6-bromoindirubin-3--oxime and Necrosis

Areca nut, a major component in area quid, possesses genotoxic and carcinogenic activities. Areca nut extract (ANE) may affect the defensive functions of neutrophils. Recent studies suggest that areca nut chewing is associated with a higher prevalence of periodontal disease as a result of the detrimental effects of ANE on the host defense system. This study examined the effects of ANE on the apoptosis pathways in human neutrophils.. Apoptosis/necrosis of neutrophils was determined using flow cytometry. Proteins involved in the apoptosis pathway were determined using western blotting analysis.. The results indicated that ANE reduced early apoptosis, but increased the primary necrosis of neutrophils. ANE may arrest neutrophils in the G0/G1 phase and reduce the apoptotic hypodiploid DNA contents. The levels of cleaved forms of poly(ADP-ribose) polymerase, and of caspase-3 and caspase-8 were decreased by treatment with ANE. Moreover, glycogen synthase kinase-3 alpha/beta may be involved in the ANE-modulated effects of neutrophils.. Areca nut may regulate death pathways in neutrophils. This may be one mechanism by which areca nut compromises the periodontal health of areca nut chewers.

Topics: Adult; Apoptosis; Areca; Caspase 8; Caspase Inhibitors; Cell Degranulation; Cell Size; Cell Survival; Chromones; DNA; Enzyme Inhibitors; Flow Cytometry; G1 Phase; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Indoles; Maleimides; Morpholines; Necrosis; Neutrophils; Nitric Oxide Synthase; Nuts; Onium Compounds; Oximes; Phosphoinositide-3 Kinase Inhibitors; Plant Extracts; Poly(ADP-ribose) Polymerases; Resting Phase, Cell Cycle; Young Adult

Glycogen synthase kinase-3beta (GSK3beta) role in human immunodeficiency virus(HIV)-associated neurodegeneration has been evidenced by previous investigations. In this study, we investigated the specificity of two GSK3beta-specific inhibitors, AR-A014418 (A) and B6B30 (B) to prevent direct neurotoxicity in primary human neurons exposed to HIV (BaL). Neurons were exposed to HIV (500 pg/ml) for 12-h and 6-day periods in the presence and absence of A (1 microM, 100 nM, 10 nM) and B (50 nM, 5 nM, 500 pM) to investigate acute and ongoing mechanisms of HIV neurotoxicity. Using an lactate dehydrogenase (LDH) assay to assess cytotoxicity, we observed a significant neurotoxic effect of HIV from control values (P < .01) that was not restored via coexposures of all concentrations of A and B. Additionally, no change in LDH levels were observed after 6 days. However, activity of the acute proapoptotic markers caspases 3 and 7 using a luminescence assay were measured and found to be increased by exposure to HIV (BaL) compared to controls (P = .022). This effect was ameliorated via coexposure to all concentrations of A and 50 nM B after 12 h (P < .01) and to all concentrations of A and B after 6 days (P < .01). Overall, the results from this study provide further evidence for the ability of GSK3beta inhibition to be neuroprotective against HIV-associated neurotoxicity by reducing HIV associated procaspase induction. These data support a role for GSK3beta as a potential therapeutic target and may have important clinical implications for treatment of HIV-associated neurocognitive disorder.

Topics: AIDS Dementia Complex; Caspase 3; Caspase 7; Cells, Cultured; Enzyme Inhibitors; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Humans; Indoles; L-Lactate Dehydrogenase; Macrophages; Necrosis; Nerve Degeneration; Neurons; Oximes; Thiazoles; Urea