Pathogenesis of HTLV-1 infection and progression biomarkers: An overview

ABSTRACT Infection by human T-cell lymphotropic virus type 1 (HTLV-1) occurs in lymphocytes, which travel throughout the body, thus affecting several target organs and causing varied clinical outcomes, particularly in populations that are underserved and do not have access to healthcare. However, the mechanism of pathogenesis is not yet fully understood. The TAX and HTLV-1 basic leucine zipper factor (HBZ) proteins maintain viral persistence and affect pathogenesis through cell proliferation and immune and inflammatory responses that accompany each clinical manifestation. TAX expression leads to inhibition of transcription error control, OX40 overexpression, and cell proliferation in adult T-cell leukemia (ATL). OX40 levels are elevated in the central nervous system (CNS), and the expression of TAX in the CNS causes neuronal damage and loss of immune reactivity among patients with HTLV-1-associated myelopathy (HAM). HBZ reduces viral replication and suppresses the immune response. Its cell compartmentalization has been associated with the pathogenesis of HAM (cytoplasmic localization) and ATL (nuclear localization). TAX and HBZ seem to act antagonistically in immune responses, affecting the pathogenesis of HTLV-1 infection. The progression from HTLV-1 infection to disease is a consequence of HTLV-1 replication in CD4+ T and CD8+ T lymphocytes and the imbalance between proinflammatory and anti-inflammatory cytokines. The compartmentalization of HBZ suggests that this protein may be an additional tool for assessing immune and inflammatory responses, in addition to those already recognized as potential biomarkers associated with progression from infection to disease (including human leukocyte antigen (HLA), killer immunoglobulin-like receptors (KIR), interleukin (IL)-6, IL-10, IL-28, Fas, Fas ligand, interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and mannose-binding lectin).

Biological functions of CREB/ATF bZIP transcription factor in metabolism and cell growth / 生理学报

Nutrient overload-caused deregulation of glucose and lipid metabolism leads to insulin resistance and metabolic disorders, which increases the risk of several types of cancers. CREB/ATF bZIP transcription factor (CREBZF), a novel transcription factor of the ATF/CREB family, has emerged as a critical mechanism bridging the gap between metabolism and cell growth. CREBZF forms a heterodimer with other proteins and functions as a coregulator for gene expression. CREBZF deficiency in the liver attenuates hepatic steatosis in high fat diet-induced insulin-resistant mice, while the expression levels of CREBZF are increased in the livers of obese mice and humans with hepatic steatosis. Intriguingly, CREBZF also regulates cell proliferation and apoptosis via interaction with several transcription factors including STAT3, p53 and HCF-1. Knockout of CREBZF in hepatocytes results in enhanced cell cycle progression and proliferation capacity in mice. Here we highlight how the CREBZF signaling network contributes to the deregulation of metabolism and cell growth, and discuss the potential of targeting these molecules for the treatment of insulin resistance, diabetes, fatty liver disease and cancer.

The rs11755527 polymorphism in the BACH2 gene and type 1 diabetes mellitus: case control study in a Brazilian population

ABSTRACT Objective Type 1 diabetes mellitus (T1DM) is an autoimmune disorder caused by a complex interaction between environmental and genetic risk factors. BTB domain and CNC homolog 2 (BACH2) gene encodes a transcription factor that acts on the differentiation and formation of B and T lymphocytes. BACH2 is also involved in the suppression of apoptosis and inflammation in pancreatic beta-cells, indicating a role for it in the development of T1DM. Therefore, the aim of this study was to evaluate the association of the BACH2 rs11755527 single nucleotide polymorphism (SNP) with T1DM. Subjects and methods This case-control study comprised 475 patients with T1DM and 598 nondiabetic individuals. The BACH2 rs11755527 (C/G) SNP was genotyped using real-time PCR with TaqMan MGB probes. Results Genotype distributions of rs11755527 SNP were in accordance with frequencies predicted by the Hardy-Weinberg equilibrium in case and control groups and were similar between groups (P = 0.729). The minor allele frequency was 43.6% in cases and 42.5% in controls (P = 0.604). Moreover, the G allele frequency did not differ between groups when considering different inheritance models and adjusting for age, gender, body mass index, and HLA DR/DQ genotypes of high-risk for T1DM. Although, well-known high-risk T1DM HLA DR/DQ genotypes were associated with T1DM in our population [OR= 7.42 (95% CI 3.34 - 17.0)], this association was not influenced by the rs11755527 SNP. Conclusion The BACH2 rs11755527 SNP seems not to be associated with T1DM in a Brazilian population.

Astragaloside Ⅳ regulates Nrf2/Bach1/HO-1 signaling pathway and inhibits H9c2 cardiomyocyte injury induced by hypoxia-reoxygenation / 中国中药杂志

Astragaloside Ⅳ(AS-Ⅳ) has protective effects against ischemia-reperfusion injury(IRI), but its mechanism of action has not yet been determined. This study aims to investigate the protective effects and mechanism of AS-Ⅳ on H9c2 cardiomyocyte injury induced by hypoxia-reoxygenation(H/R). The H/R model of myocardial cells was established by hypoxic culture for 12 hours and then reoxygenation culture for 8 hours. After AS-Ⅳ treatment, cell viability, the reactive oxygen species(ROS) levels, as well as the content or activity of superoxide dismutase(SOD), malondialdehyde(MDA), interleukin 6(IL-6), and tumor necrosis factor alpha(TNF-α), were measured to evaluate the effect of AS-Ⅳ treatment. The effect of AS-Ⅳ on HO-1 protein expression and nuclear Nrf2 and Bach1 protein expression was determined by Western blot. Finally, siRNA was used to knock down HO-1 gene expression to observe its reversal effect on AS-Ⅳ intervention. The results showed that as compared with the H/R model group, the cell viability was significantly increased(P<0.01), ROS level in the cells, MDA, hs-CRP and TNF-α in cell supernatant and nuclear protein Bach1 expression in the cells were significantly decreased(P<0.01), while SOD content, HO-1 protein expression in cells and expression of nuclear protein Nrf2 were significantly increased(P<0.01) in H/R+AS-Ⅳ group. However, pre-transfection of HO-1 siRNA into H9c2 cells by liposome could partly reverse the above effects of AS-Ⅳ after knocking down the expression of HO-1. This study suggests that AS-Ⅳ has significant protective effect on H/R injury of H9c2 cardiomyocytes, and Nrf2/Bach1/HO-1 signaling pathway may be a key signaling pathway for the effect.

HTLV-1 bZIP Factor (HBZ): Roles in HTLV-1 Oncogenesis / 病毒学报

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus demonstrated to be associated with human disease. Infection by the HTLV-1 can cause T-cell leukemia (ATL) in adults. HTLV-1 bZIP factor (HBZ) is a viral protein encoded by the minus strand of the HTLV-1 provirus. Among the regulatory and accessory genes of HTLV-1, HBZ is the only gene that remains intact and which is expressed consistently in all patients with ATL. Moreover, HBZ has a critical role in the leukemogenesis of ATL. Here, we review the function of HBZ in the oncogenesis of HTLV-1 and its molecular mechanism of action.

The expression and clinical significance of BATF2 in oral tongue squamous cell carcinoma / 中华口腔医学杂志

<p><b>OBJECTIVES</b>To investigate the expression and clinical significance of BATF2 in the oral tongue squamous cell carcinoma (OTSCC).</p><p><b>METHODS</b>Expression of BATF2 mRNA and protein in 16 paired OTSCC tissues and adjacent non-tumor mucosa were examined using quantitative PCR, western blotting analysis and immunohistochemistry assays, and the relation between BATF2 expression and clinical pathologic factor and prognosis was analyzed.</p><p><b>RESULTS</b>In 16 paired tissues, expression of BATF2 mRNA in 13 OTSCC tissues and expression of BATF2 protein in 14 OTSCC tissues were significantly lower than that in adjacent non-tumor mucosa. In 202 paraffin-embedded OTSCC samples, BATF2 was not expressed in 20 cases (9.9%), low expressed in 104 cases (51.5%) and highly expressed in 78 (38.6%). BATF2 expression level was significantly correlated with histological differentiation (P = 0.002). Patients with low BATF2 expression had significantly poorer overall survival and disease-free survival than those with high BATF2 expression (P < 0.001).</p><p><b>CONCLUSIONS</b>BATF2 was low expressed in OTSCC and related to tumor differentiation and prognosis and may serve as a prognostic biomarker and potential therapeutic target for this disease.</p>

Expression of BATF, a member of the activator protein-1 family, in renal tissues of MRL/lpr mice / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the expression of BATF, a member of the activator protein-1 family, in the renal tissues of mice with lupus nephritis.</p><p><b>METHODS</b>The renal tissues from 24-week-old female MRL/lpr mice and age- and sex-matched C57BL/6 mice were examined for BATF protein expressions using Western blotting and for expressions of BATF, RORγt and IL-17A mRNA using quantitative real-time PCR. The results of laboratory examinations were analyzed in relation with the histopathology of the mice.</p><p><b>RESULTS</b>The urinary protein and ds-DNA levels were significantly higher in MRL/lpr mice than in the control mice (P<0.05). Compared to normal control mice, MRL/lpr mice showed obvious glomerular fibrosis and inflammatory cell infiltrating with significantly increased BATF protein and mRNA expressions (P<0.05) and RORγt and IL-17 mRNA expressions in the renal tissues (P<0.05). In MRL/lpr mice, the expression of BATF mRNA was positively correlated with the RORγt and IL-17A mRNA expressions in the renal tissues.</p><p><b>CONCLUSION</b>The renal expressions of BATF protein and mRNA is increased in MRL/lpr mice. BATF may participate in the immunopathogenesis of lupus nephritis by enhancing Thl7 cell response.</p>

Biological Effects of the SARI Over-expression on K562 Cell Line / 中国实验血液学杂志

<p><b>OBJECTIVE</b>To construct a lentivirus vector carrying SARI gene and to investigate its biological effects on K562 cells.</p><p><b>METHODS</b>SARI was amplified from the plasmid containing SARI cDNA and subcloned into pLOV.CMV.eGFP virus vector. After sequencing, lentivirus packaging, titering, the viruses of SARI-pLOV.CMV.eGFP were harvested and tansfected into the K562 cells. Real-time quantitive PCR and Western blot were performed to validate the SARI expression at the level of mRNA and protein respectively. Simultaneously, the proliferation, apoptosis and cell cycle of K562 cells were detected by CCK-8 and flow cytometry respectively.</p><p><b>RESULTS</b>The SARI overexpressed lentivirus vector was successfully constructed. The mRNA and protein levels of SARI increased significantly in the pLOV.CMV.eGFP-SARI group, which was confirmed by Q-PCR and Western blot; as compared with blank and mock groups, SARI over-expression leaded to significant proliferation inhibition and increased apoptosis of K562 cells, without visible effects on cell cycle.</p><p><b>CONCLUSION</b>the over-expression of SARI gene obviously suppresses the cell proliferation of the K562 cells as well as promotes the apoptosis. The results implied that the induction of the SARI gene expression may be an important candidate therapeutic method for the CML.</p>

Influence of BCR-ABL inhibitor STI571 on SARI expression in K562 cells / 中国实验血液学杂志

In order to investigate the molecular mechanisms of SARI expression regulation in chronic myeloid leukemia (CML), 46 patients with CML and 40 healthy volunteers were recruited in this study. SARI expression in the peripheral blood mononuclear cells (PBMNC) of CML patients and healthy volunteers was assayed by using real-time quantitative PCR. K562 cells were in vitro incubated with the BCR-ABL inhibitor STI571 (imatinib) at 37°C and 5% CO2 for 24 hours, then SARI expression was detected by using real-time quantitative PCR. All experiments were repeated three times. The results showed that as compared with healthy volunteers, the expression of SARI mRNA in PBMNC of CML patients presented a lower level (p < 0.001). After exposure of K562 cells to STI571 (2.5 µmol/L) for 24 hours, the SARI expression was higher than that in K562 cells treated without STI571 (p < 0.001). It is concluded that the suppression of SARI expression is involved in CML pathogenesis, and BCR-ABL mediates the down-regulation of SARI mRNA expression in K562 cells. These findings suggest a new orientation for gene therapy in CML patients.

Regulation glutathione synthesizing and regenerating enzymes by xenobiotics in the brain of mice with targeted deletion of the NRF2 transcription factor gene gwqrzo, M.Y

Basal expression of certain antioxidant enzymes was shown to be lower in the livers of Nrf2[-/-] mice [Hhyes et al., 2000]. In order to investigate the role of Nrf2 in the regulation of GSH synthesizing and regenerating enzymes in the brain, cytbsols from the brains of Nrf2[-/-] mice treated with the antioxidant agents ethoxyquin, oltipraz, kahweol palmitate or indole-3-carbinol were analysed for glutatltione content, expression and activity of certain antioxidant enzymes. The analysis enzyme activities indicated reduction of 6 phosphogluconate dehydrogenase and Glutathione reductase activities by almost 14 and 20% in Nrf2 null compared with the wild type control respectively Treatment with chemopreventive agents increased the levels of these enzymes in Nrf2 [-/-] mice brain. But only 6-phosphogluconate dehydrogenase activity was increase in both Nif2[+/+] and Nrf2[-/-] mice brain. However, deletion of Nrf2 did not affect the protein levels of glutmyl cysteine ligase [GCL] and glutathione synthetase [GS] enzymes. Despite lack of apparent effect of the deficiency of Nr12 on the levels of proteins of GCL and GS, upon treatment with chemical additives, there was an increase in the level of GSH in both Nrf2[+/+] and Nrf2[-/-] mice brain upon treatment with chemical additives