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Hepatitis B and C are viruses causing liver infections and resulting in grave secondary diseases. While there are different treatments for chronic liver infections, the process of evolving chronic diseases is still not fully understood. This paper presents an economic-inspired model for the overall health of an infected organism. The health model is based on the results of a reaction diffusion model for describing the space-dependent dynamics of virus and T cells during a liver infection. The different treatments affect the parameters of the reaction diffusion model and influence therefore the well-being of the infected person during an infection. The health model is selected in a detailed process out of a class of possible models. The presented work provides a foundation for an optimal control problem for finding the best treatment strategy. [ABSTRACT FROM AUTHOR]

In this paper, a deterministic model characterizing the within-host infection of Hepatitis C virus (HCV) in intrahepatic and extrahepatic tissues is presented. In addition, the model also includes the effect of the cytotoxic T lymphocyte (CTL) immunity described by a linear activation rate by infected cells. Firstly, the non-negativity and boundedness of solutions of the model are established. Secondly, the basic reproduction number R 01 and immune reproduction number R 02 are calculated, respectively. Three equilibria, namely, infection-free, CTL immune response-free and infected equilibrium with CTL immune response are discussed in terms of these two thresholds. Thirdly, the stability of these three equilibria is investigated theoretically as well as numerically. The results show that when R 01 < 1 , the virus will be cleared out eventually and the CTL immune response will also disappear; when R 02 < 1 < R 01 , the virus persists within the host, but the CTL immune response disappears eventually; when R 02 > 1 , both of the virus and the CTL immune response persist within the host. Finally, a brief discussion will be given. [ABSTRACT FROM AUTHOR]

Tumor microenvironment is closely related to the occurrence and development of liver cancer. Tumor-associated macrophages (TAMs) are an important part of tumor microenvironment promoting tumor deterioration and metastasis by inhibiting immune cells. Previous studies showed that PI3Kγ inhibitor could reverse the phenotype of TAMs, relieve immunosuppression and sensitize chemotherapy drugs, suggesting that the combination of PI3Kγ inhibitor and chemotherapeutics is likely to bring new breakthroughs in the treatment of liver cancer. Based on it, this paper builds HES-TG100-115-CDM-PEG micelles with tumor microenvironment responsiveness that simultaneously loaded sorafenib and TG100-115 to synergistically treat liver cancer. Pharmacokinetic study showed that the prepared micelles had longer half-life than that of the free drug solutions, which was favorable for high propensity of extravasation through tumor vascular fenestrations. Under low pH and high α-amylasereductive conditions, micelles could depolymerize quickly due to the sensitivity of bonds and enhance significantly cytotoxic activity against Hep-3B liver cancer cell. Additionally, micelles demonstrated higher levels of antitumor efficiency and better tolerance against nude mouse with Hep-3B cell than the free drug solutions. These findings reveal that HES-TG100-115-CDM-PEG micelles are a promising drug delivery system in clinical comprehensive therapy of liver cancer. [ABSTRACT FROM AUTHOR]

Metabolic reprogramming plays a critical role in hepatocarcinogenesis. However, the mechanisms regulating metabolic reprogramming in primary liver cancer (PLC) are unknown. Differentially expressed miRNAs between PLC and normal tissues were identified using bioinformatic analysis. RT-qPCR was used to determine miR-10b-5p and SCL38A2 expression levels. IHC, WB, and TUNEL assays were used to assess the proliferation and apoptosis of the tissues. The proliferation, migration, invasion, and apoptosis of PLC cells were determined using the CCK-8 assay, Transwell assay, and flow cytometry. The interaction between miR-10b-5p and SLC38A2 was determined using dual-luciferase reporter assay. A PLC xenograft model in BALB/c nude mice was established, and tumorigenicity and SLC38A2 expression were estimated. Finally, liquid chromatography - mass spectrometry (LC-MS) untargeted metabolomics was used to analyze the metabolic profiles of xenograft PLC tissues in nude mice. miR-10b-5p was a key molecule in the regulation of PLC. Compared with para-carcinoma tissues, miR-10b-5p expression was increased in tumor tissues. miR-10b-5p facilitated proliferation, migration, and invasion of PLC cells. Mechanistically, miR-10b-5p targeted SLC38A2 to promote PLC tumor growth. Additionally, miR-10b-5p altered the metabolic features of PLC in vivo. Overexpression of miR-10b-5p resulted in remarkably higher amounts of lumichrome, folic acid, octanoylcarnitine, and Beta-Nicotinamide adenine dinucleotide, but lower levels of 2-methylpropanal, glycyl-leucine, and 2-hydroxycaproic acid. miR-10b-5p facilitates the metabolic reprogramming of PLC by targeting SLC38A2, which ultimately boosts the proliferation, migration, and invasion of PLC cells. Therefore, miR-10b-5p and SLC38A2 are potential targets for PLC diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Curcumin has been used in the treatment of several diseases; however, its low pharmacologic profile reduces its therapeutic use. Towards improving its biological activity, nanoformulations have emerged. Thus, we aimed to determine whether curcumin nanoparticles (Cur-NPs) coated with PEG/chitosan improve the treatment of liver cancer (LC) cells and underpin the molecular mechanisms underlying their anti-cancer activity. Methods: Cur-NPs were synthesised in the form of Cur-PLGA-PEG/chitosan NPs. The effect of Cur-NPs was assessed in HepG2 and Huh 7 LC cells and THLE-2 normal liver cells. Results: The size of synthesised Cur-NPS was determined in the standard range of 141.2 ± 47.5 nm. Compared to THLE-2 cells, LC cells treated with Cur-NPs exerted cytotoxicity at 6.25 μg/mL after 48h. Treatment of HepG-2 cells with 2.5 μg/mL of Cur-NPs inhibited cell migration and this inhibition was augmented at 10 μg/mL (p<0.001). Treatment of chicken embryo with 5 μg/mL Cur-NPs reduced angiogenesis (p<0.001) of 4-day-old embryos. The nanoformulation upregulated Bax and p53 and downregulated Bcl-2 in a concentration-dependent manner and subsequently induce apoptosis in HepG-2 cells. Conclusion: Treatment of LC cells with Cur-NPs decreased cell proliferation, migration, and angiogenesis, and induced cell death by promoting the proapoptotic pathway. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a frequently occurring malignant gastrointestinal cancer. The 5-year survival rate of HCC is still below 8%, and thus, identifying more effective therapeutic methods is needed. Here, we evaluated the effects of Stigmast-4-en-6β-ol-3-one (S463) on the viability and colony formation of liver cancer cells. S463 treatment decreased the viability and induced apoptosis and ferroptosis in liver cancer cells, and also increased cellular malondialdehyde (MDA) and lipid peroxidation levels. In S463 treated cells, the expression level of Bax was increased, and the expression level of GPX4 was reduced, and the cleavage of PARP was improved. We also found that S463 treatment downregulated E2F1 and upregulated p53 at both the mRNA and protein levels. Importantly, rescue experiments revealed that overexpression of E2F1 partially restored S463-induced Bax and p53 upregulation and GPX4 downregulation and counteracted the S463-induced decrease in cell viability and colony formation and the S463-induced increase in MDA and lipid peroxidation levels. Our findings suggest that S463 significantly inhibits viability and colony formation and induces apoptosis and ferroptosis in liver cancer cells via E2F1. [ABSTRACT FROM AUTHOR]

The systemic drug has historically been preferred for the treatment of the majority of pathological conditions, particularly liver cancer. Indeed, this mode of treatment is associated with adverse reactions, toxicity, off-target accumulation, and rapid hepatic and renal clearance. Numerous efforts have been made to design systemic therapeutic carriers to improve retention while decreasing side effects and clearance. Following systemic medication, local administration of therapeutic agents allows for higher 'effective' doses with fewer side effects, kidney accumulation, and clearance. Hydrogels are highly biocompatible and can be used for both imaging and therapy. Hydrogel-based drug delivery approach has fewer side effects than traditional chemotherapy and can deliver drugs to tumors for a longer time. The chemical and physical flexibility of hydrogels can be used to achieve disease-induced in situ accumulation as well as subsequent drug release and hydrogel-programmed degradation. Moreover, they can act as a biocompatible depot for localized chemotherapy when stimuli-responsive carriers are administrated. Herein, we summarize the design strategies of various hydrogels used for localized chemotherapy of liver cancer and their delivery routes, as well as recent research on smart hydrogels. [ABSTRACT FROM AUTHOR]

Hepatic stellate cells activation (HSCs) plays a crucial role in the pathogenesis of liver fibrosis. Specific microRNAs have been suggested to affect the activation of HSCs via various signalling pathways including TGF-β/smads and Wnt/β-catenin pathways. Dasatinib is a multitarget inhibitor of many tyrosine kinases has recently studied for its anti-fibrotic effects in a variety of fibrous diseases. This study investigated the role of modulation of miRNA-378 and miRNA-17 in the pathogenesis of liver fibrosis through altering Wnt/β-catenin and TGF-β/smads pathways and evaluated the beneficial effect of the tyrosine kinase inhibitor, dasatinib, in thioacetamide-induced liver fibrosis model in mice. Treatment with dasatinib down-regulated miRNA-17 expression, leading to the restoration of WiF-1 and smad-7 which cause the inhibition of both Wnt/β-catenin and TGF-β/smads signalling. In addition, it upregulated miRNA-378 leading to the decrease of Wnt-10 which contributes to the suppression of activated HSCs. [ABSTRACT FROM AUTHOR]

Fibrosis is a common pathological feature of most types of chronic liver injuries. There is no specific treatment for liver fibrosis at present. The liver microenvironment, which fosters the survival and activity of liver cells, plays an important role in maintaining the normal structure and physiological function of the liver. The aim of this review is to deeply understand the role of the liver microenvironment in the dynamic and complicated development of liver fibrosis. After searching in Elsevier ScienceDirect, PubMed and Web of Science databases using 'liver fibrosis' and 'microenvironment' as keywords, studies related to microenvironment in liver fibrosis was compiled and examined. The homeostasis of the liver microenvironment is disrupted during the development of liver fibrosis, affecting liver cell function, causing various types of cell reactions, and changing the cell-cell and cell-matrix interactions, eventually affecting fibrosis formation. Liver microenvironment may be important for identifying potential therapeutic targets, and restoring microenvironment homeostasis may be an important strategy for promoting the reversal of liver fibrosis. The homeostasis of the liver microenvironment is disrupted in liver fibrosis; A pro-fibrotic microenvironment is formed during the development of liver fibrosis; Restoring microenvironment homeostasis may be an important strategy for promoting the reversal of liver fibrosis. [ABSTRACT FROM AUTHOR]

We evaluated the fects of different levels of dietary silver nanoparticle (AgNP) powder on performance, intestinal microflora, carcass traits and blood parameters of broiler chickens. Three hundred seven-day-old Ross broiler chicks were randomly divided into five groups, each group replicated three times with 20 birds per replication. Chickens were fed the basal diet with 2.5, 5, 10 and 20 mg AgNPs per kg feed. Dietary inclusion of AgNPs improved the final body weight, cumulative weight gain and feed conversion ratio. The best broiler performance, carcass traits, and relative organ weights were observed in the group supplemented with 2.5 ppm AgNPs. Increasing the AgNP dose resulted in a significant decrease in the caecal lactose positive and enterococci bacteria populations, while lactobacilli counts were numerically increased. The silver residues in the breast and thigh muscle significantly increased (p <.05) in a dose-dependent manner. Dietary inclusion of AgNPs induced dose-dependent lesions in liver, kidney, spleen and duodenum tissues involving degeneration, necrosis, mononuclear infiltration and focal aggregation of inflammatory cells. In conclusion, despite its potential positive impacts on growth performance, carcass traits and caecal microbial population diversity at a dose of 2.5 ppm, dietary inclusion of AgNPs had the following negative effects on broilers: 1) silver residues in breast and thigh muscle, which may result in AgNPs transmission to consumers, and 2) cytotoxicity in intestinal, liver, spleen and kidney cells in a dose-dependent manner. Therefore, we suggest the use of lower doses of AgNPs (< 2.5 ppm diet) in poultry production in the future studies. Dietary inclusion of silver nanoparticles (AgNPs) in broiler diets more than 2.5 mg/kg diets had many negative effects represented by accumulation of silver residue in broiler meat and the possibility of transmission of nanosilver to consumers. AgNPs had a cytotoxic effect on intestine, liver, spleen and kidney cells in a dose-dependent manner in broilers and might be harmful to chicken and human health. Therefore, we do not recommend using AgNPs as a dietary growth promotor or antibacterial agent in broiler diets and their use and marketing should be controlled and restricted. [ABSTRACT FROM AUTHOR]

Hepatocyte-specific knockout of the essential autophagy gene Autophagy-related 7 (Atg7) is sufficient to cause hepatic carcinogenesis. A recent paper by Lee et al. unveils the molecular pathway accounting for hepatic hypertrophy and hyperplasia followed by malignant transformation. This pathway involves the overactivation of the transcription factor yes-associated protein (YAP), which turns out to be an autophagic substrate. Of note, the transcriptional signature activated in mouse hepatocytes lacking Atg7 resembles that found in non-alcoholic steatohepatitis (NASH), as well as in the steatohepatitic subtype of human hepatocellular carcinomas. [ABSTRACT FROM AUTHOR]

10-HCPT is a topoisomerase I inhibitor effective in the treatment of liver cancer but its use is hampered by its resistance. The expression of hypoxia-inducible factor-1a (HIF-1a) is reportedly upregulated in liver cancer tissues, which is directly linked to the resistance of 10-HCPT. While BBR can significantly decrease the level of HIF-1a according to the literature report. Thus, the aim of this study was to prepare a novel intravenous 10-HCPT-BBR-loaded lipid microsphere (LM) and evaluate their synergistic effect on liver cancer treatment. The optimal preparation mainly included 10.0% oil phase (medium-chain triglyceride:long-chain triglyceride = 1:1), emulsifier (egg lecithin E80 and pluronic F68), antioxidant (0.02% NaHSO3), and pH regulator (0.1 mol/L Hcl). Then, the behaviors of BBR-10-HCPT loaded LM in vitro and in vivo were systematically investigated. In vitro, it showed an obvious sustained-release effect in different release mediums, good physicochemical stability at accelerated and long-term storage conditions, and great anti-proliferative capability toward human liver cancer Hep-3B cells. In vivo, the prepared LM exhibited a longer half-life and higher AUC compared to BBR injection and 10-HCPT injection. More importantly, it was found that The LM was distributed more in the liver, spleen, and tumors, but less in the lungs and heart, especially in the lung. And then, it showed significant inhibition of tumor growth against nude mouse with Hep-3B tumor, and the tumor inhibition rate reached 91.55%. Thus, the data obtained in our study suggested that BBR combined with 10-HCPT can raise curative effect and reduce the toxicity of 10-HCPT. [ABSTRACT FROM AUTHOR]

Hepatic macroautophagy/autophagy and fatty acid metabolism are transcriptionally regulated by nuclear receptors (NRs); however, it is not known whether their transcriptional co-activators are involved in autophagy. We thus examined MED1 (mediator complex subunit 1), a key component of the Mediator Complex that directly interacts with NRs, on these processes. We found that MED1 knockdown (KD) in cultured hepatic cells decreased autophagy and mitochondrial activity that was accompanied by decreased transcription of genes involved in these processes. Lipophagy and fatty acid β-oxidation also were impaired. These effects also occurred after thyroid hormone stimulation, nutrient-replete or -deplete conditions, and in liver-specific Med1 KD (Med1 LKD) mice under fed and fasting conditions. Together, these findings showed that Med1 played a key role in hepatic autophagy, mitochondria function, and lipid metabolism under these conditions. Additionally, we identified downregulated hepatic genes in Med1 LKD mice, and subjected them to ChIP Enrichment Analysis. Our findings showed that the transcriptional activity of several NRs and transcription factors (TFs), including PPARA and FOXO1, likely were affected by Med1 LKD. Finally, Med1 expression and autophagy also were decreased in two mouse models of nonalcoholic fatty liver disease (NAFLD) suggesting that decreased Med1 may contribute to hepatosteatosis. In summary, MED1 plays an essential role in regulating hepatic autophagy and lipid oxidation during different hormonal and nutrient conditions. Thus, MED1 may serve as an integrator of multiple transcriptional pathways involved in these metabolic processes. Abbreviations: BAF: bafilomycin A1; db/db mice; Leprdb/db mice; ECAR: extracellular acidification rate; KD: knockdown; MED1: mediator complex subunit 1; NAFLD: nonalcoholic fatty liver disease; OCR: oxygen consumption rate; PPARA/PPARα: peroxisomal proliferator activated receptor alpha; TF: transcription factor; TFEB: transcription factor EB; tf-LC3: tandem fluorescence RFP-GFP-LC3; TG: triglyceride; TH: Thyroid hormone; TR: thyroid hormone receptors; V-ATPase: vacuolar-type H+-ATPase; WDF: Western diet with 15% fructose in drinking water [ABSTRACT FROM AUTHOR]

HBV pol plays a critical role in the replication of hepatitis B virus (HBV). Previous studies conducted on HBV pol have produced limited evidence on HBV pol expression due to the lack of effective detection methods. The present study used the HBV pol (159-406 aa) protein as a target to screen for specific monoclonal antibodies that recognize HBV pol and subsequently evaluate their diagnostic and therapeutic value. Four antibodies (P3, P5, P12, P20) against HBV pol were obtained. Among them, the P20 antibody indicated optimal binding with HBV pol as demonstrated by Western blotting (WB) in a cell model transfected with the HBV genome. We also expressed P5 and P12 antibodies in mouse liver cells by transfection and the results indicated significant antiviral effects caused by these two antibodies especially P12. In summary, the present study established an antibody which was denoted P20. This antibody can be used to detect HBV pol expression by four HBV genomes via WB analysis. In addition, the antibody denoted P12 could exert antiviral effects via intracellular expression, which may provide a promising approach for the treatment of chronic hepatitis B. [ABSTRACT FROM AUTHOR]

The novel curcumin analog C086, previously identified as an oral novel heat shock protein 90 (Hsp90) inhibitor, was found to exhibit anti-hepatoma activity in vitro and in vivo. However, owing to its limited aqueous solubility, the usage of C086 in the clinical application was restricted. This research focused on the increase of the aqueous solubility and bioavailability of C086 via a solid dispersion preparation to improve its accumulation in the liver, which accordingly enhanced anti-hepatoma activity. C086-solid dispersion (C086-SD) was successfully prepared by using solvent evaporation technology. As compared with bulk compound, aqueous solubility obtained with the optimal formulation (C086/PVP k30:1/6 (w/w)) was increased by 1.741 million-fold, and in the following oral administration experiment, bioavailability was found to be improved by an approximately 28-fold relative to C086-Suspension and accumulate preferably in the liver. Accordingly, C086-SD exhibited stronger potent anti-proliferative effects against liver cancer cell line (i.e. HepG2) than pure C086. Moreover, C086-SD was found to have an enhanced anti-hepatoma effect using the orthotopic hepatocellular carcinoma xenograft in BALB/C nude mice. The results above suggested the potential application of C086-SD in the treatment of liver cancer. [ABSTRACT FROM AUTHOR]

Liver cancer is a malignant tumor with extremely high morbidity and mortality. At present, traditional chemotherapy is still the most commonly used therapeutic approach. However, serious side effects lead to the treatment of liver cancer is not ideal. Therefore, it is imperative to develop a new drug delivery system based on nanotechnology and liver cancer microenvironment. In this study, a pH/reduction/α-amylase multi-sensitive hydroxyethyl starch-10-hydroxy camptothecin micelles (HES-10-HCPT-SS-Ly) targeting over-expressed amino acid (AA) transporters on the surface of liver cancer cell by applying lysine were successfully synthesized. The prepared micelles showed regular structure, suitable particle size, and intelligent drug release property. Compared with conventional HES-10-HCPT micelles and 10-HCPT injection, HES-10-HCPT-SS-Ly micelles demonstrated better in vitro anti-proliferative capability toward human liver cancer Hep-G2 cells and greater antitumor efficiency against nude mouse with Hep-G2 tumor. These findings suggest that HES-10-HCPT-SS-Ly micelles may be a promising nanomedicine for treatment of liver cancer. [ABSTRACT FROM AUTHOR]

5-Caffeoylquinic acid (5-CQA) is one of the most abundant compounds found in natural foods including coffee. We investigated whether 5-CQA had a cytoprotective effect through the NF-E2-related factor 2 (Nrf2)-antioxidant response element (ARE) signalling pathway. Nrf2 activation in response to 5-CQA treatment at the concentration of 10–100 μM is evaluated by Western blotting of Nrf2 and ARE reporter gene assay as well as its target gene expression in HepG2 cells. Intracellular reactive oxygen species (ROS) and glutathione (GSH) levels were measured in the tert-butyl hydroperoxide-induced hepatocytes to examined cytoprotective effect of 5-CQA (10–100 μM). The specific role of 5-CQA on Nrf2 activation was examined using Nrf2 knockout cells or Nrf2 specific inhibitor, ML-385. Nuclear translocation of Nrf2 is increased by 5-CQA in HepG2 cells which peaked at 6 h. Consequently, 5-CQA significantly increases the ARE reporter gene activity and downstream antioxidant proteins, including glutamate cysteine ligase (GCL), hemeoxygenase-1 (HO-1), NAD(P)H quinone oxidoreductase 1, and Sestrin2. Nrf2 deficiency or inhibition completely antagonized ability of 5-CQA to induce HO-1 and GCL expression. Cells pre-treated with 5-CQA were rescued from tert-butyl hydroperoxide-induced ROS production and GSH depletion. Nrf2 activation by 5-CQA was due to increased phosphorylation of MAPKs, AMPK and PKCδ. Taken together, our results demonstrate that as a novel Nrf2 activator, 5-CQA, may be a promising candidate against oxidative stress-mediated liver injury. Additional efforts are needed to assess 5-CQA, as a potential therapeutic in liver diseases in vivo and in humans. [ABSTRACT FROM AUTHOR]

The potential hepatotoxicity of Polygoni Multiflori Radix (PMR) has attracted much attention, but the specific mechanism of inducing hepatotoxicity is still unclear due to the complexity of its components. This study investigated the specific mechanism by which 2,3,5,4′-tetrahydroxy-stilbene-2-O-β-d-glucoside (TSG) regulates hepatotoxicity. The toxic effects of TSG (10, 100, 1000 μg/mL) on WRL-68 cells were examined using MTT, flow cytometry, and LDH assay after 24 h of incubation. Untreated cells served as the control. Gene and protein expression levels were determined by quantitative real-time PCR and Western blot, respectively. Immunofluorescence analysis was conducted to investigate the expression of light chain 3 (LC3). Luciferase activity assay was used to assess the targeted regulation of RUNX1 by miR-122. The half maximal inhibitory concentration (IC50) of TSG in WRL-68 cells was calculated as 1198.62 μg/mL. TSG (1000 μg/mL) inhibited cell viability and LDH activity and promoted WRL-68 cell apoptosis by inducing autophagy. Subsequent findings showed that TSG induced autophagy and promoted apoptosis in WRL-68 cells by downregulating the levels of p-PI3K, p-Akt, and p-mTOR proteins, while RUNX1 overexpression rescued this inhibition. Additionally, the effect of TSG on hepatocyte apoptosis was reversed by miR-122 knockdown. Furthermore, bioinformatics and dual luciferase reporter assay results indicated that miR-122 targeted RUNX1. Our data demonstrate for the first time that TSG regulates hepatotoxicity, possibly by upregulating miR-122 and inhibiting the RUNX1-mediated PI3K/Akt/mTOR pathway to promote autophagy and induce hepatocyte apoptosis. Further in vivo research is necessary to verify our conclusion. [ABSTRACT FROM AUTHOR]

The purpose of this study was to explore the associated mechanism by which MSCs-derived exosomes exerted protective effect in hepatic ischemia/reperfusion injury (IRI). Human umbilical cord blood mesenchymal stem cells (hUCB-MSCs)-derived exosomes were administrated into LO2 cells exposed to hypoxia/reoxygenation (H/R) and mice subjected to IRI. Cell viability was assessed by CCK-8 assay. Apoptosis was analyzed by flow cytometry and TUNEL staining. The expression of miR-1246 and Wnt/β-catenin pathway-related proteins was detected by quantitative real-time PCR (qRT-PCR) and western blotting. The concentration of pro-inflammatory cytokines was determined by ELISA. Luciferase activity assay was performed to confirm the interaction between miR-1246 and glycogen synthase kinase 3β (GSK3β). Hepatic function was assessed by determining serum alanine amino transferase (ALT) and aspartate amino transferase (AST) levels. Histological changes were observed using hematoxylin-eosin (H&E) staining. MiR-1246 was significantly downregulated in H/R-treated LO2 cells. Treatment with exosomes derived from hUCB-MSCs led to miR-1246 upregulation. Furthermore, hUCB-MSCs-derived exosomes induced anti-apoptotic and pro-survival effects in LO2 cells and ameliorated IRI-induced hepatic dysfunction in mice, while treatment of exosomes from miR-1246 inhibitor-transfected hUCB-MSCs showed opposite effect, which was mediated by regulating GSK3β-Wnt/β-catenin pathway. Collectively, hUCB-MSCs-derived exosomes alleviated hepatic IRI by transporting miR-1246 via regulating GSK3β-mediated Wnt/β-catenin pathway. [ABSTRACT FROM AUTHOR]

Green synthesis of nanoparticles is an emerging field of nanotechnology, preferred over physical and chemical synthesis owing to their safety, cost-effectiveness nature, bio-compatibility, eco-friendly and scalable properties. The present study includes Seripheidium quettense aqueous extract mediated green synthesis, optimization of silver nanoparticles (Sq-AgNPs) and their pharmacological evaluations. Synthesis was done considering various optimization parameters including concentrations of AgNO3, pH of the reaction mixture, extract to precursor ratio and temperature. Biosynthesis was carried out using our already optimized conditions. UV–visible spectrophotometer, FTIR, XRD and SEM analysis were used for characterization of Sq-AgNPs. The synthesized Sq-AgNPs (49.96–54.36 nm) were evaluated for their antibacterial, antifungal, anticancer and hemolytic potentials. The maximum antibacterial activity was found against Escherichia coli, Klebsiella pneumonia and Bacillus subtilis with their MICs of 11.1, 33.3 and 33.3 μg/mL, respectively. Aspergillus nigar was found as the most susceptible fungal strain with the highest zone of inhibition (13.2 ± 0.72 mm). Sq-AgNPs inhibited proliferation of human liver cancer cell lines (HepG2) with median lethal concentration (IC50s) of 62.5 µg/mL. Results of the hemolytic assay showed that SqNPs are bio-compatible and have less effect on erythrocytes even at high concentration of 100 µg/mL. [ABSTRACT FROM AUTHOR]

An estrogen (ES)-functionalized cationic liposomal system was developed and exploited for targeted delivery to osteosarcoma. Natural biocompatible chotooligosaccharides (COS, MW2-5 KDa) were covalently tethered to the liposomal surface through a disulfate bond (-SS-) to confer reduction-responsive COS detachment, whereas estrogen was grafted via polyethylene glycol (PEG 2 K) chain to achieve estrogen receptor-targeting. The liposomal carriers were prepared by the ethanol injection method and fluorescent anticancer drug doxorubicin (DOX) was loaded with ammonium sulfate gradient. The physicochemical properties, reduction-sensitivity, and the roles of estrogen on cellular uptake and tumor-targeting were studied. The Chol-SS-COS/ES/DOX liposomes were spherical with an average size about 110 nm, and high encapsulation efficiency. The liposomes were stable in physiological condition but rapidly release the payload in response to tumoral intracellular glutathione (20 mM). MTT cytotoxicity assay confirmed that Chol-SS-COS/ES/DOX liposomes exhibited higher cytotoxicity to MG63 osteosarcoma cells than to liver cells (LO2). Flow cytometry (FCM) and confocal laser scanning microscopy revealed that cellular uptake of Chol-SS-COS/ES/DOX liposomes by MG63, than the free DOX or Chol-SS-COS/DOX. Ex vivo fluorescence distribution study showed that the multifunctional liposomes selectively accumulated in the MG63 xenografts versus the organs. Chol-SS-COS/ES/DOX liposomes strongly inhibited the tumor growth and enhanced the animal survival rate. Overall, the COS grafted estrogen-functionalized cationic liposomes, fortified with glutathione-responsiveness, showed great potential for specific intracellular drug delivery to estrogen receptor-expressing tumors such as osteosarcoma. [ABSTRACT FROM AUTHOR]

Context:Eruca sativaMill. (Brassicaceae), commonly known as rocket salad, is a popular leafy-green vegetable with many health benefits. Objective:To evaluate the antidiabetic activities of this plant in major insulin-responsive tissues. Materials and methods:FiveE. sativaleaf extracts of varying polarity were prepared (aqueous extract, 70% and 95% ethanol extracts, then-hexane-soluble fraction of the 95% ethanol extract (ES3) and the defatted 95% ethanol extract).Eruca sativaextracts were investigated through a variety of cell-basedin vitrobioassays for antidiabetic activities in C2C12 skeletal muscle cells, H4IIE hepatocytes and 3T3-L1 adipocytes. Guided by the results of these bioassays, ES3 was fractionated into the saponifiable (SM) and the unspaonifiable (USM) fractions. Glucose uptake was measured using [3H]-deoxy-glucose, while the effects on hepatic glucose-6-phosphatase (G6Pase) and adipogenesis were assessed using Wako AutoKit Glucose and AdipoRed assays, respectively. Results:ES3 and its SM fraction significantly stimulated glucose uptake with EC50values of 8.0 and 5.8 μg/mL, respectively. Both extracts significantly inhibited G6Pase activity (IC50values of 4.8 and 9.3 μg/mL, respectively). Moreover, ES3 and SM showed significant adipogenic activities with EC50of 4.3 and 6.1 μg/mL, respectively. Fatty acid content of SM was identified by GC-MS.trans-Vaccenic and palmitoleic acids were the major unsaturated fatty acids, while palmitic and azelaic acids were the main saturated fatty acids. Discussion and conclusion:These findings indicate that ES3 and its fatty acid-rich fraction exhibit antidiabetic activities in insulin-responsive cell lines and may hence prove useful for the treatment of type 2 diabetes. [ABSTRACT FROM PUBLISHER]

Context:Zea maysL. (Poaceae)Stigma maydisis an underutilized product of corn cultivation finding therapeutic applications in oxidative stress-related disorders. Objectives:This study investigated its aqueous extract against acetaminophen (APAP)-perturbed oxidative insults in rat hepatocytes. Materials and methods:Hepatotoxic rats were orally pre- and post-treated with the extract (at 200 and 400 mg/kg body weight) and vitamin C (200 mg/kg body weight), respectively, for 14 days. Liver function, antioxidative and histological analyses were thereafter evaluated. Results:The APAP-induced marked (p < 0.05) increases in the activities of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, gamma glutamyl transferase and the concentrations of bilirubin, oxidized glutathione, protein carbonyls, malondialdehyde, conjugated dienes, lipid hydroperoxides and fragmented DNA were dose-dependently extenuated in the extract-treated animals. The extract also significantly (p < 0.05) improved the reduced activities of superoxide dismutase, catalase, glutathione reductase and glutathione peroxidase as well as total protein, albumin and glutathione concentrations in the hepatotoxic rats. These improvements may be attributed to the bioactive constituents as revealed by the gas chromatography–mass spectrometric chromatogram of the extract. The observed effects compared favourably with vitamin C and are informative of hepatoprotective and antioxidative attributes of the extract and were further supported by the histological analysis. Conclusion:The data from the present findings suggest thatStigma maydisaqueous extract is capable of preventing and ameliorating APAP-mediated oxidative hepatic damage via enhancement of antioxidant defence systems. [ABSTRACT FROM AUTHOR]

Context: Natural products are good sources of natural dietary antioxidants that are believed to protect the body against hepatotoxic effect induced by oxidative stress.Hedyotis diffusaWilld (Rubiaceae) (HDW) is a traditional Chinese medicinal herb that has been shown to possess a variety of antioxidant properties. Objective: The present study examines and explains the cell protective property of HDW water extract (WEHDW). Materials and methods: 2,2-Diphenyl-1-(2,4,6-trinitrophenyl) hydrazyl (DPPH) assay was used to measure the free radical scavenging property of WEHDW (0.001–10 mg/mL). The protective effect of WEHDW (0.3–10 mg/mL 2 h pretreatment) against hydrogen peroxide (H2O2,200 μM for 6 h) induced cytotoxicity in human hepatic cells, LO2, was evaluated using cell viability assay and nuclear staining. The molecular pathway of WEHDW's effect was investigated by using Western blot assay. Results: WEHDW had a 50% scavenging concentration (SC50) at 0.153 mg/mL in the DPPH assay. Exposure of LO2cells to H2O2resulted in apoptosis which could be markedly attenuated by pre-treating WEHDW in a concentration-dependent manner (0.5, 1, 3, 5, or 10 mg/mL) (all withp < 0.001, versus control). Moreover, Hoechst (nuclear) staining showed that 1 mg/mL WEHDW could protect LO2cells by attenuating apoptotic cell death mediated by H2O2. It was found that WEHDW reversed H2O2-induced activation of MEK/ERK pathway and H2O2-induced inhibition of P13-K/AKT/GSK3β pathway in LO2cells. Discussion and conclusion: WEHDW may help to improve the antioxidant defense system, resulting in prevention of oxidative stress-related fatty liver diseases. [ABSTRACT FROM AUTHOR]

Background and Aims: Decellularized liver matrix (DLM) hold great potential for reconstructing functional hepatic-like tissue (HLT) based on reseeding of hepatocytes or stem cells, but the shortage of liver donors is still an obstacle for potential application. Therefore, an appropriate alternative scaffold is needed to expand the donor pool. In this study, we explored the effectiveness of decellularized spleen matrix (DSM) for culturing of bone marrow mesenchymal stem cells (BMSCs), and promoting differentiation into hepatic-like cells. Methods: Rats' spleen were harvested for DSM preparation by freezing/thawing and perfusion procedure. Then the mesenchymal stem cells derived from rat bone marrow were reseeded into DSM for dynamic culture and hepatic differentiation by a defined induction protocol. Results: The research found that DSM preserved a 3-dimensional porous architecture, with native extracellular matrix and vascular network which was similar to DLM. The reseeded BMSCs in DSM differentiated into functional hepatocyte-like cells, evidenced by cytomorphology change, expression of hepatic-associated genes and protein markers, glycogen storage, and indocyanine green uptake. The albumin production (2.74±0.42vs. 2.07±0.28 pg/cell/day) and urea concentration (75.92±15.64vs. 52.07±11.46 pg/cell/day) in DSM group were remarkably higher than tissue culture flasks (TCF) group over the same differentiation period,P< 0.05. Conclusion: This present study demonstrated that DSM might have considerable potential in fabricating hepatic-like tissue, particularly because it can facilitate hepatic differentiation of BMSCs which exhibited higher level and more stable functions. [ABSTRACT FROM PUBLISHER]

Background and Aims:Using decellularized scaffold to reengineer liver tissue is a promising alternative therapy for end-stage liver diseases. Though the decellularized human liver matrix is the ideal scaffold for reconstruction of the liver theoretically, the shortage of liver donors is still an obstacle for potential clinical application. Therefore, an appropriate alternative scaffold is needed. In the present study, we used a tissue engineering approach to prepare a rat decellularized spleen matrix (DSM) and evaluate the effectiveness of this DSM for primary rat hepatocytes culture.Methods:Rat decellularized spleen matrix (DSM) was prepared by perfusion of a series of detergents through spleen vasculature. DSM was characterized by residual DNA and specific extracellular matrix distribution. Thereafter, primary rat hepatocytes were cultured in the DSM in a 3-dimensional dynamic culture system, and liver cell survival and biological functions were evaluated by comparison with 3-dimensional sandwich culture and also with cultured in decellularized liver matrix (DLM).Results:Our research found that DSM did not exhibit any cellular components, but preserved the main extracellular matrix and the intact vasculature evaluated by DNA detection, histology, immunohistochemical staining, vessel corrosion cast and upright metallurgical microscope. Moreover, the method of DSM preparation procedure was relatively simple with high success rate (100%). After seeding primary hepatocytes in DSM, the cultured hepatocytes survived inside DSM with albumin synthesis and urea secretion within 10 d. Additionally, hepatocytes in dynamic culture medium had better biological functions at day 10 than that in sandwich culture. Albumin synthesis was 85.67 ± 6.34 μg/107cell/24h in dynamic culture in DSM compared to 62.43 ± 4.59 μg/107cell/24h in sandwich culture (P< 0.01) and to 87.54 ± 5.25 μg/107cell/24h in DLM culture (P> 0.05); urea release was 32.14 ± 8.62 μg/107cell/24h in dynamic culture in DSM compared to 20.47 ± 4.98 μg/107cell/24h in sandwich culture (P< 0.05) and to 37.38 ± 7.29 μg/107cell/24h cultured in DLM (P> 0.05).Conclusion:The present study demonstrates that DSM can be prepared successfully using a tissue engineering approach. The DSM is an appropriate scaffold for primary hepatocytes culture. [ABSTRACT FROM PUBLISHER]

To understand the mechanism of hepatocyte differentiation during rat liver regeneration (LR) at the gene transcription level, Rat Genome 230 2.0 Array was used to determine the gene expression changes of hepatocytes. Then the genes associated with cell differentiation and their signaling pathways were searched by NCBI, QIAGEN and KEGG webs, and their signaling activities were calculated by spectral function Ep(t) based on the expression profiles. The key genes associated with the signaling pathways and cell differentiation were analyzed and verified by the same kind extraction method. The mechanism of hepatocyte differentiation during rat LR was analyzed by Ingenuity Pathway Analysis 9.0 (IPA). The results showed that 42 signaling pathways regulated cell differentiation and the Ep(t) values of IL-9 signaling pathway and its JAK/STAT and PI3K/AKT branches, PEDF signaling pathway and its NF-κB and Ras/ERK branches were significantly increased in the progression phase (6–72 h after partial hepatectomy [PH]) of rat LR, and the Ep(t) values of hepatocyte differentiation were also significantly increased. ERK/MAPK signaling pathway was significantly increased in the priming (0.5–6 h after PH) and progression phase, and hepatocyte differentiation were also significantly increased. In conclusion, among the 42 signaling pathways that regulated cell differentiation, the signaling activity of IL-9 signaling pathway and its JAK/STAT and PI3K/AKT branches, PEDF signaling activity and its NF-κB and Ras/ERK branches, and ERK/MAPK signaling activity were significantly increased and promoted hepatocyte differentiation in rat LR. Meanwhile, the expression of MYC involved in mentioned signaling pathways and expression of AGT, BCL2, IL10, CCND1, PLAT, and NF1 related to cell differentiation were increased significantly. [ABSTRACT FROM AUTHOR]

Recent studies suggest that organ decellularization is a promising approach to facilitate the clinical application of regenerative therapy by providing a platform for organ engineering. This unique strategy uses native matrices to act as a reservoir for the functional cells which may show therapeutic potential when implanted into the body. appropriate cell sources for artificial livers have been debated for some time. The desired cell type in artificial livers is primary hepatocytes, but in addition, other supportive cells may facilitate this stem cell technology. In this context, the use of mesenchymal stem cells (MSC) is an option meeting the criteria for therapeutic organ engineering. Ideally, supportive cells are required to (1) reduce the hepatic cell mass needed in an engineered liver by enhancing hepatocyte function, (2) modulate hepatic regeneration in a paracrine fashion or by direct contact, and (3) enhance the preservability of parenchymal cells during storage. here, we describe enhanced hepatic function achieved using a strategy of sequential infusion of cells and illustrate the advantages of co-cultivating bone marrow-derived MSCs with primary hepatocytes in the engineered whole-liver scaffold. These co-recellularized liver scaffolds colonized by MSCs and hepatocytes were transplanted into live animals. after blood flow was established, we show that expression of adhesion molecules and proangiogenic factors was upregulated in the graft. [ABSTRACT FROM AUTHOR]

The liver is a target of in vitro tissue engineering despite its capability to regenerate in vivo. The construction of liver tissues in vitro remains challenging. in this review, conventional 3D cultures of hepatocytes are first discussed. Recent advances in the 3D culturing of liver cells are then summarized in the context of in vitro liver tissue reconstruction at the micro- and macroscales. The application of microfluidics technology to liver tissue engineering has been introduced as a bottom-up approach performed at the microscale, whereas whole-organ bioengineering technology was introduced as a top-down approach performed at the macroscale. Mesoscale approaches are also discussed in considering the integration of micro- and macroscale approaches. Multiple parallel multiscale liver tissue engineering studies are ongoing; however, no tissue-engineered liver that is appropriate for clinical use has yet been realized. The integration of multiscale tissue engineering studies is essential for further understanding of liver reconstruction strategies. [ABSTRACT FROM AUTHOR]

In developing therapeutic alternatives to liver transplantation, we have used the strategy of applying a small intestinal segment as a scafold for hepatocyte transplantation and also as a portocaval shunt (pcs) system to address both liver dysfunction and portal hypertension. The aim of this study was to investigate the feasibility of such an intestinal segment in animal models. hepatocytes isolated from luciferase-transgenic Lewis rats were transplanted into jejunal segments of wild-type Lewis rats with mucosa removal without pcs application. Luciferase-derived luminescence from transplanted hepatocytes was stably detected for 30 d. Then, we performed autologous hepatocyte transplantation into the submucosal layer of an isolated and vascularized small intestinal segment in pigs. Transplanted hepatocytes were isolated from the resected left-lateral lobe of the liver. On day 7, hepatocyte clusters and bile duct-like structures were observed histologically. To create an intestinal pcs system in pigs, an auto-graft of the segmental ileum and interposing vessel graft were anastomosed to the portal vein trunk and inferior vena cava. however, thrombi were observed in vessels of the intestinal pcss. We measured the correlation between infusion pressure and low volume in whole intestines ex vivo in both species and found that the high pressure corresponding to portal hypertension was still insuicient to maintain the patency of the intestinal grafts. In conclusion, we demonstrated the feasibility of the small intestine as a scafold for hepatocyte transplantation in rat and pig models, but pcs using an intestinal graft failed to maintain patency in a pig model. [ABSTRACT FROM AUTHOR]

In the present study, cytotoxic effects of the polycyclic aromatic hydrocarbons benzo[a] pyrene (B[a]P) were investigated in Sparus aurata hepatocytes primary cultures after acute and chronic exposure. Cells were treated with a wide range of B[a]P doses (1 pg/mL to 100 μg/mL) for 24, 48 and 72 h. B[a]P toxicity was quantified in sea bream hepatocytes by MTT assay and immunofluorescence analysis of apoptosis after the various exposure periods, in order to evaluate the hepatic damage and toxicity range. Results showed three cytotoxic responses: B[a]P cell death for primary necrosis after exposure to high concentrations for short times, apoptosis induction with the use of sublethal doses and cell proliferation allied with neoplastic foci formation after exposure to low concentrations for long times. This responses provided an interesting correlation between the damage caused on hepatocytes and the metabolism of this toxic compound, to date mainly studied in vivo. Additionally, the statistical analysis revealed that the effects of time and dose were significant for both parameters and especially the time was extremely significant (P<0.0001), in fact B[a]P induced damage that increased over time. Our findings demonstrated and confirmed that S. aurata is a very sensitive species to B[a]P exposure since adverse effects were found at all tested doses. Furthermore, the new in vitro animal model can be considered a useful tool for studying the cellular effects induced by any contaminant harmful for farmed fish. [ABSTRACT FROM AUTHOR]

We investigated diet supplementation with shiitake mushroom fruiting bodies on biochemical and histological changes in hypercholesterolemic rats. Six-wk old female Sprague-Dawley albino rats were divided into three groups of 10 rats each. A diet containing 5% Lentinus edodes fruiting bodies given to hypercholesterolemic rats reduced plasma total cholesterol, triglyceride, low-density lipoprotein (LDL), total lipid, phospholipids, and the LDL/high-density lipoprotein ratio by 34.33, 53.21, 75.00, 34.66, 25.73, and 71.43%, respectively. Feeding mushroom also significantly reduced body weight in hypercholesterolemic rats. However, it had no detrimental effects on plasma albumin, total bilirubin, direct bilirubin, creatinine, blood urea nitrogen, uric acid, glucose, total protein, calcium, sodium, potassium, chloride, inorganic phosphate, magnesium, or enzyme profiles. Feeding mushroom increased total lipid and cholesterol excretion in feces. The plasma lipoprotein fraction, separated by agarose gel electrophoresis, indicated that L. edodes significantly reduced plasma β and pre-β-lipoprotein but increased α-lipoprotein. A histological study of hepatic cells by conventional hematoxylin-eosin and oil red-O staining showed normal findings for mushroom-fed hypercholesterolemic rats. These results suggest that shiitake mushrooms could be recommended as a natural cholesterol lowering substance in the diet. [ABSTRACT FROM AUTHOR]

Cell cycle progression is dependent on the intracellular iron level and chelators can lead to iron depletion and decrease cell proliferation. This antiproliferative effect can be inhibited by exogenous iron. In this work, we present the synthesis of some new synthetic calix[4]arene podands bearing diamino-tetraesters, diamino-tetraalcohols, diamino-tetraacid and tetraaryloxypentoxy groups at the lower rim, designed as potential iron chelators. We report their effect on cell proliferation, in comparison with the new oral chelator ICL670A (4-[3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid). The antiproliferative effect of these new compounds was studied in the human hepatocarcinoma HepaRG cell cultures using cell nuclei counting after staining with the DNA intercalating fluorescence dye, Hoechst 33342. Their cytotoxicity was evaluated by the extracellular LDH activity. Preliminary results indicated that their antiproliferative effect was mainly due to their cytotoxicity. The efficiency of these compounds, being comparable to that of ICL670, was independent of iron depletion. This effect remains to be further explored. Moreover, it also shows that the new substituted calix[4]arenes could open the way to valuable new approaches for medicinal chemistry scaffolding. [ABSTRACT FROM AUTHOR]

Cell cycle progression is dependent on the intracellular iron level, and chelators lead to iron depletion and decrease cell proliferation. This antiproliferative effect can be inhibited by exogenous iron. In this work, we present the synthesis of new synthetic calix[4]arene podands bearing alkyl acid and alkyl ester groups at the lower rim, designed as potential iron chelators. We report their effect on cell proliferation, in comparison with the new oral chelator ICL670 (4-[3,5-bis-(2-hydroxyphenyl)-1,2,4-triazol-1-yl]-benzoic acid). The antiproliferative effect of these new compounds was studied in human hepatocarcinoma HepaRG cell cultures using the MTT assay. Their cytotoxicity was evaluated by extracellular LDH activity. Preliminary results indicate that their antiproliferative effect is due to their cytotoxicity. The efficiency of these compounds, comparable to that of ICL670, was independent of iron depletion. This effect remains to be further explored. Moreover, it also shows that novel substituted calix[4]arenes could open the way to new valuable medicinal chemistry scaffolding. [ABSTRACT FROM AUTHOR]

Hepatocyte transplantation is an alternative to transplantation of the whole liver. Compared with xenogeneic hepatocytes, primary hepatocytes have some advantages, such as a more powerful function and a smaller frequency of rejection caused by the host. Cell microencapsulation prevents direct access of host cells to the graft but cannot impede transfer of transplant-derived peptides, which can cross the physical barrier. Sertoli cells are central to the immune privilege demonstrated in the testis, and their actions have been utilized to protect cell transplants. Co-microencapsulating Sertoli cells with HepG2 cells has proved to be a valuable strategy in hepatocyte transplantation. Thus mixed microcapsules of primary rat hepatocytes and primary Sertoli cells may improve metabolic function in a d-galactosamine and lipopolysaccharide-induced rat model of acute liver failure. [ABSTRACT FROM AUTHOR]

In order to define clearly the conditions leading to the outcome of acute duck hepatitis B virus (DHBV) infection, 1-day-old Pekin ducklings were infected with DHBV by different routes and given different doses of inoculum. Groups of 24 ducklings were inoculated either intravenously via the vena cruralis, or intraperitoneally with pooled serum containing either 1.6 x 107 or 1.6 x 104 DHBV genomes. One control duck from each group was inoculated with an equal volume of normal duck serum. A sensitive and reproducible real-time polymerase chain reaction assay based on TaqMan technology was developed for the detection and quantitation of DHBV DNA in the serum and liver. DHBAg was observed in the hepatocytes by immunohistochemistry. Histological changes in the liver tissue were also observed. The results demonstrate that ducklings at each time point and in all groups developed detectable viraemia. In each group, DHBV DNA in the liver was at a lower level than in serum and the peak DNA titre was found in serum earlier than in the liver. In the low-dose groups it was always at a lower level than in the high-dose groups. The DHBV replication levels appeared to be directly related to the number of DHBAg-positive hepatocytes. The variation trends of DHBAg-positive hepatocytes were similar in the high-dose groups. Histological changes were associated with liver viral DNA levels. We suggest that this dose and route of inoculation can be used as a model to study acute DHBV infections. [ABSTRACT FROM AUTHOR]

Background Although different strategies have been established for hepatic differentiation of mesenchymal stromal cells (MSC), further studies are requiredto define an efficient strategy to produce hepatocytes from stem cells and uncover the mechanisms of hepatic differentiation. Methods Bone marrow mesenchymal stromal cells (BMMSC), isolated from ICR mice, were induced by fetal liver-conditioned medium from different developmental stages, embryonic days (ED) 9.5, 11.5 and 13.5 and newborn (1 day). Differentiated cells were characterized by morphologic changes, liver-specific gene expression at mRNA and/or protein levels and in vitro functional features. Results BMMSC morphologically became epithelioid and binucleated after 7 days' exposure to fetal liver-conditioned medium from ED13.5, expressed liver-specific genes (AFP, HNF-3β, TTR, CK18, ALB and CK19) at mRNA and/or protein levels and acquired in vitro functions characteristic of liver cells, including glycogen storage, urea production and albumin secretion. Conditioned medium derived from fetal liver at ED13.5 was most efficient on hepatic differentiation of BMMSC compared from the other three developmental stages. Discussion The present study not only provides a high-performance strategy for hepatic differentiation from BMMSC, but also implies liver at different developmental stages might secrete different types of cytokines that have diverse effects on hepatic differentiation, which could support further investigation to provide insight into fundamental processes that govern development and regeneration of the liver. [ABSTRACT FROM AUTHOR]

Immunohistochemical examinations of hepatic stellate cells (HSCs) were performed on six enlarged livers from broiler chickens with malformation of the extrahepatic biliary tract (group 1) and on eight broiler livers affected with naturally occurring cholangiohepatitis without biliary malformation (group 2). The livers from both groups were grossly enlarged, firm and tan-coloured, and histologically revealed severe diffuse fibrosis with proliferation of bile ductules. HSCs positive for muscle actin and desmin actively proliferated in the perisinusoidal space and around newly formed bile ductules. There was no difference in the immunohistochemical reactivities and location of HSCs between the two groups. The findings suggest that the diffuse hepatic fibrosis found in group 2 as well as group 1 results from reactive proliferation of HSCs. [ABSTRACT FROM AUTHOR]

The article discusses the allogeneic bone marrow mesenchymal stromal cell-derived hepatocyte-like cell transplantation in homozygous familial hypercholesterolemia (FH). It defines FH as a monogenic autosomal disorder caused by loss of gene allele function encoding low-density lipoprotein (LDL) receptor. In the study conducted, human mesenchymal stromal cells (MSC) is found to have the ability to differentiate into hepatocyte-like cells that are functional.