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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]

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]

This experiment was conducted to evaluate the growth performance, growth regulating factors, and liver morphology of chicks hatched from egg-laying breeding hens dietary supplemented with additives (β-carotene). Hy-line breeding hens were allocated into three groups with three replicates/group. The dietary treatments were as follows: basal diet as a control (Con), basal diet supplemented with 120 (βc-L) or 240 (βc-H) mg/kg of β-carotene diet. After 6 weeks, the eggs were collected and incubated. The hatched chicks were fed the same diet. The results showed that chicks in the βc-L group increased in body weight at 21 days (p < 0.01). At 42 days, chicks in the βc-H group showed a significant increase in tibia length (p < 0.05). The liver index increased in the βc-L and βc-H groups at 7 days (p < 0.05). Serum HGF (7, 14, 21, and 42 days) and leptin (14 days) were significantly increased in the group supplemented with βc. Hepatic GHR (14 days), IGF-1R (14 days), and LEPR (21 days) mRNA expression were significantly increased. In addition, there was an increase in PCNA-positive cells in the liver of chicks in the βc group. In conclusion, the addition of β-carotene to the diet of laying breeder hens was more advantageous in terms of growth performance and liver development of the offspring. [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]

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]

Aflatoxin B1 (AFB1) can cause hepatocellular carcinoma (HCC) through a mutagenic mode of action but can also lead to global changes in gene expression; however, the AFB1 network of molecular pathways involved in HCC is not known. Here, we used toxicogenomic data from human liver cells exposed to AFB1 to infer the network of AFB1-responsive molecular pathways involved in HCC. The following computational tools: STRING, MCODE, cytoHubba, iRegulon, kinase enrichment tool KEA3, and DAVID were used to identify protein-protein interaction network, hub genes, transcription factors (TFs), upstream kinases, and biological processes (BPs). Predicted molecular events were validated with an external dataset, whereas the hub genes in HCC were validated using the UALCAN database. The results revealed an association between AFB1 and the hub genes involved in the cell cycle. We identified TFs that regulate the hub genes and linked them with upstream kinases including cyclin-dependent kinases, mitogen-activated protein kinase 1, and AKT. This approach enabled the construction of the AFB1-mediated regulatory network consisting of upstream kinases, TFs, hub genes, and BPs, thus revealing the signaling hierarchy and information flow that may contribute to AFB1-induced HCC. This could be a useful tool in predicting the molecular mechanisms involved in chemical-induced diseases when available toxicogenomic data exist. [ABSTRACT FROM AUTHOR]

Liver disease is known as one of the leading co-morbidities in HIV infection, with 18% of non-AIDS-related mortality. There is constant crosstalk between liver parenchymal (hepatocytes) and non-parenchymal cells (macrophages, hepatic stellate cells, endothelial cells), and extracellular vesicles (EVs) are one of the most important ways of cell-to-cell communication. We briefly cover the role of EVs in liver disease as well as what is known about the role of small EVs, exosomes, in HIV-induced liver disease potentiated by alcohol as one of the second hits. We also touch large EVs, apoptotic bodies (ABs), in HIV-induced liver injury, the mechanisms of their formation and potentiation by second hits, and their role in the progression of liver disease. Liver cells are an important source of EVs, which may provide the connection between different organs via secretion into the circulating blood (exosomes) or serve for the communication between the cells within the organ (ABs). Understanding the role of liver EVs in HIV infection and the involvement of second hits in EV generation would provide a new angle for the analysis of HIV-related liver disease pathogenesis and progression to end-stage liver disease. People living with HIV-1 (PLWH) are at risk of developing chronic liver disease. They are often coinfected with hepatitis viruses B and C and misuse alcohol. Combining these 'second hits' factors with HIV infection greatly accelerates liver damage. The exact mechanisms are not clear. The liver contains different types of cells. Most are hepatocytes, which cannot replicate HIV but can be stressed by HIV and alcohol metabolites. During this process, hepatocytes release small extracellular vesicles called exosomes. Liver exosomes can carry toxic viral proteins and nucleic acids. When hepatocyte exosomes are captured by other liver cells, such as stellate cells, Kupffer macrophages, and sinusoidal endothelial cells, they change the functions of these cells. If hepatocytes die due to high HIV and alcohol toxicity, they form large particles called apoptotic bodies. Like exosomes, these large apoptotic bodies also change the functions of neighboring cells they capture. Macrophages and stellate cells exposed to – extracellular vesicles containing HIV proteins and nucleic acids promote liver inflammation and fibrosis. [ABSTRACT FROM AUTHOR]

Associations between per- and polyfluoroalkyl substances (PFASs) and increased blood lipids have been repeatedly observed in humans, but a causal relation has been debated. Rodent studies show reverse effects, i.e. decreased blood cholesterol and triglycerides, occurring however at PFAS serum levels at least 100-fold higher than those in humans. This paper aims to present the main issues regarding the modulation of lipid homeostasis by the two most common PFASs, PFOS and PFOA, with emphasis on the underlying mechanisms relevant for humans. Overall, the apparent contrast between human and animal data may be an artifact of dose, with different molecular pathways coming into play upon exposure to PFASs at very low versus high levels. Altogether, the interpretation of existing rodent data on PFOS/PFOA-induced lipid perturbations with respect to the human situation is complex. From a mechanistic perspective, research on human liver cells shows that PFOS/PFOA activate the PPARα pathway, whereas studies on the involvement of other nuclear receptors, like PXR, are less conclusive. Other data indicate that suppression of the nuclear receptor HNF4α signaling pathway, as well as perturbations of bile acid metabolism and transport might be important cellular events that require further investigation. Future studies with human-relevant test systems would help to obtain more insight into the mechanistic pathways pertinent for humans. These studies shall be designed with a careful consideration of appropriate dosing and toxicokinetics, so as to enable biologically plausible quantitative extrapolations. Such research will increase the understanding of possible perturbed lipid homeostasis related to PFOS/ PFOA exposure and the potential implications for human health. [ABSTRACT FROM AUTHOR]

Three new feruloyl glucuronopyranosyl glycerols, 1-O-α-D-(2′-feruloyl) glucuronopyranosyl glycerol (1), 1-O-α-D-(3′-feruloyl) glucuronopyranosyl glycerol (2), and 1-O-α-D-(4′-feruloyl) glucuronopyranosyl glycerol (3) were isolated and purified from the capitulum of Eriocaulon buergerianum Koern. Their structures were identified by spectroscopic and chemical methods. Molecular docking study showed that 1 is a potential inhibitor of TGF-β1 receptor. Bioassay results revealed that 1 exhibited strong inhibitory activity against the TGF-β-induced expression of α-smooth muscle actin (α-SMA) and fibronectin in human hepatic stellate LX-2 cells. The results in this study indicated that the new feruloyl glucuronopyranosyl glycerol 1 has preventive and therapeutic potentials against hepatic fibrosis. [ABSTRACT FROM AUTHOR]

Essential oils (EOs) obtained from spices, herbs, and medicinal plants are well known in traditional medicine and are an area of interest due to their various biological activities. Therefore, the present study investigates the chemical composition, phytochemical properties, as well as the biological activity of EOs, recovered from un-irradiated and irradiated (2.5, 5, and 10 kGy) caraway seeds. Carum carvi L. seeds were irradiated with gamma irradiation at dose levels 2.5, 5, and 10 kGy, then EOs were recovered from all the samples. The chemical composition, phenols, and flavonoids content were evaluated. As well, antimicrobial and antitumor activities against the two cell lines [colorectal adenocarcinoma (Caco-2) and liver cancer (HepG-2)] were investigated. The results indicated the percentage of oil increased by radiation, especially a dose of 10 kGy, which gave the highest percentage (3.50%) compared to the control. Also, the Gas Chromatography/Mass Spectrometry (GC-MS) analysis revealed the presence of 26 compounds in the essential oil extracts. The main constituent of caraway seeds EOs was Carvone followed by Limonene. According to the results, there was an increase in the content of phenols and flavonoids by using gamma rays compared with control, the maximum increase was observed at dose level 10 kGy (13.70 and 7.38 mg/g oil, respectively) followed by 5 kGy (11.20 and 5.86 mg/g oil, respectively). The antioxidant properties of the caraway essential oils were increased by increasing the irradiation dose level (2.5–10 kGy) analyzed by DPPH radical and metal chelating activity. Caraway essential oils have an antimicrobial action against Gram-positive and Gram-negative bacteria as well as fungi. The antimicrobial activity was increased as the irradiation dose was raised and the10 kGy dose was more effective in suppressing the growth of bacteria and fungi. Additionally, the caraway essential oils have anticancer activity against the two cell lines studied; colorectal adenocarcinoma (Caco-2) and liver cancer cell line (HepG-2) as reduced the cell viability and density. The 10 kGy dose was more effective for oil yield, phenols, flavonoids, and antioxidant activity as well as antibacterial and antifungal activities. Furthermore, the caraway essential oils indicated anticancer activity against the two cell lines studied; colorectal adenocarcinoma (Caco-2) and liver cancer cell line (HepG-2) as reduced the cell viability and density. So caraway could be considered an important herb with multiple therapeutic uses. [ABSTRACT FROM AUTHOR]

PD105, a PI3Kδ inhibitor, is a candidate for the treatment of rheumatoid arthritis. This study aims to identify the metabolic profiling in vitro and in vivo by UHPLC-Q-Exactive Plus-MS. The in vitro metabolism of PD105 was studied by mouse liver microsomes and hepatocytes, while the in vivo metabolic profiling was obtained from mouse plasma, urine, and faeces. A total of 20 metabolites were tentatively identified based on accurate mass, fragment pathways, and characteristic fragment ions, including 4 in vitro and 20 in vivo. The proposed metabolic pathways of PD105 showed that there were 18 phase I metabolites and 2 phase II metabolites. The phase I metabolic pathways included oxidation, hydration, desaturation and oxidative dechlorination, while the phase II metabolic reactions were mainly methylation and arginine conjugation. Among them, oxidation was the main metabolic pathway of PD105. The comprehensive metabolic profiling contributed to further elucidation of pharmacological action and mechanism of PD105. [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]

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]

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]

Rebuilding a suitable microenvironment of liver cells is the key challenge to enhancing the expression of hepatic functions for drug screening in vitro. To improve the microenvironment by providing the specific adhesive ligands for hepatocytes in the three-dimensional dynamic culture, a perfusion bioreactor with a pectin/alginate blend porous scaffold was constructed in this study. The galactosyl component in the main chain of pectin was able to be specifically recognized by the asialoglycoprotein receptor on the surface of hepatocytes, and subsequently promoted the adhesion and aggregation of hepatocytes co-cultured with hepatic non-parenchymal cells. The bioreactor was optimized for 4 h of dynamic inoculation followed by perfusion at a flow rate of 2 mL/min, which provided adequate oxygen supply and good mass transfer to the liver cells. During dynamic cultured in the bioreactor for 14 days, more multicellular aggregates were formed and were evenly distributed in the pectin/alginate blend scaffolds. The expressions of intercellular interaction and hepatic functions of the hepatocytes in aggregates were significantly enhanced in the three-dimensional dynamic group. Furthermore, the bioreactor not only markedly upregulated the cell polarity markers expression of hepatocytes but also enhanced their metabolic capacity to acetaminophen, isoniazid, and tolbutamide, which exhibited a significant concentration-dependent manner. Therefore, the pectin/alginate blend scaffold-based perfusion bioreactor appeared to be a promising candidate in the field of drug development and liver regeneration research. [ABSTRACT FROM AUTHOR]

Microcystin-leucine arginine (MC-LR), an important hepatoxin, has the effect of promoting hepatocarcinogenesis. MicroRNA-122 (miR-122), an important tumor suppressor in liver, plays an important role in promoting cell apoptosis. Previous studies found that the expression of miR-122 was reduced after MC-LR exposure in liver. In this study, C57BL/6 mice were exposed to saline, negative control agomir, and MC-LR with or without miR-122 agomir transfection. The results indicated that MC-LR promoted the expressions of tumor suppressor genes and decreased the expressions of anti-apoptotic proteins B cell lymphoma-2 (Bcl-2) and Bcl-2-like 2 (Bcl-w), causing hepatocyte apoptosis. Under MC-LR exposure, miR-122 agomir transfection could further increase the expressions of tumor suppressor genes and the release of cytochrome-c (Cyt-c) and decrease the expressions of Bcl-2 and Bcl-w. In conclusion, miR-122 reduction can mitigate MC-LR-induced apoptosis to a certain extent, which in turn, it is likely to have contributed to MC-LR-induced hepatocarcinogenesis. [ABSTRACT FROM AUTHOR]

As a pesticide extracted from plants, rotenone is widely used to control plant pests. In order to explore the safety of rotenone in the environment, we took 60 healthy male SD rats and randomly divided them into rotenone low-dose group, rotenone medium-dose group, rotenone high-dose group, dimethyl sulfoxide group (DMSO), and control group. After 28 days of oral administration, the rat liver tissue ultrastructure, liver function, oxidative stress indexs, mitochondrial function, and apoptosis-related factors were tested to evaluate the hepatotoxicity and toxicological mechanism of rotenone. The results showed that rotenone significantly increased the hepatic index of rats and the activity of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) in serum. Rotenone can reduce the number of endoplasmic reticulum of hepatocyte, concentrate chromatin and make the hepatocyte nuclears irregular. Rotenone weakened the ATP synthesis ability in mitochondria, decreased the activity of ATP enzyme in mitochondria, and increased the mitochondrial membrane potential in the high-dose group. And it induced oxidative stress damage to the mitochondria of rat liver cells. Rotenone can upregulate the expression of pro-apoptotic factors and downregulate the expression of anti-apoptotic factors. These results indicate that oral rotenone in rats induced hepatotoxicity in a dose-dependent manner. The mechanism of rotenone poisoning is that oxidative stress damages organelles of hepatocyte such as mitochondria and endoplasmic reticulum, resulting in their function being weakened or lost, leading to hepatocyte apoptosis. [ABSTRACT FROM AUTHOR]

The use of hepatocytes to predict human hepatic metabolic clearance is the gold standard approach. However whilst enzymes are well characterised, knowledge gaps remain for transporters. Furthermore, methods to study specific transporter involvement are often complicated by overlapping substrate specificity. Selective substrates and inhibitors would aid investigations into clinically relevant pharmacokinetic effects. However, to date no consensus has been reached. This work defines selective hepatic uptake transporter substrates and inhibitors for the six main human hepatocyte transporters (OATP1B1, OATP1B3, OATP2B1, NTCP, OAT2 & OCT1), and demonstrates their use to rapidly characterise batches of human hepatocytes for uptake transporter activity. Hepatic uptake was determined across a range of substrate concentrations, allowing the definition of kinetic parameters and hence active and passive components. Systematic investigations identified a specific substrate and inhibitor for each transporter, with no overlap between the specificity of substrate and inhibitor for any given transporter. Early characterisation of compound interactions with uptake transporters will aid in early risk assessment and chemistry design. Hence, this work further highlights the feasibility of a refined methodology for rapid compound characterisation for the application of static and dynamic models, for early clinical risk assessment and guidance for the clinical development plan. [ABSTRACT FROM AUTHOR]

Nanotechnology is widely used nowadays in several fields of industry, engineering, and medicine, the biological action mechanisms of AgNPs, which mainly involve the release of silver ions (Ag+), generation of reactive oxygen species (ROS). The potential toxicity AgNPs of damages to hepatic cells, hesperidin, and naringin role for their protective effect against the increase of ROS due to AgNPs toxicity. They can be restored, most cellular biochemical parameters, genotoxicity, mutagenicity, and histopathological analysis. Toxicity was induced by an oral dose of Ag NPs of (20–100 nm) for one month, after that treated with hesperidin, naringin (100 mg/kg) for three weeks, malondialdehyde (MDA) levels, nitric oxide (NO), glutathione (GSH) and catalase were estimated. Also, aminotransferases (AST and ALT), alkaline phosphatase (ALP), γ-glutamyltransferase (GGT), albumin, and total bilirubin were determined, following Chromosomal aberrations, DNA breaks, and histological analyses hesperidin, and naringin treatment, recorded amelioration in most biochemical, genetic, and spermatogenesis disturbances Also, histological Investigations were improved. Their biological safety problems, such as potential toxicity on cells, tissue, and organs should be paid enough attention, hesperidin and naringin amelioration fundamental alterations, as hepatic architectural and DNA damage, related to its role as an antioxidant and anti-inflammatory agent. [ABSTRACT FROM AUTHOR]

The chemical composition of Gallesia integrifolia fruits essential oil was obtained by hydrodistillation using a modified Clevenger apparatus was investigated by gas chromatography coupled to mass spectrometry (GC/MS). In addition, the cytotoxicity activity against human tumor cell lines MCF-7 (breast adenocarcinoma), NCI-H460 (large cell lung carcinoma), HeLa (cervical carcinoma), and HepG2 (hepatocellular carcinoma), and non-tumor PLP2 (porcine liver primary cells) as well as the anti-inflammatory action was proposal. The compounds were predominantly organosulfates (2,8-dithianonane, dimethyl trisulfide, and lenthionine). Anti-inflammatory activity that provides 50% inhibition of nitric oxide production (55 µg/mL) of essential oil of the fruits. It also presents cytotoxic activity against MCF-7 (GI50 = 66 µg/mL), NCI-H-460 (GI50 = 147 µg/mL), HeLa (GI50 = 182 µg/mL) and HepG2 (GI50 = 240 µg/mL). The essential oil is more active in tumor cells than in non-tumor cells and the GI50 values for essential oil reported in our work support future studies. [ABSTRACT FROM AUTHOR]

Novel 3′-[4-fluoroaryl-(1,2,3-triazol-1-yl)]-3′-deoxythymidine analogues (7a-l) were developed by the Cu alkyne-azide cycloaddition (CuAAC) reaction. The obtained lead compounds were confirmed by using 1H NMR, 13C NMR, 2 D NMR, HRMS and their anticancer activities were screened against Huh-7 liver cancer cells and U87MG human glioblastoma cells. Among the synthesized fluorinated 1,2,3-triazolyl nucleosides, three compounds (7i, 7a-b) demonstrated promising anti-proliferative against Huh-7 and U87MG cell lines. Significantly, compound 7i has displayed remarkable promising anticancer activity with IC50 value in the micromole range (22.41–24.92 µM) and (18.12–21.36 µM) against Huh-7 cancer cells and U87MG glioblastoma cells, respectively. [ABSTRACT FROM AUTHOR]

Hepatic ischemia-reperfusion injury (IRI) is a severe complication frequently encountered in liver surgery, seriously affecting the therapeutic effects, tissue function. Various immune cells are involved in hepatic IRI, including macrophages, NKT cells, DCs, CD4 + T cells, and CD8 + T cells, among which CD4 + T cells play a critical role in this process. This article aims to summarize the functions and changes in various CD4 + T cell type counts and related cytokine levels in hepatic IRI and to review the possible mechanisms of mutual conversion between T cell types. We have covered the functions and changes that occur in Th1, Th17, and Treg cells in liver IRI, as well as the pathways and factors associated with them. We also discuss the prospects of clinical application and future directions for therapeutic advances. This section explores the current clinical trials involving CD4 + T cells, especially Tregs, explains the limitations of their application, and summarizes the future development trends of cell engineering and their combination with the CAT technology. We also provide new ideas and therapeutic targets for alleviating liver IRI or other liver inflammatory diseases. [ABSTRACT FROM AUTHOR]

In recent years, herbal tea consumption becomes popular because of the potential health benefits and attractive flavors. However, there is also a growing concern that herbal supplements contribute to the drug-drug/drug-herb interactions and hepatotoxicity. In this study, FL83B mouse hepatocytes were used as an in vitro mode of hepatotoxicity induced by free fatty acids, including palmitic acid (PA) and oleic acid (OA), ethanol, and acetaminophen. Herbal tea extracts were obtained from eight common herbal plants, including Verbena officinalis L., Hyssopus officinalis L., Salvia officinalis L., Urtica dioica L., Hemerocallis fulva (L.) L., Citrus maxima (Burm.) Merr., Citrus limon (L.) Osbeck, and Ficus formosana Maxim. MTT assay was used to evaluate the impact of these herbal tea extracts on hepatoxocitity. We found that these herbal tea extracts per se did not exhibit hepatotoxicity, and had no effect on OA-induced hepatotoxicity. However, extracts from Verbena officinalis L., Hyssopus officinalis L., Salvia officinalis L., and Hemerocallis fulva (L.) L. exhibited protective effect against PA-induced hepatotoxicity. In addition, herbal tea extracts from Verbena officinalis L., Hyssopus officinalis L., Salvia officinalis L., Urtica dioica L., Hemerocallis fulva (L.) L., and Ficus formosana Maxim. exhibited protective effect against acetaminophen-induced hepatotoxicity. Interestingly, all these herbal tea extracts enhanced ethanol-induced hepatotoxicity. Our results suggest that herbal tea extracts have differential effects on different modes of hepatotoxicity. [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]

Iron deficiency is the most prevalent nutritional deficiency, affecting more than 30% of the total world's population. It is a major public health problem in many countries around the world. Over the years various methods have been used with an effort to try and control iron-deficiency anemia. However, there has only been a marginal reduction in the global prevalence of anemia. Why is this so? Iron and zinc are essential trace elements for humans. These metals influence the transport and absorption of one another across the enterocytes and hepatocytes, due to similar ionic properties. This paper describes the structure and roles of major iron and zinc transport proteins, clarifies iron-zinc interactions at these sites, and provides a model for the mechanism of these interactions both at the local and systemic level. This review provides evidence that much of the massive extent of iron deficiency anemia in the world may be due to an underlying deficiency of zinc. It explains the reasons for predominance of cellular zinc status in determination of iron/zinc interactions and for the first time thoroughly explains mechanisms by which zinc brings about these changes. [ABSTRACT FROM AUTHOR]

Introduction: Hepatic stellate cells (HSCs) are essential for physiological homeostasis of the liver extracellular matrix (ECM). Excessive transdifferentiation of HSC from a quiescent to an activated phenotype contributes to disrupt this balance and can lead to liver fibrosis. Accumulating evidence has suggested that nuclear receptors (NRs) are involved in the regulation of HSC activation, proliferation, and function. Therefore, these NRs may be therapeutic targets to balance ECM homeostasis and inhibit HSC activation in liver fibrosis. Areas covered: In this review, the authors summarized the recent progress in the understanding of the regulatory role of NRs in HSCs and their potential as drug targets in liver fibrosis. Expert opinion: NRs are still potential therapy targets for inhibiting HSCs activation and liver fibrosis. However, the development of NRs agonists or antagonists to inhibit HSCs requires fully consideration of systemic effects. [ABSTRACT FROM AUTHOR]

Many nongenotoxic chemicals have been shown to produce liver tumors in mice and/or rats by a mode of action (MOA) involving activation of the constitutive androstane receptor (CAR). Studies with phenobarbital (PB) and other compounds have identified the key events for this MOA: CAR activation; increased hepatocellular proliferation; altered foci formation; and ultimately the development of adenomas/carcinomas. In terms of human relevance, the pivotal species difference is that CAR activators are mitogenic agents in mouse and rat hepatocytes, but they do not stimulate increased hepatocellular proliferation in humans. This conclusion is supported by substantial in vitro studies with cultured rodent and human hepatocytes and also by in vivo studies with chimeric mice with human hepatocytes. Examination of the literature reveals many similarities in the hepatic effects and species differences between activators of rodent CAR and the peroxisome proliferator-activated receptor alpha (PPARα), with PPARα activators also not being mitogenic agents in human hepatocytes. Overall, a critical analysis of the available data demonstrates that the established MOA for rodent liver tumor formation by PB and other CAR activators is qualitatively not plausible for humans. This conclusion is supported by data from several human epidemiology studies. [ABSTRACT FROM AUTHOR]

Glycogenolysis and gluconeogenesis are sensitive to nutritional state and their balances are disrupted in the liver by different pathological states. The regulation of the balance between glucose production and synthesis of glycogen continues to be a matter of investigation because of its implications in diseases and its value for therapeutics. We used the gluconeogenic precursor dihydroxyacetone (DHA) to study glycogen synthesis in isolated rat hepatocytes under gluconeogenic conditions. We used a glycogen phosphorylase (GP) inhibitor, 2-deoxy-2-fluoro-α-D-glucopyranosyl fluoride (F2Glc) to prevented GP from breaking up glycogen into glucose subunits and had a pool of glucose in the medium. Therefore, we evaluated the contribution of DHA as a unique source of carbohydrates on glycogen metabolism. We showed that DHA increased G6P levels that induced both GS activation and its translocation and, thus, an increment of glycogen deposition in a similar way as glucose did. [ABSTRACT FROM AUTHOR]

Food contact paperboards may be a potential source of food contamination as they can release chemicals (intentionally added or not), especially recycled paperboards. This study assessed the in vitro genotoxicity of food contact paperboard samples from a manufacturer, collected at the beginning and at the end of a recycling production chain. Samples were extracted in water to mimic a wet food contact. Different genotoxic endpoints were evaluated in two human hepatic cell lines (HepG2 and HepaRG) using bioassays: γH2AX and p53 activation, primary DNA damage with the comet assay and micronucleus formation. It was found that the samples from the beginning and the end of the production chain induced, with the same potency, γH2AX and p53-ser15 activation and DNA damage with the comet assay. The micronucleus assay was negative with the paperboard extract from the beginning of the chain, whereas positive data were observed for the end paperboard extract. These results indicate that samples from recycled food contact paperboard can induce in vitro genotoxic effects in this study's experimental conditions. [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]

Aim: The present study aims to explore the important role of Kupffer cell and its related cytokine TNF-α in immune liver injury induced by trichloroethylene (TCE). 36 female BALB/c mice were selected and randomly divided the mice into four groups. We established a BALB/c mouse model of TCE sensitization and pretreatment with GdCl3 (40 mg/kg) by intraperitoneal injection during the during the 17th and 19th days. We found F4/80, the marker of Kupffer cell, was increased in TCE positive group. GdCl3 treatment successfully blocked the activation of Kupffer cell. TNF-α was increased significantly in liver of TCE sensitized mice and decreased significantly when low-dose GdCl3 was used. We found TNF receptor 1 (TNFR1) was increased significantly and GdCl3 treatment resumed the expression of TNFR1 to normal level, as well as the F4/80, TNF-α and TNFR1 mRNA. We also found both caspase-8 and caspase-3 increased in TCE positive group and decreased in TCE + GdCl3 positive group. The number of apoptotic cells in TCE sensitized mice increased by TUNEL staining, and GdCl3 treatment alleviated this increase. Some cells showed edema and inflammatory cell aggregation in liver of TCE positive group, while in the TCE + GdCl3 positive group, the cytoplasm became loose and vacuole-like degeneration occurred. Our study unveils cross-talk between Kupffer cell activation and TNFR1 which mediate apoptosis in liver of TCE sensitized mice. [ABSTRACT FROM AUTHOR]

The outbreak of COVID-19 is a serious health threat worldwide. Different degrees of liver injury or liver dysfunctions have been reported in patients with COVID-19 infection. However, currently, it remains unclear to what extent liver diseases should be considered as significant risk factors for the severity and mortality of COVID-19. Moreover, the mechanisms involved in liver injury in severe COVID-19 infection are not yet well understood. This review summarizes the current evidence on liver function abnormalities in COVID-19 patients and the effects of preexisting liver disease on the disease severity. This review also illustrates the possible underlying mechanisms linking COVID-19 to liver injury, as well as provides recommendations to prevent liver damage in COVID-19 infection. The elevated levels of ALT, AST, GGT and bilirubin are common in more severe patients than non-severe or mild COVID-19 patients. Patients with preexisting medical conditions including chronic hepatic diseases are at higher risk for severe illness from COVID-19 infection. The drug's effects, possible viral inclusion in liver cells, systemic inflammation and hypoxia are potential causes of liver injury in severe COVID-19. Nevertheless, further studies are needed focusing on the preexisting hepatic diseases on prevention, treatment and outcome of COVID-19. [ABSTRACT FROM AUTHOR]

Gap junctions are a specialized group of cell-to-cell junctions that mediate direct intercellular communication between cells. They arise from the interaction of two hemichannels of adjacent cells, which in turn are composed of six connexin proteins. In liver, gap junctions are predominantly found in hepatocytes and play critical roles in virtually all phases of the hepatic life cycle, including cell growth, differentiation, liver-specific functionality and cell death. Liver gap junctions are directed through a broad variety of mechanisms ranging from epigenetic control of connexin expression to post-translational regulation of gap junction activity. This paper reviews established and novel aspects regarding the architecture, control and functional relevance of liver gap junctions. [ABSTRACT FROM AUTHOR]

The pulp and paper industry in Canada is developing technology for the production and use of nanocrystalline cellulose (NCC). A key component of the developmental work is an assessment of potential environmental risks. Towards this goal, NCC samples as well as carboxyl methyl cellulose (CMC), a surrogate of the parent cellulosic material, were subjected to an ecotoxicological evaluation. This involved toxicity tests with rainbow trout hepatocytes and nine aquatic species. The hepatocytes were most sensitive (EC20s between 10 and 200 mg/l) to NCC, although neither NCC nor CMC caused genotoxicity. In tests with the nine species, NCC affected the reproduction of the fathead minnow at (IC25) 0.29 g/l, but no other effects on endpoints such as survival and growth occurred in the other species at concentrations below 1 g/l, which was comparable to CMC. Based on this ecotoxicological characterization, NCC was found to have low toxicity potential and environmental risk. [ABSTRACT FROM AUTHOR]

The use of additives in different food products is growing up. It has attracted the attention towards the relation between the mutagenic potential of human diseases and food additives. Sunset yellow (SY) and sodium benzoate (NaB) are used as colorant and food additives worldwide. In the present study, genotoxic effects of different combinations of SY and NaB were assessed in vivo in female rats. Different combinations of SY and NaB were dissolved in water and administered daily to six animals groups for 12 weeks. Group 1 (control) received water, Group 2 received 5 mg/kg body weight (bw) SY plus 10 mg/kg bw NaB, group 3 received 5 mg/kg SY plus 100 mg/kg NaB, group 4 received 50 mg SY plus 100 mg/kg NaB, group 5 received 50 mg/kg SY plus 10 mg/kg NaB, group 6 received 200 mg/kg SY plus 750 mg/kg NaB, and group 7 received 20 mg/kg SY plus 75 mg/kg NaB. Genotoxicity investigations (Chromosomal aberration of bone marrow cells, Comet assay and DNA profile of liver cells) were carried out at the end of the experiment. Administration of 200 mg/kg SY plus 750 mg/kg NaB (group 6) induced the highest abnormalities percentage (1.5%) and showed structural abnormalities including end-to-end association, fragmentation, chromatid break, ring chromosome, and centric fusion break of chromosomes. Different combinations of SY and NaB induced an increase in the frequency of tailed nuclei (DNA damage) in liver cells. A concentration-dependent distinct DNA smear pattern was observed in the DNA isolated from liver cells of animals administered SY and NaB. In addition, administration of SY plus NaB resulted in an abnormal distribution of serum proteins. The results showed that the SY plus NaB could have genotoxic potential. With the increase applications of food additives, this study reported important data about screening the potential impacts. [ABSTRACT FROM AUTHOR]

Citral, 3,7-dimethyl-2,6-octadien-1-al, one of the main components of the essential oils obtained from several plants, is used as a food additive and as a fragrance for detergents, cosmetics and other toiletries. The literature shows disparity regarding citral genotoxicity. Thus, the main objective of our work was to evaluate the genotoxic effects of citral in human cell cultures, HepG2 and leukocytes. Cytotoxicity assays (trypan blue and MTT) showed citral toxic effects in HepG2 cells (with metabolizing liver enzymes), which contrasted with the absence of toxicity in leukocytes. After citral exposure, both cell types did not demonstrate clastogenic/aneugenic effects in the micronucleus test. However, for the comet assay, citral exposure lead to significant genotoxic effects in both HepG2 (even to citral low concentrations) and leukocytes. The use of citral must be viewed with caution due to its ability to induce DNA damages, especially after being metabolized by cells with active liver enzymes. [ABSTRACT FROM AUTHOR]

Accurate prediction of in vivo metabolic pathways in humans can be challenging because in vitro liver matrices may fail to produce certain in vivo metabolites. Rat and human spheroids, generated from cryopreserved hepatocytes in media that contained minimal amount of serum, maintained morphology, viability and cytochrome P450 (CYP) activities for at least a week without media exchange. With spheroid cultures, multiple Phase I and Phase II metabolites were observed in rat and human spheroid cultures that were incubated with loratadine (LOR) for multiple days. Consistent with in vivo observations, 3-hydroxydesloratadine, (3-OH-DL), along with its glucuronide, were observed in human spheroids, but not in rat spheroids. Interestingly, the putative intermediate metabolite leading to 3-OH-DL, DL-N-glucuronide, was observed in incubations with both rat and human spheroids. In conclusion, hepatocyte spheroid were capable of recapitulating the inter-species differences in metabolism between human and rat for LOR, therefore, it may represent a viable model for studying complex metabolic pathways. [ABSTRACT FROM AUTHOR]

Determine the inhibition mechanism through which cyclosporine inhibits the uptake and metabolism of atorvastatin in fresh rat hepatocytes using mechanistic models applied to data generated using a high throughput oil spin method. Atorvastatin was incubated in fresh rat hepatocytes (0.05–150 nmol/ml) with or without 20 min pre-incubation with 10 nmol/ml cyclosporine and sampled over 0.25–60 min using a high throughput oil spin method. Micro-rate constant and macro-rate constant mechanistic models were ranked based on goodness of fit values. The best fitting model to the data was a micro-rate constant mechanistic model including non-competitive inhibition of uptake and competitive inhibition of metabolism by cyclosporine (Model 2). The association rate constant for atorvastatin was 150-fold greater than the dissociation rate constant and 10-fold greater than the translocation into the cell. The association and dissociation rate constants for cyclosporine were 7-fold smaller and 10-fold greater, respectively, than atorvastatin. The simulated atorvastatin-transporter-cyclosporine complex derived using the micro-rate constant parameter estimates increased in line with the incubation concentration of atorvastatin. The increased amount of data generated with the high throughput oil spin method, combined with a micro-rate constant mechanistic model helps to explain the inhibition of uptake by cyclosporine following pre-incubation. [ABSTRACT FROM AUTHOR]

Predicting drug-induced liver injury is important in early stage drug discovery; however, an accurate prediction with existing hepatotoxicity evaluation tools is difficult. Conventional monolayer (2D) cultures have short viabilities and are therefore inappropriate for performing long-term toxicity tests. Conventionally used 200-μm spheroids also have toxicity detection limits. The goal of this study was to develop a humanized liver tissue capable of evaluating long-term toxicity with high sensitivity. Spheroids consisting of co-cultured cryopreserved primary human hepatocytes and human hepatic stellate cells were developed using a 3D bio-printer. The "3D bio-printed liver tissue", of ∼1 mm, was then used for long-term viability assessments (over 25 days) based on ATP, albumin, and urea levels. Hepatotoxicity evaluation was performed by analyzing the expression of genes involved in drug metabolism and transport over a 2-week drug exposure period. The 3D bio-printed liver tissue showed improved viability and enhanced gene expression of enzymes related to drug metabolism and transport, as compared to the controls. Additionally, the 3D bio-printed liver tissue demonstrated a high sensitivity for hepatotoxicity evaluation when combined with pathological evaluation and measurements for ATP production, and secretion of albumin and urea. In conclusion, the 3D bio-printed liver tissue was able to detect the toxicity of compounds that was, otherwise, undetected by 2D culture and conventionally used spheroids. These findings demonstrate a 3D bio-printed liver tissue with increased accuracy of hepatotoxicity prediction in the early stages of drug discovery, as compared to currently available methods. [ABSTRACT FROM AUTHOR]

Apart from using traditionally in culinary preparations, chili peppers are also important constituents of herbal medicines. Although the bioactive components are studied mostly in the fruits of Capsicum annuum, no such study reports till date is available for Ghost chili (C. chinense) from North East India. Therefore, the aim of this study was to carry out an analysis of the bioactive constituents in the naturally occurring hottest chili Ghost chili (C. chinense), and evaluate its antioxidant, pro/anti-genotoxic, and apoptotic effects in in vitro and in vivo models. Three different antioxidant assays showed that lower doses of Ghost chili extract showed higher DNA protective and antioxidant activities. Furthermore, the administration for 7 alternate days into 6 week old Swiss albino mice showed that the lower doses (50 and 100 mg/kg bw) reduced DMBA induced genotoxicity beside significantly enhancing the activities of hepatic antioxidant enzymes, while higher dose (200 mg/kg bw) induced genotoxic effect in bone marrow cells. The administration of higher dose (200 mg/kg bw) also induced apoptosis and upregulation of Bax (pro) and downregulation of Bcl-2 (anti) apoptotic genes. Dose dependent increase of apoptosis was also observed in Hep G2 and Hep 3B liver cancer cell lines. Our findings in the present study suggest that low doses of C. chinense can exert cancer chemopreventive effects. The induction of apoptosis in both cancer cell lines and mouse bone marrow cells, and up-regulation of proapoptotic genes suggests that the higher dose of C. chinense can be used for targeted cancer therapy. [ABSTRACT FROM AUTHOR]

Due to their beneficial health effects, strawberry tree (Arbutus unedo L.) leaves have for decades been used as herbal remedy in countries of the Mediterranean region. This pilot study is the first to investigate the liver function and DNA integrity in rat hepatocytes evaluated after 14 and 28 day treatments with strawberry tree water leaf extract and arbutin, administered per os to Lewis rats of both genders at a daily dose 200 mg/kg b.w. We focused on two types of biomarkers: enzyme serum markers of liver function (AST, ALT, and LDH), and primary DNA damage in the liver cells, which was estimated using the alkaline comet assay. At the tested dose, strawberry tree water leaf extract showed acceptable biocompatibility with liver tissue both in male and female rats, especially after shorter exposure. Our results also suggest that oral administration of single arbutin to rats was not associated with significant impairments either in the liver function or DNA integrity in hepatocytes. Considering that prolonged exposure to the tested compounds revealed minor changes in the studied biomarkers, future in vivo studies have to further clarify the biological and physiological relevance of these findings. [ABSTRACT FROM AUTHOR]

Genotoxic compounds may be detoxified to non-genotoxic metabolites while many pro-carcinogens require metabolic activation to exert their genotoxicity in vivo. Standard genotoxicity assays were developed and utilized for risk assessment for over 40 years. Most of these assays are conducted in metabolically incompetent rodent or human cell lines. Deficient in normal metabolism and relying on exogenous metabolic activation systems, the current in vitro genotoxicity assays often have yielded high false positive rates, which trigger unnecessary and costly in vivo studies. Metabolically active cells such as hepatocytes have been recognized as a promising cell model in predicting genotoxicity of carcinogens in vivo. In recent years, significant advances in tissue culture and biological technologies provided new opportunities for using hepatocytes in genetic toxicology. This review encompasses published studies (both in vitro and in vivo) using hepatocytes for genotoxicity assessment. Findings from both standard and newly developed genotoxicity assays are summarized. Various liver cell models used for genotoxicity assessment are described, including the potential application of advanced liver cell models such as 3D spheroids, organoids, and engineered hepatocytes. An integrated strategy, that includes the use of human-based cells with enhanced biological relevance and throughput, and applying the quantitative analysis of data, may provide an approach for future genotoxicity risk assessment. [ABSTRACT FROM AUTHOR]