Glutathione S-transferase (GST) family of enzymes are involved in a two-stage detoxification process of a wide range of environmental toxins, carcinogens and xenobiotics. The GST enzymes play important roles in oxidative stress pathways, and polymorphisms in the GSTM1 and GSTT1 genes mediate susceptibility and outcome in different diseases. Human immunodeficiency virus (HIV) infection is associated with oxidative stress, but there is limited data on the frequency of deleted GSTM1 and GSTT1 genes in HIV/AIDS patients and their effect on progression among Ghanaians. This study sought to investigate the association between homozygous deletion of GSTM1 and GSTT1 genes (both null deletion) with HIV/AIDS disease progression in Ghanaian patients. HIV-infected individuals on antiretroviral therapy (ART), ART-naïve HIV patients, and HIV seronegative individuals were recruited for the study. HIV/AIDS disease progression was assessed by measuring CD4+ cell count and viral load of the patients, and GST polymorphism was determined by amplifying the GSTT1 and GSTM1 genes using multiplex PCR, with CYP1A1 gene as an internal control. The mean CD4+ count of patients that were naïve to ART (298 ± 243 cells/mm3) was significantly lower than that of patients on ART (604 ± 294 cells/mm3), and viral load was significantly lower in the ART-experienced group (30379 ± 15073 copies/mm3) compared to the ART-naïve group (209882 ± 75045 copies/mm3). Frequencies of GSTM1 and GSTT1 deletions were shown to be 21.9% and 19.8%, respectively, in the HIV patients, and patients with homozygous deletion of both GSTM1 and GSTT1 were more likely to have their CD4+ count rising above 350 cells/mm3 (OR = 6.44, 95% CI = 0.81–51.49, p = 0.039) suggesting that patients with homozygous deletion of GSTM1 and GSTT1 genes have slower disease progression. The findings of this study show that double deletion of glutathione S-transferases M1 and T1 is statistically associated with normal CD4+ count in patients diagnosed with HIV/AIDS. Further study is required to investigate the clinical importance of the both null deletion in HIV patients.
Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) have been associated with high oxidative stress in HIV patients. The disparity in antioxidant-oxidant levels in HIV patients favours viral replication and disease progression. This study aimed at determining the effect of ART on antioxidant enzymes activities and trace elements levels in Ghanaian HIV patients. A total of 242 participants; comprising of 105 HIV-infected patients on ART, 77 HIV-infected ART-naïve, and 60 HIV seronegative controls were recruited for the study. Whole blood was collected and used for haematological profiling, and the determination of CD4 + counts, superoxide dismutase (SOD) activity and trace element levels. Serum was used for liver function tests and the determination of glutathione reductase (GR) activity, and plasma was used to estimate reduced glutathione (GSH) levels. Low levels of haemoglobin (HB), hematocrit, mean cell volume (MCV) and mean cell hemoglobin (MCH), and trace elements were found in ART-naïve patients compared to those on ART and the seronegative controls. In the ART-naïve patients, glutathione reductase (GR) activity and reduced glutathione (GSH) level were significantly low compared to patients on ART and seronegative controls. Activity of SOD was significantly reduced in ART-naïve patients compared to those on ART and the control group, and manganese is the only trace element that showed a strong negative correlation with SOD activity and a positive and significant correlation with CD4 + count, and therefore needs to be investigated further. The study suggests that assessing antioxidant levels or enzymes activities of patients infected with HIV should be considered during therapy.
Yes-associated protein 1 (YAP1) was originally discovered as a WW domain-containing SRC kinase-binding protein. 1 YAP1 is distributed in the cytoplasm and in the nucleus. 2 YAP1 interacts with various transcription factors such as the TEAD family proteins, SMAD proteins, RUNX, and p73 to regulate gene transcription in the nucleus, while YAP1 undergoes proteasome degradation in the cytoplasm. [2][3][4][5][6][7] Therefore, cytoplasmic YAP1 is thought to be inactive, while nuclear YAP1 is considered to be active. The best characterized regulatory mechanism of the subcellular distribution of YAP1is its phosphorylation mediated by large tumor suppressor kinases (LATS1/2), the core kinases of the tumor suppressive Hippo pathway. LATS1/2 phosphorylate YAP1 at 5 serine residues. 2 The phosphorylation at
objective Highly active antiretroviral therapy (HAART) has considerably reduced HIV/AIDSrelated morbidity and mortality; however, the therapy has been associated with the development of cardiovascular disease (CVD), and genetic predisposition factors may aggravate disease outcome. This study was aimed at investigating the relationship between haptoglobin phenotypes and risk factors of CVD in HIV patients.methods A total of 105 HIV sero-positive patients on HAART and 75 HIV-infected HAART-na€ ıve individuals were enrolled in the study. Socio-demographics and clinical characteristics of the participants were obtained using a well-structured questionnaire. Lipid profile, lactate dehydrogenase (LDH) and haptoglobin (Hp) phenotypes were analysed from serum whiles haemoglobin (Hb) level, CD4 + cell count and HIV viral RNA load were determined using whole blood.results Atherogenic index of plasma (AIP) was significantly higher in patients on HAART than the na€ ıve group (P < 0.05). Age, BMI, visceral fat, systolic blood pressure LDH and lipid variables strongly and positively correlated with AIP (P < 0.05), with the exception of HDL-c (P < 0.001) which showed a negative correlation. HAART was associated with hypertension (v 2 = 4.33, P = 0.037), hypercholesterolaemia (v 2 = 10.99, P < 0.001), elevated LDL-c (v 2 = 10.30, P < 0.001) and decreased HDL-c (v 2 = 3.87, P = 0.09). Hp2-2 and Hp0 collectively was strongly associated with hypertension (OR = 2.54, P = 0.011), obesity (OR = 5.97, P < 0.001) and hypercholesterolaemia (OR = 2.99, P < 0.001).
RASSF6, a member of the tumor suppressor Ras-association domain family (RASSF) proteins, regulates cell cycle arrest and apoptosis via p53 and plays a tumor suppressor role. We previously reported that RASSF6 blocks MDM2-mediated p53 degradation and enhances p53 expression. In this study, we demonstrated that RASSF6 has nuclear-localization and nuclear-export signals and that DNA damage triggers the nuclear accumulation of RASSF6. We found that RASSF6 directly binds to BAF53, the component of SWI/SNF complex. DNA damage induces CDK9-mediated phosphorylation of BAF53, which enhances the interaction with RASSF6 and increases the amount of RASSF6 in the nucleus. Subsequently, RASSF6 augments the interaction between BAF53 and BAF60a, another component of SWI/SNF complex, and further promotes the interaction of BAF53 and BAF60a with p53. BAF53 silencing or BAF60a silencing attenuates RASSF6-mediated p53-target gene transcription and apoptosis. Thus, RASSF6 is involved in the regulation of DNA damage-induced complex formation including CDK9, BAF53, BAF60a, and p53.
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