Dissertation
Dissertation > Medicine, health > Pharmacy > Pharmacology

The Preliminary Mechanisms of Cancer Cachexia Amelioration by L-carnitine Ameliorates

Author ZhangDai
Tutor Zhu
School Second Military Medical University
Course Internal Medicine
Keywords cancer cachexia of colonic ademacarcionoma L-carnitine lipidmetabolism peroxisome proliferator-activated receptor
CLC R96
Type Master's thesis
Year 2013
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BackgroundCachexia is the common complication in advanced cancer patients. The rate of deathcaused by cachexia conditions in patients suffering from end-stage malignancies has beenas high as80%. Many experts suggest that chronic systemic inflammation、metabolicabnormalities as well as increased oxidative stress contribute to the pathogenesis ofcachexia. The therapy of cachexia has been one of the dififculties in clinical.L-Carnitine can transfer long chain fatty acid from the cytoplasm into themitochondrial? producing ATP for P-oxidation. LC also stimulates gluconeogenesis andketone in liver,promote the protein degradation. At present,LC has been used in manydisease such as clinical treatment of cardiovascular disease,chronic renal failure? diabetes,lipid depositin and so on. In clinical and experimental studies? we veriifed that L-carnitineis signiifcantly decreased in the serum of cancer cachexia patients. L-carnitine also reliefthe symptoms of cancer cachexia,such as fatigue,atrophy in both adipose tissue andskeletal muscle mass,even anorexia. It has been gradually accepted that L-carnitine playsan important role in ameliorating cachexia, but the mechanism still unclear.Peroxisome proliferator-activated receptor (PPAR) is a member of nuclear receptortranscription factor superfamily which includes three subtypes: alpha? beta (or delta) andgamma. Also all these three types have resemable structures, the expression sites andfunctions are still different. PPAR is closely related with lipid metabolism in liver.Resently,many researches focus on the role of PPARa、PPAR丫. PPARa located in theliver is mainly enhanced the fatty acid beta-oxidation; while PPAR丫in adipocyte and livertissues promotes the fat acid deposition, adipocyte differentiation and increasse the insulinsensitivity. Cancer cachexia have a microinlfammatory state which can aggravate cachexiathrough killing a lot of reactive oxygen species.From the experimental cancer cachextic model,we observe the expression ofPPARa、PPAR丫in hepatic tissue? test the level of SOD,GSH-PX,MDA in serum,investigate the role of peroxisome proliferator-activated (PPAR a、PPARy) signalingpathways of hepatic lipid metabolism and oxidative stress in L-carnitine amelimoratescancer cachexia in mice. It is helpful to further clariyf the mechanisms and to provide anearly intervention time in the treatments of cachexia. Methods1.16male BALB/c mice were randomly divided into two groups: no tumor bearing group(NTB)and tumor bearing group(TB). Mice in TB were injected a suspension of106miceColon26ademacarcinoma cells subcutaneously. Food consumption and body weight wasmeasured every day. When the mice of TB got into cachexia,tested tumor weight,leftgastrocnemius muscle weight,double adipepididymdis weight,concentration of glucose、albumin> cholesterol,TNF-a and IL-6in serum immediately.2.24male BALB/c mice were randomly divided into four groups: no tumor bearing group(NTB,n=6); tumor bearing group with normal saline group as negative control (NST,n=6); tumor bearing group treated with LC (LC,n=6); tumor bearing group treated withetomoxir (ILC? n=6). Colon26ademacarcinoma cells were injected subcutaneously intoall tumor bearing group to establish cancer cachexia models. Drugs were given to all TBgroups each day for the following seven days. Then we measured food consumption andbody weight of mice every day. All mice were executed after the intervention. When themice of TB got into cachexia,tested tumor weight、left gastrocnemius muscle weight、double adipepididymdis weights concentration of glucose> albumin> cholesterol、TNF-a、IL-6,SOD、MDA、GSH-Px in serum and the levels of peroxisome Proliferator-activatedreceptor in liver immediately.Results1. The TB group got into cachexia at day11. The body weight,food consumption? leftgastrocnmius weight? glucose and albumin of TB group were lower than NTB group.Compared with NTB group the expression of cholesterol, TNF-a and IL-6weresignificantly higher in TB group (p<0.05).2. Compared with LC groups,the mice body weight out of tumor body weight、foodconsumption> blood glucose、albumin> SOD、GSH-Px were higher than NTB and ILCgroups; Compared with LC groups? the levels of cholesterol> TNF-a、IL-6、MDA werelower than NTB and ILC groups; The expression of PPARa、PPARy of LC group werehigher than NTB and ILC (all p<0.05).Conclusion1. In our study,we established the cachexia mice model. In this model,there existsnoticeable malnutrition and metabolic disorder which may be caused by change ofcytokine TNF-a and IL-6. This animal model is similar to human cancer cachexia, and it isan ideal platform for the research of cachexia. 2.In cancer cachexia, there exist obvious metabolic disorders,especially lipid metabolism.Specifically, mice’s body fat decreased,blood cholesterol increased and the expression ofPPAR in liver reduced in tumor bear group. PPAR may participate in the formation ofcancer cachexia. L-carnitine can improve cancer cachexia by adjusting metabolic disorder,reducing the level of TNF-a and IL-6in serum,increasing the expression of PPAR inliver. LC ameliorates cancer cachexia by regulating PPARa-? PPAR丫-relaetd signaliningpathways of hepatic lipid metabolism.3.In this model,there may exist signiifcant oxidative stress,as the level of GSH-Px、SODis lower than NTB group while the level of MDA is higher than NTB group. LC canimprove the oxidative stress in tumor cachexia by increasing the content of SOD、GSH-Px,decreasing the content of MDA.

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