Naringing reverses HIV-1 protease inhibitors-associated pancreatic beta-cell dysfunction in vitro.
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Abstract
Introduction: Chronic exposure to HIV-1 Protease Inhibitors (PIs) has been associated with
pancreatic β-cell dysfunction and impairment of insulin secretion. PIs have been suggested to
induce β-cell dysfunction through increasing oxidative stress leading to impaired insulin
secretion. The study investigated whether naringin, a naturally occurring antioxidant, could
reverse PIs-induced β-cell dysfunction by reducing oxidative stress.
Methods: The RIN-5F cells were cultured in RPM1-1640 medium, allowed to grow to 80%
confluence, exposed to different concentrations of PIs [nelfinavir (1-10 μM), saqanavir (1-10
μM) and atazanavir (5-20 μM)] in the presence of 11 mM glucose for 24 hr then subjected to
insulin ELISA assay to assess dose-dependent suppression of insulin of secretion by PIs. To
determine glucose-induced insulin secretion, the cells were exposed to nelfinavir (10 μM),
saquinavir (10 μM), atazanavir (20 μM) 24 hr with or without glibenclamide (10 μM) in the
presence of varying glucose concentrations (11-25 mM) then harvested and subjected to
biochemical assays for the measurement of insulin levels, lipid peroxidation, ATP generation,
Glutathione levels (GSH), Superoxide dismutase (SOD) and caspase-3 and -9 activities.
Cells were further exposed to naringin (0-50 μM) in the presence of 11 mM glucose for 24 hr
then subjected to insulin ELISA for insulin secretion determination. To investigate the role of
PIs relative to naringin on RIN-5F cells, the cells were exposed to nelfinavir (10 μM),
saquinavir (10 μM) and atazanavir (20 μM) with or without naringin (10 μM) also in the
presence of 11 mM for 24 hr and similarly subjected to biochemical assays.
Results: Linear regression analysis showed significant decrease in insulin levels in response
to nelfinavir, saqunavir and atazanavir (r2= 0.86, 0.76, 0.95, respectively) in a dose-dependent
manner. PIs significantly (p < 0.05) reduced insulin secretion and ATP production, increased
lipid peroxidation, SOD and caspase-3 and -9 activities and also reduced GSH in a glucosexv
dependent manner. These effects were reversed by glibenclamide. Naringin (0-50 μM) caused
dose-dependent increased in insulin secretion and also reduced lipid peroxidation, SOD,
caspase-3 and -9 activities, increased GSH and ATP levels in cells that were exposed to PIs.
Conclusion: PIs induced β-cell dysfunction and impairment of insulin secretion by increasing
oxidative stress and ATP depletion. Naringin ameliorated PIs-induced impairment of β-cell
dysfunction by reducing oxidative stress.
Description
M. Pharm. University of KwaZulu-Natal, Durban 2014.
Keywords
Antiretroviral agents., Pancreatic beta cells., Protease inhibitors., Theses -- Pharmacy and pharmacology.