Activation Of Hepatic Cells Research Articles

Bromelain ameliorates D-galactosamine-induced acute liver injury: role of SIRT1/LKB1/AMPK, GSK3β/Nrf2 and NF-κB p65/TNF-α/caspase-8, -9 signalling pathways.

The present research focused on estimating, for the first time, the potential protective effects of bromelain against D-galactosamine-induced acute liver injury in rats as well as identifying the possible underlying mechanisms. Silymarin (100 mg/kg/day, p.o.) as a reference drug or bromelain (20 and 40 mg/kg/day, p.o.) were administered for 10 days, and on the 8th day of the experiment, a single dose of galactosamine (400 mg/kg/i.p.) induced acute liver injury. Pretreatment with bromelain improved liver functions and histopathological alterations induced by galactosamine. Bromelain ameliorated oxidative stress by inducing SIRT1 protein expression and increasing LKB1 content. This resulted in phosphorylating the AMPK/GSK3β axis, which stimulated Nrf2 activation in hepatic cells and thus increased the activity of its downstream antioxidant enzymes [HO-1 and NQO1]. Besides, bromelain exerted significant anti-apoptotic and anti-inflammatory effects by suppressing hepatic contents of TNF-α, NF-κB p65, as well as caspase-8 and caspase-9. The protective effects of bromelain40 were proved to be better than silymarin and bromelain20 in most of the assessed parameters. Our results highlight the significant hepatoprotective effects of bromelain against acute liver injury through modulation of SIRT1/LKB1/AMPK, GSK3β/Nrf2 signalling in addition to NF-κB p65/TNF-α/ caspase-8 and -9 pathway.

The Lipid-Modulating Effect of Tangeretin on the Inhibition of Angiopoietin-like 3 (ANGPTL3) Gene Expression through Regulation of LXRα Activation in Hepatic Cells.

The excessive accumulation of TG-rich lipoproteins (TGRLs) in plasma is associated with dyslipidemia and atherosclerotic cardiovascular diseases (ASCVDs). Tangeretin is a bioactive pentamethoxyflavone mainly found in citrus peels, and it has been reported to protect against hyperlipidemia, diabetes, and obesity. The aim of this study was to investigate the lipid-modulating effects and the underlying mechanisms of tangeretin action in hepatic cells. Transcriptome and bioinformatics analyses with the Gene Ontology (GO) database showed that tangeretin significantly regulated a set of 13 differentially expressed genes (DEGs) associated with the regulation of lipoprotein lipase (LPL) activity. Among these DEGs, angiopoietin-like 3 (ANGPTL3), an essential inhibitor of LPL catalytic activity that regulates TGRL metabolism in plasma, was markedly downregulated by tangeretin. We demonstrated that tangeretin significantly inhibited the mRNA expression of ANGPTL3 in HepG2 and Huh-7 cells. Tangeretin treatment of hepatic cells also reduced the levels of both intracellular and secreted ANGPTL3 proteins. Moreover, we found that inhibition of ANGPTL3 production by tangeretin augmented LPL activity. We further demonstrated that the transcriptional activity of the ANGPTL3 promoter was significantly attenuated by tangeretin, and we identified a DNA element located between the −250 and −121 positions that responded to tangeretin. Furthermore, we found that tangeretin did not alter the levels of the nuclear liver X receptor α (LXRα) protein, an essential transcription factor that binds to the tangeretin-responsive element, but it can counteract LXRα-mediated ANGPTL3 transcription. On the basis of molecular docking analysis, tangeretin was predicted to bind to the ligand-binding domain of LXRα, which would result in suppression of LXRα activation. Our findings support the hypothesis that tangeretin exerts a lipid-lowering effect by modulating the LXRα-ANGPTL3-LPL pathway, and thus, it can be used as a potential phytochemical for the prevention or treatment of dyslipidemia.

Valproic acid influences the expression of genes implicated with hyperglycaemia-induced complement and coagulation pathways

Because the liver plays a major role in metabolic homeostasis and secretion of clotting factors and inflammatory innate immune proteins, there is interest in understanding the mechanisms of hepatic cell activation under hyperglycaemia and whether this can be attenuated pharmacologically. We have previously shown that hyperglycaemia stimulates major changes in chromatin organization and metabolism in hepatocytes, and that the histone deacetylase inhibitor valproic acid (VPA) is able to reverse some of these metabolic changes. In this study, we have used RNA-sequencing (RNA-seq) to investigate how VPA influences gene expression in hepatocytes. Interesting, we observed that VPA attenuates hyperglycaemia-induced activation of complement and coagulation cascade genes. We also observe that many of the gene activation events coincide with changes to histone acetylation at the promoter of these genes indicating that epigenetic regulation is involved in VPA action.

Tigecycline Interferes with Fibrinogen Polymerization Independent of Peripheral Interactions with the Coagulation System.

Tigecycline offers broad anti-bacterial coverage for critically ill patients with complicated infections. A described but less researched side effect is coagulopathy. The aim of this study was to test whether tigecycline interferes with fibrinogen polymerization by peripheral interactions. To study the effect of unmetabolized tigecycline, plasma of healthy volunteers were spiked with increasing concentrations of tigecycline. In a second experimental leg, immortalized human liver cells (HepG2) were treated with the same concentrations to test an inhibitory effect of hepatic tigecycline metabolites. Using standard coagulation tests, only the activated thromboplastin time in humane plasma was prolonged with increasing concentrations of tigecycline. Visualization of the fibrin network using confocal live microscopy demonstrated a qualitative difference in tigecycline treated experiments. Thrombelastometry and standard coagulation tests did not indicate an impairment of coagulation. Although the discrepancy between functional and immunologic fibrinogen levels increased in cell culture assays with tigecycline concentration, fibrinogen levels in spiked plasma samples did not show significant differences determined by functional versus immunologic methods. In our in vitro study, we excluded a direct effect of tigecycline in increasing concentrations on blood coagulation in healthy adults. Furthermore, we demonstrated a rapid loss of mitochondrial activity in hepatic cells with supra-therapeutic tigecycline dosages.

Collagen modulates functional activity of hepatic cells inside alginate-galactosylated chitosan hydrogel microcapsules

To provide comparable hepatic tissue microenvironment and induce functional behavior for hepatocytes, galctosylated-chitosan (GC) as well as collagen (Col) was added to alginate microcapsule coated with extra layer of chitosan. Four different hydrogel groups of alginate/chitosan (AC); alginate-galactosylated chitosan/chitosan (AGC/C); alginate-collagen/chitosan (ACol/C); and alginate-galactosylated chitosan-collagen/chitosan (AGCCol/C) were prepared and characterized for physical properties such as porosity, swelling, degradation rate, and stiffness. Introduction of GC as well as Col to alginate regulated significantly the physical properties of the resultant hydrogels. GC addition decreased dramatically swelling, degradation, pore size and mechanical properties of the resultant hydrogel. However, the influence of GC on the physical properties in the presence of Col (AGCCol/A) was in a reverse manner, as compared to the AGC/C hydrogel. The AGCCol/C microenvironment also promoted proliferation of microencapsulated HepG2 cells, as a model of hepatocyte, compared to the control-matched groups. Biochemical analysis after 10 days revealed a superior effect of AGCCol/C on the secretion of albumin and urea compared to other groups (P < 0.05). These features were coincided with the mRNA up-regulation of P450 and albumin in the AGCCol/C groups compared to the AGC/C and ACol/C groups (P < 0.05). The study demonstrated that enrichment of alginate-based hydrogels with Col and GC could be touted as an appropriate 3D platform for modular hepatic tissue engineering.

Fungal NOX is an essential factor for induction of TG2 in human hepatocytes.

NADPH oxidases (Nox) generate reactive oxygen species (ROS) such as superoxide anion radical (O2-) and hydrogen peroxide (H2O2). The pathogenic fungi Candida albicans and Candida glabrata enhance cellular transglutaminase 2 (TG2) activity levels in co-cultured human hepatic cells in a ROS-mediated manner. Deletion of NOX1 (CgNOX1) in C. glabrata blocks the ability of C. glabrata to induce TG2 activity. Here, we investigated whether Nox proteins from C. albicans and Saccharomyces cerevisiae are related with induction of TG2 activity in hepatic cells. C. albicans CFL11 (CaCFL11) was identified as a key factor in this fungus for hepatic TG2 induction in the co-cultures. The cfl11 mutant of C. albicans did not induce TG2 activity in hepatocytes. In addition, overexpression of YNO1, a homolog of CgNOX1, in S. cerevisiae led to induction of ROS generation and TG2 activity in hepatic cells in co-incubation experiments. These findings indicated that a fungal Nox plays a role in enhancing TG2 activity in human hepatocytes and leads to apoptosis.

Novel nanostructured iron oxide cryogels for arsenic (As(III)) removal

Novel macroporous iron oxide nanocomposite cryogels were synthesized and assessed as arsenite (As(III)) adsorbents. The two-step synthesis method, by which a porous nanonetwork of iron oxide is firstly formed, allowed a homogeneous dispersion of the iron oxide in the cryogel reaction mixture, regardless of the nature of the co-polymer forming the cryogel structure. The cryogels showed excellent mechanical properties, especially the acrylamide-based cryogel. This gel showed the highest As(III) adsorption capacity, with the maximum value estimated at 118 mg/g using the Langmuir model. The immobilization of the nanostructured iron oxide gel into the cryogel matrix resulted in slower adsorption kinetics, however the cryogels offer the advantage of a stable three-dimensional structure that impedes the release of the iron oxide nanoparticles into the treated effluent. A preliminary toxicity evaluation of the cryogels did not indicate any apparent inhibition of human hepatic cells activity, which together with their mechanical stability and high adsorption capacity for As(III) make them excellent materials for the development of nanoparticle based adsorption devices for drinking water treatment.

Biphasic modulation of cAMP levels by the contraceptive nomegestrol acetate. Impact on P-glycoprotein expression and activity in hepatic cells

ABC transporters are key players in drug excretion with alterations in their expression and activity by therapeutic agents potentially leading to drug-drug interactions. The interaction potential of nomegestrol acetate (NMGA), a synthetic progestogen increasingly used as oral contraceptive, had never been explored. In this work we evaluated (1) the effect of NMGA on ABC transporters in the human hepatic cell line HepG2 and (2) the underlying molecular mechanism. NMGA (5, 50 and 500 nM) increased P-glycoprotein (P-gp) expression at both protein and mRNA levels and reduced intracellular calcein accumulation, indicating an increase also in transporter activity. This up-regulation of P-gp was corroborated in Huh7 cells and was independent of the classical progesterone receptor. Instead, using a siRNA-mediated silencing approach, we demonstrated the involvement of membrane progesterone receptor α. Moreover, we found that the activation of this receptor by NMGA led to a falling-rising profile in intracellular cAMP levels and protein kinase A activity over time, ultimately leading to transcriptional P-gp up-regulation. Finally, we identified inhibitory G protein and phosphodiesterases as mediators of this novel biphasic modulation. These results demonstrate the ability of NMGA to selectively up-regulate hepatic P-gp expression and activity and constitute the first report of ABC transporter modulation by membrane progesterone receptor α. If a similar regulation took place in vivo, decreased bioavailability and therapeutic efficacy of NMGA-coadministered P-gp substrates could be expected. This holds special importance considering long-term administration of NMGA and broad substrate specificity of P-gp.

Synthetic Polymer with a Structure-Driven Hepatic Deposition and Curative Pharmacological Activity in Hepatic Cells

Synthetic polymers make strong contributions as tools for delivery of biological drugs and chemotherapeutics. The most praised characteristic of polymers in these applications is complete lack of pharmacological function such as to minimize the side effects within the human body. In contrast, synthetic polymers with curative pharmacological activity are truly rare. Moreover, such activity is typically nonspecific rather than structure-defined. In this work, we present the discovery of poly(ethylacrylic acid) (PEAA) as a polymer with a suit of structure-defined, unexpected, pharmacological, and pharmacokinetic properties not observed in close structural analogues. Specifically, PEAA reveals capacity to bind to albumin with ensuing natural hepatic deposition in vivo and exhibits concurrent inhibitory activity against the hepatitis C virus and inflammation in hepatic cells. Our findings provide a view on synthetic polymers as curative, functional agents and present PEAA as a unique biomedical tool with applications related to health of the human liver.

Regulation of the human lipoprotein lipase gene by the forkhead box transcription factor FOXA2/HNF-3β in hepatic cells

Lipoprotein lipase (LPL) plays a major role in the hydrolysis of triglycerides (TG) from circulating TG-rich lipoproteins. The role of LPL in the liver has been controversial but recent studies in mice with liver LPL overexpression or deficiency have revealed important new roles of the enzyme in glucose and lipid metabolism. The objective of this study was to identify regulatory elements and factors that control the transcription of the human LPL gene in hepatocytes. Deletion analysis of the human LPL promoter revealed that the proximal region which harbors a binding site for the forkhead box transcription factor FOXA2/HNF-3β at position −47/−40 is important for its hepatic cell activity. Silencing of FOXA2 in HepG2 cells reduced the LPL mRNA and protein levels. Direct binding of FOXA2 to the novel binding site was established in vitro and ex vivo. Mutagenesis of the FOXA2 site reduced the basal activity and abolished the FOXA2-mediated transactivation of the LPL promoter. Ιnsulin decreased LPL mRNA levels in HepG2 cells and this was associated with phosphorylation of AKT and nuclear export of FOXA2. In summary, the data of the present study combined with previous findings on the role of FOXA2 in HDL metabolism and gluconeogenesis, suggest that FOXA2 is a key regulator of lipid and glucose homeostasis in the adult liver. Understanding the mechanisms by which FOXA2 exerts its functions in hepatocytes may open the way to novel therapeutic strategies for patients with metabolic diseases such as dyslipidemia, diabetes and the metabolic syndrome.

Clinicopathological characteristics and prognostic factors analysis of combined hepatocellular-cholangiocarcinoma

Objective To analyze the clinicopathological characteristics and prognostic factors of combined hepatocellular-cholangiocarcinoma (cHCC-CC). Methods The retrospective cohort study was conducted. The clinicopathological data of 72 patients with primary hepatocellular carcinoma (HCC) who were admitted to the Xiangya Hospital of Central South University between January 2005 and December 2014 were collected. Thirty-two patients who were diagnosed with cHCC-CC by postoperative pathological examination were allocated into the cHCC-CC group and 40 patients who were diagnosed with HCC by postoperative pathological examination were allocated into the HCC group. Observation indicators: (1) clinicopathological characteristics: male, age>60 years, positive hepatitis B surface antigen (HBsAg), positive alpha-fetoprotein (AFP), positive CA19-9, positive carcinoembryonic antigen (CEA), liver cirrhosis, Child-Pugh grade A, tumor diameter>5 cm, tumor with capsule, solitary tumor, portal vein tumor thrombus (PVTT), cancer thrombus of the bile duct, positive lymph node metastasis, stage Ⅰ-Ⅱ of TNM stage, Edmondson-Steiner stageⅠ-Ⅱ; (2) pathological features of surgical incision specimens; (3) follow-up situations: median survival time, 1-, 3-, 5-year survival rates and tumor-free survival rate; (4) prognostic factors analysis of patients with cHCC-CC: AFP, CA19-9, liver cirrhosis, tumor diameter, tumor capsule, number of tumor, PVTT, cancer thrombus of the bile duct, lymph node metastasis, Edmondson-Steiner stage, volume of intraoperative blood loss, intraoperative blood transfusion, distant from surgical margin. Follow-up using outpatient examination and telephone interview was performed to detect survival of patients and tumor recurrence or metastasis up to October 2015. Comparison of count data was analyzed using the chi-square test. The survival curve was drawn by the Kaplan-Meier method, and the survival analysis was done using the Log-rank test. The prognostic analysis was done using the COX regression model. Results (1) Clinicopathological characteristics: positive CA19-9, tumor with capsule, cancer thrombus of the bile duct and positive lymph node metastasis were detected in 16, 4, 12, 6 patients in the cHCC-CC group and 5, 17, 1, 1 patients in the HCC group, respectively, with statistically significant differences between the 2 groups (χ2=10.471, 9.723, 13.005, 4.009, P<0.05). (2) Pathological features of surgical incision specimens: pathological results showed that surgical incision specimens in the cHCC-CC group had characteristics of HCC tissues and cholangiocarcinoma tissues. The antigenic activity of hepatic cells in paraffin sections, Cytokeratin 7, Cytokeratin 19 and progenitor cell markers were positive by immunohistochemical staining detection. Patients in the HCC group had characteristics of HCC tissues, with positive AFP using immunohistochemical staining detection. (3) Follow-up situations: all the 72 patients were followed up for 5.0-74.0 months with a median time of 41.0 months. The median survival time, 1-, 3-, 5-year survival rates, 1-, 3-, 5-year tumor-free survival rates were 14.5 months, 62.3%, 38.9%, 19.1%, 50.0%, 23.9%, 4.0% in the cHCC-CC group and 46.8 months, 82.3%, 57.4%, 38.6%, 72.9%, 35.6%, 17.6% in the HCC group, respectively, with statistically significant differences in overall survival and tumor-free survival between the 2 groups (χ2=4.231, 3.881, P<0.05). (4) Prognostic factors analysis of patients with cHCC-CC: results of univariate analysis showed that CA19-9, tumor capsule, number of tumor, cancer thrombus of the bile duct, lymph node metastasis and Edmondson-Steiner stage were related factors affecting prognosis of patients with cHCC-CC [HR=1.824, 0.227, 0.441, 1.421, 1.887, 2.745, 95% confidence interval (CI): 1.126-2.172, 0.118-0.654, 0.318- 0.764, 1.071-4.231, 1.017-5.643, 1.223-6.421, P<0.05]. Results of multivariate analysis showed that lymph node metastasis and stage Ⅲ-Ⅳ of Edmondson-Steiner stage were independent risk factors affecting prognosis of patients with cHCC-CC (RR=1.658, 2.912, 95% CI: 1.027-7.542, 1.143 - 6.582, P<0.05). Conclusions The positive CA19-9, tumor without capsule, cancer thrombus of the bile duct and positive lymph node metastasis can partly predict cHCC-CC. The prognosis of patients with cHCC-CC is worse than that with HCC. The positive lymph node metastasis and stage Ⅲ-Ⅳof Edmondson-Steiner stage are independent risk factors affecting prognosis of patients with cHCC-CC. Key words: Hepatic neoplasms; Biliary neoplasms; Mixed type; Hepatectomy; Prognosis

The flavone apigenin blocks SREBP-2 activation in hepatic cells

The flavone apigenin blocks SREBP-2 activation in hepatic cells

Establishment of a hepatocyte steatosis model using Chang liver cells

The objective of this study was to explore the experimental conditions for hepatocellular steatosis models of Chang liver cells induced by oleic acid (OA). For that, Chang liver cells were induced by different concentrations of OA for different periods. The MTT assay was used to detect hepatic cell activity, the Oil Red O staining was used to observe intracellular lipid droplets accumulation, and the glycerol phosphate oxidase method was used to detect the triglyceride (TG) content in the Chang liver cell. The hepatocellular steatosis models of Chang liver cell were established successfully by inducing with 0.2 mM OA for 24h. TG content in model cells was 379.98 ± 23.19 mg/g, which is significantly different from control cells (185.03 ± 12.68 mg/g; P < 0.01). These were considered proper conditions for establishing hepatocellular steatosis models of Chang liver cells, producing a reliable model for nonalcoholic fatty liver disease research.

Protective effects against and potential mechanisms underlying the effect of magnesium isoglycyrrhizinate in hypoxia-reoxygenation injury in rat liver cells.

We examined the protective effects of magnesium isoglycyrrhizinate (MgIG) on hypoxia-reoxygenation injury in rat liver cells. Rat liver cells in the logarithmic growth phase were divided into the hypoxia-reoxygenation injury model group and MgIG pretreatment group (0.01, 0.1, 1, 10, 100 mg/mL). After 24-h pretreatment, we detected the effects of MgIG on liver cell viability using the methyl thiazolyl tetrazolium (MTT) assay at 6-h hypoxia and 4-h reoxygenation. After 24-h pretreatment, liver cells were randomly divided into the hypoxia-reoxygenation injury model group and low-, moderate-, and high-MgIG-concentration groups (0.1, 1, 10 mg/mL, respectively), and hypoxia and reoxygenation were simulated for 6 and 4 h, respectively. Cell morphology was observed by light microscopy. Nuclear factor-kB gene expression was analyzed by quantitative reverse transcription-polymerase chain reaction. MTT results showed that MgIG (0.1, 1, 10 mg/mL) improved the A-value of anoxia-reoxygenation injury in liver cells (P < 0.01) compared with that of the model group. Cells did not survive when the MgIG concentration was 100 mg/mL. At an MgIG concentration lower than 0.01 mg/mL, the A-value of the MTT group was higher than that of the model group (P > 0.05). Nuclear factor-kB mRNA expression (0.597 ± 0.062, 0.248 ± 0.067, 0.141 ± 0.029) in the low-, moderate-, and high-concentration groups was lower than that in the model group (P < 0.01). MgIG reduced hypoxia-reoxygenation injury of liver cells, indicating that it improved hepatic cell activity, inhibited lipid peroxidation and inflammatory reactions, and decreased nuclear factor-kB mRNA expression.

Effect of functional nuclear factor-kappaB genetic polymorphisms on hepatitis B virus persistence and their interactions with viral mutations on the risk of hepatocellular carcinoma

Nonresolving inflammation and viral mutations are important in hepatitis B virus (HBV)-induced hepatocarcinogenesis. However, the effects of genetic polymorphisms affecting nuclear factor-kappaB (NF-κB) on HBV persistence and generation of hepatocellular carcinoma (HCC)-related HBV mutations remain unknown. rs28362491 (NFKB1 -94Ins > Del), rs2233406 (NFKBIA -826C > T), rs3138053 (NFKBIA -881A > G), and rs696 (NFKBIA +2758G > A) were genotyped in 1342 healthy controls, 327 HBV-clearance subjects, and 3976 HBV-positive subjects including 1495 HCC patients, using quantitative PCR. HBV mutations were determined by sequencing. The NFKBIA promoter activity was assessed by transient transfection. Multiplicative interactions of the polymorphisms and viral mutations were assessed by multivariate logistic regression. Compared with HBV-clearance subjects, rs2233406 (CT versus CC) and rs3138053 (AG or AG + GG versus AA) significantly decreased HBV persistence, especially in the genotype B HBV-infected subjects. In the genotype C HBV-infected subjects, rs2233406 variant genotypes were significantly associated with an increased risk of HCC [CT versus CC: age-, gender-adjusted odds ratio (AOR), 1.33; 95% confidence interval (CI) 1.01-1.75 in training set and AOR, 1.59; 95% CI 1.01-2.52 in validation set] compared with HCC-free HBV-infected subjects and significantly increased the frequencies of HCC-related HBV mutations (A1762T/G1764A, T1753V, preS1 start codon mutation, and preS deletion); rs28362491 (Del/Del or Ins/Del + Del/Del versus Ins/Ins) significantly increased the frequency of A1762T/G1764A and reduced the frequency of preS2 start codon mutation. The variant genotypes impaired NFKBIA promoter activity in hepatic cells. The interaction of rs2233406 variant genotypes (CT + TT versus CC) with A1762T/G1764A significantly increased HCC risk in genotype C HBV-infected subjects, with AOR of 2.61 (95% CI 1.09-6.26). Genetic polymorphisms improving NF-κB activity contribute to genotype B HBV clearance. The rs2233406 variant genotypes significantly increase HCC risk, possibly via facilitating immune selection of the HBV mutations. The host-virus interactions are important in identifying HBV-infected subjects who are more likely to develop HCC.

Curcumin enhances cell-surface LDLR level and promotes LDL uptake through downregulation of PCSK9 gene expression in HepG2 cells.

Curcumin has been demonstrated as having numerous desirable characteristics, such as antioxidant, anti-inflammatory, and antiatherogenic activities. We report the hypocholesterolemic effect and molecular mechanism of curcumin. We found that curcumin enhanced LDL receptor (LDLR) level on the cell surface, as well as LDLR activity; however, LDLR transcription and mRNA stability were not affected. Furthermore, we found that proprotein convertase subtilisin/kexin type 9 (PCSK9) gene was downregulated at the transcriptional level by curcumin, leading to an increase in LDL uptake in HepG2 cells. The curcumin-responsive element of the PCSK9 promoter, a binding site for hepatocyte nuclear factor 1α (HNF-1α), was also identified. We demonstrated that curcumin reduced the nuclear abundance of hepatocyte nuclear factor 1α, resulting in its attenuated interaction with the PCSK9 promoter and leading to a downregulation of PCSK9 expression. Finally, we showed that curcumin decreased the statin-induced PCSK9 expression and potentially synergized with statin administration. Current results indicate that curcumin suppression of PCSK9 expression is associated with increases in cell-surface LDLR and LDLR activity in hepatic cells and it acts in a molecular mechanism that is distinct from the statins. Curcumin exhibits hypolipidemic activity and may serve as a useful supplement to statin treatment for hypercholesterolemia.

Leishmania donovani Targets Dicer1 to Downregulate miR-122, Lower Serum Cholesterol, and Facilitate Murine Liver Infection

SummaryLeishmania donovani causes visceral leishmaniasis (VL) where the parasite infects and resides inside liver and spleen tissue macrophages. Given the abnormal lipid profile observed in VL patients, we examined the status of serum lipids in an experimental murine model of VL. The murine VL liver displayed altered expression of lipid metabolic genes, many of which are direct or indirect targets of the liver-specific microRNA-122. Concomitant reduction of miR-122 expression was observed in VL liver. High serum cholesterol caused resistance to L. donovani infection, while downregulation of miR-122 is coupled with low serum cholesterol in VL mice. Exosomes secreted by the infective parasites caused reduction in miR-122 activity in hepatic cells. Leishmania surface glycoprotein gp63, a Zn-metalloprotease, targets pre-miRNA processor Dicer1 to prevent miRNP formation in L. donovani-interacting hepatic cells. Conversely, restoration of miR-122 or Dicer1 levels in VL mouse liver increased serum cholesterol and reduced liver parasite burden.

Morin a Flavonoid Exerts Antioxidant Potential in Streptozotocin-induced Hepatotoxicity

Although diabetic hepatopathy is potentially less common, it may be appropriate for addition to the list of target organ conditions related to diabetes. This study was designed to evaluate the hepatoprotective activity of morin in Streptozotocin (STZ)-induced diabetes rats. Morin (15 and 30 mg/kg/day) was treated to diabetic rats for five consecutive weeks. In serum, fasting glucose and Alkaline Phosphatase (ALP) levels were estimated and found significant increase in diabetic group as compared to controls. Nucleic acids, total protein, Malondialdehyde (MDA), Total Glutathione (T-GSH), Non-Protein Sulphydral (NP-SH) levels and Superoxide Dismutase (SOD) activity was measured in hepatic cells. Oxidative stress was confirmed by increasing MDA and decreasing T-SHG, NP-SH and nucleic acid levels and SOD activity in hepatic cells of diabetic rats. Morin treatment to diabetic rats significantly reduced the STZ-induced oxidative stress by following decrease MDA and increase T-GSH, DNA levels and increase SOD activity in hepatic cells respectively. These biochemical findings were matched with histopathological verifications. The findings obtained from this study indicate that morin exerts protection to STZ-induced diabetic rats against oxidative stress. This could be due to prevention or inhibition of lipid peroxidative system by its antioxidant and hepatoprotective effect. In conclusion, morin has been shown to possess antidiabetic effect in STZ-induced detoxication and antioxidant properties. But the exact underlying mechanism needs to be elucidated.

The antioxidant effect of β-caryophyllene protects rat liver from carbon tetrachloride-induced fibrosis by inhibiting hepatic stellate cell activation

Plant-based whole foods provide thousands of bioactive metabolites to the human diet that reduce the risk of developing chronic diseases. β-Caryophyllene (CAR) is a common constituent of the essential oil of numerous plants, vegetables, fruits and medicinal herbs, and has been used as a flavouring agent since the 1930 s. Here, we report the antioxidant activity of CAR, its protective effect on liver fibrosis and its inhibitory capacity on hepatic stellate cell (HSC) activation. CAR was tested for the inhibition of lipid peroxidation and as a free radical scavenger. CAR had higher inhibitory capacity on lipid peroxidation than probucol, α-humulene and α-tocopherol. Also, CAR showed high scavenging activities against hydroxyl radical and superoxide anion. The activity of 5-lipoxygenase, an enzyme that actively participates in fibrogenesis, was significantly inhibited by CAR. Carbon tetrachloride-treated rats received CAR at 2, 20 and 200 mg/kg. CAR significantly improved liver structure, and reduced fibrosis and the expression of Col1a1, Tgfb1 and Timp1 genes. Oxidative stress was used to establish a model of HSC activation with overproduction of extracellular matrix proteins. CAR (1 and 10 μm) increased cell viability and significantly reduced the expression of fibrotic marker genes. CAR, a sesquiterpene present in numerous plants and foods, is as a natural antioxidant that reduces carbon tetrachloride-mediated liver fibrosis and inhibits hepatic cell activation.

Pathogen DNA also contributes to interferon regulatory factor 3 activation in hepatic cells: Implications for alcoholic liver diseases

Pathogen DNA also contributes to interferon regulatory factor 3 activation in hepatic cells: Implications for alcoholic liver diseases