Does Nitric Oxide Play a Critical Role in Viral Infections?

SUMMARY Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach. Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Molecular studies have indicated that viral proteases play a critical role in the life cycle of many viruses by effecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles. This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral proteases encoded by the herpesvirus, retrovirus, hepatitis C virus, and human rhinovirus families are discussed.

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Nitric Oxide to Fight Viral Infections

Advanced Science ◽

10.1002/advs.202003895 ◽

2021 ◽

pp. 2003895

Author(s):

Fabio Lisi ◽

Alexander N. Zelikin ◽

Rona Chandrawati

Keyword(s):

Nitric Oxide ◽

Viral Infections

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Characterization of key residues in the subdomain encoded by exons 8 and 9 of human inducible nitric oxide synthase: A critical role for Asp-280 in substrate binding and subunit interactions

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.181251298 ◽

2001 ◽

Vol 98 (18) ◽

pp. 10392-10397 ◽

Cited By ~ 30

Author(s):

D. K. Ghosh ◽

M. B. Rashid ◽

B. Crane ◽

V. Taskar ◽

M. Mast ◽

...

Keyword(s):

Nitric Oxide ◽

Nitric Oxide Synthase ◽

Inducible Nitric Oxide Synthase ◽

Substrate Binding ◽

Critical Role ◽

Subunit Interactions ◽

Key Residues ◽

Oxide Synthase ◽

Inducible Nitric Oxide

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Gene of the month: BECN1

Journal of Clinical Pathology ◽

10.1136/jclinpath-2014-202356 ◽

2014 ◽

Vol 67 (8) ◽

pp. 656-660 ◽

Cited By ~ 38

Author(s):

Sumit Sahni ◽

Angelica M Merlot ◽

Sukriti Krishan ◽

Patric J Jansson ◽

Des R Richardson

Keyword(s):

Neurological Disorders ◽

Viral Infections ◽

Critical Role ◽

Beclin 1 ◽

Biological Processes ◽

Disease States ◽

Binding Partners ◽

Future Drug ◽

Cellular Components ◽

Important Therapeutic Target

The BECN1 gene encodes the Beclin-1 protein, which is a well-established regulator of the autophagic pathway. It is a mammalian orthologue of the ATG6 gene in yeast and was one of the first identified mammalian autophagy-associated genes. Beclin-1 interacts with a number of binding partners in the cell which can lead to either activation (eg, via PI3KC3/Vps34, Ambra 1, UV radiation resistance-associated gene) or inhibition (eg, via Bcl-2, Rubicon) of the autophagic pathway. Apart from its role as a regulator of autophagy, it is also shown to effect important biological processes in the cell such as apoptosis and embryogenesis. Beclin-1 has also been implicated to play a critical role in the pathology of a variety of disease states including cancer, neurological disorders (eg, Alzheimer's disease, Parkinson's disease) and viral infections. Thus, understanding the functions of Beclin-1 and its interactions with other cellular components will aid in its development as an important therapeutic target for future drug development.

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Developmental changes in nitric oxide synthase isoform expression and nitric oxide production in fetal baboon lung

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00112.2002 ◽

2002 ◽

Vol 283 (6) ◽

pp. L1192-L1199 ◽

Cited By ~ 64

Author(s):

Philip W. Shaul ◽

Sam Afshar ◽

Linda L. Gibson ◽

Todd S. Sherman ◽

Jay D. Kerecman ◽

...

Keyword(s):

Nitric Oxide ◽

Critical Role ◽

Perinatal Period ◽

Postnatal Period ◽

Developmental Changes ◽

No Production ◽

Third Trimester ◽

Isoform Expression ◽

Oxide Synthase ◽

Nos Isoforms

Nitric oxide (NO), produced by NO synthase (NOS), plays a critical role in multiple processes in the lung during the perinatal period. To better understand the regulation of pulmonary NO production in the developing primate, we determined the cell specificity and developmental changes in NOS isoform expression and action in the lungs of third-trimester fetal baboons. Immunohistochemistry in lungs obtained at 175 days (d) of gestation (term = 185 d) revealed that all three NOS isoforms, neuronal NOS (nNOS), endothelial NOS (eNOS), and inducible NOS (iNOS), are primarily expressed in proximal airway epithelium. In proximal lung, there was a marked increase in total NOS enzymatic activity from 125 to 140 d gestation due to elevations in nNOS and eNOS, whereas iNOS expression and activity were minimal. Total NOS activity was constant from 140 to 175 d gestation, and during the latter stage (160–175 d gestation), a dramatic fall in nNOS and eNOS was replaced by a rise in iNOS. Studies done within 1 h of delivery at 125 or 140 d gestation revealed that the principal increase in NOS during the third trimester is associated with an elevation in exhaled NO levels, a decline in expiratory resistance, and greater pulmonary compliance. Thus, there are developmental increases in pulmonary NOS expression and NO production during the early third trimester in the primate that may enhance airway and parenchymal function in the immediate postnatal period.

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Activation of Stimulator of Interferon Genes (STING) and Sjögren Syndrome

Journal of Dental Research ◽

10.1177/0022034518760855 ◽

2018 ◽

Vol 97 (8) ◽

pp. 893-900 ◽

Cited By ~ 11

Author(s):

J. Papinska ◽

H. Bagavant ◽

G.B. Gmyrek ◽

M. Sroka ◽

S. Tummala ◽

...

Keyword(s):

Gene Expression ◽

Viral Infections ◽

Critical Role ◽

Autoimmune Disorder ◽

Sjögren Syndrome ◽

Lymphoid Cells ◽

Type I Interferons ◽

Sjogren Syndrome ◽

Type I ◽

Type I Ifns

Sjögren syndrome (SS), a chronic autoimmune disorder causing dry mouth, adversely affects the overall oral health in patients. Activation of innate immune responses and excessive production of type I interferons (IFNs) play a critical role in the pathogenesis of this disorder. Recognition of nucleic acids by cytosolic nucleic acid sensors is a major trigger for the induction of type I IFNs. Upon activation, cytosolic DNA sensors can interact with the stimulator of interferon genes (STING) protein, and activation of STING causes increased expression of type I IFNs. The role of STING activation in SS is not known. In this study, to investigate whether the cytosolic DNA sensing pathway influences SS development, female C57BL/6 mice were injected with a STING agonist, dimethylxanthenone-4-acetic acid (DMXAA). Salivary glands (SGs) were studied for gene expression and inflammatory cell infiltration. SG function was evaluated by measuring pilocarpine-induced salivation. Sera were analyzed for cytokines and autoantibodies. Primary SG cells were used to study the expression and activation of STING. Our data show that systemic DMXAA treatment rapidly induced the expression of Ifnb1, Il6, and Tnfa in the SGs, and these cytokines were also elevated in circulation. In contrast, increased Ifng gene expression was dominantly detected in the SGs. The type I innate lymphoid cells present within the SGs were the major source of IFN-γ, and their numbers increased significantly within 3 d of treatment. STING expression in SGs was mainly observed in ductal and interstitial cells. In primary SG cells, DMXAA activated STING and induced IFN-β production. The DMXAA-treated mice developed autoantibodies, sialoadenitis, and glandular hypofunction. Our study demonstrates that activation of the STING pathway holds the potential to initiate SS. Thus, apart from viral infections, conditions that cause cellular perturbations and accumulation of host DNA within the cytosol should also be considered as possible triggers for SS.

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Persistent Pulmonary Hypertension of the Newborn: Role of Nitric Oxide

Journal of Intensive Care Medicine ◽

10.1177/088506669501000602 ◽

1995 ◽

Vol 10 (6) ◽

pp. 270-282

Author(s):

Stella Kourembanas

Keyword(s):

Nitric Oxide ◽

Pulmonary Hypertension ◽

Structural Changes ◽

Critical Role ◽

Persistent Pulmonary Hypertension ◽

Cell Contractility ◽

Vasoactive Mediators ◽

Nitric Oxide Therapy

Persistent pulmonary hypertension of the newborn (PPHN) is a common cause of respiratory failure in the full-term neonate. Molecular and cellular studies in vascular biology have revealed that endothelial-derived mediators play a critical role in the pathogenesis and treatment of PPHN. Endothelial-derived vasoconstrictors, like endothelin, may increase smooth muscle cell contractility and growth, leading to the physiologic and structural changes observed in the pulmonary arterioles of infants with this disease. On the other hand, decreased production of the endothelial-derived relaxing factor, nitric oxide, may exacerbate pulmonary vasoreactivity and lead to more severe pulmonary hypertension. Exogenous (inhaled) nitric oxide therapy reduces pulmonary vascular resistance and improves oxygenation. The safety and efficacy of this therapy in reducing the need for extracorporeal membrane oxygenation and decreasing long-term morbidity is being tested in several trials nationally and abroad. Understanding the basic mechanisms that regulate the gene expression and production of these vasoactive mediators will lead to improved preventive and therapeutic strategies for PPHN.

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Inhibition of Vascular Nitric Oxide after Rat Chronic Brain Hypoperfusion: Spatial Memory and Immunocytochemical Changes

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/sj.jcbfm.9600057 ◽

2005 ◽

Vol 25 (6) ◽

pp. 663-672 ◽

Cited By ~ 78

Author(s):

Jack C. de la Torre ◽

Gjumrakch Aliev

Keyword(s):

Nitric Oxide ◽

Spatial Memory ◽

Memory Function ◽

Critical Role ◽

Artery Occlusion ◽

Carotid Artery Occlusion ◽

Significant Loss ◽

Electron Microscopic ◽

Vessel Occlusion ◽

Common Carotid Artery Occlusion

An aging rat model of chronic brain hypoperfusion (CBH) that mimics human mild cognitive impairment (MCI) was used to examine the role of nitric oxide synthase (NOS) isoforms on spatial memory function. Rats with CBH underwent bilateral common carotid artery occlusion (2-vessel occlusion (2-VO)) for either 26 or 8 weeks and were compared with nonoccluded sham controls (S-VO). The neuronal and endothelial (nNOS/eNOS) constitutive inhibitor nitro-L-arginine methyl ester (L-NAME) 20 mg/kg was administered after 26 weeks for 3 days to 2-VO and S-VO groups and spatial memory was assessed with a modified Morris watermaze test. Only 2-VO rats worsened their spatial memory ability after L-NAME. Electron microscopic immunocytochemical examination using an antibody against eNOS showed 2-VO rats had significant loss or absence of eNOS-containing positive gold particles in hippocampal endothelium and these changes were associated with endothelial cell compression, mitochondrial damage and heavy amyloid deposition in hippocampal capillaries and perivascular region. In the 8-week study, three groups of 2-VO rats were administered an acute dose of 7-NI, aminoguanidine or L-NIO, the relatively selective inhibitors of nNOS, inducible NOS and eNOS. Only rats administered the eNOS inhibitor L-NIO worsened markedly their watermaze performance ( P=0.009) when compared with S-VO nonoccluded controls. We conclude from these findings that vascular nitric oxide derived from eNOS may play a critical role in spatial memory function during CBH possibly by keeping cerebral perfusion optimal through its regulation of microvessel tone and cerebral blood flow and that disruption of this mechanism can result in spatial memory impairment. These findings may identify therapeutic targets for preventing MCI and treating Alzheimer's disease.

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NIR Bioluminescence Probe Enables Discovery of Diet-Induced Modulation of the Tumor Microenvironment via Nitric Oxide

10.26434/chemrxiv.14176835.v1 ◽

2021 ◽

Author(s):

Anuj K Yadav ◽

Michael C. Lee ◽

Melissa Lucero ◽

Christopher J. Reinhardt ◽

ShengZhang Su ◽

...

Keyword(s):

Nitric Oxide ◽

Tumor Microenvironment ◽

Tumor Progression ◽

Critical Role ◽

Cellular Systems ◽

Tissue Imaging ◽

Molecular Evidence ◽

No Production ◽

The Impact

Nitric oxide (NO) plays a critical role in acute and chronic inflammation. NO’s contributions to cancer are of particular interest due to its context-dependent bioactivities. For example, immune cells initially produce cytotoxic quantities of NO in response to the nascent tumor. However, it is believed that this fades over time and reaches a concentration that supports the tumor microenvironment (TME). These complex dynamics are further complicated by other factors, such as diet and oxygenation, making it challenging to establish a complete picture of NO’s impact on tumor progression. Although many activity-based sensing (ABS) probes for NO have been developed, only a small fraction have been employed in vivo and fewer yet are practical in cancer models where the NO concentration is < 200 nM. To overcome this outstanding challenge, we have developed BL660-NO, the first ABS probe for NIR bioluminescence imaging of NO in cancer. Owing to the low intrinsic background, high sensitivity, and deep tissue imaging capabilities of our design, BL660-NO was successfully employed to visualize endogenous NO in cellular systems, a human liver metastasis model, and a murine breast cancer model. Importantly, its exceptional performance facilitated the design of a dietary study to examine the impact of NO on the TME by varying the intake of fat. BL660-NO provides the first direct molecular evidence that intratumoral NO becomes elevated in mice fed a high-fat diet who became obese with larger tumors compared to control animals on a low-fat diet. These results indicate that an inflammatory diet can increase NO production via recruitment of macrophages and overexpression of iNOS which in turn can drive tumor progression.

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