GAPDH, Interferon γ, and Nitric Oxide: Inhibitors of Coronaviruses

As the COVID-19 pandemic finishes its second year, progress has been made against SARS-CoV-2 with vaccine candidates showing efficacy against this latest coronavirus strain. However, this pandemic presents a unique opportunity to investigate anti-viral therapies given the likely probability of another outbreak. One possible (and perhaps unlikely) therapeutic target could be GAPDH (glyceraldehyde-3-phosphate dehydrogenase). Studies have show that downregulation of GAPDH leads to a decrease in interferon gamma (IFNγ production (which is an important cytokine response against coronaviruses and viruses in general). In this light, the previous coronavirus strain (SARS-CoV) has actually been shown to downregulate GAPDH. Although perhaps better known for its role in glycolysis, GAPDH also plays a role in gene expression of a varied set of genes by binding to their mRNA to affect stability and thereby translation Moreover, GAPDH is also upregulated by nitric oxide (NO), an inhibitor against both SARS-CoV and SARS-CoV-2. Additionally, GAPDH has also been shown to be a negative transcriptional regulator of AT1R (angiotensin II receptor 1), which has been shown to bind ACE2 for eventual endocytosis of the complex implicating GAPDH's potential role in the kinetics of coronavirus entry as well in downstream inflammatory signaling resulting from AT1R activation. Lastly, another important role for GAPDH is its requirement in the assembly of the GAIT complex that is responsible for termination of translation of IFNγ-responsive genes that would be critical for the resolution of any inflammatory response. These observations would imply that sufficient levels of GAPDH are needed for immune responses to function properly during a coronaviral infection. By examining different coronavirus studies, this review explores GAPDH's role as an inhibitor of coronaviruses (at the viral transcriptional level and also as a modulator of gene expression related to inflammation), and its signal transduction links to the IFNγ and NO pathways.

Anticompulsive-like effect of nitric oxide synthase inhibitors in marble-burying test

Nitric oxide synthase (NOS) inhibitors decrease marble burying behavior (MBB), and the effect of several compounds that also attenuate MBB (such as classical antidepressants) engages the nitrergic system. In the present study, we tested the effect of the NOS inhibitor aminoguanidine (AMG) in attenuating MBB. For comparative reasons, we also tested the effect of selective inhibitors of neuronal (NOS1) and inducible (NOS2) isoforms NPA and 1400W, respectively. Our results indicate that AMG and NPA, but not 1400W, reduced the number of buried marbles in the marble burying test (MBT), which is considered an anticompulsive-like effect. No effect of AMG in the anxiety- or locomotor-related parameters of the elevated plus maze was observed. Taken together, our data is consistent with the current literature that suggests that nitric oxide inhibitors, putatively acting through the neuronal isoform of the synthesis enzyme (NOS1), exhibit anticompulsive-like properties.

Measuring stimulation and inhibition of intracellular nitric oxide production in SIM-A9 microglia using microfluidic single-cell analysis

Microfluidic single-cell analysis allows the examination of nitric oxide inhibitors and reveals a lognormal distribution of intracellular nitric oxide levels in SIM-A9 microglial cell populations.

Regulation of Hydrogen Sulfide Metabolism by Nitric Oxide Inhibitors and the Quality of Peaches during Cold Storage

Both nitric oxide (NO) and hydrogen sulfide (H2S) have been shown to have positive effects on the maintenance of fruit quality during storage; however, the mechanisms by which NO regulates the endogenous H2S metabolism remain unknown. In this experiment, peaches were immersed in solutions of NO, potassium 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (c-PTIO, as an NO scavenger), N-nitro-l-arginine methyl ester (l-NAME, as an inhibitor of nitric oxide synthase (NOS)-like activity), and sodium tungstate (as an inhibitor of nitrate reductase), and the resulting changes in the H2S metabolism of peaches were studied. The results showed that exogenous NO reduced the contents of endogenous H2S, Cys, and sulfite; decreased the activities of l-/d-cysteine desulfhydrase (l-/d-CD), O-acetylserine (thiol)lyase (OAS-TL), and sulfite reductase (SiR); and increased the activity of β-cyanoalanine synthase (β-CAS). Both c-PTIO and sodium tungstate had similar roles in increasing the H2S content by sustaining the activities of l-/d-CDs, OAS-TL, and SiR. l-NAME increased the H2S content, mainly by maintaining the d-CD activity. The results suggest that NO, c-PTIO, l-NAME, and sodium tungstate differently regulate the H2S metabolism of peaches during storage.