Synthesis, characterization and efficacy of mitochondrial targeted delivery of TPP-curcumin in rotenone-induced toxicity (original) (raw)
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Effect of Curcumin on Protein Damage Induced by Rotenone in Dopaminergic PC12 Cells
International Journal of Molecular Sciences, 2020
Oxidative stress is considered to be a key factor of the pathogenesis of Parkinson's disease, a multifactorial neurodegenerative disorder characterized by reduced dopaminergic neurons in the substantia nigra pars compacta and accumulated protein aggregates. Rotenone is a worldwide-used pesticide that induces the most common features of Parkinson's by direct inhibition of the mitochondrial complex I. Rotenone-induced Parkinson's models, as well as brain tissues from Parkinson's patients, are characterized by the presence of both lipid peroxidation and protein oxidation markers resulting from the increased level of free radical species. Oxidation introduces several modifications in protein structure, including carbonylation and nitrotyrosine formation, which severely compromise cell function. Due to the link existing between oxidative stress and Parkinson's disease, antioxidant molecules could represent possible therapeutic tools for this disease. In this study, we evaluated the effect of curcumin, a natural compound known for its antioxidant properties, in dopaminergic PC12 cells treated with rotenone, a cell model of Parkinsonism. Our results demonstrate that the treatment of PC12 cells with rotenone causes severe protein damage, with formation of both carbonylated and nitrotyrosine-derived proteins, whereas curcumin (10 µM) co-exposure exerts protective effects by reducing the levels of oxidized proteins. Curcumin also promotes proteasome activation, abolishing the inhibitory effect exerted by rotenone on this degradative system.
Biochimica et Biophysica Acta (BBA) - General Subjects, 2006
Curcumin (1,7-bis(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione, 1) is a yellow ingredient isolated from turmeric (curcumin longa). It has been shown to exhibit a variety of biological activities including antioxidative activity. In order to find more active antioxidants with 1 as the lead compound we synthesized curcumin analogues, i.e., 1-(3,4-dihydroxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-1,6heptadiene-3,5-dione (2), 1-(4-hydroxy-3-methoxyphenyl)-7-(4-hydroxyphenyl)-1,6-heptadiene-3,5-dione (3), 1,7-bis-(4-hydroxyphenyl)-1,6heptadiene-3,5-dione (4), 1-(3,4-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl)-1,6-heptadiene-3,5-dione (5), 1,7-bis(3,4-dimethoxyphenyl)-1,6-heptadiene-3,5-dione (6), and 1,7-diphenyl-1,6-heptadiene-3,5-dione , and evaluated their antioxidative activity. The in vitro oxidative damage to both lipids and proteins in rat liver mitochondria was used as a model to study the free radical-induced oxidative damage of biological lipids as well as proteins and the protective effects of these curcumin analogues. It was found that these compounds, except 6 and 7, could effectively inhibit the free radical induced lipid peroxidation and protein oxidative damage of rat liver mitochondria by H-atom abstraction from the phenolic groups. Compound 2 which bear ortho-diphenoxyl functionality exhibited remarkably higher antioxidative activity for lipids and proteins than curcumin and other analogues, and the 4-hydroxy-3-methoxyphenyl group also play an important role in the antioxidative activity. D
Parkinson's disease (PD) is a progressive neuro-degenerative movement disorder resulting from a selective loss of dopaminergic neurons. The pathogenesis of PD remains incompletely understood , but increasing evidence from human and animal studies has suggested that oxidative damage contributes to the neuronal loss in PD. In this study, we used rotenone (a mitochondrial complex I inhibitor) based cell and Drosophila models that resemble some key pathological features of PD to test whether curcumin, a potent antioxidant compound, derived from the curry spice turmeric, could protect against rote-none-induced neuronal toxicity. We found that curcumin reduced rotenone induced cell death in SH-SY5Y human neuroblastoma cells and alleviated PD-like symptoms in drosophila via reducing the intracellular and mitochondrial reac-tive oxygen species (ROS) levels and inhibiting the caspase-3/caspase-9 activity. These results suggest that curcumin is a promising therapeutic compound for PD.
Rotenone-like Action of the Branched-chain Phytanic Acid Induces Oxidative Stress in Mitochondria
Journal of Biological Chemistry, 2006
Phytanic acid (Phyt) increase is associated with the hereditary neurodegenerative Refsum disease. To elucidate the still unclear toxicity of Phyt, mitochondria from brain and heart of adult rats were exposed to free Phyt. Phyt at low micromolar concentrations (maximally: 100 nmol/mg of protein) enhances superoxide (O 2 .) 2 generation. Phyt induces O 2. in state 3 (phosphorylating), as well as in state 4 (resting). Phyt stimulates O 2. generation when the respiratory chain is fed with electrons derived from oxidation of glutamate/ malate, pyruvate/malate, or succinate in the presence of rotenone. With succinate alone, Phyt suppresses O 2. generation caused by
Research in Molecular Medicine, 2020
Background: Paraquat (PQ), as the most widely used herbicide in agriculture, induces poisoning in humans and animals mainly through oxidative stress. This study aimed to investigate the protective effects of nano-curcumin compared with curcumin against PQ-induced mitochondrial dysfunction. Materials and Methods: Thirty-six Wistar rats were used in this study. They were separated into 6 groups: control subjects and animals poisoned with PQ that received treatment with or without curcumin and nano-curcumin for 7 days. Liver mitochondria were isolated, and oxidative stress markers, including Total Antioxidant Capacity (TAC), Lipid Peroxidation (LPO), Catalase (CAT) and Superoxide Dismutase (SOD) activity, as well as viability and mitochondrial membrane potential, were assessed. Results: Poisoning by PQ significantly increased the LPO levels and considerably decreased the TAC, CAT, and SOD activity compared with the control subjects (P<0.05). PQ-induced oxidative significantly damaged the viability and membrane potential of mitochondrial compared with controls (P<0.05). Administration of nano-curcumin significantly increased the SOD activity, as well as viability and mitochondrial membrane potential in the PQ group (P<0.05). Besides, treatment by nano-curcumin in the PQ group significantly improved the lipid peroxidation process (P<0.05). Conclusion: Nanocurcumin is more effective than curcumin in reducing the PQ-induced oxidative damage.
Intracellular ROS Protection Efficiency and Free Radical-Scavenging Activity of Curcumin
PLoS ONE, 2011
Curcumin has many pharmaceutical applications, many of which arise from its potent antioxidant properties. The present research examined the antioxidant activities of curcumin in polar solvents by a comparative study using ESR, reduction of ferric iron in aqueous medium and intracellular ROS/toxicity assays. ESR data indicated that the steric hindrance among adjacent big size groups within a galvinoxyl molecule limited the curcumin to scavenge galvinoxyl radicals effectively, while curcumin showed a powerful capacity for scavenging intracellular smaller oxidative molecules such as H 2 O 2 , HO N , ROO N. Cell viability and ROS assays demonstrated that curcumin was able to penetrate into the polar medium inside the cells and to protect them against the highly toxic and lethal effects of cumene hydroperoxide. Curcumin also showed good electrontransfer capability, with greater activity than trolox in aqueous solution. Curcumin can readily transfer electron or easily donate H-atom from two phenolic sites to scavenge free radicals. The excellent electron transfer capability of curcumin is because of its unique structure and different functional groups, including a b-diketone and several p electrons that have the capacity to conjugate between two phenyl rings. Therfore, since curcumin is inherently a lipophilic compound, because of its superb intracellular ROS scavenging activity, it can be used as an effective antioxidant for ROS protection within the polar cytoplasm.
BMC Complementary and Alternative Medicine, 2017
Background: Mitochondrial dysfunction and oxidative stress are the main toxic events leading to dopaminergic neuronal death in Parkinson's disease (PD) and identified as vital objective for therapeutic intercession. This study investigated the neuro-protective effects of the demethoxycurcumin (DMC), a derivative of curcumin against rotenone induced neurotoxicity. Methods: SH-SY5Y neuroblastoma cells are divided into four experimental groups: untreated cells, cells incubated with rotenone (100 nM), cells treated with DMC (50 nM) + rotenone (100 nM) and DMC alone treated. 24 h after treatment with rotenone and 28 h after treatment with DMC, cell viability was assessed using the MTT assay, and levels of ROS and MMP, plus expression of apoptotic protein were analysed. Results: Rotenone induced cell death in SH-SY5Y cells was significantly reduced by DMC pretreatment in a dose-dependent manner, indicating the potent neuroprotective effects of DMC. Rotenone treatment significantly increases the levels of ROS, loss of MMP, release of Cyt-c and expression of pro-apoptotic markers and decreases the expression of anti-apoptotic markers. Conclusions: Even though the results of the present study indicated that the DMC may serve as a potent therapeutic agent particularly for the treatment of neurodegenerative diseases like PD, further pre-clinical and clinical studies are required.
Protective effect of curcumin on cypermethrin-induced oxidative stress in Wistar rats
Experimental and Toxicologic Pathology, 2012
The aim of present study was to investigate the protective effect of curcumin on cypermethrin-induced changes in blood biochemical markers and tissue antioxidant enzyme in rats. Rats were divided into six groups of six each: group I used as control and II and III groups were used as vehicle control. While, groups IV, V and VI were orally treated with curcumin (100 mg/kg body weight), cypermethrin (25 mg/kg body weight) and cypermethrin plus curcumin, respectively for 28 days. Serum biochemical markers were measured in the serum, and the levels of lipid peroxidation and antioxidant enzyme activity were determined in the liver, kidney and brain. Cypermethrin administration caused elevated level of blood biochemical markers in serum and lipid peroxidation in liver, kidney and brain. While the activities of non-enzymatic and enzymatic antioxidants levels were decreased except superoxide dismutase in liver, kidney and brain tissues. The presence of curcumin with cypermethrin significantly decreased the blood biochemical markers and lipid peroxidation but significantly increased the reduced glutathione, catalase and glutathione peroxidase level and preserved the normal histological architecture of the liver, kidney and brain. Our results indicate that curcumin can be potent protective agent against cypermethrininduced biochemical alterations and oxidative damage in rats.
Research Square (Research Square), 2022
Background Parkinson's disease (PD) is associated with motor and behavioral dysfunctions. Mitochondrial damage, increased oxidative stress, and the formation of Lewy bodies by misfolded proteins are major pathways for the development of PD. Using antioxidants could delay neurodegeneration in parkinsonism and improve the symptoms. We investigated the neuroprotective effects of quercetin, curcumin, and their combination on the rotenone-induced parkinsonism model. Methods PDwas induced by administration of rotenone 2mg/kg/day for 14 days in rats. Curcumin (100, 150, and 200 mg/kg), quercetin (30, 40, and 50 mg/kg),or their combination were given orally for 14 days concurrently with rotenone and for additional 14 days. On the 28th and 29th days, behavioral and histological studies were carried out. Results In the rotenone-induced parkinsonism model, curcumin and quercetin dose-dependently improved locomotor activity, motor coordination, and mobility. Also, they increased dopamine levels and mitigated the neural damage induced by rotenone. Conclusion Both curcumin and quercetin have neuroprotective effects against parkinsonism. The combination of curcumin and quercetin has more favorable effects than usingeither drug alone.
Curcumin protects against tartrazine-mediated oxidative stress and hepatotoxicity in male rats
PubMed, 2017
Objective: Synthetic dyes have been reported to exert detrimental effects on the health of humans. This study evaluated the effects of a diet containing tartrazine (Tz) on rats which included: i) biochemical parameters including hepatic enzymes, kidney functions and profiles of lipids; ii) markers of oxidative stress in cells by measuring concentrations of malondialdehyde (MDA) and glutathione (GSH); iii) activities of selected, key hepatic antioxidant enzymes including catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (GPx); iv) pathologies of liver. Also, protective effects of three doses of curcumin (CUR), a natural food coloring agent, on these parameters in rats that had been co-exposed to Tz. Materials and methods: Fifty Wistar male albino rats were randomly divided into five groups: Group I, control, where rats were fed a normal diet; Group II, rats were fed normal diets containing 7.5 mg Tz/kg diet, dry mass (dm); In Groups III, IV and V, rats were fed diets containing Tz plus 1.0, 2.0 or 4.0 g CUR/kg diet, dm, respectively. Whole blood was collected after 90 d of exposure, homogenates of liver were prepared and the above analyses were conducted. Results: Exposure to Tz in the diet caused statistically significant (p<0.05) greater concentrations of lipids, hepatic enzymes, and kidney function parameters as well as the indicator of oxidative stress MDA. Alternatively, activities of several antioxidant enzymes (i.e. CAT, SOD and GPx) and concentration of the substrate GSH, an indicator of non-enzymatic antioxidant capability, were significantly (p<0.05) less than those in control rats not exposed to Tz. Tz caused various histopathological changes in livers of rats, which were characterized by hemorrhage and dilatation of the central vein and sinusoids, hepatocyte necrosis, intracellular vacuolization. Co-administration of 2.0 (Group IV) or 4.0 g CUR/kg diet (Group V) with Tz significantly mitigated effects on functions of liver and kidney and the profile of relative concentrations of lipids. CUR significantly (p<0.05), and almost completely, reversed effects on enzymatic and non-enzymatic antioxidant and indicators of oxidative stress about rats fed Tz (Group II) to values in control rats. However, co-administration of 1.0 g CUR with Tz (Group III) exhibited a negligible effect on those parameters. The results of this study suggest benefits of the use of CUR, as a promising natural food additive to counteract oxidative stress caused by dietary exposure to the synthetic dye Tz due to potent protective antioxidant activity. Conclusions: Blending some natural food additives, such as CUR with diets containing synthetic dyes, could moderate potential effects of these artificial dyes. Decreasing or removing toxins in food is an essential step for the amelioration of human health status and decreasing risk of onset or progression of degenerative diseases.