Bixin, a New Atheroprotective Carotenoid Candidate, Prevents oxLDL-Induced Cytotoxicity and Mitochondrial Dysfunction in Macrophages: Involvement of the Nrf2 and NF-κB Pathways.

The accumulation of oxidized low-density lipoprotein (oxLDL) and its toxicity in the arterial wall have been implicated in atherosclerosis. This study aimed to investigate the mechanisms underlying the atheroprotective effect of bixin, a carotenoid obtained from the seeds of the tropical plant Bixa orellana, on Cu2+-induced LDL oxidation and oxLDL-mediated effects in J774A.1 macrophage cells. Bixin's effects were compared to those of lycopene, a carotenoid widely studied for its cardiovascular protective effects. LDL was isolated from human plasma, incubated with bixin or lycopene (positive control), and subjected to oxidation with CuSO4. Afterward, bixin or lycopene was incubated with J774A.1 macrophage cells and exposed to oxLDL. The levels of ROS, RNS, GSH, nitrite, mitochondrial function, and foam cell formation, as well as the expression of proteins related to the antioxidant and inflammatory status, were evaluated. The effect of bixin in inhibiting in vitro human-isolated LDL oxidation was more potent (5-6-fold) than that of lycopene. Bixin pretreatment reduced the atherogenic signaling triggered by oxLDL in the macrophages, namely the generation of reactive species, disturbance of nitric oxide homeostasis, mitochondrial dysfunction, and foam cell formation. The cytoprotective effects of bixin were accompanied by the upregulation of Nrf2 and the downregulation of the NF-kB pathways. Lycopene showed the same protective effect as bixin, except that it did not prevent mitochondrial dysfunction. The efficient performance of bixin makes it an ideal candidate for further trials as a new nutraceutical compound for the prevention of atherosclerosis.

Methylglyoxal disrupts the functionality of rat liver mitochondria.

Methylglyoxal (MG) is a reactive metabolite derived from different physiological pathways. Its production can be harmful to cells via glycation reactions of lipids, DNA, and proteins. But, the effects of MG on mitochondrial functioning and bioenergetic responses are still elusive. Then, the effects of MG on key parameters of mitochondrial functionality were examined here. Isolated rat liver mitochondria were exposed to 0.1-10 mM of MG to determine its toxicity in the mitochondrial viability, membrane potential (Δψm), swelling and the superoxide (O2•-) production. Besides, mitochondrial oxidative phosphorylation parameters were analyzed by high-resolution respiratory (HRR) assay. In this set of experiments, routine state, PM state (pyruvate/malate), oxidative phosphorylation (OXPHOS), LEAK respiration, electron transport system (ETS) and oxygen residual (ROX) states were evaluated. HRR showed that PM state, OXPHOS CI-Linked, LEAK respiration, ETS CI/CII-Linked and ETS CII-Linked/ROX were significantly inhibited by MG exposure. MG also inhibited the complex II activity, and decreased Δψm and the viability of mitochondria. Taken together, our data indicates that MG is an inductor of mitochondrial dysfunctions and impairs important steps of respiratory chain, effects that can alter bioenergetics responses.