Correction Of Mitochondrial Dysfunction Research Articles

Correction of mitochondrial dysfunction with trimethoxy-substituted monocarbonyl curcumin analogues in experimental Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disease that is a terminal form of dementia with an alarming spread rate. The treatment of AD usually involves symptomatic therapy, but the research field for new medicines to correct AD focus on the pathogenetic keys of the disease, i.e., a mitochondrial dysfunction.The aim of the work was to evaluate the effect of trimethoxy-substituted monocarbonyl curcumin analogues on changes in the mitochondrial function of the hippocampus in AD rats.Materials and methods. AD was modeled in female Wistar rats by the injection of β-amyloid aggregates 1-42 into the CA1 part of the hippocampus. The tested compounds AZBAX4 and AZBAX6 at a dose of 20 mg/kg each, as well as the reference donepezil at a dose of 50 mg/kg, were administered orally for 30 days after the surgery. After the specified time had passed, the changes in the cellular respiration, a citrate synthase activity, cytochrome-c-oxidase, succinate dehydrogenase, and adenosine triphosphate (ATP) concentrations were evaluated in the mitochondrial fraction of the rat hippocampus.Results. During the study, it was shown that the use of AZBAX4 and AZBAX6 compounds contributed to an increase in the intensity of aerobic metabolism by 83.9 (p <0.05) and 35.9% (p <0.05), respectively, while reducing the activity of anaerobic one by 27.7 (p <0.05) and 20.6% (p <0.05), respectively. Against the background of the tested compounds AZBAX4 and AZBAX6 administration, there was also a significant increase in the activity of citrate synthase, succinate dehydrogenase and cytochrome-c-oxidase, as well as the level of ATP in the hippocampal tissue by 112.8 (p <0.05) and 117.1% (p <0.05), respectively. The use of donepezil led to a significant increase in the intensity of aerobic reactions – by 24.0% (p <0.05), a citrate synthase activity– by 80.0% (p <0.05) and the ATP concentration – by 68.5% (p <0.05). Against the background of the use of the analyzed substances, a decrease in the apoptosis-inducing factor and mitochondrial hydrogen peroxide is also worth noting.Conclusion. Based on the obtained data, it can be assumed that the use of AZBAX4 and AZBAX6 compounds contributes to an increase in the functional activity of the mitochondria of hippocampal cells of AD rats, while surpassing the reference donepezil. It is perspective to continue a further study of AZBAX4 and AZBAX6 compounds as possible medicines of a pathogenetic correction of AD.

Correction of Mitochondrial Dysfunction in the Complex Rehabilitation of COVID-19 Patients

Objective. To study the efficacy of courses of i.v., Cytoflavin in combination with the standard rehabilitation program for postcovid syndrome for correction of postcovid asthenia. Materials and methods. Follow-up investigations were carried out in 45 patients with postcovid syndrome at the second stage of rehabilitation. Patients were divided into two groups of comparable sex and age. The volume of lung damage was also similar in both groups, at 25–80%. The 24 patients making up the comparison group received standard postcovid rehabilitation: pulsed magnetotherapy, inhalation therapy, aeroionotherapy, infrared laser therapy, courses of aerobic training, rational psychotherapy, and successive drug therapy. The 21 patients of the study group additionally received intravenous Cytoflavin daily for 10 days. The dynamics of increases in scores on the Rehabilitation Routing Scale, the Hamilton Depression Rating Scale (HDRS), the Asthenic Status Scale, and the 6-minute walk test at admission and discharge were also monitored. Results and conclusions. Addition of courses of intravenous Cytoflavin to the complex rehabilitation program for postcovid syndrome significantly improved the general functional state of the body, decreased levels of depression and asthenization, and increased physical exercise tolerance.

Methodological Approaches to the Study of Mitochondrial Respiration

Energy exchange in the cell is associated with mitochondria, which play an important role in vital processes. The Oxidative Phosphorylation System (OxРhoS), localized in the inner mitochondrial membrane, consists of five membrane enzymes. Four of the five protein complexes make up the "respiratory chain" and are involved in the transfer of electrons, which at three points is coupled with the translocation of protons across the inner mitochondrial membrane. The resulting proton gradient is used by the ATP synthase complex (the fifth enzyme complex) to phosphorylate ADP. The methods for studying the activity of the electron transport chain of mitochondria described in the article, especially their use in a complex, makes it possible to significantly detail the understanding of the pathogenesis of disorders of cell energy exchange that occurs in various diseases, which will improve the prevention and correction of mitochondrial dysfunction.

Correction of mitochondrial dysfunction by succinic acid derivatives under experimental cerebral ischemia conditions

Abstract The aim of the study. To evaluate the effect of succinic acid derivatives on changes of mitochondrial function in rats under cerebral ischemia conditions. Materials and methods. In this work, the effect of succinic acid, ethylmethylhydroxypyridine succinate, and acetylaminosuccinic acid at doses of 50 mg/kg, 100 mg/kg, and 200 mg/kg (per os) on the change of the neuronal mitochondria function was studied. Cerebral ischemia was reproduced by the Tamura method. The following parameters were evaluated: changes in aerobic/anaerobic metabolism, mitochondrial membrane potential, the opening rate of the mitochondrial pore of transitional permeability and the activity of apoptotic systems. Results. During the study, it was found that the use of the test-compounds at doses of 100 mg/kg and 200 mg/kg contributed to an increase in ATP-generating activity, as well as the maximum respiration level and respiratory capacity, while accompanied by a decrease in the intensity of anaerobic metabolism reactions. Also, upon administration of the test succinic acid derivatives, an increase in the mitochondrial membrane potential and latent opening time of the mitochondrial pore transitional permeability were observed. Moreover, the activity of caspase-3 and apoptosis-inducing factor on groups treated by test objects at doses of 100 mg/kg and 200 mg/kg was significantly lower than that in untreated animals. Conclusion. The studied succinic acid derivatives contribute to the restoration of mitochondrial function in cerebral ischemia conditions, while the most effective dose can be considered to be 100 mg/kg.

Correction of mitochondrial dysfunction in the complex rehabilitation of COVID-19

To study the effectiveness of a course of intravenous administration of cytoflavin in combination with a standard rehabilitation program for post-COVID fatigue syndrome caused by mitochondrial dysfunction. The dynamic examination of 45 patients with post-COVID syndrome at the second stage of rehabilitation was carried out. The patients were subdivided into 2 groups comparable in gender and age. The volume of lung damage in patients of both groups was also comparable at range of 25-80%. Twenty-four patients of the control group were treated with the standard post-COVID rehabilitation protocol: pulse magnetic therapy, inhalation therapy, aeroion therapy, infrared laser therapy, course aerobic training, psychotherapy, and standard drug therapy. Twenty-one patients of the main group additionally received intravenous administration of cytoflavin daily for 10 days. The dynamics of the scores on the Rehabilitation Routing Scale, HDRS, the Asthenic Status Scale, and the 6-minute walk test was analyzed. The additional intravenous administration of cytoflavin at the complex rehabilitation of post-COVID syndrome can significantly improve the therapeutic results: it significantly improves the overall functional state, reduces depression and fatigue level and increases tolerance to physical exertion.

Correction of Mitochondrial Dysfunction by 4-Hydroxy-3,5-Ditretbutyl Cinnamic Acid in Experimental Alzheimer’s Disease Induced by Aβ Injection in Rats

Background: Alzheimer’s disease is the main form of dementia, which affects more than46 million people every year. In the pathogenesis of Alzheimer’s disease, a significant roleplayed mitochondrial dysfunction, which is a promising pharmacotherapeutic target ofneuroprotective therapy. In this regard, this study aimed to evaluate the effect of the 4-hydroxy-3,5-ditretbutyl cinnamic acid on changes of mitochondrial function in experimental Alzheimer’sdisease induced by Aβ injection in rats. Methods: Alzheimer’s disease was modeled on Wistar rats by injecting a fragment of β-amyloid(Aß 1-42) into the CA1 part of the hippocampus. The test-compound (4-hydroxy-3,5-ditretbutylcinnamic acid, 100 mg/kg, per os) and the reference drugs (resveratrol, 20 mg/kg, per os andEGB671, 100 mg/kg, per os) were administered for 60 days after surgery. The restoration of amemorable trace in animals was evaluated in the Morris water maze test. The concentrationof β -amyloid, Tau-protein, and changes in parameters characterizing mitochondrial function(cellular respiration, concentration of mitochondrial ROS, activity of apoptosis reactions(caspase-3 and apoptosis induced factor) were also determined. Results: This study showed that the administration of 4-hydroxy-3,5-ditretbutyl cinnamic acidat a dose of 100 mg/kg (per os) in rats with reproduced Alzheimer’s disease contributed to thenormalization of mitochondrial respiratory function. It was expressed in the normalizationof aerobic metabolism, increased activity of respiratory complexes and stabilization ofmitochondrial membrane potential. Also, when animals were treated with 4-hydroxy-3,5-ditretbutyl cinnamic acid, there was a decrease in the concentration of intracellular calcium(by 39.7% (p<0.05)), the intensity of apoptosis reactions, and an increase of the latent time ofthe mitochondrial permeability transition pore opening (by 3.8 times (p<0.05)), and decreasesH2O2 concentration (by 21.2% (p<0.05)). Conclusion: In the course of this study, it was found that 4-hydroxy-3,5-ditretbutyl cinnamicacid exceeds the value of neuroprotective action in compared to the reference agents –resveratrol (20 mg/kg) and Ginkgo biloba extract (EGB671, 100 mg/kg).

Пирацетам и бетагистин: возможные механизмы эндотелиопротекции

Betahistine and Piracetam are routine drugs in neurological practice, which are used to correct cerebral circulation disorders. The clinical efficacy of these drugs can be caused not only by neuro-, but also by endotheliotropic action. In this review, the main information on the potential mechanisms for the implementation of vasoprotection, including metabolic, NO-ergic, anti-inflammatory and other components of the action are discussed. Betahistine as histamine receptors type 3 antagonist and histamine receptors type 1 and 2 agonist has a positive effect on cerebral and systemic hemodynamics, and due to anorexigenic action and the ability to stimulate lipolysis can ameliorate dyslipidemia. Piracetam, along with a nootropic effect, contributes to the correction of mitochondrial dysfunction, increases the fluidity of membranes and has antiplatelet properties. Both drugs suppress the synthesis of pro-inflammatory cytokines and increase the expression of endothelial NO synthase.

Target Correction of Mitochondrial Dysfunction in Parkinson's Disease by Capicor

Target Correction of Mitochondrial Dysfunction in Parkinson's Disease by Capicor

Investigation of Mitochondrial Metabolic Response to Doxorubicin in Prostate Cancer Cells: An NADH, FAD and Tryptophan FLIM Assay

Prostate cancer (PCa) is one of the leading cancers in men in the USA. Lack of experimental tools that predict therapy response is one of the limitations of current therapeutic regimens. Mitochondrial dysfunctions including defective oxidative phosphorylation (OXPHOS) in cancer inhibit apoptosis by modulating ROS production and cellular signaling. Thus, correction of mitochondrial dysfunction and induction of apoptosis are promising strategies in cancer treatment. We have used Fluorescence Lifetime Imaging Microscopy (FLIM) to quantify mitochondrial metabolic response in PCa cells by tracking auto-fluorescent NAD(P)H, FAD and tryptophan (Trp) lifetimes and their enzyme-bound fractions as markers, before and after treatment with anti-cancer drug doxorubicin. A 3-channel FLIM assay and quantitative analysis of these markers for cellular metabolism show in response to doxorubicin, NAD(P)H mean fluorescence lifetime (τm) and enzyme-bound (a2%) fraction increased, FAD enzyme-bound (a1%) fraction was decreased, NAD(P)H-a2%/FAD-a1% FLIM-based redox ratio and ROS increased, followed by induction of apoptosis. For the first time, a FRET assay in PCa cells shows Trp-quenching due to Trp-NAD(P)H interactions, correlating energy transfer efficiencies (E%) vs NAD(P)H-a2%/FAD-a1% as sensitive parameters in predicting drug response. Applying this FLIM assay as early predictor of drug response would meet one of the important goals in cancer treatment.

A critical incident during marathon competition as a result of metabolic decompensation

A case of polyorganic insufficiency syndrome associated with coma, convulsive disorder, acute hepato-renal and respiratory dysfunction, hypovolemic shock, and hyperthermal syndrome in a 46 year-old participant ofa marathon competition is reported. The clinical picture was dominated by acute hepatic insufficiency treated with remaxol to activate substrate phosphorylation under effect of exogenous succinate for slowing down the development of energy deficit in mitochondria under condition of oxygen deficit. This case can be regarded as a variant of correction of mitochondrial dysfunction with the use of a mitochondria-targeted medication such as succinate-containing remaxol. This medication reduced AST and ALT activities and utilization of endogenous enzymes for succinate synthesis from alanine and aspartate under hypoxic conditions. Prescription of remaxol as a form of direct substitution therapy was dictated by pathogenetic considerations.

Targeting Mitochondrial Dysfunction in Chronic Heart Failure: Current Evidence and Potential Approaches.

Mitochondria are cellular organelles responsible for energy production, calcium handling, controlled synthesis of reactive oxygen species (ROS), and regulation of apoptosis. All these functions are crucial for cardiac homeostasis, and may be impaired in chronic heart failure (CHF). Therefore, mitochondrial dysfunction might represent a crucial element in the onset and progression of CHF and, as such, a promising therapeutic target. Original articles and review on the treatment of mitochondrial dysfunction in CHF were searched on Medline and Scopus. The present review summarizes the current knowledge about mitochondrial modulation as a therapeutic strategy for CHF, and proposes some perspectives for future studies. Mitochondrial dysfunction can be ascribed to neuro-humoral activation and cardiac remodeling associated with CHF. Conceptually, the correction of mitochondrial dysfunction could provide an additive benefit to optimal CHF treatment. Increasing glucose metabolism and reducing oxidative stress within mitochondria are the two most promising approaches, even though further studies are required before implementing new treatments in the setting of CHF. On the other hand, inhibition of apoptosis, and normalization of calcium and mitochondrial dynamics have been assessed almost exclusively in ex vivo models, and mostly in settings other than CHF. Mitochondrial modulation in CHF is an intriguing example of translational research and a potentially rewarding field.

Correction of mitochondrial dysfunction of rabbit cardiomyocytes using substrate antihypoxants

Features of energy metabolism in children with cardiovascular diseases are of great practical importance. It is prognostically important to determine the status of the energy of cardiomyocytes to normalize bioenergetic deficit cardiomyocytes in rheumatoid arthritis, myocarditis, congenital heart diseases to decrease reduction in myocardial contractility and reduce precondition for the progression of heart failure. The experimental and clinical studies of the pathogenesis of idiopathic cardiomyopathy in children in recent years indicate directly the damage of oxidative phosphorylation in myocardial tissue due to decreased activity of the mitochondrial electron transport system. Numerous congenital diseases like syndrome Ivemark, Holt-Oram, Ellis-Van Creveld, Ivemark, Noonan, Greeg, Kugel-Stoloff, Werner, West, Adams-Stokes, MERRF include cardiomyopathy in their symptoms. Vibration-type model of hypoxic cell metabolism was suggested to estimate antihypoxant succinic acid as cardioprotective substance in in drug “Amber-antitoks” on rabbit cardiomyocytes. The experiment of bioenergy dependent reaction of native heart mitochondria was studied by polarographic method performed using a closed membrane Clarke’ electrode. Pharmacological drug “Amber-antitoks” in dose as 8.4 mg/kg prevents the formation of bioenergy dependent hypoxia of cardiomyocytes and restore the activity of NAD-dependent, and suppress hyperactivity suktsinat-degidrogenaze enzyme-substrate complex of the respiratory chain. It causes reduction of the severity of mitochondrial dysfunction and the degree of morphological myocardial tissue damage. The protective properties of drug “Amber-antitoks” allow to recommend it for using in the treatment in combination with other drugs of cardiovascular disease in children.

Abstract 3373: Contribution of microRNA-122 to the homeostasis of liver energy metabolism

Abstract MicroRNA-122 (miR-122) is a liver specific miRNA known to regulate lipid metabolism and to prevent liver tumorigenesis. Recent data suggest that miR-122 regulates the metabolism of mitochondria but its mechanistic role is unclear. We investigated how energy metabolism is regulated by miR-122 using the Mir122a-/- mouse model. We identified a distinctive expression profile of mitochondrially localized genes between WT and Mir122a-/- mice by both microarray and proteomics. KEGG and IPA database analysis further showed decreased mitochondrial respiration activity and Acetyl-CoA synthesis. Besides, the expression of genes involved in antioxidant mechanism is increased. The primary hepatocytes were used to study the energy metabolism. The physiological activities measured by XF-24 extracellular flux analyzer revealed a higher mitochondrial respiration activity (OCR) accompanied with a proton leak in the mitochondrial inner membrane of the Mir122a-/- hepatocytes. In addition, a higher glycolytic activity (ECAR) was detected in Mir122a-/- hepatocytes. Poor ATP production was detected from Mir122a-/- mitochondria. Several lines of evidence demonstrated that Mir122a-/- hepatocytes have low mitochondria membrane potential: excess cytosolic reactive oxygen species, less mitochondrial superoxide anion and lower staining with Rhodamine 123 and Mitotracker red. We further treated cells with mitochondrial inhibitors and found an excellent antioxidant capacity and ATP homeostasis in Mir122a-/- primary hepatocytes. Interestingly, we detected lower protein expression of pyruvate dehydrogenase complex subunit E1, which may partly contribute to the defective mitochondrial activity. The liver homeostasis of Mir122a-/- mice, however, is stabilized by a vigorous antioxidant activity and higher glycolysis capacity. As a result, the livers of young Mir122a-/- mice appear to have switched to aerobic glycolysis (Warburg effect), which is the hallmark of cancer cells. Therefore, correction of mitochondrial dysfunction is likely to become one of new therapeutic means for hepatocellular carcinoma (HCC). Citation Format: Ann-Ping Tsou, Shuo-Ting Wang, Tse-Wen Tao. Contribution of microRNA-122 to the homeostasis of liver energy metabolism. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3373. doi:10.1158/1538-7445.AM2014-3373

Moderate intermittent hypoxia/hyperoxia: implication for correction of mitochondrial dysfunction

Abstract The purpose of this study was to appreciate the acute hypoxia-induced mitochondrial oxidative damage development and the role of adaptation to hypoxia/hyperoxia (H/H) in correction of mitochondrial dysfunction. It was demonstrated that long-term sessions of moderate H/H [5 cycles of 5 min hypoxia (10% O2 in N2) alternated with 5 min hyperoxia (30% O2 in N2) daily for two weeks]_attenuated basal and Fe2+/ascorbate-induced lipid peroxidation (LPO) as well as production of carbonyl proteins and H2O2 in liver mitochondria of rats exposed to acute severe hypoxia (7% O2 in N2, 60 min) in comparison with untreated animals. It was shown that H/H increases the activity of glutathione peroxidase (GPx), reduces hyperactivation of Mn-SOD, and decreases Cu,Zn-SOD activity as compared with untreated rats. It has been suggested that the induction of Mn-SOD protein expression and the coordinated action of Mn-SOD and GPx could be the mechanisms underlying protective effects of H/H, which promote the correction of the acute hypoxia-induced mitochondrial dysfunction. The increase in Mn-SOD protein synthesis without changes in Mn-SOD mRNA level under H/H pretreatment indicates that the Mn-SOD activity is most likely dependent on its posttranslational modification or on the redox state of liver mitochondria.

Tryptamine-Gallic Acid Hybrid Prevents Non-steroidal Anti-inflammatory Drug-induced Gastropathy

We have investigated the gastroprotective effect of SEGA (3a), a newly synthesized tryptamine-gallic acid hybrid molecule against non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy with mechanistic details. SEGA (3a) prevents indomethacin (NSAID)-induced mitochondrial oxidative stress (MOS) and dysfunctions in gastric mucosal cells, which play a pathogenic role in inducing gastropathy. SEGA (3a) offers this mitoprotective effect by scavenging of mitochondrial superoxide anion (O(2)(·-)) and intramitochondrial free iron released as a result of MOS. SEGA (3a) in vivo blocks indomethacin-mediated MOS, as is evident from the inhibition of indomethacin-induced mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. SEGA (3a) corrects indomethacin-mediated mitochondrial dysfunction in vivo by restoring defective electron transport chain function, collapse of transmembrane potential, and loss of dehydrogenase activity. SEGA (3a) not only corrects mitochondrial dysfunction but also inhibits the activation of the mitochondrial pathway of apoptosis by indomethacin. SEGA (3a) inhibits indomethacin-induced down-regulation of bcl-2 and up-regulation of bax genes in gastric mucosa. SEGA (3a) also inhibits indometacin-induced activation of caspase-9 and caspase-3 in gastric mucosa. Besides the gastroprotective effect against NSAID, SEGA (3a) also expedites the healing of already damaged gastric mucosa. Radiolabeled ((99m)Tc-labeled SEGA (3a)) tracer studies confirm that SEGA (3a) enters into mitochondria of gastric mucosal cell in vivo, and it is quite stable in serum. Thus, SEGA (3a) bears an immense potential to be a novel gastroprotective agent against NSAID-induced gastropathy.