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

Abstract

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.

Magnesium supplementation reduces inflammation in rats with induced chronic kidney disease

“…Though a content of 0.05% has been extensively used as normal in rat experimental studies, a slightly higher dietary concentration might be required if the experimental conditions might affect the absorption of Mg. A high dietary phosphate content can reduce the absorption and/or availability of Mg, and a decreased magnesium absorption is often found in renal disease 33 . Similarly to our conditions, the contents of 0.1% or around have been also established as the normal levels in many studies addressing dietary Mg supplementation, in which a 0.6% Mg was also given as a high Mg diet 34‐37 . Our results showed that in the uraemic rats fed a normal Mg (0.1%) a systemic inflammatory response was induced, as deduced from the elevation in the plasma of the pro‐inflammatory cytokines TNF‐α, IL‐1β and IL‐6, which are related to acute‐phase responses and inflammation.…”

“…Though a content of 0.05% has been extensively used as normal in rat experimental studies, a slightly higher dietary concentration might be required if the experimental conditions might affect the absorption of Mg. A high dietary phosphate content can reduce the absorption and/or availability of Mg and a decreased magnesium absorption is often found in renal disease (33). Similarly to our conditions, contents of 0.1% or around has been also stablished as the normal levels in many studies addressing dietary Mg supplementation, in which a 0.6% Mg was also given as a high-Mg diet (34)(35)(36)(37).…”

Moringa oleifera Lam Leaf Extract Stimulates NRF2 and Attenuates ARV-Induced Toxicity in Human Liver Cells (HepG2)

“…Previous in vivo studies reported depletion of SOD1 and SOD2 by TDF in male Wistar rat kidney tissues [ 31 ]. ElZohary, Weglicki [ 96 ] suggested that the downregulation of NRF2 severely compromised the antioxidant response in HAART (containing TDF and FTC) treated rats. Previous studies also reported a significant decrease in SOD and CAT post-treatment with TDF [ 68 ]…”

Antiretroviral Therapy-Induced Dysregulation of Gene Expression and Lipid Metabolism in HIV+ Patients: Beneficial Role of Antioxidant Phytochemicals

“…In HIV-1 transgenic rats, the accumulation of total cholesterol in the liver and serum hypertriglyceridemia is concomitant with higher expression of SREBP-1 in animals treated with cART. However, the enhanced expression of SREBP-1 was suppressed by Mg-supplementation, which was associated with the reduction in serum cholesterol and triglyceride levels [ 175 ].…”