Combination ART-Induced Oxidative/Nitrosative Stress, Neurogenic Inflammation and Cardiac Dysfunction in HIV-1 Transgenic (Tg) Rats: Protection by Mg

Mak, I. Tong; Chmielinska, Joanna J.; Spurney, Christopher F.; Weglicki, William B.; Kramer, Jay H.

doi:10.3390/ijms19082409

Cited by 11 publications

(13 citation statements)

References 40 publications

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“…Male 5 week-old Hsd:HIV-1 (F344) transgenic rats and the background wild type control (Fischer 344/NHsd) rats were obtained from Envigo/Harlan Laboratory (Indianapolis, IN) as described [8]. cART components (atazanavir-ritonavir plus Truvada) were obtained from The GWU-Pharmacy.…”

Section: Methodsmentioning

confidence: 99%

“…All animal experiments were guided by the principles for the care and use of laboratory animals as recommended by the US Department of Health and Human Services and approved by The George Washington University (GWU) Animal Care and Use Committee [8]. A description of the Animal Research Facility (ARF) is online at our GWU ARF website: http://research.gwu.edu/office-animal-research.…”

Section: Methodsmentioning

confidence: 99%

“…The concurrent cART treatment on normal Mg diet, or high Mg diet was carried out for 18 weeks. At the end of the experimental period, all 8 groups of rats consumed comparable amounts of food (43–46 gm/kg/day) [8]; the averages of each group were within 6% of each other. Therefore, the final dosages of the cART components for both the control or Tg rats on normal or high Mg diets were estimated to be: atazanavir/ritonavir = 16.5/5.5 mg/kg/day; and for Truvada = 16.5 mg TDF plus 11 mg FTC/kg/day.…”

Section: Methodsmentioning

confidence: 99%

“…Nevertheless, the role of HIV-1 infection/gene expression in the potential heightened susceptibility to cART-induced metabolic toxicity and systemic oxidative stress remains unclear. In a recent concurrent study [8], by using an established HIV-1 transgenic (Tg) rat model we found that a clinically used cART, consisting of Truvada (2 NRTIs) plus atazanavir-ritonavir (2 PIs), induced early oxidative stress resulting in cardiac dysfunction. In the present study, we focused at the molecular level, on key transcriptome changes related to lipogenesis and antioxidant/nitrosative responses.…”

Section: Introductionmentioning

confidence: 99%

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Mg-supplementation attenuated lipogenic and oxidative/nitrosative gene expression caused by Combination Antiretroviral Therapy (cART) in HIV-1-transgenic rats

et al. 2019

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We determined if HIV-1 expression in transgenic (HIV-1-Tg) rats enhanced hepatic genomic changes related to oxidative/nitrosative stress and lipogenesis during cART-treatment, and assessed effects of Mg-supplementation. A clinically used cART (atazanavir-ritonavir+Truvada) was given orally to control and HIV-1-Tg rats (18 weeks) with normal or 6-fold dietary-Mg. Oxidative/nitrosative and lipogenic genes were determined by real-time RT-PCR. cART induced a 4-fold upregulation of sterol regulatory element-binding protein-1 (SREBP-1) in HIV-1-Tg-rats, but not in controls; Tg rats displayed a 2.5-fold higher expression. Both were completely prevented by Mg-supplementation. Nrf2 (Nuclear erythroid-derived factor 2), a master transcription factor controlling redox homeostasis, was down-regulated 50% in HIV-Tg rats, and reduced further to 25% in Tg+cART-rats. Two downstream antioxidant genes, heme oxygenase-1(HmOX1) and Glutathione-S-transferase(GST), were elevated in HIV-Tg alone but were suppressed by cART treatment. Decreased Nrf2 in Tg±cART were normalized by Mg-supplementation along with the reversal of altered HmOX1 and GST expression. Concomitantly, iNOS (inducible nitric oxide synthase) was upregulated 2-fold in Tg+cART rats, which was reversed by Mg-supplementation. In parallel, cART-treatment led to substantial increases in plasma 8-isoprostane, nitrotyrosine, and RBC-GSSG (oxidized glutathione) levels in HIV-1-Tg rats; all indices of oxidative/nitrosative stress were suppressed by Mg-supplementation. Both plasma triglyceride and cholesterol levels were elevated in Tg+cART rats, but were lowered by Mg-supplementation. Thus, the synergistic effects of cART and HIV-1 expression on lipogenic and oxidative/nitrosative effects were revealed at the genomic and biochemical levels. Down-regulation of Nrf2 in the Tg+cART rats suggested their antioxidant response was severely compromised; these abnormal metabolic and oxidative stress effects were effectively attenuated by Mg-supplementation at the genomic level.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mg-supplementation attenuated lipogenic and oxidative/nitrosative gene expression caused by Combination Antiretroviral Therapy (cART) in HIV-1-transgenic rats

et al. 2019

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“…Plasma samples (with 0.005% BHT added) were processed to obtained 8-isoprostane levels measured by an established enzyme immunoassay kit (Catalog No. 516351) from Cayman Chemical (MI) as described [15,16]. Briefly, duplicate 10 and 20 µL plasma samples (in 200 µL of assay volume) were used to determine free 8-isoprostane concentrations, based on the absorbance values (410 nm) of standards at known concentration.…”

Section: Plasma 8-isoprostane Assaymentioning

confidence: 99%

Deficiency in gp91Phox (NOX2) Protects against Oxidative Stress and Cardiac Dysfunction in Iron Overloaded Mice

Mak

Kramer

Chmielinska

et al. 2020

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The role of NADPH oxidase subunit, gp91phox (NOX2) in development of oxidative stress and cardiac dysfunction due to iron (Fe)-overload was assessed. Control (C57BL/6J) and gp91phox knockout (KO) mice were treated for up to 8 weeks with Fe (2.5 mg/g/wk, i.p.) or Na-dextran; echocardiography, plasma 8-isoprostane (lipid peroxidation marker), cardiac Fe accumulation (Perl’s staining), and CD11b+ (WBCs) infiltrates were assessed. Fe caused no adverse effects on cardiac function at 3 weeks. At 6 weeks, significant declines in left ventricular (LV) ejection fraction (14.6% lower), and fractional shortening (19.6% lower) occurred in the Fe-treated control, but not in KO. Prolonging Fe treatment (8 weeks) maintained the depressed LV systolic function with a trend towards diastolic dysfunction (15.2% lower mitral valve E/A ratio) in controls but produced no impact on the KO. Fe-treatment (8 weeks) caused comparable cardiac Fe accumulation in both strains, but a 3.3-fold elevated plasma 8-isoprostane, and heightened CD11b+ staining in controls. In KO mice, lipid peroxidation and CD11b+ infiltration were 50% and 68% lower, respectively. Thus, gp91phox KO mice were significantly protected against oxidative stress, and systolic and diastolic dysfunction, supporting an important role of NOX2-mediated oxidative stress in causing cardiac dysfunction during Fe overload.

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The relevance of magnesium homeostasis in COVID-19

Trapani

Rosanoff²,

Baniasadi

et al. 2021

Eur J Nutr

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Purpose In less than one and a half year, the COVID-19 pandemic has nearly brought to a collapse our health care and economic systems. The scientific research community has concentrated all possible efforts to understand the pathogenesis of this complex disease, and several groups have recently emphasized recommendations for nutritional support in COVID-19 patients. In this scoping review, we aim at encouraging a deeper appreciation of magnesium in clinical nutrition, in view of the vital role of magnesium and the numerous links between the pathophysiology of SARS-CoV-2 infection and magnesium-dependent functions. Methods By searching PubMed and Google Scholar from 1990 to date, we review existing evidence from experimental and clinical studies on the role of magnesium in chronic non-communicable diseases and infectious diseases, and we focus on recent reports of alterations of magnesium homeostasis in COVID-19 patients and their association with disease outcomes. Importantly, we conduct a census on ongoing clinical trials specifically dedicated to disclosing the role of magnesium in COVID-19. Results Despite many methodological limitations, existing data seem to corroborate an association between deranged magnesium homeostasis and COVID-19, and call for further and better studies to explore the prophylactic or therapeutic potential of magnesium supplementation. Conclusion We propose to reconsider the relevance of magnesium, frequently overlooked in clinical practice. Therefore, magnesemia should be monitored and, in case of imbalanced magnesium homeostasis, an appropriate nutritional regimen or supplementation might contribute to protect against SARS-CoV-2 infection, reduce severity of COVID-19 symptoms and facilitate the recovery after the acute phase.

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Combination ART-Induced Oxidative/Nitrosative Stress, Neurogenic Inflammation and Cardiac Dysfunction in HIV-1 Transgenic (Tg) Rats: Protection by Mg

Cited by 11 publications

References 40 publications

Mg-supplementation attenuated lipogenic and oxidative/nitrosative gene expression caused by Combination Antiretroviral Therapy (cART) in HIV-1-transgenic rats

Mg-supplementation attenuated lipogenic and oxidative/nitrosative gene expression caused by Combination Antiretroviral Therapy (cART) in HIV-1-transgenic rats

Deficiency in gp91Phox (NOX2) Protects against Oxidative Stress and Cardiac Dysfunction in Iron Overloaded Mice

The relevance of magnesium homeostasis in COVID-19

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