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Role of the Hippo pathway in liver regeneration and repair: recent advances
Full text linkAlthough the signaling pathways involved in normal liver regeneration have been well characterized, less has been done for livers affected by chronic tissue damage. These “abnormal livers” have an impaired regenerative response that leads to liver repair and fibrosis. The tumor suppressor Hippo pathway plays a key role in liver regeneration and repair. On this basis, this review discusses recent studies focusing on the involvement of the Hippo signaling pathway during “normal healthy liver regeneration” (i.e., in a normal liver after 2/3 partial hepatectomy) and “abnormal liver regeneration” (i.e., in a liver damaged by chronic disease). This could be an important question to address with respect to new therapies aimed at improving impaired liver regenerative responses. The studies reported here have shown that activation of the Hippo coactivators YAP/TAZ during normal liver regeneration promotes the formation of a new bile duct network through direct BEC proliferation or/and hepatocyte dedifferentiation to HPCs which can trans-differentiate to BECs. Moreover, YAP/TAZ signaling interaction with other signaling pathways mediates the recruitment and activation of Kupffer cells, which release mitogenic cytokines for parenchymal and/or non-parenchymal cells and engage in phagocytosis of cellular debris. In addition, YAP-mediated activation of stellate cells (HSCs) promotes liver regeneration through the synthesis of extracellular matrix. However, in chronically diseased livers, where the predetermined threshold for proper liver regeneration is exceeded, YAP/TAZ activation results in a reparative process characterized by liver fibrosis. In this condition, YAP/TAZ activation in parenchymal and non-parenchymal cells results in (i) differentiation of quiescent HSCs into myofibroblastic HSCs; (ii) recruitment of macrophages releasing inflammatory cytokines; (iii) polarization of macrophages toward the M2 phenotype. Since accumulation of damaged hepatocytes in chronic liver injury represent a significant risk factor for the development of hepatocarcinoma, this review also discussed the involvement of the Hippo pathway in the clearance of damaged cells
Comparison of tetraacetylethylendiamine + sodium perborate and sodium hypochlorite cytotoxicity on L929 fibroblasts
No full textIntroduction: Tetraacetylethylenediamine in association with sodium perborate (TAED+P) can be suggested for its use as an endodontic disinfectant because of its antimicrobial activity against different bacterial species when used at low concentrations. The purpose of this study was to measure the cytotoxicity of TAED+P on L929 fibroblasts and to compare it with that of sodium hypochlorite (NaOCl). Methods: L929 fibroblasts were grown in Dulbecco Modified Eagle Medium containing 10% fetal calf serum (FCS) at 37°C and 5% CO 2. At confluence, cells were split, plated in a 96-well plate, and incubated for 24 hours to allow attachment. The two disinfectants TAED+P and NaOCI were tested at various concentrations. The neutral red uptake and the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assays were used to evaluate the cell viability. The 50% inhibitory dose values for both disinfectants were calculated and statistically analyzed. The effect of both disinfectants on fibroblast viability was also determined in the presence of various concentrations of FCS. One-way analysis of variance with post hoc analysis using Tukey multiple comparison test was used for parametric data. Results: Both disinfectants induced a dose-related loss of cell viability; TAED+P resulted less cytotoxic than NaOCI in all the examined experimental conditions. Conclusions: These data support the possible use of TAED+P as an endodontic irrigant. Further studies are required to analyze its antibacterial activity against endodontic pathogens
α-Lipoic acid induces Endoplasmic Reticulum stress-mediated apoptosis in hepatoma cells
Full text linkHepatocellular carcinoma (HCC) is the most common liver cancer and a major cause of adult death. The current treatments for HCC suffer from drug resistance and poor prognosis; therefore, novel therapeutic agents are urgently needed. Phytochemicals have been proposed to treat a range of cancers. Among them, α-lipoic acid (α-LA), a naturally synthesized antioxidant found in various dietary animal and plant sources, prevents oxidant-mediated cell death in normal cells while inducing apoptosis in several cancer cell lines. Previously, we demonstrated that the treatment of hepatoma cells with α-LA induced apoptosis, which was preceded by the generation of reactive oxygen species (ROS) and activation of the p53 protein, a known inducer of mitochondria-mediated apoptosis. Several studies have shown that ROS-induced apoptosis is associated with endoplasmic reticulum (ER) stress and Unfolded Protein Response (UPR) activation. Herein, we investigated if α-LA-induced apoptosis in hepatoma cell lines was ER stress- and UPR-mediated by gene expression profiling analyses. UPR and ER stress pathways were the most up-regulated after treatment with α-LA. This finding, which has been confirmed by expression analyses of ER- and UPR-associated proteins, provides a better understanding of the molecular mechanisms behind the anti-tumoral action of α-LA on hepatoma cells
Solvent-Free Addition of Indole to Aldehydes: Unexpected Synthesis of Novel 1-[1-(1H-Indol-3-yl) Alkyl]-1H-Indoles and Preliminary Evaluation of Their Cytotoxicity in Hepatocarcinoma Cells
Full text linkNew 1-[1-(1H-indol-3-yl) alkyl]-1H-indoles, surprisingly, have been obtained from the addition of indole to a variety of aldehydes under neat conditions. CaO, present in excess, was fundamental for carrying out the reaction with paraformaldehyde. Under the same reaction conditions, aromatic and heteroaromatic aldehydes afforded only classical bis (indolyl) aryl indoles. In this paper, the role of CaO, together with the regiochemistry and the mechanism of the reaction, are discussed in detail. The effect of some selected 3,3′- and 1,3′-diindolyl methane derivatives on cell proliferation of the hepatoma cell line FaO was also evaluated
Compensatory regeneration, mitogen-induced liver growth, and multistage chemical carcinogenesis
No full textLiver cell proliferation has often been implicated to play a major role during different steps of the carcinogenic process. Most of the experimental studies indicating a close association between cell proliferation and liver cancer development have made use of a compensatory type of proliferative stimulus. However, liver growth may also be caused by direct hyperplasia after administration of primary mitogens. Our recent studies examined the possible differences between these two types of cell proliferation. Our studies indicate that a) increased expression of proto-oncogenes such as c-fos, c-jun, and c-myc is not necessary for entry into the cell cycle during mitogen-induced liver growth; b) mitogen-induced liver growth does not support initiation of chemical hepatocarcinogenesis; c) repeated proliferative stimuli induced by primary mitogens do not stimulate the growth of initiated cells to a focal and/or nodular stage; and d) mitogen-induced liver growth, unlike compensatory regeneration, is followed by a particular mode of cell death, namely, apoptosis. This type of cell death may be responsible for the elimination of carcinogen-initiated cells
The peroxisome proliferator BR931 kills FaO cells by p53-dependent apotosis
No full textAlthough suppression of apoptosis has been implicated as a mechanism for the hepatocarcinogenicity of peroxisome proliferators (PPs), they can also induce cell death in rat AH130 and human HepG2 hepatoma cells. To study how PPs induce cell death and to characterize the molecular events involved, we administered the hypolipidemic BR931, a peroxisome proliferator, to rat hepatoma FaO cells. Treatment with increasing concentrations of BR931 (0.015 to 0.6 mM) reduced cell viability in a dose- and time-dependent manner, associated with DNA fragmentation and morphological changes characteristic of apoptosis. BR931 also caused phosphorylation of p53 within 3 hours, translocation of the pro-apoptotic Bax protein to mitochondria, release of cytochrome-c into the cytosol, and activation of caspase-9 and -3. These results indicated that BR931 activated the intrinsic caspase cascade. Pretreatment with three different antioxidants, N-acetylcysteine, Vitamin C and Trolox, reduced apoptosis, suggesting that reactive oxygen species (ROS) plays a role in BR931-induced apoptosis. In support of this hypothesis, BR931 produced increased levels of 8-hydroxy-deoxy-guanosine, a marker of DNA oxidative damage. Antioxidants prevented the p53 phosphorylation, up-regulation of Bax and BR931-induced apoptosis. These results suggest that BR931 can increase generation of ROS, leading to DNA damage and p53 phosphorylation, which, in turn, induces the activation of Bax, release of cytochrome-c from mitochondria and activation of caspases, culminating in cell death
Two mechanisms by which ATP depletion potentiates induction of the mitochondrial permeability transition in cultured hepatocytes
No full textIncreased ROS generation and p53 activation in alpha-lipoic acid-induced apoptosis of hepatoma cells
No full textSex difference in the proliferative response of mouse hepatocytes to treatment with the CAR ligand TCPOBOP
No full textThe nuclear receptor Constitutive Androstane Receptor (CAR) binds DNA as a heterodimer with the retinoic-X receptor and activates gene transcription. Previously, in vitro studies have shown that the testosterone metabolites, androstenol and androstenol, inhibit the constitutive transcriptional activity of CAR, suggesting that differences might exist in the response to CAR-mediated gene activation between different sexes. In this study, we have analyzed the response of female and male CD-1 mice to stimulation of hepatocyte proliferation caused by the CAR ligand TCPOBOP. Results showed that the labelling index of female hepatocytes at 24, 30 and 36 h after treatment was much higher than that found in males. The higher proliferative activity of female hepatocytes was associated with increased hepatic levels of cyclin D1, cyclin A, E2F and enhanced phosphorylation of pRb and p107. The increased mitogenic response of females was associated with higher mRNA levels of CYP2B10, a known target of CAR. Administration of androstenol to TCPOBOP-treated mice caused a reduction of labelling index, which was accompanied by a decrease of CYP2B10 and CAR mRNA levels. In conclusion, the results show that, in addition to microsomal detoxification, another biological response elicited by the CAR ligand TCPOBOP, namely, hepatocyte proliferation, occurs at higher levels in female than male mice, suggesting that CAR transcriptional activity in males is partially counteracted by physiological higher levels of testosterone metabolites such as androstenol and androstenol
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