Dysfunction Of Hepatocytes Research Articles

Extra-corporeal non-liver transplant therapies for acute liver failure: Focus on plasma exchange and continuous renal replacement therapy.

The acute inflammatory milieu in patients with acute liver failure (ALF) results in 'toxic' blood in these patients. In vitro experiments have shown that the plasma obtained from ALF patients is toxic to rabbit hepatocytes and inhibits regeneration of rat hepatocytes. Treatments such as plasma exchange and continuous renal replacement therapy to cleanse the blood have improved survival in ALF patients. In the liver microcirculation, the exchange of fluid across fenestrae in liver sinusoidal endothelial cells (LSECs) is vital for proper functioning of hepatocytes. Clogging of the liver filter bed by inflammatory debris and cells ('traffic jam hypothesis') impeding blood flow in sinusoids may in turn reduce the exchange of fluid across LSEC fenestrae and cause dysfunction and necrosis of hepatocytes in ALF patients. In mouse model of paracetamol overdose, disturbances in microcirculation in the liver preceded the development of injury and necrosis of hepatocytes. This may represent a reversible pathophysiological mechanism in ALF which may be improved by the anti-inflammatory effect of plasma exchange. Wider access to urgent plasma exchange is a major advantage compared to urgent liver transplantation to treat ALF patients worldwide, especially so in resource constrained settings. Continuous hemo-filtration or dialysis is used toreduce ammonia levels and treat cerebral edema in ALF patients. In this review, we discuss the different modalities to cleanse the blood in ALF patients, with an emphasis on plasma exchange, from a hepatology perspective.

IL-22 relieves hepatic ischemia-reperfusion injury by inhibiting mitochondrial apoptosis based on the activation of STAT3

IntroductionInterleukin-22 (IL-22) has been proven to exhibit a protective role in hepatic ischemia-reperfusion injury (HIRI). This study aimed to explore the change of IL-22 and IL-22 receptor 1 (IL-22R1) axis in HIRI and its role in mitochondrial apoptosis associated with STAT3 activation. Materials and MethodsI/R mice were examined for the expression of IL-22, IL-22R1 and IL-22BP. The roles of IL-22 in hepatic histopathology and oxidative stress injuries (ALT, MDA and SOD) were determined. Oxidative stress damages of AML-12 cells were induced by H2O2, and were indicated by apoptosis, Ca2+ concentration, and mitochondrial function. The effects of IL-22 on p-STAT3Try705 were analyzed. ResultsWe found that the expression of IL-22, IL-22R1, and IL-22BP was elevated 24 h after I/R induction, while decreased 48 h after I/R induction. Furthermore, we also discovered that IL-22 rescued the morphological damages and dysfunction of hepatocytes induced by H2O2, which were antagonized by IL-22BP, an endogenous antagonist of IL-22. Additionally, increased levels of Ca2+ concentration, MDA, ROS, apoptosis and mitochondrial dysfunction were noticed in H2O2-treated hepatocytes. However, IL-22 ameliorated the effects of I/R or H2O2. The protective effects of IL-22 were reversed by AG490, a specific antagonist of STAT3. ConclusionsIn conclusion, our results indicated that IL-22 inhibited I/R-induced oxidative stress injury, Ca2+ overload, and mitochondrial apoptosis via STAT3 activation.

Insight into Tetrabromobisphenol A-Associated Liver Transcriptional Landscape via Single Cell RNA Sequencing.

In recent years, there has been growing concern over the rising incidence of liver diseases, with increasing exposure to environmental toxins as a significant contributing factor. However, the mechanisms of liver injury induced by environmental pollutants are largely unclear. Here, using tetrabromobisphenol A (TBBPA), a widely used brominated flame retardant, as an example, environmental toxin-induced liver toxicity in mice is characterized via single-cell sequencing technology. Heterogeneous gene expression profiles after exposure to TBBPA in major cell types of the liver are demonstrated. In hepatocytes, pathway analysis of differentially expressed genes reveals the enhanced interferon response and diminished metabolic processes. The disrupted endothelial functions in TBBPA-treated cells are then shown. Moreover, the activation of M2-polarization in Kupffer cells, as well as activated effector T and B cells are unveiled in TBBPA-treated cells. Finally, ligand-receptor pair analysis shows that TBBPA disrupts cell-cell communication and induces an inflammatory microenvironment. Overall, the results reveal that TBBPA-induced dysfunction of hepatocytes and endothelial cells may then activate and recruit other immune cells such as Kuffer cells, and T/NK cells into the liver, further increasing inflammatory response and liver injury. Thus, the results provide novel insight into undesiring environmental pollutant-induced liver injury.

Umbilical Cord-Derived Mesenchymal Stem Cells Attenuate S100-Induced Autoimmune Hepatitis via Modulating Th1 and Th17 Cell Responses in Mice.

Currently, the first-line treatment for autoimmune hepatitis (AIH) is still the combination of glucocorticoids or immunosuppressants. However, hormone and immunosuppressive therapy can cause serious side effects, such as Cushing syndrome and bone marrow suppression. Previous studies reported on the applicability and safety of mesenchymal stem cells (MSCs) to ameliorate liver inflammation and fibrosis. However, the characteristics of MSCs sources directly contribute to the different conclusions on the mechanisms underlying MSC-mediated immunoregulation. Bone marrow-derived MSCs can exert an immunosuppression effect to ameliorate the S100-induced AIH model by inhibiting several proinflammatory cytokines and upregulating of PD-L1 in liver tissue. It is not clear whether human umbilical cord-derived MSCs (hUC-MSCs) could directly inhibit liver inflammation and ultimately alleviate the dysfunction of hepatocytes in the AIH model. First, hUC-MSCs were extracted from umbilical cord tissue, and the basic biological properties and multilineage differentiation potential were examined. Second, 1 × 106 hUC-MSCs were administered intravenously to AIH mice. At the peak of the disease, serum levels of alanine aminotransferase and aspartate aminotransferase and pathologic damage to liver tissue were measured to evaluate liver function and degree of inflammation. We also observed that the infiltration of CD4+ T cells in the liver was significantly reduced. Furthermore, the frequency of the splenic IFNγ- and IL-17A- producing CD4+ T cells were also significantly decreased, while we only observed an increasing trend in Treg cells in liver tissue. Third, an RNA sequencing analysis of liver tissue was performed, which showed that in the UC-MSC-treated group, the transcriptional profiles of inflammation-related signaling pathways were significantly negatively regulated compared to those of phosphate-buffered saline-treated mice. Collectively, these findings indicated the potential of hUC-MSC to suppress immune responses in immune anomaly mediated liver disease, thus offering a potential clinical option to improve AIH.

Eucalyptol antagonized the apoptosis and immune dysfunction of grass carp hepatocytes induced by tetrabromobisphenol A by regulating ROS/ASK1/JNK pathway.

Tetrabromobisphenol A (TBBPA) is a common environmental pollutant which has multi-organ toxicity to mammals. Eucalyptol (EUC) has super antioxidant biological activity. However, in this experimental study, we probed into the mechanism of toxic of TBBPA exposure on Grass carp hepatocytes (L8824 cells) and the antagonistic impact of EUC on TBBPA. We treated L8824 cells with 8μg/ml TBBPA and/or 20 μM EUC for 24 h in this test research. The experiment results suggested that TBBPA exposure induced elevated levels of reactive oxygen species (ROS), led to oxidative stress, decreased SOD and CAT activities, decreased GSH and T-AOC contents, exacerbated MDA accumulation, activated ASK1/JNK signaling pathway, and further increased the contents of mitochondrial dependent apoptosis pathway related indicators (Cyt-C, Bax, Caspase 9, Caspase 3), while Bcl-2 expression decreased. In addition, TBBPA exposure induced increased expression of TNF-α, IL-6, IL-1β, and decreased expression of IL-2, IFN-γ, Hepcidin, β-defensin, LEAP2. The oxidative stress level, ASK1/JNK signal pathway expression level, apoptosis ratio and cellular immune function of cells exposed to EUC alone did not change significantly. Combined exposure of TBBPA and EUC significantly reduced the proportion of apoptosis and restored cellular immune function. Therefore, these results suggest that EUC can effectively antagonize TBBPA-induced apoptosis and immune dysfunction of L8824 cells by regulating ROS/ASK1/JNK signaling pathway.

Tannic acid through ROS/TNF-α/TNFR 1 antagonizes atrazine induced apoptosis, programmed necrosis and immune dysfunction of grass carp hepatocytes

Atrazine (ATR) is a commonly used triazine herbicide, which will remain in the water source, soil and biological muscle tissue for a long time, threatening the survival of related organisms and future generations. Tannic acid (TAN), a glucosyl compound found in gallnuts, has previously been shown to antagonize heavy metal toxicity, antioxidant activity, and inflammation. However, it is unclear whether TAN can antagonize ATR-induced Grass carp hepatocytes (L8824 cells) cytotoxicity. Therefore, we treated L8824 cells with 3 μg mL−1 ATR for 24 h to establish a toxic group model. The experimental data of flow cytometry and AO/EB staining together showed that the ratio of apoptosis and necrosis in L8824 cells after ATR exposure was significantly higher than that in the control group. Furthermore, RT-qPCR showed that inflammatory factors (TNF-α, IL-1β, IL-6, INF-γ) were up-regulated and antimicrobial peptides (hepcidin, β-defensin and LEAP2) were induced down-regulated in L8824 cells, leading to immune dysfunction. The measurement results of oxidative stress-related indicators showed that the levels of ROS and MDA increased after ATR exposure, the overall anti-oxidative system was down-regulated. Western blotting confirmed that TNF-α/TNFR 1-related genes were also up-regulated. This indicates that ATR stimulates oxidative stress in L8824 cells, which in turn promotes the binding of TNF-α to TNFR 1. In addition, TRADD, FADD, Caspase-3, P53, RIP1, RIP3 and MLKL were found to be significantly up-regulated by Western blotting and RT-qPCR. Conditioned after ATR exposure compared to controls. It indicates that ATR activates apoptosis and necrosis of TNF-α/TNFR 1 pathway by inducing oxidative stress in L8824 cells. Furthermore, the use of TAN (5 μM) significantly alleviated the toxic effects of ATR on L8824 cells mentioned above. In conclusion, TAN restrains ATR-induced apoptosis, programmed necrosis and immune dysfunction through the ROS/TNF-α/TNFR 1 pathway.

LncRNA XIST promotes mitochondrial dysfunction of hepatocytes to aggravate hepatic fibrogenesis via miR-539-3p/ADAMTS5 axis.

A previous study indicated that long non-coding RNA X-inactive-specific transcript (XIST) promoted ethanol-induced HSCs autophagy and activation. Considering the critical role of HSC activation in hepatic fibrosis, the aim of the present study was to reveal the exact role of XIST in liver fibrosis and its underlying mechanism. The expression of XIST in the liver from CCL4-induced mice and control mice as well as human fibrotic liver tissue and healthy liver tissue was examined. The mitochondrial reactive oxygen species (mtROS), mitochondrial membrane potential (MMP), and mitochondrial morphology were measured to assess the mitochondrial damage. The relationship between XIST and miR-539-3p as well as between miR-539-3p and ADAMTS5 was verified by a dual-luciferase reporter assay. The expression levels of HSCs activation markers were examined by Western blot. The results showed that the XIST was upregulated in fibrotic liver tissue, and overexpression of XIST induced mitochondrial dysfunction in hepatocytes. miR-539-3p directly targeted XIST, and ADAMTS5 mRNA was a downstream target of miR-539-3p. Knockdown of miR-539-3p led to an increased mitochondrial damage in hepatocytes in terms of reduced mitochondrial length, decreased MMP, and increased ROS production. However, the depletion of ADAMTS5 reversed the regulatory effect of XIST on mitochondrial damage in hepatocytes and the activation of HSCs. Our study revealed the critical role of the XIST/miR-539-3p/ADAMTS5 axis in regulating mitochondrial damage in hepatocytes and the activation of HSCs. This study may provide a potential therapeutic strategy for the treatment of liver fibrosis.

Hepatic Neddylation Deficiency Triggers Fatal Liver Injury via Inducing NF‐κB‐inducing Kinase and Oxidative Stress

The conjugation of NEDD8 to target proteins, termed neddylation is aberrant in many pathological diseases. Its relevance to liver function and failure remains poorly understood. Here, we first identified dysregulated expression of neddylation enzymes (e.g. NAE1, a regulatory subunit of the only NEDD8 E1 enzyme) in human HBV‐induced acute liver failure (ALF). Embryonic–onset deletion of NAE1 in hepatocytes led to severe hepatomegaly, formation of numerous cysts, inflammation, and fibrosis, which ultimately resulted in ALF in mice. Adult–onset hepatic deletion of NAE1 caused ALF with 100% mortality within 30 days post deletion. Mechanistically, hepatic neddylation deficiency triggers glutathione deficiency, oxidative stress, mitochondrial dysfunction, and reprogramming of mature hepatocytes to fetal‐like cells, potentiating liver injury. Importantly, we identified NF‐κB‐inducing kinase (NIK), a stress kinase aberrantly activated in chronic and acute liver diseases, is a novel neddylation substrate. Neddylation of NIK promotes its ubiquitination and degradation; and inhibition of neddylation caused NIK overactivation, accentuating hepatocyte damage. Notably, oral N‐acetylcysteine (NAC) administration attenuated lethal liver injury caused by hepatic NAE1 deletion, with improved liver function and mortality. Therefore, hepatic neddylation is essential in maintaining postnatal and adult liver homeostasis, and the novel neddylation targets/pathways may endow us with new insights into therapeutically intervening ALF progression.

Potential Roles and Key Mechanisms of Hawthorn Extract against Various Liver Diseases.

The genus Crataegus (hawthorn), a flowering shrub or tree, is a member of the Rosaceae family and consists of approximately 280 species that have been primarily cultivated in East Asia, North America, and Europe. Consumption of hawthorn preparations has been chiefly associated with pharmacological benefits for cardiovascular diseases, including congestive heart failure and angina pectoris. Treatment with hawthorn extracts can be related to improvements in the complex pathogenesis of various hepatic and cardiovascular disorders. In this regard, the present review described that the presence of hawthorn extracts ameliorated hepatic injury, lipid accumulation, inflammation, fibrosis, and cancer in an abundance of experimental models. Hawthorn extracts might have these promising activities, largely by enhancing the hepatic antioxidant system. In addition, several mechanisms, including AMP-activated protein kinase (AMPK) signaling and apoptosis, are responsible for the role of hawthorn extracts in repairing the dysfunction of injured hepatocytes. Specifically, hawthorn possesses a wide range of biological actions relevant to the treatment of toxic hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease, and hepatocellular carcinoma. Accordingly, hawthorn extracts can be developed as a major source of therapeutic agents for liver diseases.

Caveolin-1 attenuates acetaminophen aggravated lipid accumulation in alcoholic fatty liver by activating mitophagy via the Pink-1/Parkin pathway

Alcoholic fatty liver (AFL) is a disease characterized by the abnormal structure and dysfunction of hepatocytes caused by long-term, excessive drinking. Acetaminophen (APAP) is a commonly used painkiller, but it can aggravate lipid deposition in the liver and cause liver injury when used in fatty liver disease. Here, we investigated the effect of caveolin-1 (CAV-1), an intracellular stent protein, on the pathogenesis of APAP aggravated lipid deposition in AFL mice. This study shows that lipid accumulation was more severe in APAP groups than in alcohol-treated mice. The CAV-1 stent-like domain (CSD, 82–101 amino acids of caveolin-1), used to upregulate CAV-1 expression, could reduce lipid accumulation and activate autophagy in AFL mice treated with APAP. The levels of CAV-1 and autophagy-related proteins (LC3-II/I and Beclin-1) had decreased, whereas SREBP-1c had increased in A/O (alcohol and oleic acid) and APAP-co-treated L02 cells. CAV-1 small interfering RNA and CAV1-overexpressing plasmid were separately transfected into A/O and APAP co-treated L02 cells. When CAV-1 was downregulated, the levels of Pink-1, Parkin, and autophagy-related proteins (LC3-II/I and Beclin-1) were decreased, whereas SREBP-1c was increased. The opposite trend was observed when CAV-1 was overexpressed. The results show that CAV-1 reduced lipid accumulation in L02 cells and activated Pink-1/Parkin-related mitophagy. This study highlights the positive role of CAV-1 in APAP-increased lipid accumulation under the AFL status and provides a new understanding of the function of CAV-1 in the liver through mitophagy associated with the Pink-1/Parkin pathway.

Non-alcoholic fatty liver disease

Fatty degeneration of cells under the influence of various factors is called steatosis; most often this process is observed in the pancreas and liver. Steatosis of the liver refers to its fatty infiltration, in which fatty inclusions appear in the parenchyma of the organ, leading to dysfunction of hepatocytes. Steatosis can be focal and diffuse; in the latter case, fat cells are located over the entire surface of the liver. Until 1980, it was believed that only alcohol abuse can lead to steatosis, while fatty degeneration of the liver was noted in 90 % of alcohol abusers. Subsequently, it was found that alcoholism is not the only reason for the development of this pathological condition, after which it was proposed to divide steatosis into alcoholic and non-alcoholic. Most often, non-alcoholic steatosis develops in women over 45 years old against the background of obesity or diabetes mellitus. Also, the cause of the development of liver steatosis can be malnutrition and diseases of other digestive organs, leading to impaired absorption of nutrients, metabolic disorders, and hormonal disruptions.

Exogenous L-carnitine ameliorates burn-induced cellular and mitochondrial injury of hepatocytes by restoring CPT1 activity

BackgroundImpaired hepatic fatty acid metabolism and persistent mitochondrial dysfunction are phenomena commonly associated with liver failure. Decreased serum levels of L-carnitine, a amino acid derivative involved in fatty-acid and energy metabolism, have been reported in severe burn patients. The current study aimed to evaluate the effects of L-carnitine supplementation on mitochondrial damage and other hepatocyte injuries following severe burns and the related mechanisms.MethodsSerum carnitine and other indicators of hepatocytic injury, including AST, ALT, LDH, TG, and OCT, were analyzed in severe burn patients and healthy controls. A burn model was established on the back skin of rats; thereafter, carnitine was administered, and serum levels of the above indicators were evaluated along with Oil Red O and TUNEL staining, transmission electron microscopy, and assessment of mitochondrial membrane potential and carnitine palmitoyltransferase 1 (CPT1) activity and expression levels in the liver. HepG2 cells pretreated with the CPT1 inhibitor etomoxir were treated with or without carnitine for 24 h. Next, the above indicators were examined, and apoptotic cells were analyzed via flow cytometry. High-throughput sequencing of rat liver tissues identified several differentially expressed genes (Fabp4, Acacb, Acsm5, and Pnpla3) were confirmed using RT-qPCR.ResultsSubstantially decreased serum levels of carnitine and increased levels of AST, ALT, LDH, and OCT were detected in severe burn patients and the burn model rats. Accumulation of TG, evident mitochondrial shrinkage, altered mitochondrial membrane potential, decreased ketogenesis, and reduced CPT1 activity were detected in the liver tissue of the burned rats. Carnitine administration recovered CPT1 activity and improved all indicators related to cellular and fatty acid metabolism and mitochondrial injury. Inhibition of CPT1 activity with etomoxir induced hepatocyte injuries similar to those in burn patients and burned rats; carnitine supplementation restored CPT1 activity and ameliorated these injuries. The expression levels of the differentially expressed genes Fabp4, Acacb, Acsm5, and Pnpla3 in the liver tissue from burned rats and etomoxir-treated hepatocytes were also restored by treatment with exogenous carnitine.ConclusionExogenous carnitine exerts protective effects against severe burn-induced cellular, fatty-acid metabolism, and mitochondrial dysfunction of hepatocytes by restoring CPT1 activity.

Blueberry-derived exosomes-like nanoparticles ameliorate nonalcoholic fatty liver disease by attenuating mitochondrial oxidative stress.

Accumulating evidence indicates that mitochondrial dysfunction and oxidative stress play a pivotal role in the initiation and progression of nonalcoholic fatty liver disease (NAFLD). In this study, we found that blueberry-derived exosomes-like nanoparticles (BELNs) could ameliorate oxidative stress in rotenone-induced HepG2 cells and high-fat diet (HFD)-fed C57BL/6 mice. Preincubation with BELNs decreased the level of reactive oxygen species (ROS), increased the mitochondrial membrane potential, and prevented cell apoptosis by inducing the expression of Bcl-2 and heme oxygenase-1 (HO-1) and decreasing the content of Bax in rotenone-treated HepG2 cells. We also found that preincubation with BELNs accelerated the translocation of Nrf2, an important transcription factor of antioxidative proteins, from the cytoplasm to the nucleus in rotenone-treated HepG2 cells. Moreover, administration of BELNs improved insulin resistance, ameliorated the dysfunction of hepatocytes, and regulated the expression of detoxifying/antioxidant genes by affecting the distribution of Nrf2 in the cytoplasm and nucleus of hepatocytes of HFD-fed mice. Furthermore, BELNs supplementation prevented the formation of vacuoles and attenuated the accumulation of lipid droplets by inhibiting the expression of fatty acid synthase (FAS) and acetyl-CoA carboxylase 1 (ACC1), the two key transcription factors for de novo lipogenesis in the liver of HFD-fed mice. These findings suggested that BELNs can be used for the treatment of NAFLD because of their antioxidative activity.

The effect of cytochrome level in rats with sepsis on mitochondrial function of hepatocytes

Objective To investigate the effects of cytochrome level and oxidase activity of cytochrome C in rats with sepsis on mitochondrial bioenergy synthesis of hepatocytes and liver functions. Methods 24 SD rats were divided into normal control group (Group C) and sepsis group (Group S), with 12 rats in each group. The sepsis model of the rats was established by the cecal ligation and puncture. After 18 h of moulding, the rats were executed. Their blood was taken to test alanine aminotransferase (ALT), aspartate aminotransferase (AST) and mitochondrial aspartate aminotransferase (m-AST). The morphologies of hepatocytes and mitochondria were observed using light microscope and electron microscope respectively. Using reduced minus oxidized difference spectra, the contents of mitochondrial cytochromes C, C1, B and AA3 and the oxidase activity of cytochrome C were determined. The potential level of mitochondrial membrane was tested. The content of adenosine triphosphate (ATP) in hepatocytes was measured. Results Compared with Group C, the ALT, AST and m-AST in the serum of Group S rose significantly [(233.02±110.16) U/L vs. (29.81±13.16) U/L, (742.56±441.41) U/L vs. (99.78±41.67) U/L and (412.78±252.56) U/L vs. (46.23±24.24) U/L, P= 0.000, 0.001, 0.001, respectively]. The ATP content in hepatocytes dropped significantly [(19.27±8.76) nmol/mg vs. (94.65±17.79) nmol/mg, P=0.000]. Cytochromes c and AA3 in mitochondria declined significantly [(0.10±0.04) nmol/mg vs. (0.17±0.03) nmol/mg and (0.21±0.04) nmol/mg vs. (0.38±0.09) nmol/mg, P=0.000, 0.000]. The activity of cytochrome C oxidase was decreased significantly [(734.14±107.37) nmol/(min·mg prot) vs. (1 279.75±186.77) nmol/(min·mg prot), P=0.000]. The potential level of mitochondrial membrane dropped significantly (1.75±0.96 vs. 3.81±1.16, P=0.000). Conclusion In the case of sepsis, the content of mitochondrial cytochromes in hepatocytes decreases and the oxidase activity of cytochrome C drops. As a result, these leads to mitochondrial dysfunction and acute injury of hepatocytes. Key words: Sepsis; Liver; Mitochondrial; Cytochrome; Cytochrome C oxidase

Human hepatocyte depletion in the presence of HIV-1 infection in dual reconstituted humanized mice.

ABSTRACTHuman immunodeficiency virus type 1 (HIV-1) infection impairs liver function, and liver diseases have become a leading cause of morbidity in infected patients. The immunopathology of liver damage caused by HIV-1 remains unclear. We used chimeric mice dually reconstituted with a human immune system and hepatocytes to address the relevance of the model to pathobiology questions related to human hepatocyte survival in the presence of systemic infection. TK-NOG males were transplanted with mismatched human hematopoietic stem/progenitor cells and hepatocytes, human albumin concentration and the presence of human immune cells in blood were monitored for hepatocytes and immune reconstitution, and mice were infected with HIV-1. HIV-1-infected animals showed a decline in human albumin concentration with a significant reduction in percentage of human hepatocytes compared to uninfected mice. The decrease in human albumin levels correlated with a decline in CD4+ cells in the liver and with an increase in HIV-1 viral load. HIV-1 infection elicited proinflammatory response in the immunological milieu of the liver in HIV-infected mice compared to uninfected animals, as determined by upregulation of IL23, CXCL10 and multiple toll-like receptor expression. The inflammatory reaction associated with HIV-1 infection in vivo could contribute to the depletion and dysfunction of hepatocytes. The dual reconstituted TK-NOG mouse model is a feasible platform to investigate hepatocyte-related HIV-1 immunopathogenesis.This article has an associated First Person interview with the first author of the paper.

Endogenous Formaldehyde Is a Hematopoietic Stem Cell Genotoxin and Metabolic Carcinogen

SummaryEndogenous formaldehyde is produced by numerous biochemical pathways fundamental to life, and it can crosslink both DNA and proteins. However, the consequences of its accumulation are unclear. Here we show that endogenous formaldehyde is removed by the enzyme alcohol dehydrogenase 5 (ADH5/GSNOR), and Adh5−/− mice therefore accumulate formaldehyde adducts in DNA. The repair of this damage is mediated by FANCD2, a DNA crosslink repair protein. Adh5−/−Fancd2−/− mice reveal an essential requirement for these protection mechanisms in hematopoietic stem cells (HSCs), leading to their depletion and precipitating bone marrow failure. More widespread formaldehyde-induced DNA damage also causes karyomegaly and dysfunction of hepatocytes and nephrons. Bone marrow transplantation not only rescued hematopoiesis but, surprisingly, also preserved nephron function. Nevertheless, all of these animals eventually developed fatal malignancies. Formaldehyde is therefore an important source of endogenous DNA damage that is counteracted in mammals by a conserved protection mechanism.

Особенности функционального проявления вирусных гепатитов В и С при первичном их выявлении

In the primary dysfunction of hepatocytes in the all groups of men with hepatitis C was revealed. I the others groups of men and women with hepatitis C was found the pathological damage of liver cells with the penetration the bile in the blood. The high activity of aminotransferases particularly ALT in the all groups reflect the active cytolitic process in the liver with more sever course of it in the women and men with hepatitis C. In the group of men below thirty years old was observed the acute course of hepatitis C. It was determined the concomitant disease in the studied population. In particular, in the woman in the age of below thirty years old with hepatitis C was revealed the hurt disease.

Angiotensin II type 1 receptor blockers increase tolerance of cells to copper and cisplatin

The human pathology Wilson disease (WD) is characterized by toxic copper (Cu) accumulation in brain and liver, resulting in, among other indications, mitochondrial dysfunction and apoptosis of hepatocytes. In an effort to identify novel compounds that can alleviate Cu-induced toxicity, we screened the Pharmakon 1600 repositioning library using a Cu-toxicity yeast screen. We identified 2 members of the drug class of Angiotensin II Type 1 receptor blockers (ARBs) that could increase yeast tolerance to Cu, namely Candesartan and Losartan. Subsequently, we show that specific ARBs can increase yeast tolerance to Cu and/or the chemotherapeutic agent cisplatin (Cp). The latter also induces mitochondrial dysfunction and apoptosis in mammalian cells. We further demonstrate that specific ARBs can prevent the prevalence of Cu-induced apoptotic markers in yeast, with Candesartan Cilexetil being the ARB which demonstrated most pronounced reduction of apoptosis-related markers. Next, we tested the sensitivity of a selection of yeast knockout mutants affected in detoxification of reactive oxygen species (ROS) and Cu for Candesartan Cilexetil rescue in presence of Cu. These data indicate that Candesartan Cilexetil increases yeast tolerance to Cu irrespectively of major ROS-detoxifying proteins. Finally, we show that specific ARBs can increase mammalian cell tolerance to Cu, as well as decrease the prevalence of Cu-induced apoptotic markers. All the above point to the potential of ARBs in preventing Cu-induced toxicity in yeast and mammalian cells.

Pathogenesis of alcoholic liver disease: interactions between parenchymal and non-parenchymal cells

The development of alcoholic liver disease (ALD) is a complex process involving both the parenchymal and non-parenchymal cells in the liver. The impact of ethanol on hepatocytes can be characterized as a condition of organelle stress with multifactorial changes in hepatocellular function accumulating during ethanol exposure. These changes include oxidative stress, mitochondrial dysfunction, decreased methylation capacity, endoplasmic reticulum stress, impaired vesicular trafficking and altered proteasome function. Injury to hepatocytes is attributed, in part, to ethanol metabolism by the hepatocytes. Changes in the structural integrity of hepatic sinusoidal endothelial cells, as well as enhanced inflammation in the liver during ethanol exposure are also important contributors to injury. Activation of hepatic stellate cells initiates the deposition of extracellular matrix proteins characteristic of fibrosis. Kupffer cells, the resident macrophages in the liver, are particularly critical to the onset of ethanol-induced liver injury. Chronic ethanol exposure sensitizes Kupffer cells to activation by lipopolysaccharides via toll-like receptor 4. This sensitization enhances the production of inflammatory mediators, such as tumor necrosis factor-α and reactive oxygen species that contribute to hepatocyte dysfunction, necrosis and apoptosis of hepatocytes and the generation of extracellular matrix proteins leading to fibrosis. In this review we provide an overview of the complex interactions between parenchymal and non-parenchymal cells in the liver during the progression of ethanol-induced liver injury.

Role and Place of Hyperbaric Oxygenation in Hepatic Failure

Objective: to define the role and place of hyperbaric oxygenation (HBO) in the treatment and prevention of liver cell failure. Material and methods. The results of the author’s own studies and the data available in the literature on the impact of HBO on the functional state of the liver and the whole organism in liver cell failure were analyzed. Results: The therapeutic and preventive effects of HBO during therapy for liver cell failure were due to the ability of hyperbaric oxygen to regulate metabolic processes in the sick organism. By eliminating the impaired hepatic neutralization of ammonia, hyperbaric oxygen corrects its extrahepatic reactions in rendering harmless various toxic substances, which become active in response to the ammonia-neutralizing dysfunction of hepatocytes. This prevents the development of endogenous ammonia intoxication. In liver cell failure, HBO concurrently stimulates hepatic protein synthesis function and the cell link of the body’s antimicrobial protection. The therapeutic effect of HBO is not always attended by the elimination of hepatic hypoxia and the sick organism’s hypoxemia, but it persists long in the posthyperoxic period. Conclusion: HBO can and must be an integral part of complex therapy for liver cell failure. Key words: hyperoxia, treatment, liver, failure.