Regulation of TGF-β1-Induced Pro-Apoptotic Signaling by Growth Factor Receptors and Extracellular Matrix Receptor Integrins in the Liver

Hepatocellular carcinoma (HCC) often arises from chronically diseased livers. Persistent liver inflammation causes the accumulation of excessive extracellular matrix (ECM) proteins and impairs the liver function, finally leading to the development of HCC. A pleiotropic cytokine, transforming growth factor (TGF)-β1, plays critical roles throughout the process of fibrogenesis and hepatocarcinogenesis. In the liver, TGF-β1 inhibits the proliferation of hepatocytes and stimulates the production of ECM from hepatic stellate cells (HSCs) to maintain tissue homeostasis. During disease progression, both growth factors/cytokines and the ECM alter the TGF-β1 signals by modifying the phosphorylation of Smad proteins at their C-terminal and linker regions. TGF-β1 stimulates the expression of integrins, cellular receptors for ECM, along with an increase in ECM accumulation. The activation of integrins by the ECM modulates the response to TGF-β1 in hepatic cells, resulting in their resistance to TGF-β1-induced growth suppression in hepatocytes and the sustained production of ECM proteins in activated HSCs/myofibroblasts. Both growth factor receptors and integrins modify the expression and/or functions of the downstream effectors of TGF-β1, resulting in the escape of hepatocytes from TGF-β1-induced apoptosis. Recent studies have revealed that the alterations of Smad phosphorylation that occur as the results of the crosstalk between TGF-β1, growth factors and integrins could change the nature of TGF-β1 signals from tumor suppression to promotion. Therefore, the modification of Smad phosphorylation could be an attractive target for the prevention and/or treatment of HCC

HIV prevalence and factors associated with HIV infection among male injection drug users under 30: a cross-sectional study in Long An, Vietnam

BACKGROUND: Sufficient targeted HIV prevention activities aiming at reducing HIV transmission within and from an extremely marginalized population of injection drug users (IDUs) must urgently and efficiently be implemented in Vietnam. This study was conducted to facilitate the development of such activities by describing transmission risks of young IDUs and evaluating factors in association with HIV infection. METHODS: Thirty clusters were selected from 29 hotspot communes in Long An province by probability proportional to size (PPS) sampling method. The snowball technique was used for enrolling participants in each cluster. The cross-sectional association of factors obtained during direct structured interviews to 248 male IDUs aged 14 to 29 years old and with their HIV test results were examined. RESULTS: The HIV prevalence among the studied IDUs was 32%. Age range of 18–20 years old, low educational level, sharing injection equipment or injection drug use in the other cities were independently associated with HIV serostatus in the multivariate analysis. Sexual behaviors did not differ between HIV-positive and -negative IDUs. Among HIV seropositive IDUs who had sexual contact with primary (n = 37), casual (n = 6), and commercial (n = 15) partners, only 5.4% (n = 2), 33.3% (n = 2), and 46.7% (n = 7), respectively, responded that they had used condoms every time. CONCLUSION: About one-third of young IDUs aged less than 30 identified in the hotspot communes in Long An, Vietnam was found to be infected with HIV, and socio-demographic and injection-related factors might account for the infection risk. Prevailing risky sexual behavior of this extremely marginalized population highlights the need to reduce their high transmission risks as a public health priority

Cytotoxicity effect of oil palm (Elaeis guineensis) kernel protein hydrolysates

This study was conducted to ascertain the cytotoxicity effect of oil palm (Elaeis guineensis) kernel protein hydrolysates (OPKHs) produced from its protein isolate. A modified microplate titer WST-1 [2-(4-iodophenyl)-3-(4-nitrophenyl)-5-(2,4-disulfophenyl)-2H-tetrazolium] assay was used to investigate the cytotoxicity of hydrolysates produced from protease and pepsin-pancreatin hydrolysis at various concentrations (0.1, 1, 10, 100 μg/ml and 1 mg/ml) using HepG2 cell model. Additionally, peptide stimulation test using OPKHs at 1 mg/ml was carried out to investigate whether OPKHs could serve as growth factor for HepG2 cells other than affecting its viability. As a result, oleic acid appeared to normalize the WST-1 readings of HepG2 cells treated with both hydrolysates at 1 mg/ml. The presence of amino acids in OPKHs could stimulate the growth and prolongs the viability of HepG2 cells. Both OPKHs were non-cytotoxic to HepG2 cells at all tested concentrations even at high concentrations. This study indicated that pepsin-pancreatin and protease hydrolysates produced from oil palm kernel protein were non-cytotoxic on HepG2 cells

Regulation of tumor suppressor PDCD4 by novel protein kinase C isoforms

AbstractTransforming growth factor-β1 (TGF-β1) induces apoptosis in normal hepatocytes and hepatoma cells. PDCD4 is involved in TGF-β1-induced apoptosis via the Smad pathway. The tumor promoter 12-O-tetradecanoylphorbor-13-acetate (TPA), a protein kinase C stimulator, inhibits TGF-β1-induced apoptosis. However, the mechanisms of TPA action on PDCD4 expression remain to be elucidated. Therefore. the regulatory mechanism of PDCD4 expression by PKC was investigated. The treatment of the human hepatoma cell line, Huh7 with TPA suppressed PDCD4 protein expression and TGF-β1 failed to increase the PDCD4 protein expression. PKC inhibitors Ro-31-8425 or bisindolylmaleimide-1-hydrocholoride (pan-PKC inhibitors) and rottlerin (PKCδ inhibitor), but not Go6976 (PKCα inhibitor), enhanced the induction of PDCD4 protein by TGF-β1. Furthermore, siRNA-mediated knockdown of PKCδ and ε, but not PKCα, augmented the TGF-β1-stimulated PDCD4 protein expression. However, TPA or pan-PKC inhibitor did not alter the PDCD4 mRNA expression either under basal- and TGF-β1-treated conditions. The down-regulation of PDCD4 by TPA was restored by treatment with the proteasome inhibitor MG132. These data suggest that two isoforms of PKCs are involved in the regulation of the PDCD4 protein expression related to the proteasomal degradation pathway

Control Mechanisms of the Tumor Suppressor PDCD4: Expression and Functions

PDCD4 is a novel tumor suppressor to show multi-functions inhibiting cell growth, tumor invasion, metastasis, and inducing apoptosis. PDCD4 protein binds to the translation initiation factor eIF4A, some transcription factors, and many other factors and modulates the function of the binding partners. PDCD4 downregulation stimulates and PDCD4 upregulation inhibits the TPA-induced transformation of cells. However, PDCD4 gene mutations have not been found in tumor cells but gene expression was post transcriptionally downregulated by micro environmental factors such as growth factors and interleukins. In this review, we focus on the suppression mechanisms of PDCD4 protein that is induced by the tumor promotors EGF and TPA, and in the inflammatory conditions. PDCD4-protein is phosphorylated at 2 serines in the SCFβTRCP ubiquitin ligase binding sequences via EGF and/or TPA induced signaling pathway, ubiquitinated, by the ubiquitin ligase and degraded in the proteasome system. The PDCD4 protein synthesis is inhibited by microRNAs including miR21

HIV prevalence and factors associated with HIV infection among male injection drug users under 30: a cross-sectional study in Long An, Vietnam

Abstract Background Sufficient targeted HIV prevention activities aiming at reducing HIV transmission within and from an extremely marginalized population of injection drug users (IDUs) must urgently and efficiently be implemented in Vietnam. This study was conducted to facilitate the development of such activities by describing transmission risks of young IDUs and evaluating factors in association with HIV infection. Methods Thirty clusters were selected from 29 hotspot communes in Long An province by probability proportional to size (PPS) sampling method. The snowball technique was used for enrolling participants in each cluster. The cross-sectional association of factors obtained during direct structured interviews to 248 male IDUs aged 14 to 29 years old and with their HIV test results were examined. Results The HIV prevalence among the studied IDUs was 32%. Age range of 18–20 years old, low educational level, sharing injection equipment or injection drug use in the other cities were independently associated with HIV serostatus in the multivariate analysis. Sexual behaviors did not differ between HIV-positive and -negative IDUs. Among HIV seropositive IDUs who had sexual contact with primary (n = 37), casual (n = 6), and commercial (n = 15) partners, only 5.4% (n = 2), 33.3% (n = 2), and 46.7% (n = 7), respectively, responded that they had used condoms every time. Conclusion About one-third of young IDUs aged less than 30 identified in the hotspot communes in Long An, Vietnam was found to be infected with HIV, and socio-demographic and injection-related factors might account for the infection risk. Prevailing risky sexual behavior of this extremely marginalized population highlights the need to reduce their high transmission risks as a public health priority.</p