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Antioxidant nanozyme counteracts HIV-1 by modulating intracellular redox potential

ABSTRACT: Reactive oxygen species (ROS) regulates the replication of human immunodeficiency virus (HIV-1) during infection. However, the application of this knowledge to develop therapeutic strategies remained unsuccessful due to the harmful consequences of manipulating cellular antioxidant systems. Here, we show that vanadium pentoxide (V2O5) nanosheets functionally mimic natural glutathione peroxidase activity to mitigate ROS associated with HIV-1 infection without adversely affecting cellular physiology. Using genetic reporters of glutathione redox potential and hydrogen peroxide, we showed that V2O5-nanosheets catalyze ROS neutralization in HIV-1 infected cells and uniformly block viral reactivation and replication. Mechanistically, V2O5-nanosheets suppressed HIV-1 by affecting the expression of pathways coordinating redox balance, virus transactivation (e.g., NF-?B), inflammation, and apoptosis. Importantly, a combination of V2O5-nanosheets with a pharmacological inhibitor of NF-?B (BAY11-7082) abrogated reactivation of HIV-1. Lastly, V2O5-nanosheets inhibit viral reactivation upon prostratin stimulation of latently infected CD4+ T cells from HIV-infected patients receiving suppressive antiretroviral therapy. Our data successfully revealed the usefulness of V2O5-nanosheets against HIV and suggested nanozymes as future platforms to develop interventions against infectious diseases

SUBMITTER: Ms. Shalini Singh

PROVIDER: S-SCDT-EMM-2020-13314P | biostudies-other |

REPOSITORIES: biostudies-other

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Project description:Global warming is impacting the growth and development of economically important but sensitive crops, such as soybean (Glycine max L.). Using pleiotropic signaling molecules, melatonin can relieve the negative effects of high temperature by enhancing plant growth and development as well as modulating the defense system against abiotic stresses. However, less is known about how melatonin regulates the phytohormones and polyamines during heat stress. Our results showed that high temperature significantly increased ROS and decreased photosynthesis efficiency in soybean plants. Conversely, pretreatment with melatonin increased plant growth and photosynthetic pigments (chl a and chl b) and reduced oxidative stress via scavenging hydrogen peroxide and superoxide and reducing the MDA and electrolyte leakage contents. The inherent stress defense responses were further strengthened by the enhanced activities of antioxidants and upregulation of the expression of ascorbate-glutathione cycle genes. Melatonin mitigates heat stress by increasing several biochemicals (phenolics, flavonoids, and proline), as well as the endogenous melatonin and polyamines (spermine, spermidine, and putrescine). Furthermore, the positive effects of melatonin treatment also correlated with a reduced abscisic acid content, down-regulation of the gmNCED3, and up-regulation of catabolic genes (CYP707A1 and CYP707A2) during heat stress. Contrarily, an increase in salicylic acid and up-regulated expression of the defense-related gene PAL2 were revealed. In addition, melatonin induced the expression of heat shock protein 90 (gmHsp90) and heat shock transcription factor (gmHsfA2), suggesting promotion of ROS detoxification via the hydrogen peroxide-mediated signaling pathway. In conclusion, exogenous melatonin improves the thermotolerance of soybean plants and enhances plant growth and development by activating antioxidant defense mechanisms, interacting with plant hormones, and reprogramming the biochemical metabolism.

Project description:PurposeSonlicromanol is a phase IIB clinical stage compound developed for treatment of mitochondrial diseases. Its active component, KH176m, functions as an antioxidant, directly scavenging reactive oxygen species (ROS), and redox activator, boosting the peroxiredoxin-thioredoxin system. Here, we examined KH176m's potential to protect against acute cardiac ischemia-reperfusion injury (IRI), compare it with the classic antioxidant N-(2-mercaptopropionyl)-glycine (MPG), and determine whether protection depends on duration (severity) of ischemia.MethodsIsolated C56Bl/6N mouse hearts were Langendorff-perfused and subjected to short (20 min) or long (30 min) ischemia, followed by reperfusion. During perfusion, hearts were treated with saline, 10 μM KH176m, or 1 mM MPG. Cardiac function, cell death (necrosis), and mitochondrial damage (cytochrome c (CytC) release) were evaluated. In additional series, the effect of KH176m treatment on the irreversible oxidative stress marker 4-hydroxy-2-nonenal (4-HNE), formed during ischemia only, was determined at 30-min reperfusion.ResultsDuring baseline conditions, both drugs reduced cardiac performance, with opposing effects on vascular resistance (increased with KH176m, decreased with MPG). For short ischemia, KH176m robustly reduced all cell death parameters: LDH release (0.2 ± 0.2 vs 0.8 ± 0.5 U/min/GWW), infarct size (15 ± 8 vs 31 ± 20%), and CytC release (168.0 ± 151.9 vs 790.8 ± 453.6 ng/min/GWW). Protection by KH176m was associated with decreased cardiac 4-HNE. MPG only reduced CytC release. Following long ischemia, IRI was doubled, and KH176m and MPG now only reduced LDH release. The reduced protection against long ischemia was associated with the inability to reduce cardiac 4-HNE.ConclusionProtection against cardiac IRI by the antioxidant KH176m is critically dependent on duration of ischemia. The data suggest that with longer ischemia, the capacity of KH176m to reduce cardiac oxidative stress is rate-limiting, irreversible ischemic oxidative damage maximally accumulates, and antioxidant protection is strongly diminished.

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Antioxidant nanozyme counteracts HIV-1 by modulating intracellular redox potential

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