l-Carnitine and heart disease.

PubMed

Wang, Zhong-Yu; Liu, Ying-Yi; Liu, Guo-Hui; Lu, Hai-Bin; Mao, Cui-Ying

2018-02-01

Cardiovascular disease (CVD) is a key cause of deaths worldwide, comprising 15-17% of healthcare expenditure in developed countries. Current records estimate an annual global average of 30 million cardiac dysfunction cases, with a predicted escalation by two-three folds for the next 20-30years. Although β-blockers and angiotensin-converting-enzymes are commonly prescribed to control CVD risk, hepatotoxicity and hematological changes are frequent adverse events associated with these drugs. Search for alternatives identified endogenous cofactor l-carnitine, which is capable of promoting mitochondrial β-oxidation towards a balanced cardiac energy metabolism. l-Carnitine facilitates transport of long-chain fatty acids into the mitochondrial matrix, triggering cardioprotective effects through reduced oxidative stress, inflammation and necrosis of cardiac myocytes. Additionally, l-carnitine regulates calcium influx, endothelial integrity, intracellular enzyme release and membrane phospholipid content for sustained cellular homeostasis. Carnitine depletion, characterized by reduced expression of "organic cation transporter-2" gene, is a metabolic and autosomal recessive disorder that also frequently associates with CVD. Hence, exogenous carnitine administration through dietary and intravenous routes serves as a suitable protective strategy against ventricular dysfunction, ischemia-reperfusion injury, cardiac arrhythmia and toxic myocardial injury that prominently mark CVD. Additionally, carnitine reduces hypertension, hyperlipidemia, diabetic ketoacidosis, hyperglycemia, insulin-dependent diabetes mellitus, insulin resistance, obesity, etc. that enhance cardiovascular pathology. These favorable effects of l-carnitine have been evident in infants, juvenile, young, adult and aged patients of sudden and chronic heart failure as well. This review describes the mechanism of action, metabolism and pharmacokinetics of l-carnitine. It specifically emphasizes upon the beneficial

Acetyl-L-Carnitine as an Adjunctive Therapy in the Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents: A Placebo-Controlled Trial

ERIC Educational Resources Information Center

Abbasi, Seyed-Hesameddin; Heidari, Shahram; Mohammadi, Mohammad-Reza; Tabrizi, Mina; Ghaleiha, Ali; Akhondzadeh, Shahin

2011-01-01

The objective of this study was to test whether a previous observed Acetyl-L-carnitine (ALC) treatment effect could be repeated in an ALC adjunctive therapy treatment trial of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents. This was a six-week, randomized clinical trial undertaken in an outpatient child and adolescent…

The effect of acetyl-L-carnitine on lenticular calpain activity in prevention of selenite-induced cataractogenesis.

PubMed

Elanchezhian, R; Sakthivel, M; Geraldine, P; Thomas, P A

2009-05-01

The present study sought to determine whether acetyl-L-carnitine (ALCAR) prevents selenite cataractogenesis by mechanisms involving lenticular calpain activity, Wistar rat pups were divided into 3 groups of 15 each. Group I (normal) rats received an intraperitoneal (i.p.) injection of normal saline on postpartum day 10; Group II (cataract-untreated) rats received a single subcutaneous (s.c.) injection of sodium selenite (19micromol/kg body weight) on postpartum day 10; Group III (cataract-treated) pups received a single s.c. injection of sodium selenite on postpartum day 10 and intraperitoneal injections of acetyl-L-carnitine (200mg/kg body weight) on postpartum days 9-14. At the end of the study period (postpartum day 16), both eyes of each rat pup were examined by slit-lamp biomicroscopy. There was dense lenticular opacification in all Group II rats, minimal lenticular opacification in 33% of Group III rats, and no lenticular opacification in 67% of Group III and in all Group I rats. Group II lenses exhibited significantly lower mean values of calpain activity and Lp82 (lens-specific calpain) protein expression, decreases in relative transcript level of m-calpain mRNA and significantly higher mean Ca(2+) concentrations than Group I or Group III lenses; the values of these parameters in Group III rat lenses (ALCAR-treated) approximated those in Group I rat lenses. The results suggest that, in addition to its already-described antioxidant potential, ALCAR prevents selenite cataractogenesis by maintaining calpain activity at near normal levels. These findings may stimulate further efforts to develop ALCAR as a novel drug for prevention of cataract.

L-carnitine protects against testicular dysfunction caused by gamma irradiation in mice.

PubMed

Ahmed, Mohamed Mohamed; Ibrahim, Zein Shaban; Alkafafy, Mohamed; El-Shazly, Samir Ahmed

2014-07-01

This study was conducted on mice to evaluate the radioprotective role of L-carnitine against γ-ray irradiation-induced testicular damage. Adult male mice were exposed to whole body irradiation at a total dose of 1 Gy. Radiation exposure was continued 24 h a day (0.1 Gy/day) throughout the 10 days exposure period either in the absence and/or presence of L-carnitine at an i.p. dose of 10 mg/kg body weight/day. Results revealed that γ-rays irradiation suppressed the expression of ABP and CYP450SCC mRNA, whereas treatment with L-carnitine prior and throughout γ-rays irradiation exposure inhibited this suppression. Treatment with γ-ray irradiation or L-carnitine down-regulated expression of aromatase mRNA. With combined treatment, L-carnitine significantly normalized aromatase expression. γ-Ray irradiation up-regulated expression of FasL and Cyclin D2 mRNA, while L-carnitine inhibited these up-regulations. Results also showed that γ-ray-irradiation up-regulated TNF-α, IL1-β and IFN-γ mRNA expressions compared to either controls or the L-carnitine treated group. Moreover, γ-irradiation greatly reduced serum testosterone levels, while L-carnitine, either alone or in combination with irradiation, significantly increased serum testosterone levels compared to controls. In addition, γ-irradiation induced high levels of sperm abnormalities (43%) which were decreased to 12% in the presence of L-carnitine. In parallel with these findings, histological examination showed that γ-irradiation induced severe tubular degenerative changes, which were reduced by L-carnitine pre-treatment. These results clarified the immunostimulatory effects of L-carnitine and its radioprotective role against testicular injury. Copyright © 2014 Elsevier GmbH. All rights reserved.

Protective effect of L-carnitine and L-arginine against busulfan-induced oligospermia in adult rat.

PubMed

Abd-Elrazek, A M; Ahmed-Farid, O A H

2018-02-01

Busulfan is an anticancer drug caused variety of adverse effects for patients with cancer. But it could cause damage to the male reproductive system as one of its adverse effects. This study aimed to investigate the protective effect of L-carnitine and L-arginine on semen quality, oxidative stress parameters and testes cell energy after busulfan treatment. Adult male rats were divided into four groups: control (Con), busulfan (Bus), busulfan plus L-arginine (Bus + L-arg) and busulfan plus L-carnitine (Bus + L-car). After 28 days, the semen was collected from the epididymis and the testes were assessed. Sperm count, motility and velocity were measured by CASA, and smears were prepared for assessment of sperm morphology. Serum and testes supernatants were separated for DNA metabolites, oxidative stress and cell energy parameters. Testes tissues also subjected for caspase-3. The results showed significant improvement in sperm morphology, motility, velocity and count in the groups treated with L-arginine and L-carnitine and accompanied with an increase in MDA, GSSG and ATP, reduction in GSH, AMP, ADP, NO and 8-OHDG also recorded. These results are supported by caspase-3. Administration of L-arg and L-car attenuated the cytotoxic effects of busulfan by improving semen parameters, reducing oxidative stress and maintaining cell energy. © 2017 Blackwell Verlag GmbH.

Serum Levels of Acyl-Carnitines along the Continuum from Normal to Alzheimer's Dementia.

PubMed

Cristofano, Adriana; Sapere, Nadia; La Marca, Giancarlo; Angiolillo, Antonella; Vitale, Michela; Corbi, Graziamaria; Scapagnini, Giovanni; Intrieri, Mariano; Russo, Claudio; Corso, Gaetano; Di Costanzo, Alfonso

2016-01-01

This study aimed to determine the serum levels of free L-carnitine, acetyl-L-carnitine and 34 acyl-L-carnitine in healthy subjects and in patients with or at risk of Alzheimer's disease. Twenty-nine patients with probable Alzheimer's disease, 18 with mild cognitive impairment of the amnestic type, 24 with subjective memory complaint and 46 healthy subjects were enrolled in the study, and the levels of carnitine and acyl-carnitines were measured by tandem mass spectrometry. The concentrations of acetyl-L-carnitine progressively decreased passing from healthy subjects group (mean±SD, 5.6±1.3 μmol/L) to subjective memory complaint (4.3±0.9 μmol/L), mild cognitive impairment (4.0±0.53 μmol/L), up to Alzheimer's disease (3.5±0.6 μmol/L) group (p<0.001). The differences were significant for the comparisons: healthy subjects vs. subjective memory complaint, mild cognitive impairment or Alzheimer's disease group; and subjective memory complaint vs. Alzheimer's disease group. Other acyl-carnitines, such as malonyl-, 3-hydroxyisovaleryl-, hexenoyl-, decanoyl-, dodecanoyl-, dodecenoyl-, myristoyl-, tetradecenoyl-, hexadecenoyl-, stearoyl-, oleyl- and linoleyl-L-carnitine, showed a similar decreasing trend, passing from healthy subjects to patients at risk of or with Alzheimer's disease. These results suggest that serum acetyl-L-carnitine and other acyl-L-carnitine levels decrease along the continuum from healthy subjects to subjective memory complaint and mild cognitive impairment subjects, up to patients with Alzheimer's disease, and that the metabolism of some acyl-carnitines is finely connected among them. These findings also suggest that the serum levels of acetyl-L-carnitine and other acyl-L-carnitines could help to identify the patients before the phenotype conversion to Alzheimer's disease and the patients who would benefit from the treatment with acetyl-L-carnitine. However, further validation on a larger number of samples in a longitudinal study is needed

Serum Levels of Acyl-Carnitines along the Continuum from Normal to Alzheimer's Dementia

PubMed Central

Sapere, Nadia; La Marca, Giancarlo; Angiolillo, Antonella; Vitale, Michela; Corbi, Graziamaria; Scapagnini, Giovanni; Intrieri, Mariano; Russo, Claudio

2016-01-01

This study aimed to determine the serum levels of free L-carnitine, acetyl-L-carnitine and 34 acyl-L-carnitine in healthy subjects and in patients with or at risk of Alzheimer’s disease. Twenty-nine patients with probable Alzheimer’s disease, 18 with mild cognitive impairment of the amnestic type, 24 with subjective memory complaint and 46 healthy subjects were enrolled in the study, and the levels of carnitine and acyl-carnitines were measured by tandem mass spectrometry. The concentrations of acetyl-L-carnitine progressively decreased passing from healthy subjects group (mean±SD, 5.6±1.3 μmol/L) to subjective memory complaint (4.3±0.9 μmol/L), mild cognitive impairment (4.0±0.53 μmol/L), up to Alzheimer’s disease (3.5±0.6 μmol/L) group (p<0.001). The differences were significant for the comparisons: healthy subjects vs. subjective memory complaint, mild cognitive impairment or Alzheimer’s disease group; and subjective memory complaint vs. Alzheimer’s disease group. Other acyl-carnitines, such as malonyl-, 3-hydroxyisovaleryl-, hexenoyl-, decanoyl-, dodecanoyl-, dodecenoyl-, myristoyl-, tetradecenoyl-, hexadecenoyl-, stearoyl-, oleyl- and linoleyl-L-carnitine, showed a similar decreasing trend, passing from healthy subjects to patients at risk of or with Alzheimer’s disease. These results suggest that serum acetyl-L-carnitine and other acyl-L-carnitine levels decrease along the continuum from healthy subjects to subjective memory complaint and mild cognitive impairment subjects, up to patients with Alzheimer’s disease, and that the metabolism of some acyl-carnitines is finely connected among them. These findings also suggest that the serum levels of acetyl-L-carnitine and other acyl-L-carnitines could help to identify the patients before the phenotype conversion to Alzheimer’s disease and the patients who would benefit from the treatment with acetyl-L-carnitine. However, further validation on a larger number of samples in a longitudinal

Dietary L-carnitine supplementation in obese cats alters carnitine metabolism and decreases ketosis during fasting and induced hepatic lipidosis.

PubMed

Blanchard, Géraldine; Paragon, Bernard M; Milliat, Fabien; Lutton, Claude

2002-02-01

This study was designed to determine whether dietary carnitine supplement could protect cats from ketosis and improve carnitine and lipid metabolism in experimental feline hepatic lipidosis (FHL). Lean spayed queens received a diet containing 40 (CL group, n = 7) or 1000 (CH group, n = 4) mg/kg of L-carnitine during obesity development. Plasma fatty acid, beta-hydroxybutyrate and carnitine, and liver and muscle carnitine concentrations were measured during experimental induction of FHL and after treatment. In control cats (CL group), fasting and FHL increased the plasma concentrations of fatty acids two- to threefold (P < 0.0001) and beta-hydroxybutyrate > 10-fold (from a basal 0.22 +/- 0.03 to 1.70 +/- 0.73 after 3 wk fasting and 3.13 +/- 0.49 mmol/L during FHL). In carnitine-supplemented cats, these variables increased significantly (P < 0.0001) only during FHL (beta-hydroxybutyrate, 1.42 +/- 0.17 mmol/L). L-Carnitine supplementation significantly increased plasma, muscle and liver carnitine concentrations. Liver carnitine concentration increased dramatically from the obese state to FHL in nonsupplemented cats, but not in supplemented cats, which suggests de novo synthesis of carnitine from endogenous amino acids in control cats and reversible storage in supplemented cats. These results demonstrate the protective effect of a dietary L-carnitine supplement against fasting ketosis during obesity induction. Increasing the L-carnitine level of diets in cats with low energy requirements, such as after neutering, and a high risk of obesity could therefore be recommended.

An acetyl-L-carnitine switch on mitochondrial dysfunction and rescue in the metabolomics study on aluminum oxide nanoparticles.

PubMed

Li, Xiaobo; Zhang, Chengcheng; Zhang, Xin; Wang, Shizhi; Meng, Qingtao; Wu, Shenshen; Yang, Hongbao; Xia, Yankai; Chen, Rui

2016-01-16

Due to the wide application of engineered aluminum oxide nanoparticles and increased aluminum containing particulate matter suspending in air, exposure of human to nano-scale aluminum oxide nanoparticles (Al2O3 NPs) is becoming inevitable. In the present study, RNA microarray coupled with metabolomics analysis were used to uncover mechanisms underlying cellular responses to Al2O3 NPs and imply the potential rescue. We found that Al2O3 NPs significantly triggered down-regulation of mitochondria-related genes located in complex I, IV and V, which were involved in oxidative phosphorylation and neural degeneration pathways, in human bronchial epithelial (HBE) cells. Subsequent cell- and animal- based assays confirmed that Al2O3 NPs caused mitochondria-dependent apoptosis and oxidative stress either in vitro or in vivo, which were consistent with the trends of gene regulation. To rescue the Al2O3 NPs induced mitochondria dysfunction, disruption of small molecular metabolites of HBE were profiled using metabolomics analysis, which facilitates identification of potential antagonizer or supplement against nanoparticle-involved damages. Supplementation of an antioxidant, acetyl-L-carnitine, completely or partially restored the Al2O3 NPs modulated gene expression levels in mitochondrial complex I, IV and V. It further reduced apoptosis and oxidative damages in both Al2O3 NPs treated HBE cells and animal lung tissues. Thus, our results demonstrate the potential mechanism of respiratory system damages induced by Al2O3 NPs. Meanwhile, based on the metabolomics profiling, application of acetyl-L-carnitine is suggested to ameliorate mitochondria dysfunction associated with Al2O3 NPs.

Production of L-carnitine by secondary metabolism of bacteria

PubMed Central

Bernal, Vicente; Sevilla, Ángel; Cánovas, Manuel; Iborra, José L

2007-01-01

The increasing commercial demand for L-carnitine has led to a multiplication of efforts to improve its production with bacteria. The use of different cell environments, such as growing, resting, permeabilized, dried, osmotically stressed, freely suspended and immobilized cells, to maintain enzymes sufficiently active for L-carnitine production is discussed in the text. The different cell states of enterobacteria, such as Escherichia coli and Proteus sp., which can be used to produce L-carnitine from crotonobetaine or D-carnitine as substrate, are analyzed. Moreover, the combined application of both bioprocess and metabolic engineering has allowed a deeper understanding of the main factors controlling the production process, such as energy depletion and the alteration of the acetyl-CoA/CoA ratio which are coupled to the end of the biotransformation. Furthermore, the profiles of key central metabolic activities such as the TCA cycle, the glyoxylate shunt and the acetate metabolism are seen to be closely interrelated and affect the biotransformation efficiency. Although genetically modified strains have been obtained, new strain improvement strategies are still needed, especially in Escherichia coli as a model organism for molecular biology studies. This review aims to summarize and update the state of the art in L-carnitine production using E. coli and Proteus sp, emphasizing the importance of proper reactor design and operation strategies, together with metabolic engineering aspects and the need for feed-back between wet and in silico work to optimize this biotransformation. PMID:17910757

The possible protective effect of L-carnitine on tilmicosin-induced cardiotoxicity in mice.

PubMed

Kart, A; Yapar, K; Karapehlivan, M; Citil, M

2007-04-01

The protective effect of L-carnitine was investigated against tilmicosin-induced cardiotoxic effects including blood creatine kinase (CK), CK-MB, total sialic acid as well as the alterations in glutathione and malondialdehyde concentrations in mice. Thirty-two Balb/C mice were divided into four groups including group 1 (control), group 2 (L-carnitine, s.c., 500 mg/kg for 5 days), group 3 (tilmicosin, s.c., single dose of 75 mg/kg) and group 4 (L-carnitine plus tilmicosin). Serum CK, CK-MB and malondialdehyde (MDA) levels were significantly (P < 0.05) higher in group 3 compared with those of other groups. Total sialic acid level in group 3 was found to be significantly (P < 0.05) higher than that in groups 1 and 2, as well. Contrary to these results, glutathione level in group 3 was found to be significantly (P < 0.05) lower than that in groups 1 and 2. In group 4, serum CK, CK-MB, MDA and total sialic acid levels were found to be significantly (P < 0.05) lower than those in group 3. These results suggest that tilmicosin is cardiotoxic in mice as evidenced by higher total sialic acid, CK and CK-MB. In addition, tilmicosin caused the decrease in glutathione and increase in MDA levels. However, administration of L-carnitine could ameliorate these adverse toxic effects of tilmicosin in mice.

Protective effects of l-carnitine and piracetam against mitochondrial permeability transition and PC3 cell necrosis induced by simvastatin.

PubMed

Costa, Rute A P; Fernandes, Mariana P; de Souza-Pinto, Nadja C; Vercesi, Aníbal E

2013-02-15

Mitochondrial oxidative stress followed by membrane permeability transition (MPT) has been considered as a possible mechanism for statins cytotoxicity. Statins use has been associated with reduced risk of cancer incidence, especially prostate cancer. Here we investigated the pathways leading to simvastatin-induced prostate cancer cell death as well as the mechanisms of cell death protection by l-carnitine or piracetam. These compounds are known to prevent and/or protect against cell death mediated by oxidative mitochondrial damage induced by a variety of conditions, either in vivo or in vitro. The results provide evidence that simvastatin induced MPT and cell necrosis were sensitive to either l-carnitine or piracetam in a dose-dependent fashion and mediated by additive mechanisms. When combined, l-carnitine and piracetam acted at concentrations significantly lower than they act individually. These results shed new light into both the cytotoxic mechanisms of statins and the mechanisms underlying the protection against MPT and cell death by the compounds l-carnitine and piracetam. Copyright © 2013 Elsevier B.V. All rights reserved.

[Myocardial protective effect of L-carnitine in children with hand, foot and mouth disease caused by Coxsackie A16 virus].

PubMed

Cui, Ya-Jie; Song, Chun-Lan; Chen, Fang; Li, Peng; Cheng, Yi-Bing

2017-08-01

To investigate the myocardial protective effect of L-carnitine in children with hand, foot and mouth disease (HFMD) caused by Coxsackie A16 virus and possible mechanisms. A total of 60 HFMD children with abnormal myocardial enzyme after Coxsackie A16 virus infection were enrolled and randomly divided into L-carnitine group and fructose-1,6-diphosphate group (fructose group), with 30 children in each group. The two groups were given L-carnitine or fructose diphosphate in addition to antiviral and heat clearance treatment. Another 30 healthy children who underwent physical examination were enrolled as control group. The changes in myocardial zymogram, malondialdehyde (MDA), superoxide dismutase (SOD), and apoptosis factors sFas and sFasL after treatment were compared between groups. There was no significant difference in treatment response between the L-carnitine group and the fructose group (P>0.05). One child in the fructose group progressed to critical HFMD, which was not observed in the L-carnitine group. Before treatment, the L-carnitine group and the fructose group had significantly higher indices of myocardial zymogram and levels of MDA, sFas, and sFasL and a significantly lower level of SOD than the control group (P<0.05), while there were no significant differences in these indices between the L-carnitine group and the fructose group (P>0.05). After treatment, the L-carnitine group and the fructose group had significant reductions in the indices of myocardial zymogram and levels of MDA, sFas, and sFasL and a significant increase in the level of SOD (P<0.05); the fructose group had a significantly higher level of creatine kinase (CK) than the control group and the L-carnitine group, and there were no significant differences in other myocardial enzyme indices, MDA, sFas, and sFasL between the L-carnitine group and the fructose group, as well as between the L-carnitine and fructose groups and the control group (P>0.05). SOD level was negatively correlated with

Acetyl-L-carnitine and oxaloacetate in post-treatment against LTP impairment in a rat ischemia model. An in vitro electrophysiological study.

PubMed

Kocsis, K; Knapp, L; Mészáros, J; Kis, Z; Farkas, T; Vécsei, L; Toldi, J

2015-06-01

A high proportion of research relating to cerebral ischemia focuses on neuroprotection. The application of compounds normally present in the organism is popular, because they do not greatly influence the synaptic activity by receptor modulation, and can be administered without serious side effects. Oxaloacetate (OxAc) and acetyl-L-carnitine (ALC) are such favorable endogenous molecules. ALC can exert a protective effect by improving the energy state of the neurons under ischemic conditions. A promising neuroprotective strategy is glutamate scavenging, which can be achieved by the intravenous administration of OxAc. This study involved the possible protective effects of ALC and OxAc in different post-treatment protocols against long-term potentiation (LTP) impairment. Ischemia was induced in rats by 2-vessel occlusion, which led to a decreased LTP relative to the control group. High-dose (200 mg/kg) ALC or OxAc post-treatment resulted in a higher potentiation relative to the 2VO group, but it did not reach the control level, whereas low-dose ALC (100 mg/kg) in combination with OxAc completely restored the LTP function. Many previous studies have concluded that ALC can be protective only as pretreatment. The strategy described here reveals that ALC can also be neuroprotective when utilized as post-treatment against ischemia.

Acetyl L-carnitine targets adenosine triphosphate synthase in protecting zebrafish embryos from toxicities induced by verapamil and ketamine: An in vivo assessment.

PubMed

Guo, Xiaoqing; Dumas, Melanie; Robinson, Bonnie L; Ali, Syed F; Paule, Merle G; Gu, Qiang; Kanungo, Jyotshna

2017-02-01

Verapamil is a Ca 2 + channel blocker and is highly prescribed as an anti-anginal, antiarrhythmic and antihypertensive drug. Ketamine, an antagonist of the Ca 2 + -permeable N-methyl-d-aspartate-type glutamate receptors, is a pediatric anesthetic. Previously we have shown that acetyl l-carnitine (ALCAR) reverses ketamine-induced attenuation of heart rate and neurotoxicity in zebrafish embryos. Here, we used 48 h post-fertilization zebrafish embryos that were exposed to relevant drugs for 2 or 4 h. Heart beat and overall development were monitored in vivo. In 48 h post-fertilization embryos, 2 mm ketamine reduced heart rate in a 2 or 4 h exposure and 0.5 mm ALCAR neutralized this effect. ALCAR could reverse ketamine's effect, possibly through a compensatory mechanism involving extracellular Ca 2 + entry through L-type Ca 2 + channels that ALCAR is known to activate. Hence, we used verapamil to block the L-type Ca 2 + channels. Verapamil was more potent in attenuating heart rate and inducing morphological defects in the embryos compared to ketamine at specific times of exposure. ALCAR reversed cardiotoxicity and developmental toxicity in the embryos exposed to verapamil or verapamil plus ketamine, even in the presence of 3,4,5-trimethoxybenzoic acid 8-(diethylamino)octyl ester, an inhibitor of intracellular Ca 2 + release suggesting that ALCAR acts via effectors downstream of Ca 2 + . In fact, ALCAR's protective effect was blunted by oligomycin A, an inhibitor of adenosine triphosphate synthase that acts downstream of Ca 2 + during adenosine triphosphate generation. We have identified, for the first time, using in vivo studies, a downstream effector of ALCAR that is critical in abrogating ketamine- and verapamil-induced developmental toxicities. Published 2016. This article is a U.S. Government work and is in the public domain in the USA. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Myocardial Protective Effects of L-Carnitine on Ischemia-Reperfusion Injury in Patients With Rheumatic Valvular Heart Disease Undergoing Cardiac Surgery.

PubMed

Li, Ming; Xue, Li; Sun, Haifeng; Xu, Suochun

2016-12-01

The authors used L-carnitine as an ingredient in cardioplegic solution during valve replacement surgery to investigate the protective effect of L-carnitine on myocardial ischemia-reperfusion injury (MIRI) and its possible mechanism. Prospective, randomized study. A tertiary-care hospital. The study comprised 90 patients undergoing valve replacement under cardiopulmonary bypass. Patients were divided randomly into 3 groups. L-carnitine was added to the crystalloid cardioplegic solution for experimental group 1 (3 g/L) and experimental group 2 (6 g/L), whereas no L-carnitine was used in the control group. The remainder of the treatment was identical for all 3 groups. Serum was collected from each patient 1 hour before the surgery and at 2, 6, 24, and 72 hours after unclamping the aorta, and tissue samples were obtained before cardiac arrest and after unclamping the aorta. The postoperative levels of serum aspartate aminotransferase, creatine kinase, creatine kinase-MB isozyme, and lactic acid dehydrogenase and the apoptotic index were all lower in the 2 experimental groups than those in the control group. In addition, each of the aforementioned serum enzyme levels and the apoptotic index in all 3 groups significantly increased after unclamping the aorta compared with baseline levels taken before surgery. Bcl-2 expression was higher and Bax was lower in the 2 experimental groups compared with those of the control group after unclamping the aorta. However, there was no significant difference in all the postoperative indices between the 2 experimental groups. L-carnitine may reduce cardiopulmonary bypass-induced myocardial apoptosis through modulating the expressions of Bcl-2 and Bax, resulting in a protective effect from MIRI. Copyright © 2016 Elsevier Inc. All rights reserved.

Acetyl-L-carnitine prevents total body hydroxyl free radical and uric acid production induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in the rat.

PubMed

Loots, Du Toit; Mienie, Lodewyk J; Bergh, Jacobus J; Van der Schyf, Cornelis J

2004-07-23

Acetyl-L-carnitine (ALCAR) is intimately involved in the transport of long chain fatty acids across the inner mitochondrial membrane during oxidative phosphorylation. ALCAR also has been reported to attenuate the occurrence of parkinsonian symptoms associated with 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) in vivo, and protects in vitro against the toxicity of the neurotoxic 1-methyl-4-phenylpyridinium (MPP+) metabolite of MPTP. The mechanism for these protective effects remains unclear. ALCAR may attenuate hydroxyl (HO*) free radical production in the MPTP/MPP+ neurotoxic pathway through several mechanisms. Most studies on MPTP/MPP+ toxicity and protection by ALCAR have focused on in vivo brain chemistry and in vitro neuronal culture studies. The present study investigates the attenuative effects of ALCAR on whole body oxidative stress markers in the urine of rats treated with MPTP. In a first study, ALCAR totally prevented the MPTP-induced formation of HO* measured by salicylate radical trapping. In a second study, the production of uric acid after MPTP administration-a measure of oxidative stress mediated through xanthine oxidase-was also prevented by ALCAR. Because ALCAR is unlikely to be a potent radical scavenger, these studies suggest that ALCAR protects against MPTP/MPP+-mediated oxidative stress through other mechanisms. We speculate that ALCAR may operate through interference with organic cation transporters such as OCTN2 and/or carnitine-acylcarnitine translocase (CACT), based partly on the above findings and on semi-empirical electronic similarity calculations on ALCAR, MPP+, and two other substrates for these transporters.

Effect of Acetyl-L-Carnitine on Antioxidant Status, Lipid Peroxidation, and Oxidative Damage of Arsenic in Rat.

PubMed

Sepand, Mohammad Reza; Razavi-Azarkhiavi, Kamal; Omidi, Ameneh; Zirak, Mohammad Reza; Sabzevari, Samin; Kazemi, Ali Reza; Sabzevari, Omid

2016-05-01

Arsenic (As) is a widespread environmental contaminant present around the world in both organic and inorganic forms. Oxidative stress is postulated as the main mechanism for As-induced toxicity. This study was planned to examine the protective effect of acetyl-L-carnitine (ALC) on As-induced oxidative damage in male rats. Animals were randomly divided into four groups of control (saline), sodium arsenite (NaAsO2, 20 mg/kg), ALC (300 mg/kg), and NaAsO2 plus ALC. Animals were dosed orally for 28 successive days. Blood and tissue samples including kidney, brain, liver, heart, and lung were collected on the 28th day and evaluated for oxidative damage and histological changes. NaAsO2 exposure caused a significant lipid peroxidation as evidenced by elevation in thiobarbituric acid-reactive substances (TBARS). The activity of antioxidant enzymes such as glutathione-S-transferase (GST), catalase (CAT), superoxide dismutase (SOD), as well as sulfhydryl group content (SH group) was significantly suppressed in various organs following NaAsO2 treatment (P < 0.05). Furthermore, NaAsO2 administration increased serum values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and bilirubin. Our findings revealed that co-administration of ALC and NaAsO2 significantly suppressed the oxidative damage induced by NaAsO2. Tissue histological studies have confirmed the biochemical findings and provided evidence for the beneficial role of ALC. The results concluded that ALC attenuated NaAsO2-induced toxicity, and this protective effect may result from the ability of ALC in maintaining oxidant-antioxidant balance.

Metabolite profile of a mouse model of Charcot–Marie–Tooth type 2D neuropathy: implications for disease mechanisms and interventions

PubMed Central

Bais, Preeti; Beebe, Kirk; Morelli, Kathryn H.; Currie, Meagan E.; Norberg, Sara N.; Evsikov, Alexei V.; Miers, Kathy E.; Seburn, Kevin L.; Guergueltcheva, Velina; Kremensky, Ivo; Jordanova, Albena; Bult, Carol J.

2016-01-01

ABSTRACT Charcot–Marie–Tooth disease encompasses a genetically heterogeneous class of heritable polyneuropathies that result in axonal degeneration in the peripheral nervous system. Charcot–Marie–Tooth type 2D neuropathy (CMT2D) is caused by dominant mutations in glycyl tRNA synthetase (GARS). Mutations in the mouse Gars gene result in a genetically and phenotypically valid animal model of CMT2D. How mutations in GARS lead to peripheral neuropathy remains controversial. To identify putative disease mechanisms, we compared metabolites isolated from the spinal cord of Gars mutant mice and their littermate controls. A profile of altered metabolites that distinguish the affected and unaffected tissue was determined. Ascorbic acid was decreased fourfold in the spinal cord of CMT2D mice, but was not altered in serum. Carnitine and its derivatives were also significantly reduced in spinal cord tissue of mutant mice, whereas glycine was elevated. Dietary supplementation with acetyl-L-carnitine improved gross motor performance of CMT2D mice, but neither acetyl-L-carnitine nor glycine supplementation altered the parameters directly assessing neuropathy. Other metabolite changes suggestive of liver and kidney dysfunction in the CMT2D mice were validated using clinical blood chemistry. These effects were not secondary to the neuromuscular phenotype, as determined by comparison with another, genetically unrelated mouse strain with similar neuromuscular dysfunction. However, these changes do not seem to be causative or consistent metabolites of CMT2D, because they were not observed in a second mouse Gars allele or in serum samples from CMT2D patients. Therefore, the metabolite ‘fingerprint’ we have identified for CMT2D improves our understanding of cellular biochemical changes associated with GARS mutations, but identification of efficacious treatment strategies and elucidation of the disease mechanism will require additional studies. PMID:27288508

l-Carnitine Supplementation in Recovery after Exercise.

PubMed

Fielding, Roger; Riede, Linda; Lugo, James P; Bellamine, Aouatef

2018-03-13

Given its pivotal role in fatty acid oxidation and energy metabolism, l-carnitine has been investigated as ergogenic aid for enhancing exercise capacity in the healthy athletic population. Early research indicates its beneficial effects on acute physical performance, such as increased maximum oxygen consumption and higher power output. Later studies point to the positive impact of dietary supplementation with l-carnitine on the recovery process after exercise. It is demonstrated that l-carnitine alleviates muscle injury and reduces markers of cellular damage and free radical formation accompanied by attenuation of muscle soreness. The supplementation-based increase in serum and muscle l-carnitine contents is suggested to enhance blood flow and oxygen supply to the muscle tissue via improved endothelial function thereby reducing hypoxia-induced cellular and biochemical disruptions. Studies in older adults further showed that l-carnitine intake can lead to increased muscle mass accompanied by a decrease in body weight and reduced physical and mental fatigue. Based on current animal studies, a role of l-carnitine in the prevention of age-associated muscle protein degradation and regulation of mitochondrial homeostasis is suggested.

Nutraceuticals and chemotherapy induced peripheral neuropathy (CIPN): a systematic review.

PubMed

Schloss, Janet M; Colosimo, Maree; Airey, Caroline; Masci, Paul P; Linnane, Anthony W; Vitetta, Luis

2013-12-01

Chemotherapy induced peripheral neuropathy [CIPN] is a common significant and debilitating side effect resulting from the administration of neurotoxic chemotherapeutic agents. These pharmaco-chemotherapeutics can include taxanes, vinca alkaloids and others. Moderate to severe CIPN significantly decreases the quality of life and physical abilities of cancer patients and current pharmacotherapy for CIPN e.g. Amifostine and antidepressants have had limited efficacy and may themselves induce adverse side effects. To determine the potential use of nutraceuticals i.e. vitamin E, acetyl-L-carnitine, glutamine, glutathione, vitamin B6, omega-3 fatty acids, magnesium, calcium, alpha lipoic acid and n-acetyl cysteine as adjuvants in cancer treatments a systematic literature review was conducted. Revised clinical studies comprised of randomized clinical trials that investigated the anti-CIPN effect of nutraceuticals as the adjuvant intervention in patients administered chemotherapy. Twenty-four studies were assessed on methodological quality and limitations identified. Studies were mixed in their recommendations for nutraceuticals. Currently no agent has shown solid beneficial evidence to be recommended for the treatment or prophylaxis of CIPN. The standard of care for CIPN includes dose reduction and/or discontinuation of chemotherapy treatment. The management of CIPN remains an important challenge and future studies are warranted before recommendations for the use of supplements can be made. Copyright © 2013 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

L-carnitine prevents memory impairment induced by chronic REM-sleep deprivation.

PubMed

Alzoubi, Karem H; Rababa'h, Abeer M; Owaisi, Amani; Khabour, Omar F

2017-05-01

Sleep deprivation (SD) negatively impacts memory, which was related to oxidative stress induced damage. L-carnitine is a naturally occurring compound, synthesized endogenously in mammalian species and known to possess antioxidant properties. In this study, the effect of L-carnitine on learning and memory impairment induced by rapid eye movement sleep (REM-sleep) deprivation was investigated. REM-sleep deprivation was induced using modified multiple platform model (8h/day, for 6 weeks). Simultaneously, L-carnitine was administered (300mg/kg/day) intraperitoneally for 6 weeks. Thereafter, the radial arm water maze (RAWM) was used to assess spatial learning and memory. Additionally, the hippocampus levels of antioxidant biomarkers/enzymes: reduced glutathione (GSH), oxidized glutathione (GSSG), GSH/GSSG ratio, glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD) and thiobarbituric acid reactive substance (TBARS) were assessed. The results showed that chronic REM-sleep deprivation impaired both short- and long-term memory (P<0.05), whereas L-carnitine treatment protected against this effect. Furthermore, L-carnitine normalized chronic REM-sleep deprivation induced reduction in the hippocampus ratio of GSH/GSSG, activity of catalase, GPx, and SOD. No change was observed in TBARS among tested groups (P>0.05). In conclusion, chronic REM-sleep deprivation induced memory impairment, and treatment with L-carnitine prevented this impairment through normalizing antioxidant mechanisms in the hippocampus. Copyright © 2017 Elsevier Inc. All rights reserved.

Translating the basic knowledge of mitochondrial functions to metabolic therapy: role of L-carnitine.

PubMed

Marcovina, Santica M; Sirtori, Cesare; Peracino, Andrea; Gheorghiade, Mihai; Borum, Peggy; Remuzzi, Giuseppe; Ardehali, Hossein

2013-02-01

Mitochondria play important roles in human physiological processes, and therefore, their dysfunction can lead to a constellation of metabolic and nonmetabolic abnormalities such as a defect in mitochondrial gene expression, imbalance in fuel and energy homeostasis, impairment in oxidative phosphorylation, enhancement of insulin resistance, and abnormalities in fatty acid metabolism. As a consequence, mitochondrial dysfunction contributes to the pathophysiology of insulin resistance, obesity, diabetes, vascular disease, and chronic heart failure. The increased knowledge on mitochondria and their role in cellular metabolism is providing new evidence that these disorders may benefit from mitochondrial-targeted therapies. We review the current knowledge of the contribution of mitochondrial dysfunction to chronic diseases, the outcomes of experimental studies on mitochondrial-targeted therapies, and explore the potential of metabolic modulators in the treatment of selected chronic conditions. As an example of such modulators, we evaluate the efficacy of the administration of L-carnitine and its analogues acetyl and propionyl L-carnitine in several chronic diseases. L-carnitine is intrinsically involved in mitochondrial metabolism and function as it plays a key role in fatty acid oxidation and energy metabolism. In addition to the transportation of free fatty acids across the inner mitochondrial membrane, L-carnitine modulates their oxidation rate and is involved in the regulation of vital cellular functions such as apoptosis. Thus, L-carnitine and its derivatives show promise in the treatment of chronic conditions and diseases associated with mitochondrial dysfunction but further translational studies are needed to fully explore their potential. Copyright © 2013 Mosby, Inc. All rights reserved.

Children at risk of diabetes type 1. Treatment with acetyl-L-carnitine plus nicotinamide - case reports.

PubMed

Fernandez, Ivana Cristina; Del Carmen Camberos, María; Passicot, Gisel Anabel; Martucci, Lucía Camila; Cresto, Juan Carlos

2013-01-01

Abstract Objectives: The aim was to evaluate the treatment with acetyl-L-carnitine (50 mg/kg/day) and nicotinamide (25 mg/kg/day) in children at risk of type 1 diabetes. This treatment was effective and harmless in experimental type 1 diabetes in mice. Nine out of seventy healthy participants of the type 1 diabetes risk study were treated. They were typified for diabetes with HLA-DQB1 and positive autoantibodies. Children with a first peak of insulin response ≤48 µU were randomly distributed in control and treated patients. Children evolution was followed with an intravenous glucose tolerance test. Control children were treated when was another risk parameter was added. During their evolution all children were treated. Treatment periods differ (range: 120-16 months) because children began treatment at different times. During the treatment 4 patients recovered their parameters and the medication was suspended; 2 patients continued the treatment with favorable evolution. Two children evolved slowly with normal growth and development. One girl became diabetic because she was treated late. In children at risk, this treatment delays the development or remits the evolution of type 1 diabetes.

Acetyl-L-Carnitine Supplementation and the Treatment of Depressive Symptoms: A Systematic Review and Meta-Analysis.

PubMed

Veronese, Nicola; Stubbs, Brendon; Solmi, Marco; Ajnakina, Olesya; Carvalho, Andre F; Maggi, Stefania

Deficiency of acetyl-L-carnitine (ALC) seems to play a role in the risk of developing depression, indicating a dysregulation of fatty acid transport across the inner membrane of mitochondria. However, data about ALC supplementation in humans are limited. We thus conducted a systematic review and meta-analysis investigating the effect of ALC on depressive symptoms across randomized controlled trials (RCTs). A literature search in major databases, without language restriction, was undertaken from inception until 30 December 2016. Eligible studies were RCTs of ALC alone or in combination with antidepressant medications, with a control group taking placebo/no intervention or antidepressants. Standardized mean differences (SMDs) and 95% confidence intervals (CIs) were used for summarizing outcomes with a random-effect model. Twelve RCTs (11 of which were ALC monotherapy) with a total of 791 participants (mean age = 54 years, % female = 65%) were included. Pooled data across nine RCTs (231 treated with ALC versus 216 treated with placebo and 20 no intervention) showed that ALC significantly reduced depressive symptoms (SMD = -1.10, 95% CI = -1.65 to -0.56, I = 86%). In three RCTs comparing ALC versus antidepressants (162 for each group), ALC demonstrated similar effectiveness compared with established antidepressants in reducing depressive symptoms (SMD = 0.06, 95% CI = -0.22 to 0.34, I = 31%). In these latter RCTs, the incidence of adverse effects was significantly lower in the ALC group than in the antidepressant group. Subgroup analyses suggested that ALC was most efficacious in older adults. ALC supplementation significantly decreases depressive symptoms compared with placebo/no intervention, while offering a comparable effect with that of established antidepressant agents with fewer adverse effects. Future large scale trials are required to confirm/refute these findings.

l-Carnitine Supplementation in Recovery after Exercise

PubMed Central

Fielding, Roger; Riede, Linda; Lugo, James P.; Bellamine, Aouatef

2018-01-01

Given its pivotal role in fatty acid oxidation and energy metabolism, l-carnitine has been investigated as ergogenic aid for enhancing exercise capacity in the healthy athletic population. Early research indicates its beneficial effects on acute physical performance, such as increased maximum oxygen consumption and higher power output. Later studies point to the positive impact of dietary supplementation with l-carnitine on the recovery process after exercise. It is demonstrated that l-carnitine alleviates muscle injury and reduces markers of cellular damage and free radical formation accompanied by attenuation of muscle soreness. The supplementation-based increase in serum and muscle l-carnitine contents is suggested to enhance blood flow and oxygen supply to the muscle tissue via improved endothelial function thereby reducing hypoxia-induced cellular and biochemical disruptions. Studies in older adults further showed that l-carnitine intake can lead to increased muscle mass accompanied by a decrease in body weight and reduced physical and mental fatigue. Based on current animal studies, a role of l-carnitine in the prevention of age-associated muscle protein degradation and regulation of mitochondrial homeostasis is suggested. PMID:29534031

L-carnitine--metabolic functions and meaning in humans life.

PubMed

Pekala, Jolanta; Patkowska-Sokoła, Bozena; Bodkowski, Robert; Jamroz, Dorota; Nowakowski, Piotr; Lochyński, Stanisław; Librowski, Tadeusz

2011-09-01

L-Carnitine is an endogenous molecule involved in fatty acid metabolism, biosynthesized within the human body using amino acids: L-lysine and L-methionine, as substrates. L-Carnitine can also be found in many foods, but red meats, such as beef and lamb, are the best choices for adding carnitine into the diet. Good carnitine sources also include fish, poultry and milk. Essentially, L-carnitine transports the chains of fatty acids into the mitochondrial matrix, thus allowing the cells to break down fat and get energy from the stored fat reserves. Recent studies have started to shed light on the beneficial effects of L-carnitine when used in various clinical therapies. Because L-carnitine and its esters help reduce oxidative stress, they have been proposed as a treatment for many conditions, i.e. heart failure, angina and weight loss. For other conditions, such as fatigue or improving exercise performance, L-carnitine appears safe but does not seem to have a significant effect. The presented review of the literature suggests that continued studies are required before L-carnitine administration could be recommended as a routine procedure in the noted disorders. Further research is warranted in order to evaluate the biochemical, pharmacological, and physiological determinants of the response to carnitine supplementation, as well as to determine the potential benefits of carnitine supplements in selected categories of individuals who do not have fatty acid oxidation defects.

Pharmacokinetics of propionyl-l-carnitine in humans: evidence for saturable tubular reabsorption

PubMed Central

Pace, S; Longo, A; Toon, S; Rolan, P; Evans, A M

2000-01-01

Aims Propionyl-l-carnitine (PLC) is an endogenous compound which, along with l-carnitine (LC) and acetyl-l-carnitine (ALC), forms a component of the endogenous carnitine pool in humans and most, if not all, animal species. PLC is currently under investigation for the treatment of peripheral artery disease, and the present study was conducted to assess the pharmacokinetics of intravenous propionyl-l-carnitine hydrochloride. Methods This was a placebo-controlled, double-blind, parallel group, dose-escalating study in which 24 healthy males were divided into four groups of six. Four subjects from each group received propionyl-l-carnitine hydrochloride and two received placebo. The doses (1 g, 2 g, 4 g and 8 g) were administered as a constant rate infusion over 2 h and blood and urine were collected for 24 h from the start of the infusion. PLC, ALC and LC in plasma and urine were quantified by h.p.l.c. Results All 24 subjects successfully completed the study and the infusions were well tolerated. In addition to the expected increase in PLC levels, the plasma concentrations and urinary excretion of LC and ALC also increased above baseline values following intravenous propionyl-l-carnitine hydrochloride administration. At a dose of 1 g, PLC was found to have a mean (± s.d.) half-life of 1.09 ± 0.15 h, a clearance of 11.6 ± 0.24 l h−1 and a volume of distribution of 18.3 ± 2.4 l. None of these parameters changed with dose. In placebo-treated subjects, endogenous PLC, LC and ALC underwent extensive renal tubular reabsorption, as indicated by renal excretory clearance to GFR ratios of less than 0.1. The renal-excretory clearance of PLC, which was 0.33 ± 0.38 l h−1 under baseline condition, increased (P < 0.001) from 1.98 ± 0.59 l h−1 at a dose of 1 g to 5.55 ± 1.50 l h−1 at a dose of 8 g (95% confidence interval for the difference was 2.18,4.97). As a consequence, the percent of the dose excreted unchanged in urine increased (P < 0.001) from 18.1 ± 5.5% (1 g

Crystal Structure of an L-Carnitine Complex with Pyrogallol[4]arene

NASA Astrophysics Data System (ADS)

Fujisawa, I.; Takeuchi, D.; Kitamura, Y.; Okamoto, R.; Aoki, K.

2012-03-01

L-Carnitine is essential for the transport of long-chain fatty acids from cytosol into mitochondria for generating metabolic energy. The survey of crystal structures of carnitine-containing proteins in the Protein Data Bank reveals that carnitine can take several conformations with the quarternary trimethylammonium terminal being always bound to aromatic residues through cation-π interactions in acyltransferases or carnitine-binding proteins. In order to demonstrate the importance of cation-π interaction as a carnitine recognition mechanism in the artificial receptor-ligand system that mimics the carnitine-binding sites, we have determined the crystal structure of a complex formed between L-carnitine and pyrogallol[4]arene (pyrogallol cyclic tetramer: PCT) as a carnitine receptor, 2PCT·2(L-carnitine)·4EtOH. There form two crystallographically independent monomeric [PCT·L-carnitine] substructures, which further form an obliquely arranged capsule-like dimeric [PCT·L-carnitine]2 structure through a pair of O-H (PCT)···O (L-carnitine) hydrogen bonds. This is the first report of PCT complex with chiral molecules. In each of the two monomeric [PCT·L-carnitine] substructures, the L-carnitine molecule takes the elongated form with an intramolecular hydrogen bond between the hydroxyl group and the carboxylate oxygen, and the cationic trimethylammonium moiety is incorporated into the cavity of the bowl-shaped PCT molecule through cation-π interactions. These features are similar to those at the D-carnitine-binding site in the crystal structure of the glycine betaine/carnitine/choline-binding protein complex.

Evaluation of lenticular antioxidant and redox system components in the lenses of acetyl-L-carnitine treatment in BSO-induced glutathione deprivation.

PubMed

Elanchezhian, R; Sakthivel, M; Isai, M; Geraldine, P; Thomas, P A

2009-07-31

To investigate whether acetyl-L-carnitine (ALCAR) retards L-buthionine-(S,R)-sulfoximine (BSO)-induced cataractogenesis in Wistar rat pups. On postpartum day 3, group I pups received intraperitoneal (ip) saline and group II and group III pups received i.p. injections of BSO once daily for three consecutive days. In addition, group III pups received ip ALCAR once daily from postpartum days 3-15. Both eyes of each pup were examined up from postpartum day 16 to day 30. After sacrifice, extricated pup lenses were analyzed for antioxidant and redox system components. There was dense lenticular opacification in all group II pups, minimal opacification in 40% of group III pups, and no opacification in 60% of group III pups and in all of group I pups. Group II lenses exhibited significantly lower values of antioxidant and redox system components and higher malondialdehyde concentrations than in group I or group III lenses. ALCAR prevents cataractogenesis in the BSO-induced cataract model, possibly by inhibiting depleting antioxidant enzyme and redox system components and inhibiting lipid peroxidation.

Evaluation of lenticular antioxidant and redox system components in the lenses of acetyl-L-carnitine treatment in BSO-induced glutathione deprivation

PubMed Central

Elanchezhian, R.; Sakthivel, M.; Isai, M.; Thomas, P.A.

2009-01-01

Purpose To investigate whether acetyl-L-carnitine (ALCAR) retards L-buthionine-(S,R)-sulfoximine (BSO)-induced cataractogenesis in Wistar rat pups. Methods On postpartum day 3, group I pups received intraperitoneal (ip) saline and group II and group III pups received i.p. injections of BSO once daily for three consecutive days. In addition, group III pups received ip ALCAR once daily from postpartum days 3–15. Both eyes of each pup were examined up from postpartum day 16 to day 30. After sacrifice, extricated pup lenses were analyzed for antioxidant and redox system components. Results There was dense lenticular opacification in all group II pups, minimal opacification in 40% of group III pups, and no opacification in 60% of group III pups and in all of group I pups. Group II lenses exhibited significantly lower values of antioxidant and redox system components and higher malondialdehyde concentrations than in group I or group III lenses. Conclusions ALCAR prevents cataractogenesis in the BSO-induced cataract model, possibly by inhibiting depleting antioxidant enzyme and redox system components and inhibiting lipid peroxidation. PMID:19649174

Nicotinamide riboside, a form of vitamin B3 and NAD+ precursor, relieves the nociceptive and aversive dimensions of paclitaxel-induced peripheral neuropathy in female rats.

PubMed

Hamity, Marta V; White, Stephanie R; Walder, Roxanne Y; Schmidt, Mark S; Brenner, Charles; Hammond, Donna L

2017-05-01

Injury to sensory afferents may contribute to the peripheral neuropathies that develop after administration of chemotherapeutic agents. Manipulations that increase levels of nicotinamide adenine dinucleotide (NAD) can protect against neuronal injury. This study examined whether nicotinamide riboside (NR), a third form of vitamin B3 and precursor of NAD, diminishes tactile hypersensitivity and place escape-avoidance behaviors in a rodent model of paclitaxel-induced peripheral neuropathy. Female Sprague-Dawley rats received 3 intravenous injections of 6.6 mg/kg paclitaxel over 5 days. Daily oral administration of 200 mg/kg NR beginning 7 days before paclitaxel treatment and continuing for another 24 days prevented the development of tactile hypersensitivity and blunted place escape-avoidance behaviors. These effects were sustained after a 2-week washout period. This dose of NR increased blood levels of NAD by 50%, did not interfere with the myelosuppressive effects of paclitaxel, and did not produce adverse locomotor effects. Treatment with 200 mg/kg NR for 3 weeks after paclitaxel reversed the well-established tactile hypersensitivity in a subset of rats and blunted escape-avoidance behaviors. Pretreatment with 100 mg/kg oral acetyl-L-carnitine (ALCAR) did not prevent paclitaxel-induced tactile hypersensitivity or blunt escape-avoidance behaviors. ALCAR by itself produced tactile hypersensitivity. These findings suggest that agents that increase NAD, a critical cofactor for mitochondrial oxidative phosphorylation systems and cellular redox systems involved with fuel utilization and energy metabolism, represent a novel therapeutic approach for relief of chemotherapy-induced peripheral neuropathies. Because NR is a vitamin B3 precursor of NAD and a nutritional supplement, clinical tests of this hypothesis may be accelerated.

Ameliorative effects of l-carnitine on rats raised on a diet supplemented with lead acetate.

PubMed

El-Sherbini, El-Said; El-Sayed, Gehad; El Shotory, Rehab; Gheith, Nervana; Abou-Alsoud, Mohamed; Harakeh, Steve Mustapha; Karrouf, Gamal I

2017-09-01

Lead intoxication has been a major health hazard in humans. It affects people at all ages. Its toxicity is associated with various organs of the body and affects different metabolic pathways. Based on histological data, l-carnitine reduced the severity of tissue damage produced as a result of exposure of rats to lead acetate. The main objective of this study was to evaluate the underlying mechanism of protection offered by l-carnitine against lead acetate intoxication using male Sprague-Dawley rats. Forty male Sprague-Dawley rats were randomly divided into four groups with ten rats in each. The first group (G1) served as the control group and animals received standard diet only. The second group (G2) received lead acetate in their diet. The third group (G3) was the l-carnitine treated group and received the normal standard diet supplemented with l-carnitine. While the fourth group (G4) had a diet supplemented with both lead acetate and l-carnitine. At the end of each experiment, blood (serum and whole blood) were collected from each animal and analyzed for the following parameters: serum testosterone levels, serum nitric oxide and serum malondialdehyde. This is in addition to looking at the enzymatic activities of two important enzymes (superoxide dismutase and catalase) and on (glutathione reductase) which are indicative of the antioxidant activities in the whole blood. The results indicated that l-carnitine will counteract the undesirable effects of lead intoxication. It exerted its antioxidant potential by reducing the production of ROS and scavenging free radicals by maintaining and protecting the level of the of antioxidant enzymes SOD, CAT and glutathione peroxidase. Conclusion: l-Carnitine may play an important role in reversing the undesirable effects of lead intoxication. Future studies should be conducted to see whether such an effect is applicable in humans exposed to lead poising.

L-carnitine is an endogenous HDAC inhibitor selectively inhibiting cancer cell growth in vivo and in vitro.

PubMed

Huang, Hongbiao; Liu, Ningning; Guo, Haiping; Liao, Siyan; Li, Xiaofen; Yang, Changshan; Liu, Shouting; Song, Wenbin; Liu, Chunjiao; Guan, Lixia; Li, Bing; Xu, Li; Zhang, Change; Wang, Xuejun; Dou, Q Ping; Liu, Jinbao

2012-01-01

L-carnitine (LC) is generally believed to transport long-chain acyl groups from fatty acids into the mitochondrial matrix for ATP generation via the citric acid cycle. Based on Warburg's theory that most cancer cells mainly depend on glycolysis for ATP generation, we hypothesize that, LC treatment would lead to disturbance of cellular metabolism and cytotoxicity in cancer cells. In this study, Human hepatoma HepG2, SMMC-7721 cell lines, primary cultured thymocytes and mice bearing HepG2 tumor were used. ATP content was detected by HPLC assay. Cell cycle, cell death and cell viability were assayed by flow cytometry and MTS respectively. Gene, mRNA expression and protein level were detected by gene microarray, Real-time PCR and Western blot respectively. HDAC activities and histone acetylation were detected both in test tube and in cultured cells. A molecular docking study was carried out with CDOCKER protocol of Discovery Studio 2.0 to predict the molecular interaction between L-carnitine and HDAC. Here we found that (1) LC treatment selectively inhibited cancer cell growth in vivo and in vitro; (2) LC treatment selectively induces the expression of p21(cip1) gene, mRNA and protein in cancer cells but not p27(kip1); (4) LC increases histone acetylation and induces accumulation of acetylated histones both in normal thymocytes and cancer cells; (5) LC directly inhibits HDAC I/II activities via binding to the active sites of HDAC and induces histone acetylation and lysine-acetylation accumulation in vitro; (6) LC treatment induces accumulation of acetylated histones in chromatin associated with the p21(cip1) gene but not p27(kip1) detected by ChIP assay. These data support that LC, besides transporting acyl group, works as an endogenous HDAC inhibitor in the cell, which would be of physiological and pathological importance.

L-Carnitine Is an Endogenous HDAC Inhibitor Selectively Inhibiting Cancer Cell Growth In Vivo and In Vitro

PubMed Central

Liao, Siyan; Li, Xiaofen; Yang, Changshan; Liu, Shouting; Song, Wenbin; Liu, Chunjiao; Guan, Lixia; Li, Bing; Xu, Li; Zhang, Change; Wang, Xuejun; Dou, Q. Ping; Liu, Jinbao

2012-01-01

L-carnitine (LC) is generally believed to transport long-chain acyl groups from fatty acids into the mitochondrial matrix for ATP generation via the citric acid cycle. Based on Warburg's theory that most cancer cells mainly depend on glycolysis for ATP generation, we hypothesize that, LC treatment would lead to disturbance of cellular metabolism and cytotoxicity in cancer cells. In this study, Human hepatoma HepG2, SMMC-7721 cell lines, primary cultured thymocytes and mice bearing HepG2 tumor were used. ATP content was detected by HPLC assay. Cell cycle, cell death and cell viability were assayed by flow cytometry and MTS respectively. Gene, mRNA expression and protein level were detected by gene microarray, Real-time PCR and Western blot respectively. HDAC activities and histone acetylation were detected both in test tube and in cultured cells. A molecular docking study was carried out with CDOCKER protocol of Discovery Studio 2.0 to predict the molecular interaction between L-carnitine and HDAC. Here we found that (1) LC treatment selectively inhibited cancer cell growth in vivo and in vitro; (2) LC treatment selectively induces the expression of p21cip1 gene, mRNA and protein in cancer cells but not p27kip1; (4) LC increases histone acetylation and induces accumulation of acetylated histones both in normal thymocytes and cancer cells; (5) LC directly inhibits HDAC I/II activities via binding to the active sites of HDAC and induces histone acetylation and lysine-acetylation accumulation in vitro; (6) LC treatment induces accumulation of acetylated histones in chromatin associated with the p21cip1 gene but not p27kip1 detected by ChIP assay. These data support that LC, besides transporting acyl group, works as an endogenous HDAC inhibitor in the cell, which would be of physiological and pathological importance. PMID:23139833

Effect of L-carnitine supplementation on the body carnitine pool, skeletal muscle energy metabolism and physical performance in male vegetarians.

PubMed

Novakova, Katerina; Kummer, Oliver; Bouitbir, Jamal; Stoffel, Sonja D; Hoerler-Koerner, Ulrike; Bodmer, Michael; Roberts, Paul; Urwyler, Albert; Ehrsam, Rolf; Krähenbühl, Stephan

2016-02-01

More than 95% of the body carnitine is located in skeletal muscle, where it is essential for energy metabolism. Vegetarians ingest less carnitine and carnitine precursors and have lower plasma carnitine concentrations than omnivores. Principle aims of the current study were to assess the plasma and skeletal muscle carnitine content and physical performance of male vegetarians and matched omnivores under basal conditions and after L-carnitine supplementation. Sixteen vegetarians and eight omnivores participated in this interventional study with oral supplementation of 2 g L-carnitine for 12 weeks. Before carnitine supplementation, vegetarians had a 10% lower plasma carnitine concentration, but maintained skeletal muscle carnitine stores compared to omnivores. Skeletal muscle phosphocreatine, ATP, glycogen and lactate contents were also not different from omnivores. Maximal oxygen uptake (VO2max) and workload (P max) per bodyweight (bicycle spiroergometry) were not significantly different between vegetarians and omnivores. Sub-maximal exercise (75% VO2max for 1 h) revealed no significant differences between vegetarians and omnivores (respiratory exchange ratio, blood lactate and muscle metabolites). Supplementation with L-carnitine significantly increased the total plasma carnitine concentration (24% in omnivores, 31% in vegetarians) and the muscle carnitine content in vegetarians (13%). Despite this increase, P max and VO2max as well as muscle phosphocreatine, lactate and glycogen were not significantly affected by carnitine administration. Vegetarians have lower plasma carnitine concentrations, but maintained muscle carnitine stores compared to omnivores. Oral L-carnitine supplementation normalizes the plasma carnitine stores and slightly increases the skeletal muscle carnitine content in vegetarians, but without affecting muscle function and energy metabolism.

Methamphetamine Inhibits the Glucose Uptake by Human Neurons and Astrocytes: Stabilization by Acetyl-L-Carnitine

PubMed Central

Szlachetka, Adam M.; Haorah, James

2011-01-01

Methamphetamine (METH), an addictive psycho-stimulant drug exerts euphoric effects on users and abusers. It is also known to cause cognitive impairment and neurotoxicity. Here, we hypothesized that METH exposure impairs the glucose uptake and metabolism in human neurons and astrocytes. Deprivation of glucose is expected to cause neurotoxicity and neuronal degeneration due to depletion of energy. We found that METH exposure inhibited the glucose uptake by neurons and astrocytes, in which neurons were more sensitive to METH than astrocytes in primary culture. Adaptability of these cells to fatty acid oxidation as an alternative source of energy during glucose limitation appeared to regulate this differential sensitivity. Decrease in neuronal glucose uptake by METH was associated with reduction of glucose transporter protein-3 (GLUT3). Surprisingly, METH exposure showed biphasic effects on astrocytic glucose uptake, in which 20 µM increased the uptake while 200 µM inhibited glucose uptake. Dual effects of METH on glucose uptake were paralleled to changes in the expression of astrocytic glucose transporter protein-1 (GLUT1). The adaptive nature of astrocyte to mitochondrial β-oxidation of fatty acid appeared to contribute the survival of astrocytes during METH-induced glucose deprivation. This differential adaptive nature of neurons and astrocytes also governed the differential sensitivity to the toxicity of METH in these brain cells. The effect of acetyl-L-carnitine for enhanced production of ATP from fatty oxidation in glucose-free culture condition validated the adaptive nature of neurons and astrocytes. These findings suggest that deprivation of glucose-derived energy may contribute to neurotoxicity of METH abusers. PMID:21556365

Sibutramine and L-carnitine compared to sibutramine alone on insulin resistance in diabetic patients.

PubMed

Derosa, Giuseppe; Maffioli, Pamela; Salvadeo, Sibilla A T; Ferrari, Ilaria; Gravina, Alessia; Mereu, Roberto; D'Angelo, Angela; Palumbo, Ilaria; Randazzo, Sabrina; Cicero, Arrigo F G

2010-01-01

To evaluate the effects of one year of treatment with sibutramine plus L-carnitine compared to sibutramine on body weight, glycemic control, and insulin resistance state in type 2 diabetic patients. Two hundred and fifty-four patients with uncontrolled type 2 diabetes mellitus (T2DM) [glycated hemoglobin (HbA(1c)) >8.0%] in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomised to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline, and after 3, 6, 9, and 12 months these parameters: body weight, body mass index (BMI), glycated hemoglobin (HbA(1c)), fasting plasma glucose (FPG), post-prandial plasma glucose (PPG), fasting plasma insulin (FPI), homeostasis model assessment insulin resistance index (HOMA-IR), total cholesterol (TC), low density lipoprotein-cholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C), triglycerides (Tg), retinol binding protein-4 (RBP-4), resistin, visfatin, high sensitivity-C reactive protein (Hs-CRP). There was a decrease in body weight, BMI, HbA(1c), FPI, HOMA-IR, and RBP-4 in both groups, even when the values obtained with sibutramine plus L-carnitine were lower than the values obtained in sibutramine group. There was a faster decrease of FPG, PPG, TC, LDL-C, resistin and Hs-CRP with sibutramine plus L-carnitine even when no differences between the two groups were obtained. Furthermore, only sibutramine plus L-carnitine improved Tg, and visfatin. Sibutramine plus L-carnitine gave a faster improvement of lipid profile, insulin resistance parameters, glycemic control, and body weight compared to sibutramine.

Use of L-carnitine and humate in laying quail diets.

PubMed

Yalçin, Sakine; Ergün, A; Erol, Handan; Yalçin, Suzan; Ozsoy, B

2005-01-01

This experiment was carried out to determine the effects of using L-carnitine and humate alone or in combination in quail diets on laying performance, egg traits and blood parameters. A total of 280 Japanese quails aged 10 weeks, divided into one control group and three treatment groups, were used. The diets of the first, second and third treatment groups were supplemented with 100 mg L-carnitine/kg, 1.5 g humate (Farmagülatör Dry Plus)/kg and 100 mg L-camitine + 1.5 g humate/kg, respectively. The experimental period lasted 16 weeks. The addition of L-carnitine and sodium humate alone or in combination did not significantly affect body weight, feed consumption, egg production, feed conversion ratio, mortality, egg-shell thickness, egg yolk index and the percentages of egg-shell, albumen and yolk. Egg weight increased (P < 0.001) with L-carnitine supplementation. The values of egg albumen height (P < 0.05), egg albumen index (P < 0.01) and egg Haugh unit (P < 0.05) were increased with humate supplementation. Egg cholesterol content and blood serum parameters were not affected by the supplementation of L-carnitine with or without humate. The results in this study demonstrated that L-carnitine supplementation increased egg weight while humate addition increased egg albumen index and egg Haugh unit of laying quails. However, the combined administration of L-carnitine and humate did not have any significant effects on the parameters measured.

Distinct effects of ketamine and acetyl l-carnitine on the dopamine system in zebrafish

PubMed Central

Robinson, Bonnie L.; Dumas, Melanie; Cuevas, Elvis; Gu, Qiang; Paule, Merle G.; Ali, Syed F.; Kanungo, Jyotshna

2016-01-01

Ketamine, a noncompetitive N-methyl-d-aspartic acid (NMDA) receptor antagonist is commonly used as a pediatric anesthetic. We have previously shown that acetyl L-carnitine (ALCAR) prevents ketamine toxicity in zebrafish embryos. In mammals, ketamine is known to modulate the dopaminergic system. NMDA receptor antagonists are considered as promising anti-depressants, but the exact mechanism of their function is unclear. Here, we measured the levels of dopamine (DA) and its metabolites, 3, 4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the zebrafish embryos exposed to ketamine in the presence and absence of 0.5 mM ALCAR. Ketamine, at lower doses (0.1–0.3 mM), did not produce significant changes in DA, DOPAC or HVA levels in 52 h post-fertilization embryos treated for 24 h. In these embryos, tyrosine hydroxylase (TH) mRNA expression remained unchanged. However, 2 mM ketamine (internal embryo exposure levels equivalent to human anesthetic plasma concentration) significantly reduced DA level and TH mRNA indicating that DA synthesis was adversely affected. In the presence or absence of 2 mM ketamine, ALCAR showed similar effects on DA level and TH mRNA, but increased DOPAC level compared to control. ALCAR reversed 2 mM ketamine-induced reduction in HVA levels. With ALCAR alone, the expression of genes encoding the DA metabolizing enzymes, MAO (monoamine oxidase) and catechol-O-methyltransferase (COMT), was not affected. However, ketamine altered MAO mRNA expression, except at the 0.1 mM dose. COMT transcripts were reduced in the 2 mM ketamine-treated group. These distinct effects of ketamine and ALCAR on the DA system may shed some light on the mechanism on how ketamine can work as an anti-depressant, especially at sub-anesthetic doses that do not affect DA metabolism and suppress MAO gene expression. PMID:26898327

Interactions between N-acetyl-L-cysteine protected CdTe quantum dots and doxorubicin through spectroscopic method

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Xiupei, E-mail: xiupeiyang@163.com; College of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637000; Lin, Jia

2015-06-15

Highlights: • CdTe quantum dots with the diameter of 3–5 nm were synthesized in aqueous solution. • The modified CdTe quantum dots showed well fluorescence properties. • The interaction between the CdTe quantum dots and doxorubicin (DR) was investigated. - Abstract: N-acetyl-L-cysteine protected cadmium telluride quantum dots with a diameter of 3–5 nm were synthesized in aqueous solution. The interaction between N-acetyl-L-cysteine/cadmium telluride quantum dots and doxorubicin was investigated by ultraviolet–visible absorption and fluorescence spectroscopy at physiological conditions (pH 7.2, 37 °C). The results indicate that electron transfer has occurred between N-acetyl-L-cysteine/cadmium telluride quantum dots and doxorubicin under light illumination.more » The quantum dots react readily with doxorubicin to form a N-acetyl-L-cysteine/cadmium telluride-quantum dots/doxorubicin complex via electrostatic attraction between the −NH{sub 3}{sup +} moiety of doxorubicin and the −COO{sup −} moiety of N-acetyl-L-cysteine/cadmium telluride quantum dots. The interaction of N-acetyl-L-cysteine/cadmium telluride-quantum dots/doxorubicin complex with bovine serum albumin was studied as well, showing that the complex might induce the conformation change of bovine serum due to changes in microenvironment of bovine serum.« less

Effect of L-carnitine on diabetogenic action of streptozotocin in rats.

PubMed

Uysal, Nazan; Yalaz, Giray; Acikgoz, Osman; Gonenc, Sevil; Kayatekin, Berkant Muammer

2005-08-01

L-carnitine is a naturally compound widely distributed in the body. It has an antiradical effect and decreases lipid peroxidation. In acute or chronic streptozotocin (STZ)-induced diabetic rats, the pancreatic content of carnitine was found to be significantly lower than nondiabetic group. We investigated the effects of L-carnitine on the development of STZ-induced diabetes in rats, to determine if L-carnitine can prevent the onset of diabetes or reduce the severity of hyperglycemia and this prevention/reduction is associated with the reduction in oxidative stress. The rats were divided into 3 groups: Control, STZ-treated (65 mg/kg intraperitoneally) and L-carnitine (500 mg/kg) and STZ-treated. Oxidative stress was assessed by measuring pancreatic thiobarbituric acid reactive substance (TBARS) formation levels using the method of Rehncrona et al, pancreatic superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities using a Randox test combination (RANSOD and RANDOX). L-carnitine did not prevent the onset of diabetes at this dose. Development of diabetes was associated with an increase in pancreatic TBARS (0.028 +/- 0.008 and 0.046 +/- 0.017 nmol/mg Protein, respectively), and GPx activity (0.067 +/- 0.011 and 0.098 +/- 0.016 U/mg Protein, respectively). L-carnitine prevented this increase induced by diabetes; TBARS (0.039 +/- 0.006 nmol/mg Protein) and GPx activity (0.053 +/- 0.011 U/mg Protein). These results suggest that L-carnitine exerts anti-oxidative effect in experimental diabetes.

Blood Pressure and Metabolic Effects of Acetyl-l-Carnitine in Type 2 Diabetes: DIABASI Randomized Controlled Trial.

PubMed

Parvanova, Aneliya; Trillini, Matias; Podestà, Manuel A; Iliev, Ilian P; Aparicio, Carolina; Perna, Annalisa; Peraro, Francesco; Rubis, Nadia; Gaspari, Flavio; Cannata, Antonio; Ferrari, Silvia; Bossi, Antonio C; Trevisan, Roberto; Parameswaran, Sreejith; Chávez-Iñiguez, Jonathan S; Masnic, Fahrudin; Seck, Sidy Mohamed; Jiamjariyaporn, Teerayuth; Cortinovis, Monica; Perico, Luca; Sharma, Kanishka; Remuzzi, Giuseppe; Ruggenenti, Piero; Warnock, David G

2018-05-01

Acetyl-l-carnitine (ALC), a mitochondrial carrier involved in lipid oxidation and glucose metabolism, decreased systolic blood pressure (SBP), and ameliorated insulin sensitivity in hypertensive nondiabetic subjects at high cardiovascular risk. To assess the effects of ALC on SBP and glycemic and lipid control in patients with hypertension, type 2 diabetes mellitus (T2D), and dyslipidemia on background statin therapy. After 4-week run-in period and stratification according to previous statin therapy, patients were randomized to 6-month, double-blind treatment with ALC or placebo added-on simvastatin. Five diabetology units and one clinical research center in Italy. Two hundred twenty-nine patients with hypertension and dyslipidemic T2D >40 years with stable background antihypertensive, hypoglycemic, and statin therapy and serum creatinine <1.5 mg/dL. Oral ALC 1000 mg or placebo twice daily on top of stable simvastatin therapy. Primary outcome was SBP. Secondary outcomes included lipid and glycemic profiles. Total-body glucose disposal rate and glomerular filtration rate were measured in subgroups by hyperinsulinemic-euglycemic clamp and iohexol plasma clearance, respectively. SBP did not significantly change after 6-month treatment with ALC compared with placebo (-2.09 mm Hg vs -3.57 mm Hg, P = 0.9539). Serum cholesterol, triglycerides, and lipoprotein(a), as well as blood glucose, glycated hemoglobin, fasting insulin levels, homeostatic model assessment of insulin resistance index, glucose disposal rate, and glomerular filtration rate did not significantly differ between treatments. Adverse events were comparable between groups. Six-month oral ALC supplementation did not affect blood pressure, lipid and glycemic control, insulin sensitivity and kidney function in hypertensive normoalbuminuric and microalbuminuric T2D patients on background statin therapy.

Acetyl-L-carnitine (ALC) administration positively affects reproductive axis in hypogonadotropic women with functional hypothalamic amenorrhea.

PubMed

Genazzani, A D; Lanzoni, C; Ricchieri, F; Santagni, S; Rattighieri, E; Chierchia, E; Monteleone, P; Jasonni, V M

2011-04-01

Hypothalamic amenorrhea (HA) is characterized by neuroendocrine impairment that, in turn, negatively modulates endocrine function, mainly within the reproductive axis. HA presents with hypo-LH, hypoestrogenism and, until now, a definite therapeutic strategy has not yet been found. The aim of the following study was to test the efficacy of acetyl-L-carnitine (ALC) administration in HA-affected subjects. Twenty-four patients affected by stress-induced HA were divided into two groups according to LH plasma levels: group A, hypo-LH (LH≤3 mIU/ml; no.=16), and group B, normo-LH (LH>3 mIU/ml; no.=8), were treated with ALC (1 g/day, per os) for 16 weeks. Patients underwent baseline hormonal assessment, pulsatility test (for LH and FSH), naloxone test (for LH, FSH and cortisol) both before and after 16 weeks of treatment. Under ALC administration hypo-LH patients showed a significant increase in LH plasma levels (from 1.4±0.3 to 3.1±0.5 mIU/ml, p<0.01) and in LH pulse amplitude (p<0.001). No changes were observed in the normo-LH group. LH response to naloxone was restored under ALC therapy. Maximal LH response and area under the curve under naloxone were significantly increased (p<0.05 and p<0.01, respectively). No changes were observed in the normo-LH patients. Our data support the hypothesis of a specific role of ALC on counteracting the stress-induced abnormalities in hypo-LH patients affected by hypothalamic amenorrhea.

Reduced L-Carnitine Transport in Aortic Endothelial Cells from Spontaneously Hypertensive Rats

PubMed Central

Salsoso, Rocío; Guzmán-Gutiérrez, Enrique; Arroyo, Pablo; Salomón, Carlos; Zambrano, Sonia; Ruiz-Armenta, María Victoria; Blanca, Antonio Jesús; Pardo, Fabián; Leiva, Andrea; Mate, Alfonso; Sobrevia, Luis; Vázquez, Carmen María

2014-01-01

Impaired L-carnitine uptake correlates with higher blood pressure in adult men, and L-carnitine restores endothelial function in aortic rings from spontaneously hypertensive rat (SHR). Thus, endothelial dysfunction in hypertension could result from lower L-carnitine transport in this cell type. L-Carnitine transport is mainly mediated by novel organic cation transporters 1 (Octn1, Na+-independent) and 2 (Octn2, Na+-dependent); however, their kinetic properties and potential consequences in hypertension are unknown. We hypothesize that L-carnitine transport kinetic properties will be altered in aortic endothelium from spontaneously hypertensive rats (SHR). L-Carnitine transport was measured at different extracellular pH (pHo 5.5–8.5) in the absence or presence of sodium in rat aortic endothelial cells (RAECs) from non-hypertensive Wistar-Kyoto (WKY) rats and SHR. Octn1 and Octn2 mRNA relative expression was also determined. Dilation of endothelium-intact or denuded aortic rings in response to calcitonine gene related peptide (CGRP, 0.1–100 nmol/L) was measured (myography) in the absence or presence of L-carnitine. Total L-carnitine transport was lower in cells from SHR compared with WKY rats, an effect due to reduced Na+-dependent (Na+ dep) compared with Na+-independent (Na+ indep) transport components. Saturable L-carnitine transport kinetics show maximal velocity (V max), without changes in apparent K m for Na+ indep transport in SHR compared with WKY rats. Total and Na+ dep component of transport were increased, but Na+ indep transport was reduced by extracellular alkalization in WKY rats. However, alkalization reduced total and Na+ indep transport in cells from SHR. Octn2 mRNA was higher than Octn-1 mRNA expression in cells from both conditions. Dilation of artery rings in response to CGRP was reduced in vessels from SHR compared with WKY rats. CGRP effect was endothelium-dependent and restored by L-carnitine. All together these results suggest that reduced

[Cellular uptake of TPS-L-carnitine synthesised as transporter-based renal targeting prodrug].

PubMed

Li, Li; Zhu, Di; Sun, Xun

2012-11-01

To synthesize transporter-based renal targeting prodrug TPS-L-Carnitine and to determine its cellular uptake in vitro. Triptolide (TP) was conjugated with L-carnitine using succinate as the linker to form TPS-L-Carnitine, which could be specifically recognized by OCTN2, a cationic transporter with high affinity to L-Carnitine and is highly expressed on the apical membrane of renal proximal tubule cells. Cellular uptake assays of the prodrug and its parent drug were performed on HK-2 cells, a human proximal tubule cell line, in different temperature, concentration and in the presence of competitive inhibitors. TPS-L-Carnitine was taken up into HK-2 cells in a saturable and temperature- and concentration-dependent manner. The uptake process could be inhibited by the competitive inhibitors. The uptake of TPS-L-Carnitine was significantly higher than that of TP at 37 degrees C in the same drug concentration. TPS-L-Carnitine was taken through endocytosis mediated by transporter. TPS-L-Carnitine provides a good renal targeting property and lays the foundation for further studies in vivo.

Acetyl-l-carnitine partially prevents benzene-induced hematotoxicity and oxidative stress in C3H/He mice.

PubMed

Sun, Rongli; Zhang, Juan; Wei, Haiyan; Meng, Xing; Ding, Qin; Sun, Fengxia; Cao, Meng; Yin, Lihong; Pu, Yuepu

2017-04-01

Benzene is an environmental pollutant and occupational toxicant which induces hematotoxicity. Our previous metabonomics study suggested that acetyl-l-carnitine (ALCAR) decreased in the mouse plasma and bone marrow (BM) cells due to benzene exposure. In the present study, the topic on whether ALCAR influences hematotoxicity caused by benzene exposure was explored. Thirty-two male C3H/He mice were divided into four groups: control group (C: vehicle, oil), benzene group (150mg/kg body weight (b.w.) benzene), benzene+A1 group (150mg/kg b.w. benzene+100mg/kg b.w. ALCAR), and benzene+A2 group (150mg/kg b.w. benzene+200mg/kg b.w. ALCAR). Benzene was injected subcutaneously, and ALCAR was orally administrated via gavage once daily for 4 weeks consecutively. After the experimental period, the blood routine, BM cell number and frequency of hematopoietic stem/progenitor cell (HS/PC) were assessed. The mitochondrial membrane potential and ATP level were determined to evaluate the mitochondrial function. Reactive oxygen species (ROS), hydrogen peroxide (H 2 O 2 ) and malondialdehyde (MDA) levels were also examined, and the comet assay was performed to measure oxidative stress. Results showed that ALCAR intervention can partially reduce the benzene-induced damage on BM and HS/PCs and can simultaneously alleviate the DNA damage by reducing benzene-induced H 2 O 2, ROS, and MDA. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of L-carnitine and coenzyme q10 on impaired spermatogenesis caused by isoproterenol in male rats.

PubMed

Ghanbarzadeh, S; Garjani, A; Ziaee, M; Khorrami, A

2014-09-01

Nowadays, cardiovascular diseases and male infertility are two big health problems in industrial countries.The aim of the present study was to investigate the protective role of coenzyme Q10 and L-Carnitine pretreatment in the impaired spermatogenesis caused by isoproterenol (ISO) in male rats.Thirty-two male Wistar rats were allocated in 4 groups. ISO was injected for 2 consecutive days (100 mg/kg) in ISO treated groups. Before ISO administration, pretreatment with Coenzyme Q10 (10 mg/kg/day) and L-Carnitine (350 mg/kg/day) were conducted for 20 consecutive days. Sex hormones level, malondialdehyde (MDA) and total antioxidant concentration as well as testis, epididymis and seminal vesicle weight were investigated.Increase in the concentration of MDA and decrease in total antioxidant level was observed following ISO administration. Accordingly, the sperm viability as well as testis, epididymis and seminal vesicle weights were decreased. In the case of sex hormones, the testosterone and LH levels were decreased and the concentration of FSH was increased. Pretreatment with L-carnitine and Coenzyme Q10 significantly decreased the MDA level and increased total antioxidant, LH and testosterone levels. Pretreatment with L-carnitine and Coenzyme Q10 also improved semen parameters and organs weight which were impaired by ISO administration.L-carnitine and Coenzyme Q10 pretreatment could protect spermatogenesis in male rats with ISO administration. © Georg Thieme Verlag KG Stuttgart · New York.

Protective effects of vitamins E, B and C and L-carnitine in the prevention of cisplatin-induced ototoxicity in rats.

PubMed

Tokgöz, S Alicura; Vuralkan, E; Sonbay, N D; Çalişkan, M; Saka, C; Beşalti, Ö; Akin, İ

2012-05-01

This experimental study aimed to investigate the effects of vitamins E, B and C and L-carnitine in preventing cisplatin-induced ototoxicity. Twenty-five adult, male, Wistar albino rats were randomly allocated to receive intraperitoneal cisplatin either alone or preceded by vitamins B, E or C or L-carnitine. Auditory brainstem response (i.e. hearing thresholds and wave I-IV intervals) and distortion product otoacoustic emissions (i.e. signal-to-noise ratios) were recorded before and 72 hours after cisplatin administration. The following statistically significant differences were seen: control group pre- vs post-treatment wave I-IV interval values (p < 0.05); control vs vitamin E and B groups' I-IV interval values (p < 0.05); control vs other groups' hearing thresholds; vitamin E vs vitamin B and C and L-carnitine groups' hearing thresholds (p < 0.05); and vitamin B vs vitamin C and L-carnitine groups' hearing thresholds (p < 0.05). Statistically significant decreases were seen when comparing the initial and final signal-to-noise ratios in the control, vitamin B and L-carnitine groups (2000 and 3000 Hz; p < 0.01), and the initial and final signal-to-noise ratios in the control group (at 4000 Hz; p < 0.01). Vitamins B, E and C and L-carnitine appear to reduce cisplatin-induced ototoxicity in rats. The use of such additional treatments to decrease cisplatin-induced ototoxicity in humans is still under discussion.

Acute administration of cefepime lowers L-carnitine concentrations in early lactation stage rat milk.

PubMed

Ling, Binbing; Alcorn, Jane

2008-07-01

Our study investigated the potential for important in vivo drug-nutrient transport interactions at the lactating mammary gland using the L-carnitine transporter substrates, cefepime and L-carnitine, as proof-of-concept. On d 4 (n = 6/treatment) and d 10 (n = 6/treatment) of lactation, rats were administered cefepime (250 mg/h) or saline by continuous i.v. infusion (4 h). Serum and milk L-carnitine and cefepime concentrations were quantified by HPLC-UV. In whole mammary gland, organic cation/carnitine transporter (OCTN)1, OCTN2, OCTN3, amino acid transporter B(0,+) (ATB(0,+)), and L-carnitine transporter 2 expression were determined by quantitative RT-PCR and by western blot and immunohistochemistry when possible. Cefepime caused a 56% decrease in milk L-carnitine concentrations on lactation d 4 (P = 0.0048) but did not affect milk L-carnitine at lactation d 10 or serum L-carnitine concentrations at either time. The mean L-carnitine and cefepime milk:serum ratios (M/S) decreased from 9.1 +/- 0.4 to 4.9 +/- 0.6 (P < 0.0001) and 0.89 +/- 0.3 to 0.12 +/- 0.02 (P = 0.0473), respectively, between d 4 and d 10 of lactation. In both groups, OCTN2 (P < 0.0001), OCTN3 (P = 0.0039), and ATB(0,+) (P = 0.004) mRNA expression and OCTN2 protein (P < 0.0001) were higher in mammary glands at d 4 of lactation compared with d 10. Immunohistochemistry revealed OCTN1 and OCTN2 localization in the mammary alveolar epithelium and OCTN3 expression in the interstitial space and blood vessel endothelium. In conclusion, cefepime significantly decreased milk L-carnitine concentrations only at d 4 of lactation. Relative to d 10, enhanced expression of OCTN2 and ATB(0,+) in mammary glands at d 4 of lactation and higher M/S (L-carnitine and cefepime) suggests cefepime competes with L-carnitine for L-carnitine transporters expressed in the lactating mammary gland to adversely affect L-carnitine milk concentrations and these effects depend upon lactation stage.

L-Carnitine suppresses oleic acid-induced membrane permeability transition of mitochondria.

PubMed

Oyanagi, Eri; Yano, Hiromi; Kato, Yasuko; Fujita, Hirofumi; Utsumi, Kozo; Sasaki, Junzo

2008-10-01

Membrane permeability transition (MPT) of mitochondria has an important role in apoptosis of various cells. The classic type of MPT is characterized by increased Ca(2+) transport, membrane depolarization, swelling, and sensitivity to cyclosporin A. In this study, we investigated whether L-carnitine suppresses oleic acid-induced MPT using isolated mitochondria from rat liver. Oleic acid-induced MPT in isolated mitochondria, inhibited endogenous respiration, caused membrane depolarization, and increased large amplitude swelling, and cytochrome c (Cyt. c) release from mitochondria. L-Carnitine was indispensable to beta-oxidation of oleic acid in the mitochondria, and this reaction required ATP and coenzyme A (CoA). In the presence of ATP and CoA, L-carnitine stimulated oleic acid oxidation and suppressed the oleic acid-induced depolarization, swelling, and Cyt. c release. L-Carnitine also contributed to maintaining mitochondrial function, which was decreased by the generation of free fatty acids with the passage of time after isolation. These results suggest that L-carnitine acts to maintain mitochondrial function and suppresses oleic acid-mediated MPT through acceleration of beta-oxidation. Copyright (c) 2008 John Wiley & Sons, Ltd.

Regulatory effect of acetyl-l-carnitine on expression of lenticular antioxidant and apoptotic genes in selenite-induced cataract.

PubMed

Elanchezhian, R; Sakthivel, M; Geraldine, P; Thomas, P A

2010-03-30

Differential expression of apoptotic genes has been demonstrated in selenite-induced cataract. Acetyl-l-carnitine (ALCAR) has been shown to prevent selenite cataractogenesis by maintaining lenticular antioxidant enzyme and redox system components at near normal levels and also by inhibiting lenticular calpain activity. The aim of the present experiment was to investigate the possibility that ALCAR also prevents selenite-induced cataractogenesis by regulating the expression of antioxidant (catalase) and apoptotic [caspase-3, early growth response protein-1 (EGR-1) and cytochrome c oxidase subunit I (COX-I)] genes. The experiment was conducted on 9-day-old Wistar rat pups, which were divided into normal, cataract-untreated and cataract-treated groups. Putative changes in gene expression in whole lenses removed from the rats were determined by measuring mRNA transcript levels of the four genes by RT-PCR analysis, using glyceraldehyde-3-phosphate dehydrogenase (GAPDH) as an internal control. The expression of lenticular caspase-3 and EGR-1 genes appeared to be upregulated, as inferred by detecting increased mRNA transcript levels, while that of COX-I and catalase genes appeared to be downregulated (lowered mRNA transcript levels) in the lenses of cataract-untreated rats. However, in rats treated with ALCAR, the lenticular mRNA transcript levels were maintained at near normal (control) levels. These results suggest that ALCAR may prevent selenite-induced cataractogenesis by preventing abnormal expression of lenticular genes governing apoptosis.

Protective effects of methanolic extract of Juglans regia L. leaf on streptozotocin-induced diabetic peripheral neuropathy in rats.

PubMed

Nasiry, Davood; Khalatbary, Ali Reza; Ahmadvand, Hassan; Talebpour Amiri, Fereshteh; Akbari, Esmaeil

2017-10-02

Oxidative stress has a pivotal role in the pathogenesis and development of diabetic peripheral neuropathy (DPN), the most common and debilitating complications of diabetes mellitus. There is accumulating evidence that Juglans regia L. (GRL) leaf extract, a rich source of phenolic components, has hypoglycemic and antioxidative properties. This study aimed to determine the protective effects of Juglans regia L. leaf extract against streptozotocin-induced diabetic neuropathy in rat. The DPN rat model was generated by intraperitoneal injection of a single 55 mg/kg dose of streptozotocin (STZ). A subset of the STZ-induced diabetic rats intragastically administered with GRL leaf extract (200 mg/kg/day) before or after the onset of neuropathy, whereas other diabetic rats received only isotonic saline as the same volume of GRL leaf extract. To evaluate the effects of GRL leaf extract on the diabetic neuropathy various parameters, including histopathology and immunohistochemistry of apoptotic and inflammatory factors were assessed along with nociceptive and biochemical assessments. Degeneration of the sciatic nerves which was detected in the STZ-diabetic rats attenuated after GRL leaf extract administration. Greater caspase-3, COX-2, and iNOS expression could be detected in the STZ-diabetic rats, which were significantly attenuated after GRL leaf extract administration. Also, attenuation of lipid peroxidation and nociceptive response along with improved antioxidant status in the sciatic nerve of diabetic rats were detected after GRL leaf extract administration. In other word, GRL leaf extract ameliorated the behavioral and structural indices of diabetic neuropathy even after the onset of neuropathy, in addition to blood sugar reduction. Our results suggest that GRL leaf extract exert preventive and curative effects against STZ-induced diabetic neuropathy in rats which might be due to its antioxidant, anti-inflammatory, and antiapoptotic properties. Protection against

Effect of in situ delivery of acetyl-L-carnitine on peripheral nerve regeneration and functional recovery in transected sciatic nerve in rat.

PubMed

Farahpour, Mohammad Reza; Ghayour, Sina Jangkhahe

2014-12-01

The repair of peripheral nerve injuries is still one of the most challenging tasks and concerns in neurosurgery, plastic and orthopedic surgery. Effect of acetyl-L-carnitine (ALC) loaded chitosan conduit as an in situ delivery system of ALC in bridging the defects was studied using a rat sciatic nerve regeneration model. A 10-mm sciatic nerve defect was bridged using a chitosan conduit (CHIT/ALC) filled with 10 μL ALC (100 ng/mL). In control group (CHIT), the conduit was filled with the same volume of the phosphate buffered solution. The regenerated fibers were studied 4, 8, 12 and 16 weeks after surgery. The functional and electrophysiological studies confirmed faster recovery of the regenerated axons in ALC treated than control group (P < 0.05). The mean ratios of gastrocnemius muscles weight were measured. There was statistically significant difference between the muscle weight ratios of CHIT/ALC and CHIT groups (P<0.05). Morphometric indices of regenerated fibers showed number and diameter of the myelinated fibers in CHIT/ALC were significantly higher than in control group. In immuohistochemistry, the location of reactions to S-100 in CHIT/ALC was clearly more positive than CHIT group. ALC when loaded in a chitosan conduit resulted in improvement of functional recovery and quantitative morphometric indices of sciatic nerve. Copyright © 2014 Surgical Associates Ltd. Published by Elsevier Ltd. All rights reserved.

L-Carnitine Supplementation Improves the Behavioral Symptoms in Autistic Children

ERIC Educational Resources Information Center

Fahmy, Sarah Farid; El-hamamsy, Manal H.; Zaki, Osama K.; Badary, Osama A.

2013-01-01

L-Carnitine was proposed as a potential treatment for patients diagnosed with autism to ameliorate the behavioral symptoms associated with the disease. Thirty children diagnosed with autism were randomly assigned to receive (100 mg/kg bodyweight/day) of liquid L-carnitine (n = 16) or placebo (n = 14) for 6 months. Measurements included changes in…

Acetyl-L-carnitine for alcohol craving and relapse prevention in anhedonic alcoholics: a randomized, double-blind, placebo-controlled pilot trial.

PubMed

Martinotti, Giovanni; Reina, Daniela; Di Nicola, Marco; Andreoli, Sara; Tedeschi, Daniela; Ortolani, Ilaria; Pozzi, Gino; Iannoni, Emerenziana; D'Iddio, Stefania; Janiri, Luigi

2010-01-01

The study aimed to evaluate the efficacy of acetyl-l-carnitine (ALC), at different doses, in relapse prevention and craving in anhedonic detoxified alcohol-dependent subjects. Randomized, double-blind, placebo-controlled, pilot study in 64 alcohol-dependent anhedonic patients: 23 received ALC at a dose of 3 g/day, 21 received ALC at a dosage of 1 g/day and 20 were given placebo. Intensity of alcohol craving was evaluated by Visual Analogue Scale. Subjects were evaluated at the beginning of treatment and after 10, 30, 60 and 90 days. Survival analysis showed that patients treated with ALC remained completely abstinent for longer than those treated with placebo (Z = -2.27; P < 0.05). From the 10th day onwards, a greater reduction of craving was observed in the ALC 1 g group than with placebo (P = 0.035). The two groups did not differ in the percentage of subjects remaining abstinent for the entire study period or the number of subjects who relapsed (defined as five or more standard drinks (four for women) on a single occasion or drinking on five or more days in 1 week). The results of this study suggest that ALC can reduce craving and the time to first drink. ALC use was safe. Further studies are needed to clarify to confirm, over longer periods, these short-term outcome benefits.

L-carnitine supplementation decreases the left ventricular mass in patients undergoing hemodialysis.

PubMed

Sakurabayashi, Tai; Miyazaki, Shigeru; Yuasa, Yasuko; Sakai, Shinji; Suzuki, Masashi; Takahashi, Sachio; Hirasawa, Yoshihei

2008-06-01

Patients on long-term hemodialysis become deficient in carnitine and are frequently treated with carnitine supplementation to offset their renal anemia, lipid abnormality and cardiac dysfunction. The therapeutic value of carnitine supplementation on left ventricular hypertrophy (LVH) in patients with normal cardiac systolic function remains uncertain. The cardiac morphology and function of 10 patients given 10 mg/kg of L-carnitine orally, immediately after hemodialysis sessions 3 times per week for a 12-month period were compared with 10 untreated control patients. Using echocardiography, left ventricular fractional shortening (LVFS) and left ventricular mass index (LVMI) were measured before and after the study period. As a result, amounts of serum-free carnitine increased from 28.4+/-4.7 to 58.5+/-12.1 micromol/L. The LVMI decreased significantly from 151.8+/-21.2 to 134.0+/-16.0 g/m(2) in treated patients (p<0.01), yet the LVMI in untreated control patients did not change significantly (ie, from 153.3+/-28.2 to 167.1+/-43.1 g/m(2)). However, LVFS values remained unchanged in both groups. Although L-carnitine promoted a 31% reduction in erythropoietin requirements, hematocrit and blood pressure did not change during the study period. Supplementation with L-carnitine induced regression of LVH in patients on hemodialysis, even for those with normal systolic function.

Effects of Oral L-Carnitine on Liver Functions after Transarterial Chemoembolization in Intermediate-Stage HCC Patients.

PubMed

Hassan, Abeer; Tsuda, Yasuhiro; Asai, Akira; Yokohama, Keisuke; Nakamura, Ken; Sujishi, Tetsuya; Ohama, Hideko; Tsuchimoto, Yusuke; Fukunishi, Shinya; Abdelaal, Usama M; Arafa, Usama A; Hassan, Ali T; Kassem, Ali M; Higuchi, Kazuhide

2015-01-01

Transarterial chemoembolization (TACE) is usually followed by hepatic dysfunction. We evaluated the effects of L-carnitine on post-TACE impaired liver functions. Methods. 53 cirrhotic hepatocellular carcinoma patients at Osaka Medical College were enrolled in this study and assigned into either L-carnitine group receiving 600 mg oral L-carnitine daily or control group. Liver functions were evaluated at pre-TACE and 1, 4, and 12 weeks after TACE. Results. The L-carnitine group maintained Child-Pugh (CP) score at 1 week after TACE and exhibited significant improvement at 4 weeks after TACE (P < 0.01). Conversely, the control group reported a significant CP score deterioration at 1 week (P < 0.05) and 12 weeks after TACE (P < 0.05). L-carnitine suppressed serum albumin deterioration at 1 week after TACE. There were significant differences between L-carnitine and control groups regarding mean serum albumin changes from baseline to 1 week (P < 0.05) and 4 weeks after TACE (P < 0.05). L-carnitine caused prothrombin time improvement from baseline to 1, 4 (P < 0.05), and 12 weeks after TACE. Total bilirubin mean changes from baseline to 1 week after TACE exhibited significant differences between L-carnitine and control groups (P < 0.05). The hepatoprotective effects of L-carnitine were enhanced by branched chain amino acids combination. Conclusion. L-carnitine maintained and improved liver functions after TACE.

L-carnitine reduces susceptibility to bupivacaine-induced cardiotoxicity: an experimental study in rats.

PubMed

Wong, Gail K; Pehora, Carolyne; Crawford, Mark W

2017-03-01

The primary aim of this study was to evaluate the effect of acute administration of L-carnitine 100 mg·kg -1 iv on susceptibility to bupivacaine-induced cardiotoxicity in rats. In the first of two experiments, L-carnitine 100 mg·kg -1 iv (n = 10) or saline iv (n = 10) was administered to anesthetized and mechanically ventilated Sprague-Dawley rats following which an infusion of bupivacaine 2.0 mg·kg -1 ·min -1 iv was given until asystole occurred. The primary outcome was the probability of survival. Secondary outcomes included times to asystole, first dysrhythmia, and to 50% reductions in heart rate (HR) and mean arterial pressure (MAP). To determine whether the same dose of L-carnitine is effective in treating established bupivacaine cardiotoxicity, we also conducted a second experiment in which bupivacaine 20 mg·kg -1 iv was infused over 20 sec. Animals (n = 10 per group) received one of four iv treatments: 30% lipid emulsion 4.0 mL·kg -1 , L-carnitine 100 mg·kg -1 , 30% lipid emulsion plus L-carnitine, or saline. The primary outcome was the return of spontaneous circulation (ROSC) during resuscitation. In the first study, L-carnitine 100 mg·kg -1 increased the probability of survival during bupivacaine infusion (hazard ratio, 12.0; 95% confidence interval, 3.5 to 41.5; P < 0.001). In L-carnitine-treated animals, the times to asystole, first dysrhythmia, and to 50% reductions in HR and MAP increased by 33% (P < 0.001), 65% (P < 0.001), 71% (P < 0.001), and 63% (P < 0.001), respectively. In the second study, no animal in the control or L-carnitine alone groups achieved ROSC when compared with the lipid emulsion groups (P < 0.01). These findings suggest that acute administration of L-carnitine 100 mg·kg -1 decreases susceptibility to bupivacaine cardiotoxicity, but is ineffective during resuscitation from bupivacaine-induced cardiac arrest.

Protection of rat skeletal muscle fibers by either L-carnitine or coenzyme Q10 against statins toxicity mediated by mitochondrial reactive oxygen generation

PubMed Central

La Guardia, P. G.; Alberici, L. C.; Ravagnani, F. G.; Catharino, R. R.; Vercesi, A. E.

2013-01-01

Mitochondrial redox imbalance has been implicated in mechanisms of aging, various degenerative diseases and drug-induced toxicity. Statins are safe and well-tolerated therapeutic drugs that occasionally induce myotoxicity such as myopathy and rhabdomyolysis. Previous studies indicate that myotoxicity caused by statins may be linked to impairment of mitochondrial functions. Here, we report that 1-h incubation of permeabilized rat soleus muscle fiber biopsies with increasing concentrations of simvastatin (1–40 μM) slowed the rates of ADP-or FCCP-stimulated respiration supported by glutamate/malate in a dose-dependent manner, but caused no changes in resting respiration rates. Simvastatin (1 μM) also inhibited the ADP-stimulated mitochondrial respiration supported by succinate by 24% but not by TMPD/ascorbate. Compatible with inhibition of respiration, 1 μM simvastatin stimulated lactate release from soleus muscle samples by 26%. Co-incubation of muscle samples with 1 mM L-carnitine, 100 μM mevalonate or 10 μM coenzyme Q10 (Co-Q10) abolished simvastatin effects on both mitochondrial glutamate/malate-supported respiration and lactate release. Simvastatin (1 μM) also caused a 2-fold increase in the rate of hydrogen peroxide generation and a decrease in Co-Q10 content by 44%. Mevalonate, Co-Q10 or L-carnitine protected against stimulation of hydrogen peroxide generation but only mevalonate prevented the decrease in Co-Q10 content. Thus, independently of Co-Q10 levels, L-carnitine prevented the toxic effects of simvastatin. This suggests that mitochondrial respiratory dysfunction induced by simvastatin, is associated with increased generation of superoxide, at the levels of complexes-I and II of the respiratory chain. In all cases the damage to these complexes, presumably at the level of 4Fe-4S clusters, is prevented by L-carnitine. PMID:23720630

CaiT of Escherichia coli, a new transporter catalyzing L-carnitine/gamma -butyrobetaine exchange.

PubMed

Jung, Heinrich; Buchholz, Marion; Clausen, Jurgen; Nietschke, Monika; Revermann, Anne; Schmid, Roland; Jung, Kirsten

2002-10-18

l-Carnitine is essential for beta-oxidation of fatty acids in mitochondria. Bacterial metabolic pathways are used for the production of this medically important compound. Here, we report the first detailed functional characterization of the caiT gene product, a putative transport protein whose function is required for l-carnitine conversion in Escherichia coli. The caiT gene was overexpressed in E. coli, and the gene product was purified by affinity chromatography and reconstituted into proteoliposomes. Functional analyses with intact cells and proteoliposomes demonstrated that CaiT is able to catalyze the exchange of l-carnitine for gamma-butyrobetaine, the excreted end product of l-carnitine conversion in E. coli, and related betaines. Electrochemical ion gradients did not significantly stimulate l-carnitine uptake. Analysis of l-carnitine counterflow yielded an apparent external K(m) of 105 microm and a turnover number of 5.5 s(-1). Contrary to related proteins, CaiT activity was not modulated by osmotic stress. l-Carnitine binding to CaiT increased the protein fluorescence and caused a red shift in the emission maximum, an observation explained by ligand-induced conformational alterations. The fluorescence effect was specific for betaine structures, for which the distance between trimethylammonium and carboxyl groups proved to be crucial for affinity. Taken together, the results suggest that CaiT functions as an exchanger (antiporter) for l-carnitine and gamma-butyrobetaine according to the substrate/product antiport principle.

Oleoyl-L-carnitine inhibits glycine transport by GlyT2

PubMed Central

Carland, JE; Mansfield, RE; Ryan, RM; Vandenberg, RJ

2013-01-01

Background and Purpose Concentrations of extracellular glycine in the CNS are regulated by two Na+/Cl–-dependent glycine transporters, GlyT1 and GlyT2. Selective inhibitors of GlyT1 have been developed for the treatment of schizophrenia, whilst selective inhibitors of GlyT2 are analgesic in animal models of pain. We have assessed a series of endogenous lipids as inhibitors of GlyT1 and GlyT2. Experimental Approach Human GlyT1 and GlyT2 were expressed in Xenopus laevis oocytes, and the inhibitory actions of a series of acylcarnitines on glycine transport were measured using electrophysiological techniques. Key Results Oleoyl-l-carnitine inhibited glycine transport by GlyT2, with an IC50 of 340 nM, which is 15-fold more potent than the previously identified lipid inhibitor N-arachidonyl-glycine. Oleoyl-l-carnitine had a slow onset of inhibition and a slow washout. Using a series of chimeric GlyT1/2 transporters and point mutant transporters, we have identified an isoleucine residue in extracellular loop 4 of GlyT2 that conferred differences in sensitivity to oleoyl-l-carnitine between GlyT2 and GlyT1. Conclusions and Implications Oleoyl-l-carnitine is a potent non-competitive inhibitor of GlyT2. Previously identified GlyT2 inhibitors show potential as analgesics and the identification of oleoyl-l-carnitine as a novel GlyT2 inhibitor may lead to new ways of treating pain. PMID:22978602

Effects of combination of sibutramine and L-carnitine compared with sibutramine monotherapy on inflammatory parameters in diabetic patients.

PubMed

Derosa, Giuseppe; Maffioli, Pamela; Salvadeo, Sibilla A T; Ferrari, Ilaria; Gravina, Alessia; Mereu, Roberto; D'Angelo, Angela; Palumbo, Ilaria; Randazzo, Sabrina; Cicero, Arrigo F G

2011-03-01

The aim of the study was to evaluate the effects of 12-month treatment with sibutramine plus L-carnitine compared with sibutramine alone on body weight, glycemic control, insulin resistance, and inflammatory state in type 2 diabetes mellitus patients. Two hundred fifty-four patients with uncontrolled type 2 diabetes mellitus (glycated hemoglobin [HbA(1c)] >8.0%) in therapy with different oral hypoglycemic agents or insulin were enrolled in this study and randomized to take sibutramine 10 mg plus L-carnitine 2 g or sibutramine 10 mg in monotherapy. We evaluated at baseline and after 3, 6, 9, and 12 months these parameters: body weight, body mass index, HbA(1c), fasting plasma glucose, postprandial plasma glucose, fasting plasma insulin, homeostasis model assessment of insulin resistance index, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, leptin, tumor necrosis factor-α, adiponectin, vaspin, and high-sensitivity C-reactive protein. Sibutramine plus L-carnitine gave a faster improvement of fasting plasma glucose, postprandial plasma glucose, lipid profile, leptin, tumor necrosis factor-α, and high-sensitivity C-reactive protein compared with sibutramine alone. Furthermore, there was a better improvement of body weight, HbA(1c), fasting plasma insulin, homeostasis model assessment of insulin resistance index, vaspin, and adiponectin with sibutramine plus L-carnitine compared with sibutramine alone. Sibutramine plus L-carnitine gave a better and faster improvement of all the analyzed parameters compared with sibutramine alone without giving any severe adverse effect. Copyright © 2011 Elsevier Inc. All rights reserved.

Evaluating effects of L-carnitine on human bone-marrow-derived mesenchymal stem cells.

PubMed

Fujisawa, Koichi; Takami, Taro; Fukui, Yumi; Quintanilha, Luiz Fernando; Matsumoto, Toshihiko; Yamamoto, Naoki; Sakaida, Isao

2017-05-01

Mesenchymal stem cells (MSCs) are multipotent cells showing potential for use in regenerative medicine. Culture techniques that are more stable and methods for the more efficient production of MSCs with therapeutic efficacy are needed. We evaluate the effects of growing bone marrow (Bm)-derived MSCs in the presence of L-carnitine, which is believed to promote lipid metabolism and to suppress apoptosis. The presence of L-carnitine decreased the degree of drug-induced apoptosis and suppressed adipogenic differentiation. Metabolomic analysis by means of the exhaustive investigation of metabolic products showed that, in addition to increased β-oxidation and the expression of all carnitine derivatives other than deoxycarnitine (an intermediate in carnitine synthesis), polysaturated and polyunsaturated acids were down-regulated. An integrated analysis incorporating both serial analysis of gene expression and metabolomics revealed increases in cell survival, suggesting the utility of carnitine. The addition of carnitine elevated the oxygen consumption rate by BmMSCs that had been cultured for only a few generations and those that had become senescent following repeated replication indicating that mitochondrial activation occurred. Our exhaustive analysis of the effects of various carnitine metabolites thus suggests that the addition of L-carnitine to BmMSCs during expansion enables efficient cell production.

Protective Effect of a Mitochondria-Targeted Peptide against the Development of Chemotherapy-Induced Peripheral Neuropathy in Mice.

PubMed

Toyama, Satoshi; Shimoyama, Naohito; Szeto, Hazel H; Schiller, Peter W; Shimoyama, Megumi

2018-04-18

Several chemotherapeutic agents used for cancer treatment induce dose-limiting peripheral neuropathy that compromises patients' quality of life and limits cancer treatment. Recently, mitochondrial dysfunction has been shown to be involved in the mechanism of chemotherapy-induced peripheral neuropathy. SS-20 is a mitochondria-targeted peptide that promotes mitochondrial respiration and restores mitochondrial bioenergetics. In the present study, we examined the protective effect of SS-20 against the development of chemotherapy-induced peripheral neuropathy utilizing a murine model of peripheral neuropathy induced by oxaliplatin, a first-line chemotherapy agent for colon cancer. Weekly administrations of oxaliplatin induced peripheral neuropathy as demonstrated by the development of neuropathic pain and loss of intraepidermal nerve fibers in the hind paw. Continuous administration of SS-20 protected against the development of oxaliplatin-induced neuropathic pain and mitigated the loss of intraepidermal nerve fibers to normal levels. Our findings suggest that SS-20 may be a drug candidate for the prevention of chemotherapy-induced peripheral neuropathy.

Carnitine

USDA-ARS?s Scientific Manuscript database

Carnitine (L-g-trimethylamino-ß-hydroxybutyrate) functions metabolically as a covalent molecular chaperone of acyl compounds esterified to its hydroxyl moiety (1,2). The quintessentialmetabolic function of L-carnitine is to shuttle long-chain FAs (LCFAs)2 across the inner mitochondrial membrane to t...

The effect of acetyl-L-carnitine and R-alpha-lipoic acid treatment in ApoE4 mouse as a model of human Alzheimer's disease.

PubMed

Shenk, Justin C; Liu, Jiankang; Fischbach, Kathryn; Xu, Kui; Puchowicz, Michel; Obrenovich, Mark E; Gasimov, Eldar; Alvarez, Ludis Morales; Ames, Bruce N; Lamanna, Joseph C; Aliev, Gjumrakch

2009-08-15

We measured age-dependent effects of human ApoE4 on cerebral blood flow (CBF) using ApoE4 transgenic mice compared to age-matched wild-type (WT) mice by use of [(14)C] iodoantipyrene autoradiography. ApoE4 associated factors reduce CBF gradually to create brain hypoperfusion when compared to WT, and the differences in CBF are greatest as animals age from 6-weeks to 12-months. Transmission electron microscopy with colloidal gold immunocytochemistry showed structural damage in young and aged microvessel endothelium of ApoE4 animals extended to the cytoplasm of perivascular cells, perivascular nerve terminals and hippocampal neurons and glial cells. These abnormalities coexist with mitochondrial structural alteration and mitochondrial DNA overproliferation and/or deletion in all brain cellular compartments. Spatial memory and temporal memory tests showed a trend in improving cognitive function in ApoE4 mice fed selective mitochondrial antioxidants acetyl-l-carnitine and R-alpha-lipoic acid. Our findings indicate that ApoE4 genotype-induced mitochondrial changes and associated structural damage may explain age-dependent pathology seen in AD, indicating potential for novel treatment strategies in the near future.

L-carnitine alleviates sciatic nerve crush injury in rats: functional and electron microscopy assessments

PubMed Central

Avsar, Ümmü Zeynep; Avsar, Umit; Aydin, Ali; Yayla, Muhammed; Ozturkkaragoz, Berna; Un, Harun; Saritemur, Murat; Mercantepe, Tolga

2014-01-01

Several studies have demonstrated that L-carnitine exhibits neuroprotective effects on injured sciatic nerve of rats with diabetes mellitus. It is hypothesized that L-carnitine exhibits neuroprotective effects on injured sciatic nerve of rats. Rat sciatic nerve was crush injured by a forceps and exhibited degenerative changes. After intragastric administration of 50 and 100 mg/kg L-carnitine for 30 days, axon area, myelin sheath area, axon diameter, myelin sheath diameter, and numerical density of the myelinated axons of injured sciatic nerve were similar to normal, and the function of injured sciatic nerve also improved significantly. These findings suggest that L-carnitine exhibits neuroprotective effects on sciatic nerve crush injury in rats. PMID:25206754

Effects of dietary L-carnitine and coenzyme Q10 supplementation on performance and ascites mortality of broilers.

PubMed

Geng, Ailian; Guo, Yuming; Yuan, Jianmin

2004-12-01

The study was conducted to determine the effects of dietary L-carnitine and coenzyme Q10 (CoQ10) supplementation on growth performance and ascites mortality of broilers. A 3 x 3 factorial arrangement was employed with three levels (0, 75 and 150 mg/kg) of L-carnitine and three levels of CoQ10 (0, 20 and 40 mg/kg) supplementation during the experiment. Five hundred and forty one-day-old Arbor Acre male broiler chicks were randomly allocated into nine groups with six replicates each. All birds were fed with the basal diets from day 1 to 7 and changed to the experimental diets from day 8. During day 15 to 21 all the birds were exposed to low ambient temperature (15-18 degrees C) to induce ascites. The results showed that under this condition, growth performance of broilers were not significantly affected by CoQ10 or L-carnitine + CoQ10 supplementation during week 0-3 and 0-6, but body weight gain (BWG) of broilers was significantly reduced by 150 mg/ kg L-carnitine during week 0-6. Packed cell volume (PCV) of broilers was significantly decreased by L-carnitine and L-carnitine + CoQ10 supplementation (P < 0.05). Erythrocyte osmotic fragility (EOF), ascites heart index (AHI) and ascites mortality of broilers were significantly decreased by L-carnitine, CoQ10 and L-carnitine + CoQ10 supplementation. Though no significant changes were observed in total antioxidative capability (T-AOC), total superoxide dismutase (T-SOD) was increased by L-carnitine, CoQ10 and L-carnitine + CoQ10 supplementation (P < 0.05). Malonaldehyde (MDA) content was significantly decreased by CoQ10 and L-carnitine + CoQ10 supplementation. The results indicate that dietary L-carnitine and CoQ10 supplementation reduce ascites mortality of broilers; the reason may be partially associated with their antioxidative effects.

Carnitine prevents the early mitochondrial damage induced by methylglyoxal bis(guanylhydrazone) in L1210 leukaemia cells.

PubMed

Nikula, P; Ruohola, H; Alhonen-Hongisto, L; Jänne, J

1985-06-01

We previously found that the anti-cancer drug methylglyoxal bis(guanylhydrazone) (mitoguazone) depresses carnitine-dependent oxidation of long-chain fatty acids in cultured mouse leukaemia cells [Nikula, Alhonen-Hongisto, Seppänen & Jänne (1984) Biochem. Biophys. Res. Commun. 120, 9-14]. We have now investigated whether carnitine also influences the development of the well-known mitochondrial damage produced by the drug in L1210 leukaemia cells. Palmitate oxidation was distinctly inhibited in tumour cells exposed to 5 microM-methylglyoxal bis(guanylhydrazone) for only 7 h. Electron-microscopic examination of the drug-exposed cells revealed that more than half of the mitochondria were severely damaged. Similar exposure of the leukaemia cells to the drug in the presence of carnitine not only abolished the inhibition of fatty acid oxidation but almost completely prevented the drug-induced mitochondrial damage. The protection provided by carnitine appeared to depend on the intracellular concentration of methylglyoxal bis(guanylhydrazone), since the mitochondria-sparing effect disappeared at higher drug concentrations.

γ–Butyrobetaine is a pro-atherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO

PubMed Central

Koeth, Robert A.; Levison, Bruce S.; Culley, Miranda K.; Buffa, Jennifer A.; Wang, Zeneng; Gregory, Jill C.; Org, Elin; Wu, Yuping; Li, Lin; Smith, Jonathan D.; Wilson Tang, W. H.; DiDonato, Joseph A.; Lusis, Aldons J.; Hazen, Stanley L.

2014-01-01

Summary L- Carnitine, a nutrient in red meat, was recently reported to accelerate atherosclerosis via a metaorganismal pathway involving gut microbial trimethylamine (TMA) formation and host hepatic conversion into trimethylamine-N-oxide (TMAO). Herein we show that following L-carnitine ingestion, γ-butyrobetaine (γBB) is produced as an intermediary metabolite by gut microbes at a site anatomically proximal to and at a rate ~1000-fold higher than the formation of TMA. Moreover, we show γBB is the major gut microbial metabolite formed from dietary L-carnitine in mice, and like dietary L-carnitine, in a gut microbiota-dependent manner is converted into TMA and TMAO, and accelerates atherosclerosis. Gut microbial composition and functional metabolic studies reveal distinct taxa are associated with the production of γBB versus TMA/TMAO from dietary L-carnitine. Moreover, despite their close structural similarity, chronic dietary exposure to L-carnitine versus γBB promotes development of functionally distinct microbial communities optimized for the metabolism of L-carnitine versus γBB, respectively. PMID:25440057

Acetyl-L-carnitine supplementation to old rats partially reverts the age-related mitochondrial decay of soleus muscle by activating peroxisome proliferator-activated receptor gamma coactivator-1alpha-dependent mitochondrial biogenesis.

PubMed

Pesce, Vito; Fracasso, Flavio; Cassano, Pierluigi; Lezza, Angela Maria Serena; Cantatore, Palmiro; Gadaleta, Maria Nicola

2010-01-01

The age-related decay of mitochondrial function is a major contributor to the aging process. We tested the effects of 2-month-daily acetyl-L-carnitine (ALCAR) supplementation on mitochondrial biogenesis in the soleus muscle of aged rats. This muscle is heavily dependent on oxidative metabolism. Mitochondrial (mt) DNA content, citrate synthase activity, transcript levels of some nuclear- and mitochondrial-coded genes (cytochrome c oxidase subunit IV [COX-IV], 16S rRNA, COX-I) and of some factors involved in the mitochondrial biogenesis signaling pathway (peroxisome proliferator-activated receptor gamma [PPARgamma] coactivator-1alpha [PGC-1alpha], mitochondrial transcription factor A mitochondrial [TFAM], mitochondrial transcription factor 2B [TFB2]), as well as the protein content of PGC-1alpha were determined. The results suggest that the ALCAR treatment in old rats activates PGC-1alpha-dependent mitochondrial biogenesis, thus partially reverting the age-related mitochondrial decay.

Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis

PubMed Central

Koeth, Robert A.; Wang, Zeneng; Levison, Bruce S.; Buffa, Jennifer A.; Org, Elin; Sheehy, Brendan T.; Britt, Earl B.; Fu, Xiaoming; Wu, Yuping; Li, Lin; Smith, Jonathan D.; DiDonato, Joseph A.; Chen, Jun; Li, Hongzhe; Wu, Gary D.; Lewis, James D.; Warrier, Manya; Brown, J. Mark; Krauss, Ronald M.; Tang, W. H. Wilson; Bushman, Frederic D.; Lusis, Aldons J.; Hazen, Stanley L.

2013-01-01

Intestinal microbiota metabolism of choline/phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). Herein we demonstrate that intestinal microbiota metabolism of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis. Omnivorous subjects are shown to produce significantly more TMAO than vegans/vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. Specific bacterial taxa in human feces are shown to associate with both plasma TMAO and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predict increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (MI, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice significantly altered cecal microbial composition, markedly enhanced synthesis of TMA/TMAO, and increased atherosclerosis, but not following suppression of intestinal microbiota. Dietary supplementation of TMAO, or either carnitine or choline in mice with intact intestinal microbiota, significantly reduced reverse cholesterol transport in vivo. Intestinal microbiota may thus participate in the well-established link between increased red meat consumption and CVD risk. PMID:23563705

Natural zwitterionic l-Carnitine as efficient cryoprotectant for solvent-free cell cryopreservation.

PubMed

Zhai, Hongwen; Yang, Jing; Zhang, Jiamin; Pan, Chao; Cai, Nana; Zhu, Yingnan; Zhang, Lei

2017-07-15

Organic solvents, such as dimethyl sulfoxide (DMSO) and glycerol, have been commonly used as cryoprotectants (CPAs) in cell cryopreservation. However, their cytotoxicity and need of complex freezing protocols have impeded their applications especially in clinical cell therapy and regenerative medicine. Trehalose has been explored as a natural CPA to cryopreserve cells, but its poor cell permeability frequently results in low cryopreservation efficacy. In this work, we presented that a natural zwitterionic molecule-l-carnitine-could serve as a promising CPA for solvent-free cryopreservation. We demonstrated that l-carnitine possessed strong ability to depress water freezing point, and with ultrarapid freezing protocol, we studied the post-thaw survival efficiency of four cell lines (GLC-82 cells, MCF-7 cells, NIH-3T3 cells and Sheep Red Blood Cells) using l-carnitine without addition of any organic solvents. At the optimum l-carnitine concentration, all four cell lines could achieve above 80% survival efficiency, compared with the significantly lower efficiency using organic CPAs and trehalose. After cryopreservation, the recovered cell behaviors including cell attachment and proliferation were found to be similar to the normal cells, indicating that the cell functionalities were not affected. Moreover, l-carnitine showed no observable cytotoxicity, which was superior to the organic CPAs. This work offered an attractive alternative to traditional CPAs and held great promise to revolutionize current cryopreservation technologies, to benefit the patients in various cell-based clinical applications. Copyright © 2017 Elsevier Inc. All rights reserved.

Muscle-specific Deletion of Carnitine Acetyltransferase Compromises Glucose Tolerance and Metabolic Flexibility

PubMed Central

Muoio, Deborah M.; Noland, Robert C.; Kovalik, Jean-Paul; Seiler, Sarah E.; Davies, Michael N.; DeBalsi, Karen L.; Ilkayeva, Olga R.; Stevens, Robert D.; Kheterpal, Indu; Zhang, Jingying; Covington, Jeffrey D.; Bajpeyi, Sudip; Ravussin, Eric; Kraus, William; Koves, Timothy R.; Mynatt, Randall L.

2012-01-01

Summary The concept of “metabolic inflexibility” was first introduced to describe the failure of insulin resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing recognition as a core component of the metabolic syndrome, but the underlying mechanisms have remained elusive. Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance. By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking. Studies in muscle-specific Crat knockout mice, primary human skeletal myocytes and human subjects undergoing L-carnitine supplementation support a model wherein CrAT combats nutrient stress, promotes metabolic flexibility and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility. PMID:22560225

Muscle-specific deletion of carnitine acetyltransferase compromises glucose tolerance and metabolic flexibility.

PubMed

Muoio, Deborah M; Noland, Robert C; Kovalik, Jean-Paul; Seiler, Sarah E; Davies, Michael N; DeBalsi, Karen L; Ilkayeva, Olga R; Stevens, Robert D; Kheterpal, Indu; Zhang, Jingying; Covington, Jeffrey D; Bajpeyi, Sudip; Ravussin, Eric; Kraus, William; Koves, Timothy R; Mynatt, Randall L

2012-05-02

The concept of "metabolic inflexibility" was first introduced to describe the failure of insulin-resistant human subjects to appropriately adjust mitochondrial fuel selection in response to nutritional cues. This phenomenon has since gained increasing recognition as a core component of the metabolic syndrome, but the underlying mechanisms have remained elusive. Here, we identify an essential role for the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT), in regulating substrate switching and glucose tolerance. By converting acetyl-CoA to its membrane permeant acetylcarnitine ester, CrAT regulates mitochondrial and intracellular carbon trafficking. Studies in muscle-specific Crat knockout mice, primary human skeletal myocytes, and human subjects undergoing L-carnitine supplementation support a model wherein CrAT combats nutrient stress, promotes metabolic flexibility, and enhances insulin action by permitting mitochondrial efflux of excess acetyl moieties that otherwise inhibit key regulatory enzymes such as pyruvate dehydrogenase. These findings offer therapeutically relevant insights into the molecular basis of metabolic inflexibility. Copyright © 2012 Elsevier Inc. All rights reserved.

Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis.

PubMed

Koeth, Robert A; Wang, Zeneng; Levison, Bruce S; Buffa, Jennifer A; Org, Elin; Sheehy, Brendan T; Britt, Earl B; Fu, Xiaoming; Wu, Yuping; Li, Lin; Smith, Jonathan D; DiDonato, Joseph A; Chen, Jun; Li, Hongzhe; Wu, Gary D; Lewis, James D; Warrier, Manya; Brown, J Mark; Krauss, Ronald M; Tang, W H Wilson; Bushman, Frederic D; Lusis, Aldons J; Hazen, Stanley L

2013-05-01

Intestinal microbiota metabolism of choline and phosphatidylcholine produces trimethylamine (TMA), which is further metabolized to a proatherogenic species, trimethylamine-N-oxide (TMAO). We demonstrate here that metabolism by intestinal microbiota of dietary L-carnitine, a trimethylamine abundant in red meat, also produces TMAO and accelerates atherosclerosis in mice. Omnivorous human subjects produced more TMAO than did vegans or vegetarians following ingestion of L-carnitine through a microbiota-dependent mechanism. The presence of specific bacterial taxa in human feces was associated with both plasma TMAO concentration and dietary status. Plasma L-carnitine levels in subjects undergoing cardiac evaluation (n = 2,595) predicted increased risks for both prevalent cardiovascular disease (CVD) and incident major adverse cardiac events (myocardial infarction, stroke or death), but only among subjects with concurrently high TMAO levels. Chronic dietary L-carnitine supplementation in mice altered cecal microbial composition, markedly enhanced synthesis of TMA and TMAO, and increased atherosclerosis, but this did not occur if intestinal microbiota was concurrently suppressed. In mice with an intact intestinal microbiota, dietary supplementation with TMAO or either carnitine or choline reduced in vivo reverse cholesterol transport. Intestinal microbiota may thus contribute to the well-established link between high levels of red meat consumption and CVD risk.

[Therapy of arrhythmia induced by myocardial ischemia. Association of L-carnitine, propafenone and mexiletine].

PubMed

Mondillo, S; Faglia, S; D'Aprile, N; Mangiacotti, L; Campolo, M A; Agricola, E; Palazzuoli, V

1995-12-01

To assess the anti-arrythmic effect of L-carnitina, propafenone and mexiletine, we tested the drugs in 50 patients with effort angina and ventricular ectopic beats (VEB). The patients were randomized in 5 groups: Group A: was treated with oral L-carnitine at the dose of 2 g x 3 for two weeks. Group B: oral propafenone at the dose of 300 mg x 3 for two weeks. Group C: as group B+L-carnitine+g x 3 at the second weeks. Group D: oral mexiletine at the dose of 200 mg x 3 for two weeks. Group E: as group D+L-carnitine 2 gr x 3 at the second week. After 7 and 14 days of treatment, in all patients an Holter examination was performed. Our results show that L-carnitine exerts a significant reduction of the VEB and its administration potentiates the anti-arrythmic effect of propafenone and mexiletine.

The effect of fermented buckwheat on producing l-carnitine- and γ-aminobutyric acid (GABA)-enriched designer eggs.

PubMed

Park, Namhyeon; Lee, Tae-Kyung; Nguyen, Thi Thanh Hanh; An, Eun-Bae; Kim, Nahyun M; You, Young-Hyun; Park, Tae-Sub; Kim, Doman

2017-07-01

The potential of fermented buckwheat as a feed additive was studied to increase l-carnitine and γ-aminobutyric acid (GABA) in designer eggs. Buckwheat contains high levels of lysine, methionine and glutamate, which are precursors for the synthesis of l-carnitine and GABA. Rhizopus oligosporus was used for the fermentation of buckwheat to produce l-carnitine and GABA that exert positive effects such as enhanced metabolism, antioxidant activities, immunity and blood pressure control. A novel analytical method for simultaneously detecting l-carnitine and GABA was developed using liquid chromatography/mass spectrometry (LC/MS) and LC/MS/MS. The fermented buckwheat extract contained 4 and 34 times more l-carnitine and GABA respectively compared with normal buckwheat. Compared with the control, the fermented buckwheat extract-fed group showed enriched l-carnitine (13.6%) and GABA (8.4%) in the yolk, though only l-carnitine was significantly different (P < 0.05). Egg production (9.4%), albumen weight (2.1%) and shell weight (5.8%) were significantly increased (P < 0.05). There was no significant difference in yolk weight, and total cholesterol (1.9%) and triglyceride (4.9%) in the yolk were lowered (P < 0.05). Fermented buckwheat as a feed additive has the potential to produce l-carnitine- and GABA-enriched designer eggs with enhanced nutrition and homeostasis. These designer eggs pose significant potential to be utilized in superfood production and supplement industries. © 2016 Society of Chemical Industry. © 2016 Society of Chemical Industry.

L-carnitine mitigates UVA-induced skin tissue injury in rats through downregulation of oxidative stress, p38/c-Fos signaling, and the proinflammatory cytokines.

PubMed

Salama, Samir A; Arab, Hany H; Omar, Hany A; Gad, Hesham S; Abd-Allah, Gamil M; Maghrabi, Ibrahim A; Al Robaian, Majed M

2018-04-01

UVA comprises more than 90% of the solar UV radiation reaching the Earth. Artificial lightening lamps have also been reported to emit significant amounts of UVA. Exposure to UVA has been associated with dermatological disorders including skin cancer. At the molecular level, UVA damages different cellular biomolecules and triggers inflammatory responses. The current study was devoted to investigate the potential protective effect of L-carnitine against UVA-induced skin tissue injury using rats as a mammalian model. Rats were distributed into normal control group (NC), L-carnitine control group (LC), UVA-Exposed group (UVA), and UVA-Exposed and L-carnitine-treated group (UVA-LC). L-carnitine significantly attenuated UVA-induced elevation of the DNA damage markers 8-oxo-2'-deoxyguanosine (8-oxo-dG) and cyclobutane pyrimidine dimers (CPDs) as well as decreased DNA fragmentation and the activity of the apoptotic marker caspase-3. In addition, L-carnitine substantially reduced the levels of lipid peroxidation marker (TBARS) and protein oxidation marker (PCC) and significantly elevated the levels of the total antioxidant capacity (TAC) and the antioxidant reduced glutathione (GSH) in the skin tissues. Interestingly, L-carnitine upregulated the level of the DNA repair protein proliferating cell nuclear antigen (PCNA). Besides it mitigated the UVA-induced activation of the oxidative stress-sensitive signaling protein p38 and its downstream target c-Fos. Moreover, L-carnitine significantly downregulated the levels of the early response proinflammatory cytokines TNF-α, IL-6, and IL-1β. Collectively, our results highlight, for the first time, the potential attenuating effects of L-carnitine on UVA-induced skin tissue injury in rats that is potentially mediated through suppression of UVA-induced oxidative stress and inflammatory responses. Copyright © 2018 Elsevier B.V. All rights reserved.

Carnitine prevents the early mitochondrial damage induced by methylglyoxal bis(guanylhydrazone) in L1210 leukaemia cells.

PubMed Central

Nikula, P; Ruohola, H; Alhonen-Hongisto, L; Jänne, J

1985-01-01

We previously found that the anti-cancer drug methylglyoxal bis(guanylhydrazone) (mitoguazone) depresses carnitine-dependent oxidation of long-chain fatty acids in cultured mouse leukaemia cells [Nikula, Alhonen-Hongisto, Seppänen & Jänne (1984) Biochem. Biophys. Res. Commun. 120, 9-14]. We have now investigated whether carnitine also influences the development of the well-known mitochondrial damage produced by the drug in L1210 leukaemia cells. Palmitate oxidation was distinctly inhibited in tumour cells exposed to 5 microM-methylglyoxal bis(guanylhydrazone) for only 7 h. Electron-microscopic examination of the drug-exposed cells revealed that more than half of the mitochondria were severely damaged. Similar exposure of the leukaemia cells to the drug in the presence of carnitine not only abolished the inhibition of fatty acid oxidation but almost completely prevented the drug-induced mitochondrial damage. The protection provided by carnitine appeared to depend on the intracellular concentration of methylglyoxal bis(guanylhydrazone), since the mitochondria-sparing effect disappeared at higher drug concentrations. Images Fig. 1. PMID:3837667

Heart dysfunction induced by choline-deficiency in adult rats: the protective role of L-carnitine.

PubMed

Strilakou, Athina A; Lazaris, Andreas C; Perelas, Apostolos I; Mourouzis, Iordanis S; Douzis, Ioannis Ch; Karkalousos, Petros L; Stylianaki, Aikaterini Th; Pantos, Costas I; Liapi, Charis A

2013-06-05

Choline is a B vitamin co-factor and its deficiency seems to impair heart function. Carnitine, a chemical analog of choline, has been used as adjunct in the management of cardiac diseases. The study investigates the effects of choline deficiency on myocardial performance in adult rats and the possible modifications after carnitine administration. Wistar Albino rats (n=24), about 3 months old, were randomized into four groups fed with: (a) standard diet (control-CA), (b) choline deficient diet (CDD), (c) standard diet and carnitine in drinking water 0.15% w/v (CARN) and (d) choline deficient diet and carnitine (CDD+CARN). After four weeks of treatment, we assessed cardiac function under isometric conditions using the Langendorff preparations [Left Ventricular Developed Pressure (LVDP-mmHg), positive and negative first derivative of LVDP were evaluated], measured serum homocysteine and brain natriuretic peptide (BNP) levels and performed histopathology analyses. In the CDD group a compromised myocardium contractility compared to control (P=0.01), as assessed by LVDP, was noted along with a significantly impaired diastolic left ventricular function, as assessed by (-) dp/dt (P=0.02) that were prevented by carnitine. Systolic force, assessed by (+) dp/dt, showed no statistical difference between groups. A significant increase in serum BNP concentration was found in the CDD group (P<0.004) which was attenuated by carnitine (P<0.05), whereas homocysteine presented contradictory results (higher in the CDD+CARN group). Heart histopathology revealed a lymphocytic infiltration of myocardium and valves in the CDD group that was reduced by carnitine. In conclusion, choline deficiency in adult rats impairs heart performance; carnitine acts against these changes. Copyright © 2013 Elsevier B.V. All rights reserved.

The inhibitory effects of fluoroquinolones on L-carnitine transport in placental cell line BeWo.

PubMed

Hirano, Takeshi; Yasuda, Satoru; Osaka, Yuki; Asari, Masaru; Kobayashi, Masaki; Itagaki, Shirou; Iseki, Ken

2008-03-03

L-Carnitine plays an important role in lipid metabolism by facilitating the transport of long-chain fatty acids across the mitochondrial inner membrane followed by fatty acid beta-oxidation. It is known that members of the OCTN family play an important role in L-carnitine transport in the placenta. Investigation of drug-drug or drug-nutrient interaction in the placenta is important for establishment of safety drug medication during pregnancy. The aim of this study was to determine the effects of fluoroquinolones, inhibitors of OCTN2, on L-carnitine transport in the placenta which is known to have a high expression level of OCTN2. We investigated the inhibitory effect of five fluoroquinolones, ciprofloxacin (CPFX), gatifloxacin (GFLX), ofloxacin (OFLX), levofloxacin (LVFX) and grepafloxacin (GPFX), on L-carnitine transport mediated by OCTN2 in placental cell line BeWo cells. We found that all of the fluoroquinolones inhibited L-carnitine transport, GPFX being the strongest inhibitor. We also found that the inhibitory effects of LVFX and GPFX depended on their existence ratio of zwitterionic forms as, we reported previously. Furthermore, we elucidated the LVFX transport mechanism in BeWo cells. LVFX was transported actively by transporters. However, we found that LVFX transport was Na+-independent and l-carnitine had no inhibitory effect on LVFX transport, suggesting that LVFX acts as inhibitor of OCTN2, not as a substrate for OCTN2.

Carnitine supplementation and depletion: tissue carnitines and enzymes in fatty acid oxidation.

PubMed

Negrao, C E; Ji, L L; Schauer, J E; Nagle, F J; Lardy, H A

1987-07-01

Sixty-two male rats were randomly assigned into a 3 X 2 X 2 factorial design containing 12 groups according to carnitine treatment, exercise training (treadmill, 1 h, 5 times/wk, 8 wk, 26.8 m/min, 15% grade), and physical activity [rested for 60 h before they were killed or with an acute bout of exercise (1 h, 26.8 m/min, 15% grade) immediately before they were killed]. Isotonic saline was injected intraperitoneally 5 times/wk in the controls, whereas 750 mg/kg of L- or D-carnitine, respectively, were injected in the supplemented and depleted treatment groups. A significant increase in free and short-chain acyl carnitine concentration in skeletal muscle and heart was observed in L-carnitine supplemented rats, whereas a significant reduction in skeletal muscle, heart, and liver occurred in rats depleted of L-carnitine. Long-chain acyl carnitine in all tissues was not altered by carnitine treatment; training increased plasma and liver concentrations, whereas acute exercise decreased skeletal muscle and increased liver concentrations. An acute bout of exercise significantly increased short-chain acylcarnitine in liver, regardless of carnitine and/or training effects. beta-Hydroxyacyl-CoA dehydrogenase activity in skeletal muscle was induced by training but reduced by depletion. Carnitine acetyltransferase (CAT) was significantly increased in heart by L-carnitine supplementation, whereas it was reduced by depletion in skeletal muscle. Exercise training significantly increased CAT activity in skeletal muscle but not in heart, whereas acute exercise significantly increased activity in both tissues. Carnitine palmitoyltransferase activity was increased by acute exercise in the heart in only the supplemented and exercise-trained rats.

Deciphering the potential efficacy of acetyl-L-carnitine (ALCAR) in maintaining connexin-mediated lenticular homeostasis

PubMed Central

Muralidharan, Arumugam Ramachandran; Leema, George; Annadurai, Thangaraj; Anitha, Thirugnanasambandhar Sivasubramanian; Thomas, Philip A.

2012-01-01

Purpose To determine the putative role of acetyl-L-carnitine (ALCAR) in maintaining normal intercellular communication in the lens through connexin. Methods In the present study, Wistar rat pups were divided into 3 groups of eight each. On postpartum day ten, Group I rat pups received an intraperitoneal injection (50 µl) of 0.89% saline. Rats in Groups II and III received a subcutaneous injection (50 µl) of sodium selenite (19 µmol/kg bodyweight); Group III rat pups also received an intraperitoneal injection of ALCAR (200 mg/kg bodyweight) once daily on postpartum days 9–14. Both eyes of each pup were examined from day 16 up to postpartum day 30. Alterations in the mean activity of the channel pumps, calcium-ATPase and sodium/potassium-ATPase, were determined. The expression of genes encoding key lenticular gap junctions (connexin 46 and connexin 50) and a channel pump (plasma membrane Ca2+-ATPase [PMCA1]) was evaluated by reverse transcription-PCR. Immunoblot analysis was also performed to confirm the differential expression of key lenticular connexin proteins. In addition, bioinformatics analysis was performed to determine the interacting residues of the connexin proteins with ALCAR. Results Significantly lower mean activities of Ca2+-ATPase and Na+/K+ -ATPase were observed in the lenses of Group II rats than those in Group I rat lenses. However, the observed mean activities of Ca2+-ATPase and Na+/K+-ATPase in Group III rat lenses were significantly higher than those in Group II rat lenses. The mean mRNA transcript levels of the connexin 46 and connexin 50 genes were significantly lower, while the mean levels of PMCA1 gene transcripts were significantly higher, in Group II rat lenses than in Group I rat lenses. Immunoblot analysis also confirmed the altered expression of connexin proteins in lysates of whole lenses of Group II rats. However, the expression of connexin 46 and connexin 50 proteins in lenses from group III rats was essentially similar to that

Deciphering the potential efficacy of acetyl-L-carnitine (ALCAR) in maintaining connexin-mediated lenticular homeostasis.

PubMed

Muralidharan, Arumugam Ramachandran; Leema, George; Annadurai, Thangaraj; Anitha, Thirugnanasambandhar Sivasubramanian; Thomas, Philip A; Geraldine, Pitchairaj

2012-01-01

To determine the putative role of acetyl-L-carnitine (ALCAR) in maintaining normal intercellular communication in the lens through connexin. In the present study, Wistar rat pups were divided into 3 groups of eight each. On postpartum day ten, Group I rat pups received an intraperitoneal injection (50 µl) of 0.89% saline. Rats in Groups II and III received a subcutaneous injection (50 µl) of sodium selenite (19 µmol/kg bodyweight); Group III rat pups also received an intraperitoneal injection of ALCAR (200 mg/kg bodyweight) once daily on postpartum days 9-14. Both eyes of each pup were examined from day 16 up to postpartum day 30. Alterations in the mean activity of the channel pumps, calcium-ATPase and sodium/potassium-ATPase, were determined. The expression of genes encoding key lenticular gap junctions (connexin 46 and connexin 50) and a channel pump (plasma membrane Ca(2+)-ATPase [PMCA1]) was evaluated by reverse transcription-PCR. Immunoblot analysis was also performed to confirm the differential expression of key lenticular connexin proteins. In addition, bioinformatics analysis was performed to determine the interacting residues of the connexin proteins with ALCAR. Significantly lower mean activities of Ca(2+)-ATPase and Na(+)/K(+) -ATPase were observed in the lenses of Group II rats than those in Group I rat lenses. However, the observed mean activities of Ca(2+)-ATPase and Na(+)/K(+)-ATPase in Group III rat lenses were significantly higher than those in Group II rat lenses. The mean mRNA transcript levels of the connexin 46 and connexin 50 genes were significantly lower, while the mean levels of PMCA1 gene transcripts were significantly higher, in Group II rat lenses than in Group I rat lenses. Immunoblot analysis also confirmed the altered expression of connexin proteins in lysates of whole lenses of Group II rats. However, the expression of connexin 46 and connexin 50 proteins in lenses from group III rats was essentially similar to that noted in

Effects of metabolic modifiers such as carnitines, coenzyme Q10, and PUFAs against different forms of neurotoxic insults: metabolic inhibitors, MPTP, and methamphetamine.

PubMed

Virmani, Ashraf; Gaetani, Franco; Binienda, Zbigniew

2005-08-01

A number of strategies using the nutritional approach are emerging for the protection of the brain from damage caused by metabolic toxins, age, or disease. Neural dysfunction and metabolic imbalances underlie many diseases, and the inclusion of metabolic modifiers may provide an alternative and early intervention approach that may prevent further damage. Various models have been developed to study the impact of metabolism on brain function. These have also proven useful in expanding our understanding of neurodegeneration processes. For example, the metabolic compromise induced by inhibitors such as 3-nitropropionic acid (3-NPA), rotenone, and 1-methyl-4-phenylpyridinium (MPP+) can cause neurodegeneration in animal models and these models are thought to simulate the processes that may lead to diseases such as Huntington's and Parkinson's diseases. These inhibitors of metabolism are thought to selectively kill neurons by inhibiting various mitochondrial enzymes. However, the eventual cell death is attributed to oxidative stress damage of selectively vulnerable cells, especially highly differentiated neurons. Various studies indicate that the neurotoxicity resulting from these types of metabolic compromise is related to mitochondrial dysfunction and may be ameliorated by metabolic modifiers such as L-carnitine (L-C), creatine, and coenzyme Q10, as well as by antioxidants such as lipoic acid, vitamin E, and resveratrol. Mitochondrial function and cellular metabolism are also affected by the dietary intake of essential polyunsaturated fatty acids (PUFAs), which may regulate membrane composition and influence cellular processes, especially the inflammatory pathways. Cellular metabolic function may also be ameliorated by caloric restriction diets. L-C is a naturally occurring quaternary ammonium compound that is a vital cofactor for the mitochondrial entry and oxidation of fatty acids. Any factors affecting L-C levels may also affect ATP levels. This endogenous compound

Synthesis and biological activity of acetyl-protected hydroxybenzyl diethyl phosphates (EHBP) as potential chemotherapeutic agents.

PubMed

Kodela, Ravinder; Chattopadhyay, Mitali; Nath, Niharika; Cieciura, Lucyna Z; Pospishill, Liliya; Boring, Daniel; Crowell, James A; Kashfi, Khosrow

2011-12-01

Several acetyl-protected hydroxybenzyl diethyl phosphates (EHBPs) that are capable of forming quinone methide intermediates were synthesized and their cell growth inhibitory properties were evaluated in four different human cancer cell lines. Compounds 1, 1a, and 1b, corresponding to (4-acetyloxybenzyl diethylphosphate), (3-methyl-4-acetyloxybenzyl diethylphosphate), and (3-chloro-4-acetyloxybenzyl diethylphosphate), were significantly more potent than compounds 2 and 3, (2-acetyloxybenzyl diethylphosphate) and (3-acetyloxybenzyl diethylphosphate), respectively. Using HT-29 human colon cancer cells, compounds 1 and 3 increased apoptosis, inhibited proliferation, and caused a G(2)/M block in the cell cycle. Our data suggest that these compounds merit further investigation as potential anti-cancer agents. Copyright © 2011 Elsevier Ltd. All rights reserved.

Effect of L-Carnitine in Patients With Liver Cirrhosis on Energy Metabolism Using Indirect Calorimetry: A Pilot Study.

PubMed

Sakai, Yoshiyuki; Nishikawa, Hiroki; Enomoto, Hirayuki; Yoh, Kazunori; Iwata, Yoshinori; Hasegawa, Kunihiro; Nakano, Chikage; Kishino, Kyohei; Shimono, Yoshihiro; Takata, Ryo; Nishimura, Takashi; Aizawa, Nobuhiro; Ikeda, Naoto; Takashima, Tomoyuki; Ishii, Akio; Iijima, Hiroko; Nishiguchi, Shuhei

2016-12-01

L-carnitine supplementation has been suggested to show several favorable effects on patients with liver cirrhosis (LC). However, there have been no reports regarding the effect of L-carnitine on energy metabolism in patients with LC using indirect calorimetry which is a well-established method for assessing the degree of liver malnutrition. We examined the effect of L-carnitine in patients with LC on energy metabolism using indirect calorimetry. A total of 13 LC patients who are scheduled to be treated with L-carnitine (1,800 mg/day) were analyzed in this study. None of the patients previously received L-carnitine. An evaluation of the nutritional status was performed at the initiation of L-carnitine therapy and after 4 weeks of L-carnitine therapy. We evaluated the effect of L-carnitine on the nutritional status and energy metabolism by comparing various clinical variables at these two time points. In addition, the changes in the nutritional status of the patients were also evaluated using indirect calorimetry. After 4 weeks of L-carnitine treatment, for all cases, the mean substrate oxidation rates of carbohydrate (%C) increased from 37.6% to 48.2%, the mean substrate oxidation rates of fat (%F) decreased from 40.2% to 31.9% and the mean substrate oxidation rates of protein (%P) decreased from 22.2% to 19.9%. In a subgroup analysis of patients with baseline non-protein respiratory quotient (npRQ) < 0.85, the mean %C increased from 15.3% to 34.2%, the mean %F decreased from 59.9% to 45.1%, and the mean %P decreased from 24.8% to 20.6%. After 4 weeks of L-carnitine treatment, for all cases (n = 13), the mean value of npRQ increased in comparison with the baseline levels, although the difference was not significant (0.868 ± 0.060 vs. 0.838 ± 0.097, P = 0.19). Conversely, in patients with baseline npRQ < 0.85, the npRQ value significantly increased after 4 weeks treatment of L-carnitine compared with the baseline levels (0.827 ± 0.030 vs. 0.760 ± 0.043, P = 0

The Study of Hemodialysis Effectiveness on the Change Rate of Lipid Peroxidation and L-Carnitine Level in Hemodialysis Patients

PubMed Central

Isfahani, Maryam; Sheikh, Nasrin

2010-01-01

Carnitine is a small molecule widely present in all cells from prokaryotic to eukaryotic. It is an important element in β-oxidation of fatty acids. Carnitine is a scavenger of oxygen free radicals in mammalian tissues. Lack of carnitine in a hemodialysis patient can lead to carnitine deficiency. Oxidation of fatty acids and lipid metabolism are severly affected by carnitine deficiency. Oxidative stress is defined as imbalance between formation of free radicals and antioxidative defense mechanisms. It has been proposed to play a role in many disease states. In hemodialysis patients multiple factors can lead to a a high susceptibility to oxidative stress. The aim of this study was to determine hemodialysis effectiveness on the change rate of serum L-carnitine and lipid peroxidation. 27 patients with chronic renal failure (24-80 yrs) who undergo hemodialysis for 6-12 months were selected (M= 17, F= 10). Malondialdehyde (MDA), as an indicator of lipid peroxidation was measured colorimetrically with a standard thiobarbituric acid (TBA) method. L-carnitine was measured with enzymatic UV method (ROCHE, Spectronic Genesis 2, 340 nm). The weight mean of L-carnitine before and after hemodialysis was 7.67±3.6 mg/l and 2.07±1.6 mg/l, respectively (P<0.001). The weight mean of pre-hemodialysis MDA was 4.17±1.24 µmol/l, following hemodialysis -4.98±1.2 µmol/l (P<0.001). Results showed that 55.6% of patients suffered from carnitine defciency. Serum carnitine was found to be decreased markedly after hemodialysis (P<0.001). Our findings indicated that oxidative stress in these patients is further exacerbated by hemodialysis, as evidenced by increased lipid peroxidation. The relationship between serum L-carnitine and MDA before and after hemodialysis was observed (r=0.82; p<0.001; r=0.75; p<0.001). PMID:27683353

Functional activity of L-carnitine transporters in human airway epithelial cells.

PubMed

Ingoglia, Filippo; Visigalli, Rossana; Rotoli, Bianca Maria; Barilli, Amelia; Riccardi, Benedetta; Puccini, Paola; Dall'Asta, Valeria

2016-02-01

Carnitine plays a physiologically important role in the β-oxidation of fatty acids, facilitating the transport of long-chain fatty acids across the inner mitochondrial membrane. Distribution of carnitine within the body tissues is mainly performed by novel organic cation transporter (OCTN) family, including the isoforms OCTN1 (SLC22A4) and OCTN2 (SLC22A5) expressed in human. We performed here a characterization of carnitine transport in human airway epithelial cells A549, Calu-3, NCl-H441, and BEAS-2B, by means of an integrated approach combining data of mRNA/protein expression with the kinetic and inhibition analyses of L-[(3)H]carnitine transport. Carnitine uptake was strictly Na(+)-dependent in all cell models. In A549 and BEAS-2B cells, carnitine uptake was mediated by one high-affinity component (Km<2 μM) identifiable with OCTN2. In both these cell models, indeed, carnitine uptake was maximally inhibited by betaine and strongly reduced by SLC22A5/OCTN2 silencing. Conversely, Calu-3 and NCl-H441 exhibited both a high (Km~20 μM) and a low affinity (Km>1 mM) transport component. While the high affinity component is identifiable with OCTN2, the low affinity uptake is mediated by ATB(0,+), a Na(+), and Cl(-)-coupled transport system for neutral and cationic amino acids, as demonstrated by the inhibition by leucine and arginine, as well as by SLC6A14/ATB(0,+) silencing. The presence of this transporter leads to a massive accumulation of carnitine inside the cells and may be of peculiar relevance in pathologic conditions of carnitine deficiency, such as those associated to OCTN2 defects. Copyright © 2015 Elsevier B.V. All rights reserved.

Gender differences in locomotor and stereotypic behavior associated with l-carnitine treatment in mice.

PubMed

Benvenga, Salvatore; Itri, Elenora; Hauser, Peter; De Tolla, Louis; Yu, Sui-Foh; Testa, Giuseppe; Pappalardo, Maria Angela; Trimarchi, Francesco; Amato, Antonino

2011-02-01

The carnitines exert neuroprotective and neuromodulatory actions, and carnitine supplementation increases locomotor activity (LMA) in experimental animals. We measured 13 indexes of LMA and 3 indexes of stereotypic activity (STA) in adult male and female caged mice. In a randomized 4-week trial, 10 males and 10 females received 50 mg/kg body weight PO l-carnitine, and another 10 males and 10 females received placebo. Compared with placebo-treated females, placebo-treated males had a greater number of stereotypies (NSTs), stereotypy counts (STCs), stereotypy time (STT), and right front time (RFT), but smaller total distance traveled (TDT), margin distance (MD), number of vertical movements (NVMs), and left rear time (LRT). Compared with placebo-treated males, carnitine-treated males had greater horizontal activity (HA), movement time (MT), NVM, STT, TDT, STC, MD, LRT, and clockwise revolutions (CRs), but smaller left front time (LFT) and RFT. Compared with placebo-treated females, carnitine-treated females had greater NST, STC, STT, LFT, and RFT, but smaller NM, HA, NVM, VA, MT, anticlockwise revolutions (ACRs), CR, TDT, and MD; right rear time (RRT) remained statistically insignificant across all comparisons. In summary, l-carnitine caused gender differences to persist for STC, diminish for NST and STT, disappear for LRT and NVM, change in the opposite direction for TDT and MD, appear de novo for HA, VA, NM, MT, and LFT, and remain absent for RRT and ACR. Some indexes of LMA and STA are sexually dimorphic in adult mice, and l-carnitine differentially maintains, diminishes/cancels, inverts, or creates the sexual dimorphism of particular indexes. Copyright © 2011 Elsevier HS Journals, Inc. All rights reserved.

[The hypotriglyceridemic action of the combination of L-carnitine + simvastatin vs. L-carnitine and vs. simvastatin].

PubMed

Savica, V; Bellinghieri, G; Lamanna, F

1992-01-01

Previous studies had determined the role played by L-carnitine and simvastatin in the treatment of altered lipidemia in dialyzed patients with chronic uremia. The authors carried out a study on the above substances either singly or together administered to the same patients with chronic uremia in hemodialysis. This study was aimed at demonstrating the possible synergic normolipidemic action of both substances in comparison with their single administration, because their different mechanism of action could be metabolically enhanced. The obtained results demonstrated that the therapeutic association proposed is preferable to the use of the single substances. Moreover, a higher and more rapid normolipidemic effect was obtained after using L-carnitina associated with simvastatin with respect to the separated substances.

Acetyl-L-Carnitine Hydrochloride in Preventing Peripheral Neuropathy in Patients With Recurrent Ovarian Epithelial Cancer, Primary Peritoneal Cavity Cancer, or Fallopian Tube Cancer Undergoing Chemotherapy

ClinicalTrials.gov

2014-12-29

Fatigue; Malignant Ovarian Mixed Epithelial Tumor; Neuropathy; Neurotoxicity Syndrome; Ovarian Brenner Tumor; Ovarian Clear Cell Cystadenocarcinoma; Ovarian Endometrioid Adenocarcinoma; Ovarian Mucinous Cystadenocarcinoma; Ovarian Serous Cystadenocarcinoma; Pain; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma

Carnitine Deficiency and Pregnancy

PubMed Central

de Bruyn, Anouk; Jacquemyn, Yves; Kinget, Kristof; Eyskens, François

2015-01-01

We present two cases of carnitine deficiency in pregnancy. In our first case, systematic screening revealed L-carnitine deficiency in the first born of an asymptomatic mother. In the course of her second pregnancy, maternal carnitine levels showed a deficiency as well. In a second case, a mother known with carnitine deficiency under supplementation was followed throughout her pregnancy. Both pregnancies had an uneventful outcome. Because carnitine deficiency can have serious complications, supplementation with carnitine is advised. This supplementation should be continued throughout pregnancy according to plasma concentrations. PMID:26113999

Diabetic Neuropathy and Oxidative Stress: Therapeutic Perspectives

PubMed Central

Hosseini, Asieh; Abdollahi, Mohammad

2013-01-01

Diabetic neuropathy (DN) is a widespread disabling disorder comprising peripheral nerves' damage. DN develops on a background of hyperglycemia and an entangled metabolic imbalance, mainly oxidative stress. The majority of related pathways like polyol, advanced glycation end products, poly-ADP-ribose polymerase, hexosamine, and protein kinase c all originated from initial oxidative stress. To date, no absolute cure for DN has been defined; although some drugs are conventionally used, much more can be found if all pathophysiological links with oxidative stress would be taken into account. In this paper, although current therapies for DN have been reviewed, we have mainly focused on the links between DN and oxidative stress and therapies on the horizon, such as inhibitors of protein kinase C, aldose reductase, and advanced glycation. With reference to oxidative stress and the related pathways, the following new drugs are under study such as taurine, acetyl-L-carnitine, alpha lipoic acid, protein kinase C inhibitor (ruboxistaurin), aldose reductase inhibitors (fidarestat, epalrestat, ranirestat), advanced glycation end product inhibitors (benfotiamine, aspirin, aminoguanidine), the hexosamine pathway inhibitor (benfotiamine), inhibitor of poly ADP-ribose polymerase (nicotinamide), and angiotensin-converting enzyme inhibitor (trandolapril). The development of modern drugs to treat DN is a real challenge and needs intensive long-term comparative trials. PMID:23738033

Carnitine protects the nematode Caenorhabditis elegans from glucose-induced reduction of survival depending on the nuclear hormone receptor DAF-12

DOE Office of Scientific and Technical Information (OSTI.GOV)

Deusing, Dorothé Jenni, E-mail: Dorothe.J.Deusing@ernaehrung.uni-giessen.de; Beyrer, Melanie, E-mail: m.beyrer@web.de; Fitzenberger, Elena, E-mail: Elena.Fitzenberger@ernaehrung.uni-giessen.de

Besides its function in transport of fatty acids into mitochondria in order to provide substrates for β-oxidation, carnitine has been shown to affect also glucose metabolism and to inhibit several mechanisms associated with diabetic complications. In the present study we used the mev-1 mutant of the nematode Caenorhabditis elegans fed on a high glucose concentration in liquid media as a diabetes model and tested the effects of carnitine supplementation on their survival under heat-stress. Carnitine at 100 μM completely prevented the survival reduction that was caused by the application of 10 mM glucose. RNA-interference for sir-2.1, a candidate genes mediating the effectsmore » of carnitine revealed no contribution of the sirtuin for the rescue of survival. Under daf-12 RNAi rescue of survival by carnitine was abolished. RNA-interference for γ-butyrobetaine hydroxylase 2, encoding the key enzyme for carnitine biosynthesis did neither increase glucose toxicity nor prevent the rescue of survival by carnitine, suggesting that the effects of carnitine supplementation on carnitine levels were significant. Finally, it was demonstrated that neither the amount of lysosomes nor the proteasomal activity were increased by carnitine, excluding that protein degradation pathways, such as autophagy or proteasomal degradation, are involved in the protective carnitine effects. In conclusion, carnitine supplementation prevents the reduction of survival caused by glucose in C. elegans in dependence on a nuclear hormone receptor which displays high homologies to the vertebrate peroxisomal proliferator activated receptors. - Highlights: • Carnitine protects from glucose-induced reduction of stress-resistance. • Carnitine acts via the PPAR homolog DAF-12 on glucose toxicity. • Carnitine protects from glucose toxicity independent of protein degradation.« less

Metabolic Agents that Enhance ATP can Improve Cognitive Functioning: A Review of the Evidence for Glucose, Oxygen, Pyruvate, Creatine, and L-Carnitine

PubMed Central

Owen, Lauren; Sunram-Lea, Sandra I.

2011-01-01

Over the past four or five decades, there has been increasing interest in the neurochemical regulation of cognition. This field received considerable attention in the 1980s, with the identification of possible cognition enhancing agents or “smart drugs”. Even though many of the optimistic claims for some agents have proven premature, evidence suggests that several metabolic agents may prove to be effective in improving and preserving cognitive performance and may lead to better cognitive aging through the lifespan. Aging is characterized by a progressive deterioration in physiological functions and metabolic processes. There are a number of agents with the potential to improve metabolic activity. Research is now beginning to identify these various agents and delineate their potential usefulness for improving cognition in health and disease. This review provides a brief overview of the metabolic agents glucose, oxygen, pyruvate, creatine, and L-carnitine and their beneficial effects on cognitive function. These agents are directly responsible for generating ATP (adenosine triphosphate) the main cellular currency of energy. The brain is the most metabolically active organ in the body and as such is particularly vulnerable to disruption of energy resources. Therefore interventions that sustain adenosine triphosphate (ATP) levels may have importance for improving neuronal dysfunction and loss. Moreover, recently, it has been observed that environmental conditions and diet can affect transgenerational gene expression via epigenetic mechanisms. Metabolic agents might play a role in regulation of nutritional epigenetic effects. In summary, the reviewed metabolic agents represent a promising strategy for improving cognitive function and possibly slowing or preventing cognitive decline. PMID:22254121

L-carnitine protects against nickel-induced neurotoxicity by maintaining mitochondrial function in Neuro-2a cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

He Mindi; Xu Shangcheng; Lu Yonghui

Mitochondrial dysfunction is thought to be a part of the mechanism underlying nickel-induced neurotoxicity. L-carnitine (LC), a quaternary ammonium compound biosynthesized from the amino acids lysine and methionine in all mammalian species, manifests its neuroprotective effects by improving mitochondrial energetics and function. The purpose of this study was to investigate whether LC could efficiently protect against nickel-induced neurotoxicity. Here, we exposed a mouse neuroblastoma cell line (Neuro-2a) to different concentrations of nickel chloride (NiCl{sub 2}) (0.25, 0.5, 1, and 2 mM) for 24 h, or to 0.5 mM and 1 mM NiCl{sub 2} for various periods (0, 3, 6, 12,more » or 24 h). We found that nickel significantly increased the cell viability loss and lactate dehydrogenase (LDH) release in Neuro-2a cells. In addition, nickel exposure significantly elevated reactive oxygen species (ROS) and malondialdehyde (MDA) levels, disrupted the mitochondrial membrane potential ({Delta}{Psi}{sub m}), reduced adenosine-5'-triphosphate (ATP) concentrations and decreased mitochondrial DNA (mtDNA) copy numbers and mtRNA transcript levels. However, all of the cytotoxicities and mitochondrial dysfunctions that were triggered by nickel were efficiently attenuated by pretreatment with LC. These protective effects of LC may be attributable to its role in maintaining mitochondrial function in nickel-treated cells. Our results suggest that LC may have great pharmacological potential in protecting against the adverse effects of nickel in the nervous system.« less

Carnitine for fatigue in multiple sclerosis.

PubMed

Tejani, Aaron M; Wasdell, Michael; Spiwak, Rae; Rowell, Greg; Nathwani, Shabita

2010-02-17

Fatigue is reported to occur in up to 92% of patients with multiple sclerosis (MS) and has been described as the most debilitating of all MS symptoms by 28% to 40% of MS patients. To assess whether carnitine (enteral or intravenous) supplementation can improve the quality of life and reduce the symptoms of fatigue in patients with MS-related fatigue and to identify any adverse effects of carnitine when used for this purpose. A literature search was performed using Cochrane MS Group Trials Register (21 May 2009), Cochrane Central Register of Controlled Trials (CENTRAL) "The Cochrane Library 2009, issue 2, MEDLINE (PubMed) (1966-21 May 2009), EMBASE (1974-21 May 2009). Reference lists of review articles and primary studies were also screened. A hand search of the abstract book of recent relevant conference symposia was also conducted. Personal contact with MS experts and a manufacturer (Source Naturals, United States) of carnitine formulation was contacted to determine if they knew of other clinical trials. No language restrictions were applied. Full reports of published and unpublished randomized controlled trials and quasi-randomized trials of any carnitine intervention in adults with a clinical diagnosis of fatigue associated with multiple sclerosis were included. Data from the eligible trials was extracted and coded using a standardized data extraction form and entered into RevMan 5. Discrepancies were to be resolved by discussion with a third reviewer however this was not necessary. The quality items to be assessed were method of randomization, allocation concealment, blinding (participants, investigators, outcome assessors and data analysis), intention-to-treat analysis and completeness of follow up. The search identified one randomized cross-over trial. In this study patients were exposed to both acetyl L-carnitine (ALCAR(tm)) 2 grams daily and amantadine 200 mg daily in adult patients with relapsing-remitting and secondary progressive MS. The effects of

Automation of a spectrophotometric method for measuring L -carnitine in human blood serum.

PubMed

Galan, A; Padros, A; Arambarri, M; Martin, S

1998-01-01

A spectrometric method for the determination of L-carnitine has been developed based on the reaction of the 5,5' dithiobis-(2-nitrobenzoic) acid (DTNB) and adapted to a Technicon RA-2000 automatic analyser Química Farmacéutica Bayer, S.A.). The detection limit of the method is 13.2 mumol/l, with a measurement interval ranging from 30 to 320 mumoll1. Imprecision and accuracy are good even at levels close to the detection limit (coeffcient of variation of 5.4% for within-run imprecision for a concentration of 35 mumol/l). A good correlation was observed between the method studied and the radiometric method. The method evaluated has suffcient analytical sensitivity to diagnose carnitine deficiencies. The short time period required for sample processing (30 samples in 40min), the simple methodology and apparatus, the ease of personnel training and the low cost of the reagents make this method a good alternative to the classical radiometric method for evaluating serum L-carnitine in clinical laboratories without radioactive installations.

Automation of a spectrophotometric method for measuring L -carnitine in human blood serum

PubMed Central

Galan, Amparo; Padros, Anna; Arambarri, Marta; Martin, Silvia

1998-01-01

A spectrometric method for the determination of L-carnitine has been developed based on the reaction of the 5, 5 ′ dithiobis-(2-nitrobenzoic) acid (DTNB) and adapted to a Technicon RA-2000 automatic analyser Química Farmacéutica Bayer, S.A.). The detection limit of the method is 13.2 μmol/l, with a measurement interval ranging from 30 to 320 μmoll1. Imprecision and accuracy are good even at levels close to the detection limit (coeffcient of variation of 5.4% for within-run imprecision for a concentration of 35 μmol/l). A good correlation was observed between the method studied and the radiometric method. The method evaluated has suffcient analytical sensitivity to diagnose carnitine deficiencies. The short time period required for sample processing (30 samples in 40min), the simple methodology and apparatus, the ease of personnel training and the low cost of the reagents make this method a good alternative to the classical radiometric method for evaluating serum L-carnitine in clinical laboratories without radioactive installations. PMID:18924818

L-carnitine supplementation in patients with HIV/AIDS and fatigue: a double-blind, placebo-controlled pilot study.

PubMed

Cruciani, Ricardo A; Revuelta, Manuel; Dvorkin, Ella; Homel, Peter; Lesage, Pauline; Esteban-Cruciani, Nora

2015-01-01

The purpose of this study was to determine the effect of L-carnitine supplementation on fatigue in patients with terminal human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). In this randomized, double-blind, placebo-controlled, parallel-group study, patients who had end-stage HIV/AIDS with carnitine deficiency and fatigue received 3 g of oral L-carnitine or placebo for 2 weeks, followed by a 2-week, open-label phase with the same amount of L-carnitine for all patients. The primary outcome was the degree of fatigue according to the Brief Fatigue Inventory. Secondary outcomes included serum carnitine and lactate levels, physical, emotional, social, and functional well-being, performance status, mood, and CD4 count. Eighteen patients in the treatment arm and 17 in the placebo arm completed the trial. At the end of the double-blind phase, total and free carnitine levels in the treatment arm rose from 28±9 to 48±17 nM/L (P<0.001) and from 24±8 to 40±13 nM/L (P<0.001) respectively, with no changes in the placebo arm. The primary outcome, ie, fatigue measured at the end of the blinded phase, did not improve. Secondary outcomes of function, quality of life, and mood did not show improvement either. The secondary outcome of serum lactate decreased from baseline in the treatment group (1.45±0.76 to 1.28±0.52 mmol/L) and increased in the placebo group (1.38±0.62 to 1.84±0.74 mmol/L; P<0.005). Our study suggests that 3 g of oral L-carnitine supplementation for 2 weeks in terminally ill HIV/AIDS patients does not improve fatigue. This study might help to determine the dose and duration of treatment used in future clinical trials, as higher doses and/or longer periods of supplementation might be needed in order to detect an improvement. The reduction in serum lactate levels suggests a potential role for L-carnitine supplementation in patients undergoing certain types of antiretroviral therapy. This study contributes evidence-based data to the

Increasing skeletal muscle carnitine availability does not alter the adaptations to high-intensity interval training.

PubMed

Shannon, Christopher E; Ghasemi, Reza; Greenhaff, Paul L; Stephens, Francis B

2018-01-01

Increasing skeletal muscle carnitine availability alters muscle metabolism during steady-state exercise in healthy humans. We investigated whether elevating muscle carnitine, and thereby the acetyl-group buffering capacity, altered the metabolic and physiological adaptations to 24 weeks of high-intensity interval training (HIIT) at 100% maximal exercise capacity (Watt max ). Twenty-one healthy male volunteers (age 23±2 years; BMI 24.2±1.1 kg/m 2 ) performed 2 × 3 minute bouts of cycling exercise at 100% Watt max , separated by 5 minutes of rest. Fourteen volunteers repeated this protocol following 24 weeks of HIIT and twice-daily consumption of 80 g carbohydrate (CON) or 3 g l-carnitine+carbohydrate (CARN). Before HIIT, muscle phosphocreatine (PCr) degradation (P<.0001), glycogenolysis (P<.0005), PDC activation (P<.05), and acetylcarnitine (P<.005) were 2.3-, 2.1-, 1.5-, and 1.5-fold greater, respectively, in exercise bout two compared to bout 1, while lactate accumulation tended (P<.07) to be 1.5-fold greater. Following HIIT, muscle free carnitine was 30% greater in CARN vs CON at rest and remained 40% elevated prior to the start of bout 2 (P<.05). Following bout 2, free carnitine content, PCr degradation, glycogenolysis, lactate accumulation, and PDC activation were all similar between CON and CARN, albeit markedly lower than before HIIT. VO 2max , Watt max , and work output were similarly increased in CON and CARN, by 9, 15, and 23% (P<.001). In summary, increased reliance on non-mitochondrial ATP resynthesis during a second bout of intense exercise is accompanied by increased carnitine acetylation. Augmenting muscle carnitine during 24 weeks of HIIT did not alter this, nor did it enhance muscle metabolic adaptations or performance gains beyond those with HIIT alone. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Testicular toxicity and sperm quality following copper exposure in Wistar albino rats: ameliorative potentials of L-carnitine.

PubMed

Khushboo, Maurya; Murthy, Meesala Krishna; Devi, Maibam Sunita; Sanjeev, Sanasam; Ibrahim, Kalibulla Syed; Kumar, Nachimuthu Senthil; Roy, Vikas Kumar; Gurusubramanian, Guruswami

2018-01-01

effects of copper on seminiferous tubules damage, testes function, spermatogenesis, and sperm quality. It was validated that the use of L-carnitine at doses of 50 and 100 mg/kg protects against copper-induced testicular tissue damage and acts as a therapeutic agent for copper heavy metal toxicity.

N6-Trimethyl-lysine metabolism. 3-Hydroxy-N6-trimethyl-lysine and carnitine biosynthesis.

PubMed Central

Hoppel, C L; Cox, R A; Novak, R F

1980-01-01

Rats injected with N6-[Me-3H]trimethyl-lysine excrete in the urine five radioactively labelled metabolites. Two of these identified metabolites are carnitine and 4-trimethylammoniobutyrate. A third metabolite, identified as 5-trimethylammoniopentanoate, is not an intermediate in the biosynthesis of carnitine; the fourth and major metabolite, N2-acetyl-N6-trimethyl-lysine, is not a precursor of carnitine. The remaining metabolite (3-hydroxy-N6-trimethyl-lysine) is converted into trimethylammoniobutyrate and carnitine by rat liver slices and into trimethylammoniobutyrate by rat kidney slices. In rat liver and kidney-slice experiments, radioactivity from DL-N6-trimethyl-[1-14C]lysine and DL-N6-trimethyl-[2-14C]lysine was incorporated into N2-acetyl-N6-trimethyl-lysine and 3-hydroxy-N6-trimethyl-lysine, but not into trimethylammoniobutyrate or carnitine. A procedure was devised to purify milligram quantities of 3-hydroxy-N6-trimethyl-lysine from the urine of rats injected chronically with N6-trimethyl-lysine (100 mg/kg body wt. per day). The structure of 3-hydroxy-N6-trimethyl-lysine was confirmed chemically and by nuclear-magnetic-resonance spectrometry [Novak, Swift & Hoppel (1980) Biochem. J. 188, 521--527]. The sequence for carnitine biosynthesis in liver is: N6-trimethyl-lysine leads to 3-hydryxy-N6-trimethyl-lysine leads to leads to 4-trimethylammoniobutyrate leads to carnitine. PMID:6772168

Effects of acute L-carnitine intake on metabolic and blood lactate levels of elite badminton players.

PubMed

Eroğlu, Hüseyin; Senel, Omer; Güzel, Nevin A

2008-04-01

Purpose of this study is to research the effects of acute L-Carnitine intake on badminton players' metabolic and blood lactate values. A total of 16 Turkish national badminton players (8 male, 8 female) were voluntarily participated into study. MaxVO2, MET, energy consumption, HR (heart rate), VE (minute ventilation), R (respiratory exchange ratio), AT (anaerobic threshold), oxygen pulse and blood lactate (LA) of subjects were measured by Sensormedics VmaxST and Accutrend Lactate Analyzer. The participants were subjected to the test protocol twice before and after 2g of L-Carnitine intake. The data were evaluated by the use of SPSS 13.0 for Windows. No significant differences were found between 1st. (without L-Carnitine intake) and 2nd. (with L-Carnitine intake) measurements of female participants as regards to all measured parameters. There was a significant difference in EMHR (exercise maximum heart rate) of males between two measurements (p<0.05). However the differences in other parameters were not significant. AT values of female subjects were not significant difference (p>0.05). Respiratory exchange ratio of males was significantly different at anaerobic threshold (p<0.05). Results of this study show that L-carnitine intake one hour prior to the exercise has no effect on the metabolic and blood lactate values of badminton players.

Impact of L-carnitine on plasma lipoprotein(a) concentrations: A systematic review and meta-analysis of randomized controlled trials

PubMed Central

Serban, Maria-Corina; Sahebkar, Amirhossein; Mikhailidis, Dimitri P.; Toth, Peter P.; Jones, Steven R.; Muntner, Paul; Blaha, Michael J.; Andrica, Florina; Martin, Seth S.; Borza, Claudia; Lip, Gregory Y. H.; Ray, Kausik K.; Rysz, Jacek; Hazen, Stanley L.; Banach, Maciej

2016-01-01

We aimed to assess the impact of L-carnitine on plasma Lp(a) concentrations through systematic review and meta-analysis of available RCTs. The literature search included selected databases up to 31st January 2015. Meta-analysis was performed using fixed-effects or random-effect model according to I2 statistic. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI). The meta-analysis showed a significant reduction of Lp(a) levels following L-carnitine supplementation (WMD: −8.82 mg/dL, 95% CI: −10.09, −7.55, p < 0.001). When the studies were categorized according to the route of administration, a significant reduction in plasma Lp(a) concentration was observed with oral (WMD: −9.00 mg/dL, 95% CI: −10.29, −7.72, p < 0.001) but not intravenous L-carnitine (WMD: −2.91 mg/dL, 95% CI: −10.22, 4.41, p = 0.436). The results of the meta-regression analysis showed that the pooled estimate is independent of L-carnitine dose (slope: −0.30; 95% CI: −4.19, 3.59; p = 0.878) and duration of therapy (slope: 0.18; 95% CI: −0.22, 0.59; p = 0.374). In conclusion, the meta-analysis suggests a significant Lp(a) lowering by oral L-carnitine supplementation. Taking into account the limited number of available Lp(a)-targeted drugs, L-carnitine might be an effective alternative to effectively reduce Lp(a). Prospective outcome trials will be required to fully elucidate the clinical value and safety of oral L-carnitine supplementation. PMID:26754058

Vegetarians have a reduced skeletal muscle carnitine transport capacity.

PubMed

Stephens, Francis B; Marimuthu, Kanagaraj; Cheng, Yi; Patel, Nitin; Constantin, Despina; Simpson, Elizabeth J; Greenhaff, Paul L

2011-09-01

Ninety-five percent of the body carnitine pool resides in skeletal muscle where it plays a vital role in fuel metabolism. However, vegetarians obtain negligible amounts of carnitine from their diet. We tested the hypothesis that muscle carnitine uptake is elevated in vegetarians compared with that in nonvegetarians to maintain a normal tissue carnitine content. Forty-one young (aged ≈22 y) vegetarian and nonvegetarian volunteers participated in 2 studies. The first study consisted of a 5-h intravenous infusion of l-carnitine while circulating insulin was maintained at a physiologically high concentration (≈170 mU/L; to stimulate muscle carnitine uptake) or at a fasting concentration (≈6 mU/L). The second study consisted of oral ingestion of 3 g l-carnitine. Basal plasma total carnitine (TC) concentration, 24-h urinary TC excretion, muscle TC content, and muscle carnitine transporter [organic cation transporter 2 (OCTN2)] messenger RNA and protein expressions were 16% (P < 0.01), 58% (P < 0.01), 17% (P < 0.05), 33% (P < 0.05), and 37% (P = 0.09) lower, respectively, in vegetarian volunteers. However, although nonvegetarians showed a 15% increase (P < 0.05) in muscle TC during l-carnitine infusion with hyperinsulinemia, l-carnitine infusion in the presence or absence of hyperinsulinemia had no effect on muscle TC content in vegetarians. Nevertheless, 24-h urinary TC excretion was 55% less in vegetarians after l-carnitine ingestion. Vegetarians have a lower muscle TC and reduced capacity to transport carnitine into muscle than do nonvegetarians, possibly because of reduced muscle OCTN2 content. Thus, the greater whole-body carnitine retention observed after a single dose of l-carnitine in vegetarians was not attributable to increased muscle carnitine storage.

Lotus leaf extract and L-carnitine influence different processes during the adipocyte life cycle

PubMed Central

2010-01-01

Background The cellular and molecular mechanisms of adipose tissue biology have been studied extensively over the last two decades. Adipose tissue growth involves both an increase in fat cell size and the formation of mature adipocytes from precursor cells. To investigate how natural substances influence these two processes, we examined the effects of lotus leaf extract (Nelumbo nucifera-extract solution obtained from Silab, France) and L-carnitine on human preadipocytes and adipocytes. Methods For our in vitro studies, we used a lotus leaf extract solution alone or in combination with L-carnitine. Utilizing cultured human preadipocytes, we investigated lotus leaf extract solution-induced inhibition of triglyceride incorporation during adipogenesis and possible effects on cell viability. Studies on human adipocytes were performed aiming to elucidate the efficacy of lotus leaf extract solution to stimulate lipolytic activity. To further characterize lotus leaf extract solution-mediated effects, we determined the expression of the transcription factor adipocyte determination and differentiation factor 1 (ADD1/SREBP-1c) on the RNA- and protein level utilizing qRT-PCR and immunofluorescence analysis. Additionally, the effect of L-carnitine on beta-oxidation was analyzed using human preadipocytes and mature adipocytes. Finally, we investigated additive effects of a combination of lotus leaf extract solution and L-carnitine on triglyceride accumulation during preadipocyte/adipocyte differentiation. Results Our data showed that incubation of preadipocytes with lotus leaf extract solution significantly decreased triglyceride accumulation during adipogenesis without affecting cell viability. Compared to controls, adipocytes incubated with lotus leaf extract solution exhibited a significant increase in lipolysis-activity. Moreover, cell populations cultivated in the presence of lotus leaf extract solution showed a decrease in adipocyte differentiation capacity as indicated

Lotus leaf extract and L-carnitine influence different processes during the adipocyte life cycle.

PubMed

Siegner, Ralf; Heuser, Stefan; Holtzmann, Ursula; Söhle, Jörn; Schepky, Andreas; Raschke, Thomas; Stäb, Franz; Wenck, Horst; Winnefeld, Marc

2010-08-05

The cellular and molecular mechanisms of adipose tissue biology have been studied extensively over the last two decades. Adipose tissue growth involves both an increase in fat cell size and the formation of mature adipocytes from precursor cells. To investigate how natural substances influence these two processes, we examined the effects of lotus leaf extract (Nelumbo nucifera-extract solution obtained from Silab, France) and L-carnitine on human preadipocytes and adipocytes. For our in vitro studies, we used a lotus leaf extract solution alone or in combination with L-carnitine. Utilizing cultured human preadipocytes, we investigated lotus leaf extract solution-induced inhibition of triglyceride incorporation during adipogenesis and possible effects on cell viability. Studies on human adipocytes were performed aiming to elucidate the efficacy of lotus leaf extract solution to stimulate lipolytic activity. To further characterize lotus leaf extract solution-mediated effects, we determined the expression of the transcription factor adipocyte determination and differentiation factor 1 (ADD1/SREBP-1c) on the RNA- and protein level utilizing qRT-PCR and immunofluorescence analysis. Additionally, the effect of L-carnitine on beta-oxidation was analyzed using human preadipocytes and mature adipocytes. Finally, we investigated additive effects of a combination of lotus leaf extract solution and L-carnitine on triglyceride accumulation during preadipocyte/adipocyte differentiation. Our data showed that incubation of preadipocytes with lotus leaf extract solution significantly decreased triglyceride accumulation during adipogenesis without affecting cell viability. Compared to controls, adipocytes incubated with lotus leaf extract solution exhibited a significant increase in lipolysis-activity. Moreover, cell populations cultivated in the presence of lotus leaf extract solution showed a decrease in adipocyte differentiation capacity as indicated by a decrease in the ADD1

Effect of glycine propionyl-L-carnitine on aerobic and anaerobic exercise performance.

PubMed

Smith, Webb A; Fry, Andrew C; Tschume, Lesley C; Bloomer, Richard J

2008-02-01

The purpose of this study was to evaluate the effect of glycine propionyl-L-carnitine (GPLC) supplementation and endurance training for 8 wk on aerobic- and anaerobic-exercise performance in healthy men and women (age 18-44 yr). Participants were randomly assigned to 1 of 3 groups: placebo (n=9), 1 g/d GPLC (n=11), or 3 g/d GPLC (n=12), in a double-blind fashion. Muscle carnitine (vastus lateralis), VO(2peak), exercise time to fatigue, anaerobic threshold, anaerobic power, and total work were measured at baseline and after an 8-wk aerobic-training program. There were no statistical differences (p> .05) between or within the 3 groups for any performance-related variable or muscle carnitine concentrations after 8 wk of supplementation and training. These results suggest that up to 3 g/d GPLC for 8 wk in conjunction with aerobic-exercise training is ineffective for increasing muscle carnitine content and has no significant effects on aerobic- or anaerobic-exercise performance.

L-carnitine and pyruvate are prosurvival factors during the storage of stallion spermatozoa at room temperature.

PubMed

Gibb, Zamira; Lambourne, Sarah R; Quadrelli, Julianne; Smith, Nathan D; Aitken, Robert J

2015-10-01

The spermatozoa of many stallions do not tolerate being cooled, restricting the commercial viability of these animals and necessitating the development of a chemically defined room temperature (RT) storage medium. This study examined the impact of two major modulators of oxidative phosphorylation, pyruvate (Pyr) and L-carnitine (L-C), on the storage of stallion spermatozoa at RT. Optimal concentrations of Pyr (10 mM) and L-C (50 mM) were first identified and these concentrations were then used to investigate the effects of these compounds on sperm functionality and oxidative stress at RT. Mitochondrial and cytosolic reactive oxygen species, along with lipid peroxidation, were all significantly suppressed by the addition of L-C (48 h MitoSOX Red negative: 46.2% vs. 26.1%; 48 and 72 h dihydroethidium negative: 61.6% vs. 43.1% and 64.4% vs. 46.9%, respectively; 48 and 72 h 4-hydroxynonenal negative: 37.1% vs. 23.8% and 41.6% vs. 25.7%, respectively), while the Pyr + L-C combination resulted in significantly higher motility compared to the control at 72 h (total motility: 64.2% vs. 39.4%; progressive motility: 34.2% vs. 15.2%). In addition, supplementation with L-C significantly reduced oxidative DNA damage at 72 h (9.0% vs. 15.6%). To investigate the effects of L-C as an osmolyte, comparisons were made between media that were osmotically balanced with NaCl, choline chloride, or L-C. This analysis demonstrated that spermatozoa stored in the L-C balanced medium had significantly higher total motility (55.0% vs. 39.0%), rapid motility (44.0% vs. 25.7%), and ATP levels (70.9 vs. 12.8 ng/ml) following storage compared with the NaCl treatment, while choline chloride did not significantly improve these parameters compared to the control. Finally, mass spectrometry was used to demonstrate that a combination of Pyr and L-C produced significantly higher acetyl-L-carnitine production than any other treatment (6.7 pg/10(6) spermatozoa vs. control at 4.0 pg/10(6) spermatozoa

L-carnitine supplementation in patients with HIV/AIDS and fatigue: a double-blind, placebo-controlled pilot study

PubMed Central

Cruciani, Ricardo A; Revuelta, Manuel; Dvorkin, Ella; Homel, Peter; Lesage, Pauline; Esteban-Cruciani, Nora

2015-01-01

Background The purpose of this study was to determine the effect of L-carnitine supplementation on fatigue in patients with terminal human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS). Methods In this randomized, double-blind, placebo-controlled, parallel-group study, patients who had end-stage HIV/AIDS with carnitine deficiency and fatigue received 3 g of oral L-carnitine or placebo for 2 weeks, followed by a 2-week, open-label phase with the same amount of L-carnitine for all patients. The primary outcome was the degree of fatigue according to the Brief Fatigue Inventory. Secondary outcomes included serum carnitine and lactate levels, physical, emotional, social, and functional well-being, performance status, mood, and CD4 count. Results Eighteen patients in the treatment arm and 17 in the placebo arm completed the trial. At the end of the double-blind phase, total and free carnitine levels in the treatment arm rose from 28±9 to 48±17 nM/L (P<0.001) and from 24±8 to 40±13 nM/L (P<0.001) respectively, with no changes in the placebo arm. The primary outcome, ie, fatigue measured at the end of the blinded phase, did not improve. Secondary outcomes of function, quality of life, and mood did not show improvement either. The secondary outcome of serum lactate decreased from baseline in the treatment group (1.45±0.76 to 1.28±0.52 mmol/L) and increased in the placebo group (1.38±0.62 to 1.84±0.74 mmol/L; P<0.005). Conclusion Our study suggests that 3 g of oral L-carnitine supplementation for 2 weeks in terminally ill HIV/AIDS patients does not improve fatigue. This study might help to determine the dose and duration of treatment used in future clinical trials, as higher doses and/or longer periods of supplementation might be needed in order to detect an improvement. The reduction in serum lactate levels suggests a potential role for L-carnitine supplementation in patients undergoing certain types of antiretroviral therapy. This study

Proximate Composition, and l-Carnitine and Betaine Contents in Meat from Korean Indigenous Chicken

PubMed Central

Jung, Samooel; Bae, Young Sik; Yong, Hae In; Lee, Hyun Jung; Seo, Dong Won; Park, Hee Bok; Lee, Jun Heon; Jo, Cheorun

2015-01-01

This study investigated the proximate composition and l-carnitine and betaine content of meats from 5 lines of Korean indigenous chicken (KIC) for developing highly nutritious meat breeds with health benefits from the bioactive compounds such as l-carnitine and betaine in meat. In addition, the relevance of gender (male and female) and meat type (breast and thigh meat) was examined. A total of 595 F1 progeny (black [B], grey-brown [G], red-brown [R], white [W], and yellow-brown [Y]) from 70 full-sib families were used. The moisture, protein, fat, and ash contents of the meats were significantly affected by line, gender, and meat type (p<0.05). The males in line G and females in line B showed the highest protein and the lowest fat content of the meats. l-carnitine and betaine content showed effects of meat type, line, and gender (p<0.05). The highest l-carnitine content was found in breast and thigh meats from line Y in both genders. The breast meat from line G and the thigh meat from line R had the highest betaine content in males. The female breast and thigh meats showed the highest betaine content in line R. These data could be valuable for establishing selection strategies for developing highly nutritious chicken meat breeds in Korea. PMID:26580444

Effects of dietary L-carnitine and coenzyme Q10 at different supplemental ages on growth performance and some immune response in ascites-susceptible broilers.

PubMed

Geng, Ailian; Li, Baoming; Guo, Yuming

2007-02-01

Effects of dietary L-carnitine and coenzyme Q10 (CoQ10) at different supplemental ages on performance and some immune response were investigated in ascites-susceptible broilers. A 3 x 2 x 2 factorial design was used consisting of L-carnitine supplementation (0, 75, and 100 mg/kg), CoQ10 supplementation (0 and 40 mg/kg) and different supplemental ages (from day 1 on and from day 10 on). A total of 480 one-day-old Arbor Acre male broiler chicks were randomly allocated to 12 groups, every group had five replicates, each with eight birds. The birds were fed a corn-soybean based diet for six weeks. From day 10-21, all the birds were exposed to a low ambient temperature (12-15 degrees C) to increase the susceptibility to ascites. No significant effects were observed on growth performance by L-carnitine, CoQ10 supplementation, and different supplemental ages. Packed cell volume was significantly decreased by L-carnitine supplementation alone, and ascites heart index and ascites mortality were decreased by L-carnitine, CoQ10 supplementation alone, and L-carnitine + CoQ10 supplementation together (p < 0.05). Heart index of broilers was significantly improved by L-carnitine, CoQ10 supplementation alone during 0-3 week. Serum IgG content was improved by L-carnitine supplementation alone (p < 0.05), but lysozyme activity was increased by L-carnitine + CoQ10 supplementation together (p < 0.05). A significant L-carnitine by supplemental age interaction was observed in lysozyme activity. L-carnitine supplementation alone had no effects on the peripheral blood lymphocyte (PBL) proliferation in response to concanavalin A (ConA) and lipopolysaccharide, but supplemental CoQ10 alone and L-carnitine+ CoQ10 together decreased the PBL proliferation in response to ConA (p < 0.05). The present study suggested that L-carnitine + CoQ10 supplementation together had positive effects on some immune response of ascites-susceptible broilers, which might benefit for the reduction of broilers

Enhancement of learning capacity and cholinergic synaptic function by carnitine in aging rats.

PubMed

Ando, S; Tadenuma, T; Tanaka, Y; Fukui, F; Kobayashi, S; Ohashi, Y; Kawabata, T

2001-10-15

The effects of a carnitine derivative, acetyl-L-carnitine (ALCAR), on the cognitive and cholinergic activities of aging rats were examined. Rats were given ALCAR (100 mg/kg) per os for 3 months and were subjected to the Hebb-Williams tasks and a new maze task, AKON-1, to assess their learning capacity. The learning capacity of the ALCAR-treated group was superior to that of the control. Cholinergic activities were determined with synaptosomes isolated from the cortices. The high-affinity choline uptake by synaptosomes, acetylcholine synthesis in synaptosomes, and acetylcholine release from synaptosomes on membrane depolarization were all enhanced in the ALCAR group. This study indicates that chronic administration of ALCAR increases cholinergic synaptic transmission and consequently enhances learning capacity as a cognitive function in aging rats. Copyright 2001 Wiley-Liss, Inc.

Effects of L-carnitine on reproductive performance, milk composition, placental development and IGF concentrations in blood plasma and placental chorions in sows.

PubMed

Zhang, Shihai; Tian, Min; Song, Hanqing; Shi, Kui; Wang, Yijiang; Guan, Wutai

2018-05-29

Recent studies have shown that L-carnitine supplementation of sows during pregnancy and lactation enhances their reproductive performance, but the underlying mechanisms are still needed to be further confirmed. This study was conducted to investigate the function of L-carnitine on placental development, milk nutrient content and release of hormones in sows. In this experiment, 40 multiparous crossbred sows (Yorkshire × Landrace) were allotted to two groups fed diets with or without a supplemental 50 mg/kg L-carnitine. The experimental diets were fed from d 1 post-coitus until d 21 post-partum. L-carnitine-treated sow had fewer weak piglets (p < 0.05) and a greater percentage of oestrus by 5 after 5-d post-partum (p < 0.05) than control sows. The percentage fat from colostrum was greater in L-carnitine-treated sow than control sows (p < 0.05). L-carnitine-treated sows had greater plasma concentrations of triglyceride and insulin-like growth factor (IGF)-1 and lesser plasma concentrations of glucose and IGF-binding protein (IGFBP-3) on day 60 of pregnancy (p < 0.05). A clearer structure of chorions, better-developed capillaries and absence of necrosis were observed in L-carnitine-treated sows compared with control sows. The protein abundance of IGF-1 and IGF-2 in placental chorions was greater in L-carnitine-treated sows compared with control sows (p < 0.05). This study suggests that sows fed an L-carnitine supplemented diet during pregnancy improved reproductive performance through enhancement of placental development and by increasing IGF concentrations in blood plasma and placental chorions.

Carnitine for fatigue in multiple sclerosis.

PubMed

Tejani, Aaron M; Wasdell, Michael; Spiwak, Rae; Rowell, Greg; Nathwani, Shabita

2012-05-16

-comparator, cross-over trial. In the completed study, adult patients with relapsing-remitting and secondary progressive MS were exposed to both acetyl L-carnitine 2 grams daily and amantadine 200 mg daily The effects of carnitine on fatigue are unclear. There was no difference between carnitine and amantadine for the number of patients withdrawing from the study due to an adverse event (relative risk ratio 0.20; 95% confidence interval 0.03 to 1.55) and no patients experienced a serious adverse event in either treatment group. Mortality and quality of life were not reported. There is insufficient evidence that carnitine for the treatment of MS-related fatigue offers a therapeutic advantage over placebo or active comparators. Results of the ongoing trial are eagerly anticipated in order to provide clarity.

Pro-inflammatory and oxidative stress pathways which compromise sperm motility and survival may be altered by L-carnitine

PubMed Central

Helal, Gouda K; Al-Yahya, Abdulaziz A; Aleisa, Abdulaziz M; Al-Rejaie, Salim S; Al-Bakheet, Saleh A

2009-01-01

The testis is an immunologically privileged organ. Sertoli cells can form a blood-testis barrier and protect sperm cells from self-immune system attacks. Spermatogenesis may be inhibited by severe illness, bacterial infections and chronic inflammatory diseases but the mechanism(s) is poorly understood. Our objective is to help in understanding such mechanism(s) to develop protective agents against temporary or permanent testicular dysfunction. Lipopolysaccaride (LPS) is used as a model of animal sepsis while L-carnitine (LCR) is used as a protective agent. A total of 60 male Swiss albino rats were divided into four groups (15/group). The control group received Saline; the 2nd group was given LCR (500 mg/kg i.p, once). The third group was treated with LPS (5 mg/kg i.p once) and the fourth group received LCR then LPS after three hours. From each group, five rats were used for histopathological examination. Biochemical parameters were assessed in the remaining ten rats. At the end of the experiment, animals were lightly anaesthetized with ether where blood samples were collected and testes were dissected on ice. Sperm count and motility were evaluated from cauda epididymis in each animal. Also, oxidative stress was evaluated by measuring testicular contents of reduced glutathione (GSH), malondialdehyde (MDA) and 8-hydroxydeoxyguanosine (8-HDG, the DNA adduct for oxidative damage) in testicular DNA. The pro-inflammatory mediator nitric oxide (NO) in addition to lactate dehydrogenase (LDHx) isoenzyme-x activity as an indicator for normal spermatozoal metabolism were assessed in testicular homogenate. Serum interlukin (IL)-2 level was also assessed as a marker for T-helper cell function. The obtained data revealed that LPS induced marked reductions in sperm's count and motility, obstruction in seminiferous tubules, hypospermia and dilated congested blood vessels in testicular sections concomitant with decreased testicular GSH content and LDHx activity. Moreover, the

The effects of L-carnitine on spinal cord ischemia/reperfusion injury in rabbits.

PubMed

Tetik, O; Yagdi, T; Islamoglu, F; Calkavur, T; Posacioglu, H; Atay, Y; Ayik, F; Canpolat, L; Yuksel, M

2002-02-01

Paraplegia after distal aortic aneurysm repair remains a persistent clinical problem. We hypothesized that the tolerance of the spinal cord to an ischemic period could be improved with hypothermic Ringer's Lactate containing L-Carnitine. Twenty-eight New Zealand white rabbits were used as spinal cord ischemia models. We separated rabbits into four equal groups and clamped each animal's abdominal aorta distal to the left renal artery. We occluded the aortas above the iliac bifurcation for 30 minutes. In group I, the infrarenal aorta was clamped without infusing any solution. In group II, Ringer's Lactate solution was infused at + 25degrees C for 3 minutes at a rate of 5 ml/min into the isolated aortic segments immediately after cross-clamping and the last 3 minutes of ischemia. In group III, Ringer's Lactate solution at +3 degrees C was given in the same method as that of group II. In group IV, Ringer's Lactate solution at +3 degrees C plus 100 mg/kg of L-carnitine was infused using the same technique. We assessed the neurological status of the hind limbs 24 and 48 hours after operation according to Tarlov's criteria. All animals were sacrificed and spinal cords were harvested for histological analyses. The neurological status in groups III and IV was significantly superior to that of groups I and II. All the animals in group I had complete hind-limb paraplegia. Complete hind-limb paraplegia occurred in 5 rabbits in group II. Two of the 7 animals in group III had spastic paraplegia, and none at all in group IV. Histological analysis of the cross-clamped segments of the rabbits with paraplegia in group I, II and III revealed changes consistent with ischemic injury, while findings were normal for the normal animals in group III and IV. In this model, the infusion of hypothermic Ringer's Lactate contained L-carnitine provided sufficient spinal cord protection against ischemia. Clinically, this may be a useful adjunct for prevention of paraplegia during surgery of the

Studies concerning chronic and acute effects of L-carnitina in elite athletes.

PubMed

Drăgan, I G; Vasiliu, A; Georgescu, E; Eremia, N

1989-01-01

Chronic and acute effects of L-Carnitina (vials of 1 g L-Carnitina endovenous; per orally administered vials of 1 g L-Carnitina; tablets of 1 g L-Carnitina) were recorded in 110 top athletes (rowing, kayak-canoe, swimming, weightlifting medium and long-distance runners), 47 girls and 63 boys, by six double blind placebo trials and cross over. Significant changes were registered after L-Carnitina treatment (both for a single dose or after 3 weeks of treatment) compared to placebo, for FFA, triglycenides, lactic acid after exercise, evoked muscular potential, plasma carnitine (free and acetyl-carnitine), urine carnitine (free carnitine) and others. The authors explain these changes by the increase of free carnitine, which permits a larger quantity of FFA to enter the mitochondria and to be more extensively used as energy source in endurance and strength efforts. Based on these results the authors recommend L-Carnitina as an ergogenic aid in elite athletes, especially in endurance and strength sports.

Effects of Oral L-Carnitine Administration in Narcolepsy Patients: A Randomized, Double-Blind, Cross-Over and Placebo-Controlled Trial

PubMed Central

Miyagawa, Taku; Kawamura, Hiromi; Obuchi, Mariko; Ikesaki, Asuka; Ozaki, Akiko; Tokunaga, Katsushi; Inoue, Yuichi; Honda, Makoto

2013-01-01

Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness, cataplexy, and rapid eye movement (REM) sleep abnormalities. A genome-wide association study (GWAS) identified a novel narcolepsy-related single nucleotide polymorphism (SNP), which is located adjacent to the carnitine palmitoyltransferase 1B (CPT1B) gene encoding an enzyme involved in β-oxidation of long-chain fatty acids. The mRNA expression levels of CPT1B were associated with this SNP. In addition, we recently reported that acylcarnitine levels were abnormally low in narcolepsy patients. To assess the efficacy of oral l-carnitine for the treatment of narcolepsy, we performed a clinical trial administering l-carnitine (510 mg/day) to patients with the disease. The study design was a randomized, double-blind, cross-over and placebo-controlled trial. Thirty narcolepsy patients were enrolled in our study. Two patients were withdrawn and 28 patients were included in the statistical analysis (15 males and 13 females, all with HLA-DQB1*06:02). l-carnitine treatment significantly improved the total time for dozing off during the daytime, calculated from the sleep logs, compared with that of placebo-treated periods. l-carnitine efficiently increased serum acylcarnitine levels, and reduced serum triglycerides concentration. Differences in the Japanese version of the Epworth Sleepiness Scale (ESS) and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) vitality and mental health subscales did not reach statistical significance between l-carnitine and placebo. This study suggests that oral l-carnitine can be effective in reducing excessive daytime sleepiness in narcolepsy patients. Trial Registration University hospital Medical Information Network (UMIN) UMIN000003760 PMID:23349733

L-Carnitine/Simvastatin Reduces Lipoprotein (a) Levels Compared with Simvastatin Monotherapy: A Randomized Double-Blind Placebo-Controlled Study.

PubMed

Florentin, M; Elisaf, M S; Rizos, C V; Nikolaou, V; Bilianou, E; Pitsavos, C; Liberopoulos, E N

2017-01-01

Lipoprotein (a) [Lp(a)] is an independent risk factor for cardiovascular disease. There are currently limited therapeutic options to lower Lp(a) levels. L-Carnitine has been reported to reduce Lp(a) levels. The aim of this study was to compare the effect of L-carnitine/simvastatin co-administration with that of simvastatin monotherapy on Lp(a) levels in subjects with mixed hyperlipidemia and elevated Lp(a) concentration. Subjects with levels of low-density lipoprotein cholesterol (LDL-C) >160 mg/dL, triacylglycerol (TAG) >150 mg/dL and Lp(a) >20 mg/dL were included in this study. Subjects were randomly allocated to receive L-carnitine 2 g/day plus simvastatin 20 mg/day (N = 29) or placebo plus simvastatin 20 mg/day (N = 29) for a total of 12 weeks. Lp(a) was significantly reduced in the L-carnitine/simvastatin group [-19.4%, from 52 (20-171) to 42 (15-102) mg/dL; p = 0.01], but not in the placebo/simvastatin group [-6.7%, from 56 (26-108) to 52 (27-93) mg/dL, p = NS versus baseline and p = 0.016 for the comparison between groups]. Similar significant reductions in total cholesterol, LDL-C, apolipoprotein (apo) B and TAG were observed in both groups. Co-administration of L-carnitine with simvastatin was associated with a significant, albeit modest, reduction in Lp(a) compared with simvastatin monotherapy in subjects with mixed hyperlipidemia and elevated baseline Lp(a) levels.

Cisplatin neuropathy. Risk factors, prognosis, and protection by WR-2721

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mollman, J.E.; Glover, D.J.; Hogan, W.M.

1988-06-01

A prospective study of patients receiving cis-diaminedichloroplatin II (DDP) was carried out to determine if risk factors could be identified related to the patient's living habits or past medical history that would predict in which patients DDP neuropathy might develop. Sixty-nine patients receiving six different combinations of chemotherapeutic agents, including DDP were examined. Twenty-eight of these patients received DDP in combination with the radioprotective agent S-2-(3-aminopropylamino)-ethylphosporothioic acid (WR 2721). No risk factors were identified relating to personal habits or past medical history of the patients. However, patients receiving DDP (40 mg/m2) on 5 consecutive days had a significantly higher incidencemore » of neuropathy. Patients receiving DDP in combination with WR 2721 had a significantly lower incidence of neuropathy, and the mean dose at onset was significantly higher than the mean dose at onset of neuropathy for all other groups. In addition, five of six patients who were available for long-term follow-up demonstrated nearly complete reversal of the signs and symptoms of neuropathy.« less

In vitro susceptibility of Scedosporium isolates to N-acetyl-L-cysteine alone and in combination with conventional antifungal agents.

PubMed

Homa, Mónika; Galgóczy, László; Tóth, Eszter; Virágh, Máté; Chandrasekaran, Muthusamy; Vágvölgyi, Csaba; Papp, Tamás

2016-10-01

In recent years, Scedosporium species have been more commonly recognized from severe, difficult-to-treat human infections, such as upper respiratory tract and pulmonary infections. To select an appropriate therapeutic approach for these infections is challenging, because of the commonly observed resistance of the causative agents to several antifungal drugs. Therefore, to find a novel strategy for the treatment of pulmonary Scedosporium infections the in vitro antifungal effect of a mucolytic agent, N-acetyl-L-cysteine and its in vitro combinations with conventional antifungals were investigated. Synergistic and indifferent interactions were registered in 23 and 13 cases, respectively. Antagonism was not revealed between the compounds. © The Author 2016. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

L-carnitine supplementation for the management of fatigue in patients with hypothyroidism on levothyroxine treatment: a randomized, double-blind, placebo-controlled trial.

PubMed

An, Jee Hyun; Kim, Yoon Jung; Kim, Kyeong Jin; Kim, Sun Hwa; Kim, Nam Hoon; Kim, Hee Young; Kim, Nan Hee; Choi, Kyung Mook; Baik, Sei Hyun; Choi, Dong Seop; Kim, Sin Gon

2016-10-29

Hypothyroid patients experience fatigue-related symptoms despite adequate thyroid hormone replacement. Thyroid hormone plays an essential role in carnitine-dependent fatty acid import and oxidation. We investigated the effects of L-carnitine supplementation on fatigue in patients with hypothyroidism. In total, 60 patients (age 50.0 ± 9.2 years, 3 males, 57 females) who still experienced fatigue (fatigue severity scale [FSS] score ≥ 36) were given L-carnitine (n = 30, 990 mg L-carnitine twice daily) or placebo (n = 30) for 12 weeks. After 12 weeks, although neither the FSS score nor the physical fatigue score (PFS) changed significantly, the mental fatigue score (MFS) was significantly decreased by treatment with L-carnitine compared with placebo (from 4.5 ± 1.9 to 3.9 ± 1.5 vs. from 4.2 ± 1.8 to 4.6 ± 1.6, respectively; P < 0.01). In the L-carnitine group, 75.0%, 53.6%, and 50.0% of patients showed improvement in the FSS score, PFS, and MFS, respectively, but only 20.0%, 24.0%, and 24.0%, respectively, did so in the placebo group (all P < 0.05). Both the PFS and MFS were significantly improved in patients younger than 50 years and those with free T3 ≥ 4.0 pg/mL by treatment with L-carnitine compared with placebo. Additionally, the MFS was significantly improved in patients taking thyroid hormone after thyroid cancer surgery. These results suggest that L-carnitine supplementation may be useful in alleviating fatigue symptoms in hypothyroid patients, especially in those younger than 50 years and those who have hypothyroidism after thyroidectomy for thyroid cancer (ClinicalTrials.gov: NCT01769157).

Effects of dietary L-carnitine and ractopamine HCl on the metabolic response to handling in finishing pigs.

PubMed

James, B W; Tokach, M D; Goodband, R D; Nelssen, J L; Dritz, S S; Owen, K Q; Woodworth, J C; Sulabo, R C

2013-09-01

Two experiments (384 pigs; C22 × L326; PIC) were conducted to determine the interactive effect of dietary L-carnitine and ractopamine HCl (RAC) on the metabolic response of pigs to handling. Experiments were arranged as split-split plots with handling as the main plot and diets as subplots (4 pens per treatment). Dietary L-carnitine (0 or 50 mg/kg) was fed from 36.0 kg to the end of the experiments (118 kg), and RAC (0 or 20 mg/kg) was fed the last 4 wk of each experiment. At the end of each experiment, 4 pigs per pen were assigned to 1 of 2 handling treatments. Gently handled pigs were moved at a moderate walking pace 3 times through a 50-m course and up and down a 15° loading ramp. Aggressively handled pigs were moved as fast as possible 3 times through the same course, but up and down a 30° ramp, and shocked 3 times with an electrical prod. Blood was collected immediately before and after handling in Exp. 1 and immediately after and 1 h after handling in Exp. 2. Feeding RAC increased (P < 0.01) ADG and G:F, but there was no effect (P > 0.10) of L-carnitine on growth performance. In Exp. 1 and 2, aggressive handling increased (P < 0.01) blood lactate dehydrogenase (LDH), lactate, cortisol, and rectal temperature and decreased blood pH. In Exp. 1, there was a RAC × handling interaction (P < 0.06) for the difference in pre- and posthandling blood pH and rectal temperature. Aggressively handled pigs fed RAC had decreased blood pH and increased rectal temperature compared with gently handled pigs, demonstrating the validity of the handling model. Pigs fed RAC had increased (P < 0.01) LDH compared with pigs not fed RAC. Pigs fed L-carnitine had increased (P < 0.03) lactate compared with pigs not fed L-carnitine. In Exp. 2, pigs fed RAC had lower (P < 0.02) blood pH immediately after handling, but pH returned to control levels by 1 h posthandling. Lactate, LDH, cortisol, and rectal temperature changes from immediately posthandling to 1 h posthandling were not

N-acetyl-l-methionine is a superior protectant of human serum albumin against photo-oxidation and reactive oxygen species compared to N-acetyl-L-tryptophan.

PubMed

Kouno, Yousuke; Anraku, Makoto; Yamasaki, Keishi; Okayama, Yoshiro; Iohara, Daisuke; Ishima, Yu; Maruyama, Toru; Kragh-Hansen, Ulrich; Hirayama, Fumitoshi; Otagiri, Masaki

2014-09-01

Sodium octanoate (Oct) and N-acetyl-l-tryptophan (N-AcTrp) are widely used as stabilizers during pasteurization and storage of albumin products. However, exposure to light photo-degrades N-AcTrp with the formation of potentially toxic compounds. Therefore, we have examined the usefulness of N-acetyl-l-methionine (N-AcMet) in comparison with N-AcTrp for long-term stability, including photo stability, of albumin products. Recombinant human serum albumin (rHSA) with and without additives was photo-irradiated for 4weeks. The capability of the different stabilizers to scavenge reactive oxygen species (ROS) was examined by ESR spectrometry. Carbonyl contents were assessed by a spectrophotometric method using fluoresceinamine and Western blotting, whereas the structure of rHSA was examined by SDS-PAGE, far-UV circular dichroism and differential scanning calorimetry. Binding was determined by ultrafiltration. N-AcMet was found to be a superior ROS scavenger both before and after photo-irradiation. The number of carbonyl groups formed was lowest in the presence of N-AcMet. According to SDS-PAGE, N-AcMet stabilizes the monomeric form of rHSA, whereas N-AcTrp induces degradation of rHSA during photo-irradiation. The decrease in α-helical content of rHSA was the smallest in the presence of Oct, without or with N-AcMet. Photo-irradiation did not affect the denaturation temperature or calorimetric enthalpy of rHSA, when N-AcMet was present. The weakly bound N-AcMet is a superior protectant of albumin, because it is a better ROS-protector and structural stabilizer than N-AcTrp, and it is probable and also useful for other protein preparations. N-AcMet is an effective stabilizer of albumin during photo-irradiation, while N-Ac-Trp promotes photo-oxidative damage to albumin. Copyright © 2014 Elsevier B.V. All rights reserved.

L-Carnitine supplementation improved clinical status without changing oxidative stress and lipid profile in women with knee osteoarthritis.

PubMed

Malek Mahdavi, Aida; Mahdavi, Reza; Kolahi, Sousan; Zemestani, Maryam; Vatankhah, Amir-Mansour

2015-08-01

Considering the pathologic importance of oxidative stress and altered lipid metabolism in osteoarthritis (OA), this study aimed to investigate the effect of l-carnitine supplementation on oxidative stress, lipid profile, and clinical status in women with knee OA. We hypothesized that l-carnitine would improve clinical status by modulating serum oxidative stress and lipid profile. In this randomized double-blind, placebo-controlled trial, 72 overweight or obese women with mild to moderate knee OA were randomly allocated into 2 groups to receive 750 mg/d l-carnitine or placebo for 8 weeks. Dietary intake was evaluated using 24-hour recall for 3 days. Serum malondialdehyde (MDA), total antioxidant capacity (TAC) and lipid profile, visual analog scale for pain intensity, and patient global assessment of severity of disease were assessed before and after supplementation. Only 69 patients (33 in the l-carnitine group and 36 in the placebo group) completed the study. l-Carnitine supplementation resulted in significant reductions in serum MDA (2.46 ± 1.13 vs 2.16 ± 0.94 nmol/mL), total cholesterol (216.09 ± 34.54 vs 206.12 ± 39.74 mg/dL), and low-density lipoprotein cholesterol (129.45 ± 28.69 vs 122.05 ± 32.76 mg/dL) levels compared with baseline (P < .05), whereas these parameters increased in the placebo group. Serum triglyceride, high-density lipoprotein cholesterol, and TAC levels did not change significantly in both groups (P > .05). No significant differences were observed in dietary intake, serum lipid profile, MDA, and TAC levels between groups after adjusting for baseline values and covariates (P > .05). There were significant intragroup and intergroup differences in pain intensity and patient global assessment of disease status after supplementation (P < .05). Collectively, l-carnitine improved clinical status without changing oxidative stress and lipid profile significantly in women with knee OA. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of L-Carnitine Supplementation on Reverse Remodeling in Patients with Ischemic Heart Disease Undergoing Coronary Artery Bypass Grafting: A Randomized, Placebo-Controlled Trial.

PubMed

da Silva Guimarães, Sheila; de Souza Cruz, Wanise; da Silva, Licinio; Maciel, Gabrielle; Huguenin, Ana Beatriz; de Carvalho, Monicque; Costa, Bárbara; da Silva, Geisiane; da Costa, Carlos; D'Ippolito, João Alvaro; Colafranceschi, Alexandre; Scalco, Fernanda; Boaventura, Gilson

2017-01-01

During cardiac failure, cardiomyocytes have difficulty in using the substrates to produce energy. L-carnitine is a necessary nutrient for the transport of fatty acids that are required for generating energy. Coronary artery graft surgery reduces the plasma levels of L-carnitine and increases the oxidative stress. This study demonstrates the effect of L-carnitine supplementation on the reverse remodeling of patients undergoing coronary artery bypass graft. Patients with ischemic heart failure who underwent coronary graft surgery were randomized to group A - supplemented with L-carnitine or group B controls. Left ventricular ejection fraction, left ventricular systolic and diastolic diameters were assessed preoperatively, 60 and 180 days after surgery. Our study included 28 patients (26 [93.0%] males) with a mean age ± SD of 58.1 ± 10.5 years. The parameters for the evaluation of reverse remodeling did not improve after 60 and 180 days of coronary artery bypass grafting in comparison between groups (p > 0.05). Evaluation within the L-carnitine group showed a 37.1% increase in left ventricle ejection fraction (p = 0.002) and 14.3% (p = 0.006) and 3.3% (p > 0.05) reduction in systolic and diastolic diameters, respectively. L-carnitine supplementation at a dose of 50 mg/kg combined with artery bypass surgery did not demonstrate any additional benefit in reverse remodeling. However, evaluation within the L-carnitine group may indicate a clinical benefit of L-carnitine supplementation. © 2017 S. Karger AG, Basel.

Acetyl-L-carnitine activates the peroxisome proliferator-activated receptor-γ coactivators PGC-1α/PGC-1β-dependent signaling cascade of mitochondrial biogenesis and decreases the oxidized peroxiredoxins content in old rat liver.

PubMed

Pesce, Vito; Nicassio, Luigi; Fracasso, Flavio; Musicco, Clara; Cantatore, Palmiro; Gadaleta, Maria Nicola

2012-04-01

The behavior of the peroxisome proliferator-activated receptor-γ coactivators PGC-1α/PGC-β-dependent mitochondrial biogenesis signaling pathway, as well as the level of some antioxidant enzymes and proteins involved in mitochondrial dynamics in the liver of old rats before and after 2 months of acetyl-L-carnitine (ALCAR) supplementation, was tested. The results reveal that ALCAR treatment is able to reverse the age-associated decline of PGC-1α, PGC-1β, nuclear respiratory factor 1 (NRF-1), mitochondrial transcription factor A (TFAM), nicotinamide adenine dinucleotide (NADH) dehydrogenase subunit 1 (ND1), and cytochrome c oxidase subunit IV (COX IV) protein levels, of mitochondrial DNA (mtDNA) content, and of citrate synthase activity. Moreover, it partially reverses the mitochondrial superoxide dismutase 2 (SOD2) decline and reduces the cellular content of oxidized peroxiredoxins. These data demonstrate that ALCAR treatment is able to promote in the old rat liver a new mitochondrial population that can contribute to the cellular oxidative stress reduction. Furthermore, a remarkable decline of Drp1 and of Mfn2 proteins is reported here for the first time, suggesting a reduced mitochondrial dynamics in aging liver with no effect of ALCAR treatment.

Absolute and Relative Carnitine Deficiency in Patients on Hemodialysis and Peritoneal Dialysis.

PubMed

Naseri, Mitra; Mottaghi Moghadam Shahri, Hasan; Horri, Mohsen; Esmaeeli, Mohammad; Ghaneh Sherbaf, Fatemeh; Jahanshahi, Shohre; Moeenolroayaa, Giti; Rasoli, Zahra; Salemian, Farzaneh; Pour Hasan, Maryam

2016-01-01

Carnitine deficiency is commonly seen in dialysis patients. This study assessed the association dialysis and pediatric patients' characteristics with plasma carnitines levels. Plasma carnitine concentrations were measured by tandem mass spectrometry in 46 children on hemodialysis or peritoneal dialysis. The total carnitine, free carnitine (FC), and L-acyl carnitine (AC) levels of 40 µmol/L and less, less than 7 µmol/L, and less than 15 µmol/L were defined low, respectively. An FC less than 20 µmol/L and an AC/FC ratio greater than 0.4 were considered as absolute and relative carnitine deficiencies. The correlation between carnitines levels and AC/FC ratio and age, duration of dialysis, characteristics of dialysis, and blood urea nitrogen and serum albumin concentrations were assessed. Absolute carnitine deficiency, low total carnitine, and low AC concentrations were found in 66.7%, 82.6%, and 51% of the patients, respectively. All of the patients had relative carnitine deficiency. Carnitine measurements were not significantly different between the hemodialysis and peritoneal dialysis groups. More severe relative carnitine deficiency was found in those with lower blood urea nitrogen levels and those on peritoneal dialysis. No linear correlation was found between carnitine levels and age, duration of dialysis, characteristics of dialysis, serum albumin level, or blood urea nitrogen level. Absolute and relative carnitine deficiencies are common among children on dialysis. Patients with lower blood urea nitrogen levels and peritoneal dialysis patients are more prone to severe relative carnitine deficiency.

[Effect and safety of L-carnitine in the treatment of idiopathic oligoasthenozoospermia: a systemic review].

PubMed

Shang, Xue-jun; Wang, Ling-ling; Mo, Dun-sheng; Cai, Hong-cai; Zheng, Da-dong; Zhou, Yuan-zhong

2015-01-01

To evaluate the effect and safety of L-carnitine in the treatment of idiopathic oligoasthenozoospermia based on current clinical evidence. We searched the Cochrane Library, PubMed, MEDLINE, EMBASE, CNKI, VIP, CBM and Wanfang Database from the establishment to April 2014 for the published literature on the treatment of idiopathic oligoasthenozoospermia with L-carnitine. We conducted literature screening, data extraction, and assessment of the methodological quality of the included trials according to the inclusion and exclusion criteria, followed by statistical analysis with the RevMan 5. 2 software. Seven randomized controlled trials involving 751 patients with idiopathic oligoasthenozoospermia met the inclusion criteria, and 678 of them were included in the meta-analysis. L-carnitine treatment achieved a significantly increased rate of spontaneous pregnancy as compared with the control group (RR = 3.2, 95% CI 1.74 to 5.87, P = 0.0002). After 12-16 and 24-26 weeks of medication, total sperm motility (WMD = 5.21, 95% CI 2.78 to 7.64, P < 0.0001 and WMD = 9.29, 95% CI 1.28 to 17.29, P = 0.02) and the percentage of progressively motile sperm (WMD = 12.44, 95% CI 4.58 to 20.31, P = 0.002 and WMD = 9.76, 95% CI 3.56 to 15.97, P = 0.002) were remarkably higher than those in the control group, but no statistically significant differences were observed in sperm concentration between the two groups (WMD = 4.91, 95% CI -2.63 to 12.45, P = 0.2 and WMD = 0.93, 95% CI -3.48 to 5.34, P = 0.68). After 12-16 weeks of treatment, the percentage of morphologically abnormal sperm was markedly decreased in the L-carnitine group as compared with the control (WMD = -2.48, 95% CI -4.35 to -0.61, P = 0.009), but showed no significant difference from the latter group after 24-26 weeks (WMD = -4.38, 95% CI -9.66 to 0.89, P = 0.1). No statistically significant difference was found in the semen volume between the two groups after 12-16 or 24-26 weeks of medication (WMD = -0.13, 95% CI -0.43 to

Low-dose D-methionine and N-acetyl-L-cysteine for protection from permanent noise-induced hearing loss in chinchillas.

PubMed

Clifford, Royce E; Coleman, John K M; Balough, Ben J; Liu, Jianzhong; Kopke, Richard D; Jackson, Ronald L

2011-12-01

Despite efforts at public health awareness and stringent industrial standards for hearing protection, noise-induced hearing loss (NIHL) remains a formidable public health concern. Although many antioxidants have proven to be beneficial in the laboratory for prevention of permanent NIHL, low-dose combinations of compounds with different biochemical mechanisms of action may allow long-term administration with fewer side effects and equal efficacy. The mixture of D-methionine and N-acetyl-L-cysteine administered at levels less than 10% of standard dosing has not been previously reported. Twenty-six female adult Chinchilla laniger were placed in 4 study groups, consisting of (1) a group receiving combination 12.5 mg/kg each D-methionine and N-acetyl-L-cysteine (DMET/NAC group), (2) a group receiving 12.5 mg/kg D-methionine (DMET-only group), (3) a group receiving 12.5 mg/kg N-acetyl-L-cysteine (NAC-only group), and (4) saline controls. Laboratory. All groups received twice-daily intraperitoneal injections 2 days prior to noise exposure, 1 hour before and after exposure on day 3, and for 2 days subsequently, totaling 10 doses of 125 mg/kg for each antioxidant over 5 days. Although NAC-only animals paralleled saline control recovery during 3 weeks, the DMET-only group revealed gradual improvement with statistically significant recovery in the middle frequencies. The DMET/NAC group showed significant improvement at most frequencies compared with controls (P < .001 and P < .05). Significant recovery of hearing was observed following continuous noise exposure with either DMET only or a combination of low-dose DMET/NAC, demonstrating a considerably lower dose of antioxidants required than previously reported for hearing recovery following acoustic trauma.

Effect of dosage and application mode of L-carnitine on plasma lipid and egg-yolk cholesterol of turkeys, hatchability of eggs and post-hatch growth of their offsprings.

PubMed

Oso, A O; Fafiolu, A O; Adeleke, M A; Ladokun, O A; Sobayo, R A; Jegede, A V; Peters, S O; Oyebamiji, O A; Akinsola, J

2014-08-01

The effect of dosage and application mode of L-carnitine on plasma lipid and egg-yolk cholesterol of breeder turkeys, hatchability of eggs and post-hatch growth response was investigated using 180 breeder hens. The hens were assigned to six dietary treatments in a 2 × 3 factorial arrangements of two application modes of L-carnitine (diet and drinking water) supplemented at 0, 50 and 100 ppm (mg/kg or mg/l) levels, respectively. Each treatment was replicated five times with six hens per replicate. Dietary inclusion of 50 ppm L-carnitine showed the lowest (p < 0.01) plasma total cholesterol (TC) and low-density lipoprotein concentration (LDL). Breeder hens offered 50 ppm L-carnitine with no regard to application mode recorded the highest (p < 0.01) plasma high-density lipoprotein (HDL). Hens offered 50 and 100 ppm L-carnitine irrespective of application mode also showed reduced (p < 0.01) egg-yolk TC concentration at 32 weeks of age. Dietary supplementation of 50 ppm L-carnitine for breeder turkeys recorded the lowest (p < 0.01) egg-yolk triglyceride (TG) at 40 weeks of age. Hens offered 50 ppm L-carnitine irrespective of application mode recorded the highest (p < 0.05) hen-day egg production. Incidence of dead-in-shell also reduced (p < 0.05) with increasing dosage of L-carnitine. Dietary supplementation of 50 ppm and oral application in drinking water of 100 ppm L-carnitine for breeder turkeys resulted in highest (p < 0.05) egg fertility. Offsprings from breeder hens fed diets supplemented with L-carnitine recorded no post-hatch mortality. Highest (p < 0.05) post-hatch final live weight and weight gain was obtained with poults obtained from hens fed diet supplemented with 50 ppm L-carnitine. In conclusion, dietary supplementation of 50 ppm L-carnitine for turkey hens showed improved serum lipid profile, egg fertility, reduced dead-in-shell, egg-yolk cholesterol and resulted in improved post-hatch growth performance.

Protective effects of deferasirox and N-acetyl-L-cysteine on iron overload-injured bone marrow.

PubMed

Shen, J C; Zhang, Y C; Zhao, M F

2017-10-19

Using an iron overload mouse model, we explored the protective effect of deferasirox (DFX) and N-acetyl-L-cysteine (NAC) on injured bone marrow hematopoietic stem/progenitor cells (HSPC) induced by iron overload. Mice were intraperitoneally injected with 25 mg iron dextran every 3 days for 4 weeks to establish an iron overload (Fe) model. DFX or NAC were co-administered with iron dextran in two groups of mice (Fe+DFX and Fe+NAC), and the function of HSPCs was then examined. Iron overload markedly decreased the number of murine HSPCs in bone marrow. Subsequent colony-forming cell assays showed that iron overload also decreased the colony forming capacity of HSPCs, the effect of which could be reversed by DFX and NAC. The bone marrow hematopoiesis damage caused by iron overload could be alleviated by DFX and NAC.

[ACTION OF L-CARNITINE, CORVITIN AND THEIR COMBINATION ON FUNCTIONAL STATE OF LIVER IN EXPERIMENTAL MODEL OF REYE SYNDROME IN RATS].

PubMed

Ghonghadze, M; Antelava, N; Liluashvili, K; Okujava, M; Pachkoria, K

2017-02-01

Administration of Aacetylsalicylic acid in children with viral infections (influence B, chickenpox) can be related with development of Reye syndrome - severe encephalopathy and liver insufficiency with mortality in 50% of cases. During Reye syndrome most important is deficiency of carnitine and hepatocyte damage. Decreased amount of carnitine impairs the energy function of mitochondria and gluconeogenesis as well as production of urea. As a result develops toxic encephalopathy and liver insufficiency. The goal of the research was assessment of efficacy of L-Carnitine, Corvitin and their combination on functional state of liver in experimental model of Reye Syndrome in rats. The study was performed on mature white male Wistar rates with body mass 150-180g. 50 rats were randomly divided into 5 groups (10 rats in each group). The model of Reye syndrome was induced in accordance with A.Vengersky's method. Intraperitoneal administration of 4-pentenoic acid was performed once daily during seven days, the used dosage was 20mg/kg. The treatment of toxic hepatitis was carried with intraperitoneal administration of L-Carnitine 300mg/kg, Corvitine 100mg/kg and concurrent administration of these drugs. Monotherapy with Corvitin and L-Carnitin successfully improved liver function and equally decreased indicators of hepatocyte's cytolyses and increased levels of glucose and urea. The markers of cholestasis was slightly more improved during use of L-Carnitine. Simultaneous use of both drugs was effective in rats with Reye syndrome, indicators of liver damage normalized and herewith, no mortality outcome was observed. The most pronounced hepatoprotective effect of concurrent administration of L-Carnitine and Corvitin may be due to synergic action of these drugs and such regime can be recommended for correction of liver function during Reye syndrome.

N-acetyl cysteine, L-cysteine, and beta-mercaptoethanol augment selenium-glutathione peroxidase activity in glucose-6-phosphate dehydrogenase-deficient human erythrocytes.

PubMed

Alicigüzel, Y; Aslan, M

2004-09-01

In glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes, failure to maintain normal levels of reduced glutathione (GSH) due to decreased NADPH regeneration in the hexose monophosphate pathway results in acute hemolytic anemia following exposure to oxidative insults, such as ingestion of Vicia fava beans or use of certain drugs. GSH is a source of protection against oxidative attack, used by the selenium-dependent glutathione peroxidase (Se-GSH-Px)/reductase (GR) system to detoxify hydrogen peroxide and organic peroxides, provided that sufficient GSH is made available. In this study, Se-GSH-Px activity was analyzed in G6PD-deficient patients in the presence of reducing agents such as N-Acetyl cysteine, L-cysteine, and beta-mercaptoethanol. Se-GSH-Px activity was decreased in G6PD-deficient red blood cells (RBCs). N-Acetyl cysteine, L-cysteine, and beta-mercaptoethanol increased Se-GSH-Px activity in G6PD-deficient human erythrocytes, indicating that other reducing agents can be utilized to complement Se-GSH-Px activity in G6PD deficiency. Based on the increased susceptibility of G6PD-deficient patients to oxidative stress, the reported increase in Se-GSH-Px activity can facilitate the detoxification of reactive oxygen species.

Decrease of serum carnitine levels in patients with or without gastrointestinal cancer cachexia.

PubMed

Malaguarnera, Mariano; Risino, Corrado; Gargante, Maria Pia; Oreste, Giovanni; Barone, Gloria; Tomasello, Anna Veronica; Costanzo, Mario; Cannizzaro, Matteo Angelo

2006-07-28

To evaluate the levels of serum carnitine in patients with cancer in digestive organs and to compare them with other cancers in order to provide new insights into the mechanisms of cachexia. Fifty-five cachectic patients with or without gastrointestinal cancer were enrolled in the present study. They underwent routine laboratory investigations, including examination of the levels of various forms of carnitine present in serum (i.e., long-chain acylcarnitine, short-chain acylcarnitine, free carnitine, and total carnitine). These values were compared with those found in 60 cancer patients in good nutritional status as well as with those of 30 healthy control subjects. When the cachectic patients with gastro-intestinal cancer were compared with the cachectic patients without gastrointestinal cancer, the difference was -6.8 micromol/L in free carnitine (P < 0.005), 0.04 micromol/L in long chain acylcarnitine (P < 0.05), 8.7 micromol/L in total carnitine (P < 0.001). In the cachectic patients with or without gastrointestinal cancer, the difference was 12.2 micromol/L in free carnitine (P < 0.001), 4.60 micromol/L in short chain acylcarnitine (P < 0.001), and 0.60 micromol /L in long-chain acylcarnitine (P < 0.005) and 17.4 micromol/L in total carnitine (P < 0.001). In the cachectic patients with gastrointestinal cancer and the healthy control subjects, the difference was 15.5 micromol/L in free carnitine (P < 0.001), 5.2 micromol /L in short-chain acylcarnitine (P < 0.001), 1.0 micromol/L in long chain acylcarnitine (P < 0.001), and 21.8 micromol/L in total carnitine (P < 0.001). Low serum levels of carnitine in terminal neoplastic patients are decreased greatly due to the decreased dietary intake and impaired endogenous synthesis of this substance. These low serum carnitine levels also contribute to the progression of cachexia in cancer patients.

Pulmonary fatty acid synthesis. I. Mitochondrial acetyl transfer by rat lung in vitro.

PubMed

Evans, R M; Scholz, R W

1977-04-01

Incorporation of tritiated water into fatty acids by rat adipose tissue and lung tissue slices incubated with 5 mM glucose indicated a level of fatty acid synthesis in rat lung approximately 15% that observed in adipose tissue in vitro. (-)-Hydroxycitrate, and inhibitor of ATP citrate lyase, markedly reduced tritiated water incorporation into fatty acids by lung tissue slices. The effects of (-)-hydroxycitrate and n-butymalonate on the incorporation of 14C-labeled glucose, pyruvate, acetate, and citrate suggested that citrate is a major acetyl carrier for de novo fatty acid synthesis in lung tissue. Alternative mechanisms to citrate as an acetyl carrier were also considered. Lung mitochondrial preparations formed significant levels of acetylcarnitine in the presence of pyruvate and carnitine. However, the effect of carnitine on the incorporation of 14C-labeled glucose, pyruvate, acetate, and citrate into fatty acids by lung tissue slices indicated that acetylcarnitine may not be a significant acetyl carrier for fatty acid synthesis but may serve as an acetyl "buffer" in the control of mitochondrial acetyl-CoA levels. Additionally, it appears unlikely that either acetylaspartate or acetoacetate are of major importance in acetyl transfer in lung tissue.

Screening of Free Carnitine and Acylcarnitine Status in Children With Familial Mediterranean Fever.

PubMed

Kiykim, Ertuğrul; Aktuğlu Zeybek, Ayşe Çiğdem; Barut, Kenan; Zübarioğlu, Tanyel; Cansever, Mehmet Şerif; Alsancak, Şeyda; Kasapçopur, Özgür

2016-06-01

This study aims to demonstrate the patterns of free carnitine (FC) and acylcarnitine (AC) esters in familial Mediterranean fever (FMF) patients. A total of 205 patients (106 males, 99 females; mean age 131.3±52.1 months; range 24 to 254 months) with FMF and 50 healthy controls (27 males, 23 females; mean age 125.7±49.6 months; range 32 to 217 months) were enrolled. Fasting dried blood samples were taken for showing FC and AC ester levels with tandem mass spectrometry from both patients and controls. Screening of AC profile revealed increased FC, 3-hydroxypalmitoylcarnitine (C16-OH), and 3-Hydroxy octadecanoylcarnitine (C18:2-OH) carnitine levels, while decreased acetyl-carnitine (C2), propionyl-carnitine (C3), butyryl-carnitine (C4), tiglyl-carnitine (C5:1), hexanoyl-carnitine (C6), octanoyl-carnitine (C8), decenoylcarnitine (C10:1), decadienoylcarnitine (C10:2), malonylcarnitine (C3DC), methylmalonylcarnitine (C4DC), glutarylcarnitine (C5DC), hexadecenoylcarnitine (C16:1), 3-Hydroxy butyrylcarnitine (C4-OH), and 3-Hydroxy oleylcarnitine (C18:1-OH) carnitine levels in FMF patients compared to controls. Total AC levels (p<0.001) and AC to FC ratio (p<0.001) were also lower in FMF patients than the controls. In this study, we were able to detect some of the AC profile variations in FMF patients; however, usage of carnitine in all patients with FMF is not recommended since we were not able to demonstrate secondary carnitine deficiency in FMF patients of this study.

Carnitine Acetyltransferase Mitigates Metabolic Inertia and Muscle Fatigue during Exercise.

PubMed

Seiler, Sarah E; Koves, Timothy R; Gooding, Jessica R; Wong, Kari E; Stevens, Robert D; Ilkayeva, Olga R; Wittmann, April H; DeBalsi, Karen L; Davies, Michael N; Lindeboom, Lucas; Schrauwen, Patrick; Schrauwen-Hinderling, Vera B; Muoio, Deborah M

2015-07-07

Acylcarnitine metabolites have gained attention as biomarkers of nutrient stress, but their physiological relevance and metabolic purpose remain poorly understood. Short-chain carnitine conjugates, including acetylcarnitine, derive from their corresponding acyl-CoA precursors via the action of carnitine acetyltransferase (CrAT), a bidirectional mitochondrial matrix enzyme. We show here that contractile activity reverses acetylcarnitine flux in muscle, from net production and efflux at rest to net uptake and consumption during exercise. Disruption of this switch in mice with muscle-specific CrAT deficiency resulted in acetyl-CoA deficit, perturbed energy charge, and diminished exercise tolerance, whereas acetylcarnitine supplementation produced opposite outcomes in a CrAT-dependent manner. Likewise, in exercise-trained compared to untrained humans, post-exercise phosphocreatine recovery rates were positively associated with CrAT activity and coincided with dramatic shifts in muscle acetylcarnitine dynamics. These findings show acetylcarnitine serves as a critical acetyl buffer for working muscles and provide insight into potential therapeutic strategies for combatting exercise intolerance. Copyright © 2015 Elsevier Inc. All rights reserved.

[Animal experiment studies on the changes in lipid and protein metabolism in L-carnitine-supplemented total parenteral nutrition].

PubMed

Böhles, H; Segerer, H; Fekl, W; Stehr, K

1983-02-01

The influence of i.v. L-carnitine on parameters of lipid- and nitrogen metabolism was studied during total parenteral nutrition of mini pigs (x: 4077; n = 9). The infusion protocol was divided into isocaloric and isonitrogenous 48-hour-periods. Amino acids (3 g/kg/day) were administered throughout all three periods. 140 Cal/kg/day were given as non-protein calories, consisting only of glucose during period 1. During periods 2 and 3 an amount of glucose calorically equivalent to 4 g fat/kg/day was substituted with a lipid emulsion. In period 3, L-carnitine (1,5 mg/kg/day) was added. During the entire regime key parameters of fat and nitrogen metabolism were determined. During all three periods indirect calorimetry was performed and the respiratory quotient calculated. The results demonstrate a more effective lipolysis and oxydation of fatty acids during L-carnitine supplementation. This results in an increased energy gain from exogenously administered fat and a distinct improvement of nitrogen balance.

Acetyl-coenzyme A deacylase activity in liver is not an artifact. Subcellular distribution and substrate specificity of acetyl-coenzyme A deacylase activities in rat liver

PubMed Central

Grigat, Klaus-P.; Koppe, Klaus; Seufert, Claus-D.; Söling, Hans-D

1979-01-01

Whole liver and isolated liver mitochondria are able to release free acetate, especially under conditions of increased fatty acid oxidation. In the present paper it is shown that rat liver contains acetyl-CoA deacylase (EC 3.1.2.1) activity (0.72μmol/min per g wet wt. of liver at 30°C and 0.5mm-acetyl-CoA). At 0.5mm-acetyl-CoA 73% of total enzyme activity was found in the mitochondria, 8% in the lysosomal fraction and 19% in the postmicrosomal supernatant. Mitochondrial subfractionation shows that mitochondrial acetyl-CoA deacylase activity is restricted to the matrix space. Mitochondrial acetyl-CoA deacylase showed almost no activity with either butyryl- or hexanoyl-CoA. Acetyl-CoA hydrolase activity from purified rat liver lysosomes exhibited a very low affinity for acetyl-CoA (apparent Km>15mm compared with an apparent Km value of 0.5mm for the mitochondrial enzyme) and reacted at about the same rate with acetyl-, n-butyryl- and hexanoyl-CoA. We could not confirm the findings of Costa & Snoswell [(1975) Biochem. J. 152, 167–172] according to which mitochondrial acetyl-CoA deacylase was considered to be an artifact resulting from the combined actions of acetyl-CoA–l-carnitine acetyltransferase (EC 2.3.1.7) and acetylcarnitine hydrolase. The results are in line with the concept that free acetate released by the liver under physiological conditions stems from the intramitochondrial deacylation of acetyl-CoA. PMID:34392

Effects of dietary supplementation with L-carnitine and fat on blood acid-base responses to handling in slaughter weight pigs.

PubMed

Bertol, T M; Ellis, M; Hamilton, D N; Johnson, E W; Ritter, M J

2005-01-01

Blood acid-base responses to handling were evaluated in slaughter weight pigs fed diets supplemented with l-carnitine and fat. The study was carried out as a randomized block design with a 2 x 2 factorial arrangement of treatments: 1) dietary L-carnitine supplementation (0 vs. 150 ppm, as-fed basis); and 2) dietary fat supplementation (0 vs. 5%, as-fed basis). Sixty pigs (91.1 +/- 5.14 kg BW) were housed in mixed-gender groups of five and had ad libitum access to test diets (0.68% true ileal digestible lysine, 3,340 kcal of ME/kg, as-fed basis) for 3 wk. At the end of the feeding period (110.3 +/- 7.52 kg BW), pigs were subjected to a standard handling procedure, which consisted of moving individual animals through a facility (12.2 m long x 0.91 m wide) for eight laps (up and down the facility), using electric prods (two times per lap). There was no interaction between dietary L-carnitine and fat supplementation for any measurement. Pigs fed 150 ppm of supplemental L-carnitine had lower baseline blood glucose (P < 0.05) and higher baseline blood lactate (P < 0.05) concentrations than the nonsupplemented pigs. After handling, pigs fed L-carnitine-supplemented diets had a higher (P < 0.05) blood pH and showed a smaller (P < 0.05) decrease in blood pH and base excess than those fed the nonsupplemental diets. Baseline plasma FFA concentrations were higher (P < 0.01) in pigs fed the 5% fat diet. After the handling procedure, blood glucose, lactate, and plasma FFA were higher (P < 0.05) in pigs fed the 5 vs. 0% fat diets, but blood pH, bicarbonate, and base excess were not affected by dietary fat. The handling procedure decreased (P < 0.01) blood pH, bicarbonate, base excess, and total carbon dioxide and increased (P < 0.01) blood lactate, partial pressure of oxygen, and glucose, and also increased (P < 0.01) rectal temperature. Free fatty acid concentrations were increased by handling in pigs fed both 0 and 5% fat and 150 ppm L-carnitine. In conclusion, dietary L-carnitine

Decrease of serum carnitine levels in patients with or without gastrointestinal cancer cachexia

PubMed Central

Malaguarnera, Mariano; Risino, Corrado; Gargante, Maria Pia; Oreste, Giovanni; Barone, Gloria; Tomasello, Anna Veronica; Costanzo, Mario; Cannizzaro, Matteo Angelo

2006-01-01

AIM: To evaluate the levels of serum carnitine in patients with cancer in digestive organs and to compare them with other cancers in order to provide new insights into the mechanisms of cachexia. METHODS: Fifty-five cachectic patients with or without gastrointestinal cancer were enrolled in the present study. They underwent routine laboratory investigations, including examination of the levels of various forms of carnitine present in serum (i.e., long-chain acylcarnitine, short-chain acylcarnitine, free carnitine, and total carnitine). These values were compared with those found in 60 cancer patients in good nutritional status as well as with those of 30 healthy control subjects. RESULTS: When the cachectic patients with gastro-intestinal cancer were compared with the cachectic patients without gastrointestinal cancer, the difference was -6.8 μmol/L in free carnitine (P < 0.005), 0.04 μmol/L in long chain acylcarnitine (P < 0.05), 8.7 μmol/L in total carnitine (P < 0.001). In the cachectic patients with or without gastrointestinal cancer, the difference was 12.2 μmol/L in free carnitine (P < 0.001), 4.60 μmol/L in short chain acylcarnitine (P < 0.001), and 0.60 μmol /L in long-chain acylcarnitine (P < 0.005) and 17.4 μmol/L in total carnitine (P < 0.001). In the cachectic patients with gastrointestinal cancer and the healthy control subjects, the difference was 15.5 μmol/L in free carnitine (P < 0.001), 5.2 μmol /L in short-chain acylcarnitine (P < 0.001), 1.0 μmol/L in long chain acylcarnitine (P < 0.001), and 21.8 μmol/L in total carnitine (P < 0.001). CONCLUSION: Low serum levels of carnitine in terminal neoplastic patients are decreased greatly due to the decreased dietary intake and impaired endogenous synthesis of this substance. These low serum carnitine levels also contribute to the progression of cachexia in cancer patients. PMID:16874868

[Can the treatment with L-carnitine improve the inflammation in chronic hemodialysis patients?].

PubMed

Grazi, G; Meriggioli, M; Donati, G

2004-01-01

Inflammation in patients on chronic hemodialysis (HD) is related to malnutrition and atherosclerosis; anemia is also often present in these patients. It has been demonstrated that l-carnitina treatment, in addition to reducing the need for erythropoietin (EPO), improves nutritional parameters and cardiac performance. To evaluate the effect of l-carnitine on the inflammatory pathology in patients on chronic HD, we studied 11 patients with no sure signs of malnutrition, flogistic and infective pathologies and with C-reactive protein (CRP) <2 mg/dL. We evaluated at baseline, after 6 and 12 months CRP, serum albumin, hemoglobin (Hb),nPCR and EPO weekly requirement. We observed a reduction in CRP (from 0.88 +/- 0.65 to 0.42 +/- 0.17 mg/dL after 6 months and to 0.50 + 0.36 mg/dL after 12 months), an increase in serum albumin (from 10.9 +/- 1.23 to 2.08 +/- 1.88 and to 11.8 +/- 1.15 g/dL) and an increase in nPCR (from 0.96 +/- 0.09 to 1.15 +/- 0.2 and to 1.16 +/- 0.18 g/kg/die); EPO weekly requirement decreased (from 7363 +/- 2941 to 5909 +/- 3207 units after 6 months and to 5363 +/- 3139 units after 12 months). These results seem to underline a positive effect of l-carnitine on the inflammatory pathology of patients on chronic hemodialytic treatment.

Usefulness of L-carnitine, a naturally occurring peripheral antagonist of thyroid hormone action, in iatrogenic hyperthyroidism: a randomized, double-blind, placebo-controlled clinical trial.

PubMed

Benvenga, S; Ruggeri, R M; Russo, A; Lapa, D; Campenni, A; Trimarchi, F

2001-08-01

Old studies in animals and unblinded studies in a few hyperthyroid patients suggested that L -carnitine is a periferal antagonist of thyroid hormone action at least in some tissues. This conclusion was substantiated by our recent observation that carnitine inhibits thyroid hormone entry into the nucleus of hepatocytes, neurons, and fibroblasts. In the randomized, double-blind, placebo-controlled 6-month trial reported here, we assessed whether 2 or 4 g/d oral L-carnitine were able to both reverse and prevent/minimize nine hyperthyroidism- related symptoms. We also evaluated changes on nine thyroid hormone-sensitive biochemical parameters and on vertebral and hip mineral density (bone mineral density). Fifty women under a fixed TSH-suppressive dose of L -T(4) for all 6 months were randomly allocated to five groups of 10 subjects each. Group 0 associated placebo for 6 months; groups A2 and A4 started associating placebo (first bimester), substituted placebo with 2 or 4 g/d carnitine (second bimester), and then returned to the association with placebo. Groups B2 and B4 started associating 2 and 4 g/d carnitine for the first two bimesters, and then substituted carnitine with placebo (third bimester). Symptoms and biochemical parameters worsened in group 0. In group A, symptoms and biochemical parameters worsened during the first bimester, returned to baseline or increased minimally during the second bimester (except osteocalcin and urinary OH-proline), and worsened again in the third bimester. In group B, symptoms and biochemical parameters (except osteocalcin and urinary OH-proline) did not worsen or even improved over the first 4 months; they tended to worsen in the third bimester. In both the A and B groups, the two doses of carnitine were similarly effective. At the end of the trial, bone mineral density tended to increase in groups B and A (B > A). In conclusion, L-carnitine is effective in both reversing and preventing symptoms of hyperthyroidism and has a

Effects of carnitine and its congeners on eicosanoid discharge from rat cells: implications for release of TNFα

PubMed Central

Elliott, Graham R.; Pruimboom, Wanda M.; Zijlstra, Freek J.; Bonta, Iván L.

1993-01-01

THE acyl carrier coenzyme A (CoA) is involved in fatty acid metabolism. The carnitine/CoA ratio is of particular importance in regulating the transport of long-chain fatty acids into mitochondria for oxidation. Also CoA has a role in the formation and breakdown of products from both the cyclooxygenase and lipoxygenase pathways of the precursor arachidonic acid. In the present study the effect of 4 days feeding of 300 mg/kg/day of L-carnitine, acetyl Lcarnitine and propionyl L-carnitine on the basal and calcium ionophore (A23187) stimulated release of arachidonic acid metabolites from rat carrageenin elicited peritoneal cells was investigated. There were two series of experiments carried out. In the first, the harvested peritoneal cell population consisted of less than 90% macrophages and additional polymorphonuclear (PMN) leucocytes. The basal release of prostaglandin E2 (PGE2), 6-ketoprostaglandin F1α (6-keto-PGF1α) and leukotriene B4 (LTB4) was stimulated by all treatments. The A23187 stimulated release of 6-keto-PGF1α and LTB4 was increased by all three compounds. The 6-keto-PGF1α:TxB2 and 6-keto-PGF1α:LTB4 ratios were increased by carnitine treatment. These results suggested that carnitine could modify the macrophage component of an inflammatory site in vivo. In the second series of experiments the harvested cell population was highly purified (>95% macrophages) and none of the compounds fed to the rats caused a change of either eicosanoid or TNFα formation. Moreover the 6-keto-PGF1α:TxB2 and 6-keto-PGF1α:LTB4 ratios were not enhanced by any of the compounds tested. It is conceivable that in the first series the increased ratios 6-keto-PGF1α:TxB2 and 6-keto-PGF1α:LTB4 reflected the effect of carnitine or its congeners on PMN leucocytes rather than on macrophages. PMID:18475573

Phloem Transport of d,l-Glufosinate and Acetyl-l-Glufosinate in Glufosinate-Resistant and -Susceptible Brassica napus1

PubMed Central

Beriault, Jennifer N.; Horsman, Geoff P.; Devine, Malcolm D.

1999-01-01

Phloem transport of d,l-[14C]glufosinate, d-[14C]glufosinate, and acetyl-l-[14C]glufosinate was examined in the susceptible Brassica napus cv Excel and a glufosinate-resistant genotype (HCN27) derived by transformation of cv Excel with the phosphinothricin-N-acetyltransferase (pat) gene. Considerably more 14C was exported from an expanded leaf in HCN27 than in cv Excel following application of d,l-[14C]glufosinate (25% versus 6.3% of applied, respectively, 72 h after treatment). The inactive isomer, d-glufosinate, was much more phloem mobile in cv Excel than racemic d,l-glufosinate. Foliar or root supplementation with 1 mm glutamine increased d,l-[14C]glufosinate translocation in cv Excel but only transiently, suggesting that glutamine depletion is not the major cause of the limited phloem transport. Acetyl-l-[14C]glufosinate (applied as such or derived from l-glufosinate in pat transformants) was translocated extensively in the phloem of both genotypes. Acetyl-l-[14C]glufosinate was readily transported into the floral buds and flowers, and accumulated in the anthers in both genotypes. These results suggest that phloem transport of d,l-glufosinate is limited by rapid physiological effects of the l-isomer in source leaf tissue. The accumulation of acetyl-l-glufosinate in the anthers indicates that it is sufficiently phloem mobile to act as a foliar-applied chemical inducer of male sterility in plants expressing a deacetylase gene in the tapetum, generating toxic concentrations of l-glufosinate in pollen-producing tissues. PMID:10517854

Treatment with acetyl-l-carnitine during in vitro maturation of buffalo oocytes improves oocyte quality and subsequent embryonic development.

PubMed

Xu, Hui-Yan; Yang, Xiao-Gan; Lu, Sheng-Sheng; Liang, Xing-Wei; Lu, Yang-Qing; Zhang, Ming; Lu, Ke-Huan

2018-06-01

Oocyte quality is one of the important factors in female fertility, in vitro maturation (IVM), and subsequent embryonic development. In the present study, we assessed whether acetyl-l-carnitine (ALC) supplementation during in vitro maturation of buffalo oocytes could improve oocyte quality and subsequent embryonic development. To determine the optimal level of ALC supplementation, we matured cumulus-oocyte complexes in maturation medium supplemented with 0, 2.5, and 5 mM ALC. The oocytes with a polar body were selected for parthenogenetic activation (PA) and in vitro fertilization (IVF). We found that oocytes matured in 2.5 mM ALC had significantly higher PA blastocyst rate (P < 0.05) and blastocyst cell number than those of unsupplemented oocytes (P < 0.05) and a significantly higher IVF blastocyst rate than that of oocytes matured in 5 mM ALC (P < 0.05). In all further experiments, we supplemented the maturation medium with 2.5 mM ALC. We then tested whether ALC supplementation could improve various markers of oocytes and cumulus cells. We compared cell proliferation; concentrations of reactive oxygen species (ROS), intracellular ATP, estradiol, and progesterone; mitochondrial distribution; mitochondrial DNA copy number (mtDNA); and expression levels of four genes encoding oocyte-derived factors (GDF9, BMP15) and steroid hormones (StAR, P450scc) between the supplemented and unsupplemented oocytes and cumulus cells. Cumulus cells matured with ALC supplementation were more prolific than those matured without ALC supplementation (P < 0.05). Oocytes treated with ALC had lower concentrations of intracellular ROS (P < 0.05) and a higher rate of diffuse mitochondrial distributions (P < 0.05) than those of untreated oocytes. Additionally, the mtDNA was higher in the ALC-treated oocytes (P < 0.05) and cumulus cells (P < 0.05) than that in the untreated cells. The ALC-treated maturation medium had a higher postmaturation

High degree of efficacy in the treatment of cyclic vomiting syndrome with combined co-enzyme Q10, L-carnitine and amitriptyline, a case series

PubMed Central

2011-01-01

Background Cyclic vomiting syndrome (CVS), defined by recurrent stereotypical episodes of nausea and vomiting, is a relatively-common disabling and historically difficult-to-treat condition associated with migraine headache and mitochondrial dysfunction. Limited data suggests that the anti-migraine therapies amitriptyline and cyproheptadine, and the mitochondrial-targeted cofactors co-enzyme Q10 and L-carnitine, have efficacy in episode prophylaxis. Methods A retrospective chart review of 42 patients seen by one clinician that met established CVS diagnostic criteria revealed 30 cases with available outcome data. Participants were treated on a loose protocol consisting of fasting avoidance, co-enzyme Q10 and L-carnitine, with the addition of amitriptyline (or cyproheptadine in those < 5 years) in refractory cases. Blood level monitoring of the therapeutic agents featured prominently in management. Results Vomiting episodes resolved in 23 cases, and improved by > 75% and > 50% in three and one additional case respectively. Among the three treatment failures, two could not tolerate amitriptyline (as was also the case in the child with only > 50% efficacy) and one had multiple congenital gastrointestinal anomalies. Excluding the latter case, substantial efficacy (> 75% response) was 26/29 at the start of treatment, and 26/26 in those able to tolerate the regiment, including high dosages of amitriptyline. Conclusion Our data suggest that a protocol consisting of mitochondrial-targeted cofactors (co-enzyme Q10 and L-carnitine) plus amitriptyline (or possibly cyproheptadine in preschoolers) coupled with blood level monitoring is highly effective in the prevention of vomiting episodes. PMID:21846334

Animal Models of Peripheral Neuropathy Due to Environmental Toxicants

PubMed Central

Rao, Deepa B.; Jortner, Bernard S.; Sills, Robert C.

2014-01-01

Despite the progress in our understanding of pathogeneses and the identification of etiologies of peripheral neuropathy, idiopathic neuropathy remains common. Typically, attention to peripheral neuropathies resulting from exposure to environmental agents is limited relative to more commonly diagnosed causes of peripheral neuropathy (diabetes and chemotherapeutic agents). Given that there are more than 80,000 chemicals in commerce registered with the Environmental Protection Agency and that at least 1000 chemicals are known to have neurotoxic potential, very few chemicals have been established to affect the peripheral nervous system (mainly after occupational exposures). A wide spectrum of exposures, including pesticides, metals, solvents, nutritional sources, and pharmaceutical agents, has been related, both historically and recently, to environmental toxicant-induced peripheral neuropathy. A review of the literature shows that the toxicity and pathogeneses of chemicals adversely affecting the peripheral nervous system have been studied using animal models. This article includes an overview of five prototypical environmental agents known to cause peripheral neuropathy—namely, organophosphates, carbon disulfide, pyridoxine (Vitamin B6), acrylamide, and hexacarbons (mainly n-hexane, 2,5-hexanedione, methyl n-butyl ketone). Also included is a brief introduction to the structural components of the peripheral nervous system and pointers on common methodologies for histopathologic evaluation of the peripheral nerves. PMID:24615445

Analytical approaches to determination of carnitine in biological materials, foods and dietary supplements.

PubMed

Dąbrowska, Monika; Starek, Małgorzata

2014-01-01

l-Carnitine is a vitamin-like amino acid derivative, which is an essential factor in fatty acid metabolism as acyltransferase cofactor and in energy production processes, such as interconversion in the mechanisms of regulation of cetogenesis and termogenesis, and it is also used in the therapy of primary and secondary deficiency, and in other diseases. The determination of carnitine and acyl-carnitines can provide important information about inherited or acquired metabolic disorders, and for monitoring the biochemical effect of carnitine therapy. The endogenous carnitine pool in humans is maintained by biosynthesis and absorption of carnitine from the diet. Carnitine has one asymmetric carbon giving two stereoisomers d and l, but only the l form has a biological positive effect, thus chiral recognition of l-carnitine enantiomers is extremely important in biological, chemical and pharmaceutical sciences. In order to get more insight into carnitine metabolism and synthesis, a sensitive analysis for the determination of the concentration of free carnitine, carnitine esters and the carnitine precursors is required. Carnitine has been investigated in many biochemical, pharmacokinetic, metabolic and toxicokinetic studies and thus many analytical methods have been developed and published for the determination of carnitine in foods, dietary supplements, pharmaceutical formulations, biological tissues and body fluid. The analytical procedures presented in this review have been validated in terms of basic parameters (linearity, limit of detection, limit of quantitation, sensitivity, accuracy, and precision). This article presented the impact of different analytical techniques, and provides an overview of applications that address a diverse array of pharmaceutical and biological questions and samples. Copyright © 2013 Elsevier Ltd. All rights reserved.

Beneficial effect of butyrate, Lactobacillus casei and L-carnitine combination in preference to each in experimental colitis

PubMed Central

Moeinian, Mahsa; Ghasemi-Niri, Seyedeh Farnaz; Mozaffari, Shilan; Abdolghaffari, Amir Hossein; Baeeri, Maryam; Navaea-Nigjeh, Mona; Abdollahi, Mohammad

2014-01-01

AIM: To investigate the beneficial effect of the combination of butyrate, Lactobacillus casei, and L-carnitine in a rat colitis model. METHODS: Rats were divided into seven groups. Four groups received oral butyrate, L-carnitine, Lactobacillus casei and the combination of three agents for 10 consecutive days. The remaining groups included negative and positive controls and a sham group. Macroscopic, histopathological examinations, and biomarkers such as tumor necrosis factor-alpha (TNF-α) and interlukin-1β (IL-1β), myeloperoxidase (MPO), thiobarbituric acid reactive substances (TBARS), and ferric reduced ability of plasma (FRAP) were determined in the colon. RESULTS: The combination therapy exhibited a significant beneficial effect in alleviation of colitis compared to controls. Overall changes in reduction of TNF-α (114.66 ± 18.26 vs 171.78 ± 9.48 pg/mg protein, P < 0.05), IL-1β (24.9 ± 1.07 vs 33.06 ± 2.16 pg/mg protein, P < 0.05), TBARS (0.2 ± 0.03 vs 0.49 ± 0.04 μg/mg protein, P < 0.01), MPO (15.32 ± 0.4 vs 27.24 ± 3.84 U/mg protein, P < 0.05), and elevation of FRAP (23.46 ± 1.2 vs 15.02 ± 2.37 μmol/L, P < 0.05) support the preference of the combination therapy in comparison to controls. Although the monotherapies were also effective in improvement of colitis markers, the combination therapy was much better in improvement of colon oxidative stress markers including FRAP, TBARS, and MPO. CONCLUSION: The present combination is a suitable mixture in control of experimental colitis and should be trialed in the clinical setting. PMID:25152589

Sources of error in determinations of carnitine and acylcarnitine in plasma.

PubMed

Fishlock, R C; Bieber, L L; Snoswell, A M

1984-02-01

Radioactive and nonradioactive L-carnitine and acyl-L-carnitine were used to evaluate the washing procedures used during the determination of free, total, short-chain, and long-chain acylcarnitine in human and sheep plasma. The volume of fluid trapped by the protein precipitated by perchloric acid is approximately 24% of the total fluid volume and thus contains 24% of free carnitine and short-chain acylcarnitine. Washing twice with distilled water removes about 25% of the long-chain acylcarnitine along with the trapped free carnitine and short-chain acylcarnitines. Washing the pellet twice with a 60 g/L solution of perchloric acid completely removes the trapped free carnitine and short-chain acylcarnitine but does not remove the bound long-chain acylcarnitines. Thus washing with perchloric acid is essential for accurate measurement of long-chain acylcarnitines in plasma samples.

Muscle contraction increases carnitine uptake via translocation of OCTN2

DOE Office of Scientific and Technical Information (OSTI.GOV)

Furuichi, Yasuro; Sugiura, Tomoko; Kato, Yukio

Highlights: Black-Right-Pointing-Pointer Muscle contraction augmented carnitine uptake into rat hindlimb muscles. Black-Right-Pointing-Pointer An increase in carnitine uptake was due to an intrinsic clearance, not blood flow. Black-Right-Pointing-Pointer Histochemical analysis showed sarcolemmal OCTN2 was emphasized after contraction. Black-Right-Pointing-Pointer OCTN2 protein in sarcolemmal fraction was increased in contracting muscles. -- Abstract: Since carnitine plays an important role in fat oxidation, influx of carnitine could be crucial for muscle metabolism. OCTN2 (SLC22A5), a sodium-dependent solute carrier, is assumed to transport carnitine into skeletal muscle cells. Acute regulation of OCTN2 activity in rat hindlimb muscles was investigated in response to electrically induced contractile activity.more » The tissue uptake clearance (CL{sub uptake}) of L-[{sup 3}H]carnitine during muscle contraction was examined in vivo using integration plot analysis. The CL{sub uptake} of [{sup 14}C]iodoantipyrine (IAP) was also determined as an index of tissue blood flow. To test the hypothesis that increased carnitine uptake involves the translocation of OCTN2, contraction-induced alteration in the subcellular localization of OCTN2 was examined. The CL{sub uptake} of L-[{sup 3}H]carnitine in the contracting muscles increased 1.4-1.7-fold as compared to that in the contralateral resting muscles (p < 0.05). The CL{sub uptake} of [{sup 14}C]IAP was much higher than that of L-[{sup 3}H]carnitine, but no association between the increase in carnitine uptake and blood flow was obtained. Co-immunostaining of OCTN2 and dystrophin (a muscle plasma membrane marker) showed an increase in OCTN2 signal in the plasma membrane after muscle contraction. Western blotting showed that the level of sarcolemmal OCTN2 was greater in contracting muscles than in resting muscles (p < 0.05). The present study showed that muscle contraction facilitated carnitine uptake in skeletal muscles

Altered carnitine transport in pressure-overload hypertrophied rat hearts

DOE Office of Scientific and Technical Information (OSTI.GOV)

O'Rourke, B.; Foster, K.; Reibel, D.K.

1986-03-01

The authors have previously observed reduced carnitine levels in hypertrophied hearts of rats subjected to aortic constriction. In an attempt to determine the mechanism for reduced myocardial carnitine content, carnitine transport was examined in isolated perfused hearts. Hearts were excised from sham-operated and aortic-constricted rats 3 weeks following surgery and perfused at 60 mm Hg aortic pressure with buffer containing various concentrations of L-/sup 14/C-carnitine. Carnitine uptake by control and hypertrophied hearts was linear throughout 30 minutes of perfusion with 40 ..mu..M carnitine. Total carnitine uptake was significantly reduced by 25% in hypertrophied hearts at each time point examined. Themore » reduction in uptake by hypertrophied hearts was also evident when hearts were perfused with 100 or 200 ..mu..M carnitine. When 0.05 mM mersalyl acid was included in the buffer to inhibit the carrier-mediated component of transport, no difference in carnitine uptake was observed indicating that the transport of carnitine by diffusion was unaltered in the hypertrophied myocardium. Carrier-mediated carnitine uptake (total uptake - uptake by diffusion) was significantly reduced by approximately 40% in hypertrophied hearts at all concentrations examined. Thus, the reduction in carnitine content in the pressure-overload hypertrophied rat heart appears to be due to a reduction in carrier-mediated carnitine uptake by the heart.« less

Protein and lipid damage in maple syrup urine disease patients: l-carnitine effect.

PubMed

Mescka, Caroline Paula; Wayhs, Carlos Alberto Yasin; Vanzin, Camila Simioni; Biancini, Giovana Brondani; Guerreiro, Gilian; Manfredini, Vanusa; Souza, Carolina; Wajner, Moacir; Dutra-Filho, Carlos Severo; Vargas, Carmen Regla

2013-02-01

Maple syrup urine disease (MSUD) is an inborn error of metabolism biochemically characterized by elevated levels of the branched chain amino acids (BCAA) leucine, isoleucine, valine and the corresponding branched-chain α-keto acids. This disorder is clinically characterized by ketoacidosis, seizures, coma, psychomotor delay and mental retardation whose pathophysiology is not completely understood. Recent studies have shown that oxidative stress may be involved in neuropathology of MSUD. l-Carnitine (l-Car) plays a central role in the cellular energy metabolism because it transports long-chain fatty acids for oxidation and ATP generation. In recent years many studies have demonstrated the antioxidant role of this compound. In this work, we investigated the effect of BCAA-restricted diet supplemented or not with l-Car on lipid peroxidation and in protein oxidation in MSUD patients. We found a significant increase of malondialdehyde and of carbonyl content in plasma of MSUD patients under BCAA-restricted diet compared to controls. Furthermore, patients under BCAA-restricted diet plus l-Car supplementation presented a marked reduction of malondialdehyde content in relation to controls, reducing the lipid peroxidation. In addition, free l-Car concentrations were negatively correlated with malondialdehyde levels. Our data show that l-Car may have an antioxidant effect, protecting against the lipid peroxidation and this could represent an additional therapeutic approach to the patients affected by MSUD. Copyright © 2012 ISDN. Published by Elsevier Ltd. All rights reserved.

Efficacy of L-carnitine supplementation on frailty status and its biomarkers, nutritional status, and physical and cognitive function among prefrail older adults: a double-blind, randomized, placebo-controlled clinical trial.

PubMed

Badrasawi, M; Shahar, Suzana; Zahara, A M; Nor Fadilah, R; Singh, Devinder Kaur Ajit

2016-01-01

Frailty is a biological syndrome of decreased reserve and resistance to stressors due to decline in multiple physiological systems. Amino acid deficiency, including L-carnitine, has been proposed to be associated with its pathophysiology. Nevertheless, the efficacy of L-carnitine supplementation on frailty status has not been documented. Thus, this study aimed to determine the effect of 10-week L-carnitine supplement (1.5 g/day) on frailty status and its biomarkers and also physical function, cognition, and nutritional status among prefrail older adults in Klang Valley, Malaysia. This study is a randomized, double-blind, placebo-controlled clinical trial conducted among 50 prefrail subjects randomized into two groups (26 in L-carnitine group and 24 in placebo group). Outcome measures include frailty status using Fried criteria and Frailty Index accumulation of deficit, selected frailty biomarkers (interleukin-6, tumor necrosis factor-alpha, and insulin-like growth factor-1), physical function, cognitive function, nutritional status and biochemical profile. The results indicated that the mean scores of Frailty Index score and hand grip test were significantly improved in subjects supplemented with L-carnitine ( P <0.05 for both parameters) as compared to no change in the placebo group. Based on Fried criteria, four subjects (three from the L-carnitine group and one from the control group) transited from prefrail status to robust after the intervention. L-carnitine supplementation has a favorable effect on the functional status and fatigue in prefrail older adults.

Efficacy of L-carnitine supplementation on frailty status and its biomarkers, nutritional status, and physical and cognitive function among prefrail older adults: a double-blind, randomized, placebo-controlled clinical trial

PubMed Central

Badrasawi, M; Shahar, Suzana; Zahara, AM; Nor Fadilah, R; Singh, Devinder Kaur Ajit

2016-01-01

Background Frailty is a biological syndrome of decreased reserve and resistance to stressors due to decline in multiple physiological systems. Amino acid deficiency, including L-carnitine, has been proposed to be associated with its pathophysiology. Nevertheless, the efficacy of L-carnitine supplementation on frailty status has not been documented. Thus, this study aimed to determine the effect of 10-week L-carnitine supplement (1.5 g/day) on frailty status and its biomarkers and also physical function, cognition, and nutritional status among prefrail older adults in Klang Valley, Malaysia. Methodology This study is a randomized, double-blind, placebo-controlled clinical trial conducted among 50 prefrail subjects randomized into two groups (26 in L-carnitine group and 24 in placebo group). Outcome measures include frailty status using Fried criteria and Frailty Index accumulation of deficit, selected frailty biomarkers (interleukin-6, tumor necrosis factor-alpha, and insulin-like growth factor-1), physical function, cognitive function, nutritional status and biochemical profile. Results The results indicated that the mean scores of Frailty Index score and hand grip test were significantly improved in subjects supplemented with L-carnitine (P<0.05 for both parameters) as compared to no change in the placebo group. Based on Fried criteria, four subjects (three from the L-carnitine group and one from the control group) transited from prefrail status to robust after the intervention. Conclusion L-carnitine supplementation has a favorable effect on the functional status and fatigue in prefrail older adults. PMID:27895474

Rational design of aminoacyl-tRNA synthetase specific for p-acetyl-L-phenylalanine.

PubMed

Sun, Renhua; Zheng, Heng; Fang, Zhengzhi; Yao, Wenbing

2010-01-01

The Methanococcus jannaschii tRNA(Tyr)/tyrosyl-tRNA synthetase pair has been engineered to incorporate unnatural amino acids into proteins in Escherichia coli site-specifically. In order to add other unnatural amino acids into proteins by this approach, the amino acid binding site of M. jannaschii tyrosyl-tRNA synthetase need to be mutated. The crystal structures of M. jannaschii tyrosyl-tRNA synthetase and its mutations were determined, which provided an opportunity to design aminoacyl-tRNA synthetases specific for other unnatural amino acids. In our study, we attempted to design aminoacyl-tRNA synthetases being able to deliver p-acetyl-L-phenylalanine into proteins. p-Acetyl-L-phenylalanine was superimposed on tyrosyl in M. jannaschii tyrosyl-tRNA synthetase-tyrosine complex. Tyr32 needed to be changed to non-polar amino acid with shorter side chain, Val, Leu, Ile, Gly or Ala, in order to reduce steric clash and provide hydrophobic environment to acetyl on p-acetyl-L-phenylalanine. Asp158 and Ile159 would be changed to specific amino acids for the same reason. So we designed 60 aminoacyl-tRNA synthetases. Binding of these aminoacyl-tRNA synthetases with p-acetyl-L-phenylalanine indicated that only 15 of them turned out to be able to bind p-acetyl-L-phenylalanine with reasonable poses. Binding affinity computation proved that the mutation of Tyr32Leu and Asp158Gly benefited p-acetyl-L-phenylalanine binding. And two of the designed aminoacyl-tRNA synthetases had considerable binding affinities. They seemed to be very promising to be able to incorporate p-acetyl-L-phenylalanine into proteins in E. coli. The results show that the combination of homology modeling and molecular docking is a feasible method to filter inappropriate mutations in molecular design and point out beneficial mutations. Copyright 2009 Elsevier Inc. All rights reserved.

Screening of carnitine and biotin deficiencies on tandem mass spectrometry.

PubMed

Hagiwara, Shin-Ichiro; Kubota, Mitsuru; Nambu, Ryusuke; Kagimoto, Seiichi

2017-04-01

It is important to assess pediatric patients for nutritional deficiency when they are receiving specific interventions, such as enteral feeding. We focused on measurement of C0 and 3-hydroxyisovalerylcarnitine (C5-OH) with tandem mass spectrometry (MS/MS), which is performed as part of the newborn mass screening. The purpose of this study was to investigate the usefulness of MS/MS for screening carnitine and biotin deficiencies. Forty-two children (24 boys, 18 girls) were enrolled between December 2013 and December 2015. Blood tests, including measurement of serum free carnitine via the enzyme cycling method, and acylcarnitine analysis on MS/MS of dried blood spot (DBS), were performed for the evaluation of nutrition status. Median patient age was 2 years (range, 2 months-14 years). Mean serum free carnitine was 41.8 ± 19.2 μmol/L. In six of the 42 patients, serum free carnitine was <20 μmol/L (range, 4.0-18.7 μmol/L). C0 and C5-OH measured on MS/MS of DBS were 33.8 ± 20.2 nmol/mL and 0.48 ± 0.22 nmol/mL, respectively. There was a strong positive correlation (r = 0.89, P < 0.001) between serum free carnitine and C0 measured on the same day. In one patient on hydrolyzed formula, C5-OH was >1.00 nmol/L. Therapy-resistant eczema was improved by treatment with additional biotin and a non-hydrolyzed formula. C0 and C5-OH, measured on MS/MS of DBS, were useful for screening carnitine and biotin deficiencies. © 2016 Japan Pediatric Society.

Lifespan extension and increased resistance to environmental stressors by N-Acetyl-L-Cysteine in Caenorhabditis elegans

PubMed Central

Oh, Seung-Il; Park, Jin-Kook; Park, Sang-Kyu

2015-01-01

OBJECTIVE: This study was performed to determine the effect of N-acetyl-L-cysteine, a modified sulfur-containing amino acid that acts as a strong cellular antioxidant, on the response to environmental stressors and on aging in C. elegans. METHOD: The survival of worms under oxidative stress conditions induced by paraquat was evaluated with and without in vivo N-acetyl-L-cysteine treatment. The effect of N-acetyl-L-cysteine on the response to other environmental stressors, including heat stress and ultraviolet irradiation (UV), was also monitored. To investigate the effect on aging, we examined changes in lifespan, fertility, and expression of age-related biomarkers in C. elegans after N-acetyl-L-cysteine treatment. RESULTS: Dietary N-acetyl-L-cysteine supplementation significantly increased resistance to oxidative stress, heat stress, and UV irradiation in C. elegans. In addition, N-acetyl-L-cysteine supplementation significantly extended both the mean and maximum lifespan of C. elegans. The mean lifespan was extended by up to 30.5% with 5 mM N-acetyl-L-cysteine treatment, and the maximum lifespan was increased by 8 days. N-acetyl-L-cysteine supplementation also increased the total number of progeny produced and extended the gravid period of C. elegans. The green fluorescent protein reporter assay revealed that expression of the stress-responsive genes, sod-3 and hsp-16.2, increased significantly following N-acetyl-L-cysteine treatment. CONCLUSION: N-acetyl-L-cysteine supplementation confers a longevity phenotype in C. elegans, possibly through increased resistance to environmental stressors. PMID:26039957

The effect of dietary supplementation with calcium salts of long chain fatty acids and/or L-carnitine on ovarian activity of Rahmani ewes.

PubMed

El-Shahat, K H; Abo-El maaty, Amal M

2010-01-01

This study investigated the effect of dietary supplementation with calcium salts of long chain fatty acids with or without of l-carnitine on ovarian activity using 24 Rahmani ewes randomly allocated to four treatments. Control animals (n=6) were fed a basal diet of hay (64.2%) and barley grain (35.0%) plus minerals and vitamins (0.8%). Ewes on the three treatments received the same basal diet supplemented with calcium salts of long chain fatty acids (CSFA) at 3% of the basal diet dry matter intake (1.4 kg/ewe/d); 250 ppm l-carnitine (LC); or both these supplements (CSFA+LC). All use exhibited natural estrus on one or two occasions and were weighed at the start and the end of the study as well as body condition score was assessed at the end of study. All ewes were then synchronised for estrus using intravaginal sponges for 12 d prior to the start of the nutritional treatments and three weeks after the nutritional treatments began. The nutritional treatments were imposed for a total of 8 weeks. Blood samples were collected prior to the start of treatments and every two weeks thereafter except after sponge removal of first and second synchronisation where the blood samples were collected daily for progesterone assay. The results revealed that Rahmani ewes received basal diet (control) and l-carnitine had significantly decrease final body weight and body condition score (36.3+/-0.4; 36.8+/-0.3; 2.2+/-0.04; 2.1+/-0.05; p<0.05, respectively) than those on CSFA and CSFA+LC (38.6+/-0.9; 39.5+/-0.6; 3.3+/-0.07; 3.4+/-0.06; respectively). At the second ultrasound examination, the control animals had significantly fewer total follicles (7.3+/-0.8; p<0.05) than those on the CSFA (8.4+/-0.8), l-carnitine (8.7+/-1.5) and CSFA+LC (8.0+/-0.6) treatments. The increased numbers occurred in the medium and large categories of follicles. In addition, the ovulation rates were significantly lower (p<0.05) for control (1.3+/-0.2) and l-carnitine (1.5+/-0.00) than for CSFA (2.5+/-0.3) and

Supercritical fluid extraction of 11C-labeled metabolites in tissue using supercritical ammonia.

PubMed

Jacobson, G B; Moulder, R; Lu, L; Bergström, M; Markides, K E; Långström, B

1997-02-01

Supercritical fluid extraction (SFE) of 11C-labeled tracer compounds and their metabolites from biological tissue was performed using supercritical ammonia in an attempt to develop a rapid extraction procedure that allowed subsequent analysis of the labeled metabolites. Metabolites were extracted from kidneys and brain in rats given in vivo injections of the radiotracers O-[2-11C]acetyl-L-carnitine and N-[11C]methylpiperidyl benzilate, respectively. Only a minimal sample pretreatment of the tissue was necessary, i.e., cutting into 10-20 pieces and mixing with the drying agent Hydromatrix, before it was loaded into the extraction vessel. Extraction efficiency was measured for SFE at temperatures over the range of 70-150 degrees C and a pressure of 400 bar. For O-[2-11C]acetyl-L-carnitine, 66% of the radioactivity was trapped in the collected fractions and 12% remained in the extraction vessel. For the more lipophilic N-[11C]methylpiperidyl benzilate, 93% of the activity was collected and less than 1% remained in the extraction vessel. Labeled metabolites were analyzed by LC and also, in the case, of O-[2-11C]acetyl-L-carnitine by LC/MS. The complete extraction procedure, from removal of the biological tissue until an extract was ready for analysis, was 25 min, corresponding to about one half-life of the radionuclide 11C.

Simple determination of betaine, l-carnitine and choline in human urine using self-packed column and column-switching ion chromatography with nonsuppressed conductivity detection.

PubMed

Wei, Dan; Zhu, Yan; Guo, Ming

2018-02-01

A sequential online extraction, clean-up and separation system for the determination of betaine, l-carnitine and choline in human urine using column-switching ion chromatography with nonsuppressed conductivity detection was developed in this work. A self-packed pretreatment column (50 × 4.6 mm, i.d.) was used for the extraction and clean-up of betaine, l-carnitine and choline. The separation was achieved using self-packed cationic exchange column (150 × 4.6 mm, i.d.), followed by nonsuppressed conductivity detection. Under optimized experimental conditions, the developed method presented good analytical performance, with excellent linearity in the range of 0.60-100 μg mL -1 for betaine, 0.75-100 μg mL -1 for l-carnitine and 0.50-100 μg mL -1 for choline, with all correlation coefficients (R 2 ) >0.99 in urine. The limits of detection were 0.15 μg mL -1 for betaine, 0.20 μg mL -1 for l-carnitine and 0.09 μg mL -1 for choline. The intra- and inter-day accuracy and precision for all quality controls were within ±10.32 and ±9.05%, respectively. Satisfactory recovery was observed between 92.8 and 102.0%. The validated method was successfully applied to the detection of urinary samples from 10 healthy people. The values detected in human urine using the proposed method showed good agreement with the measurement reported previously. Copyright © 2017 John Wiley & Sons, Ltd.

Aspirin-Mediated Acetylation Protects Against Multiple Neurodegenerative Pathologies by Impeding Protein Aggregation.

PubMed

Ayyadevara, Srinivas; Balasubramaniam, Meenakshisundaram; Kakraba, Samuel; Alla, Ramani; Mehta, Jawahar L; Shmookler Reis, Robert J

2017-12-10

Many progressive neurological disorders, including Alzheimer's disease (AD), Huntington's disease, and Parkinson's disease (PD), are characterized by accumulation of insoluble protein aggregates. In prospective trials, the cyclooxygenase inhibitor aspirin (acetylsalicylic acid) reduced the risk of AD and PD, as well as cardiovascular events and many late-onset cancers. Considering the role played by protein hyperphosphorylation in aggregation and neurodegenerative diseases, and aspirin's known ability to donate acetyl groups, we asked whether aspirin might reduce both phosphorylation and aggregation by acetylating protein targets. Aspirin was substantially more effective than salicylate in reducing or delaying aggregation in human neuroblastoma cells grown in vitro, and in Caenorhabditis elegans models of human neurodegenerative diseases in vivo. Aspirin acetylates many proteins, while reducing phosphorylation, suggesting that acetylation may oppose phosphorylation. Surprisingly, acetylated proteins were largely excluded from compact aggregates. Molecular-dynamic simulations indicate that acetylation of amyloid peptide energetically disfavors its association into dimers and octamers, and oligomers that do form are less compact and stable than those comprising unacetylated peptides. Hyperphosphorylation predisposes certain proteins to aggregate (e.g., tau, α-synuclein, and transactive response DNA-binding protein 43 [TDP-43]), and it is a critical pathogenic marker in both cardiovascular and neurodegenerative diseases. We present novel evidence that acetylated proteins are underrepresented in protein aggregates, and that aggregation varies inversely with acetylation propensity after diverse genetic and pharmacologic interventions. These results are consistent with the hypothesis that aspirin inhibits protein aggregation and the ensuing toxicity of aggregates through its acetyl-donating activity. This mechanism may contribute to the neuro-protective, cardio-protective

Feeding Healthy Beagles Medium-Chain Triglycerides, Fish Oil, and Carnitine Offsets Age-Related Changes in Serum Fatty Acids and Carnitine Metabolites

PubMed Central

Hall, Jean A.; Jewell, Dennis E.

2012-01-01

The purpose of this study was to determine if feeding dogs medium-chain triglycerides (MCT), fish oil, and L-carnitine enriched foods offsets age-associated changes in serum fatty acids (FA) and carnitine metabolites. Forty-one healthy Beagles, mean age 9.9 years (range 3.1 to 14.8), were fed control or one of two treatment foods for 6 months. All foods were complete and balanced and met the nutrient requirements for adult dogs, and had similar concentrations of moisture, protein, and fat (approx. 7.4%, 14.0%, and 18.1%, respectively). The treatment diets both contained added L-carnitine (300 mg/kg) and 0.6% (treatment food 1) or 1.5% (treatment food 2) added fish oil. Treatment food 2 also had increased MCT from coconut oil, added corn oil, and reduced animal fat. Composition of serum FA was determined by gas chromatography of FA methyl esters. Metabolomic profiles of serum samples were determined from extracted supernatants that were split and run on GC/MS and LC/MS/MS platforms, for identification and relative quantification of small metabolites. Body composition was determined by dual energy x-ray absorptiometry. Among dog groups, there was no change in total-lean-body weight, or in serum total protein and serum albumin concentrations, based on time or dietary treatment. Serum concentrations of carnitine metabolites were decreased in geriatric (>7 years) vs. mature adult (≤7 years) dogs, and supplementation with L-carnitine attenuated the effects of aging. The ratio of PUFA to SFA was significantly greater in mature dogs at baseline (P≤0.05). Serum concentrations of eicosapentaenoic and docosahexaenoic FA increased in a dose-dependent manner. Dogs consuming treatment food 2 also had increased serum concentrations of lauric and myristic FA, and decreased concentrations of SFA, MUFA, and arachidonate (all P≤0.05) and their PUFA to SFA ratio increased. In summary, dietary MCT, fish oil, and L-carnitine counterbalanced the effects of aging on circulating

Feeding healthy beagles medium-chain triglycerides, fish oil, and carnitine offsets age-related changes in serum fatty acids and carnitine metabolites.

PubMed

Hall, Jean A; Jewell, Dennis E

2012-01-01

The purpose of this study was to determine if feeding dogs medium-chain triglycerides (MCT), fish oil, and L-carnitine enriched foods offsets age-associated changes in serum fatty acids (FA) and carnitine metabolites. Forty-one healthy Beagles, mean age 9.9 years (range 3.1 to 14.8), were fed control or one of two treatment foods for 6 months. All foods were complete and balanced and met the nutrient requirements for adult dogs, and had similar concentrations of moisture, protein, and fat (approx. 7.4%, 14.0%, and 18.1%, respectively). The treatment diets both contained added L-carnitine (300 mg/kg) and 0.6% (treatment food 1) or 1.5% (treatment food 2) added fish oil. Treatment food 2 also had increased MCT from coconut oil, added corn oil, and reduced animal fat. Composition of serum FA was determined by gas chromatography of FA methyl esters. Metabolomic profiles of serum samples were determined from extracted supernatants that were split and run on GC/MS and LC/MS/MS platforms, for identification and relative quantification of small metabolites. Body composition was determined by dual energy x-ray absorptiometry. Among dog groups, there was no change in total-lean-body weight, or in serum total protein and serum albumin concentrations, based on time or dietary treatment. Serum concentrations of carnitine metabolites were decreased in geriatric (>7 years) vs. mature adult (≤ 7 years) dogs, and supplementation with L-carnitine attenuated the effects of aging. The ratio of PUFA to SFA was significantly greater in mature dogs at baseline (P ≤ 0.05). Serum concentrations of eicosapentaenoic and docosahexaenoic FA increased in a dose-dependent manner. Dogs consuming treatment food 2 also had increased serum concentrations of lauric and myristic FA, and decreased concentrations of SFA, MUFA, and arachidonate (all P ≤ 0.05) and their PUFA to SFA ratio increased. In summary, dietary MCT, fish oil, and L-carnitine counterbalanced the effects of aging on circulating

Urinary biomarkers of oxidative damage in Maple syrup urine disease: the L-carnitine role.

PubMed

Guerreiro, Gilian; Mescka, Caroline Paula; Sitta, Angela; Donida, Bruna; Marchetti, Desirèe; Hammerschmidt, Tatiane; Faverzani, Jessica; Coelho, Daniella de Moura; Wajner, Moacir; Dutra-Filho, Carlos Severo; Vargas, Carmen Regla

2015-05-01

Maple syrup urine disease (MSUD) is a disorder of branched-chain amino acids (BCAA). The defect in the branched-chain α-keto acid dehydrogenase complex activity leads to an accumulation of these compounds and their corresponding α-keto-acids and α-hydroxy-acids. Studies have shown that oxidative stress may be involved in neuropathology of MSUD. L-carnitine (L-car), which has demonstrated an important role as antioxidant by reducing and scavenging free radicals formation and by enhancing the activity of antioxidant enzymes, have been used in the treatment of some metabolic rare disorders. This study evaluated the oxidative stress parameters, di-tyrosine, isoprostanes and antioxidant capacity, in urine of MSUD patients under protein-restricted diet supplemented or not with L-car capsules at a dose of 50 mg kg(-1) day(-1). It was also determined urinary α-keto isocaproic acid levels as well as blood free L-car concentrations in blood. It was found a deficiency of carnitine in patients before the L-car supplementation. Significant increases of di-tyrosine and isoprostanes, as well as reduced antioxidant capacity, were observed before the treatment with L-car. The L-car supplementation induced beneficial effects on these parameters reducing the di-tyrosine and isoprostanes levels and increasing the antioxidant capacity. It was also showed a significant increase in urinary of α-ketoisocaproic acid after 2 months of L-car treatment, compared to control group. In conclusion, our results suggest that L-car may have beneficial effects in the treatment of MSUD by preventing oxidative damage to the cells and that urine can be used to monitorize oxidative damage in patients affected by this disease. Copyright © 2015 Elsevier Ltd. All rights reserved.

Propionyl-L-Carnitine is Efficacious in Ulcerative Colitis Through its Action on the Immune Function and Microvasculature.

PubMed

Scioli, Maria Giovanna; Stasi, Maria Antonietta; Passeri, Daniela; Doldo, Elena; Costanza, Gaetana; Camerini, Roberto; Fociani, Paolo; Arcuri, Gaetano; Lombardo, Katia; Pace, Silvia; Borsini, Franco; Orlandi, Augusto

2014-03-20

Microvascular endothelial dysfunction characterizes ulcerative colitis (UC), the most widespread form of inflammatory bowel disease. Intestinal mucosal microvessels in UC display aberrant expression of cell adhesion molecules (CAMs) and increased inflammatory cell recruitment. Propionyl-L-carnitine (PLC), an ester of L-carnitine required for the mitochondrial transport of fatty acids, ameliorates propionyl-CoA bioavailability and reduces oxidative stress in ischemic tissues. The present study aimed to document the efficacy of anti-oxidative stress properties of PLC in counteracting intestinal microvascular endothelial dysfunction and inflammation. To evaluate the efficacy in vivo, we analyzed the effects in intestinal biopsies of patients with mild-to-moderate UC receiving oral PLC co-treatment and in rat TNBS-induced colitis; in addition, we investigated antioxidant PLC action in TNF-α-stimulated human intestinal microvascular endothelial cells (HIMECs) in vitro. Four-week PLC co-treatment reduced intestinal mucosal polymorph infiltration and CD4(+) lymphocytes, ICAM-1(+) and iNOS(+) microvessels compared with placebo-treated patients with UC. Oral and intrarectal administration of PLC but not L-carnitine or propionate reduced intestinal damage and microvascular dysfunction in rat TNBS-induced acute and reactivated colitis. In cultured TNF-α-stimulated HIMECs, PLC restored β-oxidation and counteracted NADPH oxidase 4-generated oxidative stress-induced CAM expression and leukocyte adhesion. Inhibition of β-oxidation by L-aminocarnitine increased reactive oxygen species production and PLC beneficial effects on endothelial dysfunction and leukocyte adhesion. Finally, PLC reduced iNOS activity and nitric oxide accumulation in rat TNBS-induced colitis and in HIMEC cultures. Our results show that the beneficial antioxidant effect of PLC targeting intestinal microvasculature restores endothelial β-oxidation and function, and reduces mucosal inflammation in UC

Carnitine in parenteral nutrition.

PubMed

Borum, Peggy R

2009-11-01

Several new functions or metabolic uses of carnitine and improvements in assessment of carnitine status impact carnitine dosing recommendations. Carnitine dosing will likely be customized for patients at different stages of the life cycle and for patients with dysfunction of different organs. Nutrition supplementation of carnitine should be 2-5 mg x kg(-1) x day(-1) and be administrated via the route used for administration of macronutrients. Pharmacologic supplementation of carnitine should be 50-100 mg x kg(-1) x day(-1) and be reserved for the removal of toxic compounds from the body.

The metabolomic signature of Leber's hereditary optic neuropathy reveals endoplasmic reticulum stress.

PubMed

Chao de la Barca, Juan Manuel; Simard, Gilles; Amati-Bonneau, Patrizia; Safiedeen, Zainab; Prunier-Mirebeau, Delphine; Chupin, Stéphanie; Gadras, Cédric; Tessier, Lydie; Gueguen, Naïg; Chevrollier, Arnaud; Desquiret-Dumas, Valérie; Ferré, Marc; Bris, Céline; Kouassi Nzoughet, Judith; Bocca, Cinzia; Leruez, Stéphanie; Verny, Christophe; Miléa, Dan; Bonneau, Dominique; Lenaers, Guy; Martinez, M Carmen; Procaccio, Vincent; Reynier, Pascal

2016-11-01

Leber's hereditary optic neuropathy (MIM#535000), the commonest mitochondrial DNA-related disease, is caused by mutations affecting mitochondrial complex I. The clinical expression of the disorder, usually occurring in young adults, is typically characterized by subacute, usually sequential, bilateral visual loss, resulting from the degeneration of retinal ganglion cells. As the precise action of mitochondrial DNA mutations on the overall cell metabolism in Leber's hereditary optic neuropathy is unknown, we investigated the metabolomic profile of the disease. High performance liquid chromatography coupled with tandem mass spectrometry was used to quantify 188 metabolites in fibroblasts from 16 patients with Leber's hereditary optic neuropathy and eight healthy control subjects. Latent variable-based statistical methods were used to identify discriminating metabolites. One hundred and twenty-four of the metabolites were considered to be accurately quantified. A supervised orthogonal partial least squares discriminant analysis model separating patients with Leber's hereditary optic neuropathy from control subjects showed good predictive capability (Q 2cumulated = 0.57). Thirty-eight metabolites appeared to be the most significant variables, defining a Leber's hereditary optic neuropathy metabolic signature that revealed decreased concentrations of all proteinogenic amino acids, spermidine, putrescine, isovaleryl-carnitine, propionyl-carnitine and five sphingomyelin species, together with increased concentrations of 10 phosphatidylcholine species. This signature was not reproduced by the inhibition of complex I with rotenone or piericidin A in control fibroblasts. The importance of sphingomyelins and phosphatidylcholines in the Leber's hereditary optic neuropathy signature, together with the decreased amino acid pool, suggested an involvement of the endoplasmic reticulum. This was confirmed by the significantly increased phosphorylation of PERK and eIF2α, as well as

Carnitine status in Thai adults.

PubMed

Tanphaichitr, V; Lerdvuthisopon, N; Dhanamitta, S; Broquist, H P

1980-04-01

Plasma carnitine and urinary carnitine levels were measured in Thai adults living in Bangkok city and Ubol villages. The mean plasma carnitine and urinary carnitine levels expressed in micromoles per liter in Bangkok adults were higher than those in Ubol adults. Their mean plasma carnitine levels were 56.6 +/- 1.8 and 50.3 +/- 1.7 whereas urinary carnitine levels were 161 +/- 19 and 127 +/- 18 micromole/liter, respectively. The nutritional status in Ubol adults was inadequate. This was evidenced by the significant decrease in urinary creatinine excretion, serum albumin, and hematocrit levels. The dietary assessment agreed with the biochemical findings. Since rice, limiting in carnitine, was the main protein and energy source consumed by Ubol adults their inadequate carnitine status could be due to the low carnitine intake. Sex affects plasma carnitine levels in Bangkok adults and urinary carnitine excretion in both groups. This could be related to the lean body mass in which most of the body carnitine resides. This is supported by the higher urinary creatinine excretion in males and the significant positive correlation between carnitine excretion and creatinine-height index.

Effects of in ovo administration of L-carnitine on hatchability performance, glycogen status and insulin-like growth factor-1 of broiler chickens.

PubMed

Shafey, T M; Al-Batshan, H A; Al-Owaimer, A N; Al-Samawei, K A

2010-02-01

1. Eggs from a meat-type breeder flock (Ross) were used in two trials to study the effects of in ovo administration of L-carnitine (carnitine) on hatchability traits (hatchability percentage, embryo deaths, pipped with live or dead embryo), chick weight at hatch as an absolute value (CWT) or expressed as a percentage of egg weight (CWT%), hatching period, glycogen status (liver and pectoral muscle) and plasma insulin-like growth factor-1 (IGF-1) of hatched chicks were investigated. There were 9 treatments with three replicates of each. Treatments were non-injected control (negative control), or injection with sterilised saline (09%, positive control), or sterilised saline with carnitine at 25, 50, 100, 200, 300, 400, and 500 microg/egg. 2. In ovo carnitine treatment increased CWT, CWT%, glycogen in the liver and pectoral muscle, glycogen index and plasma IGF-1 of hatched chicks, and did not influence hatchability traits and hatching period. The glycogen index of hatched chicks of the in ovo carnitine treatments with values (500 > 400 = 300 > 200) was higher than that of the control and in ovo carnitine at 25, 50, and 100 microg/egg treatments. The nature of response to carnitine was cubic for CWT and CWT%, and linear for glycogen in the liver and pectoral muscle, glycogen index of hatched chicks when the negative control or positive control treatment was used as base line. 3. It was concluded that in ovo administration of carnitine at 25-500 microg/egg increased chick weight at hatch and IGF-1, and did not influence hatchability traits and hatching period of eggs. The linear relationship between in ovo administration of carnitine and glycogen status of hatched chicks indicated that increasing in ovo doses improved glycogen status of hatched chicks.

Propionyl-L-Carnitine is Efficacious in Ulcerative Colitis Through its Action on the Immune Function and Microvasculature

PubMed Central

Scioli, Maria Giovanna; Stasi, Maria Antonietta; Passeri, Daniela; Doldo, Elena; Costanza, Gaetana; Camerini, Roberto; Fociani, Paolo; Arcuri, Gaetano; Lombardo, Katia; Pace, Silvia; Borsini, Franco; Orlandi, Augusto

2014-01-01

Objectives: Microvascular endothelial dysfunction characterizes ulcerative colitis (UC), the most widespread form of inflammatory bowel disease. Intestinal mucosal microvessels in UC display aberrant expression of cell adhesion molecules (CAMs) and increased inflammatory cell recruitment. Propionyl-L-carnitine (PLC), an ester of L-carnitine required for the mitochondrial transport of fatty acids, ameliorates propionyl-CoA bioavailability and reduces oxidative stress in ischemic tissues. The present study aimed to document the efficacy of anti-oxidative stress properties of PLC in counteracting intestinal microvascular endothelial dysfunction and inflammation. Methods: To evaluate the efficacy in vivo, we analyzed the effects in intestinal biopsies of patients with mild-to-moderate UC receiving oral PLC co-treatment and in rat TNBS-induced colitis; in addition, we investigated antioxidant PLC action in TNF-α-stimulated human intestinal microvascular endothelial cells (HIMECs) in vitro. Results: Four-week PLC co-treatment reduced intestinal mucosal polymorph infiltration and CD4+ lymphocytes, ICAM-1+ and iNOS+ microvessels compared with placebo-treated patients with UC. Oral and intrarectal administration of PLC but not L-carnitine or propionate reduced intestinal damage and microvascular dysfunction in rat TNBS-induced acute and reactivated colitis. In cultured TNF-α-stimulated HIMECs, PLC restored β-oxidation and counteracted NADPH oxidase 4-generated oxidative stress-induced CAM expression and leukocyte adhesion. Inhibition of β-oxidation by L-aminocarnitine increased reactive oxygen species production and PLC beneficial effects on endothelial dysfunction and leukocyte adhesion. Finally, PLC reduced iNOS activity and nitric oxide accumulation in rat TNBS-induced colitis and in HIMEC cultures. Conclusions: Our results show that the beneficial antioxidant effect of PLC targeting intestinal microvasculature restores endothelial β-oxidation and function, and

Hypothalamic carnitine metabolism integrates nutrient and hormonal feedback to regulate energy homeostasis.

PubMed

Stark, Romana; Reichenbach, Alex; Andrews, Zane B

2015-12-15

The maintenance of energy homeostasis requires the hypothalamic integration of nutrient feedback cues, such as glucose, fatty acids, amino acids, and metabolic hormones such as insulin, leptin and ghrelin. Although hypothalamic neurons are critical to maintain energy homeostasis research efforts have focused on feedback mechanisms in isolation, such as glucose alone, fatty acids alone or single hormones. However this seems rather too simplistic considering the range of nutrient and endocrine changes associated with different metabolic states, such as starvation (negative energy balance) or diet-induced obesity (positive energy balance). In order to understand how neurons integrate multiple nutrient or hormonal signals, we need to identify and examine potential intracellular convergence points or common molecular targets that have the ability to sense glucose, fatty acids, amino acids and hormones. In this review, we focus on the role of carnitine metabolism in neurons regulating energy homeostasis. Hypothalamic carnitine metabolism represents a novel means for neurons to facilitate and control both nutrient and hormonal feedback. In terms of nutrient regulation, carnitine metabolism regulates hypothalamic fatty acid sensing through the actions of CPT1 and has an underappreciated role in glucose sensing since carnitine metabolism also buffers mitochondrial matrix levels of acetyl-CoA, an allosteric inhibitor of pyruvate dehydrogenase and hence glucose metabolism. Studies also show that hypothalamic CPT1 activity also controls hormonal feedback. We hypothesis that hypothalamic carnitine metabolism represents a key molecular target that can concurrently integrate nutrient and hormonal information, which is critical to maintain energy homeostasis. We also suggest this is relevant to broader neuroendocrine research as it predicts that hormonal signaling in the brain varies depending on current nutrient status. Indeed, the metabolic action of ghrelin, leptin or insulin

Efficacy of a novel formulation of L-Carnitine, creatine, and leucine on lean body mass and functional muscle strength in healthy older adults: a randomized, double-blind placebo-controlled study.

PubMed

Evans, Malkanthi; Guthrie, Najla; Pezzullo, John; Sanli, Toran; Fielding, Roger A; Bellamine, Aouatef

2017-01-01

Progressive decline in skeletal muscle mass and function are growing concerns in an aging population. Diet and physical activity are important for muscle maintenance but these requirements are not always met. This highlights the potential for nutritional supplementation. As a primary objective, we sought to assess the effect of a novel combination of L-Carnitine, creatine and leucine on muscle mass and performance in older subjects. Forty-two healthy older adults aged 55-70 years were randomized to receive either a novel L-Carnitine (1500 mg), L-leucine (2000 mg), creatine (3000 mg), Vitamin D3 (10 μg) (L-Carnitine-combination) product ( n  = 14), L-Carnitine (1500 mg) ( n  = 14), or a placebo ( n  = 14) for eight weeks. We evaluated body mass by DXA, upper and lower strength by dynamometry, and walking distance by a 6-min walk test at baseline and after eight weeks of intervention. These measures, reflecting muscle mass, functional strength and mobility have been combined to generate a primary composite score. Quality of life, blood safety markers, and muscle biopsies for protein biomarker analysis were also conducted at baseline and the end of the study. The primary composite outcome improved by 63.5 percentage points in the L-Carnitine-combination group vs. placebo ( P  = 0.013). However, this composite score did not change significantly in the L-Carnitine group ( P =  0.232), and decreased slightly in the placebo group ( P =  0.534). Participants supplemented with the L-Carnitine-combination showed a 1.0 kg increase in total lean muscle mass ( P  = 0.013), leg lean muscle mass (0.35 kg, P =  0.005), and a 1.0 kg increase in lower leg strength ( P  = 0.029) at week 8. In addition, these increases were significant when compared to the placebo group (P =  0.034, P =  0.026, and P =  0.002, respectively). Total mTOR protein expression was increased in participants in the L-Carnitine-combination group at the end of

Toxicity of the Organophosphate Chemical Warfare Agents GA, GB, and VX: Implications for Public Protection.

PubMed Central

Munro, N

1994-01-01

The nerve agents, GA, GB, and VX are organophosphorus esters that form a major portion of the total agent volume contained in the U.S. stockpile of unitary chemical munitions. Congress has mandated the destruction of these agents, which is currently slated for completion in 2004. The acute, chronic, and delayed toxicity of these agents is reviewed in this analysis. The largely negative results from studies of genotoxicity, carcinogenicity, developmental, and reproductive toxicity are also presented. Nerve agents show few or delayed effects. At supralethal doses, GB can cause delayed neuropathy in antidote-protected chickens, but there is no evidence that it causes this syndrome in humans at any dose. Agent VX shows no potential for inducing delayed neuropathy in any species. In view of their lack of genotoxcity, the nerve agents are not likely to be carcinogens. The overreaching concern with regard to nerve agent exposure is the extraordinarily high acute toxicity of these substances. Furthermore, acute effects of moderate exposure such as nausea, diarrhea, inability to perform simple mental tasks, and respiratory effects may render the public unable to respond adequately to emergency instructions in the unlikely event of agent releaase, making early warning and exposure avoidance important. Likewise, exposure or self-contamination of first responders and medical personnel must be avoided. Control limits for exposure via surface contact of drinking water are needed, as are detection methods for low levels in water or foodstuffs. Images Figure 2. PMID:9719666

Acetyl-CoA carboxylase-a as a novel target for cancer therapy.

PubMed

Wang, Chun; Rajput, Sandeep; Watabe, Kounosuke; Liao, Duan-Fang; Cao, Deliang

2010-01-01

Acetyl-CoA carboxylases (ACC) are rate-limiting enzymes in de novo fatty acid synthesis, catalyzing ATP-dependent carboxylation of acetyl-CoA to form malonyl-CoA. Malonyl-CoA is a critical bi-functional molecule, i.e., a substrate of fatty acid synthase (FAS) for acyl chain elongation (fatty acid synthesis) and an inhibitor of carnitine palmitoyltransferase I (CPT-I) for fatty acid beta-oxidation. Two ACC isoforms have been identified in mammals, i.e. ACC-alpha (ACCA, also termed ACC1) and ACC-beta (ACCB, also designated ACC2). ACC has long been used as a target for the management of metabolic diseases, such as obesity and metabolic syndrome, and various inhibitors have been developed in clinical trials. Recently, ACCA up-regulation has been recognized in multiple human cancers, promoting lipogenesis to meet the need of cancer cells for rapid growth and proliferation. Therefore, ACCA might be effective as a potent target for cancer intervention, and the inhibitors developed for the treatment of metabolic diseases would be potential therapeutic agents for cancer therapy. This review summarizes our recent findings and updates the current understanding of the ACCA with focus on cancer research.

Comparative analysis of pharmacological treatments with N-acetyl-DL-leucine (Tanganil) and its two isomers (N-acetyl-L-leucine and N-acetyl-D-leucine) on vestibular compensation: Behavioral investigation in the cat.

PubMed

Tighilet, Brahim; Leonard, Jacques; Bernard-Demanze, Laurence; Lacour, Michel

2015-12-15

Head roll tilt, postural imbalance and spontaneous nystagmus are the main static vestibular deficits observed after an acute unilateral vestibular loss (UVL). In the UVL cat model, these deficits are fully compensated over 6 weeks as the result of central vestibular compensation. N-Acetyl-dl-leucine is a drug prescribed in clinical practice for the symptomatic treatment of acute UVL patients. The present study investigated the effects of N-acetyl-dl-leucine on the behavioral recovery after unilateral vestibular neurectomy (UVN) in the cat, and compared the effects of each of its two isomers N-acetyl-L-leucine and N-acetyl-D-leucine. Efficacy of these three drug treatments has been evaluated with respect to a placebo group (UVN+saline water) on the global sensorimotor activity (observation grids), the posture control (support surface measurement), the locomotor balance (maximum performance at the rotating beam test), and the spontaneous vestibular nystagmus (recorded in the light). Whatever the parameters tested, the behavioral recovery was strongly and significantly accelerated under pharmacological treatments with N-acetyl-dl-leucine and N-acetyl-L-leucine. In contrast, the N-acetyl-D-leucine isomer had no effect at all on the behavioral recovery, and animals of this group showed the same recovery profile as those receiving a placebo. It is concluded that the N-acetyl-L-leucine isomer is the active part of the racemate component since it induces a significant acceleration of the vestibular compensation process similar (and even better) to that observed under treatment with the racemate component only. Copyright © 2015 Elsevier B.V. All rights reserved.

Evaluation of the inhibitory effect of N-acetyl-L-cysteine on Babesia and Theileria parasites.

PubMed

Rizk, Mohamed Abdo; El-Sayed, Shimaa Abd El-Salam; AbouLaila, Mahmoud; Yokoyama, Naoaki; Igarashi, Ikuo

2017-08-01

N-acetyl-L-cysteine is known to have antibacterial, antiviral, antimalarial, and antioxidant activities. Therefore, the in vitro inhibitory effect of this hit was evaluated in the present study on the growth of Babesia and Theileria parasites. The in vitro growth of Babesia bovis, Babesia bigemina, Babesia divergens, Theileria equi, and Babesia caballi that were tested was significantly inhibited (P < 0.05) by micromolar concentrations of N-acetyl-L-cysteine. The inhibitory effect of N-acetyl-L-cysteine was synergistically potentiated when used in combination with diminazene aceturate on B. bovis and B. caballi cultures. These results indicate that N-acetyl-L-cysteine might be used as a drug for the treatment of babesiosis, especially when used in combination with diminazene aceturate. Copyright © 2017 Elsevier Inc. All rights reserved.

Pharmacokinetics and N-acetylation metabolism of S-methyl-l-cysteine and trans-S-1-propenyl-l-cysteine in rats and dogs.

PubMed

Amano, Hirotaka; Kazamori, Daichi; Itoh, Kenji

2016-11-01

1. Pharmacokinetics and N-acetylation metabolism of S-methyl-L-cysteine (SMC) and trans-S-1-propenyl-L-cysteine (S1PC) were examined in rats and dogs. SMC and S1PC (2-5 mg/kg) were well absorbed in both species with high bioavailability (88-100%). 2. SMC and S1PC were excreted only to a small extent in the urine of rats and dogs. The small renal clearance values (<0.03 l/h/kg) indicated the extensive renal reabsorption of SMC and S1PC, which potentially contributed to their long elimination half-lives (>5 h) in dogs. 3. S1PC, but not SMC, underwent N-acetylation extensively in vivo, which can be explained by the relative activities of N-acetylation of S1PC/SMC and deacetylation of their N-acetylated forms, N-acetyl-S1PC/N-acetyl-SMC, in the liver and kidney in vitro. The activities for S1PC N-acetylation were similar to or higher than those for N-acetyl-S1PC deacetylation in liver S9 fractions of rat and dog, whereas liver and kidney S9 fractions of rat and dog had little activity for SMC N-acetylation or considerably higher activities for N-acetyl-SMC deacetylation. 4. Our study demonstrated that the pharmacokinetics of SMC and S1PC in rats and dogs was characterized by high bioavailability and extensive renal reabsorption; however, the extent of undergoing the N-acetylation metabolism was extremely different between SMC and S1PC.

Protective effect of N-acetyl-L-cysteine against disulfiram-induced oxidative stress and apoptosis in V79 cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Grosicka-Maciag, Emilia; Kurpios-Piec, Dagmara; Grzela, Tomasz

2010-11-01

This work investigated the effect of N-acetyl-L-cysteine (NAC) on disulfiram (DSF) induced oxidative stress in Chinese hamster fibroblast cells (V79). An increase in oxidative stress induced by DSF was observed up to a 200 {mu}M concentration. It was evidenced by a statistically significant increase of both GSH{sub t} and GSSG levels, as well as elevated protein carbonyl (PC) content. There was no increase in lipid peroxidation (measured as TBARS). DSF increased CAT activity, but did not change SOD1 and SOD2 activities. Analysis of GSH related enzymes showed that DSF significantly increased GR activity, did not change Se-dependent GPx, but statisticallymore » significantly decreased non-Se-dependent GPx activity. DSF showed also pro-apoptotic activity. NAC alone did not produce any significant changes, besides an increase of GSH{sub t} level, in any of the variables measured. However, pre-treatment of cells with NAC ameliorated DSF-induced changes. NAC pre-treatment restored the viability of DSF-treated cells evaluated by Trypan blue exclusion assay and MTT test, GSSG level, and protein carbonyl content to the control values as well as it reduced pro-apoptotic activity of DSF. The increase of CAT and GR activity was not reversed. Activity of both GPx was significantly increased compared to their values after DSF treatment. In conclusion, oxidative properties are at least partially attributable to the cellular effects of disulfiram and mechanisms induced by NAC pre-treatment may lower or even abolish the observed effects. These observations illustrate the importance of the initial cellular redox state in terms of cell response to disulfiram exposure. -- Research Highlights: {yields}This report explores biological properties of disulfiram under a condition of modulated intra-cellular GSH level. It shows a protective role of N-acetyl-L-cysteine in V79 cells exposed to disulfiram (in GSH metabolism as well as in changes of antioxidant enzyme activity).« less

Toxicity of the organophosphate chemical warfare agents GA, GB, and VX: Implications for public protection

DOE Office of Scientific and Technical Information (OSTI.GOV)

Munro, N.B.; Ambrose, K.R.; Watson, A.P.

1994-01-01

The nerve agents, GA, GB, and VX are organophosphorus esters that form a major portion of the total agent volume contained in the U.S. stockpile of unitary chemical munitions. Congress has mandated the destruction of these agents, which is currently slated for completion in 2004. The acute, chronic, and delayed toxicity of these agents is reviewed in this analysis. The largely negative results from studies of genotoxicity, carcinogenicity, developmental, and reproductive toxicity are also presented. Nerve agents show few or delayed effects. At supralethal doses, GB can cause delayed neuropathy in antidote-protected chickens, but there is not evidence that itmore » causes this syndrome in humans at any dose. Agent VX shows no potential for inducing delayed neuropathy in any species. In view of their lack of genotoxicity, the nerve agent exposure is the extraordinarily high acute toxicity of these substances. Futhermore, acute effects of moderate exposure such as nausea, diarrhea, inability to perform simple mental tasks, and respiratory effects may render the public unable to respond adequately to emergency instructions in the unlikely event of agent release, making early warning and exposure avoidance important. Likewise, exposure or self-contamination of first responders and medical personnel must be avoided. Control limits for exposure via surface contact of drinking water are needed, as are detection methods for low levels in water or foodstuffs. 187 refs., 3 figs., 7 tabs.« less

Downregulation of Rubisco Activity by Non-enzymatic Acetylation of RbcL.

PubMed

Gao, Xiang; Hong, Hui; Li, Wei-Chao; Yang, Lili; Huang, Jirong; Xiao, You-Li; Chen, Xiao-Ya; Chen, Gen-Yun

2016-07-06

Atmospheric carbon dioxide (CO2) is assimilated by the most abundant but sluggish enzyme, ribulose-1,5-bisphosphate carboxylase/oxygenase (Rubisco). Here we show that acetylation of lysine residues of the Rubisco large subunit (RbcL), including Lys201 and Lys334 in the active sites, may be an important mechanism in the regulation of Rubisco activities. It is well known that Lys201 reacts with CO2 for carbamylation, a prerequisite for both carboxylase and oxygenase activities of Rubisco, and Lys334 contacts with ribulose-1,5-bisphosphate (RuBP). The acetylation level of RbcL in plants is lower during the day and higher at night, inversely correlating with the Rubisco carboxylation activity. A search of the chloroplast proteome database did not reveal a canonical acetyltransferase; instead, we found that a plant-derived metabolite, 7-acetoxy-4-methylcoumarin (AMC), can non-enzymatically acetylate both native Rubisco and synthesized RbcL peptides spanning Lys334 or Lys201. Furthermore, lysine residues were modified by synthesized 4-methylumbelliferone esters with different electro- and stereo-substitutes, resulting in varied Rubisco activities. 1-Chloroethyl 4-methylcoumarin-7-yl carbonate (ClMC) could transfer the chloroethyl carbamate group to lysine residues of RbcL and completely inactivate Rubisco, whereas bis(4-methylcoumarin-7-yl) carbonate (BMC) improved Rubisco activity through increasing the level of Lys201 carbamylation. Our findings indicate that RbcL acetylation negatively regulates Rubisco activity, and metabolic derivatives can be designed to dissect and improve CO2 fixation efficiency of plants through lysine modification. Copyright © 2016 The Author. Published by Elsevier Inc. All rights reserved.

Obesity and lipid stress inhibit carnitine acetyltransferase activity.

PubMed

Seiler, Sarah E; Martin, Ola J; Noland, Robert C; Slentz, Dorothy H; DeBalsi, Karen L; Ilkayeva, Olga R; An, Jie; Newgard, Christopher B; Koves, Timothy R; Muoio, Deborah M

2014-04-01

Carnitine acetyltransferase (CrAT) is a mitochondrial matrix enzyme that catalyzes the interconversion of acetyl-CoA and acetylcarnitine. Emerging evidence suggests that this enzyme functions as a positive regulator of total body glucose tolerance and muscle activity of pyruvate dehydrogenase (PDH), a mitochondrial enzyme complex that promotes glucose oxidation and is feedback inhibited by acetyl-CoA. Here, we used tandem mass spectrometry-based metabolic profiling to identify a negative relationship between CrAT activity and muscle content of lipid intermediates. CrAT specific activity was diminished in muscles from obese and diabetic rodents despite increased protein abundance. This reduction in enzyme activity was accompanied by muscle accumulation of long-chain acylcarnitines (LCACs) and acyl-CoAs and a decline in the acetylcarnitine/acetyl-CoA ratio. In vitro assays demonstrated that palmitoyl-CoA acts as a direct mixed-model inhibitor of CrAT. Similarly, in primary human myocytes grown in culture, nutritional and genetic manipulations that promoted mitochondrial influx of fatty acids resulted in accumulation of LCACs but a pronounced decrease of CrAT-derived short-chain acylcarnitines. These results suggest that lipid-induced antagonism of CrAT might contribute to decreased PDH activity and glucose disposal in the context of obesity and diabetes.

N-Acetyl-L-Leucine Accelerates Vestibular Compensation after Unilateral Labyrinthectomy by Action in the Cerebellum and Thalamus

PubMed Central

Xiong, Guoming; Potschka, Heidrun; Jahn, Klaus; Bartenstein, Peter; Brandt, Thomas; Dutia, Mayank; Dieterich, Marianne; Strupp, Michael; la Fougère, Christian; Zwergal, Andreas

2015-01-01

An acute unilateral vestibular lesion leads to a vestibular tone imbalance with nystagmus, head roll tilt and postural imbalance. These deficits gradually decrease over days to weeks due to central vestibular compensation (VC). This study investigated the effects of i.v. N-acetyl-DL-leucine, N-acetyl-L-leucine and N-acetyl-D-leucine on VC using behavioural testing and serial [18F]-Fluoro-desoxyglucose ([18F]-FDG)-μPET in a rat model of unilateral chemical labyrinthectomy (UL). Vestibular behavioural testing included measurements of nystagmus, head roll tilt and postural imbalance as well as sequential whole-brain [18F]-FDG-μPET was done before and on days 1,3,7 and 15 after UL. A significant reduction of postural imbalance scores was identified on day 7 in the N-acetyl-DL-leucine (p < 0.03) and the N-acetyl-L-leucine groups (p < 0.01), compared to the sham treatment group, but not in the N-acetyl-D-leucine group (comparison for applied dose of 24 mg i.v. per rat, equivalent to 60 mg/kg body weight, in each group). The course of postural compensation in the DL- and L-group was accelerated by about 6 days relative to controls. The effect of N-acetyl-L-leucine on postural compensation depended on the dose: in contrast to 60 mg/kg, doses of 15 mg/kg and 3.75 mg/kg had no significant effect. N-acetyl-L-leucine did not change the compensation of nystagmus or head roll tilt at any dose. Measurements of the regional cerebral glucose metabolism (rCGM) by means of μPET revealed that only N-acetyl-L-leucine but not N-acetyl-D-leucine caused a significant increase of rCGM in the vestibulocerebellum and a decrease in the posterolateral thalamus and subthalamic region on days 3 and 7. A similar pattern was found when comparing the effect of N-acetyl-L-leucine on rCGM in an UL-group and a sham UL-group without vestibular damage. In conclusion, N-acetyl-L-leucine improves compensation of postural symptoms after UL in a dose-dependent and specific manner, most likely by

N-acetyl-L-leucine accelerates vestibular compensation after unilateral labyrinthectomy by action in the cerebellum and thalamus.

PubMed

Günther, Lisa; Beck, Roswitha; Xiong, Guoming; Potschka, Heidrun; Jahn, Klaus; Bartenstein, Peter; Brandt, Thomas; Dutia, Mayank; Dieterich, Marianne; Strupp, Michael; la Fougère, Christian; Zwergal, Andreas

2015-01-01

An acute unilateral vestibular lesion leads to a vestibular tone imbalance with nystagmus, head roll tilt and postural imbalance. These deficits gradually decrease over days to weeks due to central vestibular compensation (VC). This study investigated the effects of i.v. N-acetyl-DL-leucine, N-acetyl-L-leucine and N-acetyl-D-leucine on VC using behavioural testing and serial [18F]-Fluoro-desoxyglucose ([18F]-FDG)-μPET in a rat model of unilateral chemical labyrinthectomy (UL). Vestibular behavioural testing included measurements of nystagmus, head roll tilt and postural imbalance as well as sequential whole-brain [18F]-FDG-μPET was done before and on days 1,3,7 and 15 after UL. A significant reduction of postural imbalance scores was identified on day 7 in the N-acetyl-DL-leucine (p < 0.03) and the N-acetyl-L-leucine groups (p < 0.01), compared to the sham treatment group, but not in the N-acetyl-D-leucine group (comparison for applied dose of 24 mg i.v. per rat, equivalent to 60 mg/kg body weight, in each group). The course of postural compensation in the DL- and L-group was accelerated by about 6 days relative to controls. The effect of N-acetyl-L-leucine on postural compensation depended on the dose: in contrast to 60 mg/kg, doses of 15 mg/kg and 3.75 mg/kg had no significant effect. N-acetyl-L-leucine did not change the compensation of nystagmus or head roll tilt at any dose. Measurements of the regional cerebral glucose metabolism (rCGM) by means of μPET revealed that only N-acetyl-L-leucine but not N-acetyl-D-leucine caused a significant increase of rCGM in the vestibulocerebellum and a decrease in the posterolateral thalamus and subthalamic region on days 3 and 7. A similar pattern was found when comparing the effect of N-acetyl-L-leucine on rCGM in an UL-group and a sham UL-group without vestibular damage. In conclusion, N-acetyl-L-leucine improves compensation of postural symptoms after UL in a dose-dependent and specific manner, most likely by

Peripheral neuropathy

MedlinePlus

... peripheral; Neuritis - peripheral; Nerve disease; Polyneuropathy; Chronic pain - peripheral neuropathy ... Philadelphia, PA: Elsevier; 2016:chap 107. Shy ME. Peripheral neuropathies. In: Goldman L, Schafer AI, eds. Goldman's Cecil ...

Mechanism of the inhibitory effect of zwitterionic drugs (levofloxacin and grepafloxacin) on carnitine transporter (OCTN2) in Caco-2 cells.

PubMed

Hirano, Takeshi; Yasuda, Satoru; Osaka, Yuki; Kobayashi, Masaki; Itagaki, Shirou; Iseki, Ken

2006-11-01

L-Carnitine plays an important role in lipid metabolism by facilitating the transport of long-chain fatty acids across the mitochondrial inner membrane followed by fatty acid beta-oxidation. It is known that L-carnitine exists as a zwitterion and that member of the OCTN family play an important role in its transport. The aims of this study were to characterize L-carnitine transport in the intestine by using Caco-2 cells and to elucidate the effects of levofloxacin (LVFX) and grepafloxacin (GPFX), which are zwitterionic drugs, on L-carnitine uptake. Kinetic analysis showed that the half-saturation Na+ concentration, Hill coefficient and Km value of L-carnitine uptake in Caco-2 cells were 10.3 +/- 4.5 mM, 1.09 and 8.0 +/- 1.0 microM, respectively, suggesting that OCTN2 mainly transports L-carnitine. LVFX and GPFX have two pKa values and the existence ratio of their zwitterionic forms is higher under a neutral condition than under an acidic condition. Experiments on the inhibitory effect of LVFX and GPFX on L-carnitine uptake showed that LVFX and GPFX inhibited L-carnitine uptake more strongly at pH 7.4 than at pH 5.5. It was concluded that the zwitterionic form of drugs plays an important role in inhibition of OCTN2 function.

21 CFR 172.372 - N-Acetyl-L-methionine.

Code of Federal Regulations, 2014 CFR

2014-04-01

... 21 Food and Drugs 3 2014-04-01 2014-04-01 false N-Acetyl-L-methionine. 172.372 Section 172.372 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) FOOD ADDITIVES PERMITTED FOR DIRECT ADDITION TO FOOD FOR HUMAN CONSUMPTION Special Dietary and Nutritional...

N-acetyl-L-tryptophan, a substance-P receptor antagonist attenuates aluminum-induced spatial memory deficit in rats.

PubMed

Fernandes, Joylee; Mudgal, Jayesh; Rao, Chamallamudi Mallikarjuna; Arora, Devinder; Basu Mallik, Sanchari; Pai, K S R; Nampoothiri, Madhavan

2018-06-01

Neuroinflammation plays an important role in the pathophysiology of Alzheimer's disease. Neurokinin substance P is a key mediator which modulates neuroinflammation through neurokinin receptor. Involvement of substance P in Alzheimer's disease is still plausible and various controversies exist in this hypothesis. Preventing the deleterious effects of substance P using N-acetyl-L-tryptophan, a substance P antagonist could be a promising therapeutic strategy. This study was aimed to evaluate the effect of N-acetyl-L-tryptophan on aluminum induced spatial memory alterations in rats. Memory impairment was induced using aluminum chloride (AlCl 3 ) at a dose of 10 mg/kg for 42 d. After induction of dementia, rats were exposed to 30 and 50 mg/kg of N-acetyl-L-tryptophan for 28 d. Spatial memory alterations were measured using Morris water maze. Acetylcholinesterase activity and antioxidant enzyme glutathione level were assessed in hippocampus, frontal cortex and striatum. The higher dose of N-acetyl-L-tryptophan (50 mg/kg) significantly improved the aluminum induced memory alterations. N-acetyl-L-tryptophan exposure resulted in significant increase in acetylcholinesterase activity and glutathione level in hippocampus. The neuroprotective effect of N-acetyl-L-tryptophan could be due to its ability to block substance P mediated neuroinflammation, reduction in oxidative stress and anti-apoptotic properties. To conclude, N-acetyl-L-tryptophan may be considered as a novel neuroprotective therapy in Alzheimer's disease.

Chiral discrimination in cyclodextrin complexes of amino acid derivatives: beta-cyclodextrin/N-acetyl-L-phenylalanine and N-acetyl-D-phenylalanine complexes.

PubMed

Alexander, Jennifer M; Clark, Joanna L; Brett, Tom J; Stezowski, John J

2002-04-16

In a systematic study of molecular recognition of amino acid derivatives in solid-state beta-cyclodextrin (beta-CD) complexes, we have determined crystal structures for complexes of beta-cyclodextrin/N-acetyl-L-phenylalanine at 298 and 20 K and for N-acetyl-D-phenylalanine at 298 K. The crystal structures for the N-acetyl-L-phenylalanine complex present disordered inclusion complexes for which the distribution of guest molecules at room temperature is not resolvable; however, they can be located with considerable confidence at low temperature. In contrast, the complex with N-acetyl-D-phenylalanine is well ordered at room temperature. The latter complex presents an example of a complex in this series in which a water molecule is included deeply in the hydrophobic torus of the extended dimer host. In an effort to understand the mechanisms of molecular recognition giving rise to the dramatic differences in crystallographic order in these crystal structures, we have examined the intermolecular interactions in detail and have examined insertion of the enantiomer of the D-complex into the chiral beta-CD complex crystal lattice.

Enzymes involved in L-carnitine biosynthesis are expressed by small intestinal enterocytes in mice: implications for gut health.

PubMed

Shekhawat, Prem S; Sonne, Srinivas; Carter, A Lee; Matern, Dietrich; Ganapathy, Vadivel

2013-07-01

Carnitine is essential for mitochondrial β-oxidation of long-chain fatty acids. Deficiency of carnitine leads to severe gut atrophy, ulceration and inflammation in animal models of carnitine deficiency. Genetic studies in large populations have linked mutations in the carnitine transporters OCTN1 and OCTN2 with Crohn's disease (CD), while other studies at the same time have failed to show a similar association and report normal serum carnitine levels in CD patients. In this report, we have studied the expression of carnitine-synthesizing enzymes in intestinal epithelial cells to determine the capability of these cells to synthesize carnitine de novo. We studied expression of five enzymes involved in carnitine biosynthesis, namely 6-N-trimethyllysine dioxygenase (TMLD), 4-trimethylaminobutyraldehyde dehydrogenase (TMABADH), serine hydroxymethyltransferase 1 and 2 (SHMT1 and 2) and γ-butyrobetaine hydroxylase (BBH) by real-time PCR in mice (C3H strain). We also measured activity of γ-BBH in the intestine using an ex vivo assay and localized its expression by in situ hybridization. Our investigations show that mouse intestinal epithelium expresses all five enzymes required for de novo carnitine biosynthesis; the expression is localized mainly in villous surface epithelial cells throughout the intestine. The final rate-limiting enzyme γ-BBH is highly active in the small intestine; its activity was 9.7 ± 3.5 pmol/mg/min, compared to 22.7 ± 7.3 pmol/mg/min in the liver. We conclude that mouse gut epithelium is able to synthesize carnitine de novo. This capacity to synthesize carnitine in the intestine may play an important role in gut health and can help explain lack of clinical carnitine deficiency signs in subjects with mutations with OCTN transporters. Copyright © 2012 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.

The Impact of Carnitine on Dietary Fiber and Gut Bacteria Metabolism and Their Mutual Interaction in Monogastrics

PubMed Central

Ghonimy, Abdallah; Zhang, Dong Ming; Farouk, Mohammed Hamdy; Wang, Qiuju

2018-01-01

Carnitine has vital roles in the endogenous metabolism of short chain fatty acids. It can protect and support gut microbial species, and some dietary fibers can reduce the available iron involved in the bioactivity of carnitine. There is also an antagonistic relationship between high microbial populations and carnitine bioavailability. This review shows the interactions between carnitine and gut microbial composition. It also elucidates the role of carnitine bacterial metabolism, mitochondrial function, fiber fermentability, and short chain fatty acids (SCFAs). PMID:29597260

L-carnitine and cancer cachexia. I. L-carnitine distribution and metabolic disorders in cancer cachexia.

PubMed

Szefel, Jarosław; Kruszewski, Wiesław Janusz; Ciesielski, Maciej; Szajewski, Mariusz; Kawecki, Krzysztof; Aleksandrowicz-Wrona, Ewa; Jankun, Jerzy; Lysiak-Szydłowska, Wiesława

2012-07-01

Cancer cachexia (CC), a progressive loss of body mass, is associated with decreased energy production. Abnormally low levels of L-carnitine (LC) in skeletal muscle means that mitochondrial β-oxidation of long-chain fatty acids (LCFA) does not occur efficiently in patients with CC. We assessed the influence of CC on LC distribution and the effects of parenteral lipid emulsions on plasma LC levels and urinary excretion. Fifty patients with CC were randomly assigned to total parenteral nutrition (TPN) with long-chain triglycerides (LCTs), or LCTs plus medium-chain triglycerides (MCTs) as 50/50. Patients were further separated into those with body-mass index (BMI) ≤ 19 kg/m(2) and BMI >19 kg/m(2). Plasma concentrations of total LC (TC) and free LC (FC) and their urinary excretion were measured, along with skeletal muscle LC levels. On average, plasma FC and TC were higher than reference values in all patients. Patients with BMI ≤ 19 kg/m(2) had lower plasma FC and TC than those with BMI >19 kg/m(2). Skeletal muscle FC in the BMI ≤ 19 kg/m(2) group was lower than reference value, but within the normal range in others. LC and FC urinary excretion was higher than reference values. Plasma LC and its urinary excretion were higher in patients administered pure LCTs relative to those given MCTs/LCTs. A decrease in skeletal muscle LC in cancer patients with CC (BMI ≤ 19 kg/m(2)) correlates with an increase in its plasma levels and increased renal excretion. A diet of MCTs/LCTs reduces LC release from muscle to plasma and urine more effectively than LCTs.

Acetylation of mitochondrial proteins by GCN5L1 promotes enhanced fatty acid oxidation in the heart.

PubMed

Thapa, Dharendra; Zhang, Manling; Manning, Janet R; Guimarães, Danielle A; Stoner, Michael W; O'Doherty, Robert M; Shiva, Sruti; Scott, Iain

2017-08-01

Lysine acetylation is a reversible posttranslational modification and is particularly important in the regulation of mitochondrial metabolic enzymes. Acetylation uses acetyl-CoA derived from fuel metabolism as a cofactor, thereby linking nutrition to metabolic activity. In the present study, we investigated how mitochondrial acetylation status in the heart is controlled by food intake and how these changes affect mitochondrial metabolism. We found that there was a significant increase in cardiac mitochondrial protein acetylation in mice fed a long-term high-fat diet and that this change correlated with an increase in the abundance of the mitochondrial acetyltransferase-related protein GCN5L1. We showed that the acetylation status of several mitochondrial fatty acid oxidation enzymes (long-chain acyl-CoA dehydrogenase, short-chain acyl-CoA dehydrogenase, and hydroxyacyl-CoA dehydrogenase) and a pyruvate oxidation enzyme (pyruvate dehydrogenase) was significantly upregulated in high-fat diet-fed mice and that the increase in long-chain and short-chain acyl-CoA dehydrogenase acetylation correlated with increased enzymatic activity. Finally, we demonstrated that the acetylation of mitochondrial fatty acid oxidation proteins was decreased after GCN5L1 knockdown and that the reduced acetylation led to diminished fatty acid oxidation in cultured H9C2 cells. These data indicate that lysine acetylation promotes fatty acid oxidation in the heart and that this modification is regulated in part by the activity of GCN5L1. NEW & NOTEWORTHY Recent research has shown that acetylation of mitochondrial fatty acid oxidation enzymes has greatly contrasting effects on their activity in different tissues. Here, we provide new evidence that acetylation of cardiac mitochondrial fatty acid oxidation enzymes by GCN5L1 significantly upregulates their activity in diet-induced obese mice. Copyright © 2017 the American Physiological Society.

Acetylation accumulates PFKFB3 in cytoplasm to promote glycolysis and protects cells from cisplatin-induced apoptosis.

PubMed

Li, Fu-Long; Liu, Jin-Ping; Bao, Ruo-Xuan; Yan, GuoQuan; Feng, Xu; Xu, Yan-Ping; Sun, Yi-Ping; Yan, Weili; Ling, Zhi-Qiang; Xiong, Yue; Guan, Kun-Liang; Yuan, Hai-Xin

2018-02-06

Enhanced glycolysis in cancer cells has been linked to cell protection from DNA damaging signals, although the mechanism is largely unknown. The 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) catalyzes the generation of fructose-2,6-bisphosphate, a potent allosteric stimulator of glycolysis. Intriguingly, among the four members of PFKFB family, PFKFB3 is uniquely localized in the nucleus, although the reason remains unclear. Here we show that chemotherapeutic agent cisplatin promotes glycolysis, which is suppressed by PFKFB3 deletion. Mechanistically, cisplatin induces PFKFB3 acetylation at lysine 472 (K472), which impairs activity of the nuclear localization signal (NLS) and accumulates PFKFB3 in the cytoplasm. Cytoplasmic accumulation of PFKFB3 facilitates its phosphorylation by AMPK, leading to PFKFB3 activation and enhanced glycolysis. Inhibition of PFKFB3 sensitizes tumor to cisplatin treatment in a xenograft model. Our findings reveal a mechanism for cells to stimulate glycolysis to protect from DNA damage and potentially suggest a therapeutic strategy to sensitize tumor cells to genotoxic agents by targeting PFKFB3.

Obesity and lipid stress inhibit carnitine acetyltransferase activity[S

PubMed Central

Seiler, Sarah E.; Martin, Ola J.; Noland, Robert C.; Slentz, Dorothy H.; DeBalsi, Karen L.; Ilkayeva, Olga R.; An, Jie; Newgard, Christopher B.; Koves, Timothy R.; Muoio, Deborah M.

2014-01-01

Carnitine acetyltransferase (CrAT) is a mitochondrial matrix enzyme that catalyzes the interconversion of acetyl-CoA and acetylcarnitine. Emerging evidence suggests that this enzyme functions as a positive regulator of total body glucose tolerance and muscle activity of pyruvate dehydrogenase (PDH), a mitochondrial enzyme complex that promotes glucose oxidation and is feedback inhibited by acetyl-CoA. Here, we used tandem mass spectrometry-based metabolic profiling to identify a negative relationship between CrAT activity and muscle content of lipid intermediates. CrAT specific activity was diminished in muscles from obese and diabetic rodents despite increased protein abundance. This reduction in enzyme activity was accompanied by muscle accumulation of long-chain acylcarnitines (LCACs) and acyl-CoAs and a decline in the acetylcarnitine/acetyl-CoA ratio. In vitro assays demonstrated that palmitoyl-CoA acts as a direct mixed-model inhibitor of CrAT. Similarly, in primary human myocytes grown in culture, nutritional and genetic manipulations that promoted mitochondrial influx of fatty acids resulted in accumulation of LCACs but a pronounced decrease of CrAT-derived short-chain acylcarnitines. These results suggest that lipid-induced antagonism of CrAT might contribute to decreased PDH activity and glucose disposal in the context of obesity and diabetes. PMID:24395925

Peripheral neuropathy in diabetes: it's not always what it looks like.

PubMed

Maltese, G; Tan, S V; Bruno, E; Brackenridge, A; Thomas, S

2018-06-04

Hereditary Neuropathy with liability to Pressure Palsies (HNPP) is an autosomal dominant neuropathy, associated with deletion of the Peripheral Myelin Protein-22 (PMP-22) gene, causing recurrent painless palsies with age of onset between 10 and 30 years old. Only a few cases of Type 2 Diabetes and HNPP have been described and the coexistence of HNPP and Type 1 diabetes has never been reported. A 54-year old man with a history of Type 1 diabetes, managed with continuous subcutaneous insulin infusion (CSII), presented with deterioration of long-standing motor and sensory symptoms, previously attributed to golfer's elbow, diabetic neuropathy and spinal degenerative disease. He had multilevel severe spine degenerative changes and L4/L5 and L5/S1 root impingements with a L4/L5 discectomy performed when he was 25 years old. On physical examination he had normal power and distal hypoaesthesia of the digits and plantar aspect of the feet. Investigations revealed normal full blood count, liver and renal function, electrolytes, vitamin B12 and serum folate. He suffered from primary hypothyroidism and thyroid function tests indicated adequate levothyroxine replacement. Nerve conduction studies revealed a generalized demyelinating sensorimotor neuropathy, with more severe involvement of nerves over entrapment sites. Further history that his father suffered from episodes of weakness and numbness was elicited. Genetic analysis revealed one copy of the PMP22 gene at 17p11.2 confirming the diagnosis of HNPP. In people with diabetes the evaluation of peripheral neuropathy should include a careful history, a comprehensive physical examination, blood tests and in some cases nerve conduction studies and genetic testing. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Effect of L-carnitine supplementation on growth performance, nutrient utilization, and nitrogen balance of broilers fed with animal fat.

PubMed

Murali, P; George, S K; Ally, K; Dipu, M T

2015-04-01

This experiment was conducted to evaluate the effect of L-carnitine supplementation on growth performance, nutrient utilization and nitrogen balance in broilers fed with animal fat. 80 day-old Cobb commercial broiler chicks were randomly assigned into two dietary treatment groups with four replicates of ten chicks each. The diets were isonitrogenous and isocaloric. The birds in both the control (T1) and treatment group (T2) were fed with a diet having 5% animal fat, while the treatment group (T2) was supplemented with 900 mg of L-carnitine. The birds were fed with standard broiler starter ration up to 4 weeks of age and finisher ration up to 6 weeks of age. The average body weight (g), cumulative feed intake (g) and cumulative feed conversion ratio belonging to groups T1 and T2 at 6(th) week of age were 2091.25 and 2151.11, 3976.49 and 4171.68, 1.97 and 1.96 respectively. The percentage availability of the nutrients of two experimental rations T1 and T2 was 68.23 and 68.00 for dry matter, 58.72 and 55.98 for crude protein, 73.85 and 71.35 for ether extract, 34.19 and 33.86 for crude fiber, 79.18 and 79.59 for nitrogen free extract, 70.24 and 70.03 for energy efficiency and nitrogen balance (g/day) were 2.35 and 2.39, respectively. This study suggests that the supplementation of 900 mg L-carnitine in diet with added animal fat had no effect on growth performance, nutrient utilization, and nitrogen balance of broilers.

N-Acetylcysteine Prevents Retrograde Motor Neuron Death after Neonatal Peripheral Nerve Injury.

PubMed

Catapano, Joseph; Zhang, Jennifer; Scholl, David; Chiang, Cameron; Gordon, Tessa; Borschel, Gregory H

2017-05-01

Neuronal death may be an overlooked and unaddressed component of disability following neonatal nerve injuries, such as obstetric brachial plexus injury. N-acetylcysteine and acetyl-L-carnitine improve survival of neurons after adult nerve injury, but it is unknown whether they improve survival after neonatal injury, when neurons are most susceptible to retrograde neuronal death. The authors' objective was to examine whether N-acetylcysteine or acetyl-L-carnitine treatment improves survival of neonatal motor or sensory neurons in a rat model of neonatal nerve injury. Rat pups received either a sciatic nerve crush or transection injury at postnatal day 3 and were then randomized to receive either intraperitoneal vehicle (5% dextrose), N-acetylcysteine (750 mg/kg), or acetyl-L-carnitine (300 mg/kg) once or twice daily. Four weeks after injury, surviving neurons were retrograde-labeled with 4% Fluoro-Gold. The lumbar spinal cord and L4/L5 dorsal root ganglia were then harvested and sectioned to count surviving motor and sensory neurons. Transection and crush injuries resulted in significant motor and sensory neuron loss, with transection injury resulting in significantly less neuron survival. High-dose N-acetylcysteine (750 mg/kg twice daily) significantly increased motor neuron survival after neonatal sciatic nerve crush and transection injury. Neither N-acetylcysteine nor acetyl-L-carnitine treatment improved sensory neuron survival. Proximal neonatal nerve injuries, such as obstetric brachial plexus injury, produce significant retrograde neuronal death after injury. High-dose N-acetylcysteine significantly increases motor neuron survival, which may improve functional outcomes after obstetrical brachial plexus injury.

Metabolic profiling of PPARα−/− mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation

PubMed Central

Makowski, Liza; Noland, Robert C.; Koves, Timothy R.; Xing, Weibing; Ilkayeva, Olga R.; Muehlbauer, Michael J.; Stevens, Robert D.; Muoio, Deborah M.

2009-01-01

Peroxisome proliferator-activated receptor-α (PPARα) is a master transcriptional regulator of β-oxidation and a prominent target of hypolipidemic drugs. To gain deeper insights into the systemic consequences of impaired fat catabolism, we used quantitative, mass spectrometry-based metabolic profiling to investigate the fed-to-fasted transition in PPARα+/+ and PPARα−/− mice. Compared to PPARα+/+ animals, acylcarnitine profiles of PPARα−/− mice revealed 2- to 4-fold accumulation of long-chain species in the plasma, whereas short-chain species were reduced by as much as 69% in plasma, liver, and skeletal muscle. These results reflect a metabolic bottleneck downstream of carnitine palmitoyltransferase-1, a mitochondrial enzyme that catalyzes the first step in β-oxidation. Organic and amino acid profiles of starved PPARα−/− mice suggested compromised citric acid cycle flux, enhanced urea cycle activity, and increased amino acid catabolism. PPARα−/− mice had 40–50% lower plasma and tissue levels of free carnitine, corresponding with diminished hepatic expression of genes involved in carnitine biosynthesis and transport. One week of oral carnitine supplementation conferred partial metabolic recovery in the PPARα−/− mice. In summary, comprehensive metabolic profiling revealed novel biomarkers of defective fat oxidation, while also highlighting the potential value of supplemental carnitine as a therapy and diagnostic tool for metabolic disorders.—Makowski, L., Noland, R. C., Koves, T. R., Xing, W., Ilkayeva, O. R., Muehlbauer, M. J., Stevens, R. D., Muoio, D. M. Metabolic profiling of PPARα−/− mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation. PMID:18945875

Genetic polymorphisms of SCN9A are associated with oxaliplatin-induced neuropathy.

PubMed

Sereno, María; Gutiérrez-Gutiérrez, Gerardo; Rubio, Juan Moreno; Apellániz-Ruiz, María; Sánchez-Barroso, Lara; Casado, Enrique; Falagan, Sandra; López-Gómez, Miriam; Merino, María; Gómez-Raposo, César; Rodriguez-Salas, Nuria; Tébar, Francisco Zambrana; Rodríguez-Antona, Cristina

2017-01-19

Oxaliplatin is a chemotherapy agent active against digestive tumors. Peripheral neuropathy is one of the most important dose-limiting toxicity of this drug. It occurs in around 60-80% of the patients, and 15% of them develop severe neuropathy. The pathophysiology of oxaliplatin neurotoxicity remains unclear. SCN9A is a gene codifying for a subtype sodium channel (type IX, subunit α) and mutations in this gene are involved in neuropathic perception. In this study we investigated whether SCN9A genetic variants were associated with risk of neurotoxicity in patients diagnosed of cancer on treatment with oxaliplatin. Blood samples from 94 patients diagnosed of digestive cancer that had received oxaliplatin in adjuvant or metastatic setting were obtained from three hospitals in Madrid. These patients were classified into two groups: "cases" developed oxaliplatin-induced grade 3-4 neuropathy (n = 48), and "controls" (n = 46) had no neuropathy or grade 1. The neuropathy was evaluated by an expert neurologist and included a clinical examination and classification according to validated neurological scales: National Cancer Institute Common Toxicity Criteria (NCI-CTC), Oxaliplatin-Specific Neurotoxicity Scale (OSNS) and Total Neuropathy score (TNS). Genotyping was performed for 3 SCN9A missense polymorphisms: rs6746030 (R1150W), rs74401238 (R1110Q) and rs41268673 (P610T), and associations between genotypes and neuropathy were evaluated. We found that SCN9A rs6746030 was associated with protection for severe neuropathy (OR = 0.39, 95% CI = 0.16-0.96; p = 0.041). Multivariate analysis adjusting for diabetes provided similar results (p = 0.036). No significant differences in neuropathy risk were detected for rs74401238 and rs41268673. SCN9A rs6746030 was associated with protection for severe oxaliplatin-induced peripheral neuropathy. The validation of this exploratory study is ongoing in an independent series.

Infrared and Raman spectra of N-acetyl- L-amino acid methylamides with aromatic side groups

NASA Astrophysics Data System (ADS)

Matsuura, Hiroatsu; Hasegawa, Kodo; Miyazawa, Tatsuo

Infrared and Raman spectra of N-acetyl- L-phenylalanine methylamide, N-acetyl- L-tyrosine methylamide and N-acetyl- L-tryptophan methylamide, as model compounds of aromatic amino acid residues in proteins, were measured in the solid state and in methanol solutions. Vibrational assignments of the spectra were made by utilizing the deuteration effect and by comparison with the spectra of related compounds which include toluene, p-cresol and 3-methylindole. The amide I, III and IV bands were strong in Raman scattering, but other characteristic amide bands were ill-defined. In the Raman spectra of methanol solutions, only the bands due to the aromatic side group vibrations were markedly observed, but those due to the peptide backbone vibrations were very weak, suggesting the coexistence of various molecular conformations in solution.

Therapeutic effects of N-acetyl-L-cysteine on liver damage induced by long-term CCl4 administration.

PubMed

Otrubová, Oľga; Turecký, Ladislav; Uličná, Oľga; Janega, Pavol; Luha, Ján; Muchová, Jana

2018-01-01

N-acetyl-L-cysteine (NAC) is a drug routinely used in several health problems, e.g. liver damage. There is some information emerged on its negative effects in certain situations. The aim of our study was to examine its ability to influence liver damage induced by long-term burden. We induced liver damage by CCl4 (10 weeks) and monitored the impact of parallel NAC administration (daily 150 mg/kg of b.w.) on liver morphology and some biochemical parameters (triacylglycerols, cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, bile acids, proteins, albumins and cholinesterase). NAC significantly decreased levels of bile acids and bilirubin in plasma and triacylglycerols in liver, all of them elevated by impairment with CCl4. Reduction of cholesterol induced by CCl4 was completely recovered in the presence of NAC as indicated by its elevation to control levels. NAC administration did not improve the histological parameters. Together with protective effects of NAC, we found also its deleterious properties: parallel administration of CCl4 and NAC increased triacylglycerols, ALT and AST activity and significantly increased plasma cholinesterase activity. We have observed nonsignificantly increased percentage of liver tissue fibrosis. Our results have shown that NAC administered simultaneously with liver damaging agent CCl4, exhibits not only protective, but also deleterious effects as indicated by several biochemical parameters.

Propionyl-L-carnitine limits chronic ventricular dilation after myocardial infarction in rats.

PubMed

Micheletti, R; Di Paola, E D; Schiavone, A; English, E; Benatti, P; Capasso, J M; Anversa, P; Bianchi, G

1993-04-01

To determine whether propionyl-L-carnitine (PLC) administration ameliorates ventricular remodeling after myocardial infarction, we performed coronary occlusion in rats and examined the long-term effects of the drug 19-24 wk after surgery. In view of the well-established role of angiotensin-converting enzyme (ACE) inhibitors in the reduction of ventricular dilation after infarction, the therapeutic impact of oral PLC (60 mg/kg) was compared with that of enalapril (1 mg/kg). Infarct size measured planimetrically was found to be comparable in untreated, PLC-treated, and enalapril-treated rats, averaging 40-46% of the left ventricular free wall. Heart weight was increased 14, 16, and 11% with no treatment, with PLC, and with enalapril, respectively. The relationship between left ventricular filling pressure and chamber volume demonstrated that PLC and enalapril significantly prevented the expansion in cavitary size after infarction. These protective influences were observed throughout the range of filling pressures measured, from 0 to 30 mmHg. At a uniform reference point of filling pressure of 4 mmHg, untreated infarcted hearts showed an expansion in ventricular volume of 2.17-fold (P < 0.0001). Corresponding increases in this parameter after PLC and enalapril were 36 and 43%, respectively, both not statistically significant. Moreover, PLC was capable of reducing the alterations in myocardial compliance associated with myocardial infarction. In conclusion, PLC reduces the magnitude of decompensated eccentric hypertrophy produced by myocardial infarction in a manner similar to that found with ACE inhibition.

Genetics Home Reference: primary carnitine deficiency

MedlinePlus

... 1 link) NIH Office of Dietary Supplements: Carnitine Educational Resources (5 links) Disease InfoSearch: Renal carnitine transport defect Orphanet: Systemic primary carnitine deficiency Screening, Technology, and Research in Genetics The Linus Pauling Institute: ...

Bromine catalyzed conversion of S-tert-butyl groups into versatile and, for self-assembly processes accessible, acetyl-protected thiols.

PubMed

Blaszczyk, Alfred; Elbing, Mark; Mayor, Marcel

2004-10-07

The facile and efficient conversion of a tert-butyl protecting group to an acetyl protecting group for thiols by catalytic amounts of bromine in acetyl chloride and the presence of acetic acid has been developed. The fairly mild reaction conditions are of particular interest for new protecting group strategies for sulfur functionalised target structures. Copyright 2004 The Royal Society of Chemistry

Genotype-Phenotype Correlation in Primary Carnitine Deficiency

PubMed Central

Rose, Emily Cornforth; di San Filippo, Cristina Amat; Ndukwe Erlingsson, Uzochi C.; Ardon, Orly; Pasquali, Marzia; Longo, Nicola

2011-01-01

Primary carnitine deficiency is caused by defective OCTN2 carnitine transporters encoded by the SLC22A5 gene. Lack of carnitine impairs fatty acid oxidation resulting in hypoketotic hypoglycemia, hepatic encephalopathy, skeletal and cardiac myopathy. Recently, asymptomatic mothers with primary carnitine deficiency were identified by low carnitine levels in their infant by newborn screening. Here we evaluate mutations in the SLC22A5 gene and carnitine transport in fibroblasts from symptomatic patients and asymptomatic women. Carnitine transport was significantly reduced in fibroblasts obtained from all patients with primary carnitine deficiency, but was significantly higher in the asymptomatic women’s than in the symptomatic patients’ fibroblasts (p<0.01). By contrast, ergothioneine transport (a selective substrate of the OCTN1 transporter, tested here as a control) was similar in cells from controls and patients with carnitine deficiency. DNA sequencing indicated an increased frequency of nonsense mutations in symptomatic patients (p<0.001). Expression of the missense mutations in CHO cells indicated that many mutations retained residual carnitine transport activity, with no difference in the average activity of missense mutations identified in symptomatic versus asymptomatic patients. These results indicate that cells from asymptomatic women have on average higher levels of residual carnitine transport activity as compared to that of symptomatic patients due to the presence of at least one missense mutation. PMID:21922592

Oxygen Glucose Deprivation in Rat Hippocampal Slice Cultures Results in Alterations in Carnitine Homeostasis and Mitochondrial Dysfunction

PubMed Central

Rau, Thomas F.; Lu, Qing; Sharma, Shruti; Sun, Xutong; Leary, Gregory; Beckman, Matthew L.; Hou, Yali; Wainwright, Mark S.; Kavanaugh, Michael; Poulsen, David J.; Black, Stephen M.

2012-01-01

Mitochondrial dysfunction characterized by depolarization of mitochondrial membranes and the initiation of mitochondrial-mediated apoptosis are pathological responses to hypoxia-ischemia (HI) in the neonatal brain. Carnitine metabolism directly supports mitochondrial metabolism by shuttling long chain fatty acids across the inner mitochondrial membrane for beta-oxidation. Our previous studies have shown that HI disrupts carnitine homeostasis in neonatal rats and that L-carnitine can be neuroprotective. Thus, this study was undertaken to elucidate the molecular mechanisms by which HI alters carnitine metabolism and to begin to elucidate the mechanism underlying the neuroprotective effect of L-carnitine (LCAR) supplementation. Utilizing neonatal rat hippocampal slice cultures we found that oxygen glucose deprivation (OGD) decreased the levels of free carnitines (FC) and increased the acylcarnitine (AC): FC ratio. These changes in carnitine homeostasis correlated with decreases in the protein levels of carnitine palmitoyl transferase (CPT) 1 and 2. LCAR supplementation prevented the decrease in CPT1 and CPT2, enhanced both FC and the AC∶FC ratio and increased slice culture metabolic viability, the mitochondrial membrane potential prior to OGD and prevented the subsequent loss of neurons during later stages of reperfusion through a reduction in apoptotic cell death. Finally, we found that LCAR supplementation preserved the structural integrity and synaptic transmission within the hippocampus after OGD. Thus, we conclude that LCAR supplementation preserves the key enzymes responsible for maintaining carnitine homeostasis and preserves both cell viability and synaptic transmission after OGD. PMID:22984394

N-acetyl-L-cysteine protects against cadmium-induced neuronal apoptosis by inhibiting ROS-dependent activation of Akt/mTOR pathway in mouse brain

PubMed Central

Chen, Sujuan; Ren, Qian; Zhang, Jinfei; Ye, Yangjing; Zhang, Zhen; Xu, Yijiao; Guo, Min; Ji, Haiyan; Xu, Chong; Gu, Chenjian; Gao, Wei; Huang, Shile; Chen, Long

2014-01-01

Aims This study explores the neuroprotective effects and mechanisms of N-acetyl-L-cysteine (NAC) in mice exposed to cadmium (Cd). Methods NAC (150 mg/kg) was intraperitoneally administered to mice exposed to Cd (10-50 mg/L) in drinking water for 6 weeks. The changes of cell damage and death, reactive oxygen species (ROS), antioxidant enzymes, as well as Akt/mammalian target of rapamycin (mTOR) signaling pathway in brain neurons were assessed. To verify the role of mTOR activation in Cd-induced neurotoxicity, mice also received a subacute regimen of intraperitoneally administered Cd (1 mg/kg) with/without rapamycin (7.5 mg/kg) for 11 days. Results Chronic exposure of mice to Cd induced brain damage or neuronal cell death, due to ROS induction. Co-administration of NAC significantly reduced Cd levels in the plasma and brain of the animals. NAC prevented Cd-induced ROS and significantly attenuated Cd-induced brain damage or neuronal cell death. The protective effect of NAC was mediated, at least partially, by elevating the activities of Cu/Zn-superoxide dismutase, catalase and glutathione peroxidase, as well as the level of glutathione in the brain. Furthermore, Cd-induced activation of Akt/mTOR pathway in the brain was also inhibited by NAC. Rapamycin in vitro and in vivo protected against Cd-induced neurotoxicity. Conclusions NAC protects against Cd-induced neuronal apoptosis in mouse brain partially by inhibiting ROS-dependent activation of Akt/mTOR pathway. The findings highlight that NAC may be exploited for prevention and treatment of Cd-induced neurodegenerative diseases. PMID:24299490

Intense Exercise and Aerobic Conditioning Associated with Chromium or L-Carnitine Supplementation Modified the Fecal Microbiota of Fillies

PubMed Central

Feringer, Walter Heinz; Carvalho, Júlia Ribeiro Garcia; Rodrigues, Isadora Mestriner; Jordão, Lilian Rezende; Fonseca, Mayara Gonçalves; Carneiro de Rezende, Adalgiza Souza; de Queiroz Neto, Antonio; Weese, J. Scott; da Costa, Márcio Carvalho

2016-01-01

Recent studies performed in humans and rats have reported that exercise can alter the intestinal microbiota. Athletic horses perform intense exercise regularly, but studies characterizing horse microbiome during aerobic conditioning programs are still limited. Evidence has indicated that this microbial community is involved in the metabolic homeostasis of the host. Research on ergogenic substances using new sequencing technologies have been limited to the intestinal microbiota and there is a considerable demand for scientific studies that verify the effectiveness of these supplements in horses. L-carnitine and chromium are potentially ergogenic substances for athletic humans and horses since they are possibly able to modify the metabolism of carbohydrates and lipids. This study aimed to assess the impact of acute exercise and aerobic conditioning, associated either with L-carnitine or chromium supplementation, on the intestinal microbiota of fillies. Twelve “Mangalarga Marchador” fillies in the incipient fitness stage were distributed into four groups: control (no exercise), exercise, L-carnitine (10g/day) and chelated chromium (10mg/day). In order to investigate the impact of acute exercise or aerobic conditioning on fecal microbiota all fillies undergoing the conditioning program were analyzed as a separate treatment. The fillies underwent two incremental exercise tests before and after training on a treadmill for 42 days at 70–80% of the lactate threshold intensity. Fecal samples were obtained before and 48 h after acute exercise (incremental exercise test). Bacterial populations were characterized by sequencing the V4 region of the 16S rRNA gene using the MiSeq Illumina platform, and 5,224,389 sequences were obtained from 48 samples. The results showed that, overall, the two most abundant phyla were Firmicutes (50.22%) followed by Verrucomicrobia (15.13%). The taxa with the highest relative abundances were unclassified Clostridiales (17.06%) and "5 genus

Intense Exercise and Aerobic Conditioning Associated with Chromium or L-Carnitine Supplementation Modified the Fecal Microbiota of Fillies.

PubMed

Almeida, Maria Luiza Mendes de; Feringer, Walter Heinz; Carvalho, Júlia Ribeiro Garcia; Rodrigues, Isadora Mestriner; Jordão, Lilian Rezende; Fonseca, Mayara Gonçalves; Carneiro de Rezende, Adalgiza Souza; de Queiroz Neto, Antonio; Weese, J Scott; Costa, Márcio Carvalho da; Lemos, Eliana Gertrudes de Macedo; Ferraz, Guilherme de Camargo

2016-01-01

Recent studies performed in humans and rats have reported that exercise can alter the intestinal microbiota. Athletic horses perform intense exercise regularly, but studies characterizing horse microbiome during aerobic conditioning programs are still limited. Evidence has indicated that this microbial community is involved in the metabolic homeostasis of the host. Research on ergogenic substances using new sequencing technologies have been limited to the intestinal microbiota and there is a considerable demand for scientific studies that verify the effectiveness of these supplements in horses. L-carnitine and chromium are potentially ergogenic substances for athletic humans and horses since they are possibly able to modify the metabolism of carbohydrates and lipids. This study aimed to assess the impact of acute exercise and aerobic conditioning, associated either with L-carnitine or chromium supplementation, on the intestinal microbiota of fillies. Twelve "Mangalarga Marchador" fillies in the incipient fitness stage were distributed into four groups: control (no exercise), exercise, L-carnitine (10g/day) and chelated chromium (10mg/day). In order to investigate the impact of acute exercise or aerobic conditioning on fecal microbiota all fillies undergoing the conditioning program were analyzed as a separate treatment. The fillies underwent two incremental exercise tests before and after training on a treadmill for 42 days at 70-80% of the lactate threshold intensity. Fecal samples were obtained before and 48 h after acute exercise (incremental exercise test). Bacterial populations were characterized by sequencing the V4 region of the 16S rRNA gene using the MiSeq Illumina platform, and 5,224,389 sequences were obtained from 48 samples. The results showed that, overall, the two most abundant phyla were Firmicutes (50.22%) followed by Verrucomicrobia (15.13%). The taxa with the highest relative abundances were unclassified Clostridiales (17.06%) and "5 genus

Chemotherapy-induced peripheral neuropathy: an update on the current understanding.

PubMed

Addington, James; Freimer, Miriam

2016-01-01

Chemotherapy-induced peripheral neuropathy is a common side effect of selected chemotherapeutic agents. Previous work has suggested that patients often under report the symptoms of chemotherapy-induced peripheral neuropathy and physicians fail to recognize the presence of such symptoms in a timely fashion. The precise pathophysiology that underlies chemotherapy-induced peripheral neuropathy, in both the acute and the chronic phase, remains complex and appears to be medication specific. Recent work has begun to demonstrate and further clarify potential pathophysiological processes that predispose and, ultimately, lead to the development of chemotherapy-induced peripheral neuropathy. There is increasing evidence that the pathway to neuropathy varies with each agent. With a clearer understanding of how these agents affect the peripheral nervous system, more targeted treatments can be developed in order to optimize treatment and prevent long-term side effects.

[Related factor of serum carnitine deficiency and influence of its deficiency on the length of hospital stay in critical ill patients].

PubMed

Zhou, Zhaoxiong; Qiu, Chunfang; Chen, Chuanxi; Wang, Luhao; Chen, Juan; Chen, Minying; Guan, Xiangdong; Ouyang, Bin

2014-12-01

To investigate the related factors of serum carnitine deficiency in critical ill patients, and the influence of its deficiency on the length of hospital stay. A prospective study was conducted. Critical ill patients with acute physiology and chronic health evaluation II (APACHEII) score>12 admitted to Department of Critical Care Medicine of the First Affiliated Hospital of Sun Yat-sen University from March 2013 to September 2013 were enrolled. Serum carnitine concentration and indexes of organ function were determined, and the tolerance of enteral nutrition within 5 days, the length of hospital stay, the length of intensive care unit (ICU) stay, and the hospital mortality were recorded. The relationship between serum carnitine and indexes mentioned above was analyzed. Thirty critically ill patients were enrolled. Serum carnitine concentration was very low in all critically ill patients, i.e. (8.92 ± 5.05) μmol/L (normal reference value at 43.5 μmol/L) at hospital admission. Serum carnitine concentration in patients with APACHEII score>23 (7 cases) was significantly lower than that in those with APACHEII score 12-23 (23 cases, μmol/L: 5.33 ± 1.72 vs. 10.02 ± 5.24, t=2.300, P=0.001). Serum carnitine concentration in patients with serum total bilirubin(TBil)>19 μmol/L (9 cases) was significantly lower than that in those with TBil≤19 μmol/L (21 cases, μmol/L: 5.54 ± 2.70 vs. 9.84 ± 5.08, t=2.750, P=0.014). Serum carnitine concentration was negatively correlated with the APACHEII score and the TBil (r=-0.387, P=0.035; r=-0.346, P=0.048). During the 5-day observation period, enteral feeding amount [(5 134 ± 1 173) mL] was positively correlated with serum carnitine concentration(r=0.430, P=0.022). In 30 critical patients, the incidence of abdominal distension was 40.0% (12/30), and the serum carnitine concentration of patients with abdominal distension was lower compared with that of patients without abdominal distension (μmol/L: 7.83 ± 4.98 vs. 9.12 ± 5

[Micronutrients in oncology. Current data about vitamin D, selenium, L-carnitine and vitamin C].

PubMed

Gröber, Uwe; Mücke, Ralph; Holzhauer, Peter; Kisters, Klaus

2013-04-01

Many patients receiving cancer treatment use micronutrient supplements, with the intention to complement their cancer treatment, or help them cope with the therapy- and disease-associated side-effects. Up to 90% of the cancer patients are adding antioxidants without the knowledge of the treating physician. There are many concerns that antioxidants might decrease the effectiveness of chemotherapy, but increasing evidence suggests a benefit when antioxidants and other micronutrients, such as selenium, L-carnitine and vitamin D are added to conventional cytotoxic therapies. It is imperative that physicians discuss the use ofantioxidant and other micronutrient supplements with their cancer patients and educate them about potentially negative, but also potentially beneficial effects.

The Effect of L-Carnitine Treatment on Levels of Malondialdehyde and Glutathione in Patients with Age Related Macular Degeneration

PubMed Central

Ates, Orhan; Alp, H. Hakan; Mumcu, Ugur; Azizi, Sedat; Cinici, Emine; Kiziltunc, Ahmet; Baykal, Orhan

2008-01-01

Objective: The aim of this study was to determine the antioxidant properties of the L-carnitine (LC) in the treatment of patients with age-related macular degeneration (AMD). Materials and Methods: This study involved 60 patients diagnosed with early AMD. The patients were divided into two groups. Group I was the study group that received LC supplementation for 3 months. Group II was the control group and did not consent to LC supplementation over the 3 months. At the end of the 3-month period, markers of lipid peroxidation, malondialdehyde (MDA) and reduced glutathione (GSH) were measured in the two groups. Results: In the study group, the MDA level was significantly reduced, while the GSH level was significantly increased at the end of the 3-month period (P<0.001). Conclusion: Our results suggest that LC may protect against oxidative damage by decreasing the MDA level, a marker of lipid peroxidation, and increasing GSH. PMID:25610013

Carnitine deficiency presenting with a decreased mental state in a patient with amyotrophic lateral sclerosis receiving long-term tube feeding: a case report.

PubMed

Isse, Naohi; Miura, Yoh; Obata, Toshiyuki; Takahara, Noriko

2013-12-30

L-carnitine is an important metabolic mediator involved in fatty acid transport. It is obtained from the diet, particularly from animal products, such as red meat. Previous reports have revealed that long-term tube feeding with a commercial product containing no or low levels of carnitine can lead to an altered mental state caused by hyperammonemia. A 72-year-old Japanese man had a 12-year history of amyotrophic lateral sclerosis. He was bedridden and had required mechanical ventilation and enteral tube feeding for 10 years at home. His main enteral solution was a commercial product that contained low carnitine levels, and he sometimes received coffee and homemade products such as miso soup. Our patient's ability to communicate gradually deteriorated over a period of one year. His serum total carnitine level was abnormally low, at 26.7μmol/L (normal range, 45 to 91μmol/L), but his ammonium level was normal. His mental state improved dramatically after starting L-carnitine supplementation (600mg twice daily). This case highlights the importance of avoiding carnitine deficiency in patients with amyotrophic lateral sclerosis undergoing long-term tube feeding. These patients experience progressive muscle atrophy that might cause impaired carnitine storage and might manifest as communication difficulties. Carnitine deficiency can be misdiagnosed as a progression of systemic muscle atrophy. Clinicians should be aware of this disorder and should consider periodically measuring carnitine levels, regardless of the patient's serum ammonium levels.

Downregulation of carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion.

PubMed

Soni, Mufaddal S; Rabaglia, Mary E; Bhatnagar, Sushant; Shang, Jin; Ilkayeva, Olga; Mynatt, Randall; Zhou, Yun-Ping; Schadt, Eric E; Thornberry, Nancy A; Muoio, Deborah M; Keller, Mark P; Attie, Alan D

2014-11-01

We previously demonstrated that micro-RNAs (miRNAs) 132 and 212 are differentially upregulated in response to obesity in two mouse strains that differ in their susceptibility to obesity-induced diabetes. Here we show the overexpression of miRNAs 132 and 212 enhances insulin secretion (IS) in response to glucose and other secretagogues including nonfuel stimuli. We determined that carnitine acyl-carnitine translocase (CACT; Slc25a20) is a direct target of these miRNAs. CACT is responsible for transporting long-chain acyl-carnitines into the mitochondria for β-oxidation. Small interfering RNA-mediated knockdown of CACT in β-cells led to the accumulation of fatty acyl-carnitines and enhanced IS. The addition of long-chain fatty acyl-carnitines promoted IS from rat insulinoma β-cells (INS-1) as well as primary mouse islets. The effect on INS-1 cells was augmented in response to suppression of CACT. A nonhydrolyzable ether analog of palmitoyl-carnitine stimulated IS, showing that β-oxidation of palmitoyl-carnitine is not required for its stimulation of IS. These studies establish a link between miRNA-dependent regulation of CACT and fatty acyl-carnitine-mediated regulation of IS. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Toxicity studies on agents Gb and Gd (Phase 2): Delayed neuropathy study of soman in SPF white leghorn chickens. Final technical report, July 1985-August 1991

DOE Office of Scientific and Technical Information (OSTI.GOV)

Bucci, T.J.; Parker, R.M.; Gosnell, P.A.

1992-05-01

A dose rangefinding study, a delayed neuropathy study, and a neurotoxic esterase study, were performed in White Leghorn chickens using the organophosphate ester Soman. The hens used for the Rangefinding study were dosed once orally with 500, 250, 100, 50, 25, or 0 microns g/Kg GD, on Day 1. They were pretreated and protected daily through Day 7 with atropine. Surviving hens were euthanized with sodium pentobarbital on Day 21. The maximum tolerated dose (MTD) to be used in the Delayed Neuropathy Study was chosen based upon the rangefinding data. Fifty hens were assigned to a Single Dose Delayed Neuropathymore » study. Groups of ten hens were given 14.2 (MTD), 7.1 (MTD/2), 3.5 (MTD/4), 0 (negative control) microns/Kg GD or 51 0 mg/Kg tri-ortho-cresyl phosphate (TOCP) (positive control). Rangefinding study. They were evaluated for signs of neurologic toxicity/ataxia. Necropsy examination was performed on all animals. Sections of cerebellum, medulla, spinal cord (cervical, thoracic, and lumbar), both sciatic nerves and their tibial branch were examined microscopically.... Delayed neuropathy; Agents; Soman; Chickens.« less

l-Carnitine Modulates Epileptic Seizures in Pentylenetetrazole-Kindled Rats via Suppression of Apoptosis and Autophagy and Upregulation of Hsp70.

PubMed

Hussein, Abdelaziz M; Adel, Mohamed; El-Mesery, Mohamed; Abbas, Khaled M; Ali, Amr N; Abulseoud, Osama A

2018-03-14

l-Carnitine is a unique nutritional supplement for athletes that has been recently studied as a potential treatment for certain neuropsychiatric disorders. However, its efficacy in seizure control has not been investigated. Sprague Dawley rats were randomly assigned to receive either saline (Sal) (negative control) or pentylenetetrazole (PTZ) 40 mg/kg i.p. × 3 times/week × 3 weeks. The PTZ group was further subdivided into two groups, the first received oral l-carnitine (l-Car) (100 mg/kg/day × 4 weeks) (PTZ + l-Car), while the second group received saline (PTZ + Sal). Daily identification and quantification of seizure scores, time to the first seizure and the duration of seizures were performed in each animal. Molecular oxidative markers were examined in the animal brains. l-Car treatment was associated with marked reduction in seizure score ( p = 0.0002) that was indicated as early as Day 2 of treatment and continued throughout treatment duration. Furthermore, l-Car significantly prolonged the time to the first seizure ( p < 0.0001) and shortened seizure duration ( p = 0.028). In addition, l-Car administration for four weeks attenuated PTZ-induced increase in the level of oxidative stress marker malondialdehyde (MDA) ( p < 0.0001) and reduced the activity of catalase enzyme ( p = 0.0006) and increased antioxidant GSH activity ( p < 0.0001). Moreover, l-Car significantly reduced PTZ-induced elevation in protein expression of caspase-3 ( p < 0.0001) and β-catenin ( p < 0.0001). Overall, our results suggest a potential therapeutic role of l-Car in seizure control and call for testing these preclinical results in a proof of concept pilot clinical study.

Effects of propionyl-L-carnitine on ischemia-reperfusion injury in hamster cheek pouch microcirculation.

PubMed

Lapi, Dominga; Sabatino, Lina; Altobelli, Giovanna Giuseppina; Mondola, Paolo; Cimini, Vincenzo; Colantuoni, Antonio

2010-01-01

Propionyl-l-carnitine (pLc) exerts protective effects in different experimental models of ischemia-reperfusion (I/R). The aim of the present study was to assess the effects of intravenously and topically applied pLc on microvascular permeability increase induced by I/R in the hamster cheek pouch preparation. The hamster cheek pouch microcirculation was visualized by fluorescence microscopy. Microvascular permeability, leukocyte adhesion to venular walls, perfused capillary length, and capillary red blood cell velocity (V(RBC)) were evaluated by computer-assisted methods. E-selectin expression was assessed by in vitro analysis. Lipid peroxidation and reactive oxygen species (ROS) formation were determined by thiobarbituric acid-reactive substances (TBARS) and 2'-7'-dichlorofluorescein (DCF), respectively. In control animals, I/R caused a significant increase in permeability and in the leukocyte adhesion in venules. Capillary perfusion and V(RBC) decreased. TBARS levels and DCF fluorescence significantly increased compared with baseline. Intravenously infused pLc dose-dependently prevented leakage and leukocyte adhesion, preserved capillary perfusion, and induced vasodilation at the end of reperfusion, while ROS concentration decreased. Inhibition of nitric oxide synthase prior to pLc caused vasoconstriction and partially blunted the pLc-induced protective effects; inhibition of the endothelium-derived hyperpolarizing factor (EDHF) abolished pLc effects. Topical application of pLc on cheek pouch membrane produced the same effects as observed with intravenous administration. pLc decreased the E-selectin expression. pLc prevents microvascular changes induced by I/R injury. The reduction of permeability increase could be mainly due to EDHF release induce vasodilatation together with NO. The reduction of E-selectin expression prevents leukocyte adhesion and permeability increase.

Effects of Propionyl-L-Carnitine on Ischemia–Reperfusion Injury in Hamster Cheek Pouch Microcirculation

PubMed Central

Lapi, Dominga; Sabatino, Lina; Altobelli, Giovanna Giuseppina; Mondola, Paolo; Cimini, Vincenzo; Colantuoni, Antonio

2010-01-01

Background and purpose Propionyl-l-carnitine (pLc) exerts protective effects in different experimental models of ischemia–reperfusion (I/R). The aim of the present study was to assess the effects of intravenously and topically applied pLc on microvascular permeability increase induced by I/R in the hamster cheek pouch preparation. Methods The hamster cheek pouch microcirculation was visualized by fluorescence microscopy. Microvascular permeability, leukocyte adhesion to venular walls, perfused capillary length, and capillary red blood cell velocity (VRBC) were evaluated by computer-assisted methods. E-selectin expression was assessed by in vitro analysis. Lipid peroxidation and reactive oxygen species (ROS) formation were determined by thiobarbituric acid-reactive substances (TBARS) and 2′-7′-dichlorofluorescein (DCF), respectively. Results In control animals, I/R caused a significant increase in permeability and in the leukocyte adhesion in venules. Capillary perfusion and VRBC decreased. TBARS levels and DCF fluorescence significantly increased compared with baseline. Intravenously infused pLc dose-dependently prevented leakage and leukocyte adhesion, preserved capillary perfusion, and induced vasodilation at the end of reperfusion, while ROS concentration decreased. Inhibition of nitric oxide synthase prior to pLc caused vasoconstriction and partially blunted the pLc-induced protective effects; inhibition of the endothelium-derived hyperpolarizing factor (EDHF) abolished pLc effects. Topical application of pLc on cheek pouch membrane produced the same effects as observed with intravenous administration. pLc decreased the E-selectin expression. Conclusions pLc prevents microvascular changes induced by I/R injury. The reduction of permeability increase could be mainly due to EDHF release induce vasodilatation together with NO. The reduction of E-selectin expression prevents leukocyte adhesion and permeability increase. PMID:21423374

Effects of sinensetin on lipid metabolism in mature 3T3-L1 adipocytes.

PubMed

Kang, Seong-Il; Shin, Hye-Sun; Ko, Hee-Chul; Kim, Se-Jae

2013-01-01

Sinensetin is a rare polymethoxylated flavone found in certain citrus fruits. In this study, we investigated the effects of sinensetin on lipid metabolism in mature 3T3-L1 adipocytes. Sinensetin decreased the expression of sterol regulatory element-binding protein 1c (SREBP1c), suggesting its antiadipogeneic property via downreguation of SREBP1c. Also, sinensetin increased the phosphorylation of protein kinase A and hormone-sensitive lipase, indicating its lipolytic property via a cAMP-mediated signaling pathway. Moreover, sinensetin inhibited insulin-stimulated glucose uptake by decreasing the phosphorylation of insulin receptor substrate and Akt. Furthermore, sinensetin increased the phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase. It also upregulated mRNA expression of carnitine palmitoyltransferase-1a, suggesting that sinensetin enhances fatty acid β-oxidation through the AMPK pathway. Taken together, these results suggest that sinensetin may have potential as a natural agent for prevention/improvement of obesity. Copyright © 2012 John Wiley & Sons, Ltd.

Microtubule-Targeting Agents Eribulin and Paclitaxel Differentially Affect Neuronal Cell Bodies in Chemotherapy-Induced Peripheral Neuropathy.

PubMed

Benbow, Sarah J; Wozniak, Krystyna M; Kulesh, Bridget; Savage, April; Slusher, Barbara S; Littlefield, Bruce A; Jordan, Mary Ann; Wilson, Leslie; Feinstein, Stuart C

2017-07-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of anticancer treatment with microtubule-targeted agents (MTAs). The frequency of severe CIPN, which can be dose limiting and even life threatening, varies widely among different MTAs. For example, paclitaxel induces a higher frequency of severe CIPN than does eribulin. Different MTAs also possess distinct mechanisms of microtubule-targeted action. Recently, we demonstrated that paclitaxel and eribulin differentially affect sciatic nerve axons, with paclitaxel inducing more pronounced neurodegenerative effects and eribulin inducing greater microtubule stabilizing biochemical effects. Here, we complement and extend these axonal studies by assessing the effects of paclitaxel and eribulin in the cell bodies of sciatic nerve axons, housed in the dorsal root ganglia (DRG). Importantly, the microtubule network in cell bodies is known to be significantly more dynamic than in axons. Paclitaxel induced activating transcription factor 3 expression, a marker of neuronal stress/injury. Paclitaxel also increased expression levels of acetylated tubulin and end binding protein 1, markers of microtubule stability and growth, respectively. These effects are hypothesized to be detrimental to the dynamic microtubule network within the cell bodies. In contrast, eribulin had no significant effect on any of these parameters in the cell bodies. Taken together, DRG cell bodies and their axons, two distinct neuronal cell compartments, contain functionally distinct microtubule networks that exhibit unique biochemical responses to different MTA treatments. We hypothesize that these distinct mechanistic actions may underlie the variability seen in the initiation, progression, persistence, and recovery from CIPN.

A novel acetylation cycle of transcription co-activator Yes-associated protein that is downstream of Hippo pathway is triggered in response to SN2 alkylating agents.

PubMed

Hata, Shoji; Hirayama, Jun; Kajiho, Hiroaki; Nakagawa, Kentaro; Hata, Yutaka; Katada, Toshiaki; Furutani-Seiki, Makoto; Nishina, Hiroshi

2012-06-22

Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to S(N)2 alkylating agents. We show that after treatment of cells with the S(N)2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C-terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by S(N)2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage.

A Novel Acetylation Cycle of Transcription Co-activator Yes-associated Protein That Is Downstream of Hippo Pathway Is Triggered in Response to SN2 Alkylating Agents*

PubMed Central

Hata, Shoji; Hirayama, Jun; Kajiho, Hiroaki; Nakagawa, Kentaro; Hata, Yutaka; Katada, Toshiaki; Furutani-Seiki, Makoto; Nishina, Hiroshi

2012-01-01

Yes-associated protein (YAP) is a transcriptional co-activator that acts downstream of the Hippo signaling pathway and regulates multiple cellular processes. Although cytoplasmic retention of YAP is known to be mediated by Hippo pathway-dependent phosphorylation, post-translational modifications that regulate YAP in the nucleus remain unclear. Here we report the discovery of a novel cycle of acetylation/deacetylation of nuclear YAP induced in response to SN2 alkylating agents. We show that after treatment of cells with the SN2 alkylating agent methyl methanesulfonate, YAP phosphorylation mediated by the Hippo pathway is markedly reduced, leading to nuclear translocation of YAP and its acetylation. This YAP acetylation occurs on specific and highly conserved C-terminal lysine residues and is mediated by the nuclear acetyltransferases CBP (CREB binding protein) and p300. Conversely, the nuclear deacetylase SIRT1 is responsible for YAP deacetylation. Intriguingly, we found that YAP acetylation is induced specifically by SN2 alkylating agents and not by other DNA-damaging stimuli. These results identify a novel YAP acetylation cycle that occurs in the nucleus downstream of the Hippo pathway. Intriguingly, our findings also indicate that YAP acetylation is involved in responses to a specific type of DNA damage. PMID:22544757

L-Carnitine halts apoptosis and myelosuppression induced by carboplatin in rat bone marrow cell cultures (BMC).

PubMed

Abd-Allah, Adel R A; Al-Majed, Abdulhakeem A; Al-Yahya, Abdulaziz A; Fouda, Soliman I; Al-Shabana, Othman A

2005-07-01

Carboplatin (CP), a second generation platinum compound, is effective against various types of cancers, producing less nephrotoxicity and ototoxicity but more myelotoxicity than cisplatinum. CP-myelosuppression is the rate-limiting step of its clinical use. Prevention of CP-myelosuppression is a major target in the field of chemotherapy. Therefore, the present study investigates the use of L-carnitine (LCR)-an antioxidant, cardioprotective, neuroprotective, and immunostimulant nontoxic natural compound-to protect against CP-induced myelosuppression. The viability of BMC was studied using a trypan blue exclusion technique following incubation with CP and/or LCR as a function of time and concentration. Apoptosis was tested for by detecting the amount of DNA fragmentation and the visualization of DNA ladders upon gel electrophoresis. Bone marrow progenitor cell function was examined by colony forming unit assay. Cellular contents of glutathione (GSH) and malondialdehyde (MDA) were also estimated. Results revealed that LC50 of CP is 4.7 mM and the highest safe concentration of LCR is 5 mM. Co-exposure of LCR+CP rescued BMC viability by 37% compared to the CP-treated cultures. The LCR halts CP-induced apoptosis and it significantly improves the function of the bone marrow progenitors by increasing the number of colony-forming units as a response to granulocyte/macrophage colony stimulating factors. Finally, LCR restores CP-induced GSH depletion and prevents MDA elevation in BMC. In summary, the results suggest that LCR is able to protect against CP-induced myelosuppression, which suggests its use as an adjuvant therapy. This finding merits further investigation into the mechanism(s) of such protection as well as its interaction with CP antitumor activity.

Effect of Carnitine and herbal mixture extract on obesity induced by high fat diet in rats.

PubMed

Amin, Kamal A; Nagy, Mohamed A

2009-10-16

Obesity-associated type 2 diabetes is rapidly increasing throughout the world. It is generally recognized that natural products with a long history of safety can modulate obesity. To investigate the development of obesity in response to a high fat diet (HFD) and to estimate the effect of L-carnitine and an Egyptian Herbal mixture formulation (HMF) (consisting of T. chebula, Senae, rhubarb, black cumin, aniseed, fennel and licorice) on bodyweight, food intake, lipid profiles, renal, hepatic, cardiac function markers, lipid Peroxidation, and the glucose and insulin levels in blood and liver tissue in rats. White male albino rats weighing 80-90 gm, 60 days old. 10 rats were fed a normal basal diet (Cr), 30 rats fed a high-fat diet (HFD) for 14 weeks during the entire study. Rats of the HFD group were equally divided into 3 subgroups each one include 10 rats. The first group received HFD with no supplement (HFD), the 2nd group HFD+L-carnitine and the third group received HFD+HMF. Carnitine and HMF were administered at 10th week (start time for treatments) for 4 weeks.Body weight, lipid profile & renal function (urea, uric acid creatinine) ALT & AST activities, cardiac markers, (LDH, C.K-NAC and MB) the oxidative stress marker reduced glutathione (GSH), and Malondialdehyde (MDA) catalase activity, in addition to glucose, insulin, and insulin resistance in serum & tissues were analyzed. Data showed that feeding HFD diet significantly increased final body weight, triglycerides (TG), total cholesterol, & LDL concentration compared with controls, while significantly decreasing HDL; meanwhile treatment with L-carnitine, or HMF significantly normalized the lipid profile.Serum ALT, urea, uric acid, creatinine, LDH, CK-NAC, CK-MB were significantly higher in the high fat group compared with normal controls; and administration of L-carnitine or herbal extract significantly lessened the effect of the HFD. Hyperglycemia, hyperinsulinemia, and high insulin resistance (IR

Propionyl-L-Carnitine Enhances Wound Healing and Counteracts Microvascular Endothelial Cell Dysfunction

PubMed Central

Scioli, Maria Giovanna; Lo Giudice, Pietro; Bielli, Alessandra; Tarallo, Valeria; De Rosa, Alfonso; De Falco, Sandro; Orlandi, Augusto

2015-01-01

Background Impaired wound healing represents a high cost for health care systems. Endothelial dysfunction characterizes dermal microangiopathy and contributes to delayed wound healing and chronic ulcers. Endothelial dysfunction impairs cutaneous microvascular blood flow by inducing an imbalance between vasorelaxation and vasoconstriction as a consequence of reduced nitric oxide (NO) production and the increase of oxidative stress and inflammation. Propionyl-L-carnitine (PLC) is a natural derivative of carnitine that has been reported to ameliorate post-ischemic blood flow recovery. Methods and Results We investigated the effects of PLC in rat skin flap and cutaneous wound healing. A daily oral PLC treatment improved skin flap viability and associated with reactive oxygen species (ROS) reduction, inducible nitric oxide synthase (iNOS) and NO up-regulation, accelerated wound healing and increased capillary density, likely favoring dermal angiogenesis by up-regulation for iNOS, vascular endothelial growth factor (VEGF), placental growth factor (PlGF) and reduction of NADPH-oxidase 4 (Nox4) expression. In serum-deprived human dermal microvascular endothelial cell cultures, PLC ameliorated endothelial dysfunction by increasing iNOS, PlGF, VEGF receptors 1 and 2 expression and NO level. In addition, PLC counteracted serum deprivation-induced impairment of mitochondrial β-oxidation, Nox4 and cellular adhesion molecule (CAM) expression, ROS generation and leukocyte adhesion. Moreover, dermal microvascular endothelial cell dysfunction was prevented by Nox4 inhibition. Interestingly, inhibition of β-oxidation counteracted the beneficial effects of PLC on oxidative stress and endothelial dysfunction. Conclusion PLC treatment improved rat skin flap viability, accelerated wound healing and dermal angiogenesis. The beneficial effects of PLC likely derived from improvement of mitochondrial β-oxidation and reduction of Nox4-mediated oxidative stress and endothelial dysfunction

Dietary, anthropometric, and biochemical factors influencing plasma choline, carnitine, trimethylamine, and trimethylamine-N-oxide concentrations.

PubMed

Malinowska, Anna M; Szwengiel, Artur; Chmurzynska, Agata

2017-06-01

The objective of the study was to evaluate the nutritional, anthropometric, and biochemical factors that influence choline, l-carnitine, trimethylamine (TMA), and trimethylamine-N-oxide (TMAO) metabolism in elderly women. The volunteers' diet was assessed using a food frequency questionnaire. Dietary patterns were estimated using a self-established score method. Body mass index (BMI), serum glucose, total, HDL, LDL cholesterol, triacylglycerol, homocysteine (tHcy), free choline (fchol), L-carnitine, TMA, and TMAO were assessed. Higher concentrations of l-carnitine, fchol, and TMAO were found in those women who had more western-style dietary patterns. Nor choline or betaine intake affected plasma fchol, TMA, or TMAO. BMI was positively correlated with fchol and TMA. tHcy was positively correlated with fchol, TMA, and TMAO, while fchol was also positively correlated with TMA and TMAO. Dietary patterns and plasma tHcy concentration influence fchol, TMA, and TMAO plasma concentration. Plasma TMA and fchol may be associated with BMI.

Radiolysis of N-acetyl amino acids as model compounds for radiation degradation of polypeptides

NASA Astrophysics Data System (ADS)

Wayne Garrett, R.; Hill, David J. T.; Ho, Sook-Ying; O'Donnell, James H.; O'Sullivan, Paul W.; Pomery, Peter J.

Radiation chemical yields of (i) the volatile radiolysis products and (ii) the trapped free radicals from the y-radiolysis of the N-acetyl derivatives of glycine, L-valine, L-phenylalanine and L-tyrosine in the polycrystalline state have been determined at room temperature (303 K). Carbon dioxide was found to be the major molecular product for all these compounds with G(CO 2) varying from 0.36 for N-acetyl-L-tyrosine to 8 for N-acetyl-L-valine. There was evidence for some scission of the N-C α bond, indicated by the production of acetamide and the corresponding aliphatic acid, but the determination reaction was found to be of much lesser importance than the decarboxylation reaction. A protective effect of the aromatic ring in N-acetyl-L-phenylalanine and in N-acetyl-L-tyrosine was indicated by the lower yields of volatile products for these compounds. The yields of trapped free radicals were found to vary with the nature of the amino acid side chain, increasing with chain length and chain branching. The radical yields were decreased by incorporation of an aromatic moiety in the side chain, this effect being greater for the tyrosyl side chain than for the phenyl side chain. The G(R·) values showed a good correlation with G(CO 2) indicating that a common reaction may be involved in radical production and carbon dioxide formation.

Acetyl diacylglycerol produced by modified camelina (Camelina sativa)

USDA-ARS?s Scientific Manuscript database

Acetyl diacylglyceride (Acetyl-TAG) is a component of a commercial product, ACETEM, manufactured by transesterification reaction of triglycerides, glycerol, and triacetin or by acetylation of mono- and diglycerides with acetic acid anhydride. ACETEM is commonly used as foaming agents and coatings in...

Assessment of pharmacokinetic interaction between piracetam and l-carnitine in healthy subjects.

PubMed

Mendes, Gustavo D; Zaffalon, Gabriela Traldi; Silveira, Antonio Sérgio; Ramacciato, Juliana Cama; Motta, Rogério Heládio Lopes; Gagliano-Jucá, Thiago; Lopes, Anibal Gil; de Almeida Magalhães, José Cássio; De Nucci, Gilberto

2016-04-01

A rapid, sensitive and specific method for quantifying piracetam in human plasma using Piracetam d-8 as the internal standard (IS) is described. The analyte and the IS were extracted from plasma by one-step precipitation of protein using an acetonitrile (100%). The extracts were analyzed by high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (HPLC-MS/MS). The method had a chromatographic run time of 3.8 min and a linear calibration curve over the range 0.5-50 µg/mL (r > 0.99). This LC-MS-MS procedure was used to assess the bioavailability of two piracetam formulations: piracetam + l-carnitine (Piracar®; 270/330 mg tablet) and piracetam (Nootropil®; 800 mg tablet) in healthy volunteers of both sexes. The geometric means with corresponding 90% confidence interval (CI) for test/reference percentage ratios were 88.49% (90% CI = 81.19 - 96.46) for peak concentration/dose and 102.55% (90% CI = 100.62 - 104.51) for AUCinf /dose. The limit of quantitation of 0.5 µg/mL is well suited for pharmacokinetic studies in healthy volunteers. It was concluded that piracetam (Piracar®; 270/330 mg tablet) has a bioavailability equivalent to the piracetam (Nootropil®; 800 mg tablet) formulation with regard to both the rate and the extent of absorption. Copyright © 2015 John Wiley & Sons, Ltd.

Cardiac autonomic neuropathy: Risk factors, diagnosis and treatment

PubMed Central

Serhiyenko, Victoria A; Serhiyenko, Alexandr A

2018-01-01

Cardiac autonomic neuropathy (CAN) is a serious complication of diabetes mellitus (DM) that is strongly associated with approximately five-fold increased risk of cardiovascular mortality. CAN manifests in a spectrum of things, ranging from resting tachycardia and fixed heart rate (HR) to development of “silent” myocardial infarction. Clinical correlates or risk markers for CAN are age, DM duration, glycemic control, hypertension, and dyslipidemia (DLP), development of other microvascular complications. Established risk factors for CAN are poor glycemic control in type 1 DM and a combination of hypertension, DLP, obesity, and unsatisfactory glycemic control in type 2 DM. Symptomatic manifestations of CAN include sinus tachycardia, exercise intolerance, orthostatic hypotension (OH), abnormal blood pressure (BP) regulation, dizziness, presyncope and syncope, intraoperative cardiovascular instability, asymptomatic myocardial ischemia and infarction. Methods of CAN assessment in clinical practice include assessment of symptoms and signs, cardiovascular reflex tests based on HR and BP, short-term electrocardiography (ECG), QT interval prolongation, HR variability (24 h, classic 24 h Holter ECG), ambulatory BP monitoring, HR turbulence, baroreflex sensitivity, muscle sympathetic nerve activity, catecholamine assessment and cardiovascular sympathetic tests, heart sympathetic imaging. Although it is common complication, the significance of CAN has not been fully appreciated and there are no unified treatment algorithms for today. Treatment is based on early diagnosis, life style changes, optimization of glycemic control and management of cardiovascular risk factors. Pathogenetic treatment of CAN includes: Balanced diet and physical activity; optimization of glycemic control; treatment of DLP; antioxidants, first of all α-lipoic acid (ALA), aldose reductase inhibitors, acetyl-L-carnitine; vitamins, first of all fat-soluble vitamin B1; correction of vascular endothelial

S-Nitroso-N-acetyl-L-cysteine ethyl ester (SNACET) and N-acetyl-L-cysteine ethyl ester (NACET)-Cysteine-based drug candidates with unique pharmacological profiles for oral use as NO, H2S and GSH suppliers and as antioxidants: Results and overview.

PubMed

Tsikas, Dimitrios; Schwedhelm, Kathrin S; Surdacki, Andrzej; Giustarini, Daniela; Rossi, Ranieri; Kukoc-Modun, Lea; Kedia, George; Ückert, Stefan

2018-02-01

S -Nitrosothiols or thionitrites with the general formula RSNO are formally composed of the nitrosyl cation (NO + ) and a thiolate (RS - ), the base of the corresponding acids RSH. The smallest S -nitrosothiol is HSNO and derives from hydrogen sulfide (HSH, H 2 S). The most common physiological S -nitrosothiols are derived from the amino acid L-cysteine (CysSH). Thus, the simplest S -nitrosothiol is S -nitroso-L-cysteine (CysSNO). CysSNO is a spontaneous potent donor of nitric oxide (NO) which activates soluble guanylyl cyclase to form cyclic guanosine monophosphate (cGMP). This activation is associated with multiple biological actions that include relaxation of smooth muscle cells and inhibition of platelet aggregation. Like NO, CysSNO is a short-lived species and occurs physiologically at concentrations around 1 nM in human blood. CysSNO can be formed from CysSH and higher oxides of NO including nitrous acid (HONO) and its anhydride (N 2 O 3 ). The most characteristic feature of RSNO is the S-transnitrosation reaction by which the NO + group is reversibly transferred to another thiolate. By this way numerous RSNO can be formed such as the low-molecular-mass S -nitroso- N -acetyl-L-cysteine (SNAC) and S -nitroso-glutathione (GSNO), and the high-molecular-mass S -nitrosol-L-cysteine hemoglobin (HbCysSNO) present in erythrocytes and S -nitrosol-L-cysteine albumin (AlbCysSNO) present in plasma at concentrations of the order of 200 nM. All above mentioned RSNO exert NO-related biological activity, but they must be administered intravenously. This important drawback can be overcome by lipophilic charge-free RSNO. Thus, we prepared the ethyl ester of SNAC, the S -nitroso- N -acetyl-L-cysteine ethyl ester (SNACET), from synthetic N -acetyl-L-cysteine ethyl ester (NACET). Both NACET and SNACET have improved pharmacological features over N -acetyl-L-cysteine (NAC) and S -nitroso- N -acetyl-L-cysteine (SNAC), respectively, including higher oral bioavailability. SNACET

Peripheral Neuropathy Due to Vitamin Deficiency, Toxins, and Medications

PubMed Central

Staff, Nathan P.; Windebank, Anthony J.

2014-01-01

Purpose of Review: Peripheral neuropathies secondary to vitamin deficiencies, medications, or toxins are frequently considered but can be difficult to definitively diagnose. Accurate diagnosis is important since these conditions are often treatable and preventable. This article reviews the key features of different types of neuropathies caused by these etiologies and provides a comprehensive list of specific agents that must be kept in mind. Recent Findings: While most agents that cause peripheral neuropathy have been known for years, newly developed medications that cause peripheral neuropathy are discussed. Summary: Peripheral nerves are susceptible to damage by a wide array of toxins, medications, and vitamin deficiencies. It is important to consider these etiologies when approaching patients with a variety of neuropathic presentations; additionally, etiologic clues may be provided by other systemic symptoms. While length-dependent sensorimotor axonal peripheral neuropathy is the most common presentation, several examples present in a subacute severe fashion, mimicking Guillain-Barré syndrome. PMID:25299283

Overexpression of mutant HSP27 causes axonal neuropathy in mice.

PubMed

Lee, Jinho; Jung, Sung-Chul; Joo, Jaesoon; Choi, Yu-Ri; Moon, Hyo Won; Kwak, Geon; Yeo, Ha Kyung; Lee, Ji-Su; Ahn, Hye-Jee; Jung, Namhee; Hwang, Sunhee; Rheey, Jingeun; Woo, So-Youn; Kim, Ji Yon; Hong, Young Bin; Choi, Byung-Ok

2015-06-19

Mutations in heat shock 27 kDa protein 1 (HSP27 or HSPB1) cause distal hereditary motor neuropathy (dHMN) or Charcot-Marie-Tooth disease type 2 F (CMT2F) according to unknown factors. Mutant HSP27 proteins affect axonal transport by reducing acetylated tubulin. We generated a transgenic mouse model overexpressing HSP27-S135F mutant protein driven by Cytomegalovirus (CMV) immediate early promoter. The mouse phenotype was similar to dHMN patients in that they exhibit motor neuropathy. To determine the phenotypic aberration of transgenic mice, behavior test, magnetic resonance imaging (MRI), electrophysiological study, and pathology were performed. Rotarod test showed that founder mice exhibited lowered motor performance. MRI also revealed marked fatty infiltration in the anterior and posterior compartments at calf level. Electrophysiologically, compound muscle action potential (CMAP) but not motor nerve conduction velocity (MNCV) was reduced in the transgenic mice. Toluidine staining with semi-thin section of sciatic nerve showed the ratio of large myelinated axon fiber was reduced, which might cause reduced locomotion in the transgenic mice. Electron microscopy also revealed abundant aberrant myelination. Immunohistochemically, neuronal dysfunctions included elevated level of phosphorylated neurofilament and reduced level of acetylated tubulin in the sural nerve of transgenic mice. There was no additional phenotype besides motor neuronal defects. Overexpression of HSP27-S135F protein causes peripheral neuropathy. The mouse model can be applied to future development of therapeutic strategies for dHMN or CMT2F.

Relative Carnitine Deficiency in Autism

ERIC Educational Resources Information Center

Filipek, Pauline A.; Juranek, Jenifer; Nguyen, Minh T.; Cummings, Christa; Gargus, J. Jay

2004-01-01

A random retrospective chart review was conducted to document serum carnitine levels on 100 children with autism. Concurrently drawn serum pyruvate, lactate, ammonia, and alanine levels were also available in many of these children. Values of free and total carnitine ([rho] less than 0.001), and pyruvate ([rho]=0.006) were significantly reduced…

Converting drugs into gelators: supramolecular hydrogels from N-acetyl-L-cysteine and coinage-metal salts.

PubMed

Casuso, Pablo; Carrasco, Pedro; Loinaz, Iraida; Grande, Hans J; Odriozola, Ibon

2010-12-07

Here we present the concept of metallophilic hydrogels, supramolecular systems in which the gelator species are metal-thiolates that self-assemble through metallophilic attractions. The principle is applied for a small drug, the mucolytic agent N-acetyl-l-cysteine (NAC), which readily forms hydrogels in the presence of Au(iii), Ag(i) and Cu(ii) salts. The resulting transparent hydrogels present pH induced sol/gel transition. Scanning electron microscopy (SEM) measurements reveal a microporous structure in form of flakes for the three of them. The low pH at which these hydrogels are formed (pH < 4) limits their direct use as drug-delivery systems, but still this system constitutes a novel method for easy and fast conversion of small drugs into potent hydrogelators. Future developments will help to fully develop the idea in order to create a new class of supramolecular drug-delivery systems.

[L-carnitine treatment and fish odor syndrome: an unwaited adverse effect].

PubMed

Rocher, F; Caruba, C; Broly, F; Lebrun, C

2011-01-01

Levocarnitine treatment is usually well tolerated, with essentially dose-dependent diarrhea as the main induced adverse effect. We report a case of fish odor syndrome during levocarnitine treatment which resolved after levocarnitine discontinuation. This adverse effect seems to be correlated with excedent carnitine intake and might be expressed when the elimination pathway becomes saturated or in a situation of deficiency enzymatic metabolism. Copyright © 2011 Elsevier Masson SAS. All rights reserved.

Effects of L-carnitine pretreatment in methamphetamine and 3-nitropropionic acid-induced neurotoxicity.

PubMed

Binienda, Zbigniew K; Przybyla, Beata D; Robinson, Bonnie L; Salem, Nadia; Virmani, Ashraf; Amato, Antonino; Ali, Syed F

2006-08-01

Adult, male Sprague-Dawley rats were injected with 3-ni-tropropionic acid (3-NPA) at 30 mg/kg or methamphetamine (METH) at 20 mg/kg alone or following pretreatment with L-cartnitine (LC) at 100 mg/kg. Rectal temperature was measured before and 4 h following treatment. Animals were sacrificed at 4 h posttreatment. Monoamine neurotransmitters, dopamine (DA) and serotonin (5-HT), and their metabolites were analyzed in the striatum using high-performance liquid chromatography method coupled with electrochemical detection (HPLC/ED). Transcripts of several genes related to DA metabolism were quantified using real time reverse transciption polymerase chain reaction (RT-PCR). Core temperature decreased significantly after 3-NPA acid and increased in METH-treated rats (P < 0.05). Temperature change at 4 h exhibited a significant LC effect for 3-NPA, preventing hypothermia (P < 0.05) and no effect for METH. Concentration of DA and 5-HT, and their metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (5-HIAA), increased significantly in 3-NPA and decreased in METH-treated rats. An increase in DOPAC/DA turnover and serotonin observed after 3-NPA was abolished in LC-/3-NPA-treated rats. In both 3-NPA- and METH-treated rats, LC prevented an increase in DA receptor D(1) gene expression. It appears that carnitine effect preventing hypothermia after 3-NPA treatments may be related not only to its mitochondriotropic actions but also to inhibitory effect on the DA and 5-HT systems activated after the exposure to 3-NPA. The same effect observed at the transcriptional level, at least for the DA receptor D(1), may account for protection against METH toxicity.

Inhibition of Methylglyoxal-Induced AGEs/RAGE Expression Contributes to Dermal Protection by N-Acetyl-L-Cysteine.

PubMed

Yang, Chun-Tao; Meng, Fu-Hui; Chen, Li; Li, Xiang; Cen, Lai-Jian; Wen, Yu-Hua; Li, Cai-Chen; Zhang, Hui

2017-01-01

Accumulation of advanced glycation end products (AGEs) is a major cause of diabetes mellitus (DM) skin complications. Methylglyoxal (MGO), a reactive dicarbonyl compound, is a crucial intermediate of AGEs generation. N-acetyl-L-cysteine (NAC), an active ingredient of some medicines, can induce endogenous GSH and hydrogen sulfide generation, and set off a condensation reaction with MGO. However, there is rare evidence to show NAC can alleviate DM-induced skin injury through inhibition of AGEs generation or toxicity. The present study aimed to observe the effects of NAC on MGO-induced inflammatory injury and investigate the roles of AGEs and its receptor (RAGE) in NAC's dermal protection in human HaCaT keratinocytes. The cells were exposed to MGO to simulate a high MGO status in diabetic blood or tissues. The content of AGEs in serum or cell medium was measured with ELISA. The protective effects of NAC against MGO-induce injury were evaluated by administration before MGO one hour, in virtue of cell viability, mitochondrial membrane potential, inflammation reaction, nuclear factor (NF)-κB activation, matrix metalloproteinase (MMP)-9 expression, as well as cellular behavioral function. We found the AGEs levels of patients with DM were elevated comparing with healthy volunteers. The in vitro AGEs generation was also able to be enhanced by the exposure of HaCaT cells to MGO, which reduced dose-dependently cellular viability, damaged mitochondrial function, triggered secretion of interleukin (IL)-6 and IL-8, activated NF-κB and upregulated MMP-9 expression. Furthermore, the exposure caused cellular adhesion and migration dysfunction, as well as collagen type I inhibition. Importantly, before the exposure to MGO, the preconditioning with NAC significantly attenuated MGO-induced AGEs generation, improved cellular viability and mitochondrial function, partially reversed the overexpression of proinflammatory factors and MMP-9, as well as the activation of NF-κB. Lastly

L-Carnitine treatment reduces severity of physical and mental fatigue and increases cognitive functions in centenarians: a randomized and controlled clinical trial.

PubMed

Malaguarnera, Mariano; Cammalleri, Lisa; Gargante, Maria Pia; Vacante, Marco; Colonna, Valentina; Motta, Massimo

2007-12-01

Centenarians are characterized by weakness, decreasing mental health, impaired mobility, and poor endurance. L-Carnitine is an important contributor to cellular energy metabolism. This study evaluated the efficacy of L-carnitine on physical and mental fatigue and on cognitive functions of centenarians. This was a placebo-controlled, randomized, double-blind, 2-phase study. Sixty-six centenarians with onset of fatigue after even slight physical activity were recruited to the study. The 2 groups received either 2 g levocarnitine once daily (n = 32) or placebo (n = 34). Efficacy measures included changes in total fat mass, total muscle mass, serum triacylglycerol, total cholesterol, HDL cholesterol, LDL cholesterol, Mini-Mental State Examination (MMSE), Activities of Daily Living, and a 6-min walking corridor test. At the end of the study period, the levocarnitine-treated centenarians, compared with the placebo group, showed significant improvements in the following markers: total fat mass (-1.80 compared with 0.6 kg; P < 0.01), total muscle mass (3.80 compared with 0.8 kg; P < 0.01), plasma concentrations of total carnitine (12.60 compared with -1.70 mumol; P < 0.05), plasma long-chain acylcarnitine (1.50 compared with -0.1 micromol; P < 0.001), and plasma short-chain acylcarnitine (6.0 compared with -1.50 micromol; P < 0.001). Significant differences were also found in physical fatigue (-4.10 compared with -1.10; P < 0.01), mental fatigue (-2.70 compared with 0.30; P < 0.001), fatigue severity (-23.60 compared with 1.90; P < 0.001), and MMSE (4.1 compared with 0.6; P < 0.001). Our study indicates that oral administration of levocarnitine produces a reduction of total fat mass, increases total muscular mass, and facilitates an increased capacity for physical and cognitive activity by reducing fatigue and improving cognitive functions.

Carnitine Palmitoyltransferase 1A P479L and Infant Death: Policy Implications of Emerging Data

PubMed Central

Fohner, Alison E.; Garrison, Nanibaa’ A.; Austin, Melissa A.; Burke, Wylie

2017-01-01

Carnitine Palmitoyltransferase 1 Isoform A (CPT1A) is a crucial enzyme for the transport of long chain fatty acids into the mitochondria. The CPT1A P479L variant is found in high frequencies among indigenous populations residing on the west and north coasts of Alaska and Canada and in northeast Siberia and Greenland. Epidemiological studies have reported a statistical association between P479L homozygosity and infant death in Alaska Native and Canadian Inuit populations. Here, we review the available evidence about the P479L variant and apply to these data the epidemiological criteria for assessing causal associations. We find insufficient evidence to support a causal association with infant death and further, that if a causal association is present, the genotype is likely to be only one of a complex set of factors contributing to an increased risk of infant death. We conclude that additional research is needed to clarify the observed association and to inform effective preventative measures for infant death. In light of these findings, we discuss the policy implications for public health efforts, as policies based on the observed association between P479L homozygosity and infant death data are premature. PMID:28125087

Nephroprotective potential of carnitine against glycerol and contrast-induced kidney injury in rats through modulation of oxidative stress, proinflammatory cytokines, and apoptosis

PubMed Central

Kunak, Celalettin S; Ugan, Rustem A; Karakus, Emre; Polat, Beyzagul; Halici, Zekai; Saritemur, Murat; Atmaca, Hasan T; Karaman, Adem

2016-01-01

Objective: Contrast media (CM) are a major cause of nephropathy in high-risk patients. The aim of this study was to examine the effects of carnitine (CAR) in advanced nephrotoxicity due to CM administration in rats with glycerol-induced renal functional disorder. Methods: 40 rats were divided randomly into five groups (n = 8): (1) healthy group; (2) glycerol only (GLY); (3) glycerol and CM (GLY + CM); (4) glycerol, CM and 200 mg kg−1 carnitine (CAR200, Carnitene®; Sigma-tau/Santa Farma, Istanbul, Turkey); and (5) glycerol, CM and 400 mg kg−1 carnitine (CAR400). Kidney injury was induced with a single-dose, intramuscular injection of 10 ml kg−1 body weight (b.w.) of GLY. CAR was administered intraperitoneally. CM (8 ml kg−1 b.w. iohexol, Omnipaque™; Opakim Medical Products, Istanbul, Turkey) was infused via the tail vein to the rats in Groups 3–5. Results: l-carnitine administration significantly decreased serum creatinine and blood urea nitrogen levels. Superoxide dismutase and glutathione activity increased significantly in the treatment groups compared with the nephrotoxic groups. CAR400 significantly reduced malondialdehyde levels to healthy levels. In the treatment groups, tumour necrosis factor (TNF)-α, transforming growth factor 1β, interleukin 1β and caspase-3 gene expression decreased compared with the nephrotoxic groups. TNF-α and nuclear factor kappa-beta (NF-κB) protein expression increased after CM and CAR administration reduced both TNF-α and NF-κB expressions. Histopathologically, hyaline and haemorrhagic casts and necrosis in proximal tubules increased in the nephrotoxicity groups and decreased in the CAR groups. Conclusion: The results reveal that l-carnitine protects the oxidant/antioxidant balance and decreases proinflammatory cytokines and apoptosis in CM-induced nephrotoxicity in rats with underlying pathology. Advances in knowledge: Depending on the underlying kidney pathologies, the incidence of CM

Autonomic neuropathy

MedlinePlus

... Philadelphia, PA: Elsevier; 2016:chap 107. Shy ME. Peripheral neuropathies. In: Goldman L, Schafer AI, eds. Goldman-Cecil ... Editorial team. Autonomic Nervous System Disorders Read more Peripheral Nerve Disorders Read more NIH MedlinePlus Magazine Read more A. ...

Intravenous Lidocaine Infusion to Treat Chemotherapy-Induced Peripheral Neuropathy.

PubMed

Papapetrou, Peter; Kumar, Aashish J; Muppuri, Rudram; Chakrabortty, Shushovan

2015-11-01

Chemotherapy-induced peripheral neuropathy is a debilitating side effect of chemotherapy, which manifests as paresthesias, dysesthesias, and numbness in the hands and feet. Numerous chemoprotective agents and treatments have been used with limited success to treat chemotherapy-induced peripheral neuropathy. We report a case in which a patient presenting with chemotherapy-induced peripheral neuropathy received an IV lidocaine infusion over the course of 60 minutes with complete symptomatic pain relief for a prolonged period of 2 weeks.

Infectious optic neuropathies: a clinical update

PubMed Central

Kahloun, Rim; Abroug, Nesrine; Ksiaa, Imen; Mahmoud, Anis; Zeghidi, Hatem; Zaouali, Sonia; Khairallah, Moncef

2015-01-01

Different forms of optic neuropathy causing visual impairment of varying severity have been reported in association with a wide variety of infectious agents. Proper clinical diagnosis of any of these infectious conditions is based on epidemiological data, history, systemic symptoms and signs, and the pattern of ocular findings. Diagnosis is confirmed by serologic testing and polymerase chain reaction in selected cases. Treatment of infectious optic neuropathies involves the use of specific anti-infectious drugs and corticosteroids to suppress the associated inflammatory reaction. The visual prognosis is generally good, but persistent severe vision loss with optic atrophy can occur. This review presents optic neuropathies caused by specific viral, bacterial, parasitic, and fungal diseases. PMID:28539795

Peroxisomal fatty acid oxidation and inhibitors of the mitochondrial carnitine palmitoyltransferase I in isolated rat hepatocytes.

PubMed Central

Skorin, C; Necochea, C; Johow, V; Soto, U; Grau, A M; Bremer, J; Leighton, F

1992-01-01

Fatty acid oxidation was studied in the presence of inhibitors of carnitine palmitoyltransferase I (CPT I), in normal and in peroxisome-proliferated rat hepatocytes. The oxidation decreased in mitochondria, as expected, but in peroxisomes it increased. These two effects were seen, in variable proportions, with (+)-decanoylcarnitine, 2-tetradecylglycidic acid (TDGA) and etomoxir. The decrease in mitochondrial oxidation (ketogenesis) affected saturated fatty acids with 12 or more carbon atoms, whereas the increase in peroxisomal oxidation (H2O2 production) affected saturated fatty acids with 8 or more carbon atoms. The peroxisomal increase was sensitive to chlorpromazine, a peroxisomal inhibitor. To study possible mechanisms, palmitoyl-, octanoyl- and acetyl-carnitine acyltransferase activities were measured, in homogenates and in subcellular fractions from control and TDGA-treated cells. The palmitoylcarnitine acyltransferase was inhibited, as expected, but the octanoyltransferase activity also decreased. The CoA derivative of TDGA was synthesized and tentatively identified as being responsible for inhibition of the octanoylcarnitine acyltransferase. These results show that inhibitors of the mitochondrial CPT I may also inhibit the peroxisomal octanoyl transferase; they also support the hypothesis that the octanoyltransferase has the capacity to control or regulate peroxisomal fatty acid oxidation. PMID:1736904

Genetics Home Reference: carnitine palmitoyltransferase II deficiency

MedlinePlus

... Zierz S. Muscle carnitine palmitoyltransferase II deficiency: clinical and molecular genetic features and diagnostic aspects. Arch Neurol. 2005 Jan; ... K, Hermann T, Zierz S. Carnitine palmitoyltransferase II deficiency: molecular and biochemical analysis of 32 ... Bulletins Genetics Home Reference Celebrates Its ...

A systematic review to evaluate the effectiveness of carnitine supplementation in improving walking performance among individuals with intermittent claudication.

PubMed

Delaney, Christopher L; Spark, J Ian; Thomas, Jolene; Wong, Yew Toh; Chan, Lok Tsung; Miller, Michelle D

2013-07-01

To evaluate the evidence for the use of carnitine supplementation in improving walking performance among individuals with intermittent claudication. Systematic review. An electronic search of the literature was performed using MEDLINE (PubMed), Scopus, Cochrane Central Register of Controlled Trials and The Cochrane Library from inception through to November 2012. Search terms included peripheral arterial disease, intermittent claudication and carnitine. Reference lists of review articles and primary studies were also examined. Full reports of published experimental studies including randomized controlled trials and pre-test/post-test trials were selected for inclusion. A quality assessment was undertaken according to the Jadad scale. A total of 40 articles were retrieved, of which 23 did not meet the inclusion criteria. The 17 included articles reported on a total of 18 experimental studies of carnitine supplementation (5 pre-test/post-test; 8 parallel RCT; 5 cross-over RCT) for improving walking performance in adults with intermittent claudication. For pre-test/post-test studies, 300-2000 mg propionyl-L-carnitine (PLC) was administered orally or intravenously for a maximum of 90 days (7-42 participants) with statistically significant improvements of between 74 m and 157 m in pain free walking distance and between 71 m and 135 m in maximal walking distance across 3 out of 5 studies. Similarly, PLC (600 mg-3000 mg) was administered orally in 7 out of 8 parallel RCTs (22-485 participants), the longest duration being 12 months. All but one of the smallest trials demonstrated statistically significant improvements in walking performance between 31 and 54 m greater than placebo for pain free walking distance and between 9 and 86 m greater than placebo for maximal walking distance. A double-blind parallel RCT of cilostazol plus 2000 mg oral L-carnitine or placebo for 180 days (145 participants) did not demonstrate any significant improvement in walking performance. Of 5

Impact of protective agents and drying methods on desiccation tolerance of Salix nigra L. seeds.

PubMed

Santagapita, Patricio R; Ott Schneider, Helena; Agudelo-Laverde, Lina M; Buera, M Pilar

2014-09-01

Willow seeds are classified as orthodox, but they show some recalcitrant characteristics, as they lose viability in a few weeks at room temperature. The aim of this work was to improve the desiccation tolerance of willow seeds (Salix nigra L.), as a model of sensitive materials to dehydration, through imbibition in solutions and later vacuum (VD) or freeze-drying (FD). Imbibition was conducted with 45% w/v trehalose or polyethylene glycol 400 -PEG- or water prior to dehydration treatments. Water- and especially trehalose-imbibed seeds subjected to VD showed better germination capability with respect to the freeze-dried ones. Water crystallization was mainly responsible for the great loss of capability germination observed in water- or trehalose-imbibed seeds subjected to FD. PEG behavior was better when seeds were FD instead of VD. DSC thermograms of seeds allowed to identify two thermal transitions corresponding to lipids melting and to proteins denaturation. This last transition reveals information about proteins state/functionality. Dehydration of control and PEG- or water-imbibed seeds affected proteins functionality leading to lower germinability. In the case of trehalose-imbibed seeds subjected to VD, proteins maintained their native state along dehydration, and the seeds showed a great germination capacity for all the water content range. Germinated seeds showed higher luminosity (L*), greenness (a*) and yellowness (b*) values than not-germinated seeds independently of the employed agent. Present work reveals that the presence of adequate protective agents as well the dehydration method were the main critical factors involved in willow seed desiccation tolerance. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Clioquinol-zinc chelate: a candidate causative agent of subacute myelo-optic neuropathy.

PubMed Central

Arbiser, J. L.; Kraeft, S. K.; van Leeuwen, R.; Hurwitz, S. J.; Selig, M.; Dickersin, G. R.; Flint, A.; Byers, H. R.; Chen, L. B.

1998-01-01

BACKGROUND: 5-chloro-7-iodo-8-hydroxyquinoline (clioquinol) was used clinically three decades ago as an oral antiparasitic agent and to increase intestinal absorption of zinc in patients with acrodermatitis enteropathica, a genetic disorder of zinc absorption. Use of clioquinol was epidemiologically linked to subacute myelo-optic neuropathy (SMON), characterized by peripheral neuropathy and blindness, which affected 10,000 patients in Japan. Discontinuation of oral clioquinol use led to elimination of SMON, however, the mechanism of how clioquinol induces neurotoxicity is unclear. MATERIALS AND METHODS: We tested the effect of clioquinol-metal chelates on neural crest-derived melanoma cells. The effect of clioquinol chelates on cells was further studied by electron microscopy and by a mitochondrial potential-sensitive fluorescent dye. RESULTS: Of the ions tested, only clioquinol-zinc chelate demonstrated cytotoxicity. The cytotoxicity of clioquinol-zinc chelate was extremely rapid, suggesting that its primary effect was on the mitochondria. Electron microscopic analysis demonstrated that clioquinol-zinc chelate caused mitochondrial damage. This finding was further confirmed by the observation that clioquinol-zinc chelate caused a decrease in mitochondrial membrane potential. CONCLUSIONS: We demonstrate that clioquinol, in the presence of zinc, is converted to a potent mitochondrial toxin. The phenomenon of clioquinol mediated toxicity appears to be specific to zinc and is not seen with other metals tested. Since clioquinol has been shown to cause increased systemic absorption of zinc in humans, it is likely that clioquinol-zinc chelate was present in appreciable levels in patients with SMON and may be the ultimate causative toxin of SMON. Images Fig. 2 Fig. 3 PMID:9848083

Evaluation of the Effects of S-Allyl-L-cysteine, S-Methyl-L-cysteine, trans-S-1-Propenyl-L-cysteine, and Their N-Acetylated and S-Oxidized Metabolites on Human CYP Activities.

PubMed

Amano, Hirotaka; Kazamori, Daichi; Itoh, Kenji

2016-01-01

Three major organosulfur compounds of aged garlic extract, S-allyl-L-cysteine (SAC), S-methyl-L-cysteine (SMC), and trans-S-1-propenyl-L-cysteine (S1PC), were examined for their effects on the activities of five major isoforms of human CYP enzymes: CYP1A2, 2C9, 2C19, 2D6, and 3A4. The metabolite formation from probe substrates for the CYP isoforms was examined in human liver microsomes in the presence of organosulfur compounds at 0.01-1 mM by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Allicin, a major component of garlic, inhibited CYP1A2 and CYP3A4 activity by 21-45% at 0.03 mM. In contrast, a CYP2C9-catalyzed reaction was enhanced by up to 1.9 times in the presence of allicin at 0.003-0.3 mM. SAC, SMC, and S1PC had no effect on the activities of the five isoforms, except that S1PC inhibited CYP3A4-catalyzed midazolam 1'-hydroxylation by 31% at 1 mM. The N-acetylated metabolites of the three compounds inhibited the activities of several isoforms to a varying degree at 1 mM. N-Acetyl-S-allyl-L-cysteine and N-acetyl-S-methyl-L-cysteine inhibited the reactions catalyzed by CYP2D6 and CYP1A2, by 19 and 26%, respectively, whereas trans-N-acetyl-S-1-propenyl-L-cysteine showed weak to moderate inhibition (19-49%) of CYP1A2, 2C19, 2D6, and 3A4 activities. On the other hand, both the N-acetylated and S-oxidized metabolites of SAC, SMC, and S1PC had little effect on the reactions catalyzed by the five isoforms. These results indicated that SAC, SMC, and S1PC have little potential to cause drug-drug interaction due to CYP inhibition or activation in vivo, as judged by their minimal effects (IC 50 >1 mM) on the activities of five major isoforms of human CYP in vitro.

Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice.

PubMed

Trammell, Samuel A J; Weidemann, Benjamin J; Chadda, Ankita; Yorek, Matthew S; Holmes, Amey; Coppey, Lawrence J; Obrosov, Alexander; Kardon, Randy H; Yorek, Mark A; Brenner, Charles

2016-05-27

Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD(+) metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP(+) and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies.

Carnitine acetyltransferase (CRAT) expression in macrophages is dispensable for nutrient stress sensing and inflammation.

PubMed

Goldberg, Emily L; Dixit, Vishwa Deep

2017-02-01

Fatty acid oxidation in macrophages is thought to regulate inflammatory status and insulin-sensitivity. An important unanswered question in this field is whether carnitine acetyl-transferase (CrAT) that regulates fatty acid oxidation and mitochondrial acetyl-CoA balance is required to integrate nutrient stress sensing to inflammatory response in macrophages. Mice with myeloid lineage-specific Crat deletion were subjected to several metabolic stressors, including high-fat diet-induced obesity, fasting, and LPS-induced endotoxemia. Their metabolic homeostasis was compared to that of Crat-sufficient littermate controls. Inflammatory potential of Crat-deficient and Crat-sufficient macrophages were measured both in vitro and in vivo . Our studies revealed that ablation of CrAT in myeloid lineage cells did not impact glucose homeostasis, insulin-action, adipose tissue leukocytosis, and inflammation when animals were confronted with a variety of metabolic stressors, including high-fat diet, fasting, or LPS-induced acute endotoxemia. These findings demonstrate that unlike muscle cells, substrate switch mechanisms that control macrophage energy metabolism and mitochondrial short-chain acyl-CoA pools during nutrient stress are controlled by pathways that are not solely reliant on CrAT.

[3H]Indole-3-acetyl-myo-inositol hydrolysis by extracts of Zea mays L. vegetative tissue

NASA Technical Reports Server (NTRS)

Hall, P. J.; Bandurski, R. S.

1986-01-01

[3H]Indole-3-acetyl-myo-inositol was hydrolyzed by buffered extracts of acetone powders prepared from 4 day shoots of dark grown Zea mays L. seedlings. The hydrolytic activity was proportional to the amount of extract added and was linear for up to 6 hours at 37 degrees C. Boiled or alcohol denatured extracts were inactive. Analysis of reaction mixtures by high performance liquid chromatography demonstrated that not all isomers of indole-3-acetyl-myo-inositol were hydrolyzed at the same rate. Buffered extracts of acetone powders were prepared from coleoptiles and mesocotyls. The rates of hydrolysis observed with coleoptile extracts were greater than those observed with mesocotyl extracts. Active extracts also catalyzed the hydrolysis of esterase substrates such as alpha-naphthyl acetate and the methyl esters of indoleacetic acid and naphthyleneacetic acid. Attempts to purify the indole-3-acetyl-myo-inositol hydrolyzing activity by chromatographic procedures resulted in only slight purification with large losses of activity. Chromatography over hydroxylapatite allowed separation of two enzymically active fractions, one of which catalyzed the hydrolysis of both indole-3-acetyl-myo-inositol and esterase substrates. With the other enzymic hydrolysis of esterase substrates was readily demonstrated, but no hydrolysis of indole-3-acetyl-myo-inositol was ever detected.

Erasers of Histone Acetylation: The Histone Deacetylase Enzymes

PubMed Central

Seto, Edward; Yoshida, Minoru

2014-01-01

Histone deacetylases (HDACs) are enzymes that catalyze the removal of acetyl functional groups from the lysine residues of both histone and nonhistone proteins. In humans, there are 18 HDAC enzymes that use either zinc- or NAD+-dependent mechanisms to deacetylate acetyl lysine substrates. Although removal of histone acetyl epigenetic modification by HDACs regulates chromatin structure and transcription, deacetylation of nonhistones controls diverse cellular processes. HDAC inhibitors are already known potential anticancer agents and show promise for the treatment of many diseases. PMID:24691964

Nicotinamide Riboside Opposes Type 2 Diabetes and Neuropathy in Mice

PubMed Central

Trammell, Samuel A.J.; Weidemann, Benjamin J.; Chadda, Ankita; Yorek, Matthew S.; Holmes, Amey; Coppey, Lawrence J.; Obrosov, Alexander; Kardon, Randy H.; Yorek, Mark A.; Brenner, Charles

2016-01-01

Male C57BL/6J mice raised on high fat diet (HFD) become prediabetic and develop insulin resistance and sensory neuropathy. The same mice given low doses of streptozotocin are a model of type 2 diabetes (T2D), developing hyperglycemia, severe insulin resistance and diabetic peripheral neuropathy involving sensory and motor neurons. Because of suggestions that increased NAD+ metabolism might address glycemic control and be neuroprotective, we treated prediabetic and T2D mice with nicotinamide riboside (NR) added to HFD. NR improved glucose tolerance, reduced weight gain, liver damage and the development of hepatic steatosis in prediabetic mice while protecting against sensory neuropathy. In T2D mice, NR greatly reduced non-fasting and fasting blood glucose, weight gain and hepatic steatosis while protecting against diabetic neuropathy. The neuroprotective effect of NR could not be explained by glycemic control alone. Corneal confocal microscopy was the most sensitive measure of neurodegeneration. This assay allowed detection of the protective effect of NR on small nerve structures in living mice. Quantitative metabolomics established that hepatic NADP+ and NADPH levels were significantly degraded in prediabetes and T2D but were largely protected when mice were supplemented with NR. The data justify testing of NR in human models of obesity, T2D and associated neuropathies. PMID:27230286

Cisplatin impairs rat liver mitochondrial functions by inducing changes on membrane ion permeability: prevention by thiol group protecting agents.

PubMed

Custódio, José B A; Cardoso, Carla M P; Santos, Maria S; Almeida, Leonor M; Vicente, Joaquim A F; Fernandes, Maria A S

2009-05-02

Cisplatin (CisPt) is the most important platinum anticancer drug widely used in the treatment of head, neck, ovarian and testicular cancers. However, the mechanisms by which CisPt induces cytotoxicity, namely hepatotoxicity, are not completely understood. The goal of this study was to investigate the influence of CisPt on rat liver mitochondrial functions (Ca(2+)-induced mitochondrial permeability transition (MPT), mitochondrial bioenergetics, and mitochondrial oxidative stress) to better understand the mechanism underlying its hepatotoxicity. The effect of thiol group protecting agents and some antioxidants against CisPt-induced mitochondrial damage was also investigated. Treatment of rat liver mitochondria with CisPt (20nmol/mg protein) induced Ca(2+)-dependent mitochondrial swelling, depolarization of membrane potential (DeltaPsi), Ca(2+) release, and NAD(P)H fluorescence intensity decay. These effects were prevented by cyclosporine A (CyA), a potent and specific inhibitor of the MPT. In the concentration range of up to 40nmol/mg protein, CisPt slightly inhibited state 3 and stimulated state 2 and state 4 respiration rates using succinate as respiratory substrate. The respiratory indexes, respiratory control ratio (RCR) and ADP/O ratios, the DeltaPsi, and the ADP phosphorylation rate were also depressed. CisPt induced mitochondrial inner membrane permeabilization to protons (proton leak) but did not induce significant changes on mitochondrial H(2)O(2) generation. All the effects induced by CisPt on rat liver mitochondria were prevented by thiol group protecting agents namely, glutathione (GSH), dithiothreitol (DTT), N-acetyl-L-cysteine (NAC) and cysteine (CYS), whereas superoxide-dismutase (SOD), catalase (CAT) and ascorbate (ASC) were without effect. In conclusion, the anticancer drug CisPt: (1) increases the sensitivity of mitochondria to Ca(2+)-induced MPT; (2) interferes with mitochondrial bioenergetics by increasing mitochondrial inner membrane

Herpes Zoster Optic Neuropathy.

PubMed

Kaufman, Aaron R; Myers, Eileen M; Moster, Mark L; Stanley, Jordan; Kline, Lanning B; Golnik, Karl C

2018-06-01

Herpes zoster optic neuropathy (HZON) is a rare manifestation of herpes zoster ophthalmicus (HZO). The aim of our study was to better characterize the clinical features, therapeutic choices, and visual outcomes in HZON. A retrospective chart review was performed at multiple academic eye centers with the inclusion criteria of all eyes presenting with optic neuropathy within 1 month of cutaneous zoster of the ipsilateral trigeminal dermatome. Data were collected regarding presenting features, treatment regimen, and visual acuity outcomes. Six patients meeting the HZON inclusion criteria were identified. Mean follow-up was 2.75 months (range 0.5-4 months). Herpes zoster optic neuropathy developed at a mean of 14.1 days after initial rash (range 6-30 days). Optic neuropathy was anterior in 2 eyes and retrobulbar in 4 eyes. Other manifestations of HZO included keratoconjunctivitis (3 eyes) and iritis (4 eyes). All patients were treated with systemic antiviral therapy in addition to topical and/or systemic corticosteroids. At the last follow-up, visual acuity in 3 eyes had improved relative to presentation, 2 eyes had worsened, and 1 eye remained the same. The 2 eyes that did not receive systemic corticosteroids had the best observed final visual acuity. Herpes zoster optic neuropathy is an unusual but distinctive complication of HZO. Visual recovery after HZON is variable. Identification of an optimal treatment regiment for HZON could not be identified from our patient cohort. Systemic antiviral agents are a component of HZON treatment regimens. Efficacy of systemic corticosteroids for HZON remains unclear and should be considered on a case-by-case basis.

Creatine, L-Carnitine, and ω3 Polyunsaturated Fatty Acid Supplementation from Healthy to Diseased Skeletal Muscle

PubMed Central

D'Antona, Giuseppe; Nabavi, Seyed Mohammad; Micheletti, Piero; Aquilani, Roberto; Nisoli, Enzo; Rondanelli, Mariangela; Daglia, Maria

2014-01-01

Myopathies are chronic degenerative pathologies that induce the deterioration of the structure and function of skeletal muscle. So far a definitive therapy has not yet been developed and the main aim of myopathy treatment is to slow the progression of the disease. Current nonpharmacological therapies include rehabilitation, ventilator assistance, and nutritional supplements, all of which aim to delay the onset of the disease and relieve its symptoms. Besides an adequate diet, nutritional supplements could play an important role in the treatment of myopathic patients. Here we review the most recent in vitro and in vivo studies investigating the role supplementation with creatine, L-carnitine, and ω3 PUFAs plays in myopathy treatment. Our results suggest that these dietary supplements could have beneficial effects; nevertheless continued studies are required before they could be recommended as a routine treatment in muscle diseases. PMID:25243159

Structures of the N-acetyltransferase domain of Xylella fastidiosa N-acetyl-L-glutamate synthase/kinase with and without a His tag bound to N-acetyl-L-glutamate.

PubMed

Zhao, Gengxiang; Jin, Zhongmin; Allewell, Norma M; Tuchman, Mendel; Shi, Dashuang

2015-01-01

Structures of the catalytic N-acetyltransferase (NAT) domain of the bifunctional N-acetyl-L-glutamate synthase/kinase (NAGS/K) from Xylella fastidiosa bound to N-acetyl-L-glutamate (NAG) with and without an N-terminal His tag have been solved and refined at 1.7 and 1.4 Å resolution, respectively. The NAT domain with an N-terminal His tag crystallized in space group P4(1)2(1)2, with unit-cell parameters a=b=51.72, c=242.31 Å. Two subunits form a molecular dimer in the asymmetric unit, which contains ∼41% solvent. The NAT domain without an N-terminal His tag crystallized in space group P21, with unit-cell parameters a=63.48, b=122.34, c=75.88 Å, β=107.6°. Eight subunits, which form four molecular dimers, were identified in the asymmetric unit, which contains ∼38% solvent. The structures with and without the N-terminal His tag provide an opportunity to evaluate how the His tag affects structure and function. Furthermore, multiple subunits in different packing environments allow an assessment of the plasticity of the NAG binding site, which might be relevant to substrate binding and product release. The dimeric structure of the X. fastidiosa N-acetytransferase (xfNAT) domain is very similar to that of human N-acetyltransferase (hNAT), reinforcing the notion that mammalian NAGS is evolutionally derived from bifunctional bacterial NAGS/K.

Benzamide Derivatives as Protective Agents against the Action of Xenotoxic Agents on Human Cells.

DTIC Science & Technology

1984-05-31

4D-AlI45 396 BENZAMIDE DERIVATIVES AS PROTECTIVE AGENTS AGAINST THE I/i ACTION OF XENOTOXI..(U) OHIO STATE UNIV RESEARCH I FOUNDATION COLUMBUS G E...AS PROTECTIVE AGENTS AGAINST THE ACTION OF XENOTOXIC AGENTS ON HUMAN CELLS CD George E. Milo * Department of Physiological Chemistry and...TITLE (and Subtitle) S. .YPE OF REPORT & PERIOD COVERED Benzamide Derivatives as Protective Agents Annual Scientific Report 5 Against the Action of

Chemopreventive efficacy of anethole trithione, N-acetyl-L-cysteine, miconazole and phenethylisothiocyanate in the DMBA-induced rat mammary cancer model.

PubMed

Lubet, R A; Steele, V E; Eto, I; Juliana, M M; Kelloff, G J; Grubbs, C J

1997-07-03

The chemopreventive efficacy of N-acetyl-L-cysteine (NAC), anethole trithione, miconazole and phenethylisothiocyanate (PEITC), each of which would be expected to alter carcinogen metabolism, was examined in the dimethylbenzanthracene (DMBA) mammary carcinogenesis model. In this protocol, animals were exposed to non-toxic doses of the chemopreventives in the diet beginning 7 days prior to DMBA administration and then continuously throughout the duration of the assay (100 days post carcinogen). Miconazole, an antifungal agent with relatively broad inhibitory activity toward a variety of cytochromes P450, increased mammary tumor latency, decreased tumor incidence at the highest dose and decreased tumor multiplicity up to 60%. Anethole trithione, a substituted dithiolthione and an analog of the relatively broad-spectrum chemopreventive oltipraz, was administered in the diet and significantly inhibited mammary cancer multiplicity but not cancer incidence. NAC, an antimucolytic agent, failed to inhibit DMBA-induced mammary tumorigenesis. Surprisingly, treatment with DMBA plus PEITC, a potent inhibitor of cytochrome P450 2E1, actually increased the multiplicity of tumors relative to that observed with DMBA alone.

Efficacy of carnitine in treatment of tinnitus: evidence from audiological and MRI measures-a case study.

PubMed

Gopal, Kamakshi V; Thomas, Binu P; Mao, Deng; Lu, Hanzhang

2015-03-01

Tinnitus, or ringing in the ears, is an extremely common ear disorder. However, it is a phenomenon that is very poorly understood and has limited treatment options. The goals of this case study were to identify if the antioxidant acetyl-L-carnitine (ALCAR) provides relief from tinnitus, and to identify if subjective satisfaction after carnitine treatment is accompanied by changes in audiological and imaging measures. Case Study. A 41-yr-old female with a history of hearing loss and tinnitus was interested in exploring the benefits of antioxidant therapy in reducing her tinnitus. The patient was evaluated using a standard audiological/tinnitus test battery and magnetic resonance imaging (MRI) recordings before carnitine treatment. After her physician's approval, the patient took 500 mg of ALCAR twice a day for 30 consecutive days. The audiological and MRI measures were repeated after ALCAR treatment. Pure-tone audiometry, tympanometry, distortion-product otoacoustic emissions, tinnitus questionnaires (Tinnitus Handicap Inventory and Tinnitus Reaction Questionnaire), auditory brainstem response, functional MRI (fMRI), functional connectivity MRI, and cerebral blood flow evaluations were conducted before intake of ALCAR and were repeated 30 days after ALCAR treatment. The patient's pretreatment pure-tone audiogram indicated a mild sensorineural hearing loss at 6 kHz in the right ear and 4 kHz in the left ear. Posttreatment evaluation indicated marginal improvement in the patient's pure-tone thresholds, but was sufficient to be classified as being clinically normal in both ears. Distortion-product otoacoustic emissions results showed increased overall emissions after ALCAR treatment. Subjective report from the patient indicated that her tinnitus was less annoying and barely noticeable during the day after treatment, and the posttreatment tinnitus questionnaire scores supported her statement. Auditory brainstem response peak V amplitude growth between stimulus intensity

Serum carnitine and acyl-carnitine in patients with meningitis due to tick-borne encephalitis virus infection.

PubMed

Kępka, Alina; Janas, Roman M; Pancewicz, Sławomir A; Świerzbińska, Renata

2017-01-01

Hard ticks are the main vectors of tick-borne encephalitis virus (TBEV). Free carnitine (FC) and acylcarnitines (AC) have the basic role in β-oxidation as well as the modulation of immune and nervous system. Homeostasis of carnitines in the TBE patients was not studied so far. This study aimed to evaluate FC and AC serum concentrations in patients with meningitis due to TBEV infection before and after 14 ± 3 days of treatment. The study was performed in 14 patients aged 48 ± 29 years that were divided a posteriori (based on their FC level before and after treatment) into 2 subgroups: 1-8 and 9-14. Diagnosis was based on the neurological, serological and pleocytosis evaluation. The FC level in patients 1-8 before treatment (24.1 ± 8.1) was significantly lower than in patients post-treatment (34.4 ± 8.3), lower than in the control group (40.5 ± 7.6), and lower than in patients 9-14 before treatment (40.0 ± 13.5) but not lower than in the patients 9-14 after treatment (24.7 ± 7.3 μmol/L), respectively, p < 0.05. AC concentration in the patients 1-8 before treatment (4.7 ± 2.2) was apparently lower than in patients post-treatment (9.5 ± 3.9 μmol/L) but the values were not significantly different. In patients 9-14 before treatment the AC concentration (16.3 ± 12.6) was higher than in patients after treatment (5.3 ± 4.0 μmol/L), but the difference was not statistically significant. FC and AC homeostasis in circulation was disturbed in the patients with meningitis due to TBEV infection patients. The mean levels of FC and AC in 60% of the patients were below the normal range but normalized after treatment whereas in 40% of the patients they were near or at a normal range and significantly decreased after treatment. Explanation of this intriguing finding and its clinical significance is not easy without further studies.

Metabolic profiling of PPARalpha-/- mice reveals defects in carnitine and amino acid homeostasis that are partially reversed by oral carnitine supplementation.

PubMed

Makowski, Liza; Noland, Robert C; Koves, Timothy R; Xing, Weibing; Ilkayeva, Olga R; Muehlbauer, Michael J; Stevens, Robert D; Muoio, Deborah M

2009-02-01

Peroxisome proliferator-activated receptor-alpha (PPARalpha) is a master transcriptional regulator of beta-oxidation and a prominent target of hypolipidemic drugs. To gain deeper insights into the systemic consequences of impaired fat catabolism, we used quantitative, mass spectrometry-based metabolic profiling to investigate the fed-to-fasted transition in PPARalpha(+/+) and PPARalpha(-/-) mice. Compared to PPARalpha(+/+) animals, acylcarnitine profiles of PPARalpha(-/-) mice revealed 2- to 4-fold accumulation of long-chain species in the plasma, whereas short-chain species were reduced by as much as 69% in plasma, liver, and skeletal muscle. These results reflect a metabolic bottleneck downstream of carnitine palmitoyltransferase-1, a mitochondrial enzyme that catalyzes the first step in beta-oxidation. Organic and amino acid profiles of starved PPARalpha(-/-) mice suggested compromised citric acid cycle flux, enhanced urea cycle activity, and increased amino acid catabolism. PPARalpha(-/-) mice had 40-50% lower plasma and tissue levels of free carnitine, corresponding with diminished hepatic expression of genes involved in carnitine biosynthesis and transport. One week of oral carnitine supplementation conferred partial metabolic recovery in the PPARalpha(-/-) mice. In summary, comprehensive metabolic profiling revealed novel biomarkers of defective fat oxidation, while also highlighting the potential value of supplemental carnitine as a therapy and diagnostic tool for metabolic disorders.

Gene Therapy for the Treatment of Diabetic Neuropathy

PubMed Central

Mata, Marina; Chattopadhyay, Munmun; Fink, David J

2009-01-01

Neuropathy is a common, untreatable complication of both type 1 and type 2 diabetes. In animal models peptide neurotrophic factors can be used to protect against the development of neuropathy, but the combination of short half-life and off-target effects of these potent pleiotropic peptides has limited translation to human therapy. Gene transfer is a promising strategy that might circumvent these limitations. In this essay we review the basic methods of gene transfer and the preclinical data in rodent models that support the utility of this approach in the treatment of diabetic neuropathy. The path to a clinical applications and potential pitfalls in developing gene therapy for the treatment of diabetic neuropathy are considered. PMID:18990298

epsilon-N-trimethyllysine availability regulates the rate of carnitine biosynthesis in the growing rat

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rebouche, C.J.; Lehman, L.J.; Olson, L.

1986-05-01

Rates of carnitine biosynthesis in mammals depend on the availability of substrates and the activity of enzymes subserving the pathway. This study was undertaken to test the hypothesis that the availability of epsilon-N-trimethyllysine is rate-limiting for synthesis of carnitine in the growing rat and to evaluate diet as a source of this precursor for carnitine biosynthesis. Rats apparently absorbed greater than 90% of a tracer dose of (methyl-/sup 3/H)epsilon-N-trimethyllysine, and approximately 30% of that was incorporated into tissues as (/sup 3/H)carnitine. Rats given oral supplements of epsilon-N-trimethyllysine (0.5-20 mg/d), but no dietary carnitine, excreted more carnitine than control animals receivingmore » no dietary epsilon-N-trimethyllysine or carnitine. Rates of carnitine excretion increased in a dose-dependent manner. Tissue and serum levels of carnitine also increased with dietary epsilon-N-trimethyllysine supplementation. There was no evidence that the capacity for carnitine biosynthesis was saturated even at the highest level of oral epsilon-N-trimethyllysine supplementation. Common dietary proteins (casein, soy protein and wheat gluten) were found to be poor sources of epsilon-N-trimethyllysine for carnitine biosynthesis. The results of this study indicate that the availability of epsilon-N-trimethyllysine limits the rate of carnitine biosynthesis in the growing rat.« less

Microglia as Primary Mediators of Nerve Agent Neuropathy

DTIC Science & Technology

2010-01-01

16. Thomas DM, Francescutti-Verbeem DM and Kuhn DM. Methamphetamine -induced neurotoxicity and microglial activation are not mediated by fractalkine...1-24. Berry WK and Davies DR. The use of carbamates and atropine in the protection of animals against poisoning by 1,2,2-trimethylpropyl...633-8. Dirnhuber P, French MC, Green DM, Leadbeater L and Stratton JA. The protection of primates against soman poisoning by pretreatment with

Selective antagonism of muscarinic receptors is neuroprotective in peripheral neuropathy

PubMed Central

Smith, Darrell R.; Frizzi, Katie; Sabbir, Mohammad Golam; Chowdhury, Subir K. Roy; Mixcoatl-Zecuatl, Teresa; Saleh, Ali; Muttalib, Nabeel; Van der Ploeg, Randy; Ochoa, Joseline; Gopaul, Allison; Tessler, Lori; Wess, Jürgen; Jolivalt, Corinne G.

2017-01-01

Sensory neurons have the capacity to produce, release, and respond to acetylcholine (ACh), but the functional role of cholinergic systems in adult mammalian peripheral sensory nerves has not been established. Here, we have reported that neurite outgrowth from adult sensory neurons that were maintained under subsaturating neurotrophic factor conditions operates under cholinergic constraint that is mediated by muscarinic receptor–dependent regulation of mitochondrial function via AMPK. Sensory neurons from mice lacking the muscarinic ACh type 1 receptor (M1R) exhibited enhanced neurite outgrowth, confirming the role of M1R in tonic suppression of axonal plasticity. M1R-deficient mice made diabetic with streptozotocin were protected from physiological and structural indices of sensory neuropathy. Pharmacological blockade of M1R using specific or selective antagonists, pirenzepine, VU0255035, or muscarinic toxin 7 (MT7) activated AMPK and overcame diabetes-induced mitochondrial dysfunction in vitro and in vivo. These antimuscarinic drugs prevented or reversed indices of peripheral neuropathy, such as depletion of sensory nerve terminals, thermal hypoalgesia, and nerve conduction slowing in diverse rodent models of diabetes. Pirenzepine and MT7 also prevented peripheral neuropathy induced by the chemotherapeutic agents dichloroacetate and paclitaxel or HIV envelope protein gp120. As a variety of antimuscarinic drugs are approved for clinical use against other conditions, prompt translation of this therapeutic approach to clinical trials is feasible. PMID:28094765

Clinical Neuropathy Scales in Neuropathy Associated with Impaired Glucose Tolerance

PubMed Central

Zilliox, Lindsay A.; Ruby, Sandra K.; Singh, Sujal; Zhan, Min; Russell, James W.

2015-01-01

AIMS Disagreement exists on effective and sensitive outcome measures in neuropathy associated with impaired glucose tolerance (IGT). Nerve conduction studies and skin biopsies are costly, invasive and may have their problems with reproducibility and clinical applicability. A clinical measure of neuropathy that has sufficient sensitivity and correlates to invasive measures would enable significant future research. METHODS Data was collected prospectively on patients with IGT and symptomatic early neuropathy (neuropathy symptoms < 2 years) and normal controls. The seven scales that were examined were the Neuropathy Impairment Score of the Lower Limb (NIS-LL), Michigan Diabetic Neuropathy Score (MNDS), modified Toronto Clinical Neuropathy Scale (mTCNS), Total Neuropathy Score (Clinical) (TNSc), The Utah Early Neuropathy Scale (UENS), the Early Neuropathy Score (ENS), and the Neuropathy Disability Score (NDS). RESULTS All seven clinical scales were determined to be excellent in discriminating between patients with neuropathy from controls without neuropathy. The strongest discrimination was seen with the mTCNS. The best sensitivity and specificity for the range of scores obtained, as determined by using receiver operating characteristic curves, was seen for the mTCNS followed by the TNSc. Most scales show a stronger correlation with measures of large than small fiber neuropathy. CONCULSIONS All seven scales identify patients with neuropathy. For the purpose of screening potential patients for a clinical study, the mTCNS followed by the TNSc would be most helpful to select patients with neuropathy. PMID:25690405

Acetyl salicylic acid protected against heat stress damage in chicken myocardial cells and may associate with induced Hsp27 expression.

PubMed

Wu, Di; Xu, Jiao; Song, Erbao; Tang, Shu; Zhang, Xiaohui; Kemper, N; Hartung, J; Bao, Endong

2015-07-01

We investigated whether acetyl salicylic acid (ASA) protects chicken myocardial cells from heat stress-mediated damage in vivo and whether the induction of Hsp27 expression is connected with this function. Pathological changes, damage-related enzyme levels, and Hsp27 expression were studied in chickens following heat stress (40 ± 1 °C for 0, 1, 2, 3, 5, 7, 10, 15, or 24 h, respectively) with or without ASA administration (1 mg/kg BW, 2 h prior). Appearance of pathological lesions such as degenerations and karyopyknosis as well as the myocardial damage-related enzyme activation indicated that heat stress causes considerable injury to the myocardial cells in vivo. Myocardial cell injury was most serious in chickens exposed to heat stress without prior ASA administration; meanwhile, ASA pretreatment acted protective function against high temperature-induced injury. Hsp27 expression was induced under all experimental conditions but was one-fold higher in the ASA-pretreated animals (0.3138 ± 0.0340 ng/mL) than in untreated animals (0.1437 ± 0.0476 ng/mL) 1 h after heat stress exposure, and such an increase was sustained over the length of the experiment. Our findings indicate that pretreatment with ASA protects chicken myocardial cells from acute heat stress in vivo with almost no obvious side effects, and this protection may involve an enhancement of Hsp27 expression. However, the detailed mechanisms underlying this effect require further investigation.

High-dose 8% capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy: single-center experience.

PubMed

Filipczak-Bryniarska, Iwona; Krzyzewski, Roger M; Kucharz, Jakub; Michalowska-Kaczmarczyk, Anna; Kleja, Justyna; Woron, Jarosław; Strzepek, Katarzyna; Kazior, Lucyna; Wordliczek, Jerzy; Grodzicki, Tomasz; Krzemieniecki, Krzysztof

2017-08-17

High-dose capsaicin patch is effective in treatment of neuropathic pain in HIV-associated neuropathy and diabetic neuropathy. There are no studies assessing effectiveness of high-dose capsaicin patch in treatment of chemotherapy-induced peripheral neuropathy. We sought to determine the effectiveness of treatment of pain associated with chemotherapy-induced peripheral neuropathy with high-dose capsaicin patch. Our study group consisted of 18 patients with clinically confirmed oxaliplatin-induced neuropathy. Baseline characteristic including underling disease, received cumulative dose of neurotoxic agent, neuropathic symptoms, prior treatment and initial pain level were recorded. Pain was evaluated with Numeric Rating Scale prior to treatment with high-dose capsaicin and after 1.8 day and after 8 and 12 weeks after introducing treatment. Patients were divided into two groups accordingly to the amount of neurotoxic agent that caused neuropathy (high sensitivity and low sensitivity group). Most frequent symptoms of chemotherapy-induced neuropathy were: pain (88.89%), paresthesis (100%), sock and gloves sensation (100%) and hypoesthesis (100%). Initial pain level was 7.45 ± 1.14. Mean cumulative dose of oxaliplatin after which patients developed symptoms was 648.07 mg/m 2 . Mean pain level after 12 weeks of treatment was 0.20 ± 0.41. When examined according to high and low sensitivity to neurotoxic agent patients with low sensitivity had higher pain reduction, especially after 8 days after introducing treatment (69.55 ± 12.09 vs. 49.40 ± 20.34%; p = 0.02) and after 12 weeks (96.96 ± 5.56 vs. 83.93 ± 18.59%; p = 0.04). High-dose capsaicin patch is an effective treatment for pain associated with chemotherapy-induced neuropathy in patients treated with oxaliplatin. Patients with lower sensitivity to neurotoxic agents have better response to treatment and pain reduction.

Epidemiology of Peripheral Neuropathy: An Indian Perspective

PubMed Central

Trivedi, Sweety; Pandit, Alak; Ganguly, Goutam; Das, Shyamal Kumar

2017-01-01

Peripheral neuropathy (PN) is a common disorder and presents as diagnostic and therapeutic challenge to physicians and neurologists. In epidemiological studies from India from various regions the overall prevalence of PN varied from 5 to 2400 per 10,000 population in various community studies. India is composed of a multiethnic, multicultural population who are exposed to different adverse environmental factors such as arsenic and lead. Use of different chemotherapeutic agents with propensity to affect peripheral nerves, increasing methods of diagnosis of connective tissue disorders and use of immunomodulating drugs, growing aging population is expected to change the spectrum and burden of peripheral neuropathy in the community. The other important aspect of peripheral neuropathies is in terms of the geographical and occupational distribution especially of toxic neuropathies like arsenic which is common in eastern belt; lead, mercury and organo-phosphorous compounds where occupational exposures are major sources. Inflammatory neuropathies either due to vasculitis or G B Syndrome, chronic inflammatory polyradiculopathies are another major group of neuropathies which is increasing due to increase longevity of Indian subjects and immunological impairment, also adds to morbidity of the patients and are potentially treatable. Leprous neuropathy is common in India and although its frequency is significantly decreasing because of national control program yet pure neuritic form still remains a cause of concern and similar is the case with another infective cause like diptheric neurpathy. Thus this article is an attempt to cover major categories and also highlight the areas where further studies are needed. PMID:28904445

Carnitine status and lactate increase in patients with type I juvenile diabetes.

PubMed

Evangeliou, A; Gourgiotis, D; Karagianni, C; Markouri, M; Anogianaki, N; Mamoulakis, D; Maropoulos, G; Tsakalidis, C; Frentzayias, A; Nicolaidou, P

2010-12-01

In 32 juvenile patients suffering from insulin dependent diabetes we observed a carnitine imbalance (increase in acylcarnitine and reduction of free carnitine), which was higher in patients with the highest levels of glycosylated hemoglobin. Parallel to that, in patients with the most prominent carnitine imbalance, there was the highest increase in the postprandial lactic acid level and the highest increase in the lactate/pyruvate ratio, without relating to ketosis. In addition, we observed a decrease in free carnitine related to the length of time after appearance of diabetes. This was a prospective study of a cohort of 32 children and young adolescents with insulin dependent diabetes mellitus. All patients were on insulin treatment. Plasma concentrations of total, free and acyl-Carnitine were evaluated in 12 hours fasting blood samples and before the morning administration of insulin. Blood glucose, cholesterol, triglycerides, and lactate, pyruvate, beta-hydroxybutyrate and free fatty acid levels were measured. The postprandial highest increase of the lactate and lactate/pyruvate ratio observed in patients with the highest degree of carnitine imbalance, namely with poorliest regulated diabetes, raises the question of a coincidental mitochondrial dysfunction. On the ground of our own data, such a claim cannot be substantiated for our patients. In contrast we suggest that the role of other factors like increased gluconeogenesis, degree of ketosis need to be sought. In order to clarify the role of carnitine in the pathophysiology of disease we need also data from other tissues. Carnitine in the peripheral blood reflects only the 1% of the total body carnitine ; furthermore, patients with diabetes exhibit changes in carnitine status not only in the peripheral blood but also in other body tissues, mainly in muscles.

SNEDDS curcumin formulation leads to enhanced protection from pain and functional deficits associated with diabetic neuropathy: an insight into its mechanism for neuroprotection.

PubMed

Joshi, Rayanta P; Negi, Geeta; Kumar, Ashutosh; Pawar, Yogesh B; Munjal, Bhushan; Bansal, Arvind K; Sharma, Shyam S

2013-08-01

Curcumin has shown to be effective against various diabetes related complications. However major limitation with curcumin is its low bioavailability. In this study we formulated and characterized self nano emulsifying drug delivery system (SNEDDS) curcumin formulation to enhance its bioavailability and then evaluated its efficacy in experimental diabetic neuropathy. Bioavailability studies were performed in male Sprague Dawley rats. Further to evaluate the efficacy of formulation in diabetic neuropathy various parameters like nerve function and sensorimotor perception were assessed along with study of inflammatory proteins (NF-κB, IKK-β, COX-2, iNOS, TNF-α and IL-6). Nanotechnology based formulation resulted in prolonged plasma exposure and bioavailability. SNEDDS curcumin provided better results against functional, behavioural and biochemical deficits in experimental diabetic neuropathy, when compared with naive curcumin. Further western blot analysis confirmed the greater neuroprotective action of SNEDDS curcumin. SNEDDS curcumin formulation due to higher bioavailability was found to afford enhanced protection in diabetic neuropathy. In this study the authors formulated and characterized a self-emulsifying drug delivery system for formulation to enhance curcumin bioavailability in experimental diabetic neuropathy. Enhanced efficacy was demonstrated in a rat model. Copyright © 2013 Elsevier Inc. All rights reserved.

Challenges Evaluating Chemotherapy-Induced Peripheral Neuropathy in Childhood Cancer Survivors.

PubMed

Mohrmann, Caroline; Armer, Jane; Hayashi, Robert J

Children treated for cancer are exposed to a variety of chemotherapeutic agents with known toxicity to the peripheral nervous system. The side effect of peripheral neuropathy can cause changes in sensation, function, and even cause pain. Although peripheral neuropathy is recognized by pediatric oncology nurses as an important and significant side effect, measuring neuropathy can be quite complex for clinical care and research efforts. With more children surviving a cancer diagnosis today, this issue is increasingly important for childhood cancer survivors. This article has reviewed existing literature examining peripheral neuropathy in childhood cancer survivors with particular interest paid to measurement tools available and needs for future research. It is important for nurses to choose appropriate measures for clinical care and research methods in order to have an impact on patients experiencing this condition.

Carnitine insufficiency caused by aging and overnutrition compromises mitochondrial performance and metabolic control.

PubMed

Noland, Robert C; Koves, Timothy R; Seiler, Sarah E; Lum, Helen; Lust, Robert M; Ilkayeva, Olga; Stevens, Robert D; Hegardt, Fausto G; Muoio, Deborah M

2009-08-21

In addition to its essential role in permitting mitochondrial import and oxidation of long chain fatty acids, carnitine also functions as an acyl group acceptor that facilitates mitochondrial export of excess carbons in the form of acylcarnitines. Recent evidence suggests carnitine requirements increase under conditions of sustained metabolic stress. Accordingly, we hypothesized that carnitine insufficiency might contribute to mitochondrial dysfunction and obesity-related impairments in glucose tolerance. Consistent with this prediction whole body carnitine diminution was identified as a common feature of insulin-resistant states such as advanced age, genetic diabetes, and diet-induced obesity. In rodents fed a lifelong (12 month) high fat diet, compromised carnitine status corresponded with increased skeletal muscle accumulation of acylcarnitine esters and diminished hepatic expression of carnitine biosynthetic genes. Diminished carnitine reserves in muscle of obese rats was accompanied by marked perturbations in mitochondrial fuel metabolism, including low rates of complete fatty acid oxidation, elevated incomplete beta-oxidation, and impaired substrate switching from fatty acid to pyruvate. These mitochondrial abnormalities were reversed by 8 weeks of oral carnitine supplementation, in concert with increased tissue efflux and urinary excretion of acetylcarnitine and improvement of whole body glucose tolerance. Acetylcarnitine is produced by the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT). A role for this enzyme in combating glucose intolerance was further supported by the finding that CrAT overexpression in primary human skeletal myocytes increased glucose uptake and attenuated lipid-induced suppression of glucose oxidation. These results implicate carnitine insufficiency and reduced CrAT activity as reversible components of the metabolic syndrome.

Carnitine Insufficiency Caused by Aging and Overnutrition Compromises Mitochondrial Performance and Metabolic Control*

PubMed Central

Noland, Robert C.; Koves, Timothy R.; Seiler, Sarah E.; Lum, Helen; Lust, Robert M.; Ilkayeva, Olga; Stevens, Robert D.; Hegardt, Fausto G.; Muoio, Deborah M.

2009-01-01

In addition to its essential role in permitting mitochondrial import and oxidation of long chain fatty acids, carnitine also functions as an acyl group acceptor that facilitates mitochondrial export of excess carbons in the form of acylcarnitines. Recent evidence suggests carnitine requirements increase under conditions of sustained metabolic stress. Accordingly, we hypothesized that carnitine insufficiency might contribute to mitochondrial dysfunction and obesity-related impairments in glucose tolerance. Consistent with this prediction whole body carnitine dimunition was identified as a common feature of insulin-resistant states such as advanced age, genetic diabetes, and diet-induced obesity. In rodents fed a lifelong (12 month) high fat diet, compromised carnitine status corresponded with increased skeletal muscle accumulation of acylcarnitine esters and diminished hepatic expression of carnitine biosynthetic genes. Diminished carnitine reserves in muscle of obese rats was accompanied by marked perturbations in mitochondrial fuel metabolism, including low rates of complete fatty acid oxidation, elevated incomplete β-oxidation, and impaired substrate switching from fatty acid to pyruvate. These mitochondrial abnormalities were reversed by 8 weeks of oral carnitine supplementation, in concert with increased tissue efflux and urinary excretion of acetylcarnitine and improvement of whole body glucose tolerance. Acetylcarnitine is produced by the mitochondrial matrix enzyme, carnitine acetyltransferase (CrAT). A role for this enzyme in combating glucose intolerance was further supported by the finding that CrAT overexpression in primary human skeletal myocytes increased glucose uptake and attenuated lipid-induced suppression of glucose oxidation. These results implicate carnitine insufficiency and reduced CrAT activity as reversible components of the metabolic syndrome. PMID:19553674

Risk factors for the development of paclitaxel-induced neuropathy in breast cancer patients.

PubMed

Robertson, Jetter; Raizer, Jeffrey; Hodges, James S; Gradishar, William; Allen, Jeffrey A

2018-06-01

Peripheral neuropathy is a common side effect of many chemotherapeutic agents including paclitaxel. We prospectively evaluated demographic and laboratory data in a cohort of 61 woman with breast cancer prior to paclitaxel exposure to explore factors that predispose to neuropathy development. Neuropathy was graded based on the total neuropathy score reduced version (rTNS) at baseline and at 4 months after initiation of chemotherapy. A multivariate analysis identified predictors with the strongest association with a change in rTNS. Serum albumin (P = .002), paclitaxel dose (P = .001), and body surface area (P = .006) were statistically significantly associated with a positive rTNS change (worsening neuropathy). These results suggest that poor nutritional status and obesity increase the risk of paclitaxel induced neuropathy, and that screening for these factors prior to chemotherapy exposure may improve early neuropathy detection or decrease risk with dietary modifications. © 2018 Peripheral Nerve Society.

Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy.

PubMed

Kramer, Rita; Bielawski, Jacek; Kistner-Griffin, Emily; Othman, Alaa; Alecu, Irina; Ernst, Daniela; Kornhauser, Drew; Hornemann, Thorsten; Spassieva, Stefka

2015-11-01

Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and cisplatin chemotherapy. In the current study, we tested the involvement of a novel class of neurotoxic sphingolipids, the 1-deoxysphingolipids. 1-Deoxysphingolipids are produced when the enzyme serine palmitoyltransferase uses l-alanine instead of l-serine as its amino acid substrate. We tested whether treatment of cells with paclitaxel (250 nM, 1 µM) and cisplatin (250 nM, 1 µM) would result in elevated cellular levels of 1-deoxysphingolipids. Our results revealed that paclitaxel, but not cisplatin treatment, caused a dose-dependent elevation of 1-deoxysphingolipids levels and an increase in the message and activity of serine palmitoyltransferase (P < 0.05). We also tested whether there is an association between peripheral neuropathy symptoms [evaluated by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-chemotherapy-induced peripheral neuropathy-20 (CIPN20) instrument] and the 1-deoxysphingolipid plasma levels (measured by mass spectrometry) in 27 patients with breast cancer who were treated with paclitaxel chemotherapy. Our results showed that there was an association between the incidence and severity of neuropathy and the levels of very-long-chain 1-deoxyceramides such as C24 (P < 0.05), with the strongest association being with motor neuropathy (P < 0.001). Our data from cells and from patients with breast cancer suggest that 1-deoxysphingolipids, the very-long-chain in particular, play a role as molecular intermediates of paclitaxel-induced peripheral neuropathy. © FASEB.

Dose- dependent ameliorative effects of quercetin and l-Carnitine against atrazine- induced reproductive toxicity in adult male Albino rats.

PubMed

Abdel Aziz, Rabie L; Abdel-Wahab, Ahmed; Abo El-Ela, Fatma I; Hassan, Nour El-Houda Y; El-Nahass, El-Shaymaa; Ibrahim, Marwa A; Khalil, Abdel-Tawab A Y

2018-06-01

This study aimed to determine the protective effects of co-administration of Quercetin (QT) or l-Carnitine (LC) against the oxidative stress induced by Atrazine (ATZ) in the reproductive system of intact male Albino rats. 36 rats were divided equally into 6 groups. Rats in the control negative "CNT" group received 1.5 ml distilled water for 21 days. All rats in the other groups received ATZ (120 mg/kg bw) through gavage. Groups 3 and 4 were co-administered with either low or high dose of QT (10 "ATZLQT" and 50 "ATZHQT" mg/kg bw, respectively). Groups 5 and 6 were co-administered with either low or high dose of LC (200 "ATZLLC" and 400 "ATZHLC" mg/kg bw, respectively). At the end of the experiment, animals were sacrificed and all samples were collected. ATZ significantly increased serum level of malondialdehyde (MDA) and decreased total antioxidant capacity (TAC). Also, ATZ increased significantly the sperm cell abnormalities and reduced both testicular IgA and serum testosterone levels. Testicular DNA laddering % and CYP17A1 mRNA expression were significantly reduced in ATZ group. Interestingly, co-administration with low dose QT or different doses of LC succeeded to counteract the negative toxic effects of ATZ on serum oxidative stress indicators, serum testosterone levels, testicular IgA level and improved testicular CYP17A1 mRNA expression. In conclusion, QT in low dose and LC in both low and high doses exerted a significant protective action against the reproductive toxicity of ATZ, while higher dose of QT failed induce immune-stimulant effect against ATZ in adult male Albino rats. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy

PubMed Central

Kramer, Rita; Bielawski, Jacek; Kistner-Griffin, Emily; Othman, Alaa; Alecu, Irina; Ernst, Daniela; Kornhauser, Drew; Hornemann, Thorsten; Spassieva, Stefka

2015-01-01

Peripheral neuropathy is a major dose-limiting side effect of paclitaxel and cisplatin chemotherapy. In the current study, we tested the involvement of a novel class of neurotoxic sphingolipids, the 1-deoxysphingolipids. 1-Deoxysphingolipids are produced when the enzyme serine palmitoyltransferase uses l-alanine instead of l-serine as its amino acid substrate. We tested whether treatment of cells with paclitaxel (250 nM, 1 µM) and cisplatin (250 nM, 1 µM) would result in elevated cellular levels of 1-deoxysphingolipids. Our results revealed that paclitaxel, but not cisplatin treatment, caused a dose-dependent elevation of 1-deoxysphingolipids levels and an increase in the message and activity of serine palmitoyltransferase (P < 0.05). We also tested whether there is an association between peripheral neuropathy symptoms [evaluated by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-chemotherapy-induced peripheral neuropathy-20 (CIPN20) instrument] and the 1-deoxysphingolipid plasma levels (measured by mass spectrometry) in 27 patients with breast cancer who were treated with paclitaxel chemotherapy. Our results showed that there was an association between the incidence and severity of neuropathy and the levels of very-long-chain 1-deoxyceramides such as C24 (P < 0.05), with the strongest association being with motor neuropathy (P < 0.001). Our data from cells and from patients with breast cancer suggest that 1-deoxysphingolipids, the very-long-chain in particular, play a role as molecular intermediates of paclitaxel-induced peripheral neuropathy.—Kramer, R., Bielawski, J., Kistner-Griffin, E., Othman, A., Alecu, I., Ernst, D., Kornhauser, D., Hornemann, T., Spassieva, S. Neurotoxic 1-deoxysphingolipids and paclitaxel-induced peripheral neuropathy. PMID:26198449

Hypoglycemic Effect of Lipoic Acid, Carnitine and Nigella Sativa in Diabetic Rat Model

PubMed Central

Salama, Ragaa Hamdy Mohamed

2011-01-01

Objectives Evaluation of therapeutic potentials of α-lipoic acid (α-LA), L-carnitine, Nigella sativa (N. sativa) or combination of them in carbohydrate and lipid metabolism of DM type I. Methods Rat model of diabetes was induced by single i.p injection of Streptozocin (STZ) 65 mg/kg. The rats were randomly assigned to 6 groups (G): healthy reference (HR), diabetic (DM), DM treated with α-lipoic acid, DM treated with L-carnitine, DM treated with N. sativa, and DM treated with combination of the 3 compounds. After 30 days from onset of diabetes, serum and tissue homogenate were obtained for evaluation of glucose metabolism as fasting blood glucose, insulin, insulin sensitivity, HOMA, C-peptide, and pyruvate dehydrogenase (PDH) activity. For lipid metabolism evaluation, total cholesterol and triacylglycerol (TG) were determined. Markers of antioxidants and oxidative status as total antioxidant capacity (TAC), glutathione-S-transeferase (GST), 8-hydroxy-2-deoxyguanosine (8-OH-dG) were measured. Results Either α-LA or N. sativa significantly reduced the elevated blood glucose level. The combination of 3 compounds significantly increased the level of insulin and C-peptide. Also, increased the antioxidant activity measured by TAC and decreased the oxidative damage of DNA as measured by 8-OH-dG. HOMA- β increased in G3 and G6 compared to G2. However, the decrease in TG, and total cholesterol levels were non-significant in all groups. Conclusion Combination of α-LA, L-carnitine and N. sativa will contribute significantly in improvement of the carbohydrate metabolism and to less extent lipid metabolism in diabetic rats, thus increasing the rate of success in management of DM. Also, this combination will have implications in clinical studies and clinical applications. PMID:23267290

Hypoglycemic effect of lipoic Acid, carnitine and nigella sativa in diabetic rat model.

PubMed

Salama, Ragaa Hamdy Mohamed

2011-07-01

Evaluation of therapeutic potentials of α-lipoic acid (α-LA), L-carnitine, Nigella sativa (N. sativa) or combination of them in carbohydrate and lipid metabolism of DM type I. Rat model of diabetes was induced by single i.p injection of Streptozocin (STZ) 65 mg/kg. The rats were randomly assigned to 6 groups (G): healthy reference (HR), diabetic (DM), DM treated with α-lipoic acid, DM treated with L-carnitine, DM treated with N. sativa, and DM treated with combination of the 3 compounds. After 30 days from onset of diabetes, serum and tissue homogenate were obtained for evaluation of glucose metabolism as fasting blood glucose, insulin, insulin sensitivity, HOMA, C-peptide, and pyruvate dehydrogenase (PDH) activity. For lipid metabolism evaluation, total cholesterol and triacylglycerol (TG) were determined. Markers of antioxidants and oxidative status as total antioxidant capacity (TAC), glutathione-S-transeferase (GST), 8-hydroxy-2-deoxyguanosine (8-OH-dG) were measured. Either α-LA or N. sativa significantly reduced the elevated blood glucose level. The combination of 3 compounds significantly increased the level of insulin and C-peptide. Also, increased the antioxidant activity measured by TAC and decreased the oxidative damage of DNA as measured by 8-OH-dG. HOMA- β increased in G3 and G6 compared to G2. However, the decrease in TG, and total cholesterol levels were non-significant in all groups. Combination of α-LA, L-carnitine and N. sativa will contribute significantly in improvement of the carbohydrate metabolism and to less extent lipid metabolism in diabetic rats, thus increasing the rate of success in management of DM. Also, this combination will have implications in clinical studies and clinical applications.

A cross-sectional study of carnitine deficiency and fatigue in pediatric cancer patients.

PubMed

Lai, Jin-Shei; Haertling, Tracy; Weinstein, Joanna; Rademaker, Alfred W; Goldman, Stewart

2016-03-01

Carnitine deficiency has been found in cancer patients and has been associated with fatigue. This study aimed to explore the prevalence of carnitine deficiency in pediatric cancer patients and its relationship with fatigue and other potential contributing factors. Children with cancer or Langerhans cell histiocytosis who were receiving treatment or had completed therapy were eligible. Patients completed the Pediatric Functional Assessment of Chronic Illness-Fatigue, the Pediatric Quality of Life Inventory Multidimensional Fatigue Scale, a numeric fatigue rating, and had carnitine levels obtained. Carnitine deficiency was defined as a total and/or free carnitine level less than normal for age or an acylcarnitine value higher than normal for age. Data from 142 children aged 8-17 were analyzed. Twenty-eight of 142 (19.7 %) had decreased total and 42.8 % (12/28) had decreased free carnitine levels. No patients had elevated acylcarnitine levels or elevated ratios. Patients with versus without carnitine deficiency differed by age (p = 0.043), treatment (p = 0.037), duration since last chemotherapy (p = 0.020), and body mass index (p = 0.010), but not fatigue, when all data were analyzed together. Yet, a negative relationship between fatigue and carnitine levels was found on a subgroup (off-therapy; fatigue worse than the norm). No significant association between fatigue and carnitine level was demonstrated when data from all patients were analyzed together; however, a significant yet unexpected relationship was found for patients who completed therapy and reported elevated fatigue. Given the small sample size, these results should be interpreted with caution. Future studies to explore impact upon excessive carnitine levels are warranted.

Nanoparticles increase the efficacy of cancer chemopreventive agents in cells exposed to cigarette smoke condensate.

PubMed

Pulliero, Alessandra; Wu, Yun; Fenoglio, Daniela; Parodi, Alessia; Romani, Massimo; Soares, Christiane P; Filaci, Gilberto; Lee, James L; Sinkam, Patrick N; Izzotti, Alberto

2015-03-01

Lung cancer is a leading cause of death in developed countries. Although smoking cessation is a primary strategy for preventing lung cancer, former smokers remain at high risk of cancer. Accordingly, there is a need to increase the efficacy of lung cancer prevention. Poor bioavailability is the main factor limiting the efficacy of chemopreventive agents. The aim of this study was to increase the efficacy of cancer chemopreventive agents by using lipid nanoparticles (NPs) as a carrier. This study evaluated the ability of lipid NPs to modify the pharmacodynamics of chemopreventive agents including N-acetyl-L-cysteine, phenethyl isothiocyanate and resveratrol (RES). The chemopreventive efficacy of these drugs was determined by evaluating their abilities to counteract cytotoxic damage (DNA fragmentation) induced by cigarette smoke condensate (CSC) and to activate protective apoptosis (annexin-V cytofluorimetric staining) in bronchial epithelial cells both in vitro and in ex vivo experiment in mice. NPs decreased the toxicity of RES and increased its ability to counteract CSC cytotoxicity. NPs significantly increased the ability of phenethyl isothiocyanate to attenuate CSC-induced DNA fragmentation at the highest tested dose. In contrast, this potentiating effect was observed at all tested doses of RES, NPs dramatically increasing RES-induced apoptosis in CSC-treated cells. These results provide evidence that NPs are highly effective at increasing the efficacy of lipophilic drugs (RES) but are not effective towards hydrophilic agents (N-acetyl-L-cysteine), which already possess remarkable bioavailability. Intermediate effects were observed for phenethyl isothiocyanate. These findings are relevant to the identification of cancer chemopreventive agents that would benefit from lipid NP delivery. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of L-Carnitine Supplementation on Apelin and Apelin Receptor (Apj) Expression in Cardiac Muscle of Obese Diabetic Rats.

PubMed

Ranjbar Kohan, Neda; Nazifi, Saeed; Tabandeh, Mohammad Reza; Ansari Lari, Maryam

2018-10-01

L-carnitine (LC) has been shown to protect cardiac metabolism in diabetes patients with cardiovascular diseases (CVDs). Apelin, a newly discovered adipocytokines, is an important regulator of cardiac muscle function; however, the role of the level of expression of Apelin axis in improvement of cardiac function by LC in diabetic patients, is not clear. In the present study, obese insulin-resistant rats were used to determine the effect of LC, when given orally with a high-calorie diet, on Apelin and Apelin receptor (Apj) expression in cardiac muscle. In this experimental study, rats were fed with high-fat/high-carbohydrate diet for five weeks and subsequently were injected with streptozotocin 30 mg/kg for induction of obesity and insulin resistance. After confirming the induction of diabetes (serum glucose above 7.5 mmol/L), the animals received LC 300 mg/kg in drinking water for 28 days. On days 0, 14 and 28 after treatment, cardiac Apelin and Apj gene expression was evaluated by real time polymerase chain reaction (PCR) analysis. Serum levels of insulin, Apelin, glucose, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and the homeostasis model assessment of insulin resistance (HOMA-IR) were also measured using commercial kits. Cardiac Apelin and Apj expression and serum Apelin were increased in obese rats, while LC supplementation decreased the serum levels of Apelin and down-regulated Apelin and Apj expression in cardiac muscle. These changes were associated with reduced insulin resistance markers and serum inflammatory factors and improved lipid profile. We concluded that LC supplementation could attenuate the over-expression of Apelin axis in heart of diabetic rats, a novel mechanism by which LC improves cardiovascular complications in diabetic patients. Copyright© by Royan Institute. All rights reserved.

The development and validation of a neuropathy- and foot ulcer-specific quality of life instrument.

PubMed

Vileikyte, Loretta; Peyrot, Mark; Bundy, Christine; Rubin, Richard R; Leventhal, Howard; Mora, Pablo; Shaw, Jonathan E; Baker, Paul; Boulton, Andrew J M

2003-09-01

The purpose of this study was to develop a questionnaire that measures patients' perceptions of the impact of diabetic peripheral neuropathy and foot ulcers on their quality of life and to assess the psychometric properties of this instrument in a sample of patients with varying severity and symptomatology of diabetic peripheral neuropathy. The neuropathy- and foot ulcer-specific quality of life instrument (NeuroQoL), generated from interviews with patients with (n = 47) and without (n = 15) diabetic peripheral neuropathy, was administered to 418 consecutive patients with diabetic peripheral neuropathy (35% with foot ulcer history) attending either U.K. (n = 290) or U.S. (n = 128) diabetes centers. Psychometric tests of NeuroQoL included factor analyses and internal consistency of scales; a series of multivariate analyses were performed to establish its criterion, construct, and incremental validity. Results were compared with those obtained using the Short Form (SF)-12 measure of health-related functioning. Factor analyses of NeuroQoL revealed three physical symptom measures and two psychosocial functioning measures with good reliability (alpha = 0.86-0.95). NeuroQoL was more strongly associated with measures of neuropathic severity than SF-12, more fully mediated the relationship of diabetic peripheral neuropathy with overall quality of life, and significantly increased explained variance in overall quality of life over SF-12. NeuroQoL reliably captures the key dimensions of the patients' experience of diabetic peripheral neuropathy and is a valid tool for studying the impact of neuropathy and foot ulceration on quality of life.

TNF-Alpha in Peripheral Neuropathy Patients with Impaired Glucose Regulation.

PubMed

Li, Xia; Zhu, Ju; Liu, Na; Liu, Jie; Zhang, Zhecheng

2017-01-01

Impaired glucose regulation (IGR) is the prestate of diabetes; about 1/3 of IGR patients will develop to diabetes finally. In this study, we investigated the serum tumor necrosis factor-alpha (TNF- α ) and interleukin-6 (IL-6) levels in peripheral neuropathy impaired patients with impaired glucose regulation (IGR). A total of 70 IGR patients received the conventional nerve conduction test, including 30 patients with peripheral neuropathy (PN) and 40 patients without peripheral neuropathy (NPN). The other 40 healthy individuals were recruited as controls. The serum TNF- α and IL-6 in IGR patients were higher than in control group, and serum TNF- α and IL-6 levels in IGR-PN group were higher than in IGR-NPN group (27.7 ± 17.8 versus 13.1 ± 6.7 pg/mL and 18.1 ± 17.7 versus 6.4 ± 3.7 pg/mL, resp., both p < 0.05). Multifactors logistic regression analysis showed that TNF- α (OR = 0.893; p = 0.009) was an independent factor affecting whether IGR could combine with peripheral neuropathy. TNF- α and IL-6 could aggregate peripheral neuropathy in impaired glucose regulation patients; TNF- α might be independent risk factor for peripheral neuropathy in glucose regulation impaired patients.

[Risk factors in the epidemic neuropathy of Cuba].

PubMed

Molina-Esquivel, E; Pita-Rodríguez, G; Monterrey-Gutiérrez, P A; Clúa-Calderín, A M

1998-01-01

A case control study to find out if Cuba's epidemic neuropathy was a result of one of the following causes: (1) an infectious process, (2) exposure to one or more toxical agents, (3) low intake of one or more nutrients, or (4) more than one of such causes and their interactions. A total of 311 cases of epidemic neuropathy with optic and peripheral symptoms and 377 controls were studied. A questionnaire with 55 items was employed to document exposure to factors determined by the etiologic hypothesis. Data analysis was done separately for the optical and peripheral types of the disease. No association was found between illness and any deficiency of basic sanitation for both types of neuropathy. Acute stress, irregularities in food intake, body weight loss in the last 12 months and other indicators of nutritional deficiencies were associated to both clinical manifestations, although they were also high in the controls. Low frequency of illness was found for people living with diseased persons. Females had a significant high risk of illness in the peripheral manifestations whereas smoking was the only toxical risk factor in optical neuropathy. Nutritional deficiencies together with unidentified personal factors were the main associations for illness outcome; smoking increased significantly the risk of optical neuropathy. 1. The infection etiology was unsupported in the study. 2. Smoking appeared as a factor for the optical neuropathy. 3. Stress induced by vital events were significantly associated with the disease. 4. Both types of the neuropathy were associated to body weight loss and other indicators of nutritional deficit.

Chemotherapy-Induced Peripheral Neuropathy: A Current Review

PubMed Central

Staff, Nathan P.; Grisold, Anna; Grisold, Wolfgang; Windebank, Anthony J.

2017-01-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a common dose-limiting side effect experienced by patients receiving treatment for cancer. Approximately 30–40% of patients treated with neurotoxic chemotherapy will develop CIPN and there is considerable variability in its severity between patients. It is often sensory-predominant with pain and can lead to long-term morbidity in survivors. The prevalence and burden of CIPN late effects will likely increase as cancer survival rates continue to improve. In this review, we discuss the approach to peripheral neuropathy in patients with cancer and address the clinical phenotypes and pathomechanisms of specific neurotoxic chemotherapeutic agents. PMID:28486769

Antimicrobial and demelanizing activity of Ganoderma lucidum extract, p-hydroxybenzoic and cinnamic acids and their synthetic acetylated glucuronide methyl esters.

PubMed

Heleno, Sandrina A; Ferreira, Isabel C F R; Esteves, Ana P; Ćirić, Ana; Glamočlija, Jasmina; Martins, Anabela; Soković, Marina; Queiroz, Maria João R P

2013-08-01

Mushroom extracts or isolated compounds may be useful in the search of new potent antimicrobial agents. Herein, it is described the synthesis of protected (acetylated) glucuronide derivatives of p-hydroxybenzoic and cinnamic acids, two compounds identified in the medicinal mushroom Ganoderma lucidum. Their antimicrobial and demelanizing activities were evaluated and compared to the parent acids and G. lucidum extract. p-Hydroxybenzoic and cinnamic acids, as also their protected glucuronide derivatives revealed high antimicrobial (antibacterial and antifungal) activity, even better than the one showed by commercial standards. Despite the variation in the order of parent acids and the protected glucuronide derivatives, their antimicrobial activity was always higher than the one revealed by the extract. Nevertheless, the extract was the only one with demelanizing activity against Aspergillus niger. The acetylated glucuronide derivatives could be deprotected to obtain glucuronide metabolites, which circulate in the human organism as products of the metabolism of the parent compounds. Copyright © 2013 Elsevier Ltd. All rights reserved.

Postmortem Toxicology Findings of Acetyl Fentanyl, Fentanyl, and Morphine in Heroin Fatalities in Tampa, Florida

PubMed Central

Pearson, Julia; Poklis, Justin; Poklis, Alphonse; Wolf, Carl; Mainland, Mary; Hair, Laura; Devers, Kelly; Chrostowski, Leszek; Arbefeville, Elise; Merves, Michele

2017-01-01

In the last two years, an epidemic of 40 fatal heroin overdose cases has occurred in the Tampa area of Florida. Of these cases, 14 involved fentanyl and acetyl fentanyl. Victim demographics, case histories, toxicology findings, and causes and manners of death for all 40 deaths are presented. In 26 deaths in which acetyl fentanyl or fentanyl were not involved, free and total peripheral blood morphine concentrations were consistent with fatal heroin intoxications, averaging 0.16 mg/L and 0.35 mg/L, respectively. In the heroin cases with fentanyl present (n=7), the average free morphine concentration was 0.040 mg/L, the average total morphine concentration was 0.080 mg/L, and the average fentanyl concentration was 0.012 mg/L. In the cases with heroin, fentanyl, and acetyl fentanyl (n=3), the average free morphine concentration was 0.010 mg/L, the average total morphine concentration was 0.030 mg/L, the average fentanyl concentration was 0.018 mg/L, and the average acetyl fentanyl concentration was 0.008 mg/L. In the cases involving only acetyl fentanyl (without heroin or fentanyl, n=4), the average acetyl fentanyl concentration was 0.47 mg/L and the average acetyl norfentanyl concentration was 0.053 mg/L. The presented cases, with associated drug concentrations, case histories, demographics, and causes and manners of death may help provide assistance with the interpretation of the postmortem findings. Based on case circumstances, autopsy results, and toxicology results, it is evident that fentanyl and/or acetyl fentanyl, when present, contributed to the cause of death. PMID:29034049

Partial purification and characterization of an inducible indole-3-acetyl-L-aspartic acid hydrolase from Enterobacter agglomerans

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chou, Jyh-Ching; Cohen, J.D.; Mulbry, W.W.

1996-11-01

Indole-3-acetyl-amino acid conjugate hydrolases are believed to be important in the regulation of indole-3-acetic acid (IAA) metabolism in plants and therefore have potential uses for the alteration of plant IAA metabolism. To isolate bacterial strains exhibiting significant indole-3-acetyl-aspartate (IAA-Asp) hydrolase activity, a sewage sludge inoculation was cultured under conditions in which IAA-Asp served as the sole source of carbon and nitrogen. One isolate, Enterobacter agglomerans, showed hydrolase activity inducible by IAA-L-Asp or N-acetyl-L-Asp but not by IAA, (NH{sub 4}){sub 2}SO{sub 4}, urea, or indoleacetamide. Among a total of 17 IAA conjugates tested as potential substrates, the enzyme had an exclusivelymore » high substrate specificity for IAA-L-Asp of 13.5 mM. The optimal pH for this enzyme was between 8.0 and 8.5. In extraction buffer containing 0.8 mM Mg{sup 2+} the hydrolase activity was inhibited to 80% by 1 mM dithiothreitol and to 60% by 1 mm CuSO{sub 4}; the activity was increased by 40% with 1mM MnSO{sub 4}. However, in extraction buffer with no trace elements, the hydrolase activity was inhibited to 50% by either 1 mM dithiothreitol or 1% Triton X-100 (Sigma). These results suggest that disulfide bonding might be essential for enzyme activity. Purification of the hydrolase by hydroxyapatite and TSK-phenyl (HP-Genenchem, South San Francisco, CA) preparative high-performance liquid chromatography yielded a major 45-kD polypeptide as shown by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. 45 refs., 5 figs., 3 tabs.« less

Agmatine co-treatment attenuates allodynia and structural abnormalities in cisplatin-induced neuropathy in rats.

PubMed

Donertas, Basak; Cengelli Unel, Cigdem; Aydin, Sule; Ulupinar, Emel; Ozatik, Orhan; Kaygisiz, Bilgin; Yildirim, Engin; Erol, Kevser

2018-06-01

Cisplatin is a widely used antineoplastic agent in the treatment of various cancers. Peripheral neuropathy is a well-known side effect of cisplatin and has potential to result in limiting and/or reducing the dose, decreasing the quality of life. Thus, effective treatments are needed. Agmatine is an endogenous neuromodulator that has been shown to exert antiallodynic effects in various animal studies. The first aim of this study was to investigate the in vitro effects of agmatine on cisplatin-induced neurotoxicity. Primary cultures of dorsal root ganglia (DRG) which are the primary target of drug injury were prepared. DRG cells were incubated with cisplatin (100, 200, 500 μm). Then, agmatine (10, 100, 500 μm) was administered with the submaximal concentration of cisplatin. Cisplatin caused concentration-dependent neurotoxicity, and agmatine did not alter this effect. The second aim was to investigate the effects of agmatine on cisplatin-induced peripheral neuropathy in rats and the influence of nitric oxide synthase (NOS) inhibitor, L-NAME, in this effect. Female Sprague Dawley rats received intraperitoneal saline (control), cisplatin (3 mg/kg), cisplatin+agmatine (100 mg/kg), or cisplatin+agmatine+L-NAME (10 mg/kg) once a week for 5 weeks. The mechanical allodynia, hot plate, and tail clip tests were performed, and DRG cells and sciatic nerves were analyzed. Agmatine and agmatine+L-NAME combination attenuated CIS-induced mechanical allodynia and degeneration in DRG cells and sciatic nerves. However, L-NAME did not potentiate the antiallodynic or neuroprotective effect of agmatine. These findings indicate that agmatine co-administration ameliorates cisplatin-induced neuropathy and may be a therapeutic alternative. © 2018 Société Française de Pharmacologie et de Thérapeutique.

Chemical Glucosylation of Labile Natural Products Using a (2-Nitrophenyl)acetyl-Protected Glucosyl Acetimidate Donor.

PubMed

Weber, Julia; Schwarz, Markus; Schiefer, Andrea; Hametner, Christian; Häubl, Georg; Fröhlich, Johannes; Mikula, Hannes

2018-06-07

The synthesis of (2-nitrophenyl)acetyl (NPAc)-protected glucosyl donors is described that were designed for the neighboring-group assisted glucosylation of base-labile natural products also being sensitive to hydrogenolysis. Glycosylation conditions were optimized using a trichloroacetimidate glucosyl donor, and cyclohexylmethanol and (+)-menthol as model acceptors. The approach was then extended to a one-pot procedure for the synthesis of 1,2- trans -glycosides. This method was finally applied for improved synthesis of the masked mycotoxin T2- O -β,d-glucoside.

Electrode Potentials of l-Tryptophan, l-Tyrosine, 3-Nitro-l-tyrosine, 2,3-Difluoro-l-tyrosine, and 2,3,5-Trifluoro-l-tyrosine.

PubMed

Mahmoudi, Leila; Kissner, Reinhard; Nauser, Thomas; Koppenol, Willem H

2016-05-24

Electrode potentials for aromatic amino acid radical/amino acid couples were deduced from cyclic voltammograms and pulse radiolysis experiments. The amino acids investigated were l-tryptophan, l-tyrosine, N-acetyl-l-tyrosine methyl ester, N-acetyl-3-nitro-l-tyrosine ethyl ester, N-acetyl-2,3-difluoro-l-tyrosine methyl ester, and N-acetyl-2,3,5-trifluoro-l-tyrosine methyl ester. Conditional potentials were determined at pH 7.4 for all compounds listed; furthermore, Pourbaix diagrams for l-tryptophan, l-tyrosine, and N-acetyl-3-nitro-l-tyrosine ethyl ester were obtained. Electron transfer accompanied by proton transfer is reversible, as confirmed by detailed analysis of the current waves, and because the slopes of the Pourbaix diagrams obey Nernst's law. E°'(Trp(•),H(+)/TrpH) and E°'(TyrO(•),H(+)/TyrOH) at pH 7 are 0.99 ± 0.01 and 0.97 ± 0.01 V, respectively. Pulse radiolysis studies of two dipeptides that contain both amino acids indicate a difference in E°' of approximately 0.06 V. Thus, in small peptides, we recommend values of 1.00 and 0.96 V for E°'(Trp(•),H(+)/TrpH) and E°'(TyrO(•),H(+)/TyrOH), respectively. The electrode potential of N-acetyl-3-nitro-l-tyrosine ethyl ester is higher, while because of mesomeric stabilization of the radical, those of N-acetyl-2,3-difluoro-l-tyrosine methyl ester and N-acetyl-2,3,5-trifluoro-l-tyrosine methyl ester are lower than that of tyrosine. Given that the electrode potentials at pH 7 of E°'(Trp(•),H(+)/TrpH) and E°'(TyrO(•),H(+)/TyrOH) are nearly equal, they would be, in principle, interchangeable. Proton-coupled electron transfer pathways in proteins that use TrpH and TyrOH are thus nearly thermoneutral.

Paraneoplastic neuropathies.

PubMed

Antoine, Jean-Christophe; Camdessanché, Jean-Philippe

2017-10-01

To review recent advances in paraneoplastic neuropathies with emphasis on their definition, different forms and therapeutic development. A strict definition of definite paraneoplastic neuropathies is necessary to avoid confusion. With carcinoma, seronegative sensory neuronopathies and neuronopathies and anti-Hu and anti-CV2/Contactin Response Mediator Protein 5 antibodies are the most frequent. With lymphomas, most neuropathies occur with monoclonal gammopathy including AL amyloidosis, Polyneuropathy-Organomegaly-Endocrinopathy-M component-Skin changes (POEMS) syndrome, type I cryoglobulinemia and antimyelin-associated glycoprotein (MAG) neuropathies and Waldenström's disease. Neuropathies improving with tumor treatment are occasional, occur with a variety of cancer and include motor neuron disease, chronic inflammatory demyelinating neuropathy and nerve vasculitis. If antibodies toward intracellular antigens are well characterized, it is not the case for antibodies toward cell membrane proteins. Contactin-associated protein-2 antibodies occur with neuromyotonia and thymoma with the Morvan's syndrome in addition to Netrin 1 receptor antibodies but may not be responsible for peripheral nerve hyperexcitability. The treatment of AL amyloidosis, POEMS syndrome, anti-MAG neuropathy and cryoglobulinemia is now relatively well established. It is not the case with onconeural antibodies for which the rarity of the disorders and a short therapeutic window are limiting factors for the development of clinical trials. A strict definition of paraneoplastic neuropathies helps their identification and is necessary to allow an early diagnosis of the underlying tumor.

Vasculitic Neuropathies.

PubMed

Naddaf, Elie; Dyck, P James Bonham

2015-10-01

From pathological standpoint, we divide vasculitic neuropathies in two categories: nerve large arteriole vasculitides and nerve microvasculitis. It is also important to determine whether a large arteriole vasculitis has an infectious etiology as it entails different treatment approach. Treatment of non-infectious large arteriole vasculitides consists initially of induction therapy with corticosteroids. Adding an immunosuppressant, mainly cyclophosphamide, is often needed. Treatment of infectious large arteriole vasculitides needs a multidisciplinary approach to target both the underlying infection and the vasculitis. Corticosteroids are the first-line therapy for classic non-systemic vasculitic neuropathy. Stable or improving patients without biopsy evidence of active vasculitis can be either observed or treated. Currently, adding an immunosuppressant is only indicated for patients who continue to progress on corticosteroids alone or patients with a rapidly progressive course. The treatment of the radiculoplexus neuropathies such as diabetic lumbosacral radiculoplexus neuropathy, lumbosacral radiculoplexus neuropathy (in non-diabetic patients), and diabetic cervical radiculoplexus neuropathy, as well as painless diabetic motor neuropathy, is not well established yet. We treat patients, if they present early on in the disease course or if they have severe disabling symptoms, with IV methylprednisolone 1 g once a week for 12 weeks.

Oral carnitine supplementation reduces body weight and insulin resistance in women with polycystic ovary syndrome: a randomized, double-blind, placebo-controlled trial.

PubMed

Samimi, Mansooreh; Jamilian, Mehri; Ebrahimi, Faraneh Afshar; Rahimi, Maryam; Tajbakhsh, Banafsheh; Asemi, Zatollah

2016-06-01

Limited data are available for evaluating the effects of oral carnitine supplementation on weight loss and metabolic profiles of women with polycystic ovary syndrome (PCOS). This study was designed to determine the effects of oral carnitine supplementation on weight loss, and glycaemic and lipid profiles in women with PCOS. In a prospective, randomized, double-blind, placebo-controlled trial, 60 overweight patients diagnosed with PCOS were randomized to receive either 250 mg carnitine supplements (n = 30) or placebo (n = 30) for 12 weeks. Fasting blood samples were obtained at the beginning and the end of the study to quantify parameters of glucose homoeostasis and lipid concentrations. At the end of the 12 weeks, taking carnitine supplements resulted in a significant reduction in weight (-2·7 ± 1·5 vs +0·1 ± 1·8 kg, P < 0·001), BMI (-1·1 ± 0·6 vs +0·1 ± 0·7 kg/m(2) , P < 0·001), waist circumference (WC) (-2·0 ± 1·3 vs -0·3 ± 2·0 cm, P < 0·001) and hip circumference (HC) (-2·5 ± 1·5 vs -0·3 ± 1·8 cm, P < 0·001) compared with placebo. In addition, compared with placebo, carnitine administration in women with PCOS led to a significant reduction in fasting plasma glucose (-0·38 ± 0·36 vs +0·11 ± 0·97 mmol/l, P = 0·01), serum insulin levels (-14·39 ± 25·80 vs +3·01 ± 37·25 pmol/l, P = 0·04), homoeostasis model of assessment-insulin resistance (-0·61 ± 1·03 vs +0·11 ± 1·43, P = 0·04) and dehydroepiandrosterone sulphate (-3·64 ± 7·00 vs -0·59 ± 3·20 μmol/l, P = 0·03). Overall, 12 weeks of carnitine administration in PCOS women resulted in reductions in weight, BMI, WC and HC, and beneficial effects on glycaemic control; however, it did not affect lipid profiles or free testosterone. © 2015 John Wiley & Sons Ltd.

N-Acetyl-L-cysteine protects thyroid cells against DNA damage induced by external and internal irradiation.

PubMed

Kurashige, Tomomi; Shimamura, Mika; Nagayama, Yuji

2017-11-01

We evaluated the effect of the antioxidant N-acetyl-L-cysteine (NAC) on the levels of reactive oxygen species (ROS), DNA double strand breaks (DSB) and micronuclei (MN) induced by internal and external irradiation using a rat thyroid cell line PCCL3. In internal irradiation experiments, ROS and DSB levels increased immediately after 131 I addition and then gradually declined, resulting in very high levels of MN at 24 and 48 h. NAC administration both pre- and also post- 131 I addition suppressed ROS, DSB and MN. In external irradiation experiments with a low dose (0.5 Gy), ROS and DSB increased shortly and could be prevented by NAC administration pre-, but not post-irradiation. In contrast, external irradiation with a high dose (5 Gy) increased ROS and DSB in a bimodal way: ROS and DSB levels increased immediately after irradiation, quickly returned to the basal levels and gradually rose again after >24 h. The second phase was in parallel with an increase in 4-hydroxy-2-nonenal. The number of MN induced by the second wave of ROS/DSB elevations was much higher than that by the first peak. In this situation, NAC administered pre- and post-irradiation comparably suppressed MN induced by a delayed ROS elevation. In conclusion, a prolonged ROS increase during internal irradiation and a delayed ROS increase after external irradiation with a high dose caused serious DNA damage, which were efficiently prevented by NAC. Thus, NAC administration even both after internal or external irradiation prevents ROS increase and eventual DNA damage.

Composition, disintegrative properties, and labeling compliance of commercially available taurine and carnitine dietary products.

PubMed

Bragg, Rebecca R; Freeman, Lisa M; Fascetti, Andrea J; Yu, Zengshou

2009-01-15

To test the quality, disintegration properties, and compliance with labeling regulations for representative commercially available taurine and carnitine dietary products. Evaluation study. 11 commercially available taurine and 10 commercially available carnitine products. For each product, the amount of taurine or carnitine was determined and compared with the label claim. All products were evaluated for concentrations of mercury, arsenic, and selenium. Disintegration properties of 5 taurine and 8 carnitine products were determined in vitro. Labels were evaluated for compliance with FDA guidelines. 10 of 11 taurine and 10 of 10 carnitine products were within 10% of the stated label claim. Three of 11 taurine and 6 of 10 carnitine products were within 5% of the stated label claim. The median percentage difference between laboratory analysis and label claim was -5.7% (range, -26.3% to 2.5%) for taurine and 3.6% (range, -2.6% to 8.8%) for carnitine. No substantial amount of contamination with mercury, arsenic, or selenium was found in any of the products. During disintegration testing, 1 of 5 taurine products and 5 of 8 carnitine products did not disintegrate within 45 minutes during at least 1 test. Disintegration time for those that did disintegrate ranged from 1.7 to 37.0 minutes. All product labels conformed with FDA regulations. Taurine and carnitine products evaluated in this study closely adhered to manufacturer claims and labeling guidelines. However, disintegration testing suggested high variability in some products, possibly limiting uptake and use by animals that receive them.

Reengineering of the feedback-inhibition enzyme N-acetyl-L-glutamate kinase to enhance L-arginine production in Corynebacterium crenatum.

PubMed

Zhang, Jingjing; Xu, Meijuan; Ge, Xiaoxun; Zhang, Xian; Yang, Taowei; Xu, Zhenghong; Rao, Zhiming

2017-02-01

N-acetyl-L-glutamate kinase (NAGK) catalyzes the second step of L-arginine biosynthesis and is inhibited by L-arginine in Corynebacterium crenatum. To ascertain the basis for the arginine sensitivity of CcNAGK, residue E19 which located at the entrance of the Arginine-ring was subjected to site-saturated mutagenesis and we successfully illustrated the inhibition-resistant mechanism. Typically, the E19Y mutant displayed the greatest deregulation of L-arginine feedback inhibition. An equally important strategy is to improve the catalytic activity and thermostability of CcNAGK. For further strain improvement, we used site-directed mutagenesis to identify mutations that improve CcNAGK. Results identified variants I74V, F91H and K234T display higher specific activity and thermostability. The L-arginine yield and productivity of the recombinant strain C. crenatum SYPA-EH3 (which possesses a combination of all four mutant sites, E19Y/I74V/F91H/K234T) reached 61.2 and 0.638 g/L/h, respectively, after 96 h in 5 L bioreactor fermentation, an increase of approximately 41.8% compared with the initial strain.

Carnitine palmitoyltransferase II deficiency

PubMed Central

Roe, C R.; Yang, B-Z; Brunengraber, H; Roe, D S.; Wallace, M; Garritson, B K.

2008-01-01

Background: Carnitine palmitoyltransferase II (CPT II) deficiency is an important cause of recurrent rhabdomyolysis in children and adults. Current treatment includes dietary fat restriction, with increased carbohydrate intake and exercise restriction to avoid muscle pain and rhabdomyolysis. Methods: CPT II enzyme assay, DNA mutation analysis, quantitative analysis of acylcarnitines in blood and cultured fibroblasts, urinary organic acids, the standardized 36-item Short-Form Health Status survey (SF-36) version 2, and bioelectric impedance for body fat composition. Diet treatment with triheptanoin at 30% to 35% of total daily caloric intake was used for all patients. Results: Seven patients with CPT II deficiency were studied from 7 to 61 months on the triheptanoin (anaplerotic) diet. Five had previous episodes of rhabdomyolysis requiring hospitalizations and muscle pain on exertion prior to the diet (two younger patients had not had rhabdomyolysis). While on the diet, only two patients experienced mild muscle pain with exercise. During short periods of noncompliance, two patients experienced rhabdomyolysis with exercise. None experienced rhabdomyolysis or hospitalizations while on the diet. All patients returned to normal physical activities including strenuous sports. Exercise restriction was eliminated. Previously abnormal SF-36 physical composite scores returned to normal levels that persisted for the duration of the therapy in all five symptomatic patients. Conclusions: The triheptanoin diet seems to be an effective therapy for adult-onset carnitine palmitoyltransferase II deficiency. GLOSSARY ALT = alanine aminotransferase; AST = aspartate aminotransferase; ATP = adenosine triphosphate; BHP = β-hydroxypentanoate; BKP = β-ketopentanoate; BKP-CoA = β-ketopentanoyl–coenzyme A; BUN = blood urea nitrogen; CAC = citric acid cycle; CoA = coenzyme A; CPK = creatine phosphokinase; CPT II = carnitine palmitoyltransferase II; LDL = low-density lipoprotein; MCT

Investigation of electroacupuncture and manual acupuncture on carnitine and glutathione in muscle.

PubMed

Toda, Shizuo

2011-01-01

Electroacupuncture (EA) and manual acupuncture (MA) have therapeutic effects on muscle fatigue in muscle disease. The deficiencies of carnitine and glutathione induce muscle fatigue. This report investigated the effects of EA and MA on carnitine and glutathione in muscle. After the mice of EA group were fixed in the animal cage, right Zusanli (ST36) and Jiexi (ST41) were acupunctured and stimulated with uniform reinforcing and reducing method by twirling the acupuncture needle for 15 min. And then, the needle handles were connected to an electric stimulator for stimulating the acupoint with dense-sparse waves. After the mice of MA group were fixed in an animal cage, right ST36 and ST41 were acupunctured and allowed for 15 min. The mice of normal control group were not acupunctured and stimulated for 15 min. The mice of all groups were killed for collecting muscle tissue 1 h after the final treatment. Carnitine and glutathione in homogenate of muscle tissue were determined with carnitine (Kainos Laboratories Co., Tokyo, Japan) and glutathione assay kit (Dojin Chemicals Co., Kumamoto, Japan). Carnitine level in muscle tissue of MA group was significantly higher than those of EA group and normal control group. Carnitine level in muscle tissue of EA group was not significantly different from that of normal control group. Glutathione levels in muscle tissue of EA group and MA group were significantly higher than that of normal control group. This report presented that carnitine in muscle is increased by MA, and not increased by EA, and that glutathione in muscle is increased by EA and MA.

O-Acetylation of Arabidopsis Hemicellulose Xyloglucan Requires AXY4 or AXY4L, Proteins with a TBL and DUF231 Domain[W][OA

PubMed Central

Gille, Sascha; de Souza, Amancio; Xiong, Guangyan; Benz, Monique; Cheng, Kun; Schultink, Alex; Reca, Ida-Barbara; Pauly, Markus

2011-01-01

In an Arabidopsis thaliana forward genetic screen aimed at identifying mutants with altered structures of their hemicellulose xyloglucan (axy mutants) using oligosaccharide mass profiling, two nonallelic mutants (axy4-1 and axy4-2) that have a 20 to 35% reduction in xyloglucan O-acetylation were identified. Mapping of the mutation in axy4-1 identified AXY4, a type II transmembrane protein with a Trichome Birefringence-Like domain and a domain of unknown function (DUF231). Loss of AXY4 transcript results in a complete lack of O-acetyl substituents on xyloglucan in several tissues, except seeds. Seed xyloglucan is instead O-acetylated by the paralog AXY4like, as demonstrated by the analysis of the corresponding T-DNA insertional lines. Wall fractionation analysis of axy4 knockout mutants indicated that only a fraction containing xyloglucan is non-O-acetylated. Hence, AXY4/AXY4L is required for the O-acetylation of xyloglucan, and we propose that these proteins represent xyloglucan-specific O-acetyltransferases, although their donor and acceptor substrates have yet to be identified. An Arabidopsis ecotype, Ty-0, has reduced xyloglucan O-acetylation due to mutations in AXY4, demonstrating that O-acetylation of xyloglucan does not impact the plant’s fitness in its natural environment. The relationship of AXY4 with another previously identified group of Arabidopsis proteins involved in general wall O-acetylation, reduced wall acetylation, is discussed. PMID:22086088

Leptin Induces Oxidative Stress Through Activation of NADPH Oxidase in Renal Tubular Cells: Antioxidant Effect of L-Carnitine.

PubMed

Blanca, Antonio J; Ruiz-Armenta, María V; Zambrano, Sonia; Salsoso, Rocío; Miguel-Carrasco, José L; Fortuño, Ana; Revilla, Elisa; Mate, Alfonso; Vázquez, Carmen M

2016-10-01

Leptin is a protein involved in the regulation of food intake and in the immune and inflammatory responses, among other functions. Evidences demonstrate that obesity is directly associated with high levels of leptin, suggesting that leptin may directly link obesity with the elevated cardiovascular and renal risk associated with increased body weight. Adverse effects of leptin include oxidative stress mediated by activation of NADPH oxidase. The aim of this study was to evaluate the effect of L-carnitine (LC) in rat renal epithelial cells (NRK-52E) exposed to leptin in order to generate a state of oxidative stress characteristic of obesity. Leptin increased superoxide anion (O2 (•) -) generation from NADPH oxidase (via PI3 K/Akt pathway), NOX2 expression and nitrotyrosine levels. On the other hand, NOX4 expression and hydrogen peroxide (H2 O2 ) levels diminished after leptin treatment. Furthermore, the expression of antioxidant enzymes, catalase, and superoxide dismutase, was altered by leptin, and an increase in the mRNA expression of pro-inflammatory factors was also found in leptin-treated cells. LC restored all changes induced by leptin to those levels found in untreated cells. In conclusion, stimulation of NRK-52E cells with leptin induced a state of oxidative stress and inflammation that could be reversed by preincubation with LC. Interestingly, LC induced an upregulation of NOX4 and restored the release of its product, hydrogen peroxide, which suggests a protective role of NOX4 against leptin-induced renal damage. J. Cell. Biochem. 117: 2281-2288, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Neutralization of Schwann Cell-Secreted VEGF Is Protective to In Vitro and In Vivo Experimental Diabetic Neuropathy

PubMed Central

Taiana, Michela M.; Lombardi, Raffaella; Porretta-Serapiglia, Carla; Ciusani, Emilio; Oggioni, Norberto; Sassone, Jenny; Bianchi, Roberto; Lauria, Giuseppe

2014-01-01

The pathogenetic role of vascular endothelial growth factor (VEGF) in long-term retinal and kidney complications of diabetes has been demonstrated. Conversely, little is known in diabetic neuropathy. We examined the modulation of VEGF pathway at mRNA and protein level on dorsal root ganglion (DRG) neurons and Schwann cells (SC) induced by hyperglycaemia. Moreover, we studied the effects of VEGF neutralization on hyperglycemic DRG neurons and streptozotocin-induced diabetic neuropathy. Our findings demonstrated that DRG neurons were not affected by the direct exposition to hyperglycaemia, whereas showed an impairment of neurite outgrowth ability when exposed to the medium of SC cultured in hyperglycaemia. This was mediated by an altered regulation of VEGF and FLT-1 receptors. Hyperglycaemia increased VEGF and FLT-1 mRNA without changing their intracellular protein levels in DRG neurons, decreased intracellular and secreted protein levels without changing mRNA level in SC, while reduced the expression of the soluble receptor sFLT-1 both in DRG neurons and SC. Bevacizumab, a molecule that inhibits VEGF activity preventing the interaction with its receptors, restored neurite outgrowth and normalized FLT-1 mRNA and protein levels in co-cultures. In diabetic rats, it both prevented and restored nerve conduction velocity and nociceptive thresholds. We demonstrated that hyperglycaemia early affected neurite outgrowth through the impairment of SC-derived VEGF/FLT-1 signaling and that the neutralization of SC-secreted VEGF was protective both in vitro and in vivo models of diabetic neuropathy. PMID:25268360

Muscle carnitine availability plays a central role in regulating fuel metabolism in the rodent.

PubMed

Porter, Craig; Constantin-Teodosiu, Dumitru; Constantin, Despina; Leighton, Brendan; Poucher, Simon M; Greenhaff, Paul L

2017-09-01

Meldonium inhibits endogenous carnitine synthesis and tissue uptake, and accelerates urinary carnitine excretion, although the impact of meldonium-mediated muscle carnitine depletion on whole-body fuel selection, and muscle fuel metabolism and its molecular regulation is under-investigated. Ten days of oral meldonium administration did not impact on food or fluid intake, physical activity levels or body weight gain in the rat, whereas it depleted muscle carnitine content (all moieties), increased whole-body carbohydrate oxidation and muscle and liver glycogen utilization, and reduced whole-body fat oxidation. Meldonium reduced carnitine transporter protein expression across muscles of different contractile and metabolic phenotypes. A TaqMan PCR low-density array card approach revealed the abundance of 189 mRNAs regulating fuel selection was altered in soleus muscle by meldonium, highlighting the modulation of discrete cellular functions and metabolic pathways. These novel findings strongly support the premise that muscle carnitine availability is a primary regulator of fuel selection in vivo. The body carnitine pool is primarily confined to skeletal muscle, where it regulates carbohydrate (CHO) and fat usage. Meldonium (3-(2,2,2-trimethylhydrazinium)-propionate) inhibits carnitine synthesis and tissue uptake, although the impact of carnitine depletion on whole-body fuel selection, muscle fuel metabolism and its molecular regulation is under-investigated. Male lean Zucker rats received water (control, n = 8) or meldonium-supplemented water (meldonium, n = 8) for 10 days [1.6 g kg -1 body mass (BM) day -1 days 1-2, 0.8 g kg -1  BM day -1 thereafter]. From days 7-10, animals were housed in indirect calorimetry chambers after which soleus muscle and liver were harvested. Food and fluid intake, weight gain and physical activity levels were similar between groups from days 7 to 10. Compared to control, meldonium depleted muscle total carnitine (P < 0

Efficacy and Safety of L-Carnitine Treatment for Chronic Heart Failure: A Meta-Analysis of Randomized Controlled Trials.

PubMed

Song, Xiaolong; Qu, Huiyan; Yang, Zongguo; Rong, Jingfeng; Cai, Wan; Zhou, Hua

2017-01-01

Background . Whether additional benefit can be achieved with the use of L-carnitine (L-C) in patients with chronic heart failure (CHF) remains controversial. We therefore performed a meta-analysis of randomized controlled trials (RCTs) to evaluate the effects of L-C treatment in CHF patients. Methods . Pubmed, Ovid Embase, Web of Science, and Cochrane Library databases, Chinese National Knowledge Infrastructure (CNKI) database, Wanfang database, Chinese Biomedical (CBM) database, and Chinese Science and Technology Periodicals database (VIP) until September 30, 2016, were identified. Studies that met the inclusion criteria were systematically evaluated by two reviewers independently. Results . 17 RCTs with 1625 CHF patients were included in this analysis. L-C treatment in CHF was associated with considerable improvement in overall efficacy (OR = 3.47, P < 0.01), left ventricular ejection fraction (LVEF) (WMD: 4.14%, P = 0.01), strike volume (SV) (WMD: 8.21 ml, P = 0.01), cardiac output (CO) (WMD: 0.88 L/min, P < 0.01), and E/A (WMD: 0.23, P < 0.01). Moreover, treatment with L-C also resulted in significant decrease in serum levels of BNP (WMD: -124.60 pg/ml, P = 0.01), serum levels of NT-proBNP (WMD: -510.36 pg/ml, P < 0.01), LVESD (WMD: -4.06 mm, P < 0.01), LVEDD (WMD: -4.79 mm, P < 0.01), and LVESV (WMD: -20.16 ml, 95% CI: -35.65 to -4.67, P < 0.01). However, there were no significant differences in all-cause mortality, 6-minute walk, and adverse events between L-C and control groups. Conclusions . L-C treatment is effective for CHF patients in improving clinical symptoms and cardiac functions, decreasing serum levels of BNP and NT-proBNP. And it has a good tolerance.

Exacerbation of Charcot-Marie-Tooth type 2E neuropathy following traumatic nerve injury.

PubMed

Villalón, Eric; Dale, Jeffrey M; Jones, Maria; Shen, Hailian; Garcia, Michael L

2015-11-19

Charcot-Marie-Tooth disease (CMT) is the most commonly inherited peripheral neuropathy. CMT disease signs include distal limb neuropathy, abnormal gait, sensory defects, and deafness. We generated a novel line of CMT2E mice expressing hNF-L(E397K), which displayed muscle atrophy of the lower limbs without denervation, proximal reduction in large caliber axons, and decreased nerve conduction velocity. In this study, we challenged wild type, hNF-L and hNF-L(E397K) mice with crush injury to the sciatic nerve. We analyzed functional recovery by measuring toe spread and analyzed gait using the Catwalk system. hNF-L(E397K) mice demonstrated reduced recovery from nerve injury consistent with increased susceptibility to neuropathy observed in CMT patients. In addition, hNF-L(E397K) developed a permanent reduction in their ability to weight bear, increased mechanical allodynia, and premature gait shift in the injured limb, which led to increasingly disrupted interlimb coordination in hNF-L(E397K). Exacerbation of neuropathy after injury and identification of gait alterations in combination with previously described pathology suggests that hNF-L(E397K) mice recapitulate many of clinical signs associated with CMT2. Therefore, hNF-L(E397K) mice provide a model for determining the efficacy of novel therapies. Copyright © 2015 Elsevier B.V. All rights reserved.

Lactose-egg yolk diluent supplemented with N-acetyl-D-glucosamine affect acrosome morphology and motility of frozen-thawed boar sperm.

PubMed

Yi, Y J; Im, G S; Park, C S

2002-12-16

These experiments were carried out to investigate the effect of N-acetyl-D-glucosamine, and to obtain additional information about the effect of orvus es paste (OEP) and egg yolk concentration in the freezing of boar sperm in the maxi-straw. The highest post-thaw acrosomes of normal apical ridge (NAR) and motility were obtained with 0.025 or 0.05% N-acetyl-D-glucosamine concentration in the first diluent. However, there were no effects of N-acetyl-D-glucosamine among the diluents with or without N-acetyl-D-glucosamine at the second dilution. The N-acetyl-D-glucosamine in the first and second diluents was added at room temperatures (20-23 degrees C) and 5 degrees C, respectively. It is suggested that the temperature of N-acetyl-D-glucosamine addition is important for the effect of boar sperm protection during freezing and thawing. When the 0.05% N-acetyl-D-glucosamine was supplemented in the first diluent, the optimum final OEP content was 0.5%. The optimum content of egg yolk in the diluent with 0.05% N-acetyl-D-glucosamine concentration was 20% and egg yolk was one of the main cryoprotective agents. In conclusion, we found out that the diluent with 0.025 or 0.05% soluble N-acetyl-D-glucosamine in the first diluent, 0.5% final orvus es paste concentration and 20% egg yolk concentration significantly enhanced NAR acrosomes and motility of boar sperm after freezing and thawing. Copyright 2002 Elsevier Science B.V.

Computational Study of Environmental Effects on Torsional Free Energy Surface of N-Acetyl-N'-methyl-L-alanylamide Dipeptide

ERIC Educational Resources Information Center

Carlotto, Silvia; Zerbetto, Mirco

2014-01-01

We propose an articulated computational experiment in which both quantum mechanics (QM) and molecular mechanics (MM) methods are employed to investigate environment effects on the free energy surface for the backbone dihedral angles rotation of the small dipeptide N-Acetyl-N'-methyl-L-alanylamide. This computation exercise is appropriate for an…

Investigation of Electroacupuncture and Manual Acupuncture on Carnitine and Glutathione in Muscle

PubMed Central

Toda, Shizuo

2011-01-01

Electroacupuncture (EA) and manual acupuncture (MA) have therapeutic effects on muscle fatigue in muscle disease. The deficiencies of carnitine and glutathione induce muscle fatigue. This report investigated the effects of EA and MA on carnitine and glutathione in muscle. After the mice of EA group were fixed in the animal cage, right Zusanli (ST36) and Jiexi (ST41) were acupunctured and stimulated with uniform reinforcing and reducing method by twirling the acupuncture needle for 15 min. And then, the needle handles were connected to an electric stimulator for stimulating the acupoint with dense-sparse waves. After the mice of MA group were fixed in an animal cage, right ST36 and ST41 were acupunctured and allowed for 15 min. The mice of normal control group were not acupunctured and stimulated for 15 min. The mice of all groups were killed for collecting muscle tissue 1 h after the final treatment. Carnitine and glutathione in homogenate of muscle tissue were determined with carnitine (Kainos Laboratories Co., Tokyo, Japan) and glutathione assay kit (Dojin Chemicals Co., Kumamoto, Japan). Carnitine level in muscle tissue of MA group was significantly higher than those of EA group and normal control group. Carnitine level in muscle tissue of EA group was not significantly different from that of normal control group. Glutathione levels in muscle tissue of EA group and MA group were significantly higher than that of normal control group. This report presented that carnitine in muscle is increased by MA, and not increased by EA, and that glutathione in muscle is increased by EA and MA. PMID:19592478

Hereditary sensory neuropathy type I.

PubMed

Auer-Grumbach, Michaela

2008-03-18

Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin

Hereditary sensory neuropathy type I

PubMed Central

Auer-Grumbach, Michaela

2008-01-01

Hereditary sensory neuropathy type I (HSN I) is a slowly progressive neurological disorder characterised by prominent predominantly distal sensory loss, autonomic disturbances, autosomal dominant inheritance, and juvenile or adulthood disease onset. The exact prevalence is unknown, but is estimated as very low. Disease onset varies between the 2nd and 5th decade of life. The main clinical feature of HSN I is the reduction of sensation sense mainly distributed to the distal parts of the upper and lower limbs. Variable distal muscle weakness and wasting, and chronic skin ulcers are characteristic. Autonomic features (usually sweating disturbances) are invariably observed. Serious and common complications are spontaneous fractures, osteomyelitis and necrosis, as well as neuropathic arthropathy which may even necessitate amputations. Some patients suffer from severe pain attacks. Hypacusis or deafness, or cough and gastrooesophageal reflux have been observed in rare cases. HSN I is a genetically heterogenous condition with three loci and mutations in two genes (SPTLC1 and RAB7) identified so far. Diagnosis is based on the clinical observation and is supported by a family history. Nerve conduction studies confirm a sensory and motor neuropathy predominantly affecting the lower limbs. Radiological studies, including magnetic resonance imaging, are useful when bone infections or necrosis are suspected. Definitive diagnosis is based on the detection of mutations by direct sequencing of the SPTLC1 and RAB7 genes. Correct clinical assessment and genetic confirmation of the diagnosis are important for appropriate genetic counselling and prognosis. Differential diagnosis includes the other hereditary sensory and autonomic neuropathies (HSAN), especially HSAN II, as well as diabetic foot syndrome, alcoholic neuropathy, neuropathies caused by other neurotoxins/drugs, immune mediated neuropathy, amyloidosis, spinal cord diseases, tabes dorsalis, lepra neuropathy, or decaying skin

Dynamics of L-Carnitine in Plasma and Urine in Patients Undergoing Cisplatin Chemotherapy.

PubMed

Gomi, Daisuke; Tanaka, Aika; Fukushima, Toshirou; Kobayashi, Takashi; Matsushita, Hirohide; Sekiguchi, Nodoka; Sakamoto, Akiyuki; Sasaki, Shigeru; Mamiya, Keiko; Koizumi, Tomonobu

2017-01-01

Several studies have indicated that cisplatin (cis-diamminedichloroplatinum II; CDDP) causes urinary excretion of L-carnitine (LC). However, the underlying cofactors affecting the increased urinary excretion remain unclear. The present study was performed to evaluate the dynamics of LC in plasma and urine after CDDP chemotherapy and to examine the relations with clinical parameters, such as gender, body mass index (BMI), and renal function. Twenty-two patients treated with CDDP therapy were selected. Blood and urine samples were taken from patients before starting CDDP treatment (day 0), on the next day (day 1), and on the seventh day (day 7). We measured plasma and urine concentrations of total, free, and acyl-LC, and examined the relationships with gender, age, treatment cycle, skeletal muscle mass, BMI, glomerular filtration rate, and change in creatinine concentration after CDDP administration. Both urinary and plasma concentrations of 3 types of LC increased markedly on day 1 and subsequently reverted to the pre-CDDP level on day 7. There was a positive correlation between the % changes in plasma and urine LC (correlation coefficient 0.59, p = 0.003) on day 1, but no significant relations were seen in other clinical parameters. CDDP transiently increased plasma LC levels. The mechanism seemed to involve recruitment for marked urinary loss of LC. However, these changes in plasma and urinary LC levels were not related to clinical factors, suggesting that the dynamics of LC were independent of preexisting physical parameters. © 2017 S. Karger AG, Basel.

Global profiling of lysine acetylation in human histoplasmosis pathogen Histoplasma capsulatum.

PubMed

Xie, Longxiang; Fang, Wenjie; Deng, Wanyan; Yu, Zhaoxiao; Li, Juan; Chen, Min; Liao, Wanqing; Xie, Jianping; Pan, Weihua

2016-04-01

Histoplasma capsulatum is the causative agent of human histoplasmosis, which can cause respiratory and systemic mycosis in immune-compromised individuals. Lysine acetylation, a protein posttranslational protein modification, is widespread in both eukaryotes and prokaryotes. Although increasing evidence suggests that lysine acetylation may play critical roles in fungus physiology, very little is known about its extent and function in H. capsulatum. To comprehensively profile protein lysine acetylation in H. capsulatum, we performed a global acetylome analysis through peptide prefractionation, antibody enrichment, and LC-MS/MS analysis, identifying 775 acetylation sites on 456 acetylated proteins; and functionally analysis showing their involvement in different biological processes. We defined six types of acetylation site motifs, and the results imply that lysine residue of polypeptide with tyrosine at the -1 and +1 positions, histidine at the +1 position, and phenylalanine (F) at the +1 and +2 position is a preferred substrate of lysine acetyltransferase. Moreover, some virulence factors candidates including calmodulin and DnaK are acetylated. In conclusion, our data set may serve as an important resource for the elucidation of associations between functional protein lysine acetylation and virulence in H. capsulatum. Copyright © 2016 Elsevier Ltd. All rights reserved.

Assessment Tools for Peripheral Neuropathy in Pediatric Oncology: A Systematic Review From the Children's Oncology Group.

PubMed

Smolik, Suzanne; Arland, Lesley; Hensley, Mary Ann; Schissel, Debra; Shepperd, Barbara; Thomas, Kristin; Rodgers, Cheryl

Peripheral neuropathy is a known side effect of several chemotherapy agents, including vinca alkaloids and platinum-based chemotherapy. Early recognition and monitoring of this side effect is an important role of the pediatric oncology nurse. There are a variety of peripheral neuropathy assessment tools currently in use, but the usefulness of these tools in identifying and grading neuropathy in children varies, and there is currently no standardized tool in place to evaluate peripheral neuropathy in pediatric oncology. A systematic review was performed to identify the peripheral neuropathy assessment tools that best evaluate the early onset and progression of peripheral neuropathy in pediatric patients receiving vincristine. Because of the limited information available in pediatric oncology, this review was extended to any pediatric patient with neuropathy. A total of 8 studies were included in the evidence synthesis. Based on available evidence, the pediatric-modified Total Neuropathy Scale (ped-m TNS) and the Total Neuropathy Score-pediatric version (TNS-PV) are recommended for the assessment of vincristine-induced peripheral neuropathy in children 6 years of age and older. In addition, several studies demonstrated that subjective symptoms alone are not adequate to assess for vincristine-induced peripheral neuropathy. Nursing assessment of peripheral neuropathy should be an integral and regular part of patient care throughout the course of chemotherapy treatment.

A novel curcumin derivative for the treatment of diabetic neuropathy.

PubMed

Daugherty, Daniel J; Marquez, Alexandra; Calcutt, Nigel A; Schubert, David

2018-02-01

Neuropathy is a common complication of long-term diabetes. Proposed mechanisms of neuronal damage caused by diabetes that are downstream of hyperglycemia and/or loss of insulin signaling include ischemic hypoxia, inflammation and loss of neurotrophic support. The curcumin derivative J147 is a potent neurogenic and neuroprotective drug candidate initially developed for the treatment of neurodegenerative conditions associated with aging that impacts many pathways implicated in the pathogenesis of diabetic neuropathy. Here, we demonstrate efficacy of J147 in ameliorating multiple indices of neuropathy in the streptozotocin-induced mouse model of type 1 diabetes. Diabetes was determined by blood glucose, HbA1c, and insulin levels and efficacy of J147 by behavioral, physiologic, biochemical, proteomic, and transcriptomic assays. Biological efficacy of systemic J147 treatment was confirmed by its capacity to decrease TNFα pathway activation and several other markers of neuroinflammation in the CNS. Chronic oral treatment with J147 protected the sciatic nerve from progressive diabetes-induced slowing of large myelinated fiber conduction velocity while single doses of J147 rapidly and transiently reversed established touch-evoked allodynia. Conduction slowing and allodynia are clinically relevant markers of early diabetic neuropathy and neuropathic pain, respectively. RNA expression profiling suggests that one of the pathways by which J147 imparts its protection against diabetic induced neuropathy may be through activation of the AMP kinase pathway. The diverse biological and therapeutic effects of J147 suggest it as an alternative to the polypharmaceutical approaches required to treat the multiple pathogenic mechanisms that contribute to diabetic neuropathy. Copyright © 2017 Elsevier Ltd. All rights reserved.

Pharmacological Treatment of Painful HIV-Associated Sensory Neuropathy: A Systematic Review and Meta-Analysis of Randomised Controlled Trials

PubMed Central

Phillips, Tudor J. C.; Cherry, Catherine L.; Cox, Sarah; Marshall, Sarah J.; Rice, Andrew S. C.

2010-01-01

Background Significant pain from HIV-associated sensory neuropathy (HIV-SN) affects ∼40% of HIV infected individuals treated with antiretroviral therapy (ART). The prevalence of HIV-SN has increased despite the more widespread use of ART. With the global HIV prevalence estimated at 33 million, and with infected individuals gaining increased access to ART, painful HIV-SN represents a large and expanding world health problem. There is an urgent need to develop effective pain management strategies for this condition. Method and Findings Objective: To evaluate the clinical effectiveness of analgesics in treating painful HIV-SN. Design: Systematic review and meta-analysis. Data sources: Medline, Cochrane central register of controlled trials, www.clinicaltrials.gov, www.controlled-trials.com and the reference lists of retrieved articles. Selection criteria: Prospective, double-blinded, randomised controlled trials (RCTs) investigating the pharmacological treatment of painful HIV-SN with sufficient quality assessed using a modified Jadad scoring method. Review methods: Four authors assessed the eligibility of articles for inclusion. Agreement of inclusion was reached by consensus and arbitration. Two authors conducted data extraction and analysis. Dichotomous outcome measures (≥30% and ≥50% pain reduction) were sought from RCTs reporting interventions with statistically significant efficacies greater than placebo. These data were used to calculate RR and NNT values. Results Of 44 studies identified, 19 were RCTs. Of these, 14 fulfilled the inclusion criteria. Interventions demonstrating greater efficacy than placebo were smoked cannabis NNT 3.38 95%CI(1.38 to 4.10), topical capsaicin 8%, and recombinant human nerve growth factor (rhNGF). No superiority over placebo was reported in RCTs that examined amitriptyline (100mg/day), gabapentin (2.4g/day), pregabalin (1200mg/day), prosaptide (16mg/day), peptide-T (6mg/day), acetyl-L-carnitine (1g/day), mexilitine (600mg

Alcoholic neuropathy: possible mechanisms and future treatment possibilities

PubMed Central

Chopra, Kanwaljit; Tiwari, Vinod

2012-01-01

Chronic alcohol consumption produces painful peripheral neuropathy for which there is no reliable successful therapy, mainly due to lack of understanding of its pathobiology. Alcoholic neuropathy involves coasting caused by damage to nerves that results from long term excessive drinking of alcohol and is characterized by spontaneous burning pain, hyperalgesia and allodynia. The mechanism behind alcoholic neuropathy is not well understood, but several explanations have been proposed. These include activation of spinal cord microglia after chronic alcohol consumption, oxidative stress leading to free radical damage to nerves, activation of mGlu5 receptors in the spinal cord and activation of the sympathoadrenal and hypothalamo-pituitary-adrenal (HPA) axis. Nutritional deficiency (especially thiamine deficiency) and/or the direct toxic effect of alcohol or both have also been implicated in alcohol-induced neuropathic pain. Treatment is directed towards halting further damage to the peripheral nerves and restoring their normal functioning. This can be achieved by alcohol abstinence and a nutritionally balanced diet supplemented by all B vitamins. However, in the setting of ongoing alcohol use, vitamin supplementation alone has not been convincingly shown to be sufficient for improvement in most patients. The present review is focused around the multiple pathways involved in the development of peripheral neuropathy associated with chronic alcohol intake and the different therapeutic agents which may find a place in the therapeutic armamentarium for both prevention and management of alcoholic neuropathy. PMID:21988193

Quality of Life in Patients with Gluten Neuropathy: A Case-Controlled Study.

PubMed

Zis, Panagiotis; Sarrigiannis, Ptolemaios Georgios; Rao, Dasappaiah Ganesh; Hadjivassiliou, Marios

2018-05-23

Gluten neuropathy (GN) is defined as an otherwise idiopathic peripheral neuropathy in the presence of serological evidence of gluten sensitivity (positive native gliadin antibodies and/or transglutaminase or endomysium antibodies). We aimed to compare the quality of life (QoL) of GN patients with that of control subjects and to investigate the effects of a gluten-free diet (GFD) on the QoL. All consecutive patients with GN attending a specialist neuropathy clinic were invited to participate. The Overall Neuropathy Limitations Scale (ONLS) was used to assess the severity of the neuropathy. The 36-Item Short Form Survey (SF-36) questionnaire was used to measure participants’ QoL. A strict GFD was defined as effectively being able to eliminate all circulating gluten sensitivity-related antibodies. Fifty-three patients with GN and 53 age- and gender-matched controls were recruited. Compared to controls, GN patients showed significantly worse scores in the physical functioning, role limitations due to physical health, energy/fatigue, and general health subdomains of the SF-36. After adjusting for age, gender, and disease severity, being on a strict GFD correlated with better SF-36 scores in the pain domain of the SF-36 (beta 0.317, p = 0.019) and in the overall health change domain of the SF-36 (beta 0.306, p = 0.017). In GN patients, physical dysfunctioning is the major determinant of poor QoL compared to controls. Routine checking of the elimination of gluten sensitivity-related antibodies that results from a strict GFD should be encouraged, as such elimination ameliorates the overall pain and health scores, indicating a better QoL.

Chemotherapy-Induced Peripheral Neuropathy in Long-term Survivors of Childhood Cancer: Clinical, Neurophysiological, Functional, and Patient-Reported Outcomes.

PubMed

Kandula, Tejaswi; Farrar, Michelle Anne; Cohn, Richard J; Mizrahi, David; Carey, Kate; Johnston, Karen; Kiernan, Matthew C; Krishnan, Arun V; Park, Susanna B

2018-05-14

In light of the excellent long-term survival of childhood cancer patients, it is imperative to screen for factors affecting health, function, and quality of life in long-term survivors. To comprehensively assess chemotherapy-induced peripheral neuropathy in childhood cancer survivors to define disease burden and functional effect and to inform screening recommendations. In this cross-sectional observational study, cancer survivors who were treated with chemotherapy for extracranial malignancy before age 17 years were recruited consecutively between April 2015 and December 2016 from a single tertiary hospital-based comprehensive cancer survivorship clinic and compared with healthy age-matched controls. Investigators were blinded to the type of chemotherapy. A total of 169 patients met inclusion criteria, of whom 48 (28.4%) were unable to be contacted or declined participation. Chemotherapy agents known to be toxic to peripheral nerves. The clinical peripheral neurological assessment using the Total Neuropathy Score was compared between recipients of different neurotoxic chemotherapy agents and control participants and was correlated with neurophysiological, functional, and patient-reported outcome measures. Of the 121 childhood cancer survivors included in this study, 65 (53.7%) were male, and the cohort underwent neurotoxicity assessments at a median (range) age of 16 (7-47) years, a median (range) 8.5 (1.5-29) years after treatment completion. Vinca alkaloids and platinum compounds were the main neurotoxic agents. Clinical abnormalities consistent with peripheral neuropathy were common, seen in 54 of 107 participants (50.5%) treated with neurotoxic chemotherapy (mean Total Neuropathy Score increase, 2.1; 95% CI, 1.4-2.9; P < .001), and were associated with lower limb predominant sensory axonal neuropathy (mean amplitude reduction, 5.8 μV; 95% CI, 2.8-8.8; P < .001). Functional deficits were seen in manual dexterity, distal sensation, and balance. Patient

N-acetyl-L-cysteine combined with mesalamine in the treatment of ulcerative colitis: Randomized, placebo-controlled pilot study

PubMed Central

Guijarro, Luis G; Mate, Jose; Gisbert, Javier P; Perez-Calle, Jose Luis; Marín-Jimenez, Ignacio; Arriaza, Encarna; Olleros, Tomás; Delgado, Mario; Castillejo, Maria S; Prieto-Merino, David; Lara, Venancio Gonzalez; Peña, Amado Salvador

2008-01-01

AIM: To evaluate the effectiveness and safety of oral N-acetyl-L-cysteine (NAC) co-administration with mesalamine in ulcerative colitis (UC) patients. METHODS: Thirty seven patients with mild to moderate UC were randomized to receive a four-wk course of oral mesalamine (2.4 g/d) plus N-acetyl-L-cysteine (0.8 g/d) (group A) or mesalamine plus placebo (group B). Patients were monitored using the Modified Truelove-Witts Severity Index (MTWSI). The primary endpoint was clinical remission (MTWSI ≤ 2) at 4 wk. Secondary endpoints were clinical response (defined as a reduction from baseline in the MTWSI of ≥ 2 points) and drug safety. The serum TNF-α, interleukin-6, interleukin-8 and MCP-1 were evaluated at baseline and at 4 wk of treatment. RESULTS: Analysis per-protocol criteria showed clinical remission rates of 63% and 50% after 4 wk treatment with mesalamine plus N-acetyl-L-cysteine (group A) and mesalamine plus placebo (group B) respectively (OR = 1.71; 95% CI: 0.46 to 6.36; P = 0.19; NNT = 7.7). Analysis of variance (ANOVA) of data indicated a significant reduction of MTWSI in group A (P = 0.046) with respect to basal condition without significant changes in the group B (P = 0.735) during treatment. Clinical responses were 66% (group A) vs 44% (group B) after 4 wk of treatment (OR = 2.5; 95% CI: 0.64 to 9.65; P = 0.11; NNT = 4.5). Clinical improvement in group A correlated with a decrease of IL-8 and MCP-1. Rates of adverse events did not differ significantly between both groups. CONCLUSION: In group A (oral NAC combined with mesalamine) contrarily to group B (mesalamine alone), the clinical improvement correlates with a decrease of chemokines such as MCP-1 and IL-8. NAC addition not produced any side effects. PMID:18473409

Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in healthy geriatric cats fed reduced protein foods enriched with fish oil, L-carnitine, and medium-chain triglycerides.

PubMed

Hall, J A; Yerramilli, M; Obare, E; Yerramilli, M; Yu, S; Jewell, D E

2014-12-01

The purpose of this study was to determine whether feeding cats reduced protein and phosphorus foods with added fish oil, L-carnitine, and medium-chain triglycerides (MCT) altered serum biomarkers of renal function. Thirty-two healthy cats, mean age 14.0 (8.3-19.6) years, were fed control food or one of two experimental foods for 6 months. All foods had similar concentrations of moisture, protein, and fat (approximately 8.0%, 26.5%, and 20.0%, respectively). Both experimental foods contained added fish oil (1.5%) and L-carnitine (500 mg/kg). Experimental-food 2 also contained increased MCT (10.5% from coconut oil), 1.5% added corn oil, and reduced animal fat. Glomerular filtration rate (GFR), serum biochemistries, renal function biomarkers including serum creatinine (sCr) and symmetrical dimethylarginine (SDMA), and plasma metabolomic profiles were measured at baseline, and at 1.5, 3, and 6 months. Body composition was determined by dual-energy X-ray absorptiometry. Although both experimental foods altered plasma fatty acids, carnitine and related metabolites, and lysophospholipid concentrations, there were no changes in renal function biomarkers. There was, however, a benefit in using SDMA versus sCr to assess renal function in older cats with less total lean mass. Compared with cats <12 years, those >15 years had lower total lean mass (P < 0.01), lower GFR (P = 0.04), and lower sCr concentrations (P < 0.01). However, SDMA concentrations (P < 0.01) were higher in older cats. This study shows that in cats, serum SDMA concentration is more highly correlated with GFR than sCr concentration, and, unlike sCr, which declines with age because of muscle wasting, SDMA increases as GFR declines with age. Copyright © 2014 Elsevier Ltd. All rights reserved.

Toxicity of cephaloridine to carnitine transport and fatty acid metabolism in rabbit renal cortical mitochondria: structure-activity relationships.

PubMed

Tune, B M; Hsu, C Y

1994-09-01

Cephaloridine (Cld), the most widely studied nephrotoxic cephalosporin, has significant structural homology with carnitine, which facilitates the transport of long-chain fatty acids into the mitochondrial inner matrix. Because of this homology, and evidence of a role of lipids in cephaloglycin (Cgl) nephrotoxicity, protocols were designed to compare the effects of Cld and Cgl on renal cortical mitochondrial carnitine transport, on long-chain fatty acylcarnitine-mediated respiration and on the in situ mitochondrial pools and urinary excretion of carnitine and acylcarnitines. The following was found: 1) both cephalosporins reduced carnitine-facilitated pyruvate oxidation (CFPO) and palmitoylcarnitine-mediated respiration (PCMR) by 40 to 50% in mitochondria exposed in vivo (300 mg/kg b.wt., 1 hr). CFPO could be decreased by reduction of carnitine uptake, pyruvate oxidation or carnitine acetyltransferase activity; 2) neither cephalosporin reduced mitochondrial carnitine acetyltransferase or carnitine palmitoyltransferase; 3) with in vitro exposure (2000 micrograms/ml, immediate effect) Cgl had no significant toxicity to mitochondrial CFPO. Cld inhibited CFPO in a dose-dependent manner, up to 100% at 2000 micrograms/ml; this effect was reduced by increasing carnitine concentrations; 4) in vitro Cld prevented the potentiation of PCMR by preloading with carnitine, reduced mitochondrial acetylcarnitine/carnitine exchange by 70% and reduced PCMR by 30%; 5) in vivo Cld increased mitochondrial-free carnitine in the in situ kidney by 100%; and 6) in vivo Cld increased the fractional renal excretion of carnitine from 0 +/- 0 to 0.29 +/- 0.03 and the fractional excretion of long-chain acylcarnitines from 0.06 +/- 0.01 to 0.79 +/- 0.17.(ABSTRACT TRUNCATED AT 250 WORDS)

Acupuncture and Reflexology for Chemotherapy-Induced Peripheral Neuropathy in Breast Cancer

PubMed Central

Ben-Horin, Idan; Kahan, Peretz; Ryvo, Larisa; Inbar, Moshe; Lev-Ari, Shahar; Geva, Ravit

2017-01-01

Background: Treatment of chemotherapy-induced peripheral neuropathy (CIPN), which affects approximately 30% to 40% of patients treated with neuropathy-causing agents, is mainly symptomatic. Currently available interventions are of little benefit. Study Design: This study was conducted as a retrospective analysis of the efficacy of acupuncture and reflexology in alleviating CIPN in breast cancer patients. Methods: Medical records of 30 consecutive breast cancer patients who received both chemotherapy and treatment for CIPN according to our Acupuncture and Reflexology Treatment for Neuropathy (ART-N) protocol between 2011 and 2012 were reviewed. Symptom severity was rated at baseline, during, and after treatment. Results: The records of 30 breast cancer patients who had been concomitantly treated with chemotherapy and ART-N for CIPN were retrieved. Two records were incomplete, leaving a total of 28 patients who were enrolled into the study. Twenty patients (71%) had sensory neuropathy, 7 (25%) had motor neuropathy, and 1 (4%) had both sensory and motor neuropathy. Only 2 (10%) of the 20 patients with grades 1 to 2 neuropathy still reported symptoms at 12 months since starting the ART-N protocol. All 8 patients who presented with grades 3 to 4 neuropathy were symptom-free at the 12-month evaluation. Overall, 26 patients (93%) had complete resolution of CIPN symptoms. Conclusion: The results of this study demonstrated that a joint protocol of acupuncture and reflexology has a potential to improve symptoms of CIPN in breast cancer patients. The protocol should be validated on a larger cohort with a control group. It also warrants testing as a preventive intervention. PMID:28150504

Acupuncture and Reflexology for Chemotherapy-Induced Peripheral Neuropathy in Breast Cancer.

PubMed

Ben-Horin, Idan; Kahan, Peretz; Ryvo, Larisa; Inbar, Moshe; Lev-Ari, Shahar; Geva, Ravit

2017-09-01

Treatment of chemotherapy-induced peripheral neuropathy (CIPN), which affects approximately 30% to 40% of patients treated with neuropathy-causing agents, is mainly symptomatic. Currently available interventions are of little benefit. This study was conducted as a retrospective analysis of the efficacy of acupuncture and reflexology in alleviating CIPN in breast cancer patients. Medical records of 30 consecutive breast cancer patients who received both chemotherapy and treatment for CIPN according to our Acupuncture and Reflexology Treatment for Neuropathy (ART-N) protocol between 2011 and 2012 were reviewed. Symptom severity was rated at baseline, during, and after treatment. The records of 30 breast cancer patients who had been concomitantly treated with chemotherapy and ART-N for CIPN were retrieved. Two records were incomplete, leaving a total of 28 patients who were enrolled into the study. Twenty patients (71%) had sensory neuropathy, 7 (25%) had motor neuropathy, and 1 (4%) had both sensory and motor neuropathy. Only 2 (10%) of the 20 patients with grades 1 to 2 neuropathy still reported symptoms at 12 months since starting the ART-N protocol. All 8 patients who presented with grades 3 to 4 neuropathy were symptom-free at the 12-month evaluation. Overall, 26 patients (93%) had complete resolution of CIPN symptoms. The results of this study demonstrated that a joint protocol of acupuncture and reflexology has a potential to improve symptoms of CIPN in breast cancer patients. The protocol should be validated on a larger cohort with a control group. It also warrants testing as a preventive intervention.

L-carnitine is a survival factor for chilled storage of rooster semen for a long time.

PubMed

Fattah, A; Sharafi, M; Masoudi, R; Shahverdi, A; Esmaeili, V

2017-02-01

Rooster sperm is sensitive to cooling, which restricts procedures to store sperms for extended periods of time for artificial insemination of commercial flocks. This study was conducted to evaluate the suitability of adding L-carnitine (LC) to chilled-storage of rooster sperm and its effects on sperm quality parameters and its fertility potential during storage at 5 °C. Pooled semen from roosters were divided into six equal aliquots and diluted with media supplemented with different concentrations of LC (0, 0.5, 1, 2, 4 and 8 mM LC). Diluted semen samples were cooled to 5 °C and stored over 48 h. Motility, viability, membrane functionality, lipid peroxidation and mitochondria activity of the sperm were assessed at 0, 24 and 48 h of storage. Moreover, fertility potential of chilled stored sperm was considered at 24 h of storage. While sperm quality was not affected by LC at the beginning of storage (0 h), supplementation of extender with 1 and 2 mM of LC significantly improved the percentage of sperm motility, viability, membrane integrity and mitochondria activity at 24 h and 48 h compared to other groups. Lipid peroxidation was significantly reduced in sperm samples diluted with 1 and 2 mM LC at 24 h (2.15 ± 0.52 nmol/ml and 2.21 ± 0.52 nmol/ml) and 48 h (3.42 ± 0.49 nmol/ml and 3.38 ± 0.49 nmol/ml) compared to other groups. Furthermore, fertility rates during artificial insemination using sperms cooled for 24 h in the presence of 1 and 2 mM LC were significantly higher (78%) than in the control group (64%). These findings suggest that optimum doses of LC could protect rooster sperm against cool storage-induced functional and structural damages. Copyright © 2016 Elsevier Inc. All rights reserved.

Newer anti-epileptic drugs, vitamin status and neuropathy: A cross-sectional analysis.

PubMed

Cahill, V; McCorry, D; Soryal, I; Rajabally, Y A

Whether new antiepileptic drugs (AEDs) may result in neuropathy is unknown but possible given their effects on vitamin metabolism. This analysis aimed to determine frequency and correlates of neuropathy in subjects treated with new AEDs in relation to drug used, length of exposure and serum vitamin B12 and folate levels. We performed a cross-sectional study of 52 consecutive epileptic subjects. Presence of neuropathy was determined using the Utah Early Neuropathy Score (UENS). Exposure to anti-epileptic drugs was quantified. Serum vitamin B12 and folate levels were measured. Commonly used AEDs were levetiracetam (28/52), carbamazepine (20/52), lamotrigine (20/52), sodium valproate (10/52) and zonisamide (10/52). Eight of 52 (15.4%) patients had neuropathy. There was no association with any particular AED. Neuropathy correlated with age (P=0.038) and total exposure to AEDs (P=0.032). UENS correlated with age (P=0.001), total AED exposure (P=0.001) and serum vitamin B12<240ng/L (P=0.018). Independent association of neuropathy was found with total AED exposure (P=0.032), but not age. UENS was independently associated with total exposure to AEDs (P<0.001), vitamin B12<240ng/L (P=0.002), but not age. Serum vitamin B12 and folate levels were highly inter-correlated (P<0.001). Neuropathy appears to be associated with the length of exposure to new AEDs. This may relate to the effects of new AEDs on vitamin B12 and folate metabolism. Although further research from controlled studies is needed and despite the presence of other possible confounding factors, monitoring for neuropathy and vitamin B12 and folate levels merits consideration in patients on long-term treatment with new AEDs. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Process for the preparation of protected dihydroxypropyl trialkylammonium salts and derivatives thereof

DOEpatents

Hollingsworth, Rawle I.; Wang, Guijun

2000-01-01

A process for the preparation of protected dihydroxypropyl trialkylammonium salts, particularly in chiral form is described. In particular, a process for the preparation of (2,2-dimethyl-1,3-dioxolan-4-ylmethyl)trialkylammonium salts, particularly in chiral form is described. Furthermore, a process is described wherein the (2,2-dimethyl-1,3-dioxolan-4ylmethyl)trialkylammonium salts is a 2,2-dimethyl-1,3-dioxolan-4-ylmethyl trimethylammonium salt, preferably in chiral form. The protected dihydroxypropyl trialkylammonium salts lead to L-carnitine (9) when in chiral form (5).

Inhibited Carnitine Synthesis Causes Systemic Alteration of Nutrient Metabolism in Zebrafish

PubMed Central

Li, Jia-Min; Li, Ling-Yu; Qin, Xuan; Degrace, Pascal; Demizieux, Laurent; Limbu, Samwel M.; Wang, Xin; Zhang, Mei-Ling; Li, Dong-Liang; Du, Zhen-Yu

2018-01-01

Impaired mitochondrial fatty acid β-oxidation has been correlated with many metabolic syndromes, and the metabolic characteristics of the mammalian models of mitochondrial dysfunction have also been intensively studied. However, the effects of the impaired mitochondrial fatty acid β-oxidation on systemic metabolism in teleost have never been investigated. In the present study, we established a low-carnitine zebrafish model by feeding fish with mildronate as a specific carnitine synthesis inhibitor [0.05% body weight (BW)/d] for 7 weeks, and the systemically changed nutrient metabolism, including carnitine and triglyceride (TG) concentrations, fatty acid (FA) β-oxidation capability, and other molecular and biochemical assays of lipid, glucose, and protein metabolism, were measured. The results indicated that mildronate markedly decreased hepatic carnitine concentrations while it had no effect in muscle. Liver TG concentrations increased by more than 50% in mildronate-treated fish. Mildronate decreased the efficiency of liver mitochondrial β-oxidation, increased the hepatic mRNA expression of genes related to FA β-oxidation and lipolysis, and decreased the expression of lipogenesis genes. Mildronate decreased whole body glycogen content, increased glucose metabolism rate, and upregulated the expression of glucose uptake and glycolysis genes. Mildronate also increased whole body protein content and hepatic mRNA expression of mechanistic target of rapamycin (mtor), and decreased the expression of a protein catabolism-related gene. Liver, rather than muscle, was the primary organ targeted by mildronate. In short, mildronate-induced hepatic inhibited carnitine synthesis in zebrafish caused decreased mitochondrial FA β-oxidation efficiency, greater lipid accumulation, and altered glucose and protein metabolism. This reveals the key roles of mitochondrial fatty acid β-oxidation in nutrient metabolism in fish, and this low-carnitine zebrafish model could also be used

Inhibited Carnitine Synthesis Causes Systemic Alteration of Nutrient Metabolism in Zebrafish.

PubMed

Li, Jia-Min; Li, Ling-Yu; Qin, Xuan; Degrace, Pascal; Demizieux, Laurent; Limbu, Samwel M; Wang, Xin; Zhang, Mei-Ling; Li, Dong-Liang; Du, Zhen-Yu

2018-01-01

Impaired mitochondrial fatty acid β-oxidation has been correlated with many metabolic syndromes, and the metabolic characteristics of the mammalian models of mitochondrial dysfunction have also been intensively studied. However, the effects of the impaired mitochondrial fatty acid β-oxidation on systemic metabolism in teleost have never been investigated. In the present study, we established a low-carnitine zebrafish model by feeding fish with mildronate as a specific carnitine synthesis inhibitor [0.05% body weight (BW)/d] for 7 weeks, and the systemically changed nutrient metabolism, including carnitine and triglyceride (TG) concentrations, fatty acid (FA) β-oxidation capability, and other molecular and biochemical assays of lipid, glucose, and protein metabolism, were measured. The results indicated that mildronate markedly decreased hepatic carnitine concentrations while it had no effect in muscle. Liver TG concentrations increased by more than 50% in mildronate-treated fish. Mildronate decreased the efficiency of liver mitochondrial β-oxidation, increased the hepatic mRNA expression of genes related to FA β-oxidation and lipolysis, and decreased the expression of lipogenesis genes. Mildronate decreased whole body glycogen content, increased glucose metabolism rate, and upregulated the expression of glucose uptake and glycolysis genes. Mildronate also increased whole body protein content and hepatic mRNA expression of mechanistic target of rapamycin ( mtor ), and decreased the expression of a protein catabolism-related gene. Liver, rather than muscle, was the primary organ targeted by mildronate. In short, mildronate-induced hepatic inhibited carnitine synthesis in zebrafish caused decreased mitochondrial FA β-oxidation efficiency, greater lipid accumulation, and altered glucose and protein metabolism. This reveals the key roles of mitochondrial fatty acid β-oxidation in nutrient metabolism in fish, and this low-carnitine zebrafish model could also be

Prevention of perioperative limb neuropathies in abdominal free flap breast reconstruction.

PubMed

Blackburn, Adam; Taghizadeh, Rieka; Hughes, David; O'Donoghue, Joseph M

2016-01-01

Perioperative peripheral neuropathies are a significant cause of post-operative morbidity in patients undergoing prolonged procedures. The aims of this study were to determine the incidence and possible causes of peripheral neuropathy in patients undergoing abdominal free flap breast reconstruction and to develop methods of ameliorating this problem. A 4-year retrospective study of patients undergoing abdominal free flap breast reconstruction by a single surgeon and anaesthetist was undertaken to determine the incidence and potential causes of perioperative neuropathy. A new positioning protocol was introduced to minimise the stretch on the brachial plexus and to protect peripheral nerves from compression forces. In addition, regular intraoperative physiotherapy was introduced. A prospective study was then conducted on patients managed by the same team to evaluate the effect of this change in practice on the subsequent incidence of peripheral neuropathies. Over the 4-year retrospective period, 93 consecutive patients underwent abdominal free flap breast reconstruction, six of whom (6.5%) developed a peripheral neuropathy. Following the introduction of the new positioning protocol, prospective data collected on 65 consecutive patients showed no further occurrences of perioperative neuropathy (p = 0.04). There were no significant differences in the characteristics between the two cohorts. Perioperative peripheral neuropathy in abdominal free flap breast reconstruction is a preventable problem. This paper presents a peripheral neuropathy prevention protocol for managing these patients. Copyright © 2015. Published by Elsevier Ltd.

Alcoholic neuropathy

MedlinePlus

Neuropathy - alcoholic; Alcoholic polyneuropathy ... The exact cause of alcoholic neuropathy is unknown. It likely includes both a direct poisoning of the nerve by the alcohol and the effect of poor nutrition ...

In HepG2 cells, coexisting carnitine deficiency masks important indicators of marginal biotin deficiency.

PubMed

Bogusiewicz, Anna; Boysen, Gunnar; Mock, Donald M

2015-01-01

A large number of birth defects are related to nutrient deficiencies; concern that biotin deficiency is teratogenic in humans is reasonable. Surprisingly, studies indicate that increased urinary 3-hydroxyisovalerylcarnitine (3HIAc), a previously validated marker of biotin deficiency, is not a valid biomarker in pregnancy. In this study we hypothesized that coexisting carnitine deficiency can prevent the increase in 3HIAc due to biotin deficiency. We used a 2-factor nutrient depletion design to induce isolated and combined biotin and carnitine deficiency in HepG2 cells and then repleted cells with carnitine. To elucidate the metabolic pathogenesis, we quantitated intracellular and extracellular free carnitine, acylcarnitines, and acylcarnitine ratios using liquid chromatography-tandem mass spectrometry. Relative to biotin-sufficient, carnitine-sufficient cells, intracellular acetylcarnitine increased by 90%, propionylcarnitine more than doubled, and 3HIAc increased by >10-fold in biotin-deficient, carnitine-sufficient (BDCS) cells, consistent with a defensive mechanism in which biotin-deficient cells transesterify the acyl-coenzyme A (acyl-CoA) substrates of the biotin-dependent carboxylases to the related acylcarnitines. Likewise, in BDCS cells, the ratio of acetylcarnitine to malonylcarnitine and the ratio of propionylcarnitine to methylmalonylcarnitine both more than tripled, and the ratio of 3HIAc to 3-methylglutarylcarnitine (MGc) increased by >10-fold. In biotin-deficient, carnitine-deficient (BDCD) cells, the 3 substrate-derived acylcarnitines changed little, but the substrate:product ratios were masked to a lesser extent. Moreover, carnitine repletion unmasked biotin deficiency in BDCD cells as shown by increases in acetylcarnitine, propionylcarnitine, and 3HIAc (each increased by >50-fold). Likewise, ratios of acetylcarnitine:malonylcarnitine, propionylcarnitine:methylmalonylcarnitine, and 3HIAc:MGc all increased by >8-fold. Our findings provide strong

A new unifying hypothesis for lathyrism, konzo and tropical ataxic neuropathy: nitriles are the causative agents.

PubMed

Llorens, Jordi; Soler-Martín, Carla; Saldaña-Ruíz, Sandra; Cutillas, Blanca; Ambrosio, Santiago; Boadas-Vaello, Pere

2011-03-01

Konzo and lathyrism are associated with consumption of cassava and grass pea, respectively. Cassava consumption has also been associated with a third disease, tropical ataxic neuropathy (TAN). This review presents a new unifying hypothesis on the causative agents for these diseases: namely, that they are nitriles, compounds containing cyano groups. The diseases may be caused by different but similar nitriles through direct neurotoxic actions not mediated by systemic cyanide release. Both cassava and Lathyrus contain nitriles, and other unidentified nitriles can be generated during food processing or in the human body. Available data indicate that several small nitriles cause a variety of neurotoxic effects. In experimental animals, 3,3'-iminodipropionitrile (IDPN), allylnitrile and cis-crotononitrile cause sensory toxicity, whereas hexadienenitrile and trans-crotononitrile induce selective neuronal degeneration in discrete brain regions. IDPN also induces a neurofilamentous axonopathy, and dimethylaminopropionitrile is known to cause autonomic (genito-urinary) neurotoxicity in both humans and rodents. Some of these actions depend on metabolic bioactivation of the parental nitriles, and sex- and species-dependent differences in susceptibility have been recorded. Recently, neuronal degeneration has been found in rats exposed to acetone cyanohydrin. Taken together, the neurotoxic properties of nitriles make them excellent candidates as causative agents for konzo, lathyrism and TAN. Copyright © 2010 Elsevier Ltd. All rights reserved.

EPR investigation of gamma-irradiated L-citrulline, α-methyl-DL-serine, 3-fluoro-DL-valine and N-acetyl-L-cysteine

NASA Astrophysics Data System (ADS)

Osmanoğlu, Y. Emre; Sütçü, Kerem; Başkan, M. Halim

2017-02-01

The spectroscopic parameters of the paramagnetic species produced in gamma-irradiated L-citrulline, α-methyl-DL-serine, 3-fluoro-DL-valine and N-acetyl-L-cysteine were investigated at room temperature at a dose of 20 kGy by using EPR technique. The paramagnetic species were attributed to NH2CONH(CH2)3ĊNH2COOH, HOCH2ĊCH3COOH and HOĊHCCH3NH2COOH, CH3CH3ĊCHNH2COOH and SHCH2ĊNHCOCH3COOH radicals, respectively. EPR data of the unpaired electron with the environmental protons and 14N nucleus were used to characterize the contributing radicals produced in gamma irradiated compounds. In this paper, the stability of these compounds at room temperature after irradiation was also studied.

Genetics Home Reference: carnitine-acylcarnitine translocase deficiency

MedlinePlus

... translocase deficiency Orphanet: Carnitine-acylcarnitine translocase deficiency Screening, Technology, and Research in Genetics Patient Support and Advocacy Resources (3 links) Children Living with Inherited Metabolic Diseases (CLIMB) FOD (Fatty ...

L-carnitine significantly decreased aging of rat adipose tissue-derived mesenchymal stem cells.

PubMed

Mobarak, Halimeh; Fathi, Ezzatollah; Farahzadi, Raheleh; Zarghami, Nosratollah; Javanmardi, Sara

2017-03-01

Mesenchymal stem cells are undifferentiated cells that have the ability to divide continuously and tissue regeneration potential during the transplantation. Aging and loss of cell survival, is one of the main problems in cell therapy. Since the production of free radicals in the aging process is effective, the use of antioxidant compounds can help in scavenging free radicals and prevent the aging of cells. The aim of this study is evaluate the effects of L-carnitine (LC) on proliferation and aging of rat adipose tissue-derived mesenchymal stem cells (rADSC). rADSCs were isolated from inguinal region of 5 male Rattus rats. Oil red-O, alizarin red-S and toluidine blue staining were performed to evaluate the adipogenic, osteogenic and chondrogenic differentiation of rADSCs, respectively. Flow cytometric analysis was done for investigating the cell surface markers. The methyl thiazol tetrazolium (MTT) method was used to determine the cell proliferation of rADSCs following exposure to different concentrations of LC. rADSCs aging was evaluated by beta-galactosidase staining. The results showed significant proliferation of rADSCs 48 h after treatment with concentrations of 0.2 mM LC. In addition, in the presence of 0.2 mM LC, rADSCs appeared to be growing faster than control group and 0.2 mM LC supplementation could significantly decrease the population doubling time and aging of rADSCs. It seems that LC would be a good antioxidant to improve lifespan of rADSCs due to the decrease in aging.

Acquired neuropathies.

PubMed

Lozeron, Pierre; Trocello, Jean-Marc; Kubis, Nathalie

2013-09-01

Acquired neuropathies represent most of the neuropathies encountered in clinical practice. Hundreds of causes have been identified even though up to 41% of patients are still classified as idiopathic (Rajabally and Shah in J Neurol 258:1431-1436, 1). Routine evaluation relies on comprehensive medical history taking, clinical examination, nerve conduction studies and laboratory tests. Other investigations such as nerve biopsy or nerve or muscle imaging are performed in specific settings. This review focuses on recent advances in acquired neuropathies.

Autonomic neuropathies

NASA Technical Reports Server (NTRS)

Low, P. A.

1998-01-01

A limited autonomic neuropathy may underlie some unusual clinical syndromes, including the postural tachycardia syndrome, pseudo-obstruction syndrome, heat intolerance, and perhaps chronic fatigue syndrome. Antibodies to autonomic structures are common in diabetes, but their specificity is unknown. The presence of autonomic failure worsens prognosis in the diabetic state. Some autonomic neuropathies are treatable. Familial amyloid polyneuropathy may respond to liver transplantation. There are anecdotal reports of acute panautonomic neuropathy responding to intravenous gamma globulin. Orthostatic hypotension may respond to erythropoietin or midodrine.

PPAR-γ Regulates Carnitine Homeostasis and Mitochondrial Function in a Lamb Model of Increased Pulmonary Blood Flow

PubMed Central

Rafikov, Ruslan; Kumar, Sanjiv; Hou, Yali; Oishi, Peter E.; Datar, Sanjeev A.; Raff, Gary; Fineman, Jeffrey R.; Black, Stephen M.

2012-01-01

Objective Carnitine homeostasis is disrupted in lambs with endothelial dysfunction secondary to increased pulmonary blood flow (Shunt). Our recent studies have also indicated that the disruption in carnitine homeostasis correlates with a decrease in PPAR-γ expression in Shunt lambs. Thus, this study was carried out to determine if there is a causal link between loss of PPAR-γ signaling and carnitine dysfunction, and whether the PPAR-γ agonist, rosiglitazone preserves carnitine homeostasis in Shunt lambs. Methods and Results siRNA-mediated PPAR-γ knockdown significantly reduced carnitine palmitoyltransferases 1 and 2 (CPT1 and 2) and carnitine acetyltransferase (CrAT) protein levels. This decrease in carnitine regulatory proteins resulted in a disruption in carnitine homeostasis and induced mitochondrial dysfunction, as determined by a reduction in cellular ATP levels. In turn, the decrease in cellular ATP attenuated NO signaling through a reduction in eNOS/Hsp90 interactions and enhanced eNOS uncoupling. In vivo, rosiglitazone treatment preserved carnitine homeostasis and attenuated the development of mitochondrial dysfunction in Shunt lambs maintaining ATP levels. This in turn preserved eNOS/Hsp90 interactions and NO signaling. Conclusion Our study indicates that PPAR-γ signaling plays an important role in maintaining mitochondrial function through the regulation of carnitine homeostasis both in vitro and in vivo. Further, it identifies a new mechanism by which PPAR-γ regulates NO signaling through Hsp90. Thus, PPAR-γ agonists may have therapeutic potential in preventing the endothelial dysfunction in children with increased pulmonary blood flow. PMID:22962578

Neuropathy Tests

MedlinePlus

... Mutation Mycophenolic Acid Mycoplasma Myoglobin Nicotine and Cotinine Non-High Density Lipoprotein Cholesterol Opioid Testing Osmolality Ova ... that make neuropathy worse Detect and evaluate complications Non-laboratory tests The diagnostic workup for neuropathy begins ...

Tacrolimus Optic Neuropathy.

PubMed

Rasool, Nailyn; Boudreault, Katherine; Lessell, Simmons; Prasad, Sashank; Cestari, Dean M

2018-06-01

Tacrolimus (FK506, Prograf) is a potent immunosuppressant, which inhibits cytokine synthesis and blocks T-cell development. Optic neuropathy from tacrolimus toxicity is very uncommon but, when present, can result in severe vision loss. Case series and review of the literature. We present 3 patients with tacrolimus optic neuropathy after bone marrow transplantation complicated by graft-vs-host disease and demonstrate the differing clinical and radiologic presentation of this presumed toxic optic neuropathy. Tacrolimus optic neuropathy can manifest in a multitude of clinical presentations and can have devastating visual consequences.

Treating Diabetic Neuropathy: Present Strategies and Emerging Solutions

PubMed Central

Javed, Saad; Alam, Uazman; Malik, Rayaz A.

2015-01-01

Diabetic peripheral neuropathies (DPN) are a heterogeneous group of disorders caused by neuronal dysfunction in patients with diabetes. They have differing clinical courses, distributions, fiber involvement (large or small), and pathophysiology. These complications are associated with increased morbidity, distress, and healthcare costs. Approximately 50% of patients with diabetes develop peripheral neuropathy, and the projected rise in the global burden of diabetes is spurring an increase in neuropathy. Distal symmetrical polyneuropathy (DSPN) with painful diabetic neuropathy, occurring in around 20% of diabetes patients, and diabetic autonomic neuropathy (DAN) are the most common manifestations of DPN. Optimal glucose control represents the only broadly accepted therapeutic option though evidence of its benefit in type 2 diabetes is unclear. A number of symptomatic treatments are recommended in clinical guidelines for the management of painful DPN, including antidepressants such as amitriptyline and duloxetine, the γ-aminobutyric acid analogues gabapentin and pregabalin, opioids, and topical agents such as capsaicin. However, monotherapy is frequently not effective in achieving complete resolution of pain in DPN. There is a growing need for head-to-head studies of different single-drug and combination pharmacotherapies. Due to the ubiquity of autonomic innervation in the body, DAN causes a plethora of symptoms and signs affecting cardiovascular, urogenital, gastrointestinal, pupillomotor, thermoregulatory, and sudomotor systems. The current treatment of DAN is largely symptomatic, and does not correct the underlying autonomic nerve deficit. A number of novel potential candidates, including erythropoietin analogues, angiotensin II receptor type 2 antagonists, and sodium channel blockers are currently being evaluated in phase II clinical trials. PMID:26676662

[Evaluation of serum total carnitine values in persons with severe motor and intellectual disabilities with enteral (tube) feeding].

PubMed

Ohtaki, Ushio; Ozawa, Hiroshi; Ishizuka, Takehiro; Kamiishi, Akiko; Sasaki, Kyoko; Nakajima, Suemi; Katayama, Ayako; Arimoto, Kiyoshi; Yagihashi, Tatsuhiko; Kimiya, Satoshi

2012-09-01

The nutritive evaluation and the serum carnitine values were measured for persons with severe motor and intellectual disabilities with enteral (tube) feeding. In Shimada Rehabilitation Center, twenty one people who had serum albumin levels of 3.4 g/dl or less, and were taking nutrition with enteral (tube) feeding, were tested. Body weight, blood samples, and serum carnitine levels were measured. The total carnitine value was less than the standard value in 19 patients. The total carnitine value decreased in the group taking valporate sodium (VPA), compared to the values from the group non-taking VPA. From our evaluation, we think that daily carnitine supplements is essential for persons with sever motor and intellectual disabilities taking VPA to maintain carnitine levels in the blood, and regular urine test should be done for earlier detection secondary lack complications from the secondary lack of carnitine.

Reversal of diabetic peripheral neuropathy and new wound incidence: the role of MIRE.

PubMed

Powell, Mark W; Carnegie, Dale E; Burke, Thomas J

2004-01-01

To determine if improved foot sensitivity to the Semmes-Weinstein 10-g (5.07) monofilament, originally impaired because of diabetic peripheral neuropathy, might be associated with a reduced incidence of new diabetic foot wounds. Retrospective cohort study using a health status questionnaire. Sixty-eight individuals over age 64 with diabetes, diabetic peripheral neuropathy, and loss of protective sensation who had clinically demonstrable increases in foot sensation to the Semmes-Weinstein monofilament after treatment with monochromatic near infrared photo energy. After reversal of diabetic peripheral neuropathy following treatment with monochromatic near infrared photo energy, only 1 of 68 patients developed a new diabetic foot wound, for an incidence of 1.5%. Comparatively, the incidence previously reported in the Medicare-aged population with diabetes was 7.3%. Improved foot sensitivity to the Semmes-Weinstein monofilament in patients previously suffering from loss of protective sensation due to diabetic neuropathy appears to be associated with a lower incidence of new diabetic foot ulcers when compared with the expected incidence in the Medicare-aged population with diabetes. Therapeutic interventions that effectively improve foot sensitivity that has been previously diminished due to diabetic peripheral neuropathy may substantially reduce the incidence of new foot wounds in the Medicare-aged population with diabetes.

Antioxidative and myocardial protective effects of L-arginine in oxygen radical-induced injury of isolated perfused rat hearts.

PubMed

Suessenbacher, Astrid; Lass, Achim; Mayer, Bernd; Brunner, Friedrich

2002-04-01

Oxygen-derived free radicals and oxidants (reactive oxygen intermediates, ROI) have been implicated in cardiovascular diseases. The protective role of nitric oxide (NO) against ROI-mediated tissue injury is not resolved. We tested the effects of exogenous NO, L- and D-arginine and a NO synthase inhibitor on electrolysis-induced cardiac injury and the generation of ROI by electrolysis. Superoxide dismutase (SOD) and catalase were used for comparison. Hearts ( n=7) from male rats (350+/-30 g) were perfused in vitro at 10 ml min(-1) g(-1), ROI generated by electrolysis of the perfusion medium (15 mA, 10 s), and cardiac function and the level of isoluminol-derived chemiluminescence in electrolysed perfusion medium documented for 15 min ( n=4). The ROI-induced maximal reduction of left ventricular developed pressure to 55+/-5% of baseline, and a 2.2+/-0.1-fold rise in coronary perfusion pressure 3 min after electrolysis, were prevented by SOD (50 U ml(-1)), catalase (100 U ml(-1)), S-nitroso- N-acetyl- D,L-penicillamine (SNAP, 100 nmol l(-1)); L-arginine (1 mmol l(-1)), N(G)-nitro- L-arginine (L-NNA, 200 micromol l(-1)) or D-arginine (1 mmol l(-1)). The effect of L-arginine was concentration dependent. In all cases, the beneficial effects were closely matched by a near-total reduction of ROI in the perfusion medium.We conclude that, besides mimicking or enhancing NO activity, L-arginine and donor-derived exogenous NO are cardioprotective by reducing ROI-mediated tissue injury. The protective effect of L-NNA and D-arginine implies that the protection results from a direct chemical interaction between the drug and the oxidizing species.

Immunohistochemical determination of the extracellular matrix modulation in a rat model of choline-deprived myocardium: the effects of carnitine.

PubMed

Strilakou, Athina; Perelas, Apostolos; Lazaris, Andreas; Papavdi, Asteria; Karkalousos, Petros; Giannopoulou, Ioanna; Kriebardis, Anastasios; Panayiotides, Ioannis; Liapi, Charis

2016-02-01

Choline has been identified as an essential nutrient with crucial role in many vital biological functions. Recent studies have demonstrated that heart dysfunction can develop in the setting of choline deprivation even in the absence of underlying heart disease. Matrix metalloproteinases (MMPs) are responsible for extracellular matrix degradation, and the dysregulation of MMP-2 and MMP-9 has been involved in the pathogenesis of various cardiovascular disorders. The aim of the study was to investigate the role of MMPs and their inhibitors (TIMPs), in the pathogenesis of choline deficiency-induced cardiomyopathy, and the way they are affected by carnitine supplementation. Male Wistar Albino adult rats were divided into four groups and received standard or choline-deficient diet with or without L-carnitine in drinking water (0.15% w/v) for 1 month. Heart tissue immunohistochemistry for MMP-2, MMP-9, TIMP-1, and TIMP-2 was performed. Choline deficiency was associated with suppressed immunohistochemical expression of MMP-2 and an increased expression of TIMP-2 compared to control, while it had no impact on TIMP-1. MMP-9 expression was decreased without, however, reaching statistical significance. Carnitine did not affect MMP-2, MMP-9, TIMP-1 or TIMP-2 expression. The pattern of TIMP and MMP modulation observed in a choline deficiency setting appears to promote fibrosis. Carnitine, although shown to suppress fibrosis, does not seem to affect MMP-2, MMP-9, TIMP-1 or TIMP-2 expression. Further studies will be required to identify the mechanism underlying the beneficial effects of carnitine. © 2015 Société Française de Pharmacologie et de Thérapeutique.

[Chemotherapy-induced peripheral neuropathies: an integrative review of the literature].

PubMed

Costa, Talita Cassanta; Lopes, Miriam; Anjos, Anna Cláudia Yokoyama Dos; Zago, Marcia Maria Fontão

2015-04-01

To identify scientific studies and to deepen the knowledge of peripheral neuropathies induced by chemotherapy antineoplastic, seeking evidence for assistance to cancer patients. Integrative review of the literature conducted in the databases Latin American and Caribbean Health Sciences (LILACS), Scientific Electronic Library Online (SciELO), Medical Literature Analysis (PubMed/MEDLINE), the Cochrane Library and the Spanish Bibliographic Index Health Sciences (IBECS). The sample consisted of 15 studies published between 2005-2014 that met the inclusion criteria. Studies showed aspects related to advanced age, main symptoms of neuropathy and chemotherapy agents as important adverse effect of neuropathy. We identified a small number of studies that addressed the topic, as well as low production of evidence related to interventions with positive results. It is considered important to develop new studies proposed for the prevention and/or treatment, enabling adjustment of the patient's cancer chemotherapy and consequently better service.

Peripheral neuropathy in liver cirrhosis.

PubMed

Kharbanda, Parampreet S; Prabhakar, Sudesh; Chawla, Yogesh K; Das, Chandi P; Syal, Puneet

2003-08-01

Neuropathy in association with chronic liver disease, including cirrhosis, is recognized; however, there are differences in the incidence and type of neuropathy reported. The causal relationship of liver disease to neuropathy has been questioned. This study was designed to evaluate the incidence and character of peripheral neuropathy in patients with liver cirrhosis. The effect of alcohol consumption, severity of liver disease and encephalopathy on the incidence and severity of neuropathy were also studied. Patients having an identifiable cause of peripheral neuropathy, except alcohol, were excluded from the study. Patients with evidence of vitamin B12 deficiency or diabetes were also excluded from the study. In this study, 33 patients with liver cirrhosis were evaluated clinically and electrophysiologically to detect any evidence of peripheral neuropathy. Nerve conduction studies were performed in the upper and lower limbs using surface electrodes. These patients also underwent a detailed clinical examination. Clinical signs of peripheral neuropathy were found in seven (21%) patients. Nerve conduction studies were abnormal in 24 (73%) patients. The pattern of involvement was predominantly of an axonal sensory motor polyneuropathy. Neuropathy was found both in patients with alcohol-related and non-alcohol-related cirrhosis. The presence of encephalopathy did not have a significant bearing on the incidence and severity of neuropathy. The neuropathy was also not significantly related to the severity of liver disease. The present study reveals that a significant number of patients with liver cirrhosis show evidence of peripheral neuropathy, which is present regardless of the etiology of cirrhosis, and is subclinical in a majority of these patients. The cause of neuropathy was probably the liver disease itself, as the incidence and severity of neuropathy in the alcohol-related cirrhosis, although higher, was not significantly different from the neuropathy in patients

Cerebral involvement in axonal Charcot-Marie-Tooth neuropathy caused by mitofusin2 mutations.

PubMed

Brockmann, Knut; Dreha-Kulaczewski, Steffi; Dechent, Peter; Bönnemann, Carsten; Helms, Gunther; Kyllerman, Marten; Brück, Wolfgang; Frahm, Jens; Huehne, Kathrin; Gärtner, Jutta; Rautenstrauss, Bernd

2008-07-01

Mutations in the mitofusin 2 (MFN2) gene are a major cause of primary axonal Charcot- Marie-Tooth (CMT) neuropathy. This study aims at further characterization of cerebral white matter alterations observed in patients with MFN2 mutations. Molecular genetic, magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), and diffusion tensor imaging (DTI) investigations were performed in four unrelated patients aged 7 to 38 years with early onset axonal CMT neuropathy. Three distinct and so far undescribed MFN2 mutations were detected. Two patients had secondary macrocephaly and mild diffuse predominantly periventricular white matter alterations on MRI. In addition, one boy had symmetrical T2-hyperintensities in both thalami. Two patients had optic atrophy, one of them with normal MRI. In three patients proton MRS revealed elevated concentrations of total N-acetyl compounds (neuronal marker), total creatine (found in all cells) and myo-inositol (astrocytic marker) in cerebral white and gray matter though with regional variation. These alterations were most pronounced in the two patients with abnormal MRI. DTI of these patients revealed mild reductions of fractional anisotropy and mild increase of mean diffusivity in white matter. The present findings indicate an enhanced cellular density in cerebral white matter of MFN2 neuropathy which is primarily due to a reactive gliosis without axonal damage and possibly accompanied by mild demyelination.

Recommendations to enable drug development for inherited neuropathies: Charcot-Marie-Tooth and Giant Axonal Neuropathy

PubMed Central

Sames, Lori; Moore, Allison; Arnold, Renee; Ekins, Sean

2014-01-01

Approximately 1 in 2500 Americans suffer from Charcot-Marie-Tooth (CMT) disease. The underlying disease mechanisms are unique in most forms of CMT, with many point mutations on various genes causing a toxic accumulation of misfolded proteins. Symptoms of the disease often present within the first two decades of life, with CMT1A patients having reduced compound muscle and sensory action potentials, slow nerve conduction velocities, sensory loss, progressive distal weakness, foot and hand deformities, decreased reflexes, bilateral foot drop and about 5% become wheelchair bound. In contrast, the ultra-rare disease Giant Axonal Neuropathy (GAN) is frequently described as a recessively inherited condition that results in progressive nerve death. GAN usually appears in early childhood and progresses slowly as neuronal injury becomes more severe and leads to death in the second or third decade. There are currently no treatments for any of the forms of CMTs or GAN. We suggest that further clinical studies should analyse electrical impedance myography as an outcome measure for CMT. Further, additional quality of life (QoL) assessments for these CMTs are required, and we need to identify GAN biomarkers as well as develop new genetic testing panels for both diseases. We propose that using the Global Registry of Inherited Neuropathy (GRIN) could be useful for many of these studies. Patient advocacy groups and professional organizations (such as the Hereditary Neuropathy Foundation (HNF), Hannah's Hope Fund (HHF), The Neuropathy Association (TNA) and the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM) can play a central role in educating clinicians and patients. Undertaking these studies will assist in the correct diagnosis of disease recruiting patients for clinical studies, and will ultimately improve the endpoints for clinical trials. By addressing obstacles that prevent industry investment in various forms of inherited neuropathies, we can

Clinical practice guidelines on the evidence-based use of integrative therapies during and following breast cancer treatment

PubMed Central

Greenlee, Heather; DuPont-Reyes, Melissa J.; Balneaves, Lynda G.; Carlson, Linda E.; Cohen, Misha R.; Deng, Gary; Johnson, Jillian A.; Mumber, Matthew; Seely, Dugald; Zick, Suzanna; Boyce, Lindsay; Tripathy, Debu

2018-01-01

Patients with breast cancer commonly use complementary and integrative therapies as supportive care during cancer treatment and to manage treatment-related side effects. However, evidence supporting the use of such therapies in the oncology setting is limited. This report provides updated clinical practice guidelines from the Society for Integrative Oncology on the use of integrative therapies for specific clinical indications during and after breast cancer treatment, including anxiety/stress, depression/mood disorders, fatigue, quality of life/physical functioning, chemotherapy-induced nausea and vomiting, lymphedema, chemotherapy-induced peripheral neuropathy, pain, and sleep disturbance. Clinical practice guidelines are based on a systematic literature review from 1990 through 2015. Music therapy, meditation, stress management, and yoga are recommended for anxiety/stress reduction. Meditation, relaxation, yoga, massage, and music therapy are recommended for depression/mood disorders. Meditation and yoga are recommended to improve quality of life. Acupressure and acupuncture are recommended for reducing chemotherapy-induced nausea and vomiting. Acetyl-L-carnitine is not recommended to prevent chemotherapy-induced peripheral neuropathy due to a possibility of harm. No strong evidence supports the use of ingested dietary supplements to manage breast cancer treatment-related side effects. In summary, there is a growing body of evidence supporting the use of integrative therapies, especially mind-body therapies, as effective supportive care strategies during breast cancer treatment. Many integrative practices, however, remain understudied, with insufficient evidence to be definitively recommended or avoided. PMID:28436999

Postmortem Tissue Distribution of Acetyl Fentanyl, Fentanyl and their Respective Nor-Metabolites Analyzed by Ultrahigh Performance Liquid Chromatography with Tandem Mass Spectrometry

PubMed Central

Poklis, Justin; Poklis, Alphonse; Wolf, Carl; Mainland, Mary; Hair, Laura; Devers, Kelly; Chrostowski, Leszek; Arbefeville, Elise; Merves, Michele; Pearson, Julia

2015-01-01

In the last two years, an epidemic of fatal narcotic overdose cases has occurred in the Tampa area of Florida. Fourteen of these deaths involved fentanyl and/or the new designer drug, acetyl fentanyl. Victim demographics, case histories, toxicology findings and causes and manners of death, as well as, disposition of fentanyl derivatives and their nor-metabolites in postmortem heart blood, peripheral blood, bile, brain, liver, urine and vitreous humor are presented. In the cases involving only acetyl fentanyl (without fentanyl, n=4), the average peripheral blood acetyl fentanyl concentration was 0.467 mg/L (range 0.31 to .60 mg/L) and average acetyl norfentanyl concentration was 0.053 mg/L (range 0.002 to 0.086 mg/L). In the cases involving fentanyl (without acetyl fentanyl, n=7), the average peripheral blood fentanyl concentration was 0.012 mg/L (range 0.004 to 0.027 mg/L) and average norfentanyl blood concentration was 0.001 mg/L (range 0.0002 to 0.003 mg/L). In the cases involving both acetyl fentanyl and fentanyl (n=3), the average peripheral blood acetyl fentanyl concentration was 0.008 mg/L (range 0.006 to 0.012 mg/L), the average peripheral blood acetyl norfentanyl concentration was 0.001 mg/L (range 0.001 to 0.002 mg/L), the average peripheral blood fentanyl concentration was 0.018 mg/L (range 0.015 to 0.021 mg/L) and the average peripheral blood norfentanyl concentration was 0.002 mg/L (range 0.001 mg/L to 0.003 mg/L). Based on the toxicology results, it is evident that when fentanyl and/or acetyl fentanyl were present, they contributed to the cause of death. A novel ultrahigh performance liquid chromatography (UPLC) tandem mass spectrometry (MS/MS) method to identify and quantify acetyl fentanyl, acetyl norfentanyl, fentanyl and norfentanyl in postmortem fluids and tissues is also presented. PMID:26583960

N-acetyl-l-cysteine and Mn2+ attenuate Cd2+-induced disturbance of the intracellular free calcium homeostasis in cultured cerebellar granule neurons.

PubMed

Isaev, Nickolay K; Avilkina, Svetlana; Golyshev, Sergey A; Genrikhs, Elisaveta E; Alexandrova, Olga P; Kapkaeva, Marina R; Stelmashook, Elena V

2018-01-15

Cadmium is a highly toxic heavy metal that is capable of accumulating in the body via direct exposure or through the alimentary and respiratory tract, leading to neurodegeneration. In this article, we show that the application of CdCl 2 (0.001-0.005mM) for 48h induced high dose-dependent death rate of cultured cerebellar granule neurons (CGNs). Unlike Trolox or vitamin E, antioxidant N-acetyl-l-cysteine (NAC, 1mM) and Mn 2+ (0.0025-0.005mM) significantly protected CGNs from this toxic effect. Using Fluo-4 AM, measurements of intracellular calcium ions demonstrated that 24h-exposure to Cd 2+ induced intensive increase of Fluo-4 fluorescence in neurons accompanied by mitochondria swelling. These data imply that the cadmium-induced Ca 2+ increase is an important element in the death of neurons due to toxic effect of cadmium and the mechanism of protective action of manganese and NAC is mediated by the prevention of increase in calcium levels. Copyright © 2017 Elsevier B.V. All rights reserved.

γ-BUTYROBETAINE AS A SPECIFIC ANTAGONIST FOR CARNITINE IN THE DEVELOPMENT OF THE EARLY CHICK EMBRYO

PubMed Central

Ito, Toshio; Fraenkel, G.

1957-01-01

The effect of γ-butyrobetaine alone and with the addition of carnitine on the development of the early excised chick embryo has been studied. γ-Butyrobetaine in appropriate amounts exerts an inhibitory effect which can be relieved or annulled by the inclusion of appropriate amounts of carnitine. This has been interpreted as a metabolite-antimetabolite relationship, in which the normal metabolite, carnitine, is antagonized by the structurally closely related γ-butyrobetaine, and is regarded as evidence of an important role of carnitine in the metabolism of the developing chick embryo. PMID:13475691

Protection against radiation-induced oxidative stress in cultured human epithelial cells by treatment with antioxidant agents

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wan, X. Steven; Ware, Jeffrey H.; Zhou, Zhaozong

2006-04-01

Purpose: To evaluate the protective effects of antioxidant agents against space radiation-induced oxidative stress in cultured human epithelial cells. Methods and Materials: The effects of selected concentrations of N-acetylcysteine, ascorbic acid, sodium ascorbate, co-enzyme Q10, {alpha}-lipoic acid, L-selenomethionine, and vitamin E succinate on radiation-induced oxidative stress were evaluated in MCF10 human breast epithelial cells exposed to radiation with X-rays, {gamma}-rays, protons, or high mass, high atomic number, and high energy particles using a dichlorofluorescein assay. Results: The results demonstrated that these antioxidants are effective in protecting against radiation-induced oxidative stress and complete or nearly complete protection was achieved by treatingmore » the cells with a combination of these agents before and during the radiation exposure. Conclusion: The combination of antioxidants evaluated in this study is likely be a promising countermeasure for protection against space radiation-induced adverse biologic effects.« less

In HepG2 Cells, Coexisting Carnitine Deficiency Masks Important Indicators of Marginal Biotin Deficiency123

PubMed Central

Bogusiewicz, Anna; Boysen, Gunnar; Mock, Donald M

2015-01-01

Background: A large number of birth defects are related to nutrient deficiencies; concern that biotin deficiency is teratogenic in humans is reasonable. Surprisingly, studies indicate that increased urinary 3-hydroxyisovalerylcarnitine (3HIAc), a previously validated marker of biotin deficiency, is not a valid biomarker in pregnancy. Objective: In this study we hypothesized that coexisting carnitine deficiency can prevent the increase in 3HIAc due to biotin deficiency. Methods: We used a 2-factor nutrient depletion design to induce isolated and combined biotin and carnitine deficiency in HepG2 cells and then repleted cells with carnitine. To elucidate the metabolic pathogenesis, we quantitated intracellular and extracellular free carnitine, acylcarnitines, and acylcarnitine ratios using liquid chromatography–tandem mass spectrometry. Results: Relative to biotin-sufficient, carnitine-sufficient cells, intracellular acetylcarnitine increased by 90%, propionylcarnitine more than doubled, and 3HIAc increased by >10-fold in biotin-deficient, carnitine-sufficient (BDCS) cells, consistent with a defensive mechanism in which biotin-deficient cells transesterify the acyl-coenzyme A (acyl-CoA) substrates of the biotin-dependent carboxylases to the related acylcarnitines. Likewise, in BDCS cells, the ratio of acetylcarnitine to malonylcarnitine and the ratio of propionylcarnitine to methylmalonylcarnitine both more than tripled, and the ratio of 3HIAc to 3-methylglutarylcarnitine (MGc) increased by >10-fold. In biotin-deficient, carnitine-deficient (BDCD) cells, the 3 substrate-derived acylcarnitines changed little, but the substrate:product ratios were masked to a lesser extent. Moreover, carnitine repletion unmasked biotin deficiency in BDCD cells as shown by increases in acetylcarnitine, propionylcarnitine, and 3HIAc (each increased by >50-fold). Likewise, ratios of acetylcarnitine:malonylcarnitine, propionylcarnitine:methylmalonylcarnitine, and 3HIAc:MGc all increased

The Use of Drugs to Reduce Hearing Loss Following Acute Acoustic Trama

DTIC Science & Technology

2012-07-01

noise exposure: (1) L-N- acetylcysteine (L-NAC); (2) D-Methionine (D-MET); (3) Ebselen SPI-1005; (4) Acetyl-L-carnitine (ALCAR) and (5) Src-PTK inhibitor...exposed to a 4.0 kHz octave band of noise for 6 hours at 105 dB SPL: (1) L-N- acetylcysteine (L-NAC); (2) D-Methionine (D-MET); (3) Ebselen SPI-1005...effectively absent or severely depressed from 2 kHz and above (Figs. 14 & 15). Individual cochleograms for this group are shown in Figure 16. The

Vestibular evoked myogenic potential (VEMP) in patients with auditory neuropathy: Auditory neuropathy or audiovestibular neuropathy?

PubMed

Sazgar, Amir Arvin; Yazdani, Nasrin; Rezazadeh, Nima; Yazdi, Alireza Karimi

2010-10-01

Our results suggest that isolated auditory or vestibular involvement is unlikely and in fact audiovestibular neuropathy can better explain auditory neuropathy. The purpose of this study was to investigate saccule and related neural pathways in auditory neuropathy patients. Three males and five females diagnosed with auditory neuropathy were included in this prospective study. Patients' ages ranged from 21 to 45 years with a mean age of 28.6 ± 8.1 years and the history of disease was between 4 and 19 years. A group of 30 normal subjects served as the control group. The main outcome measures were the mean peak latency (in ms) of the two early waves (p13 and n23) of the vestibular evoked myogenic potential (VEMP) test in patients and controls. Of the 8 patients (16 ears), normal response was detected in 3 ears (1 in right and 2 in left ears). There were unrepeatable waves in four ears and absent VEMPs in nine ears.

Pharmacokinetic and toxicodynamic evaluation of oxaliplatin-induced neuropathy and hematological toxicity in rats.

PubMed

Ito, Yukako; Kobuchi, Shinji; Shimizu, Risa; Katsuyama, Yosuke

2018-01-01

Oxaliplatin (L-OHP) is a third-generation, platinum-based chemotherapeutic agent and is widely used in gastroenterological cancer regimens. It is important to complete chemotherapy cycles to improve treatment efficacy for cancer patients. However, undesirable side effects, including acute and chronic neuropathies, and myelosuppression, lead to the discontinuation of chemotherapy in some treatment regimens. To predict and prevent the onset of side effects, and to establish appropriate dose adjustment, pharmacokinetic and toxicodynamic studies were performed to investigate the effects of L-OHP in rats. Rats were administered intravenous L-OHP, once a week for 4 weeks, at doses of 3, 5, or 8 mg/kg. Pharmacokinetic profiles were observed on Day 1 and Day 22. Acute and chronic neuropathies were evaluated over 4 weeks; cold allodynia was evaluated using an acetone test and mechanical allodynia using the von Frey test. Hematological parameters were also investigated during the same period. The mean AUC0-∞ values for L-OHP were 0.4 ± 0.2, 2.4 ± 0.4, and 3.5 ± 0.9 ng h/mL, increasing dose-dependently on Day 1. The accumulation of L-OHP on Day 22 was observed after repeated administration of L-OHP, as shown by mean AUC0-∞ values of 0.6 ± 0.2, 4.0 ± 1.0, and 14.1 ± 9.8 ng·h/mL, for the three doses. Cold allodynia was observed from Day 3 in the 5 and 8 mg/kg groups, and the extent of this response was dose-dependent. Mechanical allodynia was also observed from Day 10 in the 5 and 8 mg/kg groups. Moreover, the platelet count was the most sensitive among the hematological parameters. These results provide useful experimental data for clinical cancer patients undergoing chemotherapy, to establish a pharmacokinetic and toxicodynamic model of L-OHP for adequate dose adjustment.

Optic Neuropathy Associated with Primary Sjögren's Syndrome: A Case Series.

PubMed

Bak, Eunoo; Yang, Hee Kyung; Hwang, Jeong-Min

2017-04-01

To determine the diverse clinical features of optic neuropathy associated with primary Sjögren's syndrome in Korean patients. Five women with acute and/or chronic optic neuropathy who were diagnosed as primary Sjögren's syndrome were retrospectively evaluated. Primary Sjögren's syndrome was diagnosed by signs and symptoms of keratoconjunctivitis sicca, positive serum anti-Ro/SSA and/or anti-La/SSB antibodies, and/or minor salivary gland biopsy. All patients underwent a complete ophthalmologic examination. Among the five patients diagnosed as optic neuropathy related to primary Sjögren's syndrome, four patients had bilateral optic neuropathy and one patient was unilateral. The clinical course was chronic in three patients and one of them showed acute exacerbation and was finally diagnosed with neuromyelitis optica spectrum disorder. The other two patients presented as acute optic neuritis and one was diagnosed with neuromyelitis optica spectrum disorder. Sicca symptoms were present in four patients, but only two patients reported these symptoms before the onset of optic neuropathy. Patients showed minimal response to systemic corticosteroids or steroid dependence, requiring plasmapheresis in the acute phase and immunosuppressive agents for maintenance therapy. Optic neuropathy associated with primary Sjögren's syndrome may show variable clinical courses, including acute optic neuritis, insidious progression of chronic optic atrophy, or in the context of neuromyelitis optica spectrum disorders. Optic neuropathy may be the initial manifestation of primary Sjögren's syndrome without apparent sicca symptoms, which makes the diagnosis often difficult. The presence of specific antibodies including anti-Ro/SSA, anti-La/SSB, and anti-aquaporin-4 antibodies are supportive for the diagnosis and treatment in atypical cases of optic neuropathy.

Comparison of plasma, liver, and skeletal muscle carnitine concentrations in cats with idiopathic hepatic lipidosis and in healthy cats.

PubMed

Jacobs, G; Cornelius, L; Keene, B; Rakich, P; Shug, A

1990-09-01

Concentrations of total, free, and esterified carnitine were determined in plasma, liver, and skeletal muscle from cats with idiopathic hepatic lipidosis and compared with values from healthy cats. The mean concentrations of plasma, liver, and skeletal muscle total carnitine; plasma and skeletal muscle free carnitine; and plasma and liver esterified carnitine were greater (P less than 0.05) in cats with idiopathic hepatic lipidosis than in control cats. The mean for the ratio of free/total carnitine in plasma and liver was lower (P less than 0.05) in cats with idiopathic hepatic lipidosis than in control cats. These data suggest that carnitine deficiency does not contribute to the pathogenesis of feline idiopathic hepatic lipidosis.

Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials

PubMed Central

Till, Cathee; Wright, Jason D.; Awad, Danielle; Ramsey, Scott D.; Barlow, William E.; Minasian, Lori M.; Unger, Joseph

2016-01-01

Background Neuropathy is a debilitating toxicity associated with various chemotherapy agents. We evaluated the association between common comorbid conditions and the development of peripheral neuropathy in patients treated with taxane-based chemotherapy. Methods We examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy from 1999 to 2011. We linked the Southwest Oncology Group clinical records to Medicare claims data according to Social Security number, sex, and date of birth. The following disease conditions potentially associated with peripheral neuropathy were evaluated: diabetes, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune diseases. Multivariate logistic regression was used to model the odds of experiencing grade 2 to 4 neuropathy. Results A total of 1,401 patients from 23 studies were included in the analysis. Patients receiving paclitaxel were more likely to experience grade 2 to 4 neuropathy compared with docetaxel (25% v 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P < .001). The inclusion of a platinum agent was also associated with greater neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). For each increase in age of 1 year, the odds of neuropathy increased 4% (P = .006). Patients with complications from diabetes had more than twice the odds of having neuropathy (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002) compared with patients with no diabetes. In contrast, patients with autoimmune disease were half as likely to experience neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). The other conditions were not associated with neuropathy. Conclusion We found that in addition to drug-related factors, age and history of diabetes were independent predictors of the development of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with reduced odds of

Comorbidities and Risk of Chemotherapy-Induced Peripheral Neuropathy Among Participants 65 Years or Older in Southwest Oncology Group Clinical Trials.

PubMed

Hershman, Dawn L; Till, Cathee; Wright, Jason D; Awad, Danielle; Ramsey, Scott D; Barlow, William E; Minasian, Lori M; Unger, Joseph

2016-09-01

Neuropathy is a debilitating toxicity associated with various chemotherapy agents. We evaluated the association between common comorbid conditions and the development of peripheral neuropathy in patients treated with taxane-based chemotherapy. We examined the Southwest Oncology Group database to identify phase II and III trials that included taxane therapy from 1999 to 2011. We linked the Southwest Oncology Group clinical records to Medicare claims data according to Social Security number, sex, and date of birth. The following disease conditions potentially associated with peripheral neuropathy were evaluated: diabetes, hypothyroidism, hypercholesterolemia, hypertension, varicella zoster, peripheral vascular disease, and autoimmune diseases. Multivariate logistic regression was used to model the odds of experiencing grade 2 to 4 neuropathy. A total of 1,401 patients from 23 studies were included in the analysis. Patients receiving paclitaxel were more likely to experience grade 2 to 4 neuropathy compared with docetaxel (25% v 12%, respectively; OR, 2.20; 95% CI, 1.52 to 3.18; P < .001). The inclusion of a platinum agent was also associated with greater neuropathy (OR, 1.68; 95% CI, 1.18 to 2.40; P = .004). For each increase in age of 1 year, the odds of neuropathy increased 4% (P = .006). Patients with complications from diabetes had more than twice the odds of having neuropathy (OR, 2.13; 95% CI, 1.31 to 3.46; P = .002) compared with patients with no diabetes. In contrast, patients with autoimmune disease were half as likely to experience neuropathy (OR, 0.49; 95% CI, 0.24 to 1.02; P = .06). The other conditions were not associated with neuropathy. We found that in addition to drug-related factors, age and history of diabetes were independent predictors of the development of chemotherapy-induced peripheral neuropathy. Interestingly, we also observed that a history of autoimmune disease was associated with reduced odds of neuropathy. Patients with diabetic

Oleo gum resin of Ferula assa-foetida L. ameliorates peripheral neuropathy in mice.

PubMed

Homayouni Moghadam, Farshad; Dehghan, Maryam; Zarepur, Ehsan; Dehlavi, Reyhaneh; Ghaseminia, Fatemeh; Ehsani, Shima; Mohammadzadeh, Golnaz; Barzegar, Kazem

2014-05-28

According to the Chinese, European, Iranian and Indian traditional medicines, oleo gum resin of Ferula assa-foetida (asafoetida) has therapeutic effects on different kinds of diseases. Some of these effects are related to the diseases of nervous system such as hysteresis and convulsion. In recent studies, some anti-epileptic and neuroprotective roles were also considered for it and we examined its possible role on treatment of peripheral neuropathy. in vitro studies were carried out to identify the response of isolated sciatic nerves to different concentrations of oleo gum resin of asafoetida solved in Lock׳s solution. Then, in vivo studies were conducted to evaluate its effect on amelioration of peripheral neuropathy in mice. Peripheral neuropathy was induced by intraperiotoneal injection of high doses of pyridoxine in adult Balb/c male mice. Tail flick tests were performed to identify the incidence of neuropathy in animals. After 10 days treatment with asafoetida, the efficiency of treatment was assessed by behavioral, electrophysiological and histological studies. in vitro experiments confirmed that incubating the nerves in aqueous extract of oleo gum rein of asafoetida increased the amplitude and decreased the latent period of nerve compound action potential (CAP). Nerve conduction velocity (NCV) and amplitude of CAP also improved in asafoetida treated animals. Histological and behavioral studies showed that asafoetida was able to facilitate the healing process in peripheral nerves. in vitro experiments showed that asafoetida is a nerve stimulant and its administration in neuropathic mice exerted neuroprotecting effects through stimulating axonal regeneration and remyelination and decrement of lymphocyte infiltration. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Vitamin D deficiency increases the risk of peripheral neuropathy in Chinese patients with type 2 diabetes.

PubMed

He, Rui; Hu, Yanyun; Zeng, Hui; Zhao, Jun; Zhao, Jungong; Chai, Yimin; Lu, Fengdi; Liu, Fang; Jia, Weiping

2017-02-01

Vitamin D deficiency was reported to be associated with diabetic peripheral neuropathy. But the association in Chinese population and the screening value of vitamin D deficiency for diabetic peripheral neuropathy were unknown. A total of 861 patients with type 2 diabetes were recruited in this cross-sectional study. Vitamin D deficiency was defined as serum circulating 25-hydroxyvitamin D(25(OH)D) level < 20 ng/mL. Peripheral neuropathy was evaluated by neurological symptoms, neurological signs, neurothesiometer and electromyogram. The patients with diabetic peripheral neuropathy had significantly lower serum 25(OH)D concentration (15.59 ± 7.68 ng/mL) and higher prevalence of vitamin D deficiency (80%) than patients with signs of diabetic peripheral neuropathy (17.66 ± 7.50 ng/mL; 64.5%) and non-DPN patients (18.35 ± 6.60; 61.7%) (all p < 0.01). Spearman's correlation analysis showed that serum circulating 25(OH)D level was closely associated with DPN (r = 0.121) and signs of DPN (r = 0.111) (both p < 0.01). After adjusting for all potential confounders, VDD was still linked with increased risk of DPN [odds ratio 2.59 (1.48-4.53)] (p < 0.01). Logistical regression analysis further revealed that VDD was an independent risk factor for DPN (β = 0.88) (p < 0.01). Receiver operating characteristic analysis indicated that serum 25(OH)D < 17.22 ng/mL hinted the signs of DPN and serum 25(OH)D < 16.01 ng/mL predicted the occurrence of DPN (both p < 0.01). Vitamin D deficiency is an independent risk factor for diabetic peripheral neuropathy and may be a potential biomarker for peripheral neuropathy in Chinese patients with type 2 diabetes. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Diagnostic capability of retinal thickness measures in diabetic peripheral neuropathy.

PubMed

Srinivasan, Sangeetha; Pritchard, Nicola; Sampson, Geoff P; Edwards, Katie; Vagenas, Dimitrios; Russell, Anthony W; Malik, Rayaz A; Efron, Nathan

thickness was 97μm, with 81% sensitivity and 72% specificity. The GCC FLV can differentiate individuals with diabetic neuropathy from healthy controls, while the inferior RNFL thickness is able to differentiate those with greater degrees of neuropathy from those with mild or no neuropathy, both with an acceptable level of accuracy. Optical coherence tomography represents a non-invasive technology that aids in detection of retinal structural changes in patients with established diabetic neuropathy. Further refinement of the technique and the analytical approaches may be required to identify patients with minimal neuropathy. Copyright © 2016 Spanish General Council of Optometry. Published by Elsevier España, S.L.U. All rights reserved.

Role of the Astroglial Glutamate Exchanger xCT in Ventral Hippocampus in Resilience to Stress.

PubMed

Nasca, Carla; Bigio, Benedetta; Zelli, Danielle; de Angelis, Paolo; Lau, Timothy; Okamoto, Masahiro; Soya, Hideyo; Ni, Jason; Brichta, Lars; Greengard, Paul; Neve, Rachael L; Lee, Francis S; McEwen, Bruce S

2017-10-11

We demonstrate that stress differentially regulates glutamate homeostasis in the dorsal and ventral hippocampus and identify a role for the astroglial xCT in ventral dentate gyrus (vDG) in stress and antidepressant responses. We provide an RNA-seq roadmap for the stress-sensitive vDG. The transcription factor REST binds to xCT promoter in co-occupancy with the epigenetic marker H3K27ac to regulate expression of xCT, which is also reduced in a genetic mouse model of inherent susceptibility to depressive-like behavior. Pharmacologically, modulating histone acetylation with acetyl-L-carnitine (LAC) or acetyl-N-cysteine (NAC) rapidly increases xCT and activates a network with mGlu2 receptors to prime an enhanced glutamate homeostasis that promotes both pro-resilient and antidepressant-like responses. Pharmacological xCT blockage counteracts NAC prophylactic effects. GFAP + -Cre-dependent overexpression of xCT in vDG mimics pharmacological actions in promoting resilience. This work establishes a mechanism by which vDG protection leads to stress resilience and antidepressant responses via epigenetic programming of an xCT-mGlu2 network. Copyright © 2017 Elsevier Inc. All rights reserved.

Synthesis of polyrotaxanes from acetyl-β-cyclodextrin

NASA Astrophysics Data System (ADS)

Ristić, I. S.; Nikolić, L.; Nikolić, V.; Ilić, D.; Budinski-Simendić, J.

2011-12-01

Polyrotaxanes are intermediary products in the synthesis of topological gels. They are created by inclusion complex formation of hydrophobic linear macromolecules with cyclodextrins or their derivatives. Then, pairs of cyclodextrin molecules with covalently linkage were practically forming the nodes of the semi-flexible polymer network. Such gels are called topological gels and they can absorb huge quantities of water due to the net flexibility allowing the poly(ethylene oxide) chains to slide through the cyclodextrin cavities, without being pulled out altogether. For polyrotaxane formation poly(ethylene oxide) was used like linear macromolecules. There are hydroxyl groups at poly(ethylene oxide) chains, whereby the linking of the voluminous molecules should be made. To avoid the reaction of cyclodextrin OH groups with stoppers, they should be protected by, e.g., acetylation. In this work, the acetylation of the OH groups of β-cyclodextrin was performed by acetic acid anhydride with iodine as the catalyst. The acetylation reaction was assessed by the FTIR and HPLC method. By the HPLC analysis was found that the acetylation was completed in 20 minutes. Inserting of poly(ethylene oxide) with 4000 g/mol molecule mass into acetyl-β-cyclodextrin with 2:1 poly(ethylene oxide) monomer unit to acetyl-β-cyclodextrin ratio was also monitored by FTIR, and it was found that the process was completed in 12 h at the temperature of 10°C. If the process is performed at temperatures above 10°C, or for periods longer than 12 hours, the process of uncontrolled hydrolysis of acetate groups was initiated.

Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment

PubMed Central

Mo, Michelle; Erdelyi, Ildiko; Szigeti-Buck, Klara; Benbow, Jennifer H.; Ehrlich, Barbara E.

2012-01-01

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating side effect that occurs in many patients undergoing chemotherapy. It is often irreversible and frequently leads to early termination of treatment. In this study, we have identified two compounds, lithium and ibudilast, that when administered as a single prophylactic injection prior to paclitaxel treatment, prevent the development of CIPN in mice at the sensory-motor and cellular level. The prevention of neuropathy was not observed in paclitaxel-treated mice that were only prophylactically treated with a vehicle injection. The coadministration of lithium with paclitaxel also allows for administration of higher doses of paclitaxel (survival increases by 60%), protects against paclitaxel-induced cardiac abnormalities, and, notably, does not interfere with the antitumor effects of paclitaxel. Moreover, we have determined a mechanism by which CIPN develops and have discovered that lithium and ibudilast inhibit development of peripheral neuropathy by disrupting the interaction between paclitaxel, neuronal calcium sensor 1 (NCS-1), and the inositol 1,4,5-trisphosphate receptor (InsP3R) to prevent treatment-induced decreases in intracellular calcium signaling. This study shows that lithium and ibudilast are candidate therapeutics for the prevention of paclitaxel-induced neuropathy and could enable patients to tolerate more aggressive treatment regimens.—Mo, M., Erdelyi, I., Szigeti-Buck, K., Benbow, J. H., Ehrlich, B. E. Prevention of paclitaxel-induced peripheral neuropathy by lithium pretreatment. PMID:22889832

Evidence for the role of oxidative stress in the acetylation of histone H3 by ethanol in rat hepatocytes

PubMed Central

Choudhury, Mahua; Park, Pil-Hoon; Jackson, Daniel; Shukla, Shivendra D.

2010-01-01

The relationship between ethanol induced oxidative stress and acetylation of histone H3 at lysine 9 (H3AcK9) remains unknown and was therefore investigated in primary cultures of rat hepatocytes. Cells were treated with ethanol and a select group of pharmacological agents and the status of H3AcK9 and reactive oxygen species (ROS) were monitored. When hepatocytes were exposed to ethanol (50 mM, 24 hr) in the presence of N-acetyl cystein (ROS reducer) or dietary antioxidants (quercetin, resveratrol), or NADPH oxidase inhibitor apocynin, ethanol induced increases in ROS and H3AcK9, both were significantly reduced. On the other hand, l-buthionine-sulfoximine (ROS inducer) and inhibitor of mitochondrial complex I (rotenone) and III (antimycin) increased ethanol induced H3AcK9 (p<0.01). Oxidative stress also affected ethanol induced alcohol dehydrogenase 1 (ADH1) mRNA expression. These results demonstrate for the first time that oxidative stress is involved in the ethanol induced histone H3 acetylation in hepatocytes. PMID:20705415

Evidence for the role of oxidative stress in the acetylation of histone H3 by ethanol in rat hepatocytes.

PubMed

Choudhury, Mahua; Park, Pil-Hoon; Jackson, Daniel; Shukla, Shivendra D

2010-09-01

The relationship between ethanol-induced oxidative stress and acetylation of histone H3 at lysine 9 (H3AcK9) remains unknown and was therefore investigated in primary cultures of rat hepatocytes. Cells were treated with ethanol, and a select group of pharmacological agents and the status of H3AcK9 and reactive oxygen species (ROS) were monitored. Pretreatment of hepatocytes with N-acetyl cystein (ROS reducer), or dietary antioxidants (quercetin, reserveratrol), or NADPH (reduced nicotinamide adenine dinucleotide phosphate) oxidase inhibitor apocynin, significantly reduced ethanol (50 mM, 24 h) induced increases in ROS and H3AcK9. In contrast, l-buthionine sulfoximine (ROS inducer) and inhibitor of mitochondrial complexes I (rotenone) and III (antimycin) increased ethanol-induced H3AcK9 (P<.01). Oxidative stress also affected ethanol-induced alcohol dehydrogenase 1 mRNA expression. These results demonstrate for the first time that oxidative stress is involved in the ethanol-induced histone H3 acetylation in hepatocytes. Copyright © 2010 Elsevier Inc. All rights reserved.

Guaifenesin derivatives promote neurite outgrowth and protect diabetic mice from neuropathy.

PubMed

Hadimani, Mallinath B; Purohit, Meena K; Vanampally, Chandrashaker; Van der Ploeg, Randy; Arballo, Victor; Morrow, Dwane; Frizzi, Katie E; Calcutt, Nigel A; Fernyhough, Paul; Kotra, Lakshmi P

2013-06-27

In diabetic patients, an early index of peripheral neuropathy is the slowing of conduction velocity in large myelinated neurons and a lack of understanding of the basic pathogenic mechanisms hindered therapeutics development. Racemic (R/S)-guaifenesin (1) was identified as a potent enhancer of neurite outgrowth using an in vitro screen. Its R-enantiomer (R)-1 carried the most biological activity, whereas the S-enantiomer (S)-1 was inactive. Focused structural variations to (R/S)-1 was conducted to identify potentially essential groups for the neurite outgrowth activity. In vivo therapeutic studies indicated that both (R/S)-1 and (R)-1 partially prevented motor nerve conduction velocity slowing in a mouse model of type 1 diabetes. In vitro microsomal assays suggested that compounds (R)-1 and (S)-1 are not metabolized rapidly, and PAMPA assay indicated moderate permeability through the membrane. Findings revealed here could lead to the development of novel drugs for diabetic neuropathy.

Tang-Tong-Fang Confers Protection against Experimental Diabetic Peripheral Neuropathy by Reducing Inflammation

PubMed Central

Li, Mingdi; Huang, Da; Liu, Xiaoxing; Lin, Lan

2015-01-01

Tang-tong-fang (TTF) is a Chinese herbal formula that has been shown to be beneficial in diabetic peripheral neuropathy (DPN), a common complication secondary to diabetic microvascular injury. However, the underlying mechanism of protection in nerve ischemia provided by TTF is still unclear. We hypothesized that TTF alleviates DPN via inhibition of ICAM-1 expression. Therefore, we tested the effect of TTF in a previously established DPN model, in which nerve injury was induced by ischemia/reperfusion in streptozotocin-induced diabetic rats. We found that the conduction velocity and amplitude of action potentials of sciatic nerve conduction were reduced in the DPN model group but were rescued by TTF treatment. In addition, TTF treatment also attenuated the effect of DPN on other parameters including histology and ultrastructural changes, expression of ICAM-1, MPO, and TNF-α in rat sciatic nerves, and plasma sICAM-1 and MPO levels. Together, our data suggest that TTF treatment may alleviate DPN via ICAM-1 inhibition. PMID:26539228

Interventions for preventing neuropathy caused by cisplatin and related compounds.

PubMed

Albers, James W; Chaudhry, Vinay; Cavaletti, Guido; Donehower, Ross C

2014-03-31

heterogeneity precluded pooling of the results in most cases. Nonetheless, a larger number of trials reported the results of secondary (non-quantitative and subjective) measures such as the National Cancer Institute Common Toxicity Criteria (NCI-CTC) for neuropathy (15 trials), and these results we pooled and reported as meta-analysis. Amifostine showed a significantly reduced risk of developing neurotoxicity NCI-CTC (or equivalent) ≥ 2 compared to placebo (RR 0.26, 95% CI 0.11 to 0.61). Glutathione was also efficacious with an RR of 0.29 (95% CI 0.10 to 0.85). In three vitamin E studies subjective measures not suitable for combination in meta analysis each favoured vitamin E. For other interventions the qualitative toxicity measures were either negative (N-acetyl cysteine, Ca/Mg, DDTC and retinoic acid) or not evaluated (oxcarbazepine and Org 2766).Adverse events were infrequent or not reported for most interventions. Amifostine was associated with transient hypotension in 8% to 62% of participants, retinoic acid with hypocalcaemia in 11%, and approximately 20% of participantss withdrew from treatment with DDTC because of toxicity. At present, the data are insufficient to conclude that any of the purported chemoprotective agents (acetylcysteine, amifostine, calcium and magnesium, diethyldithiocarbamate, glutathione, Org 2766, oxcarbazepine, retinoic acid, or vitamin E) prevent or limit the neurotoxicity of platin drugs among human patients, as determined using quantitative, objective measures of neuropathy. Amifostine, calcium and magnesium, glutathione, and vitamin E showed modest but promising (borderline statistically significant) results favouring their ability to reduce the neurotoxicity of cisplatin and related chemotherapies, as measured using secondary, non-quantitative and subjective measures such as the NCI-CTC neuropathy grading scale. Among these interventions, the efficacy of only vitamin E was evaluated using quantitative nerve conduction studies; the results

Sensory Neuropathy Due to Loss of Bcl-w

PubMed Central

Courchesne, Stephanie L.; Karch, Christoph; Pazyra-Murphy, Maria F.; Segal, Rosalind A.

2010-01-01

Small fiber sensory neuropathy is a common disorder in which progressive degeneration of small diameter nociceptors causes decreased sensitivity to thermal stimuli and painful sensations in the extremities. In the majority of patients, the cause of small fiber sensory neuropathy is unknown, and treatment options are limited. Here, we show that Bcl-w (Bcl-2l2) is required for the viability of small fiber nociceptive sensory neurons. Bcl-w −/− mice demonstrate an adult-onset progressive decline in thermosensation and a decrease in nociceptor innervation of the epidermis. This denervation occurs without cell body loss, indicating that lack of Bcl-w results in a primary axonopathy. Consistent with this phenotype, we show that Bcl-w, in contrast to the closely related Bcl-2 and Bcl-xL, is enriched in axons of sensory neurons and that Bcl-w prevents the dying back of axons. Bcl-w −/− sensory neurons exhibit mitochondrial abnormalities, including alterations in axonal mitochondrial size, axonal mitochondrial membrane potential, and cellular ATP levels. Collectively, these data establish bcl-w −/− mice as an animal model of small fiber sensory neuropathy, and provide new insight regarding the role of bcl-w and of mitochondria in preventing axonal degeneration. PMID:21289171

Regulatable Transgene Expression for Prevention of Chemotherapy-Induced Peripheral Neuropathy.

PubMed

Kawata, Daisuke; Wu, Zetang

2017-09-15

Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating complication associated with drug treatment of cancer for which there are no effective strategies of prevention or treatment. In this study, we examined the effect of intermittent expression of neurotophin-3 (NT-3) or interleukin-10 (IL-10) from replication-defective herpes simplex virus (HSV)-based regulatable vectors delivered by subcutaneous inoculation to the dorsal root ganglion (DRG) on the development of paclitaxel-induced peripheral neuropathy. We constructed two different tetracycline (tet)-on-based regulatable HSV vectors, one expressing NT-3 and the other expressing IL-10, in which the transactivator expression in the tet-on system was under the control of HSV latency-associated promoter 2 (LAP-2), and expression of the transgene was controlled by doxycycline (DOX). We examined the therapeutic effect of intermittent expression of the transgene in animals with paclitaxel-induced peripheral neuropathy modeled by intraperitoneal injection of paclitaxel (16 mg/kg) once a week for 5 weeks. Intermittent expression of either NT-3 or IL-10 3 days before and 1 day after paclitaxel administration protected animals against paclitaxel-induced peripheral neuropathy over the course of 5 weeks. These results suggest the potential of regulatable vectors for prevention of chemotherapy-induced peripheral neuropathy.

Axon Transport and Neuropathy

PubMed Central

Tourtellotte, Warren G.

2017-01-01

Peripheral neuropathies are highly prevalent and are most often associated with chronic disease, side effects from chemotherapy, or toxic-metabolic abnormalities. Neuropathies are less commonly caused by genetic mutations, but studies of the normal function of mutated proteins have identified particular vulnerabilities that often implicate mitochondrial dynamics and axon transport mechanisms. Hereditary sensory and autonomic neuropathies are a group of phenotypically related diseases caused by monogenic mutations that primarily affect sympathetic and sensory neurons. Here, I review evidence to indicate that many genetic neuropathies are caused by abnormalities in axon transport. Moreover, in hereditary sensory and autonomic neuropathies. There may be specific convergence on gene mutations that disrupt nerve growth factor signaling, upon which sympathetic and sensory neurons critically depend. PMID:26724390

Determination of Free and Total Choline and Carnitine in Infant Formula and Adult/Pediatric Nutritional Formula by Liquid Chromatography/Tandem Mass Spectrometry (LC/MS/MS): Single-Laboratory Validation, First Action 2015.10.

PubMed

Ellingson, David J; Shippar, Jeffrey J; Gilmore, Justin M

2016-01-01

Analytical methods for the analysis of both L-carnitine and choline are needed for reliable and accurate determination in infant formula and adult/pediatric nutritional formula. These compounds are different in how they are utilized by the human body, but are structurally similar. L-carnitine and choline are quaternary ammonium compounds, enabling both to be retained under acidic conditions with strong cation exchange (SCX) chromatography. This method analyzes both compounds simultaneously as either the free forms or as a total amount that includes bound sources such as phosphatidylcholine or acetylcarnitine. The free analysis consists of water extraction and analysis by LC/MS/MS, while the total analysis consists of extraction by acid assisted microwave hydrolysis and analysis by LC/MS/MS. Calibration standards used for calculations are extracted with all samples in the batch. A single laboratory validation (SLV) was performed following the guidelines of the AOAC Stakeholder Panel on Infant Formula and Adult Nutritionals (SPIFAN) utilizing the kit of materials provided. The results achieved meet the requirements of SMPR 2012.010 and 2012.013 for L-carnitine and total choline, respectively.

Non-stoichiometric O-acetylation of Shigella flexneri 2a O-specific polysaccharide: synthesis and antigenicity.

PubMed

Gauthier, Charles; Chassagne, Pierre; Theillet, François-Xavier; Guerreiro, Catherine; Thouron, Françoise; Nato, Farida; Delepierre, Muriel; Sansonetti, Philippe J; Phalipon, Armelle; Mulard, Laurence A

2014-06-28

Synthetic functional mimics of the O-antigen from Shigella flexneri 2a are seen as promising vaccine components against endemic shigellosis. Herein, the influence of the polysaccharide non-stoichiometric di-O-acetylation on antigenicity is addressed for the first time. Three decasaccharides, representing relevant internal mono- and di-O-acetylation profiles of the O-antigen, were synthesized from a pivotal protected decasaccharide designed to tailor late stage site-selective O-acetylation. The latter was obtained via a convergent route involving the imidate glycosylation chemistry. Binding studies to five protective mIgGs showed that none of the acetates adds significantly to broad antibody recognition. Yet, one of the five antibodies had a unique pattern of binding. With IC50 in the micromolar to submicromolar range mIgG F22-4 exemplifies a remarkable tight binding antibody against diversely O-acetylated and non-O-acetylated fragments of a neutral polysaccharide of medical importance.

The Relationship Between Total Neuropathy Score-reduced, Neuropathy Symptoms and Function

NASA Astrophysics Data System (ADS)

Abulhaija, Ashraf

Chemotherapy Induced Peripheral Neuropathy (CIPN) is a common problem among cancer patients who receive a wide range of chemotherapy. This problem causes a decline in quality of life and increased disabilities. CIPN assessment instruments are either subjective, objective, or a combination of both. So far, there is no agreement on the best way for assessment. The goal of this study was to explore the relationships among subjective and objective CIPN assessment instruments. Specifically, this study aimed to 1) evaluate the relationship between the Total Neuropathy Score-reduced (mainly objective) and patients' function, as measured by the interference scale of the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (subjective); and 2) evaluate the relationship between the Total Neuropathy Score-reduced and neuropathy symptom experience, as measured by the symptom experience scale of the Chemotherapy-Induced Peripheral Neuropathy Assessment Tool (Subjective). To achieve those aims, a secondary data analysis for 56 participants who participated in a study entitled: Group Acupuncture for Treatment of Neuropathy from Chemotherapy was done. After Pearson correlations were calculated, the study found that there is a positive, weak relationship between the TNSr and the symptom experience scale of the CIPNAT(r=0.34). A positive, week relationship was found between the TNSr and the interference with activity scale of the CIPNAT(r=0.28). These results suggest that objective and subjective assessment are not highly correlated, and likely measure different aspects of CIPN. A comprehensive assessment approach is needed for decision making in the clinical oncology setting.

Organic cation/carnitine transporter OCTN3 is present in astrocytes and is up-regulated by peroxisome proliferators-activator receptor agonist.

PubMed

Januszewicz, Elzbieta; Pajak, Beata; Gajkowska, Barbara; Samluk, Lukasz; Djavadian, Rouzanna L; Hinton, Barry T; Nałecz, Katarzyna A

2009-12-01

In the brain beta-oxidation, which takes place in astrocytes, is not a major process of energy supply. Astrocytes synthesize important lipid metabolites, mainly due to the processes taking place in peroxisomes. One of the compounds necessary in the process of mitochondrial beta-oxidation and export of acyl moieties from peroxisomes is l-carnitine. Two Na-dependent plasma membrane carnitine transporters were shown previously to be present in astrocytes: a low affinity amino acid transporter B(0,+) and a high affinity cation/carnitine transporter OCTN2. The expression of OCTN2 is known to increase in peripheral tissues upon the stimulation of peroxisome proliferators-activator receptor alpha (PPARalpha), a nuclear receptor known to up-regulate several enzymes involved in fatty acid metabolism. The present study was focused on another high affinity carnitine transporter-OCTN3, its presence, regulation and activity in astrocytes. Experiments using the techniques of real-time PCR, Western blot and immunocytochemistry analysis demonstrated the expression of octn3 in rat astrocytes and, out of two rat sequences ascribed as similar to mouse OCTN3, XM_001073573 was found in these cells. PPARalpha activator-2-[4-chloro-6-[(2,3-dimethylphenyl)amino]-2-pyrimidinyl]thio]acetic acid (WY-14,643) stimulated by 50% expression of octn3, while, on the contrary to peripheral tissues, it did not change the expression of octn2. This observation was correlated with an increased Na-independent activity of carnitine transport. Analysis by transmission electron microscopy showed an augmented intracellular localization of OCTN3 upon PPARalpha stimulation, mainly in peroxisomes, indicating a physiological role of OCTN3 as peroxisomal membrane transporter. These observations point to an important role of OCTN3 in peroxisomal fatty acid metabolism in astrocytes.

Whole-Exome Sequencing Identifies Homozygous AFG3L2 Mutations in a Spastic Ataxia-Neuropathy Syndrome Linked to Mitochondrial m-AAA Proteases

PubMed Central

Martinelli, Paola; Cherukuri, Praveen F.; Teer, Jamie K.; Hansen, Nancy F.; Cruz, Pedro; Mullikin for the NISC Comparative Sequencing Program, James C.; Blakesley, Robert W.; Golas, Gretchen; Kwan, Justin; Sandler, Anthony; Fuentes Fajardo, Karin; Markello, Thomas; Tifft, Cynthia; Blackstone, Craig; Rugarli, Elena I.; Langer, Thomas; Gahl, William A.; Toro, Camilo

2011-01-01

We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C) in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7). Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28), a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2Y616C gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2Y616C complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other “mitochondrial” features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias. PMID:22022284

Hereditary neuropathy with liability to pressure palsies presenting with sciatic neuropathy.

PubMed

Topakian, Raffi; Wimmer, Sibylle; Pischinger, Barbara; Pichler, Robert

2014-10-17

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal-dominant disorder associated with recurrent mononeuropathies following compression or trivial trauma. Reports on sciatic neuropathy as the presenting manifestation of HNPP are very scarce. We report on a 21-year-old previously healthy man who was admitted with sensorimotor deficits in his left leg. He had no history of preceding transient episodes of weakness or sensory loss. Clinical and electrophysiological examinations were consistent with sciatic neuropathy. Cerebrospinal fluid investigation and MRI of the nerve roots, plexus, and sciatic nerve did not indicate the underlying aetiology. When extended electrophysiological tests revealed multiple subclinical compression neuropathies in the upper limbs, HNPP was contemplated and eventually confirmed by genetic testing. 2014 BMJ Publishing Group Ltd.

Protection of rats against 3-butene-1,2-diol-induced hepatotoxicity and hypoglycemia by N-acetyl-L-cysteine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sprague, Christopher L.; Elfarra, Adnan A.

2005-09-15

3-Butene-1,2-diol (BDD), an allylic alcohol and major metabolite of 1,3-butadiene, has previously been shown to cause hepatotoxicity and hypoglycemia in male Sprague-Dawley rats, but the mechanisms of toxicity were unclear. In this study, rats were administered BDD (250 mg/kg) or saline, ip, and serum insulin levels, hepatic lactate levels, and hepatic cellular and mitochondrial GSH, GSSG, ATP, and ADP levels were measured 1 or 4 h after treatment. The results show that serum insulin levels were not causing the hypoglycemia and that the hypoglycemia was not caused by an enhancement of the metabolism of pyruvate to lactate because hepatic lactatemore » levels were either similar (1 h) or lower (4 h) than controls. However, both hepatic cellular and mitochondrial GSH and GSSG levels were severely depleted 1 and 4 h after treatment and the mitochondrial ATP/ADP ratio was also lowered 4 h after treatment relative to controls. Because these results suggested a role for hepatic cellular and mitochondrial GSH in BDD toxicity, additional rats were administered N-acetyl-L-cysteine (NAC; 200 mg/kg) 15 min after BDD administration. NAC treatment partially prevented depletion of hepatic cellular and mitochondrial GSH and preserved the mitochondrial ATP/ADP ratio. NAC also prevented the severe depletion of serum glucose concentration and the elevation of serum alanine aminotransferase activity after BDD treatment without affecting the plasma concentration of BDD. Thus, depletion of hepatic cellular and mitochondrial GSH followed by the decrease in the mitochondrial ATP/ADP ratio was likely contributing to the mechanisms of hepatotoxicity and hypoglycemia in the rat.« less

Nrf2 inhibits oxaliplatin-induced peripheral neuropathy via protection of mitochondrial function.

PubMed

Yang, Yang; Luo, Lan; Cai, Xueting; Fang, Yuan; Wang, Jiaqi; Chen, Gang; Yang, Jie; Zhou, Qian; Sun, Xiaoyan; Cheng, Xiaolan; Yan, Huaijiang; Lu, Wuguang; Hu, Chunping; Cao, Peng

2018-05-20

Oxaliplatin-induced peripheral neuropathy (OIPN) is a severe, dose-limiting toxicity associated with cancer chemotherapy. The efficacy of antioxidant administration in OIPN is debatable, as the promising preliminary results obtained with a number of antioxidants have not been confirmed in larger clinical trials. Besides its antioxidant activity, the transcription factor, nuclear factor-erythroid 2 (NF-E2) p45-related factor 2 (Nrf2) plays a crucial role in the maintenance of mitochondrial homeostasis, and mitochondrial dysfunction is a key contributor to OIPN. Here, we have investigated the protective properties of Nrf2 in OIPN. Nrf2 -/- mice displayed severe mechanical allodynia and cold sensitivity and thus experienced increased peripheral nervous system injury compared to Nrf2 +/+ mice. Furthermore, Nrf2 knockout aggravated oxaliplatin-induced reactive oxygen species production, decreased the mitochondrial membrane potential, led to abnormal intracellular calcium levels, and induced cytochrome c-related apoptosis and overexpression of the TRP protein family. Sulforaphane-induced activation of the Nrf2 signaling pathway alleviated morphological alterations, mitochondrial dysfunction in dorsal root ganglion neurons, and nociceptive sensations in mice. Our findings reveal that Nrf2 may play a critical role in ameliorating OIPN, through protection of mitochondrial function by alleviating oxidative stress and inhibiting TRP protein family expression. This suggests that pharmacological or therapeutic activation of Nrf2 may be used to prevent or slow down the progression of OIPN. Copyright © 2018 Elsevier Inc. All rights reserved.

Lowering plasma 1-deoxysphingolipids improves neuropathy in diabetic rats.

PubMed

Othman, Alaa; Bianchi, Roberto; Alecu, Irina; Wei, Yu; Porretta-Serapiglia, Carla; Lombardi, Raffaella; Chiorazzi, Alessia; Meregalli, Cristina; Oggioni, Norberto; Cavaletti, Guido; Lauria, Giuseppe; von Eckardstein, Arnold; Hornemann, Thorsten

2015-03-01

1-Deoxysphingolipids (1-deoxySLs) are atypical neurotoxic sphingolipids that are formed by the serine-palmitoyltransferase (SPT). Pathologically elevated 1-deoxySL concentrations cause hereditary sensory and autonomic neuropathy type 1 (HSAN1), an axonal neuropathy associated with several missense mutations in SPT. Oral L-serine supplementation suppressed the formation of 1-deoxySLs in patients with HSAN1 and preserved nerve function in an HSAN1 mouse model. Because 1-deoxySLs also are elevated in patients with type 2 diabetes mellitus, L-serine supplementation could also be a therapeutic option for diabetic neuropathy (DN). This was tested in diabetic STZ rats in a preventive and therapeutic treatment scheme. Diabetic rats showed significantly increased plasma 1-deoxySL concentrations, and L-serine supplementation lowered 1-deoxySL concentrations in both treatment schemes (P < 0.0001). L-serine had no significant effect on hyperglycemia, body weight, or food intake. Mechanical sensitivity was significantly improved in the preventive (P < 0.01) and therapeutic schemes (P < 0.001). Nerve conduction velocity (NCV) significantly improved in only the preventive group (P < 0.05). Overall NCV showed a highly significant (P = 5.2E-12) inverse correlation with plasma 1-deoxySL concentrations. In summary, our data support the hypothesis that 1-deoxySLs are involved in the pathology of DN and that an oral L-serine supplementation could be a novel therapeutic option for treating DN. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

Effects of resveratrol, oxyresveratrol, and their acetylated derivatives on cellular melanogenesis.

PubMed

Park, Jiaa; Park, Joon Heum; Suh, Hwa-Jin; Lee, In Chul; Koh, Jaesook; Boo, Yong Chool

2014-07-01

Resveratrol and oxyresveratrol are naturally occurring phenolic compounds with various bioactivities, but their uses in cosmetics have been partly limited by their chemical instabilities. This study was performed to examine the anti-melanogenic effects of the acetylated derivatives from resveratrol and oxyresveratrol. Resveratrol and oxyresveratrol were chemically modified to triacetyl resveratrol and tetraacetyl oxyresveratrol, respectively. The acetylated compounds were less susceptible than the parent compounds to oxidative discoloration. The acetylated compounds inhibited the activities of tyrosinases less than parent compounds in vitro, but they were as effective at cellular melanogenesis inhibition, indicating bioconversion to parent compounds inside cells. Supporting this notion, the parent compounds were regenerated when the acetylated compounds were digested with cell lysates. Although resveratrol and triacetyl resveratrol inhibited tyrosinase activity less effectively than oxyresveratrol and tetraacetyl oxyresveratrol in vitro, they inhibited cellular melanogenesis more effectively. This discrepancy was explained by strong inhibition of tyrosinase expression by resveratrol and triacetyl resveratrol. Experiments using a reconstituted skin model indicated that resveratrol derivatives can affect melanin synthesis and cell viability to different extents. Collectively, this study suggests that acetylated derivatives of resveratrol have great potential as anti-melanogenic agents for cosmetic use in terms of efficacy, safety, and stability.

A multi-ingredient containing carbohydrate, proteins L-glutamine and L-carnitine attenuates fatigue perception with no effect on performance, muscle damage or immunity in soccer players.

PubMed

Naclerio, Fernando; Larumbe-Zabala, Eneko; Cooper, Robert; Allgrove, Judith; Earnest, Conrad P

2015-01-01

We investigated the effects of ingesting a multi-ingredient (53 g carbohydrate, 14.5 g whey protein, 5 g glutamine, 1.5 g L-carnitine-L-tartrate) supplement, carbohydrate only, or placebo on intermittent performance, perception of fatigue, immunity, and functional and metabolic markers of recovery. Sixteen amateur soccer players ingested their respective treatments before, during and after performing a 90-min intermittent repeated sprint test. Primary outcomes included time for a 90-min intermittent repeated sprint test (IRS) followed by eleven 15 m sprints. Measurements included creatine kinase, myoglobin, interleukine-6, Neutrophil; Lymphocytes and Monocyte before (pre), immediately after (post), 1 h and 24 h after exercise testing period. Overall, time for the IRS and 15 m sprints was not different between treatments. However, the perception of fatigue was attenuated (P<0.001) for the multi-ingredient (15.9±1.4) vs. placebo (17.8±1.4) but not for the carbohydrate (17.0±1.9) condition. Several changes in immune/inflammatory indices were noted as creatine kinase peaked at 24 h while Interleukin-6 and myoglobin increased both immediately after and at 1 h compared with baseline (P<0.05) for all three conditions. However, Myoglobin (P<0.05) was lower 1 h post-exercise for the multi-ingredient (241.8±142.6 ng·ml(-1)) and CHO (265.4±187.8 ng·ml(-1)) vs. placebo (518.6±255.2 ng·ml(-1)). Carbohydrate also elicited lower neutrophil concentrations vs. multi-ingredient (3.9±1.5 10(9)/L vs. 4.9±1.8 10(9)/L, P = 0.016) and a reduced (P<0.05) monocytes count (0.36±0.09 10(9)/L) compared to both multi-ingredient (0.42±0.09 10(9)/L) and placebo (0.42±0.12 10(9)/L). In conclusion, multi-ingredient and carbohydrate supplements did not improve intermittent performance, inflammatory or immune function. However, both treatments did attenuate serum myoglobin, while only carbohydrate blunted post-exercise leukocytosis.

A Multi-Ingredient Containing Carbohydrate, Proteins L-Glutamine and L-Carnitine Attenuates Fatigue Perception with No Effect on Performance, Muscle Damage or Immunity in Soccer Players

PubMed Central

Naclerio, Fernando; Larumbe-Zabala, Eneko; Cooper, Robert; Allgrove, Judith; Earnest, Conrad P.

2015-01-01

We investigated the effects of ingesting a multi-ingredient (53g carbohydrate, 14.5g whey protein, 5g glutamine, 1.5g L-carnitine-L-tartrate) supplement, carbohydrate only, or placebo on intermittent performance, perception of fatigue, immunity, and functional and metabolic markers of recovery. Sixteen amateur soccer players ingested their respective treatments before, during and after performing a 90-min intermittent repeated sprint test. Primary outcomes included time for a 90-min intermittent repeated sprint test (IRS) followed by eleven 15 m sprints. Measurements included creatine kinase, myoglobin, interleukine-6, Neutrophil; Lymphocytes and Monocyte before (pre), immediately after (post), 1h and 24h after exercise testing period. Overall, time for the IRS and 15 m sprints was not different between treatments. However, the perception of fatigue was attenuated (P<0.001) for the multi-ingredient (15.9±1.4) vs. placebo (17.8±1.4) but not for the carbohydrate (17.0±1.9) condition. Several changes in immune/inflammatory indices were noted as creatine kinase peaked at 24h while Interleukin-6 and myoglobin increased both immediately after and at 1h compared with baseline (P<0.05) for all three conditions. However, Myoglobin (P<0.05) was lower 1h post-exercise for the multi-ingredient (241.8±142.6 ng·ml-1) and CHO (265.4±187.8 ng·ml-1) vs. placebo (518.6±255.2 ng·ml-1). Carbohydrate also elicited lower neutrophil concentrations vs. multi-ingredient (3.9±1.5 109/L vs. 4.9±1.8 109/L, P = 0.016) and a reduced (P<0.05) monocytes count (0.36±0.09 109/L) compared to both multi-ingredient (0.42±0.09 109/L) and placebo (0.42±0.12 109/L). In conclusion, multi-ingredient and carbohydrate supplements did not improve intermittent performance, inflammatory or immune function. However, both treatments did attenuate serum myoglobin, while only carbohydrate blunted post-exercise leukocytosis. PMID:25915424

Familial auditory neuropathy.

PubMed

Wang, Qiuju; Gu, Rui; Han, Dongyi; Yang, Weiyan

2003-09-01

Auditory neuropathy is a sensorineural hearing disorder characterized by absent or abnormal auditory brainstem responses and normal cochlear outer hair cell function as measured by otoacoustic emission recordings. Many risk factors are thought to be involved in its etiology and pathophysiology. Four Chinese pedigrees with familial auditory neuropathy were presented to demonstrate involvement of genetic factors in the etiology of auditory neuropathy. Probands of the above-mentioned pedigrees, who had been diagnosed with auditory neuropathy, were evaluated and followed in the Department of Otolaryngology-Head and Neck Surgery, China People Liberation Army General Hospital (Beijing, China). Their family members were studied, and the pedigree maps established. History of illness, physical examination, pure-tone audiometry, acoustic reflex, auditory brainstem responses, and transient evoked and distortion-product otoacoustic emissions were obtained from members of these families. Some subjects received vestibular caloric testing, computed tomography scan of the temporal bone, and electrocardiography to exclude other possible neuropathic disorders. In most affected patients, hearing loss of various degrees and speech discrimination difficulties started at 10 to 16 years of age. Their audiological evaluation showed absence of acoustic reflex and auditory brainstem responses. As expected in auditory neuropathy, these patients exhibited near-normal cochlear outer hair cell function as shown in distortion product otoacoustic emission recordings. Pure-tone audiometry revealed hearing loss ranging from mild to profound in these patients. Different inheritance patterns were observed in the four families. In Pedigree I, 7 male patients were identified among 43 family members, exhibiting an X-linked recessive pattern. Affected brothers were found in Pedigrees II and III, whereas in pedigree IV, two sisters were affected. All the patients were otherwise normal without evidence of

Diabetic Neuropathy: Mechanisms to Management