Severe Liver Damage Research Articles

Identification of microRNAs Implicated in Modulating Senecionine-Induced Liver Toxicity in HepaRG Cells.

1,2-unsaturated Pyrrolizidine Alkaloids (PAs) are secondary plant metabolites that occur as food contaminants. Upon consumption, they can cause severe liver damage. PAs have been shown to induce apoptosis, to have cytotoxic and genotoxic effects, and to impair bile acid homeostasis in the human hepatoma cell line HepaRG. The major mode of action of PAs is DNA- and protein-adduct formation. Beyond that, nuclear receptor activation has only been observed for one receptor and two PAs, yielding the possibility that other cellular mediators are involved in PA-mediated toxicity. Here, the mode of action of Senecionine (Sc), a prominent and ubiquitous representative of hepatotoxic PAs, was investigated by analyzing 7 hepatic microRNAs (miRNAs) in HepaRG cells. Ultimately, 11 target genes that were predicted with Ingenuity Pathway Analysis software (IPA) were found to be significantly downregulated, while their assigned miRNAs showed significant upregulation of gene expression. According to IPA, these targets are positively correlated with apoptosis and cellular death and are involved in diseases such as hepatocellular carcinoma. Subsequent antagomiR-inhibition analysis revealed a significant correlation between PA-induced miRNA-4434 induction and P21-Activated Kinase-1 (PAK1) downregulation. PAK1 downregulation is usually associated with cell cycle arrest, suggesting a new function of Sc-mediated toxicity in human liver cells.

A new animal model of atrophy\u2013hypertrophy complex and liver damage following Yttrium-90 lobar selective internal radiation therapy in rabbits

Lobar selective internal radiation therapy (SIRT) is widely used to treat liver tumors inducing atrophy of the treated lobe and contralateral hypertrophy. The lack of animal model has precluded further investigations to improve this treatment. We developed an animal model of liver damage and atrophy–hypertrophy complex after SIRT. Three groups of 5–8 rabbits received transportal SIRT with Yttrium 90 resin microspheres of the cranial lobes with different activities (0.3, 0.6 and 1.2 GBq), corresponding to predicted absorbed radiation dose of 200, 400 and 800 Gy, respectively. Another group received non-loaded microspheres (sham group). Cranial and caudal lobes volumes were assessed using CT volumetry before, 15 and 30 days after SIRT. Liver biochemistry, histopathology and gene expression were evaluated. Four untreated rabbits were used as controls for gene expression studies. All animals receiving 1.2 GBq were euthanized due to clinical deterioration. Cranial SIRT with 0.6 GBq induced caudal lobe hypertrophy after 15 days (median increase 34% -ns-) but produced significant toxicity. Cranial SIRT with 0.3 GBq induced caudal lobe hypertrophy after 30 days (median increase 82%, p = 0.04). No volumetric changes were detected in sham group. Transient increase in serum transaminases was detected in all treated groups returning to normal values at 15 days. There was dose-dependent liver dysfunction with bilirubin elevation and albumin decrease. Histologically, 1.2 GBq group developed permanent severe liver damage with massive necrosis, 0.6 and 0.3 GBq groups developed moderate damage with inflammation and portal fibrosis at 15 days, partially recovering at 30 days. There was no difference in the expression of hepatocyte function and differentiation genes between 0.3 GBq and control groups. Cranial SIRT with 0.3 GBq of 90Y resin microspheres in rabbits is a reliable animal model to analyse the atrophy–hypertrophy complex and liver damage without toxicity.

Crosstalk between Irisin Levels, Liver Fibrogenesis and Liver Damage in Non-Obese, Non-Diabetic Individuals with Non-Alcoholic Fatty Liver Disease.

Background: Insulin resistance plays a relevant role in the onset of non-alcoholic fatty liver disease (NAFLD) and its progression to non-alcoholic steatohepatitis (NASH) and fibrosis. Irisin is an exercise-induced myokine involved in the regulation of energy homeostasis and glucose metabolism. Additionally, pre-clinical models have shown a potential role of irisin in the pathogenesis of NAFLD. The aim of this study is to explore the association between irisin, histological features and biomarkers of liver fibrogenesis in non-diabetic, non-obese, biopsy-proven NAFLD individuals. Methods: Forty-one patients with histological evidence of NAFLD were included. Circulating irisin and direct markers of fibrogenesis N-terminal type III collagen propeptide (PRO-C3) and type VI collagen cleavage product (PRO-C6) were measured by ELISA. Results: Median age of the cohort was 45 years (41–51) and 80.4% were male. Significant fibrosis (stage ≥ 2) was present in 36.6% of cases. Circulating irisin, PRO-C3 and PRO-C6 levels were significantly higher in subjects with fibrosis stage ≥ 2 when compared to those with fibrosis stage < 2 (5.96 ng/mL (95% CI = 4.42–9.19) vs. 2.42 ng/mL (95% CI = 1.73–5.95), p = 0.033; 9.5 ng/mL (95% CI = 7.7–13.6) vs. 6.2 ng/mL (95% CI = 4.9–8.9), p = 0.016; 6.6 ng/mL (95% CI = 5.6–7.9) vs. 5.1 ng/mL (95% CI = 4.2–5.4), p = 0.013, respectively). Irisin levels were similarly distributed between the features of NASH. Circulating irisin positively correlated with both PRO-C3 and PRO-C6 levels (r = 0.47, p = 0.008 and r = 0.46, p = 0.002). Conclusions: Increased circulating irisin levels may identify a more aggressive phenotype of liver disease with increased fibrogenesis and more severe liver damage.

Investigation of dysregulated lipid metabolism in diabetic mice via targeted metabolomics of bile acids in enterohepatic circulation

The mechanism of lipid metabolism disorder in type 2 diabetes (T2DM) remains unclear. This study aimed to reveal the mechanism underlying dysregulated lipid metabolism in T2DM through bile acid metabolism. A db/db mouse model was employed to investigate the alteration of bile acid profiles in T2DM. Ultrahigh-performance liquid chromatography with tandem mass spectrometry was used to quantify the detailed bile acid levels in each compartment of enterohepatic circulation. The pathological change of mouse liver was assessed by liver histology and serum biochemical assays. The expression level of bile acid-related transporters and synthases was measured with Western blot analysis. The results showed that T2DM can result in severe liver fat accumulation and liver damage. In addition, compared to the control group, in T2DM mice, bile acid synthesis is reduced, while the level of bile acids is increased at the storage sites and the reabsorption sites, but there are subtle gender differences. Further, the ratio of conjugated bile acids in total bile acid in the liver of T2DM mice increased significantly relative to the control group for both female and male mice. In T2DM, bile acid metabolism is disordered in both male and female mice, which could be the underlying mechanism of dysregulated lipid metabolism in T2DM.

Comparing Frequency of Cardiovascular Autonomic Neuropathy in Diabetic Cirrhotic with Non Diabetic Cirrhotic Patients

Cardiac autonomic neuropathy is most common secondary complication of diabetes mellitusis frequently undiagnosed and neglected complication even though it is an independent predictor of mortality and morbidity. This phenomenon can be further exacerbated with co-morbidities like cirrhosis. High prevalence of diabetes as well as cirrhosis has been reported in Pakistan. However, proper knowledge and information regarding incidence of diabetesin cirrhosis induced cardiovascular autonomic neuropathy in is lacking.So, its early detection and timely management is needed to prevent cirrhotic and diabetic cardiomyopathy. Our objective is to determine and compare the frequency of cardiovascular autonomic neuropathy in diabetic cirrhotic and non-diabetic cirrhotic patients. Methods:Cross sectional study was done on120 patients enrolled in Mufti Mehmood Memorial Teaching Hospital, Dera Ismail Khan. Two groups, diabetic cirrhotic and nondiabetic cirrhotic patients were taken.Those diabetic cirrhotic patients were selected, who had controlled glycemic levels due to proper medication, and patients of both groups had a definite diagnosis of cirrhosis liver. Cardiac autonomic neuropathy was determined in each patient using five standard tests. There after Bellavere,s scoring system was applied to assess the extent of cardiac autonomic dysfunction in each subject. Results: There were 33 males and 27 females in diabetic cirrhotic group and 31 males and 29 females in non-diabetic cirrhotic group. The mean age was 57.48 ± 10.80 years in diabetic cirrhotic patients whereas in the non-diabetic cirrhotic patients, mean age was 51.92 ± 14.21 years. In the diabetic cirrhotic group, 52 patients had parasympathetic tests derangement and 50 patients had sympathetic tests derangement. In non-diabetic cirrhotic 48 patients had parasympathetic tests derangement and 47 patients had sympathetic test derangement. After analysing the results of frequency of cardiovascular autonomic neuropathy, the comparison between the two groups reveal that there is no significant difference between the two groups. Conclusions:This study shows that cardiovascular autonomic neuropathy develops frequently in cirrhotic subjects, that it is found with comparable frequency in diabetics and non-diabetics, and that it increases in severity with increase in severity of liver damage, suggesting that liver damage contributes to the neurological deficit.

Image Segmentation based Deep Learning for Biliary Tree Diagnosis

Dilation of biliary tree can be an indicator of several diseases such as stones, tumors, benign strictures, and some cases cancer. This dilation can be due to many reasons such as gallstones, inflammation of the bile ducts, trauma, injury, severe liver damage. Automatic measurement of the biliary tree in magnetic resonance images (MRI) is helpful to assist hepatobiliary surgeons for minimally invasive surgery. In this paper, we proposed a model to segment biliary tree MRI images using a Fully Convolutional Neural (FCN) network. Based on the extracted area, seven features that include Entropy, standard deviation, RMS, kurtosis, skewness, Energy and maximum are computed. A database of images from King Hussein Medical Center (KHMC) is used in this work, containing 800 MRI images; 400 cases with normal biliary tree; and 400 images with dilated biliary tree labeled by surgeons. Once the features are extracted, four classifiers (Multi-Layer perceptron neural network, support vector machine, k-NN and decision tree) are applied to predict the status of patient in terms of biliary tree (normal or dilated). All classifiers show high accuracy in terms of Area Under Curve except support vector machine. The contributions of this work include introducing a fully convolutional network for biliary tree segmentation, additionally scientifically correlate the extracted features with the status of biliary tree (normal or dilated) that have not been previously investigated in the literature from MRI images for biliary tree status determinations.

Sub-acute exposure to nanoplastics via two-chain trophic transfer: From brine shrimp Artemia franciscana to small yellow croaker Larimichthys polyactis

This study investigated the trophic transfer of nanoplastics in marine food chains. We fed nanoplastic-exposed Artemia franciscana (brine shrimp) to Larimichthys polyactis (small yellow croaker) daily for eight days. Subsequently, the overall health condition, histopathological damage to the liver and digestive tract, and swimming ability of the fish were measured. After the sub-acute exposure to nanoplastics via trophic transfer, the fish showed inhibited growth, severe liver damage, as well as a poorer swimming ability compared to the control. The swimming ability was especially affected, in terms of the overall movement as well as thigmotaxis. The results thus clarified that even an indirect exposure to nanoplastics could induce neurotoxic effects and affect the swimming ability of the fish. As fish are well-known human food resources, the possibility of such trophic transfers affecting higher trophic level organisms, such as humans, cannot be ruled out.

Combination of molecular docking and liver transcription sequencing analysis for the evaluation of salt-processed psoraleae fructus-induced hepatotoxicity in ovariectomized mice

Ethnopharmacological relevanceSalt-processed Psoraleae fructus (SPF) is widely used as a phytoestrogen-like agent in the treatment of osteoporosis. However, SPF-associated hepatotoxicity is a known health hazard. Cholestasis is often associated with SPF-induced hepatotoxicity. Notably, clinical liver injury is a common side effect of SPF in the treatment of osteoporosis; however, the exact mechanism underlying this phenomenon is unclear.Aim of the study: To evaluate SPF-induced hepatotoxicity in an ovariectomized murine model of estrogen deficiency and examine the mechanisms underlying this process. Materials and methodsTo explore the molecular mechanism of SPF-induced cholestatic liver injury, different concentrations of SPF (5 and 10 g/kg) were intragastrically administered to ovariectomized and non-ovariectomized female ICR mice for 30 days. ResultsSPF-treated mice showed noticeably swollen hepatocytes, dilated bile ducts, and elevated levels of serum biochemical markers. Compared to ovariectomized mice, these changes were more prominent in non-ovariectomized mice. According to the sequence data, a total of 6689 mRNAs were identified. Compared with the control group, 1814 differentially expressed mRNAs were identified in the group treated with high SPF doses (SPHD), including 939 upregulated and 875 downregulated mRNAs. Molecular docking and Western blot experiments showed that liver injury was closely related to the estrogen levels. Compared with the negative control group, the expression levels of FXR, Mrp2, CYP7a1, BSEP, SULT1E1, HNF4a, and Nrf2 decreased in the estradiol-treated (E2), low-dose SPF-treated (SPLD), and SPHD groups. Interestingly, the expression levels of FXR, CYP7a1, SULT1E1, and HNF4α were significantly higher in the ovariectomized groups than in the non-ovariectomized groups (#P < 0.05; ###P < 0.001). ConclusionsOverall, this study demonstrates that SPF downregulates key enzymes involved in cholesterol and bile acid biosyntheses, posing a risk for cholestatic liver injury. SPF also regulates the FXR-SULT1E signaling pathway via HNF4α, which is an important causative factor of cholestasis. Moreover, the severity of liver damage was significantly lower in the ovariectomized groups than in the non-ovariectomized group. These results suggest that the estrogen level is the most critical factor determining liver injury.

Applying data mining techniques to classify patients with suspected hepatitis C virus infection

BackgroundHepatitis C virus (HCV) has a high prevalence worldwide, and the progression of the disease can cause irreversible damage to severe liver damage or even death. Therefore, developing prediction models using machine learning techniques is beneficial. This study was conducted to classify suspected patients with HCV infection using different classification models. MethodsThe study was conducted using a dataset derived from the University of California, Irvine (UCI) Machine Learning Repository. Since the HCV dataset was imbalanced, the synthetic minority oversampling technique (SMOTE) was applied to balance the dataset. After cleaning the dataset, it was divided into training and test data for developing six classification models. These six algorithms included the support vector machine (SVM), Gaussian Naïve Bayes (NB), decision tree (DT), random forest (RF), logistic regression (LR), and K-nearest neighbors (KNN) algorithm. The Python programming language was used to develop the classifiers. Receiver operating characteristic curve analysis and other metrics were used to evaluate the performance of the proposed models. ResultsAfter the evaluation of the models using different metrics, the RF classifier had the best performance among the six methods. The accuracy of the RF classifier was 97.29%. Accordingly, the area under the curve (AUC) for LR, KNN, DT, SVM, Gaussian NB, and RF models were 0.921, 0.963, 0.953, 0.972, 0.896, and 0.998, respectively, RF showing the best predictive performance. ConclusionVarious machine learning techniques for classifying healthy and unhealthy patients were used in this study. Additionally, the developed models might identify the stage of HCV based on trained data.

Возможности и перспективы применения клеточных технологий при острой печеночной недостаточности в эксперименте

The article provides information on the relevance of the problem of treating acute liver failure.The main etiological factors and the general concept of pathogenesis are reflected according to the modernachievements of hepatology. An imbalance in the immune system is considered as one of the main links inthe pathogenesis of acute liver failure. At the same time, cell therapy is presented as a promising directionin the treatment of severe acute liver damage. The article specifies the possibilities of using hepatocytetransplantation in liver failure.

FREQUENCY OF RISK FACTORS FOR DEVELOPMENT OF METABOLIC FATTY LIVER DISEASE (MAFLD) IN A CENTER OF CONCENTRATION OF LIVER DISEASES

Metabolic fatty liver disease (MAFLD) includes a wide spectrum of presentations, ranging from simple steatosis and non-alcoholic steatohepatitis to liver cirrhosis, leading to hepatocellular carcinoma; the etiology of this is multifactorial, with few studies on risk factors in the Mexican population. Determine the frequency of risk factors in patients with MAFLD in a liver disease center: CEIHET, Mexico. Material and methods: An observational, cross-sectional and retrospective study selected 587 records from the CEIHET, Hidalgo, of patients with a diagnosis of MAFLD, from January 2017 to May 2020. Determine the frequency of risk factors. Statistical analysis was performed through measures of central tendency, dispersion and correlation. 587 files were analyzed, 56% (n = 329) women; mean age of 51.4 years. The group with simple steatosis had a mean age of 38 years, while in advanced liver cirrhosis, it was 63 years (p 0.005). In schooling, basic education was found for liver cirrhosis in 73.12% (n = 215), and, in previous stages, it was 21.84% (n = 64). In the AHF and APP, type 2 diabetes is shown as the main risk factor with 65.92% (n = 387) and 58.77% (n = 345), respectively; 6 out of 10 patients had two or more risk factors. 77.3% (n = 454) of patients did not meet the standards of adequate physical activity. Regarding BMI, 73% of patients with simple steatosis were overweight or obese, while, with liver cirrhosis, it was present in 98% without ascites or edema. A prevalence of fatty liver disease of 55.75% was found, being the main reason for liver Disease consultation, constituting the major cause of liver damage in females. The age of patients increases in direct proportion to the severity of liver damage. Of relevance is education, showing RR of 9.2 (p = 0.001), which indicates that the lower the level of education, a later detection is carried out. 77.3% of these patients did not comply with the physical activity standards established by the WHO. When studying the BMI, we noticed the presence of overweight/obesity in at least 88% of the population, correlating with that established in studies in the USA, where the Latino population has the highest BMI and in the highest frequency. The present study shows that sedentary lifestyle, overweight, obesity and type 2 diabetes are the main determining factors for the presence of MAFLD in the Mexican population, and therefore the importance of its detection and management, to prevent its progression and improve the quality of life of patients. The authors declare that there is no conflict of interest.

Elucidation of the hepatoprotective effect and mechanism of Melastoma dodecandrum Lour. based on network pharmacology and experimental validation

To systematically explore the effect and mechanism of melastomatis dodecandri herba ( Melastoma dodecandrum Lour.) in the treatment of hepatitis based on network pharmacology. We evaluated the hepatoprotective effects of M. dodecandrum in concanavalin A (Con A)-induced hepatitis in mice by assessing survival rate, histological analysis, serum transaminases, and related cytokines. Then the mechanism of action was predicted by a network pharmacology-based strategy. Based on the results, we measured the hepatic expression of related genes at mRNA level and proteins related to the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) and nuclear factor-kappa B (NF-кB) pathways. Our study results clearly demonstrated that M. dodecandrum pretreatment significantly alleviated liver injury. This was demonstrated by an increase in survival rate, decreased severity of liver damage, and reduced serum transaminase levels compared with those in the Con A group. Moreover, M. dodecandrum significantly reduced the serum levels of tumor necrosis factor-α, interleukin-6, and interferon-γ and increased the liver levels of superoxide dismutase, which indicated that M. dodecandrum exhibits anti-inflammatory and antioxidant activities. On the basis of network pharmacology, 50 nodes were selected as major hubs based on their topological importance. Pathway enrichment analyses indicated that the putative targets of M. dodecandrum mostly participate in various pathways associated with the anti-inflammation response, which implies the underlying mechanism by which M. dodecandrum acts on hepatitis. Real-time fluorescent quantitative PCR analysis showed that M. dodecandrum downregulates the mRNA expression of interleukin-6, Toll-like receptor 7, interleukin-1 receptor-associated kinase-4, NF-кB and tumor necrosis factor-α in liver tissues. Western blotting showed that M. dodecandrum pretreatment protected against inflammation through activating the PI3K-Akt pathway by upregulating phosphorylated Akt (p-Akt) expression and suppressing NF-кB activation by inhibiting the phosphorylation of IKK, IκBα, and p65. The present work demonstrated the hepatoprotective effects of M. dodecandrum by regulating the PI3K/Akt and NF-кB pathways in Con A-induced mice, which provide insights into the treatment of hepatitis using M. dodecandrum .

AGK regulates the progression to NASH by affecting mitochondria complex I function

Background: Impaired mitochondrial function contributes to non-alcoholic steatohepatitis (NASH). Acylglycerol kinase (AGK) is a subunit of the translocase of the mitochondrial inner membrane 22 (TIM22) protein import complex. AGK mutation is the leading cause of Sengers syndrome, characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, lactic acidosis, and liver dysfunction. The potential roles and mechanisms of AGK in NASH are not yet elucidated.Methods: Hepatic-specific AGK-deficient mice and AGK G126E mutation (AGK kinase activity arrest) mice were on a choline-deficient and high-fat diet (CDAHFD) and a methionine choline-deficient diet (MCD). The mitochondrial function and the molecular mechanisms underlying AGK were investigated in the pathogenesis of NASH.Results: The levels of AGK were significantly downregulated in human NASH liver samples. AGK deficiency led to severe liver damage and lipid accumulation in mice. Aged mice lacking hepatocyte AGK spontaneously developed NASH. AGK G126E mutation did not affect the structure and function of hepatocytes. AGK deficiency, but not AGK G126E mice, aggravated CDAHFD- and MCD-induced NASH symptoms. AGK deficiency-induced liver damage could be attributed to hepatic mitochondrial dysfunction. The mechanism revealed that AGK interacts with mitochondrial respiratory chain complex I subunits, NDUFS2 and NDUFA10, and regulates mitochondrial fatty acid metabolism. Moreover, the AGK DGK domain might directly interact with NDUFS2 and NDUFA10 to maintain the hepatic mitochondrial respiratory chain complex I function.Conclusions: The current study revealed the critical roles of AGK in NASH. AGK interacts with mitochondrial respiratory chain complex I to maintain mitochondrial integrity via the kinase-independent pathway.

The difference of chows affects mouse physiological conditions.

Acetaminophen-induced liver injury in mice is a model system of human acetaminophen overdose and oxidative stress in vivo. The system is technically established, and we usually obtain severe liver damage in the treated mice; however, it is possible that the degree of liver damage is affected by the type of chow fed to mice. Thus, in this experiment, we investigated the effect of different chows on mice by comparing acetaminophen-induced liver damage, liver antioxidant level, and serum amino-acid concentrations. The results showed that differences in chows, even standard ones, affected mouse physiological conditions, with the response to oxidative stress greatly affected.

METTL3 inhibition ameliorates liver damage in mouse with hepatitis B virus-associated acute-on-chronic liver failure by regulating miR-146a-5p maturation

Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (ACLF) is a clinical syndrome of severe liver damage. HBV infection is affected by N6-methyladenosine (m6A) RNA modification. Here, we investigated whether methyltransferase-like 3 (METTL3)-mediated m6A methylation can affect ACLF. Human hepatic cells (THLE-2) were treated with lipopolysaccharide (LPS) to induce cell damage. Proliferation, apoptosis and m6A modification were measured by MTT assay, flow cytometry and Dot blot assay. Our results showed that HBV infection significantly enhanced the levels of m6A modification and elevated the expression of METTL3 and mature-miR-146a-5p in THLE-2 cells, which was repressed by cycloleucine (m6A inhibitor). METTL3 overexpression enhanced m6A modification and promoted mature-miR-146a-5p expression. METTL3 overexpression promoted HBV replication and apoptosis, enhanced the levels of pro-inflammatory cytokines, hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg), and repressed cell proliferation in THLE-2 cells, which attributed to repress miR-146a-5p maturation. Moreover, a severe liver failure mouse model was established by HBV infection to verify the impact of METTL3 knockdown on liver damage in vivo. HBV-infection led to a severe liver damage and increase of apoptosis in hepatic tissues of mice, which was abolished by METTL3 knockdown. METTL3 knockdown reduced METTL3 expression and impeded miR-146a-5p maturation in HBV-infected mice. In conclusion, this work demonstrates that METTL3 inhibition ameliorates liver damage in mouse with HBV-associated ACLF, which contributes to repress miR-146a-5p maturation. Thus, this article suggests a novel therapeutic avenue to prevent and treat HBV-associated ACLF.

Percutaneous biliary stent combined with brachytherapy using 125I seeds for treatment of unresectable malignant obstructive jaundice: A meta-analysis.

BACKGROUNDMalignant obstructive jaundice (MOJ) is a common pathologic manifestation of malignant biliary obstruction. Recently, several clinical trials have explored the clinical effectiveness of intraluminal 125I seed-based brachytherapy for MOJ patients, and various outcomes have been reported.AIMTo assess the efficacy and safety of percutaneous biliary stents with 125I seeds compared to conventional metal stents in patients with unresectable MOJ.METHODSA systematic search of English-language databases (PubMed, Embase, Cochrane Library, and Web of Science) was performed to identify studies published prior to June 2020 that compared stents with or without 125I seeds in the treatment of unresectable MOJ. The outcomes analyzed included primary outcomes (stent patency and overall survival) and secondary outcomes (complications and liver function parameters).RESULTSSix randomized controlled trials and four retrospective studies involving 875 patients were eligible for the analysis. Of the 875 included patients, 404 were treated with 125I seed stents, while 471 were treated with conventional stents. Unadjusted pooled analysis demonstrated that compared to conventional stents, 125I seed stents extended the stent patency time [hazard ratio (HR) = 0.36, 95% confidence interval (CI) = 0.28-0.45, P < 0.0001] and overall survival period (HR = 0.52, 95%CI = 0.42–0.64, P < 0.00001). Subgroup analyses based on the type of 125I seed stent and type of study design showed consistent results. However, there were no significant differences in the occurrence of total complications [odds ratio (OR) = 1.12, 95%CI = 0.75-1.67, P = 0.57], hemobilia (OR = 1.02, 95%CI = 0.45-2.3, P = 0.96), pancreatitis (OR = 1.79, 95%CI = 0.42-7.53, P = 0.43), cholangitis (OR = 1.13, 95%CI = 0.60-2.13, P = 0.71), or pain (OR = 0.67, 95%CI = 0.22-2, P = 0.47). In addition, there were no reductions in the levels of serum indices, including total bilirubin [mean difference (MD) = 10.96, 95%CI = -3.56-25.49, P = 0.14], direct bilirubin (MD = 7.37, 95%CI = -9.76-24.5, P = 0.4), alanine aminotransferase (MD = 7.52, 95%CI = -0.71-15.74, P = 0.07), and aspartate aminotransferase (MD = -4.77, 95%CI = -19.98-10.44, P = 0.54), after treatment. Publication bias was detected regarding the outcome overall survival; however, the conclusions were not changed after the adjustment.CONCLUSIONPlacement of stents combined with brachytherapy using 125I seeds contributes to a longer stent patency and higher overall survival than placement of conventional stents without extra complications or severe liver damage. Thus, it can be considered an effective and safe treatment for unresectable MOJ.

Organic Cation Transporter I and Na+ /taurocholate Co-Transporting Polypeptide are Involved in Retrorsine- and Senecionine-Induced Hepatotoxicity in HepaRG cells.

1,2-unsaturated pyrrolizidine alkaloids (PAs) are secondary plant metabolites that are found in many plant species throughout the world. They are of concern for risk assessment as consumption of contaminated foodstuff can cause severe liver damage. Of late, transporter-mediated uptake and transport has advanced as a vital determinant of PA toxicity. In this study, the authors investigate a transporter-mediated uptake of PAs and its implications in PA toxicity. We show that transporter expression levels are significantly affected by treatment with the PAs senecionine (Sc) and retrorsine (Re) in the human hepatoma cell line HepaRG. Furthermore, the specific contribution to PA uptake of the two transporters Na+ /taurocholate co-transporting polypeptide (SLC10A1) and organic cation transporter I (SLC22A1), both belonging to the heterogeneous solute carrier super family, is investigated by means of a siRNA-mediated knockdown approach. Knockdown of both uptake transporters result in reduced uptake of Re and Sc in a time-dependent manner and attenuated PA-mediated cytotoxic effects in HepaRG cells. Our results confirm previous findings of active transport mechanisms of PAs into hepatocytes and highlight the importance of toxicokinetic studies for the risk assessment of PAs.

Inducible T-Cell Costimulator Mediates Lymphocyte/Macrophage Interactions During Liver Repair.

The liver capacity to recover from acute liver injury is a critical factor in the development of acute liver failure (ALF) caused by viral infections, ischemia/reperfusion or drug toxicity. Liver healing requires the switching of pro-inflammatory monocyte-derived macrophages(MoMFs) to a reparative phenotype. However, the mechanisms involved are still incompletely characterized. In this study we investigated the contribution of T-lymphocyte/macrophage interaction through the co-stimulatory molecule Inducible T-cell co-stimulator (ICOS; CD278) and its ligand (ICOSL; CD275) in modulating liver repair. The role of ICOS/ICOSL dyad was investigated during the recovery from acute liver damage induced by a single dose of carbon tetrachloride (CCl4). Flow cytometry of non-parenchymal liver cells obtained from CCl4-treated wild-type mice revealed that the recovery from acute liver injury associated with a specific up-regulation of ICOS in CD8+ T-lymphocytes and with an increase in ICOSL expression involving CD11bhigh/F4-80+ hepatic MoMFs. Although ICOS deficiency did not influence the severity of liver damage and the evolution of inflammation, CCl4-treated ICOS knockout (ICOS-/- ) mice showed delayed clearance of liver necrosis and increased mortality. These animals were also characterized by a significant reduction of hepatic reparative MoMFs due to an increased rate of cell apoptosis. An impaired liver healing and loss of reparative MoMFs was similarly evident in ICOSL-deficient mice or following CD8+ T-cells ablation in wild-type mice. The loss of reparative MoMFs was prevented by supplementing CCl4-treated ICOS-/- mice with recombinant ICOS (ICOS-Fc) which also stimulated full recovery from liver injury. These data demonstrated that CD8+ T-lymphocytes play a key role in supporting the survival of reparative MoMFs during liver healing trough ICOS/ICOSL-mediated signaling. These observations open the possibility of targeting ICOS/ICOSL dyad as a novel tool for promoting efficient healing following acute liver injury.

Loss of hepatic miR-194 promotes liver regeneration and protects from acetaminophen-induced acute liver injury

The two microRNAs miR-192 and miR-194 are abundantly expressed in the liver and are considered serum biomarkers of liver injury. However, their role in the development of liver injury has not yet been determined. In this study, we generated miR-192/194 mutant mice and determined the effect of miR-192/194 loss on acetaminophen (APAP)-induced acute liver injury. With genetic depletion of miR-192/194, mutant mice were fertile and normally developed. No spontaneous liver injuries were observed in mutant mice. After APAP administration, mutant mice developed less severe liver damage than control mice. Specifically, mutant mice exhibited significantly lower serum alanine transaminase (ALT) levels and pericentral necrosis/apoptosis than control mice receiving APAP. β-catenin signaling was activated during the early phase of liver injury. Activated β-catenin signaling led to faster cellular proliferation and higher expression of AXIN2 and glutamine synthetases. After partial hepatectomy, the miR-192/194 mutant hepatocytes were more regenerative than control hepatocytes (as shown by BrdU incorporation). Moreover, in vitro experiments indicated that miR-194, but not miR-192, specifically repressed β-catenin signaling, while animal experiments revealed that chemical-mediated knockdown of β-catenin signaling compromised APAP resistance that liver protected from miR-192/194 genetic depletion. Collectively, our data indicated that the loss of miR-194 promoted liver regeneration and protected the liver from APAP-induced injury.

Effects of alcohol consumption on viral hepatitis B and C.

The liver is the main target organ for hepatitis viruses and the vital organ for alcohol metabolism. These two factors of viral hepatitis and alcohol abuse in combination can exert dual harmful actions, leading to enhanced damage to the liver. Epidemiological studies have revealed a higher prevalence of hepatitis C virus (HCV) infection among alcoholics than the general population. The interaction of alcohol with viral hepatitis [e.g., hepatitis B virus (HBV), HCV] and the underlying mechanisms are not fully understood. The effects of alcohol on viral hepatitis include promoted viral replication, weakened immune response, and increased oxidative stress. Clinically, alcohol abuse is correlated with an increased risk of developing end-stage liver cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B and C, suggesting that the combination of alcohol and HBV/HCV lead to more severe liver damage. The influence of mild to moderate alcohol drinking on the HBV-induced liver fibrosis, cirrhosis, and hepatocellular carcinoma among patients infected with HBV remains unclear. Unlike HBV infected patients, no safe level of alcohol intake has been established for patients with HCV. Even light to moderate alcohol use can exert a synergistic effect with viral hepatitis, leading to the rapid progression of liver disease. Furthermore, interferon-based therapy is less effective in alcohol drinkers than in control patients, even after abstinence from alcohol for a period of time. Therefore, abstaining from alcohol is highly recommended to protect the liver, especially in individuals with HBV/HCV infection, to improve the clinical efficacy of antiviral treatment and prevent the rapid progression of chronic viral hepatitis.