Repression of Nrf2/ARE regulated antioxidant genes and dysregulation of the cellular redox environment by the HIV Transactivator of Transcription

Simenauer, Ari; Assefa, Betelhem; Rios-Ochoa, Jose; Geraci, Kara; Hybertson, Brooks M.; Gao, Bifeng; McCord, Joe M.; Elajaili, Hanan; Nozik‐Grayck, Eva; Cota‐Gomez, Adela

doi:10.1016/j.freeradbiomed.2019.06.015

Cited by 13 publications

(13 citation statements)

References 42 publications

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“…The authors suggested that this down-modulation was responsible for the rapidly generated ROS causing lung inflammation and oxidative damage [37]. HIV Tat protein has been shown to induce Nrf2 pathway [38], even though in another study it has been shown that a dysregulation of this pathway increased Tat-induced oxidative burden [39].…”

Section: Viral Infections and Redox Statementioning

confidence: 99%

Redox-Modulating Agents in the Treatment of Viral Infections

Checconi

Angelis

Marcocci

et al. 2020

IJMS

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Viruses use cell machinery to replicate their genome and produce viral proteins. For this reason, several intracellular factors, including the redox state, might directly or indirectly affect the progression and outcome of viral infection. In physiological conditions, the redox balance between oxidant and antioxidant species is maintained by enzymatic and non-enzymatic systems, and it finely regulates several cell functions. Different viruses break this equilibrium and induce an oxidative stress that in turn facilitates specific steps of the virus lifecycle and activates an inflammatory response. In this context, many studies highlighted the importance of redox-sensitive pathways as novel cell-based targets for therapies aimed at blocking both viral replication and virus-induced inflammation. In the review, we discuss the most recent findings in this field. In particular, we describe the effects of natural or synthetic redox-modulating molecules in inhibiting DNA or RNA virus replication as well as inflammatory pathways. The importance of the antioxidant transcription factor Nrf2 is also discussed. Most of the data reported here are on influenza virus infection. We believe that this approach could be usefully applied to fight other acute respiratory viral infections characterized by a strong inflammatory response, like COVID-19.

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Section: Viral Infections and Redox Statementioning

confidence: 99%

Redox-Modulating Agents in the Treatment of Viral Infections

Checconi

Angelis

Marcocci

et al. 2020

IJMS

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“…For example, recently published studies have suggested that lung disease in PWH could be related to factors such as a potential latent lung HIV reservoir, persistent viral protein production (e.g. Nef and Tat), oxidative stress, and alterations in the respiratory microbiome [23][24][25][26][27].…”

Section: Discussionmentioning

confidence: 99%

Respiratory symptoms and chronic bronchitis in people with and without HIV infection

Sabin¹,

Kunisaki

Bagkeris³

et al. 2020

HIV Medicine

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High rates of respiratory symptoms and chronic bronchitis (CB) are reported in people with HIV infection (PWH). We investigated the prevalence of respiratory symptoms and CB in PWH and HIV-negative people in the Pharmacokinetic and clinical Observations in PeoPle over fiftY (POPPY) study. Methods Assessment of respiratory symptoms and CB was undertaken using the modified form of the St. George's Respiratory Questionnaire for chronic obstructive pulmonary disease (COPD). Univariate (v 2 tests, Mann-Whitney U tests and Spearman's rank correlation) and multivariable (linear and logistic regression) analyses were performed to consider associations of respiratory symptoms with demographic, lifestyle and HIV-related parameters, and with depressive symptoms and quality of life. Results Among the 619 participants, respiratory Symptom scores were higher in older and younger PWH compared to older HIV-negative people, with median (interquartile range) scores of 17.7 (6.2, 39.5), 17.5 (0.9, 30.0) and 9.0 (0.9, 17.5), respectively (P = 0.0001); these differences remained significant after confounder adjustment. Sixty-three participants (10.2%) met the criteria for CB [44 (14.0%) older PWH, 14 (9.2%) younger PWH, and five (3.3%) older HIV-negative people; P = 0.002], with these differences also remaining after adjustment for confounding variables, particularly smoking status [older vs. younger PWH: odds ratio (OR) 4.48 (95% confidence interval (CI) 1.64, 12.30); P = 0.004; older PWH vs. HIV-negative people: OR 4.53 (95% CI 1.12, 18.28); P = 0.03]. Respiratory symptoms and CB were both associated with greater depressive symptom scores and poorer quality of life. No strong associations were reported between CB and immune function, HIV RNA or previous diagnosis of any AIDS event. Conclusions Respiratory symptoms and CB are more common in PWH than in demographically and lifestylesimilar HIV-negative people and are associated with poorer mental health and quality of life.

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“…Hence, the administration of antioxidants like Vitamin C, which has been proved to be preventive against viral pneumonia, can serve as an ideal prevention strategy against viral infections; however, ROS induction can be superlative in disease therapy ( Hemilä and Louhiala, 2013 ; Kim et al, 2013 ). Further, there are several host redox and other associated genes which are modulated during a viral infection enabling the viral propagation and pathogenesis as depicted in Table 1 (( Ahmed and Rahman, 2006 ; Bender and Hildt, 2019 ; Bottino-Rojas et al, 2018 ; Checconi et al, 2020 ; Chen et al, 2020a ; Cuadrado et al, 2020 ; Jacoby and Choi, 1994 ; Lee, 2018a ; Simenauer et al, 2019 ; Zhang et al, 2020 ).…”

Section: Insights Into Targeting Viral Rna By Ros Inducersmentioning

confidence: 99%

“… S. No. Redox and other associated genes activated during RNA viral infections Reference 1 Superoxide dismutase 3 (SOD3) ( Ahmed and Rahman, 2006 ) 2 Activating transcription factor 4 (ATF4) 3 Metallothionein 2A (M2TA) 4 Nuclear factor erythroid 2-related factor 2 (NRF-2) ( Bottino-Rojas et al, 2018 ; McCord et al, 2020) 5 Heme oxygenase (HMOX1) ( Cuadrado et al, 2020 ; Singh et al, 2018 ) 6 Sulfiredoxin-1 (SRXN-1) ( Simenauer et al, 2019 ) 7 NADPH quinone dehydrogenase 1 (NQO1) 8 Glutamate cysteine ligase catalytic and regulatory subunits (GCLC and GCLM) ( Lee, 2018a ) 9 Glutathione S-transferase (GST) 10 Uridine diphosphate glucuronosyltransferase (UDPGT) 11 Catalase (CAT) 12 Glucose 6 phosphate dehydrogenase (G6PD) 13 Glutathione peroxidase-1 (GPx) 14 Glutathione disulfide reductase (GSR) Checconi et al (2020) 15 Copper/zinc superoxide dismutase (Cu/ZnSOD) ( Jacoby and Choi, 1994 ) 16 Manganese superoxide dismutase (MnSOD) 17 Indole- amine dioxygenase (IDO) 18 Mel...…”

Section: Insights Into Targeting Viral Rna By Ros Inducersmentioning

confidence: 99%

Perspectives on mechanistic implications of ROS inducers for targeting viral infections

Nadhan

Patra

Krishnan

et al. 2021

European Journal of Pharmacology

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In this perspective, we propose to leverage reactive oxygen species (ROS) induction as a potential therapeutic measure against viral infections. Our rationale for targeting RNA viral infections by pro-oxidants is routed on the mechanistic hypothesis that ROS based treatment paradigm could impair RNA integrity faster than the other macromolecules. Though antiviral drugs with antioxidant properties confer potential abilities for preventing viral entry, those with pro-oxidant properties could induce the degradation of nascent viral RNA within the host cells, as RNAs are highly prone to ROS mediated degradation than DNA/proteins. We have previously established that Plumbagin is a highly potent ROS inducer, which acts through shifting of the host redox potential. Besides, it has been reported that Plumbagin treatment has the potential for interrupting viral RNA replication within the host cells. Since the on-going Corona Virus Disease - 2019 (COVID-19) global pandemic mediated by Severe Acute Respiratory Syndrome Corona Virus-2 (SARS-CoV-2) exhibits high infectivity, the development of appropriate antiviral therapeutic strategies remains to be an urgent unmet race against time. Therefore, additional experimental validation is warranted to determine the appropriateness of repurposable drug candidates, possibly ROS inducers, for fighting the pandemic which could lead to saving many lives from being lost to COVID-19.

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Repression of Nrf2/ARE regulated antioxidant genes and dysregulation of the cellular redox environment by the HIV Transactivator of Transcription

Cited by 13 publications

References 42 publications

Redox-Modulating Agents in the Treatment of Viral Infections

Redox-Modulating Agents in the Treatment of Viral Infections

Respiratory symptoms and chronic bronchitis in people with and without HIV infection

Perspectives on mechanistic implications of ROS inducers for targeting viral infections

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