

Background: Teucrium polium is an herb utilized in traditional medicine for its biological activity. In the present study, T. polium leaves ethanolic extract (TPLEE) was investigated for its effects on coccidiosis resulting from Eimeria papillata infection in mice. Methods: In vivo, TPLEE (150 mg/kg) was administered for its antioxidant and hepatoprotective properties. The anticoccidial and anti-inflammatory effects of TPLEE were evaluated by measuring oocyst suppression and assessing liver histopathology, respectively. Result: Indicated that treatment with 150 mg/kg TPLEE led to oocyst suppression percentage of 91.2±4.1, similar to the efficacy of the reference drug amprolium (93.2±3.9) and was associated with a significant decrease in the number of developmental parasitic stages in jejunal sections. Infection with the parasite causes metabolic disturbance, inflammation and liver injury, as evidenced by histopathological changes such as Kupffer cell activation, vacuolated hepatocytes and increases in inflammatory cellular infiltration. In addition, infection led to a significant increase in malondialdehyde (MAD) and nitric oxide (NO) and a significant decrease in superoxide dismutase (SOD) and glutathione (GSH). The TPLEE showed significant hepatoprotective ability by improving the above parameters. TPLEE demonstrated both anticoccidial properties and the ability to alleviate preexisting liver damage caused by Eimeria infection.

Carbon monoxide-loaded red blood cells ameliorate metabolic dysfunction-associated steatohepatitis progression via enhancing AMP-activated protein kinase activity and inhibiting Kupffer cell activation

Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of nonalcoholic fatty liver disease characterised by fat accumulation, inflammation, oxidative stress, fibrosis, and impaired liver regeneration. In this study, we found that heme oxygenase-1 (HO-1) is induced in both MASH patients and in a MASH mouse model. Further, hepatic carbon monoxide (CO) levels in MASH model mice were >2-fold higher than in healthy mice, suggesting that liver HO-1 is activated as MASH progresses. Based on these findings, we used CO-loaded red blood cells (CO-RBCs) as a CO donor in the liver, and evaluated their therapeutic effect in methionine-choline deficient diet (MCDD)-induced and high-fat-diet (HFD)-induced MASH model mice. Intravenously administered CO-RBCs effectively delivered CO to the MASH liver, where they prevented fat accumulation by promoting fatty acid oxidation via AMP-activated protein kinase (AMPK) activation and peroxisome proliferator-activated receptor induction. They also markedly suppressed Kupffer cell activation and their corresponding anti-inflammatory and antioxidative stress activities in MASH mice. CO-RBCs also helped to restore liver regeneration in mice with HFD-induced MASH by activating AMPK. We confirmed the underlying mechanisms by performing in vitro experiments in RAW264.7 cells and palmitate-stimulated HepG2 cells. Taken together, CO-RBCs show potential as a promising cellular treatment for MASH.

Investigating the Anti-inflammatory Effect of Quinoline Derivative: N1-(5-methyl-5H-indolo[2,3-b]quinolin-11-yl)benzene-1,4-diamine Hydrochloride Loaded Soluble Starch Nanoparticles Against Methotrexate-induced Inflammation in Experimental Model

BackgroundIt is necessary to develop advanced therapies utilizing natural ingredients with anti-inflammatory qualities in order to lessen the negative effects of chemotherapeutics.ResultsThe bioactive N1-(5-methyl-5H-indolo[2,3-b]quinolin-11-yl)benzene-1,4-diamine hydrochloride (NIQBD) was synthesized. After that, soluble starch nanoparticles (StNPs) was used as a carrier for the synthesized NIQBD with different concentrations (50 mg, 100 mg, and 200 mg). The obtained StNPs loaded with different concentrations of NIQBD were coded as StNPs-1, StNPs-2, and StNPs-3. It was observed that, StNPs-1, StNPs-2, and StNPs-3 exhibited an average size of 246, 300, and 328 nm, respectively. Additionally, they also formed with homogeneity particles as depicted from polydispersity index values (PDI). The PDI values of StNPs-1, StNPs-2, and StNPs-3 are 0.298, 0.177, and 0.262, respectively.In vivo investigation of the potential properties of the different concentrations of StNPs loaded with NIQBD against MTX-induced inflammation in the lung and liver showed a statistically substantial increase in levels of reduced glutathione (GSH) accompanied by a significant decrease in levels of oxidants such as malondialdehyde (MDA), nitric oxide (NO), advanced oxidation protein product (AOPP), matrix metalloproteinase 9/Gelatinase B (MMP-9), and levels of inflammatory mediators including interleukin 1-beta (IL-1β), nuclear factor kappa-B (NF-κB) in both lung and liver tissues, and a significant decrease in levels of plasma homocysteine (Hcy) compared to the MTX-induced inflammation group. The highly significant results were obtained by treatment with a concentration of 200 mg/mL.Histopathological examination supported these results, where treatment showed minimal inflammatory infiltration and congestion in lung tissue, a mildly congested central vein, and mild activation of Kupffer cells in liver tissues.ConclusionCombining the treatment of MTX with natural antioxidant supplements may help reducing the associated oxidation and inflammation.

Association of Circulating Markers of Microbial Translocation and Hepatic Inflammation with Liver Injury in Patients with Type 2 Diabetes.

Virtually the entire spectrum of liver disease is observed in association with type 2 diabetes mellitus (T2DM); indeed, T2DM is now the most common cause of liver disease in the U.S. We conducted a pilot study to investigate the relevance of increased microbial translocation and systemic inflammation in the development of liver injury in patients with T2DM. Patients with T2DM (n = 17) and non-diabetic controls (NDC; n = 11) aged 25-80 yrs. participated in this study. Serum levels of endotoxin, calprotectin, soluble CD14 and CD163, and several inflammatory cytokines were measured. In addition to standard liver injury markers, ALT and AST, novel serum markers of liver injury, keratin 18 (K-18) M30 (apoptosis-associated caspase-cleaved keratin 18), and M65 (soluble keratin 18) were evaluated. Statistical analyses were performed using the Mann-Whitney test to assess differences between study groups. Pearson's correlation analysis was performed to determine the strength of association between two variables using GraphPad Prism 9.5.0 software. Patients with T2DM had significantly higher levels of sCD14 in comparison to NDC, suggesting an increase in gut permeability, microbial translocation, and monocyte/macrophage activation. Importantly, relevant to the ensuing inflammatory responses, the increase in sCD14 in patients with T2DM was accompanied by a significant increase in sCD163, a marker of hepatic Kupffer cell activation and inflammation. Further, a positive correlation was observed between sCD163 and endotoxin and sCD14 in T2DM patients but not in NDC. In association with these changes, keratin 18 (K-18)-based serum markers (M65 and M30) that reflect hepatocyte death were significantly higher in the T2DM group indicating ongoing liver injury. Notably, both M65 and M30 levels correlated with sCD14 and sCD163, suggesting that immune cell activation and hepatic inflammation may be linked to the development of liver injury in T2DM. These findings suggest that the pathogenic changes in the gut-liver axis, marked by increased microbial translocation, may be a major component in the etiology of hepatocyte inflammation and injury in patients with T2DM. However, larger longitudinal studies, including histological evidence, are needed to confirm these observations.

Gossypetin targets the liver-brain axis to alleviate pre-existing liver fibrosis and hippocampal neuroinflammation in mice.

Liver fibrosis occurs in response to chronic damage and inflammation to the liver. Leaving untreated, it can lead to decreased liver function and can eventually progress to cirrhosis, a more advanced and irreversible state of liver damage. Clinical investigations showed that chronic liver disease associated with neurological symptoms including anxiety, depression, and cognitive decline. However, few therapeutic options are available for treating liver and related brain pathologies simultaneously. In this study, we aim to find therapeutic candidates that target the liver-brain axis. Gossypetin, a flavonoid from sedum, shows promising capability in treating liver and brain pathologies in CCl4-induced mouse model. Short term of gossypetin administration is sufficient to ameliorate impaired liver function and pre-existing liver fibrosis, suppress MKK3/6-p38 MAPK and p53 activation, and abolish the activation of hepatic stellate cells and Kupffer cells. Although we observe no neuronal loss in the brain of mice with liver fibrosis, we do observe astrogliosis and microglial activation in certain brain regions, especially the hippocampus. Brief gossypetin administration also shows potential in alleviating neuroinflammation in these regions. These results suggest that gossypetin can target the liver-brain axis and be a promising candidate for treating chronic liver fibrosis patients with neurological symptoms.

TLR8 agonist selgantolimod regulates Kupffer cell differentiation status and impairs HBV entry into hepatocytes via an IL-6-dependent mechanism

ObjectiveAchieving HBV cure will require novel combination therapies of direct-acting antivirals and immunomodulatory agents. In this context, the toll-like receptor 8 (TLR8) agonist selgantolimod (SLGN) has been investigated in preclinical...

Hybrid Bioactive Hydrogel Promotes Liver Regeneration through the Activation of Kupffer Cells and ECM Remodeling After Partial Hepatectomy.

Partial hepatectomy is an essential surgical technique used to treat advanced liver diseases such as liver tumors, as well as for performing liver transplants from living donors. However, postoperative complications such as bleeding, abdominal adhesions, wound infections, and inadequate liver regeneration pose significant challenges and increase morbidity and mortality rates. A self-repairing mixed hydrogel (O5H2/Cu2+/SCCK), containing stem cell derived cytokine (SCCK) derived from human umbilical cord mesenchymal stem cells (HUMSCs) treated with the traditional Chinese remedy Tanshinone IIA (TSA), is developed. This SCCK, in conjunction with O5H2, demonstrates remarkable effects on Kupffer cell activation and extracellular matrix (ECM) remodeling. This leads to the secretion of critical growth factors promoting enhanced proliferation of hepatocytes and endothelial cells, thereby facilitating liver regeneration and repair after partial hepatectomy. Furthermore, the hydrogel, featuring macrophage-regulating properties, effectively mitigates inflammation and oxidative stress damage in the incision area, creating an optimal environment for postoperative liver regeneration. The injectability and strong adhesion of the hydrogel enables rapid hemostasis at the incision site, while its physical barrier function prevents postoperative abdominal adhesions. Furthermore, the hydrogel's incorporation of Cu2+ provides comprehensive antibacterial effects, protecting against a wide range of bacteria types and reducing the chances of infections after surgery.

Effects of Saikosaponin-A on Insulin Resistance in Obesity: Computational and Animal Experimental Study.

Obesity is known to be associated with increased inflammation and dysregulated autophagy, both of which contribute to insulin resistance. Saikosaponin-A (SSA) has been reported to exhibit anti-inflammatory and lipid-lowering properties. In this research, we employed a combination of computational modeling and animal experiments to explore the effects of SSA. Male C57BL/6 mice were categorized into four groups: normal diet, high-fat diet (HFD), HFD + atorvastatin 10 mg/kg, and HFD + SSA 10 mg/kg. We conducted oral glucose and fat tolerance tests to assess metabolic parameters and histological changes. Furthermore, we evaluated the population of Kupffer cells (KCs) and examined gene expressions related to inflammation and autophagy. Computational analysis revealed that SSA displayed high binding affinity to tumor necrosis factor (TNF)-α, nuclear factor (NF)-κB, fibroblast growth factor 21 (FGF21), and autophagy-related 7 (ATG7). Animal study demonstrated that SSA administration improved fasting and postprandial glucose levels, homeostatic model assessment of insulin resistance (HOMA-IR) index, as well as triglyceride, free fatty acid, total cholesterol, low-density lipoprotein cholesterol (LDL-C)-cholesterol, and high-density lipoprotein cholesterol (HDL-C)-cholesterol levels in HFD-fed mice. Moreover, SSA significantly reduced liver weight and fat accumulation, while inhibiting the infiltration and M1 activation of KCs. At the mRNA level, SSA downregulated TNF-α and NF-κB expression, while upregulating FGF21 and ATG7 expression. In conclusion, our study suggests that SSA may serve as a therapeutic agent for addressing the metabolic complications associated with obesity. This potential therapeutic effect is attributed to the suppression of inflammatory cytokines and the upregulation of FGF21 and ATG7.

MDIVI-1 ALLEVIATES SEPSIS-INDUCED LIVER INJURY BY INHIBITING STING SIGNALING ACTIVATION.

Proinflammatory hyperactivation of Kupffer cells (KCs) is foremost involved in the pathogenesis of sepsis-induced liver injury. Our previous study found that stimulator of interferon genes (STING) signaling was activated in KCs in response of lipopolysaccharide (LPS) and knocking down dynamin-related protein 1 (DRP1) in KCs effectively inhibited the activation of STING signaling and the subsequent production of proinflammatory cytokines. In this study, we demonstrated that in vivo treatment with mitochondrial division inhibitor 1 (Mdivi-1), a selective inhibitor of DRP1, alleviated cecal ligation and puncture (CLP)-induced liver injury with the improvement of liver pathology and function. Moreover, we found that STING in liver was mainly concentrated in KCs and STING signaling was significantly activated in KCs after CLP. The STING deficiency effectively ameliorated liver injury and decreased the mortality of septic mice, which were reversely worsened by the enhanced activation of STING with DMXAA. The further study showed that Mdivi-1 markedly attenuated STING signaling activation in KCs and inhibited systemic inflammatory response. Importantly, DMXAA application in CLP mice blunted Mdivi-1's liver protection effect. Taken together, our study confirmed Mdivi-1 effectively alleviated CLP-induced liver injury partially through inhibiting STING signaling activation in KCs, which provides new insights and a novel potential pharmacological therapeutic target for treating septic liver injury.

MicroRNA-7 deficiency ameliorates d-galactose-induced aging in mice by regulating senescence of Kupffer cells.

Aging is intricately linked to immune system dysfunction. Recent studies have highlighted the biological function of microRNA-7 (miR-7) as a novel regulator of immune cell function and related diseases. However, the potential role of miR-7 in aging remains unexplored. Here, we investigated the contribution of miR-7 to d-gal-induced aging in mice, focusing on its regulation of senescent Kupffer cells. Our findings revealed that miR-7 deficiency significantly ameliorated the aging process, characterized by enhanced CD4+ T-cell activation. However, the adoptive transfer of miR-7-deficient CD4+T cells failed to improve the age-related phenotype. Further analysis showed that miR-7 deficiency significantly reduced IL-1β production in liver tissue, and inhibiting IL-1β invivo slowed down the aging process in mice. Notably, IL-1β is mainly produced by senescent Kupffer cells in the liver tissue of aging mice, and miR-7 expression was significantly up-regulated in these cells. Mechanistically, KLF4, a target of miR-7, was down-regulated in senescent Kupffer cells in aging mouse model. Furthermore, miR-7 deficiency also modulated the NF-κB activation and IL-1β production in senescent Kupffer cells through KLF4. In conclusion, our findings unveil the role of miR-7 in d-gal-induced aging in mice, highlighting its regulation of KLF4/NF-κB/IL-1β pathways in senescent Kupffer cells. This research may enhance our understanding of miRNA-based aging immune cells and offer new avenues for new intervention strategies in aging process.

Histopathological effects of Cryptococcus neoformans on liver and kidney in mice

This study provides a brief review of approaches for the detection of histopathological effects of Cryptococcus neoformans on the liver and kidney in mice that were injected I/P with 105 yeast cells of C. neoformans suspended in 1 ml phosphate-buffered saline at a single dose. After 14 days, the mice were sacrificed, and histopathological sections from the liver and kidney were prepared and stained with Haematoxylin and Eosin by the P.A.S. method. The results show that the liver was infiltrated with inflammatory cells, primarily mononuclear cells, in the portal. In addition to the activation of Kupffer cells and vacillation of hepatocytes, most blood vessels were congested. The section of the kidney shows sluffing of epithelia lining tubules and destruction of glomeruli, in addition to infiltration of mononuclear cells. These results suggested that the fungus invasiveness of mice has substantial effects on vital organs and may lead to death. Keywords: Cryptococcus neoformans, Hepatic cryptococcal infection, Cryptococcus

Hydrophilic extract of Pistacia vera pericarp protects against phenylhydrazine-induced hepatotoxicity and hemolytic anemia.

Pistacia vera is commonly used in traditional medicine to treat various disorders. This study aims to investigate the anti-anemia and hepatoprotective effects of Pistacia vera pericarp extract (PVPE) in a rat model of phenylhydrazine (PHZ)-induced anemia. PVPE was prepared using the maceration method. The extract was administered at doses of 20, 80, and 160 mg/kg for 28 days to normal and PHZ-treated rats. The effects of PVPE were evaluated in terms of changes in biochemical, histological, hematological, and molecular biomarkers in the liver and blood. Administration of PVPE to the anemic animals significantly restored these deleterious effects on hematological parameters compared to the anemic group. Kupffer cell activation was seen in the liver tissue of the anemic rats. Administration of PVPE mitigated these deleterious effects. PVPE has potent antioxidant activity and may represent a promising treatment for anemia and liver protection in clinical settings.

Activation of GPR3-β-arrestin2-PKM2 pathway in Kupffer cells stimulates glycolysis and inhibits obesity and liver pathogenesis

Kupffer cells are liver resident macrophages and play critical role in fatty liver disease, yet the underlying mechanisms remain unclear. Here, we show that activation of G-protein coupled receptor 3 (GPR3) in Kupffer cells stimulates glycolysis and protects mice from obesity and fatty liver disease. GPR3 activation induces a rapid increase in glycolysis via formation of complexes between β-arrestin2 and key glycolytic enzymes as well as sustained increase in glycolysis through transcription of glycolytic genes. In mice, GPR3 activation in Kupffer cells results in enhanced glycolysis, reduced inflammation and inhibition of high-fat diet induced obesity and liver pathogenesis. In human fatty liver biopsies, GPR3 activation increases expression of glycolytic genes and reduces expression of inflammatory genes in a population of disease-associated macrophages. These findings identify GPR3 activation as a pivotal mechanism for metabolic reprogramming of Kupffer cells and as a potential approach for treating fatty liver disease.

Acetaminophen Hepatotoxicity: Paradigm for Understanding Mechanisms of Drug-Induced Liver Injury.

Acetaminophen (APAP) overdose is the clinically most relevant drug hepatotoxicity in western countries, and, because of translational relevance of animal models, APAP is mechanistically the most studied drug. This review covers intracellular signaling events starting with drug metabolism and the central role of mitochondrial dysfunction involving oxidant stress and peroxynitrite. Mitochondria-derived endonucleases trigger nuclear DNA fragmentation, the point of no return for cell death. In addition, adaptive mechanisms that limit cell death are discussed including autophagy, mitochondrial morphology changes, and biogenesis. Extensive evidence supports oncotic necrosis as the mode of cell death; however, a partial overlap with signaling events of apoptosis, ferroptosis, and pyroptosis is the basis for controversial discussions. Furthermore, an update on sterile inflammation in injury and repair with activation of Kupffer cells, monocyte-derived macrophages, and neutrophils is provided. Understanding these mechanisms of cell death led to discovery of N-acetylcysteine and recently fomepizole as effective antidotes against APAP toxicity.