Mitochondria‐Targeted Antioxidants and Uncouplers of Oxidative Phosphorylation in Treatment of the Systemic Inflammatory Response Syndrome (SIRS)

Zakharova, Vlada V.; Pletjushkina, Olga Yu.; Zinovkin, Roman A.; Попова, Е. Н.; Chernyak, Boris V.

doi:10.1002/jcp.25626

Cited by 17 publications

(11 citation statements)

References 103 publications

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“…Mitochondria are one of the most important sources of ROS in the cells and it was shown that Tat could perturb the normal mitochondrial function that in turn could regulate the redox state of the cells [78] , [79] , [80] . To test whether Tat induced mitochondrial ROS production in B-cells, we used rotenone (10 µM), an inhibitor of the mitochondrial complex I, SkQ1 (20 ng/ml), a specific mitochondria-targeting antioxidant [81] , [82] and 2,4-dinitrophenol (DNP) (10 µM), an uncoupler of oxidative phosphorylation [83] . We treated B-cells with these different molecules simultaneously with 250 ng/ml Tat for 6 h and observed that Tat-induced ROS production was inhibited in their presence to the control levels, indicating that mitochondria were a source of ROS in Tat-treated cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

HIV-1 Tat protein induces DNA damage in human peripheral blood B-lymphocytes via mitochondrial ROS production

El-Amine¹,

Germini

Zakharova³

et al. 2018

Redox Biology

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Human immunodeficiency virus (HIV) infection is associated with B-cell malignancies in patients though HIV-1 is not able to infect B-cells. The rate of B-cell lymphomas in HIV-infected individuals remains high even under the combined antiretroviral therapy (cART) that reconstitutes the immune function. Thus, the contribution of HIV-1 to B-cell oncogenesis remains enigmatic. HIV-1 induces oxidative stress and DNA damage in infected cells via multiple mechanisms, including viral Tat protein. We have detected elevated levels of reactive oxygen species (ROS) and DNA damage in B-cells of HIV-infected individuals. As Tat is present in blood of infected individuals and is able to transduce cells, we hypothesized that it could induce oxidative DNA damage in B-cells promoting genetic instability and malignant transformation. Indeed, incubation of B-cells isolated from healthy donors with purified Tat protein led to oxidative stress, a decrease in the glutathione (GSH) levels, DNA damage and appearance of chromosomal aberrations. The effects of Tat relied on its transcriptional activity and were mediated by NF-κB activation. Tat stimulated oxidative stress in B-cells mostly via mitochondrial ROS production which depended on the reverse electron flow in Complex I of respiratory chain. We propose that Tat-induced oxidative stress, DNA damage and chromosomal aberrations are novel oncogenic factors favoring B-cell lymphomas in HIV-1 infected individuals.

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Section: Resultsmentioning

confidence: 99%

HIV-1 Tat protein induces DNA damage in human peripheral blood B-lymphocytes via mitochondrial ROS production

El-Amine¹,

Germini

Zakharova³

et al. 2018

Redox Biology

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“…Excessive inflammatory reactions may result in the development of fatal multiple organ failure. The important role of mitochondrial ROS in SIRS was reviewed recently [60].…”

Section: Structure and Functions Of Mitochondriamentioning

confidence: 99%

Mitochondria-Targeted Drugs

Zinovkin

Zamyatnin

2019

CMP

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145

100

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Background:Targeting of drugs to the subcellular compartments represents one of the modern trends in molecular pharmacology. The approach for targeting mitochondria was developed nearly 50 years ago, but only in the last decade has it started to become widely used for delivering drugs. A number of pathologies are associated with mitochondrial dysfunction, including cardiovascular, neurological, inflammatory and metabolic conditions.Objective:This mini-review aims to highlight the role of mitochondria in pathophysiological conditions and diseases, to classify and summarize our knowledge about targeting mitochondria and to review the most important preclinical and clinical data relating to the antioxidant lipophilic cations MitoQ and SkQ1.Methods:This is a review of available information in the PubMed and Clinical Trials databases (US National Library of Medicine) with no limiting period.Results and Conclusion:Mitochondria play an important role in the pathogenesis of many diseases and possibly in aging. Both MitoQ and SkQ1 have shown many beneficial features in animal models and in a few completed clinical trials. More clinical trials and research efforts are needed to understand the signaling pathways influenced by these compounds. The antioxidant lipophilic cations have great potential for the treatment of a wide range of pathologies.

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“…Although the clinical application of antioxidants for skin inflammatory disorders is not widespread, we wanted to test it using a combination of natural molecules. Consequently, EP2311454 treatment main components are resveratrol, taurine and ascorbyl-Lpalmitate previously defined as antioxidant in humans and indomethacin which is anti-inflammatory in low doses associated to several human diagnosis (20,21). The aim of this study is evaluate the clinical efficiency of the treatment in moderate and severe AD patients whereas mild AD patients have a better treatment.…”

Section: Discussionmentioning

confidence: 99%

EP2311454 treatment for atopic dermatitis: therapeutic efficiency in patients and anti-inflammatory in vitro

Umbert¹

2017

cderm

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SummaryBackground. Atopic Dermatitis (AD) is a common, chronic skin disorder caused by complex genetic, immunological, and environmental interactions. The current standard treatments for AD are improvable with a low efficiency, particularly in severe cases. Using well characterized molecules the "Ignacio Umbert Dermatology Institute" (IUDI) has developed topical treatments differentiated from the standards (European patent number EP2311454). Objective. Evaluate the therapeutic efficacy of EP2311454 treatment in AD patients and its antiinflammatory effect in vitro. Materials and methods. Using a cellular model for human macrophages (THP-1 cell line) the principal components of EP2311454 treatment was evaluated. Expression of proinflammatory cytokines was measured through RNA quantification and ELISA technique. Therapeutically EP231154 treatment was tested in forty three AD patients and SCORing Atopic Dermatitis (SCORAD) and Dermatology Quality of Life Index (DLQI) was evaluated before and after the treatment. Results. The effect was significantly anti-inflammatory towards IL6 and COX2. The therapeutic efficacy was demonstrated by obtaining a reduction of initial SCORAD levels in the 97,7% of patients besides EP2311454 treatment reduces DLQI significantly. Conclusions.Clinically, EP2311454 treatment is effective, especially in severe cases, getting a reduction of 80% initial levels at the end of the evaluation period. Moreover, the effect was detected from the first week.

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Mitochondria‐Targeted Antioxidants and Uncouplers of Oxidative Phosphorylation in Treatment of the Systemic Inflammatory Response Syndrome (SIRS)

Cited by 17 publications

References 103 publications

HIV-1 Tat protein induces DNA damage in human peripheral blood B-lymphocytes via mitochondrial ROS production

HIV-1 Tat protein induces DNA damage in human peripheral blood B-lymphocytes via mitochondrial ROS production

Mitochondria-Targeted Drugs

EP2311454 treatment for atopic dermatitis: therapeutic efficiency in patients and anti-inflammatory in vitro

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