curcumin and Mitochondrial-Diseases

Mitochondria are cytoplasmic double-membraned organelles that are involved in a myriad of key cellular regulatory processes. The loss of mitochondrial function is related to the pathogenesis of several human diseases. Over the last decades, an increasing number of studies have shown that dietary polyphenols can regulate mitochondrial redox status, and in some cases, prevent or delay disease progression. This paper aims to review the role of four dietary polyphenols - resveratrol, curcumin, epigallocatechin-3-gallate nd quercetin - in molecular pathways regulated by mitochondria and their potential impact on human health. Cumulative evidence showed that the aforementioned polyphenols improve mitochondrial functions in different in vitro and in vivo experiments. The mechanisms underlying the polyphenols' beneficial effects include, among others, the attenuation of oxidative stress, the regulation of mitochondrial metabolism and biogenesis and the modulation of cell-death signaling cascades, among other mitochondrial-independent effects. The understanding of the chemicalbiological interactions of dietary polyphenols, namely with mitochondria, may have a huge impact on the treatment of mitochondrial dysfunction-related disorders.

Topics: Animals; Catechin; Curcumin; Humans; Mitochondria; Mitochondrial Diseases; Oxidative Stress; Quercetin; Resveratrol

The effects of curcumin (CCM) on cerebral ischemia/reperfusion injury are not well understood. The aim of this study was to investigate whether CCM attenuates inflammation and mitochondrial dysfunction in a rat model of cerebral ischemia/reperfusion injury and whether Sirt1 is involved in these potential protective effects. Sirtinol, a Sirt1 inhibitor, was used to elucidate the underlying mechanism. Rats were subjected to 2h of transient middle cerebral artery occlusion (MCAO), followed by reperfusion for 24h. Brain magnetic resonance imaging (MRI) was used to detect infarct volumes. Neurological scores and brain water content were also assessed. Levels of tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) in the brain were detected using commercial enzyme-linked immunosorbent assay (ELISA) kits. Expression of SIRT1, acetylated p53 (Ac-p53), Bcl-2, and Bax was measured by western blotting. Our results suggested that CCM exerted a neuroprotective effect, as shown by reduced infarct volumes and brain edema and improved neurological scores. CCM also exerted anti-inflammatory effects, as indicated by decreased TNF-α and IL-6 levels in the brain. CCM elevated mitochondrial membrane potential, mitochondrial complex I activity, and mitochondrial cytochrome c levels, but reduced cytosolic cytochrome c levels. Moreover, CCM upregulated SIRT1 and Bcl-2 expression and downregulated Ac-p53 and Bax expression. These effects of CCM were abolished by sirtinol. In conclusion, our results demonstrate that CCM treatment attenuates ischemic stroke-induced brain injury via activation of SIRT1.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Brain Edema; Curcumin; Disease Models, Animal; Drug Administration Schedule; Gene Expression Regulation; Histocompatibility Antigens Class I; Infarction, Middle Cerebral Artery; Inflammation; Male; Membrane Potential, Mitochondrial; Mitochondrial Diseases; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Reperfusion Injury; Signal Transduction; Sirtuin 1

Chronic exposure of acrylamide (ACR) leads to neuronal damage in both experimental animals and humans. The primary focus of this study was to assess the ameliorative effect of geraniol, (a natural monoterpene) against ACR-induced oxidative stress, mitochondrial dysfunction and neurotoxicity in a Drosophila model and compare its efficacy to that of curcumin, a spice active principle with pleiotropic biological activity. Adult male flies (8-10 days) were exposed (7 days) to ACR (5 mM) with or without geraniol and curcumin (5-10 μM) in the medium. Both phytoconstituents significantly reduced the incidence of ACR-induced mortality, rescued the locomotor phenotype and alleviated the enhanced levels of oxidative stress markers in head/body regions. The levels of reduced glutathione (GSH) and total thiols (TSH) resulting from ACR exposure was also restored with concomitant elevation in the activities of detoxifying enzymes. Interestingly, ACR induced mitochondrial dysfunctions (MTT reduction, activities of SDH and citrate synthase enzymes) were alleviated by both phytoconstituents. While ACR elevated the activity of acetylcholinesterase in head/body regions, marked diminution in enzyme activity ensued with co-exposure to phytoconstituents suggesting their potency to mitigate cholinergic function. Furthermore, phytoconstituents also restored the dopamine levels in head/body regions. The neuroprotective effect of geraniol was comparable to curcumin in terms of phenotypic and biochemical markers. Based on our evidences in fly model we hypothesise that geraniol possess significant neuromodulatory propensity and may be exploited for therapeutic application in human pathophysiology associated with neuropathy. However, the precise mechanism/s by which geraniol offers neuroprotection needs to be investigated in appropriate neuronal cell models.

Topics: Acetylcholinesterase; Acrylamide; Acyclic Monoterpenes; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Citrate (si)-Synthase; Curcumin; Dopamine; Drosophila melanogaster; Drug Evaluation, Preclinical; Glutathione; Locomotion; Male; Mitochondrial Diseases; Neurotoxicity Syndromes; Oxidative Stress; Phytotherapy; Succinate Dehydrogenase; Sulfhydryl Compounds; Terpenes

The present study was designed to characterize the mitochondrial dysfunction induced by catecholamines and to investigate whether curcumin, a natural antioxidant, induces cardioprotective effects against catecholamine-induced cardiotoxicity by preserving mitochondrial function. Because mitochondria play a central role in ischemia and oxidative stress, we hypothesized that mitochondrial dysfunction is involved in catecholamine toxicity and in the potential protective effects of curcumin. Male Wistar rats received subcutaneous injection of 150 mg·kg(-1)·day(-1) isoprenaline (ISO) for two consecutive days with or without pretreatment with 60 mg·kg(-1)·day(-1) curcumin. Twenty four hours after, cardiac tissues were examined for apoptosis and oxidative stress. Expression of proteins involved in mitochondrial biogenesis and function were measured by real-time RT-PCR. Isolated mitochondria and permeabilized cardiac fibers were used for swelling and mitochondrial function experiments, respectively. Mitochondrial morphology and permeability transition pore (mPTP) opening were assessed by fluorescence in isolated cardiomyocytes. ISO treatment induced cell damage, oxidative stress, and apoptosis that were prevented by curcumin. Moreover, mitochondria seem to play an important role in these effects as respiration and mitochondrial swelling were increased following ISO treatment, these effects being again prevented by curcumin. Importantly, curcumin completely prevented the ISO-induced increase in mPTP calcium susceptibility in isolated cardiomyocytes without affecting mitochondrial biogenesis and mitochondrial network dynamic. The results unravel the importance of mitochondrial dysfunction in isoprenaline-induced cardiotoxicity as well as a new cardioprotective effect of curcumin through prevention of mitochondrial damage and mPTP opening.

Topics: Adrenergic beta-Agonists; Animals; Apoptosis; Cardiomegaly; Cardiotonic Agents; Catecholamines; Curcumin; Disease Models, Animal; Drug Interactions; Enzyme Inhibitors; Isoproterenol; Male; Mitochondrial Diseases; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocarditis; Oxidative Stress; Rats; Rats, Wistar

Mitochondrial dysfunctions cause numerous human disorders. A platform technology based on biodegradable polymers for carrying bioactive molecules to the mitochondrial matrix could be of enormous potential benefit in treating mitochondrial diseases. Here we report a rationally designed mitochondria-targeted polymeric nanoparticle (NP) system and its optimization for efficient delivery of various mitochondria-acting therapeutics by blending a targeted poly(d,l-lactic-co-glycolic acid)-block (PLGA-b)-poly(ethylene glycol) (PEG)-triphenylphosphonium (TPP) polymer (PLGA-b-PEG-TPP) with either nontargeted PLGA-b-PEG-OH or PLGA-COOH. An optimized formulation was identified through in vitro screening of a library of charge- and size-varied NPs, and mitochondrial uptake was studied by qualitative and quantitative investigations of cytosolic and mitochondrial fractions of cells treated with blended NPs composed of PLGA-b-PEG-TPP and a triblock copolymer containing a fluorescent quantum dot, PLGA-b-PEG-QD. The versatility of this platform was demonstrated by studying various mitochondria-acting therapeutics for different applications, including the mitochondria-targeting chemotherapeutics lonidamine and α-tocopheryl succinate for cancer, the mitochondrial antioxidant curcumin for Alzheimer's disease, and the mitochondrial uncoupler 2,4-dinitrophenol for obesity. These biomolecules were loaded into blended NPs with high loading efficiencies. Considering efficacy, the targeted PLGA-b-PEG-TPP NP provides a remarkable improvement in the drug therapeutic index for cancer, Alzheimer's disease, and obesity compared with the nontargeted construct or the therapeutics in their free form. This work represents the potential of a single, programmable NP platform for the diagnosis and targeted delivery of therapeutics for mitochondrial dysfunction-related diseases.

Topics: 2,4-Dinitrophenol; Adipogenesis; alpha-Tocopherol; Analysis of Variance; Bioengineering; Curcumin; Drug Delivery Systems; Humans; Indazoles; Mitochondrial Diseases; Nanoparticles; Polyethylene Glycols; Polyglactin 910; Polymers

Oxidative stress and mitochondrial dysfunction have been implicated in the pathogenesis of indomethacin-induced enteropathy. We evaluated the potential of curcumin, a known cytoprotectant, as an agent to protect against such effects. Rats were pretreated with curcumin (40 mg/kg by intra-peritoneal injection) before administration of indomethacin (20 mg/kg by gavage). One hour later, the small intestine was isolated and used for assessment of parameters of oxidative stress. Mitochondria, brush border membranes (BBM) and surfactant-like particles (SLP) were also isolated from the tissue. Mitochondria were used for assessment of functional integrity, estimation of products of lipid peroxidation and lipid content. BBM were used for estimation of products of lipid peroxidation and lipid content, while the SLP were used for measurement of lipid content. The results showed that oxidative stress and mitochondrial dysfunction occurred in the small intestine of indomethacin-treated rats. Pre-treatment with curcumin was found to ameliorate these drug-induced changes. Significant changes were seen in some of the lipids in the mitochondria, BBM and SLP in response to indomethacin. However, curcumin did not have any significant effect on these drug-induced changes. We conclude that curcumin, by attenuating oxidative stress and mitochondrial dysfunction, holds promise as an agent that can potentially reduce NSAID-induced adverse effects in the small intestine.

Topics: Alkaline Phosphatase; Animals; Anti-Inflammatory Agents, Non-Steroidal; Curcumin; Indomethacin; Intestinal Diseases; Lipid Metabolism; Lipid Peroxidation; Male; Microvilli; Mitochondria; Mitochondrial Diseases; Oxidative Stress; Rats; Rats, Wistar; Surface-Active Agents