ubiquinone and Fibrosis

Coenzyme Q10 (CoQ10) is a vitamin-like substance which functions as an electron carrier within the mitochondrial respiratory chain, as well as serving as an important intracellular antioxidant. Most of the body's CoQ10 requirements are met by endogenous synthesis, although the capacity for CoQ10 production decreases substantially with increasing age. In this article we have reviewed the potential role of CoQ10 supplementation in the treatment of tissue fibrosis, which has been implicated in the age-related loss of function of various organs including the heart. Clinical studies have indicated that CoQ10 supplementation may decrease the level of cardiovascular fibrosis to which older individuals are subjected, and thereby improve cardiovascular function and reduce the risk of cardiovascular associated mortality. Although the factors responsible for the anti-fibrotic action of CoQ10 have yet to be fully elucidated, its antioxidant and anti-inflammatory functions are thought to be major contributors to its clinical efficacy in the treatment of this age-related disorder.

Topics: Antioxidants; Cardiovascular Diseases; Fibrosis; Humans; Ubiquinone

Selenium and coenzyme Q10 have synergistic antioxidant functions. In a four-year supplemental trial in elderly Swedes with a low selenium status, we found improved cardiac function, less cardiac wall tension and reduced cardiovascular mortality up to 12 years of follow-up. Here we briefly review the main results, including those from studies on biomarkers related to cardiovascular risk that were subsequently conducted. In an effort, to explain underlying mechanisms, we conducted a structured analysis of the inter-relationship between biomarkers.. Selenium yeast (200 µg/day) and coenzyme Q10 (200 mg/ day), or placebo was given to 443 elderly community-living persons, for 48 months. Structural Equation Modelling (SEM) was used to investigate the statistical inter-relationships between biomarkers related to inflammation, oxidative stress, insulin-like growth factor 1, expression of microRNA, fibrosis, and endothelial dysfunction and their impact on the clinical effects. The main study was registered at Clinicaltrials.gov at 30th of September 2011, and has the identifier NCT01443780.. In addition to positive clinical effects, the intervention with selenium and coenzyme Q10 was also associated with favourable effects on biomarkers of cardiovascular risk. Using these results in the SEM model, we showed that the weights of the first-order factors inflammation and oxidative stress were high, together forming a second-order factor inflammation/oxidative stress influencing the factors, fibrosis (β = 0.74; p < 0.001) and myocardium (β = 0.65; p < 0.001). According to the model, the intervention impacted fibrosis and myocardium through these factors, resulting in improved cardiac function and reduced CV mortality.. Selenium reduced inflammation and oxidative stress. According to the SEM analysis, these effects reduced fibrosis and improved myocardial function pointing to the importance of supplementation in those low on selenium and coenzyme Q10.

Topics: Aged; Biomarkers; Cardiovascular Diseases; Dietary Supplements; Double-Blind Method; Fibrosis; Humans; Inflammation; Latent Class Analysis; Oxidative Stress; Prospective Studies; Selenium; Sweden; Ubiquinone

In an intervention study where 221 healthy elderly persons received selenium and coenzyme Q10 as a dietary supplement, and 222 received placebo for 4 years we observed improved cardiac function and reduced cardiovascular mortality. As fibrosis is central in the aging process, we investigated the effect of the intervention on biomarkers of fibrogenic activity in a subanalysis of this intervention study.. In the present subanalysis 122 actively treated individuals and 101 controls, the effect of the treatment on eight biomarkers of fibrogenic activity were assessed. These biomarkers were: Cathepsin S, Endostatin, Galectin 3, Growth Differentiation Factor-15 (GDF-15), Matrix Metalloproteinases 1 and 9, Tissue Inhibitor of Metalloproteinases 1 (TIMP 1) and Suppression of Tumorigenicity 2 (ST-2). Blood concentrations of these biomarkers after 6 and 42 months were analyzed by the use of T-tests, repeated measures of variance, and factor analyses.. Compared with placebo, in those receiving supplementation with selenium and coenzyme Q10, all biomarkers except ST2 showed significant decreased concentrations in blood. The changes in concentrations, that is, effects sizes as given by partial eta. The significantly decreased biomarker concentrations in those on active treatment with selenium and coenzyme Q10 compared with those on placebo after 36 months of intervention presumably reflect less fibrogenic activity as a result of the intervention. These observations might indicate that reduced fibrosis precedes the reported improvement in cardiac function, thereby explaining some of the positive clinical effects caused by the intervention. © 2017 BioFactors, 44(2):137-147, 2018.

Topics: Aged; Aged, 80 and over; Biomarkers; Cardiovascular Diseases; Cardiovascular System; Cathepsins; Dietary Supplements; Endostatins; Female; Fibrosis; Galectin 3; Growth Differentiation Factor 15; Humans; Interleukin-1 Receptor-Like 1 Protein; Male; Matrix Metalloproteinase 1; Matrix Metalloproteinase 9; Prospective Studies; Selenium; Survival Analysis; Tissue Inhibitor of Metalloproteinase-1; Ubiquinone

A proteomic approach was used to characterize potential mediators involved in the improvement in cardiac fibrosis observed with the administration of the mitochondrial antioxidant MitoQ in obese rats. Male Wistar rats were fed a standard diet (3.5% fat; CT) or a high-fat diet (35% fat; HFD) and treated with vehicle or MitoQ (200 μM) in drinking water for 7 weeks. Obesity modulated the expression of 33 proteins as compared with controls of the more than 1000 proteins identified. These include proteins related to endoplasmic reticulum (ER) stress and oxidative stress. Proteomic analyses revealed that HFD animals presented with an increase in cardiac transthyretin (TTR) protein levels, an effect that was prevented by MitoQ treatment in obese animals. This was confirmed by plasma levels, which were associated with those of cardiac levels of both binding immunoglobulin protein (BiP), a marker of ER stress, and fibrosis. TTR stimulated collagen I production and BiP in cardiac fibroblasts. This upregulation was prevented by the presence of MitoQ. In summary, the results suggest a role of TTR in cardiac fibrosis development associated with obesity and the beneficial effects of treatment with mitochondrial antioxidants.

Topics: Animals; Antioxidants; Diet, High-Fat; Fibrosis; Male; Obesity; Oxidative Stress; Prealbumin; Proteomics; Rats; Rats, Wistar; Ubiquinone

Cardiovascular disease is associated with high morbidity and mortality. Doxorubicin (DOX) is an effective adjunct to cancer chemotherapy but leads to cardiovascular-related side effects. Because coenzyme Q10 (CoQ10) has been shown to protect against cardiac damage, this study was conducted to investigate the protective effects of CoQ10 against cardiac damage in mice.. We randomly divided six-week-old male C57BL/6 mice into four groups: control (n = 7), CoQ10 (n = 7), heart failure (HF) (n = 7), and HF+CoQ10 (n = 6) groups. HF group was induced via intraperitoneal injections with DOX (5 mg/kg) once weekly for 4 weeks. CoQ10 was solube in corn oil. The mice of CoQ10 and HF+CoQ10 group were given CoQ10 (100 mg/kg) once a day for 8 weeks. All mice were subjected to different treatment regimens for eight weeks. Metabolic characteristics, cardiac damage, oxidative stress markers (SIRT1, SIRT3, eNOS, TE, P53, SIRT5, CAT, HO-1, and SOD), energy metabolism markers (PARP-1 and PPAR-γ), myocardial fibrosis markers (Smad3 and TGF-β), and apoptosis markers (BAK, BCL-XL, and caspase-8) were analyzed at eight weeks after the different treatments.. CoQ10 reduced the levels of molecules related to cardiac damage, oxidative stress, energy metabolism, and myocardial fibrosis in mice with doxorubicin-induced HF. CoQ10 also exerted anti-apoptotic effects in HF mice.. CoQ10 may be useful for preventing cardiac damage in DOX-induced HF.

Topics: Animals; Doxorubicin; Fibrosis; Heart Failure; Male; Mice; Mice, Inbred C57BL; Oxidative Stress; Ubiquinone

Radiation enteropathy is one the most common clinical issue for patients receiving radiotherapy for abdominal/pelvic tumors which severely affect the quality of life of cancer patients due to dysplastic lesions (ischemia, ulcer, or fibrosis) that aggravate the radiation damage. Herein, this study demonstrated the prophylactic role of coenzyme Q10 (CoQ10), a powerful antioxidant, against radiotherapy-induced gastrointestinal injury. Male Sprague Dawley rats were divided into four groups: group 1 was defined as control, and group 2 was the irradiated group. Group 3 and 4 were CoQ10 control and radiation plus CoQ10 groups, respectively. CoQ10 (10 mg/kg) was orally administered for 10 days before 10 Gy whole-body radiation and was continued for 4 days post-irradiation. CoQ10 administration protected rats delivered a lethal dose of ϒ-radiation from changes in crypt-villus structures and promoted regeneration of the intestinal epithelium. CoQ10 attenuated radiation-induced oxidative stress by decreasing lipid peroxidation and increasing the antioxidant enzyme catalase activity and reduced glutathione level. CoQ10 also counteracts inflammatory response mediated after radiation exposure through downregulating intestinal NF-ĸB expression which subsequently decreased the level of inflammatory cytokine IL-6 and the expression of COX-2. Radiation-induced intestinal fibrosis confirmed via Masson's trichrome staining occurred through upregulating transforming growth factor (TGF)-β1 and matrix metalloproteinase (MMP)-9 expression, while CoQ10 administration significantly diminishes these effects which further confirmed the anti-fibrotic property of CoQ10. Therefore, CoQ10 is a promising radioprotector that could prevent intestinal complications and enhance the therapeutic ratio of radiotherapy in patients with pelvic tumors through suppressing the NF-kB/TGF-β1/MMP-9 signaling pathway.

Topics: Animals; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Inflammation; Intestinal Diseases; Male; Matrix Metalloproteinase 9; NF-kappa B; Radiation Injuries; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Ubiquinone; Vitamins

Topics: Animals; Antioxidants; Apoptosis; Cytokines; Fibrosis; Hemodynamics; Hepatitis; Liver; Liver Cirrhosis; Male; Mitochondria, Liver; Organophosphorus Compounds; Oxidative Stress; Rats; Rats, Sprague-Dawley; Spleen; Ubiquinone

Increasing evidence indicates that mitochondrial-associated redox signaling contributes to the pathophysiology of heart failure (HF). The mitochondrial-targeted antioxidant, mitoquinone (MitoQ), is capable of modifying mitochondrial signaling and has shown beneficial effects on HF-dependent mitochondrial dysfunction. However, the potential therapeutic impact of MitoQ-based mitochondrial therapies for HF in response to pressure overload is reliant upon demonstration of improved cardiac contractile function and suppression of deleterious cardiac remodeling. Using a new (patho)physiologically relevant model of pressure overload-induced HF we tested the hypothesis that MitoQ is capable of ameliorating cardiac contractile dysfunction and suppressing fibrosis. To test this C57BL/6J mice were subjected to left ventricular (LV) pressure overload by ascending aortic constriction (AAC) followed by MitoQ treatment (2 µmol) for 7 consecutive days. Doppler echocardiography showed that AAC caused severe LV dysfunction and hypertrophic remodeling. MitoQ attenuated pressure overload-induced apoptosis, hypertrophic remodeling, fibrosis and LV dysfunction. Profibrogenic transforming growth factor-β1 (TGF-β1) and NADPH oxidase 4 (NOX4, a major modulator of fibrosis related redox signaling) expression increased markedly after AAC. MitoQ blunted TGF-β1 and NOX4 upregulation and the downstream ACC-dependent fibrotic gene expressions. In addition, MitoQ prevented Nrf2 downregulation and activation of TGF-β1-mediated profibrogenic signaling in cardiac fibroblasts (CF). Finally, MitoQ ameliorated the dysregulation of cardiac remodeling-associated long noncoding RNAs (lncRNAs) in AAC myocardium, phenylephrine-treated cardiomyocytes, and TGF-β1-treated CF. The present study demonstrates for the first time that MitoQ improves cardiac hypertrophic remodeling, fibrosis, LV dysfunction and dysregulation of lncRNAs in pressure overload hearts, by inhibiting the interplay between TGF-β1 and mitochondrial associated redox signaling.

Topics: Animals; Apoptosis; Biomarkers; Cardiomegaly; Disease Models, Animal; Echocardiography; Fibroblasts; Fibrosis; Heart Failure; Immunohistochemistry; Male; Mice; Models, Biological; Myocardium; Organophosphorus Compounds; Signal Transduction; Stress, Mechanical; Transforming Growth Factor beta; Ubiquinone; Ventricular Dysfunction, Left; Ventricular Remodeling

Pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis. Any remedies that inhibit the activation of PSCs can be potential candidates for therapeutic strategies in pancreatic fibrosis-related pancreatic ductal adenocarcinoma (PDAC) and chronic pancreatitis (CP). Our study is aimed at exploring the protective effect of coenzyme Q10 (CoQ10) against pancreatic fibrosis.. Pancreatic fibrosis was induced by 20% L-arginine (250 mg/100 g) at 1 h intervals twice per week for 8 weeks in C57BL/6 mice. CoQ10 was administered for 4 weeks. Isolated primary PSCs from C57BL/6 mice were treated with 100 . Pretreatment and posttreatment of CoQ10 decreased autophagy, activation of PSCs, oxidative stress, histological changes, and collagen deposition in the CP mouse model. In primary PSCs, expression levels of p-PI3K, p-AKT, and p-mTOR were upregulated with CoQ10. A rescue experiment using specific inhibitors of the PI3K-AKT-mTOR pathway demonstrated that the PI3K-AKT-mTOR signaling pathway was the underlying mechanism by which CoQ10 ameliorated fibrosis. With the addition of Rosup, expression levels of the autophagy biomarkers LC3 and Atg5 were elevated. Meanwhile, the levels of p-PI3K, p-AKT, and p-mTOR were lower.. Our findings demonstrated that CoQ10 alleviates pancreatic fibrosis by the ROS-triggered PI3K/AKT/mTOR signaling pathway. CoQ10 may be a therapeutic candidate for antifibrotic methods.

Topics: Animals; Fibrosis; Humans; Male; Mice; Mice, Inbred C57BL; Pancreatic Neoplasms; Reactive Oxygen Species; TOR Serine-Threonine Kinases; Ubiquinone

The objective of the present study aimed to investigate the effect of CoQ10 treatment on isoprenaline (ISO)-induced cardiac remodeling in rats.. Rats were divided into three groups namely Control group, ISO treated group and CoQ10 + ISO treated group, each consisting of 6 rats. The cardiac specific CK-MB, AST, ALT activity and other oxidative stress parameters were estimated in heart and kidneys. Additionally histological examination was also performed to visualize the inflammatory cells infiltration and fibrosis in both tissues.. Administration of ISO resulted in an increase in the heart-to-body weight (HW/BW) ratio and an also increased the serum CK-MB, AST and ALT enzyme activity. Serum levels of lipid peroxidation products, and oxidative stress markers showed significant increase in ISO-treated rats. Histopathological examination of heart tissue revealed focal areas of endocardium degeneration, mononuclear cells infiltration, fibrous tissue deposition, and increased thickness of the myocardium of left ventricle. Similar degeneration was also found in kidneys. Treatment with CoQ10 (100 mg/kg) significantly improved the oxidative stresses in ISO treated rats. Moreover, CoQ10 treatment prevented inflammatory cells infiltration and reduced fibrosis in ISO administered rats.. In conclusion, our study provides evidence that CoQ10 may prevent the development of cardiac remodeling, and fibrosis in ISO administered rats.

Topics: Aging; Animals; Fibrosis; Isoproterenol; Male; Oxidative Stress; Rats; Rats, Long-Evans; Ubiquinone; Ventricular Remodeling

To evaluate protective effect of coenzyme Q10 (CoQ10) in lacrimal glands against high-dose radioactive iodine (RAI)-associated oxidative damage.. Thirty Wistar albino rats were randomly divided into three groups. Group 1 was the control group. Group 2 received 3 mCi/kg RAI via gastric gavage but no medication. Group 3 received 3 mCi/kg RAI via gastric gavage and 30 mg/kg/day CoQ10 intraperitoneally. CoQ10 was started at day one just before RAI administration and continued for five days. Seven days after RAI therapy, the animals were anesthetized and decapitated. Intraorbital (IG), extraorbital (EG), and Harderian (HG) lacrimal glands were removed bilaterally for histopathological and tissue cytokine level assessments.. Abnormal lobular pattern, acinar fibrosis, lipofuscin-like accumulations, perivascular infiltration, cell size variation, abnormal cell outlines, irregular nucleus shapes in all lacrimal gland types (p < 0.05 for each), periductal fibrosis, periductal and periacinar fibrosis in EG (p = 0.01, 0.044, respectively) and in HG (p = 0.036, 0.044, respectively), periductal infiltration in HG (p = 0.039) and IG (p = 0.029), acinar atrophy in EG (p = 0.044), and cell shape variation in IG (p = 0.036) were observed more frequently in group 2 than in other groups. RAI caused significant increase in TNF-α, IL-6, nuclear factor kappa B, and total oxidant status, and decrease in IL-2, IL-10, and total antioxidant status levels (p < 0.05 for each). Addition of CoQ10 decreased all cytokine levels, increased nuclear factor kappa B levels more, and increased total antioxidant status levels significantly (p < 0.05 for each).. RAI administration causes prominent inflammatory response in lacrimal glands. Addition of CoQ10 ameliorates the oxidative damage and protects lacrimal glands both in histopathological and tissue cytokine level assessments. Protection of lacrimal glands against oxidative damage may become a new era of CoQ10 use in the future.

Topics: Animals; Atrophy; Cytokines; Dry Eye Syndromes; Fibrosis; Iodine Radioisotopes; Lacrimal Apparatus Diseases; Oxidative Stress; Radiation Injuries, Experimental; Rats; Rats, Wistar; Ubiquinone; Vitamins

Mitochondrial production of ROS (reactive oxygen species) is thought to be associated with the cellular damage resulting from chronic exposure to high glucose in long-term diabetic patients. We hypothesized that a mitochondria-targeted antioxidant would prevent kidney damage in the Ins2(+/)⁻(AkitaJ) mouse model (Akita mice) of Type 1 diabetes. To test this we orally administered a mitochondria-targeted ubiquinone (MitoQ) over a 12-week period and assessed tubular and glomerular function. Fibrosis and pro-fibrotic signalling pathways were determined by immunohistochemical analysis, and mitochondria were isolated from the kidney for functional assessment. MitoQ treatment improved tubular and glomerular function in the Ins2(+/)⁻(AkitaJ) mice. MitoQ did not have a significant effect on plasma creatinine levels, but decreased urinary albumin levels to the same level as non-diabetic controls. Consistent with previous studies, renal mitochondrial function showed no significant change between any of the diabetic or wild-type groups. Importantly, interstitial fibrosis and glomerular damage were significantly reduced in the treated animals. The pro-fibrotic transcription factors phospho-Smad2/3 and β-catenin showed a nuclear accumulation in the Ins2(+/)⁻(AkitaJ) mice, which was prevented by MitoQ treatment. These results support the hypothesis that mitochondrially targeted therapies may be beneficial in the treatment of diabetic nephropathy. They also highlight a relatively unexplored aspect of mitochondrial ROS signalling in the control of fibrosis.

Topics: Animals; beta Catenin; Blood Glucose; Cell Nucleus; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Fibrosis; Glomerular Mesangium; Immunohistochemistry; Insulin; Kidney; Kidney Tubules; Male; Mice; Mice, Inbred C57BL; Mice, Mutant Strains; Microscopy, Electron; Mitochondria; Phosphorylation; Smad2 Protein; Smad3 Protein; Ubiquinone

Duchenne muscular dystrophy (DMD) is a severe and still incurable disease, with heart failure as a leading cause of death. The identification of a disease-modifying therapy may require early-initiated and long-term administration, but such type of therapeutic trial is not evident in humans. We have performed such a trial of SNT-MC17/idebenone in the mdx mouse model of DMD, based on the drug's potential to improve mitochondrial respiratory chain function and reduce oxidative stress.. In this study, 200 mg/kg bodyweight of either SNT-MC17/idebenone or placebo was given from age 4 weeks until 10 months in mdx and wild-type mice. All evaluators were blinded to mouse type and treatment groups. Idebenone treatment significantly corrected cardiac diastolic dysfunction and prevented mortality from cardiac pump failure induced by dobutamine stress testing in vivo, significantly reduced cardiac inflammation and fibrosis, and significantly improved voluntary running performance in mdx mice.. We have identified a novel potential therapeutic strategy for human DMD, as SNT-MC17/idebenone was cardioprotective and improved exercise performance in the dystrophin-deficient mdx mouse. Our data also illustrate that the mdx mouse provides unique opportunities for long-term controlled prehuman therapeutic studies.

Topics: Animals; Antioxidants; Biomarkers; Cardiotonic Agents; Diastole; Dobutamine; Echocardiography; Fibrosis; Male; Mice; Mice, Inbred mdx; Mitochondrial Diseases; Muscle, Skeletal; Muscular Dystrophy, Animal; Myocardium; Oxidative Stress; Physical Conditioning, Animal; Placebos; Single-Blind Method; Time Factors; Troponin I; Ubiquinone

Cardiovascular alterations and periodontal disease have been associated, although cardiovascular disease treatments have not yet been tested against periodontal alterations. We investigated effects of squalene, hydroxytyrosol and coenzyme Q(10) on gingival tissues of rabbits fed on an atherosclerotic diet. Forty-eight rabbits were distributed in six groups. Control group was fed on standard chow for 80 days. The rest were fed with an atherogenic diet for 50 days. After that, a group was sacrificed and the rest were subjected for another extra 30 days on commercial chow alone or supplemented with coenzyme Q(10), squalene or hydroxytyrosol. Atherosclerotic rabbits had higher fibrosis and endothelial activation and lower cellularity in gingival mucosa than controls (P<0.05). Hydroxytyrosol reduced endothelial activation (P<0.05) and squalene additionally decreased fibrosis (P<0.05). Results suggest that gingival vascular changes after the atherosclerotic diet have been reversed by hydroxytyrosol and squalene, natural products from the minor fraction of virgin olive oil.

Topics: Animals; Antioxidants; Arteries; Atherosclerosis; Collagen; Diet, Atherogenic; Disease Models, Animal; Drug Therapy, Combination; Endothelium, Vascular; Fibrosis; Gingiva; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mouth Mucosa; Olive Oil; Periodontal Diseases; Phenylethyl Alcohol; Plant Oils; Rabbits; Squalene; Ubiquinone

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors have been shown to prevent or reverse hypertrophy of the LV in several models of left ventricular hypertrophy. The aim of the present study was to determine whether treatment with simvastatin can prevent hypertension, reduction of tissue nitric oxide synthase activity and left ventricular (LV) remodeling in NG-nitro-L-arginine methyl ester(L-NAME)-induced hypertension. Four groups of rats were investigated: control, simvastatin (10 mg/kg), L-NAME (40 mg/kg) and L-NAME + simvastatin (in corresponding doses). Animals were sacrificed and studied after 6 weeks of treatment. The decrease of NO-synthase activity in the LV, kidney and brain was associated with hypertension, LV hypertrophy and fibrosis development and remodeling of the aorta in the L-NAME group. Simvastatin attenuated the inhibition of NO-synthase activity in kidney and brain, partly prevented hypertension development and reduced the concentration of coenzyme Q in the LV. Nevertheless, myocardial hypertrophy, fibrosis and enhancement of DNA concentration in the LV, and remodeling of the aorta were not prevented by simultaneous simvastatin treatment in the L-NAME treated animals. We conclude that the HMG-CoA reductase inhibitor simvastatin improved nitric oxide production and partially prevented hypertension development, without preventing remodeling of the left ventricle and aorta in NO-deficient hypertension.

Topics: Animals; Aorta; Blood Pressure; Body Weight; Coenzymes; DNA; Enzyme Inhibitors; Fibrosis; Hemodynamics; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypertension; Male; Myocardium; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Organ Size; Rats; Rats, Wistar; Simvastatin; Ubiquinone; Ventricular Remodeling