The protective roles of citrus flavonoids, naringenin, and naringin on endothelial cell dysfunction in diseases.

The endothelial cells (ECs) make up the inner lining of blood vessels, acting as a barrier separating the blood and the tissues in several organs. ECs maintain endothelium integrity by controlling the constriction and relaxation of the vasculature, blood fluidity, adhesion, and migration. These actions of ECs are efficiently coordinated via an intricate signaling network connecting receptors, and a wide range of cellular macromolecules. ECs are naturally quiescent i.e.; they are not stimulated and do not proliferate. Upon infection or disease, ECs become activated, and this alteration is pivotal in the pathogenesis of a spectrum of human neurological, cardiovascular, diabetic, cancerous, and viral diseases. Considering the central position that ECs play in disease pathogenesis, therapeutic options have been targeted at improving ECs integrity, assembly, functioning, and health. The dietary intake of flavonoids present in citrus fruits has been associated with a reduced risk of endothelium dysfunction. Naringenin (NGN) and Naringin (NAR), major flavonoids in grapefruit, tomatoes, and oranges possess anti-inflammatory, antioxidant properties, and cell survival potentials, which improve the health of the vascular endothelium. In this review, we provide a comprehensive summary and present the advances in understanding of the mechanisms through which NGN and NAR modulate the biomarkers of vascular dysfunction and protect the endothelium against unresolved inflammation, oxidative stress, atherosclerosis, and angiogenesis. We also provide perspectives and suggest further studies that will help assess the efficacy of citrus flavonoids in the therapeutics of human vascular diseases.

Interactions and toxicity of non-essential heavy metals (Cd, Pb and Hg): lessons from Drosophila melanogaster.

Some heavy metals are essential in trace amounts, enhancing enzyme functioning and other intracellular molecules. Others are explicitly toxic at low concentrations, increasing the risk of organ-related toxicity. Non-essential metals have similar mechanisms of toxicity to essential metals. These include the modifiable change in oxidation states, interaction with sulfhydryl moieties of proteins and indirect modification of nucleic acids. Ultimately, oxidative stress is generated, and potentiation of damage ensues. The susceptibility, sensitivity, genetic resources, and cellular response of Drosophila melanogaster to heavy metal exposure and toxicity have made this insect appropriate for toxicological studies. In this review, we focus on the toxicological impacts of non-essential metals (Cd, Pb, and Hg) in Drosophila and discuss its cellular and developmental responses to increasing concentrations of these metals. We also suggest current or proposed therapeutic alternatives, as well as dimensions that may improve the studies of non-essential metal biology.

Metallobiology and therapeutic chelation of biometals (copper, zinc and iron) in Alzheimer's disease: Limitations, and current and future perspectives.

BACKGROUND: Alzheimer's disease (AD) is the most prevalent cause of cognitive impairment and dementia worldwide. The pathobiology of the disease has been studied in the form of several hypotheses, ranging from oxidative stress, amyloid-beta (Aß) aggregation, accumulation of tau forming neurofibrillary tangles (NFT) through metal dysregulation and homeostasis, dysfunction of the cholinergic system, and to inflammatory and autophagic mechanism. However, none of these hypotheses has led to confirmed diagnostics or approved cure for the disease. OBJECTIVE: This review is aimed as a basic and an encyclopedic short course into metals in AD and discusses the advances in chelation strategies and developments adopted in the treatment of the disease. Since there is accumulating evidence of the role of both biometal dyshomeostasis (iron (Fe), copper (Cu), and zinc (Zn)) and metal-amyloid interactions that lead to the pathogenesis of AD, this review focuses on unraveling therapeutic chelation strategies that have been considered in the treatment of the disease, aiming to sequester free and protein-bound metal ions and reducing cerebral metal burden. Promising compounds possessing chemically modified moieties evolving as multi-target ligands used as anti-AD drug candidates are also covered. RESULTS AND CONCLUSION: Several multidirectional and multifaceted studies on metal chelation therapeutics show the need for improved synthesis, screening, and analysis of compounds to be able to effectively present chelating anti-AD drugs. Most drug candidates studied have limitations in their physicochemical properties; some enhance redistribution of metal ions, while others indirectly activate signaling pathways in AD. The metal chelation process in vivo still needs to be established and the design of potential anti-AD compounds that bi-functionally sequester metal ions as well as inhibit the Aß aggregation by competing with the metal ions and reducing metal-induced oxidative damage and neurotoxicity may signal a bright end in chelation-based therapeutics of AD.

Curcumin attenuates copper-induced oxidative stress and neurotoxicity in Drosophila melanogaster.

Curcumin is a hydrophobic polyphenol derived from the rhizome of the Herb Curcuma longa belonging to the family Zingiberaceae. Curcumin possesses antioxidative, anti-inflammatory and anti-depressant-like properties. In this study, we evaluated the rescue role of Curcumin in Copper2+-induced toxicity in D. melanogaster. Adult, wild type flies were exposed to Cu2+ (1 mM) and/or Curcumin (0.2 and 0.5 mg/kg diet) in the diet for 7 days. The results indicated that Cu2+- fed flies had reduced survival compared to the control group. Copper toxicity was also associated with a marked decrease in total thiol (T-SH), as well as catalase and glutathione S-transferase activities, contemporaneous with increased acetylcholinesterase (AChE) activity, nitric oxide (nitrate and nitrite) and dopamine levels. Co-exposure of flies to Cu2+ and Curcumin prevented mortality, inhibited AChE activity and restored dopamine to normal levels (p < 0.05). Moreover, Curcumin restored eclosion rates, and the cellular antioxidant status, as well as alleviated the accumulation of nitric oxide level in the flies. Curcumin ameliorated oxidative damage in the flies as evidenced by the survival rates, longevity assay as well as the restoration of antioxidant status. Our findings thus suggest that Curcumin ameliorated Cu2+-induced neurotoxicity in D. melanogaster and as such could be considered an effective therapeutic agent in the prevention and treatment of disorders, where oxidative stress is implicated.