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

The World Health Organization (WHO) reported that there are 37 million individuals living with the human immunodeficiency virus (HIV) worldwide, with the majority in South Africa. This chronic disease is managed by the effective use of antiretroviral (ARV) drugs. However, with prolonged use, ARV drug-induced toxicity remains a clinically complex problem. This study investigated the toxicity of ARV drugs on mitochondria and the NRF2 antioxidant pathway and its possible amelioration using Moringa oleifera Lam (MO) leaf extracts. This medicinal plant has a range of functional bioactive compounds. Liver (HepG2) cells were treated with individual ARV drugs: Tenofovir disoproxil fumarate (TDF), Emtricitabine (FTC), and Lamivudine (3TC) for 96 h, followed by MO leaf extracts for 24 h. Intracellular ROS, cytotoxicity, lipid peroxidation, total and reduced glutathione (GSH), ATP, and mitochondrial polarisation were determined. Finally, protein (pNRF2, NRF2, SOD2, CAT, and Sirt3) and mRNA (NRF2, CAT, NQO1 SOD2, Sirt3, and PGC1α) expression were measured using Western blot and qPCR, respectively. TDF, FTC, and 3TC significantly increased intracellular ROS and extracellular levels of both MDA and LDH. ARVs also reduced the GSH and ATP levels and altered the mitochondrial polarization. Further, ARVs reduced the expression of NRF2 SOD2, Sirt3, CAT, NQO1, UCP2 and PGC1α mRNA and consequently pNRF2, NRF2, SOD2, Sirt3 and CAT protein. In contrast, there was a significant reduction in the extracellular MDA and LDH levels post-MO treatment. MO significantly reduced intracellular ROS while significantly increasing GSH, ATP, and mitochondrial membrane polarization. The addition of MO to ARV-treated cells significantly upregulated the expression of NRF2, SOD2, Sirt3, CAT, UCP2, PGC1α, and NQO1 mRNA and pNRF2, NRF2, SOD2, Sirt3 proteins. Thus, MO ameliorates ARV-induced hepatotoxicity by scavenging oxidants by inducing the NRF2 antioxidant pathway. MO shows great therapeutic potential and may be considered a potential supplement to ameliorate ARV drug toxicity.

The Potential of Moringa oleifera to Ameliorate HAART-Induced Pathophysiological Complications.

Highly active antiretroviral therapy (HAART) comprises a combination of two or three antiretroviral (ARV) drugs that are administered together in a single tablet. These drugs target different steps within the human immunodeficiency virus (HIV) life cycle, providing either a synergistic or additive antiviral effect; this enhances the efficiency in which viral replication is suppressed. HIV cannot be completely eliminated, making HAART a lifetime treatment. With long-term HAART usage, an increasing number of patients experience a broadening array of complications, and this significantly affects their quality of life, despite cautious use. The mechanism through which ARV drugs induce toxicity is associated with metabolic complications such as mitochondrial dysfunction, oxidative stress, and inflammation. To address this, it is necessary to improve ARV drug formulation without compromising its efficacy; alternatively, safe supplementary medicine may be a suitable solution. The medicinal plant Moringa oleifera (MO) is considered one of the most important sources of novel nutritionally and pharmacologically active compounds that have been shown to prevent and treat various diseases. MO leaves are rich in polyphenols, vitamins, minerals, and tannins; studies have confirmed the therapeutic properties of MO. MO leaves provide powerful antioxidants, scavenge free radicals, promote carbohydrate metabolism, and repair DNA. MO also induces anti-inflammatory, hepatoprotective, anti-proliferative, and anti-mutagenic effects. Therefore, MO can be a source of affordable and safe supplement therapy for HAART-induced toxicity. This review highlights the potential of MO leaves to protect against HAART-induced toxicity in HIV patients.

Bridelia ferruginea Benth. (Euphorbiaceae) mitigates oxidative imbalance and lipotoxicity, with concomitant modulation of insulin signaling pathways via GLUT4 upregulation in hepatic tissues of diabetic rats.

ETHNOPHARMACOLOGICAL RELEVANCE: Bridelia ferruginea Benth. (Euphorbiaceae) is among the medicinal plants commonly used for the management of type 2 diabetes (T2D) and its complications. AIM OF THE STUDY: The hepato-therapeutic effect of the butanol fraction of Bridelia ferruginea leaves was investigated in diabetic rats. METHODS: The butanol fraction of B. ferruginea was given to type 2 diabetic rats at both low and high doses (150 and 300 mg/kg bodyweight, respectively), while metformin and glibenclamide served as the standard anti-diabetic drugs. A normal toxicological group was administered a high dose of the fraction. At the end of the experimental period, the rats were sacrificed, and their livers and psoas muscle collected. The liver was assayed for oxidative stress markers, liver glycogen content, lipid metabolite profile (using GC-MS) and their metabolic pathways were analyzed using the MetaboAnalyst 5.0 online server. The expression of GLUT4 was also assayed in the liver and muscle as well as the identification of signaling pathways associated with GLUT4 expression using the Enrichr online server. In silico molecular docking was used to investigate the molecular interactions of some postulated compound found in B. ferruginea with GLUT4. The ability of the fraction to stimulate muscle glucose uptake was determined in isolated rat psoas muscle ex vivo. RESULTS: Treatment with the high dose of fraction caused an inhibition of lipid peroxidation as well as the elevation of catalase, SOD, glutathione reductase and glutathione peroxidase activities in the rat liver. There was an increased expression of GLUT4 in livers and muscles of diabetic rats following treatment with B. ferruginea. Treatment with the fraction also caused inactivation of diabetes-activated pathways and changes in the distribution of the hepatic lipid metabolites. Molecular docking analysis revealed strong molecular interactions of pyrogallol and sitosterol with GLUT4. CONCLUSIONS: These data illustrate the hepato-protective effect of B. ferruginea in diabetic rats which compare favorably with the tested anti-diabetic drugs (metformin and glibenclamide).