Case Report: Carnitine Palmitoyl Transferase II (CPT II) Deficiency

Carnitine Palmitoyl Transferase II (CPTII) is a very important enzyme that helps with the oxidation of long-chain fatty acid to produce energy. Deficiency in CPTII will lead to energy deficiency in the case of fasting and the accumulation of the long chain fatty in the body. There are three types of CPT II deficiency, the myopathic form, the severe infantile hepatocardiomuscular form and the lethal neonatal form. They are all inherited as an autosomal recessive. Diagnosis of the CPTII are 1) tandem mass spectrometry (MS/MS) in adult form and 2) CPTII polymorphism (F352C), which is linked to reducing the activity of CPTII in infantile form [1]. Glucose is the primary management and medium-chain fatty acid is an alternative due to the bypass of the CPTII enzyme in the pathway. For the prevention of CPTII deficiency are to avoid long chain fatty acid (C12-fatty acid), fasting, prolonged exercise, known triggers, and certain medications such as anti-epileptics and general anesthesia. During the rhabdomyolysis and myoglobinuria attack, it is very important to maintain hydration to avoid acute renal failure. If, however, renal failure occurs, dialysis is recommended. We present a case of a 27-year-old African American woman with the significant past medical history of CPT II deficiency leading to recurrent rhabdomyolysis and myoglobinuria. Together with all the research studies from diagnosis to treatment of CPTII deficiency will help in clinical management of patients. And this case report will add to the existing case reports of patients who have CPTII deficiency in terms of how we diagnose, how we treat, and how we prevent symptoms from re-occurring.

Mitochondrial carnitine palmitoyltransferase-Ⅱ dysfunction: A possible novel mechanism for nonalcoholic fatty liver disease in hepatocarcinogenesis

Nonalcoholic fatty liver disease(NAFLD)or metabolic-associated fatty liver disease has been characterized by the lipid accumulation with injury of hepatocytes and has become one of the most common chronic liver diseases in the world.The complex mechanisms of NAFLD formation are still under identification.Carnitine palmitoyltransferase-Ⅱ(CPT-Ⅱ)on inner mitochondrial membrane(IMM)regulates long chain fatty acidβ-oxidation,and its abnormality has had more and more attention paid to it by basic and clinical research in NAFLD.The sequences of its peptide chain and DNA nucleotides have been identified,and the catalytic activity of CPT-Ⅱ is affected on its gene mutations,deficiency,enzymatic thermal instability,circulating carnitine level and so on.Recently,the CPT-Ⅱ dysfunction has been discovered in models of liver lipid accumulation.Meanwhile,the malignant transformation of hepatocyte-related CD44^(+) stem T cell activation,high levels of tumor-related biomarkers(AFP,GPC3)and abnormal activation of Wnt3a expression as a key signal molecule of the Wnt/β-catenin pathway run parallel to the alterations of hepatocyte pathology.This review focuses on some of the progress of CPT-Ⅱ inactivity on IMM with liver fatty accumulation as a possible novel pathogenesis for NAFLD in hepatocarcinogenesis.

Progression of diethylnitrosamine-induced hepatic carcinogenesis in carnitine-depleted rats

AIM:To investigate whether carnitine deficiency is a risk factor during the development of diethylnitrosamine (DENA)-induced hepatic carcinogenesis. METHODS:A total of 60 male Wistar albino rats were divided into six groups with 10 animals in each group.Rats in group 1(control group)received a single intraperitoneal(i.p.)injection of normal saline. Animals in group 2(carnitine-supplemented group) were given L-carnitine(200 mg/kg per day)in drinking water for 8 wk.Animals in group 3(carnitine-depleted group)were given D-carnitine(200 mg/kg per day)and mildronate(200 mg/kg per day)in drinking water for 8 wk.Rats in group 4(DENA group)were injected with a single dose of DENA(200 mg/kg,i.p.)and 2 wk later received a single dose of carbon tetrachloride(2 mL/kg) by gavage as 1:1 dilution in corn oil.Animals in group 5(DENA-carnitine depleted group)received the same treatment as group 3 and group 4.Rats in group 6 (DENA-carnitine supplemented group)received the same treatment as group 2 and group 4.RESULTS:Administration of DENA resulted in a significant increase in alanine transaminase(ALT), gamma-glutamyl transferase(G-GT),alkaline phosphatase(ALP),total bilirubin,thiobarbituric acid reactive substances(TBARS)and total nitrate/ nitrite(NOx)and a significant decrease in reduced glutathione(GSH),glutathione peroxidase(GSHPx), catalase(CAT)and total carnitine content in liver tissues.In the carnitine-depleted rat model,DENA induced a dramatic increase in serum ALT,G-GT,ALP and total bilirubin,as well as a progressive reduction in total carnitine content in liver tissues.Interestingly, L-carnitine supplementation resulted in a complete reversal of the increase in liver enzymes,TBARS and NOx,and a decrease in total carnitine,GSH,GSHPx, and CAT induced by DENA,compared with the control values.Histopathological examination of liver tissues confirmed the biochemical data,where L-carnitine prevented DENA-induced hepatic carcinogenesis while D-carnitine-mildronate aggravated DENA-induced hepatic damage. CONCLUSION:Data from this study suggest for the first time that:(1)carnitine deficiency is a risk factor and should be viewed as a mechanism in DENA- induced hepatic carcinogenesis;(2)oxidative stress plays an important role but is not the only cause of DENA-induced hepatic carcinogenesis;and(3) long-term L-carnitine supplementation prevents the development of DENA-induced liver cancer.

Acylcarnitine: Useful biomarker for early diagnosis of hepatocellular carcinoma in non-steatohepatitis patients

BACKGROUND Early diagnosis of hepatocellular carcinoma(HCC)is necessary to improve the prognosis of patients.However,the currently available tumor biomarkers are insufficient for the early detection of HCC.Acylcarnitine is essential in fatty acid metabolic pathways.A recent study reported that a high level of acylcarnitine may serve as a useful biomarker for the early diagnosis of HCC in steatohepatitis(SH)patients.In contrast,another study reported that the level of acetylcarnitine(AC2)-one of the acylcarnitine species-in non-SH patients with HCC was decreased vs that reported in those without HCC.AIM To investigate the usefulness of acylcarnitine as a biomarker for the early diagnosis of HCC in non-SH patients.METHODS Thirty-three non-SH patients(14 with HCC and 19 without HCC)were enrolled in this study.Blood samples were obtained from patients at the time of admission.The levels of acylcarnitine and AC2 in the serum were determined through tandem mass spectrometry.The levels of vascular endothelial growth factor(VEGF)and VEGF receptor 2(VEGFR-2)were determined by enzymelinked immunosorbent assay.Univariate and multivariate analyses were used to determine early diagnostic factors of HCC.RESULTS The level of acylcarnitine was significantly lower in non-SH patients with HCC vs those without HCC(P<0.05).In contrast,the level of lens culinaris agglutininreactive fraction ofα-fetoprotein(AFP)-AFP-L3%-was significantly higher in non-SH patients with HCC vs those without HCC(P<0.05).However,the levels of total carnitine,free carnitine,AFP,des-γ-carboxy prothrombin,VEGF,and VEGFR-2 were not different between patients with and without HCC.The multivariate analysis showed that a low level of acylcarnitine was the only independent factor for the early diagnosis of HCC.The patients with a low level of AC2 had a significantly higher level of VEGF vs those with a high level of AC2(P<0.05).CONCLUSION The metabolic pathways of fatty acids may differ between SH HCC and non-SH HCC.Further studies are warranted to investigate these differences.

Enantiomeric Resolution on L-Carnitine Selective Polymers Prepared by Molecular Imprinting

L-carnitine selective polymers were prepared by molecular imprinting using methacrylic acid as the functional monomer. The acid function of the monomer is expected to form hydrogen bond and ionic interactions with the amine function of the target molecule L-carnitine. The imprinted polymers were used as stationary phases in high-performance liquid chromatography (HPLC). It was shown that L-carnitine imprinted polymer exhibited a higher affinity to its template molecule, while the non-imprinted polymer had no affinity to the compounds tested. Racemic carnitine hydrochloride was efficiently resolved on the L-carnitine imprinted polymer, and the separation factor is 1.9.

Changes of plasma fasting carnitine ester profile in patients with ulcerative colitis

AIM： To determine the plasma carnitine ester profile in adult patients with ulcerative culitis （UC） and compared with healthy control subjects. METHOD： Using ESI triple quadrupole tandem mass spectrometry, the carnitine ester profile was measured in 44 patients with UC and 44 age- and sex-matched healthy controls. RESULTS： There was no significant difference in the fasting free carnitine level between the patients with UC and the healthy controls. The fasting propionyl- （0.331 ± 0.019 vs 0.392 ± 0.017 μmol/L）, butyryl- （0.219 ± 0.014 vs 0.265 ± 0.012）, and isovalerylcarniUne （0.111 ± 0.008 vs 0.134 ± 0.008） levels were decreased in the UC patients. By contrast, the level of octanoyl- （0.147 ± 0.009 vs 0.114 ± 0.008）, decanoyl- （0.180 ± 0.012 vs 0.137 ± 0.008）, myristoyl- （0.048 ± 0.003 vs 0.039 ± 0.003）, palmitoyl- （0.128 ± 0.006 vs 0.109 ± 0.004）, palmitoleyl- （0.042±0.003 vs 0.031 ± 0.002） and oleylcarnitine （0.183 ± 0.007 vs 0.163 ± 0.007; P 〈 0.05 in all comparisons） were increased in the patients with UC. CONCLUSION： Our data suggest selective involvement of the carnitine esters in UC patients, probably due to their altered metabolism.

Effects of L-carnitine in patients with hepatic encephalopathy

AIM： To evaluate the influence of Locarnitine on mental conditions and ammonia effects on patients with hepatic encephalopathy （HE）. METHODS： One hundred and fifty patients （10 patients with alcoholism, 41 patients with hepatitis virus B infection, 78 patients with hepatitis C virus infection, 21 patients with cryptogenetic cirrhosis） meeting the inclusion criteria were randomized into group A receiving a 90-d treatment with L-carnitine （2 g twice a day） or into group B receiving placebo in double blind. RESULTS： At the end of the study period, a significant decrease in NI-14 fasting serum levels was found in patients with hepatic encephalopathy （P〈0.0S） after the treatment with levocarnitine （LC）. Significant differences were also found between symbol digit modalities test and block design in patients with hepatic encephalopathy （P〈0.0S）. CONCLUSION： Results of our study suggest an important protective effect of L-carnitine against ammonia-precipitated encephalopathy in cirrhotic patients.

A study of the ameliorating effects of carnitine on hepatic steatosis induced by total parenteral nutrition in rats

AIM To investigate the effects of carnitine on ameliorating hepatic steatosis induced by total parenteral nutrition (TPN) in animal model. METHODS Eighteen normal Wistar rats and 19 cirrhotic Wistar rats induced by carbon tetrachloride were randomly divided into three groups, i.e., free access to food and drink (group A), TPN (group B) and TPN+carnitine (group C) for one week, respectively. Hepatic function, histology and its fat content were determined on the 7th day. RESULTS Hepatic triglyceride (TG) and cholesterol (CHO) contents were significantly higher in groups B and C than in group A, and significantly lower in group C than in group B in both normal and cirrhotic rats (all P <0 05). Histopathological examinations revealed that hepatic steatosis was more severe in group B than in group C in both normal and cirrhotic rats. CONCLUSION Carnitine can ameliorate hepatic steatosis associated with TPN in both non cirrhotic and cirrhotic rats.

Mitochondrial carnitine palmitoyl transferase-Ⅱ inactivity aggravates lipid accumulation in rat hepatocarcinogenesis

AIM To investigate the dynamic alteration of mitochondrial carnitine palmitoyl transferase Ⅱ(CPT-Ⅱ) expression during malignant transformation of rat hepatocytes.METHODS Sprague-Dawley male rats were fed with normal, high fat(HF), and HF containing 2-fluorenylacetamide(2-FAA) diet, respectively. According to the Hematoxylin and Eosin staining of livers, rats were divided into control, fatty liver, degeneration, pre-cancerous, and cancerous groups. Liver lipids were dyed with Oil Red O, CPT-Ⅱ alterations were analyzed by immunohistochemistry, and compared with CPT-Ⅱ specific concentration(μg/mg protein). Levels of total cholesterol(Tch), triglyceride(TG), and aminotransferases [alanine aminotransferase(ALT), aspartate aminotransferase(AST)] were determined by the routine methods.RESULTS After intake of HF and/or HF+2-FAA diets, the rat livers showed mass lipid accumulation. The lipid level in the control group was significantly lower than that in other groups. The changes of serum TG and Tch levels were abnormally increasing, 2-3 times more than those in the controls(P < 0.05). During the rat liver morphological changes from normal to cancer development process with hepatocyte injury, serum AST and ALT levels were significantly higher(4-8 times, P < 0.05) than those in the control group. The specific concentration of CPT-Ⅱ in liver tissues progressively decreased during hepatocyte malignant transformation, with the lowest CPT-Ⅱ levels in the cancer group than in any of the other groups(P < 0.05).CONCLUSION Low CPT-Ⅱ expression might lead to abnormal hepatic lipid accumulation, which should promote the malignant transformation of hepatocytes.

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

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： Fifthy-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 gastrointestinal 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.

Plasma carnitine ester profile in adult celiac disease patients maintained on long-term gluten free diet

AIM： To determine the fasting plasma carnitine ester in patients with celiac disease. METHODS： We determined the fasting plasma carnitine ester profile using ESI triple quadrupol mass spectrometry in 33 adult patients with biopsy-confirmed maturity onset celiac disease maintained on long term gluten free diet. RESULTS： The level of free camibine did not differ as the celiac disease patients were compared with the healthy controls, whereas the acetylcarnitine level was markedly reduced （4.703± 0.205 vs 10.227 ± 0.368 nmol/mL, P〈0.01）. The level of propionylcarnitine was 61.5%, butyrylcarnitine 56.9%, hexanoylcarnitine 75%, octanoylcarnitine 71.1%, octenoylcarnitine 52.1%, decanoylcarnitine 73.1%, cecenoylcarnitine 58.3%, lauroylcarnitine 61.5%, miristoylcarnitine 66.7%, miristoleylcarnitine 62.5% and oleylcarnitine 81.1% in the celiac disease patients compared to the control values, respectively （P〈0.01）. CONCLUSION： The marked decrease of circulating acetylcarnitine with 50-80 % decrease of 11 other carnitine esters shows that the carnitine ester metabolism can be influenced even in clinically asymptomatic and well being adult celiac disease patients, and gluten withdrawal alone does not necessarily normalize all elements of the disturbed carnitine homeostasis.

Autism and carnitine: A possible link

Patients with autism spectrum disorders(ASD) present deficits in social interactions and communication, they also show limited and stereotypical patterns of behaviors and interests. The pathophysiological bases of ASD have not been defined yet. Many factors seem to be involved in the onset of this disorder. These include genetic and environmental factors, but autism is not linked to a single origin, only. Autism onset can be connected with various factors such as metabolic disorders: including carnitine deficiency. Carnitine is a derivative of two amino acid lysine and methionine. Carnitine is a cofactor for a large family of enzymes: the carnitine acyltransferases. Through their action these enzymes(and L-carnitine) are involved in energy production and metabolic homeostasis. Some people with autism(less than 20%) seem to have L-carnitine metabolism disorders and for these patients, a dietary supplementation with Lcarnitine is beneficial. This review summarizes the available information on this topic.

L-carnitine protects C2C12 cells against mitochondrial superoxide overproduction and cell death

AIM To identify and characterize the protective effect that L-carnitine exerted against an oxidative stress in C2C12 cells.METHODS Myoblastic C2C12 cells were treated with menadione, a vitamin K analog that engenders oxidative stress, and the protective effect of L-carnitine(a nutrient involved in fatty acid metabolism and the control of the oxidative process), was assessed by monitoring various parameters related to the oxidative stress, autophagy and cell death. RESULTS Associated with its physiological function, a muscle cell metabolism is highly dependent on oxygen and may produce reactive oxygen species(ROS), especially under pathological conditions. High levels of ROS are known to induce injuries in cell structure as they interact at many levels in cell function. In C2C12 cells, a treatment with menadione induced a loss of transmembrane mitochondrial potential, an increase in mitochondrial production of ROS; it also induces autophagy and was able to provoke cell death. Pre-treatment of the cells with L-carnitine reduced ROS production, diminished autophagy and protected C2C12 cells against menadione-induced deleterious effects. CONCLUSION In conclusion, L-carnitine limits the oxidative stress in these cells and prevents cell death.

Diabetic Cardiovascular Risk and Carnitine Deficiency <br/>—Carnitine Deficiency in Clinical Diabetes Mellitus

Background: Type 1 diabetes mellitus increases the risk of coronary heart disease. The Pittsburgh IDDM morbidity and mortality study reported greater than 10 fold coronary heart disease mortality compared with US national data?[1]. Adults with diabetes have heart disease death rates 2 to 4 times higher than adults without diabetes [2]. Diabetic cardiomyopathy explains much of this survival difference and carnitine deficiency is a cause of cardiomyopathy. Research Design and Methods: Adult subjects (40) with type 1 diabetes mellitus were seen for a routine annual visit having no clinical complaints. Fasting serum samples were collected for annual chemistries and the measurement of carnitine. Results: The mean total (40.8 ± 8.8) [40 - 80 nmol/ml] and free (32.9 ± 7.9) [30 - 60 nmol/ml] carnitine levels for this group included 43% low total and 28% low free carnitine. The mean esterified/free (E/F) carnitine ratio (0.25 ± 0.09) for this group was elevated indicating carnitine insufficiency. Conclusions: Fatty acids are the primary energy source for diabetic heart muscle, and carnitine is essential for intracellular fatty acid transport and ATP production. Therefore, mild carnitine deficiency can compromise fatty acid energy production in a failing heart. Carnitine deficiency in subjects at high risk for cardiovascular failure is a possible unrecognized reason for the 4 fold increased death rate in patients with type 1 diabetes. Supplementation with oral carnitine could reduce that increased risk of heart failure, in patients with type 1 diabetes. Intravenous carnitine may be life saving when managing acute cardiac failure in patients with diabetes mellitus. Normal carnitine levels in patients with type 1 diabetes may provide a biochemical environment that prevents the long recognized idiopathic heart failure that occurs in insulin requiring diabetics as first reported in the 1974 Framingham Study.

Malonylcarnitine in Newborns with Non-syndromic Cleft Lip with or without Cleft Palate

Aim Malonyl-CoA is regarded as a key signaling molecule in mammalian ceils. It is converted to acetyl-CoA, and to a lesser extent, to malonyl acid and malonylcamitine （C3DC）. Availability of carnitine has been reported to be essential for the developing fetus. The objectives of the present study were to analyze associations of malonylcarnitine, acetylcarnitine （C2）, and free carnitine （CO） in subjects with orofacial clefts. Methodology We performed a retrospective analysis of carnitine concentration obtained from a newborn screening program carried out in our institution. Concentrations of whole blood malonylcarnitine, acetylcarnitine, and free carnitine were measured using tandem mass spectrometry. The study group consisted of 51 children with nonsyndromic cleft lip with or without cleft palate. In total, 106 healthy children without congenital anomalies served as controls. Cut-off points were established using likeli-hood ratio values. Results The mean concentration of malonylcarnitine in the cleft group was lower than that of the control group, 0.048 μmol.L^1 vs. 0.058 μmol.L^-1, respectively （P=-0.009）. In patients with orofacial cleft, low malonylcarnitine levels （〈0.047 μmol.L-1） were 1.7 times more predominant than in healthy individuals （P=-0.03）. The mean concentration of acetylcarnitine was also lower in affected newborns in comparison to controls, 33.8 μol.L^-1 vs. 37.8 μmol·L^-1, respectively （P=-0.026）. After analysis of acetylearnitine and free carnitine concentrations, the likelihood ratio test did not indicate valuable cut-offpoints. Conclusion The study provides initial data indicating a potential association between decreased malonylcarnitine and abnormal palatogenesis.

Carnitine Deficiency and Improvement of Muscle Cramp by Administration of Carnitine in Patients with Liver Cirrhosis

Aim: We measured carnitine levels in patients with carnitine including dialysis patients, and examined whether administration of L-carnitine improved muscle symptoms. Methods: We measured carnitine levels in 27 patients with liver cirrhosis who were receiving treatment in our hospital, and administered L-carnitine (600 mg - 1800 mg) to patients having muscle cramps for approximately one month and examined the presence/absence of the symptom. We measured carnitine concentration before and after dialysis, before dialysis after the administration to eight dialysis patients, before and after the administration to 19 nondialytic patients. Results: The total carnitine levels before the dialysis of dialysis patients were an average of 42.2 μmol/L and fell to 17.7 μmol/L after more dialysis, but it was increased to 155 μmol/L after the administration of L-carnitine. In the nondialytic patients, the total carnitine levels were significantly increased from 71.7 μmol/L to 101.7 μmol/L after the administration of L-carnitine (P = 0.038). For symptomatic patients, significant improvement of muscle clamps was observed in the L-carnitine administrated group when compared with the non-administrated group (P = 0.0002). Conclusions: Total carnitine levels were low even before dialysis in the dialysis patients with liver cirrhosis in particular and they further decreased after the dialysis. Administration of L-carnitine increased the total carnitine levels and improved the symptom. Based on these results, we conclude that L-carnitine is useful for carnitine deficiency in patients with liver cirrhosis.

Quality Evaluation of Carnitine for Proper Use of Supplement

In recent years, consumers are becoming more health-conscious. Supplements are becoming popular as they can be purchased easily. In Japan, the “Food with Function Claims” system began in 2015;the market for supplements is expected to continue to expand. However, the use of some supplements has not been supported with sufficient scientific evidence;some products have even caused health problems. In addition, consumers may not be able to make correct decisions based on the information from the Internet. Unlike medicine, the instruction on the usage of supplements is not precise. Therefore, improving the quality of the information on the supplements will become more necessary in the future. This study aims to improve the quality of the information on supplements by surveying the disintegration and dissolution behavior of the carnitine-containing supplements and evaluated their quality. The products tested here were supplements containing commercial carnitine. Disintegration test and dissolution test were conducted according to the Japanese Pharmacopoeia. Carnitine was quantified by high-performance liquid chromatography. The disintegration tests revealed that the products had different disintegration times, varying from 35 to 100 minutes;some products took more than 5 hours to disintegrate. Thus, some products had a slow rise in their dissolution rate. These results suggest that the carnitine-containing supplements used in this study may affect the absorption process. Therefore, in the case of oral administration, the expected effect might not be achieved depending on the product.

Carnitine palmitoyl transferase 1C regulates tumor cell senescence

OBJECTIVE Passage-dependent cel ular senescence is a complex process limiting the proliferative lifespan of tumor cells but the mechanism of this process is not understood.METHODS Replicative senescenceof pancreatic carcinoma-derived PANC-1 cells wasanalyzed.Metabolomics and transcriptomic analyses were performed to find endogenous metabolites changed andassociated genes.Mitochondrial function,cell survival andtumorigenesis of replicative senescent PANC-1 cellswere analyzed.PANC-1 cells were transfected with RNAi CPT1C to specifically knockdown CPT1C expressions,then mitochondrial function,cellular senescence,cell survival and tumorigenesis were investigated.MDA-MB-231,HCT116,A549,MCF7,and He Lacells werealso transfected with si RNA CPT1C and cellular senescence were monitored.RESULTS Replicative senescenceof PANC-1 cells was confirmed.Metabolomic and transcriptomicanalyses revealed that acylcarnitines and their upstream regulator carnitine palmitoyltransferase 1C(CPT1C),an enzyme that catalyzes the initiating step of fatty acidβ-oxidation,were markedly decreased in senescent PANC-1 cells.Furthermore,low CPT1C expression caused abnormal energy metabolism and mitochondrial dysfunction of PANC-1 cells,resulting in decreased cell survival and a suppressed tumorigenesis.Most importantly,loss of CPT1C triggered mitochondrial dysfunction,leading to senescence-like growth suppression and cellular senescence,suppressed cell survival under metabolic stress,and lower tumorigenesis in a mouse xenograft model.Silencing of CPT1C also induced cellular senescence in five other tumor cell lines.CONCLUSION Low CPT1C expression is a novel biomarker and key regulator of cellular senescence in tumor cell lines.Inhibition of CPT1C may be a new cancer therapeutic target impacting cellular senescence and tumorigenesis through modulation of mitochondrial function.

Effect of Acupuncture on Carnitine for Skeletal Muscle Fatigue

Skeletal muscle fatigue is a common symptom in various diseases, works and exercises. These were generally induced by neuron, metabolic conditions, overused muscle, and stress. But, there have been few principles about it. Many researchers have reported that acupuncture therapy has been useful to skeletal muscle fatigue on various diseases and conditions. However, it has never been shown why acupuncture therapy has the effect on skeletal muscle fatigue. The deficiency of carnitine induces fatigue, weakness, and disorder of skeletal muscle. It has showed that acupuncture induces the increase of carnitine in skeletal muscle. These findings demonstrated that acupuncture on skeletal muscle fatigue could increase carnitine as a possible affection mechanism.

EFFECTS OF ELECTROACUPUNCTURE ON CARNITINE IN SERUM AND BRAIN

Objective Electroacupuncture （EA） has been shown to have therapeutic effect on chronic fatigue syndrome. But its action has not been made clear. Methods After the rats of EA group were fixed in an animal cage, bilateral Shènshū （肾俞 BL23） were punctured and stimulated with uniform reinforcing and reducing method by twirling the acupuncture needle for one minute. And then the needle handles were connected to an electric stimulator for stimulating the acupoint with dense-sparse waves, frequency of 3 Hz for 30 minutes, and amplitude： positive： 50 V, negative： 25 V. Electrocupuncture was given once a day, continuously for 5 days. The rats of normal control group were not punctured and stimulated. The rats of all groups were killed for collecting blood and brain tissue on the next day after the final treatment. Carnitine in serum and brain tissue was determined. Results Oarnitine contents in serum of EA group and of normal control group were 5.10±0.50 μmol/L and 2.17±0.46 μmol/L, respectively. Oarnitine contents in brain tissue of elctroacupuncture group and of normal control group were 44.66 ± 2.67 μmol/L and 24.05 ± 3.65 μmol/L, respectively. Oarnitine levels in serum and brain of EA group were significantly higher than those of normal control group. （P〈0.001） Conclusion This report presented that carnitine in serum and brain is increased by EA, suggesting that EA may affect energy metabolism and may have effects on fatigue.