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1.
SLC22A5 (OCTN2) Carnitine Transporter-Indispensable for Cell Metabolism, a Jekyll and Hyde of Human Cancer.
Juraszek, B, Nałęcz, KA
Molecules (Basel, Switzerland). 2019;(1)
Abstract
Oxidation of fatty acids uses l-carnitine to transport acyl moieties to mitochondria in a so-called carnitine shuttle. The process of β-oxidation also takes place in cancer cells. The majority of carnitine comes from the diet and is transported to the cell by ubiquitously expressed organic cation transporter novel family member 2 (OCTN2)/solute carrier family 22 member 5 (SLC22A5). The expression of SLC22A5 is regulated by transcription factors peroxisome proliferator-activated receptors (PPARs) and estrogen receptor. Transporter delivery to the cell surface, as well as transport activity are controlled by OCTN2 interaction with other proteins, such as PDZ-domain containing proteins, protein phosphatase PP2A, caveolin-1, protein kinase C. SLC22A5 expression is altered in many types of cancer, giving an advantage to some of them by supplying carnitine for β-oxidation, thus providing an alternative to glucose source of energy for growth and proliferation. On the other hand, SLC22A5 can also transport several chemotherapeutics used in clinics, leading to cancer cell death.
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2.
[Immunomodulating effects of using L-carnitine and coenzyme Q10 in the nutrition of junior athletes].
Trushina, EN, Vybornov, VD, Riger, NA, Mustafina, OK, Solntsevа, TN, Timonin, AN, Zilova, IS, Rajabkadiev, RM
Voprosy pitaniia. 2019;(2):40-49
Abstract
Nowdays, much attention is paid to the study of disorders of immune regulation and methods of effective immune correction in athletes. In this regard, the use of specialized sport foods (SSF), containing nutrients with immunomodulatory properties, is of particular relevance in youth sports. The aim of the work is to study the immunomodulating activity of L-carnitine and coenzyme Q10 in junior athletes during the training period. Material and methods. The object of the study were 30 junior athletes (masters of sports and candidates for masters of sports in swimming) aged 14-18 years, including 9 girls and 21 boys. Athletes were divided into 3 groups of 10 people each. Athletes of the 1st and 2nd main groups received L-carnitine (600 mg per day) and coenzyme Q10 (60 mg/day), respectively, for 4 weeks in addition to the basic diet. The dosage of SSF used in the study was 200% of the adequate level of consumption and did not exceed the upper permissible level of consumption. Athletes of the 3rd group (control) received only basic diet without sports' nutrition. Examination of athletes of all groups was performed at the beginning and after 4 weeks of the observation period. Results and discussion. As a result of a comprehensive survey of junior athletes, the positive effect of L-carnitine intake on erythrocyte hemoglobin content (30.2±0.4 vs 28.3±0.3 pg at the beginning) was observed. The relative content of basophilic leukocytes in athletes of the main groups statistically significantly decreased by the end of the observation period: in the L-carnitine group, from 0.64±0.05 to 0.45±0.04%, in the coenzyme Q10 group, from 0.66±0.07 to 0.50±0.04%, which indicated an increase in the body's resistance to allergic reactions. Conclusion. The biomarkers of the immunotropic effect of L-carnitine and coenzyme Q10 are a decrease in the expression of the apoptotic marker CD95/Fas on peripheral blood lymphocytes and suppression of the production of pro-inflammatory cytokines synthesized by Th1-lymphocytes with switching the response to humoral immunity. An evidence base for the effectiveness of the use of L-carnitine and coenzyme Q10 in sports nutrition for restoring immune dysfunction and adaptive potential of junior athletes has been provided.
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3.
L-Carnitine Reduces Oxidative Stress and Promotes Cells Differentiation and Bone Matrix Proteins Expression in Human Osteoblast-Like Cells.
Terruzzi, I, Montesano, A, Senesi, P, Villa, I, Ferraretto, A, Bottani, M, Vacante, F, Spinello, A, Bolamperti, S, Luzi, L, et al
BioMed research international. 2019;:5678548
Abstract
Bone fragility and associated fracture risk are major problems in aging. Oxidative stress and mitochondrial dysfunction play a key role in the development of bone fragility. Mitochondrial dysfunction is closely associated with excessive production of reactive oxygen species (ROS). L-Carnitine (L-C), a fundamental cofactor in lipid metabolism, has an important antioxidant property. Several studies have shown how L-C enhances osteoblastic proliferation and activity. In the current study, we investigated the potential effects of L-C on mitochondrial activity, ROS production, and gene expression involved in osteoblastic differentiation using osteoblast-like cells (hOBs) derived from elderly patients. The effect of 5mM L-C treatment on mitochondrial activity and L-C antioxidant activity was studied by ROS production evaluation and cell-based antioxidant activity assay. The possible effects of L-C on hOBs differentiation were assessed by analyzing gene and protein expression by Real Time PCR and western blotting, respectively. L-C enhanced mitochondrial activity and improved antioxidant defense of hOBs. Furthermore, L-C increased the phosphorylation of Ca2+/calmodulin-dependent protein kinase II. Additionally, L-C induced the phosphorylation of ERK1/2 and AKT and the main kinases involved in osteoblastic differentiation and upregulated the expression of osteogenic related genes, RUNX2, osterix (OSX), bone sialoprotein (BSP), and osteopontin (OPN) as well as OPN protein synthesis, suggesting that L-C exerts a positive modulation of key osteogenic factors. In conclusion, L-C supplementation could represent a possible adjuvant in the treatment of bone fragility, counteracting oxidative phenomena and promoting bone quality maintenance.
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4.
The protective effects of L-carnitine on myocardial ischaemia-reperfusion injury in patients with rheumatic valvular heart disease undergoing CPB surgery are associated with the suppression of NF-κB pathway and the activation of Nrf2 pathway.
Li, M, Xu, S, Geng, Y, Sun, L, Wang, R, Yan, Y, Wang, H, Li, Y, Yi, Q, Zhang, Y, et al
Clinical and experimental pharmacology & physiology. 2019;(11):1001-1012
Abstract
Myocardial ischaemia-reperfusion injury (MIRI) is a main pathophysiologic change following CPB surgery. L-carnitine, a natural amino acid, is able to transport fatty acids for generating energy and has a protective effect on MIRI. We aim to investigate the protective effect of L-carnitine on MIRI in patients with rheumatic valvular heart disease (RVHD) performed CPB surgical operation and the underlying mechanism. In this study, patients were randomized to three groups. L-carnitine was added to the crystalloid cardioplegic solution for experimental group 1 (6 g/L) and experimental group 2 (12 g/L), whereas no L-carnitine was used in the control group. Our results showed that L-carnitine significantly attenuated myocardial injury after surgery in these patients. L-carnitine decreased serum markers of myocardial injury including CK-MB, cTnI, hs-cTnT and IMA. L-carnitine increased left ventricular ejection fraction (LVEF) but reduced wall motion score index (WMSI) after operation. L-carnitine also inhibited myeloperoxidase (MPO) activity and inflammatory cytokines in the myocardium of patients after unclamping the aorta. Additionally, L-carnitine increased levels of superoxide dismutase (SOD) and catalase (CAT) while decreased levels of malondialdehyde (MDA) and protein carbonyl content in the myocardium of patients after unclamping the aorta. Moreover, L-carnitine suppressed the activation of nuclear factor kappa B (NF-κB) and activated nuclear factor erythroid 2-related factor 2 (Nrf2). There was also no significant difference in these indices between two experimental groups after unclamping the aorta. Taken together, L-carnitine had a protective effect against CPB-induced MIRI in patients with RVHD, which might be related to its modulation of NF-κB and Nrf2 activities.
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5.
Effect of L-carnitine on liver enzymes and biochemical factors in hepatic encephalopathy: A systematic review and meta-analysis.
Abbasnezhad, A, Choghakhori, R, Kashkooli, S, Alipour, M, Asbaghi, O, Mohammadi, R
Journal of gastroenterology and hepatology. 2019;(12):2062-2070
Abstract
BACKGROUND AND AIMS We aimed to investigate the effect of L-carnitine on biochemical factors including ammonia, bilirubin, albumin, alanine aminotransferase, aspartate aminotransferase (AST), blood urea nitrogen (BUN), and creatinine (Cr) in patients with hepatic encephalopathy (HE). METHODS A systematic search was carried out in Web of Science, PubMed, Scopus, and Cochrane Library databases to find articles related to the effect of L-carnitine supplementation in patients with HE, up to 7 February 2019. There was no language and time limitation. Meta-analyses were carried out using both the random and fixed effects models where appropriate, and I2 index was used to evaluate the heterogeneity. RESULTS Search yielded 3462 publications. Nine randomized clinical trials with 779 patients were eligible. L-carnitine supplementation significantly reduced blood levels of ammonia. Furthermore, our results indicated that L-carnitine supplementation significantly reduced blood levels of bilirubin, AST, BUN, and Cr in patients with HE. Subgroup analysis demonstrated that L-carnitine significantly reduced ammonia in patients with all the ages, long and short duration of the supplementation, doses less or higher than 4000 mg/day, any route of treatment (intravenous or oral), and in patients with any grade of the symptoms of HE. Moreover, we found that L-carnitine significantly increased circulating levels of albumin in HE patients. CONCLUSIONS Present systematic review and meta-analysis revealed that L-carnitine supplementation significantly reduced blood levels of ammonia, bilirubin, AST, BUN, and Cr in HE patients. Moreover, we found that L-carnitine significantly increased circulating levels of albumin. However, further large-scale randomized clinical trials are needed.
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6.
The effects of concurrent Coenzyme Q10, L-carnitine supplementation in migraine prophylaxis: A randomized, placebo-controlled, double-blind trial.
Hajihashemi, P, Askari, G, Khorvash, F, Reza Maracy, M, Nourian, M
Cephalalgia : an international journal of headache. 2019;(5):648-654
Abstract
PURPOSE The present study aimed to determine the effects of combined supplementation of Coenzyme Q10 with L-carnitine on mitochondrial metabolic disorders marker and migraine symptoms among migraine patients. METHODS A total of 56 men and women, between 20-40 years of age with migraine headache, participated in this randomized, double-blind, placebo-controlled, parallel study. The subjects were randomly assigned to receive either 30 mg/day Coenzyme Q10 and 500 mg/day L-carnitine at the same time and/or placebo tablets for 8 weeks. The measurements were completed at the beginning and end of the study. The primary outcome was severity of headache attacks. The secondary outcomes included duration, frequency of headache attacks, the headache diary results (HDR), and serum levels of lactate. RESULTS A significant reduction was obtained in serum levels of lactate (-2.28 mg/dl, 95% CI: -3.65, -0.90; p = 0.002), severity (-3.03, 95% CI: -3.65, -2.40; p ≤ 0.001), duration (-7.67, 95% CI: -11.47, -3.90; p ≤ 0.001), frequency (-5.42, 95% CI: -7.31, -3.53; p ≤ 0.001) and HDR (-103.03, 95% CI: -145.76, -60.29; p ≤ 0.001) after 8 weeks. CONCLUSION This double-blind parallel study provides evidences supporting the beneficial effects of Coenzyme Q10 and L-carnitine supplements on serum levels of lactate and migraine symptoms. TRIAL REGISTRATION IRCT20121216011763N21.
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7.
Prevention by L-carnitine of DNA damage induced by 3-hydroxy-3-methylglutaric and 3-methylglutaric acids and experimental evidence of lipid and DNA damage in patients with 3-hydroxy-3-methylglutaric aciduria.
Delgado, CA, Balbueno Guerreiro, GB, Diaz Jacques, CE, de Moura Coelho, D, Sitta, A, Manfredini, V, Wajner, M, Vargas, CR
Archives of biochemistry and biophysics. 2019;:16-22
Abstract
3-hydroxy-3-methylglutaric aciduria (HMGA) is an inherited disorder of the leucine catabolic pathway in which occurs a deficiency of the 3-hydroxy-3-methylglutaryl-CoA lyase enzyme. Therefore, the organic acids 3-hydroxy-3-methylglutaric (HMG) and 3-methylglutaric (MGA), mainly, accumulate in tissues of affected patients. Lately, much attention has been focused on free radicals as mediators of tissue damage in human diseases, causing lipid peroxidation, protein oxidation and DNA damage. The treatment of this disease is based in a restricted protein ingest and supplementation with l-carnitine (LC), an antioxidant and detoxifying agent. In the present work, we investigated the in vitro oxidative damage to DNA induced by the accumulation of organic acids and oxidative stress parameters in vivo of patients with 3-HMG, as well as the effect of the recommended therapy. The in vitro DNA damage was analyzed by the alkaline comet assay in leukocytes incubated with HMG and MGA (1 mM, 2.5 mM and 5 mM) and co-incubated with LC (90 μM and 150 μM). The in vivo urinary 15-F2t-isoprostane levels and urinary oxidized guanine species were measured by ELISA kits in patient's urine before and after the treatment with LC. HMG and MGA induced a DNA damage index (DI) significantly higher than that of the control group. The DI was significantly reduced in the presence of LC. It was also verified a significant increase of oxidized guanine species and urinary isoprostane levels, biomarker of oxidative DNA damage and lipid peroxidation respectively, in patients before treatment. After the treatment and supplementation with LC, patients presented significantly lower levels of those biomarkers. Analyzing the data together, we can conclude that HMGA patients present oxidative lipid and DNA damage, which is induced by HMG and MGA, and the antioxidant therapy with LC can prevent that kind of injuries.
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8.
Can levocarnitine supplementation improve fatigue caused by sunitinib as a treatment for renal cell carcinoma? A single-center prospective pilot study.
Shindo, T, Kobayashi, K, Tanaka, T, Masumori, N
Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2019;(4):1491-1496
Abstract
PURPOSE To evaluate the potential role of levocarnitine supplementation for cancer-related fatigue in patients treated with sunitinib. METHODS Patients treated with sunitinib for unresectable or metastatic renal cell carcinoma were enrolled prospectively. Assessment of fatigue in each patient was done using the Brief Fatigue Inventory (BFI) questionnaire. Evaluation of fatigue and the serum carnitine level was done at baseline, 2 weeks, and 4 weeks after sunitinib therapy was initiated. All patients were treated with sunitinib 37.5 mg or 50 mg/day orally, with a 4-week administration and 2-week discontinuation schedule. RESULTS Ten patients were finally enrolled in the study. Seven of them had worsened fatigue at the 2-week assessment and levocarnitine was administrated. All these seven patients whose serum carnitine level at 2 weeks was worse than at the baseline improved after 2-week-L-carnitine supplementation. For six of the seven (85.7%) patients who had L-carnitine supplementation, the BFI score at 4 weeks decreased compared to that at 2 weeks, which indicated improvement of fatigue. CONCLUSIONS Levocarnitine supplementation for cancer-related fatigue in patients treated with sunitinib appears to have a potential benefit. However, further study with a larger number of patients and longer follow-up is crucial to confirm this.
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9.
Relation of plasma carnitine and aminotransferases to alcohol dose and time of dependence.
Kępka, A, Zwierz, P, Chojnowska, S, Ochocińska, A, Skorupa, E, Szczepański, M, Szajda, SD, Waszkiewicz, N
Alcohol (Fayetteville, N.Y.). 2019;:62-69
Abstract
BACKGROUND Serum aspartate, alanine aminotransferases (AST, ALT), and plasma carnitine are all indirect biomarkers of alcohol abuse. Carnitine transfers long-chain fatty acids from cytoplasm to mitochondria for β-oxidation. The aim of the study was to determine the relationship between daily alcohol intake, time of alcohol dependence, plasma carnitine, and serum aminotransferases. PATIENTS We studied 26 men who were addicted for 2-30 years, consuming ethanol from 75 to 700 g/day (alcoholic group), as well as 17 healthy men (control group). RESULTS In alcoholics, compared to the controls, we found: a significant increase in serum: AST (p = 0.0014), ALT (p = 0.0071), AST/ALT ratio (p < 0.000); significantly lower plasma free carnitine (FC) (p = 0.0316) and total carnitine (TC) (p = 0.0349); and a significant negative correlation between FC (r = -0.6200; R2 = 0.3844; p = 0.0007), TC (r = -0.4365; R2 = 0.1905; p = 0.0258), and time of alcohol dependence, suggesting carnitine as an indirect marker of alcohol abuse. We did not find any significant correlation between FC, TC, and levels of alcohol or aminotransferase activity. CONCLUSION In the alcoholic group, there was an increase in serum activity of AST, ALT, and AST/ALT ratio that confirms liver injury. In addition, we found low plasma FC and TC, which may indicate damage to mitochondrial β-oxidation caused by alcohol metabolites. The significantly higher plasma FC and TC in patients consuming the most, compared to patients consuming smaller doses of alcohol, may be caused by a lower carnitine demand of injured liver cells, decreased urinary carnitine excretion by impaired renal tubules, and leakage of carnitine into the blood from damaged muscles by the higher quantities of alcohol. The negative correlation between carnitine concentration and time of alcohol dependence may suggest the potential use of carnitine for treatment of alcohol abuse.
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10.
Effects of carnitine supplementation on liver aminotransferase enzymes: A systematic review and meta-analysis of randomized controlled clinical trials.
Yousefi Rad, E, Eslampour, E, Falahi, E, Mardani, M, Hekmatdoost, A, Asbaghi, O, Saboori, S
Indian journal of gastroenterology : official journal of the Indian Society of Gastroenterology. 2019;(6):470-479
Abstract
BACKGROUND AND AIMS This meta-analysis of the randomized controlled trials was performed to assess effects of carnitine supplementation on serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. METHODS A comprehensive literature search of PubMed, Cochrane's library, Web of Science, Scopus, and Embase was performed up to May 2018. From a total of 2012 articles identified initially, only 17 articles were included in the final meta-analysis to evaluate the effects of carnitine supplementation on serum levels of ALT and AST enzymes. RESULTS Random effects model meta-analysis showed that carnitine supplementation led to reduction in serum ALT (weighted mean difference [WMD] - 10.25 IU/L; 95% CI = - 15.73, - 4.77; p < 0.001) and AST levels (WMD - 7.85 IU/L; 95% CI = - 11.85, - 3.86; p < 0.001). The results of subgroup analysis showed that carnitine could reduce serum AST levels at dosages equal to 2000 mg/day (p = 0.014) or more than 2000 mg/day (p < 0.001). However, carnitine supplementation at dosages of ≤ 1000 mg/day (p = 0.035) or equal to 2000 mg/day (p = 0.013) resulted in significant reduction in ALT level, while doses more than 2000 mg/day did not change ALT significantly. Carnitine exerts its reducing effect on serum ALT and AST levels only when these aminotransferases are raised or when the duration of supplementation lasts at least 3 months. CONCLUSION Results of the current meta-analysis showed that carnitine supplementation can decrease serum AST and ALT levels significantly, especially when supplementation lasts 3 months or more in patients with elevated serum aminotransferase levels.