Role of Tocotreinols in Reducing Homocysteine Induced Aortic Dysfunction - Literature review Example

Role of Tocotreinols in reducing Homocysteine induced Aortic Dysfunction: Name: Institution Affiliation: Literature review Abstract According to Miyazawa et al (2008), Tocotrienols are a group of agents that are under the vitamin E family. They form the rarest group of all. A series of studies have been conducted to determine their role in normal health. They have varied properties which make the class a viable entity in health care. The key feature that has been under scrutiny of these agents is their cardioprotective properties. They have been attributed to having hypocholesterolemic properties. This is a property that is spread across the actions of the agents. Some of the actions include the atherogenic features which are the ability of the agents to lower the apolipoproteins and lipoprotein plasma levels. There is the aspect of the agents having antioxidant properties. This property is significant in terms of the use of these agents in the treatment of cancer. There are also the antithrombotic effects that are quite evident with the use of these agents. All these properties have an inclination in the management of cardiovascular cases. There will be a lot evaluation of the Tocotrienols in depth and more focus will be on the ability to reduce Homocysteine. In terms of the sources of these agents, they have a wide variety sources that range from rice bran, palm oil and any other edible oils that are inexistence. There have been a lot of studies regarding this class of agents and their role in the management of heart conditions. It is an enormous entity in the world of research and most studies have an important contribution to the subject. Sun et al (2009) validates that the normal health status of an individual, the dietary constituents have to comprise of vitamins. They are an essential feature in good nutrition and thus more effective in the nurturing of good health. Vitamin E to be specific has great antioxidant properties which makes it the best agent when it comes to the prevention any form of toxicities related to oxidation. This makes the family of vitamin E an important entity in the management of cancer. Sun et al (2009) establishes the great influence that a family has in the management of heart diseases and also as an antitumor agent. Tocotrienols have a great property that makes them more advantageous to use. They are in the vitamin E family which is fat soluble in nature thus making it effective in any forms of management. The trend of studying the Tocotrienols has increased greatly and it is absolutely due to the cardioprotective, neuroprotective and antioxidant properties. There four different types of Tocotrienols and this have different chemical structure. Rickmann et al (2011), explores the difference is usually in the methyl group positions. In comparison to their counterparts the tocopherols, they happen to have the tendency to impart on various physiological processes. The Tocotrienols function in a number of ways that range from regulating the HMG CoA reductase enzyme, suppressing p53 and inducing a cell cycle arrest. This are the key processes that enable the agents have the cardiac effects of protection. With the recent studies, it is quite clear that the Tocotrienols have an excellent property and thus are likely to revolutionize the pharmacology of cardiac conditions management. There are number of circumstances that Tocotrienols have a great importance in terms of their use. The kinds of problems that arise in the presence of elevated levels of homocysteine in body are mostly related to the chemical reactions that are associated with it. Tocotrienols tend to work against the homocysteine and thus it is an entity that creates great prospects in terms of cardiac therapy. Shah et al (2014) indicates that homocysteine is an agent that is usually formed as a result many chemical reactions in the body. This is usually a product of a chemical reaction known as methylation. It is an important reaction in the human body as it enhances various functions. Methylation has been subjected to a lot of studies and currently it forms significant feature in the field of medicine. With respect to the number of deaths that result from cardiac problems, it is a field that has taken another dimension with the intention of ensuring adequate preventive and treatment options of heart disease. The key element that is focused on is the formation of homocysteine and its regulation. The reaction process here is methylation. Understanding the chemical process enables proper regulation. It has been an interesting phenomenon and many researchers have been geared in this direction. Methylation reaction entails the addition of a methyl group to a substrate. This is a group that contains one carbon atom and three hydrogen atoms in combination. This reaction is essential in bodily functions. For instance, it plays a key role in gene modulation. It usually enables arrest of any processes that are unwanted. Any changes in this reaction or any problems may result in negative consequences. This can lead to varied changes in the physiologic state and thus diseases may ensue. To be specific, disruption of the methylation process acts as a gateway for environmental toxins and varied inflammatory changes that could lead to the cardiovascular diseases. Eitsuka et al (2011), explains that methylation reactions tend to have homocysteine as by product hence this can lead to its accumulation in the body. With this there can be problems that may ensue like the one in question; aortic dysfunction. There has to be ways to curb the rising levels of homocysteine so as to avoid any drastic consequences. In describing homocysteine, it is usually an amino acid with a sulfur group that is usually an intermediate product in the synthesis of methionine. The times when there are excesses of homocysteine, there is usually a regulatory mechanism that is involved with the reduction of the excesses. The product usually has two options and this is whether to form methionine or being converted to cysteine. In the scenario where there is still excess of homocysteine, it is upon the liver and the kidney to regulate the excess of which if still a problem then there are likely to be severe consequences. In regard to how homocysteine causes all the unwanted effects. There are a number of postulated ways as to how these problems arise. These can be evaluated various ways. These hypothesized ways include; the oxidative stress that is usually associated with elevated levels of homocysteine. A high level of this product has been associated with endothelial dysfunction of vessels. There is depletion of nitric oxide which creates a scenario of having reduced vessel compliance. The thrombotic property of homocysteine can be linked to the fact that platelets are usually affected by the high levels. This then influences the coagulation process. Homocysteine has been attributed to increasing the vascular lumen size. This based its ability to enhance vascular cell proliferation. There is also the aspect of endothelial cytotoxicity that has been under great evaluation. According to Samant et al (2006), excess homocysteine is an inflammatory risk factor for cardiovascular disease. Based on the above stated mechanisms, there is need to reduce the level of homocysteine. There are a number of ways which have been postulated regarding the reduction of homocysteine and this appears to be helpful in any form of management. There are certain vitamins that have been useful. Using the vitamin B6 and B12 together with folic acid have great benefits. These are beneficial when it comes to the alleviation of oxidative stress that is the key cause of dysfunction. The process of aortic dysfunction revolves around a series of physiological reactions. These processes tend to be potentiated by hyperhomocystenemia. There is the accumulation of macrophages that usually occurs. This is usually associated with muscle growth and eventually there will be formation of plaques that are likely to lead to atheromatous formation. With this, the aortic function is likely to deteriorate and eventually lead to heart diseases. The plaques that are usually formed could lead to thrombosis and thus it is quite clear that having elevated levels of homocysteine is detrimental feature in the health of an individual. Using Tocotrienols has set a great pace in the management of such conditions and thus it is of great value studying this class of agents. Tocotrienols tend to curb all the stated pathological phenomena that are likely to arise following the elevation of homocysteine. It has been appreciated what the agents can do and thus indicating a great advancement in the management of cardiovascular diseases. Shibata et al (2009) validates the correlationship between the use of tocotrienols and the occurrence of cardiovascular diseases. It is an important agent in the management of cardiovascular disease. This has been proved to be beneficial in a number of ways. Tocotrienols have a hypocholesterolemic property as it has the ability to lower cholesterol levels. It is a key feature that has been employed in the pharmacology of cardiac therapy. The agents play a significant role in the regulation of the enzyme HMG CoA that is usually associated with the formation of cholesterol. With proper regulation of this enzyme, the cholesterol levels are usually controlled and in turn this prevents formation of any plaques. It is the plaques that are deposited in the endothelium of the aorta and any other vessel thus with reduction in cholesterol levels, this is halted in so many ways. Shibata et al (2009) establishes the benefits of the effects of Tocotrienols. Some rats were fed with palm oil that was rich in Tocotrienols and it was quite clear that the results concurred with the expected effects on cholesterol levels. The rats that had Tocotrienols in the diet had sixty percent lower cholesterol than the other rats without the agents in the diet. This proved that they are actually beneficial in the cholesterol lowering aspect. Tocotrienols have captured a lot of interest in the practice of medicine and it is an evolution that has made great changes in the management of heart conditions. Khanna et al (2010) indicates that an estimation of about half of the population consuming the western diet are likely to succumb to the high cholesterol in the diet. The high content of cholesterol is implicated in a number of heart conditions. There is usually the propensity of developing coronary artery disease and this to some extent can be fatal. Hypercholesterolemia is a feature that is quite distinct in ensuring there is actual development of the coronary artery disease. High cholesterol levels have also the ability to trigger inflammation. This in combination with other factors form complex that creates a lot of distress to the cardiovascular system. Tocotrienols are agents that are found in widespread plant foods. They range from rice, oats and barley and this have the ability to lower the cholesterol levels as previously stated. With respect to this ability, there is reduced chance of developing cardiovascular disease that is quite appealing when it comes to health care. There have been areas that seek clarification hence making generalization a problem with this study. Khanna et al (2010) has conducted many studies indicate some contradictions especially with the degree at which the cholesterol is lowered. In the rats it has been an excellent evolution. However, in the human population there is just slight decrease in the cholesterol levels. This raises the question as to whether it has substantial effect on the cholesterol levels in general and whether cardiac protection can still be achieved. With this kind of factors in the studies, there are a lot of gaps that still need to be evaluated and clarified. Any study regarding the Tocotrienols has been subjected to a certain degree of doubt and thus various reviews on the same are still being executed. The deficits that are usually found in the study of Tocotrienols are majorly in the aspect of cholesterol levels and thus clarifications with this regard will be able to channel studies to a more focused research. Zhou et al (2014) validates the effects of Tocotrienols on cholesterol levels in the body. The study commenced with volunteers being given capsules containing the Tocotrienols in different proportions. There was a palm oil vitamin E concentrate that had the combination of the tocopherols and the Tocotrienols in different proportions. This was accompanied by palm olein that was used for thirty days. There were different results in terms of the cholesterol levels that were achieved in terms of the reduction. The total cholesterol levels were reduced in the range of 5% to 39.5% and the Low density lipoproteins were in the range of 0.9% to 37%. The entire results depicted the cholesterol levels were lowered. This was attributed to the use of Tocotrienols that were quite effective. Tocopherols were found to have no effect at all in the lowering of the cholesterol levels. It was a distinct process and the generated results had great significance when it comes to the benefits of the Tocotrienols. Zhou et al (2014) conducted other studies using the palm oil vitamin E concentrate and corn oil indicated the strength of the regimen clearly. This was done in a number of individuals in a period of eight weeks. There was already an effect half way in the period. There was substantial decrease in cholesterol level during the fourth week. Approximately 31% was the recorded amount of reduction. The effects of Tocotrienols persisted for awhile even after discontinuation of the regimen. This gives the agents an upper hand when it comes to substantiating the results of the experimental study. In relation lipoprotein reduction, there is a certain subtype that was found to respond well to the effects of Tocotrienols. Lipoprotein-a demonstrated a great decrease that has never been reported with the other lipid lowering agents. Comitato et al (2014) explains a series of trials have been done and a number of things noted. There are certain ways in which the Tocotrienols have an added advantage in the management if certain medical conditions. There have trials to demonstrate the antioxidant properties of the agents and recently individuals with cerebrvascular disease were subjected to a trial of a mixture of the Tocotrienols and tocopherols. The results were good as it showed some benefits when the mixture was used. There were appropriate results in relation to the use of these agents. It was also evident that the use these agents in conjunction with lovastatins were quite beneficial as there was enhancement in the lipid lowering property of the agents. The results that were registered were significant and thus enhancing the idea that the Tocotrienols were effective when it comes to lipid lowering. This has boosted the previous studies in justifying the use of these regimens in the management of cardiovascular system. There are benefits that are recorded in relation to the effects of the agents in cardioprotection as earlier stated. It has been established that the use of these agents can have great effects based on the dose that is administered. Tocotrienols can exhibit large effects depending on the dose that is administered. It is a dose dependent therapy and the advantage of it revolves around the fact that the agents have no adverse effects. This creates more room when it comes to achieving a certain target. Upadhyay et al (2009) explains studies that tend to contradict the effects of tocotrienols on cholesterol levels, there have been quite distinct experiments that are in agreement with the contradiction. In a randomized placebo trial done in individuals that had mild hypercholesterolemia, a mixture of tocotrienols and tocopherols for four weeks, it was quite clear that the tocotrienols lacked any effect on the serum cholesterol levels. There have been speculations that the tocopherols in the mixture might have had an effect on the reactions that reduce the cholesterol levels. However, this has just been a suspicion. There is the aspect of alpha tocopherols which have been attributed to neutralizing some of the inhibitory effects of tocotrienols on the HMG CoA reductase activity. This in a way potentiates the enzyme and thus no effect on the cholesterol levels is noted. There have been further evaluations of the effects of the four types of tocotrienols that are in existent and the state of cholesterol still not decreasing any way. Even with supplementation of the agents, there was still no effect and this was a clear indication that there is likely to be a lot of debate regarding the agents’ effects on cholesterol levels. Upadhyay et al (2009) validates the effects of tocotrienols with the presence of absolute limitation in lipid peroxidation. This was the only feature that was in concurrence with the antioxidant effects of the agents. Van Haaften et al (2012) explains that there has been another study evaluating the effects of tocotrienol rich vitamin E on the plasma isomers, arterial compliance, aortic blood pressure, the plasma total antioxidant and the cholesterol levels in healthy men. This study entailed the use of three dosages of the regimen in a number of individuals. It was a randomized placebo trial and the different dosages were taken by the subjects for two months. At the beginning of the study, the baseline readings of the isomers were taken. It was noted that at the end of the study, there was a marked increase in the isomers. The was no significant change that was noted with the arterial compliance, aortic systolic blood pressure, the pulse wave velocity, both the total and low density lipoprotein levels at the end of the experiment. The groups that were being administered doses of 160mg or 320mg exhibited great reduction their aortic systolic blood pressures. There was also marked improvement in the total plasma antioxidant of the individuals. Oxidative stress a feature if excess homocysteine is catered for by the effects of tocotrienols. This indicates some of the major ways in which these agents tend to prevent the dysfunctions that come about in cases of hyperhomocystenemia. The agents are quite effective in acting upon the etiological agents of the problems of the aorta. It is usually a multifactorial phenomenon that requires great intervention. A single agent like tocotrienol has great influence in all the changes associated with the pathologies making it excellent drug of choice when it comes to management. There have been benefits that have been reported with the use of tocotrienols in patients who are type two diabetics. These patients have the highest propensity to developing cardiovascular complications. Tocotrienols have effect on the lipid profiles. There is no effect when it comes to the glucose levels. Therefore efforts to treat the likely complications should focus more on both glucose and lipid levels as this will also lead to oxidative stress and thus perpetrate aortic dysfunction. Kobayashi et al (2012) establishes the correlationship between homocysteine and the damage to any vessel. Excess levels of homocysteine have detrimental effects in the human bodily functions. It has the propensity to damage vessels like the aorta by atherosclerosis. This is the commonest method associated with homocysteine and efforts are in place to establish a tocotrienol regimen that can curb the problem. Kobayashi et al (2012) establishes the linkage between reduction of homocysteine levels and the risk to cardiovascular diseases. There is the aspect of homocysteine being a causative agent of oxidative stress. Oxidative stress especially in vessels has been associated with endothelial dysfunction and this creates a cascade of events such as vascular smooth muscle proliferation. This in turn has been associated with the creation of lack of compliance in the vessels. The oxidative stress has also the potential of causing lipid peroxidation and thus creating the problem of atheromatous plaques. This kind of situation has been associated with a number of complications in relation to heart disease. Homocysteine should be regulated adequately unless more complications ensue. The New Vitamin E. Spacedocnet (2010) explains the previous findings regarding the effects of homocysteine were based on a number of physiological processes. The findings were based on the mononuclear cells activation homocysteine induced endothelial dysfunction. There was also the treatment of homocysteine induced endothelial damage with statins which indicated great potential in terms of protection from the adverse effects of homocysteine. It was quite clear that the processes that led to damage of the endothelium revolved around inflammation and oxidative stress caused by excess homocysteine. Therefore it can be recommended that there should be an addition of the use of anti inflammatory agents and antioxidants to serve as the therapeutic strategy. It is of great value as this will curtail any changes that are likely to trigger cardiovascular changes that might be detrimental. The New Vitamin E. Spacedocnet (2010) shows the correlationship between the propensity of hyperhomocystenemia causing atherothrombotic problems. The New Vitamin E. Spacedocnet (2010) estab;lsihes the correlationship by carrying out both in vitro and in vivo studies and both concurred with postulated phenomenon. This was attributed to the fact that, homocysteine was associated with thrombosis. Sundram et al (2009) validates that thrombosis is a feature that was as result of platelet activation. It is a process that was found to recruit varied events as there was also increase in the level of thrombin with lack of thrombolysis. With endothelial damage due to oxidative stress there was a clear indication that coagulation was possible. A metanalysis regarding the general effects of homocysteine indicated that the lesser the amount of serum homocysteine the lower the risk for one developing ischemic heart disease. This was a clear depiction of the significance of making sure homocysteine levels are never in excess. There are many ways in which homocysteine levels can be elevated. Some of these are lifestyle changes for example smoking and alcoholism. There are also certain diseases that may elevate the homocysteine levels. Some of these diseases include diabetes, thyroid disease, psoriasis and cancer. It is paramount that early screenings for homocysteine done before such complications arise. Homocysteine triggers oxidative stress by cellular respiration. This has been associated with the peroxidation of lipids and atheromatous plaques. This usually results in the formation of harmful oxygen radicals that further damage the endothelium of a vessel like the aorta. Homocysteine has been implicated in causing inhibitory effects on the nitrous oxide by the formation of the s nitrosohomocysteine. This is usually a phosphorylation reaction that forms as substrate that blocks vessel vasodilation. It usually worsens the endothelial damage. The basis of endothelial damage due to homocysteine excess is the accumulation of reactive oxygen species that are an insult to the vessel wall. There is also the elevation of the asymmetric dimethylarginine which is usually an inhibitor of nitric oxide synthase. The bioavailability of nitric oxide is usually impaired thus limiting compliance of a vessel. According to Kato et al (2013, p45), there has been demonstration of elevation of superoxide ion by the treatment of homocysteine. A substantial increase in the intracellular ion was noted. This was associated with the recruitment of chemoattractant proteins the interleukins. There was formation of a chemokine receptor on monocytes which had detrimental effects on their survival. The monocytes after the homocysteine treatment were found to be susceptible to endotoxins. Homocysteine seems to have a greater effect on the monocytes following the formation of the monocytes chemotactic protein 1 receptor. This receptor seems to enhance adherence. The chemotactic response is great which enhances recruitment of many cytokines and chemokine. The inflammatory changes enhance the damage of endothelial cells consequently vessel injury. Homocysteine creates a poor vessel condition that can cause widespread complications. The superoxide ion is usually as a result of the effects of the NADPH oxidase enzyme. This enzyme has great influence in the process of inflammation. It is usually contributory in the atherogenesis that usually develops. The process of endothelial damage entails recruitment of vast amounts of toxins and this creates a locus that cannot be reversed even with therapy. The main aim of treatment or correction of endothelial damage should be based on the reduction of the toxins. Any a process or chemical reaction that seems to trigger these drastic changes should be taken into account. Qureshi et al (2012) explains that in homocysteine induced endothelial damage, there is an associated increase uric acid levels. The uric acid levels can trigger widespread changes in the vasculature. There has to be proper regulation to ensure minimal complications. Uric acid has been attributed to the further damage of the endothelium. There is a lot of debate regarding the effects of uric acid and thus there is no accurate link between the uric acid and damage to the endothelium. It is suspected to have a wide variety of effects and these ranges from it having antioxidant properties or it being a protective molecule in terms of endothelial damage. Qureshi et al (2012) compares the effects of uric acid and establish the exact effects of the agent have been done. These studies have been done normal cells and cells that have homocysteine induced endothelial damage. The results indicated different changes especially when it came to the level of nitric oxide. It was quite clear that uric acid restored the level of nitric oxide back to the normal state. This was just a step towards excluding uric acid as a cause of noncompliance of vessels. Qureshi et al (2012) clearly points out the fact that uric acid restored nitric oxide levels though at controlled dosages. Any further increment in the dose achieved nothing. There was also the expression of the endothelial nitric oxide synthase that was not changed. Neither was the phosphorylation triggered. An important entity was the increase in superoxide levels that was a key feature noted with increase in the uric acid dose. According to Dunphy et al (2009) plasma levels of homocysteine have been associated with coronary artery disease and thus any in interventions that are geared to lowering homocysteine levels suffice. The levels of homocysteine in the blood of a patient who has established coronary artery disease can be used as a prognostic value. It can also be used as a predictive value in terms of mortality and morbidity of cases associated with high levels of homocysteine. There is a normal range of 5-15 micromoles per liter and thus any forms of derangements from the normal are classified into various categories. These are for the purpose of management of complications. Homocystenemia has been implicated in a myriad of complications thus any methods that aim at putting the levels in a regulated position are advocated for greatly. It is quite clear that the levels of homocysteine are dependent on number factors. Factors that determine homocysteine levels are grouped into environmental, genetic and lifestyle modifications. They come in handy when there is the need to establish a causative agent and the kind of intervention that will suffice. These factors do not exhibit independence and thus they can be intertwined in how they affect the levels of homocysteine. Homocysteine is dangerous at elevated levels and any attempts to reduce the underlying cause of such a condition should be advocated for critically. According to Dunphy et al (2009), the lowering the levels of homocysteine with the use of vitamins is effective. In addition to the vitamins, tocotrienols have a great impact in terms of therapy. They are a great entity in the therapeutic approach. They have the advantage of coming from plants and foods. There is a low probability of developing adverse reactions to these agents. They are well tolerated and have a great effect in the lowering of homocysteine. Qureshi et al (2012) explores the agents that are useful in the management of homocysteine induced endothelial damage include the use of vitamins and folate derivatives. These agents have proven to be effective in various ways. There is the aspect of them being antioxidants which plays a significant role in the therapeutic approach. Specifically the nature of the results in how the agents enable proper functioning of the vessels is categorized into a number of processes. It is reported that these agents improve aortic distension and thus enabling compliance of the aorta. The aorta is one of the great vessels that are pertinent in the survival of human beings. It needs to at its proper functioning as any changes might lead to drastic complications. The dysfunction of the aorta that usually results from damage to the endothelium can result into formation of aneurysms. An aortic aneurysm is a fragile feature that can lead to death in case it ruptures. The agents that are used in therapy also have the ability to enhance the endothelial dependent vasodilation of vessels. It is essential for vessels to have the ability to be compliant to different pressure levels. Any rigidity in vessels is a risky phenomenon and should be managed with great care. The vessel wall is an important feature in the vascular system. The intima media is an important layer and thus any changes that might occur in this layer should be prevented promptly. The use of tocotrienols has the ability to improve the thickness of the layer. This will increase the strength of the vessel wall. The most important step in the therapeutic approach is to ensure there is proper methylation in the cells of the body. It is this step that is the source of homocysteine. Ensuring a proper methylation reaction provides less trouble as there will be no accumulation in levels that could prove toxic for vessels. Sen et al ( 2011) validates the information in relation to tocopherols compared to the tocotrienols. According to Sen et al ( 2011), tocotrienols have better biological properties than tocopherols. Based on the above discussed properties of tocotrienols it is quite clear that there is the need to incorporate tocotrienols in medicine. Especially in the management and treatment of aortic dysfunction that results from accumulated levels of homocysteine. The properties stated above which include the expected antioxidant tendencies and anti-inflammatory properties have proved them to be useful in the proper management of conditions such as cancer, diabetes, neurodegenerative disease and any cardiovascular diseases. It is a requirement for more studies on the tocotrienols as there is so much disappointment associated with the tocopherols. The following figures will explain the various changes that take place in the presence of elevated levels of tocotrienols. General Lifestyle factors Diet Diseases or inherited causes. Drugs that increase homocysteine Increase in age Male gender Menopause Alcohol consumption Coffee Smoking Low fruits in the diet. No consumption of multivitamins. Cystathione synthase deficiency. Some epileptic drugs like Phenobarbital, diuretic therapy, methotrexate and nitrous oxide. Stuhlinger et al (2012) establishes the kind of factors that determine the levels of homocysteine in the table above. These range from lifestyle modifications to diseases. Inflammation and its actions Determines plaque stability. Increases free oxygen radicals. Processes that modify inflammatory activity Lipid lowering reduces plaque formation. Lipid lowering can be achieved by tocotrienols Excess cholesterol may increase the dysfunction of aorta. The table explains some of the causes of inflammation and the agents that can be used to lower the agents. Tocotrienols are quite effective in lipid lowering. Oxidative stress in relation to homocysteine levels: Hurt et al (2012) uses the figures as a representation of the effects of phosphorylation of nitric oxide that happens in the presence of excess homocysteine. Electrical stimulation in the cavernous nerve is affected in different ways as depicted by the times. The chart above indicates the different patterns associated with homocysteine levels and the lowering agents; tocotrienols. The work focuses on the average effects. 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Stanford, JL, 2000, Oral folate reduces plasma homocyst(e)ine levels in hemodialysis patients with cardiovascular disease. Cardiovasc Surg. 2000;8(7):567-571. Manns, B, 2001, Oral vitamin B12 and high-dose folic acid in hemodialysis patients with hyper- homocyst(e)inemia. Kidney Int. 2001;59(3):1103-1109. Beaulieu AJ, 1999, Enhanced reduction of fasting total homocysteine levels with supraphysiological versus standard multivitamin dose folic acid supplementation in renal transplant recipients. Arterioscler Thromb Vasc Biol.;19(12):2918-2921. Sakai M, Okabe, M, Tachibana, H, Yamada, K, 2006, Apoptosis induction by gamma-tocotrienol in human hepatoma Hep3B cells. J Nutr Biochem ;17:672–6. Xu, WL, Liu, JR, Liu HK, Qi, GY, Sun, XR, Sun, WG, 2009, Inhibition of proliferation and induction of apoptosis by gamma-tocotrienol in human colon carcinoma HT-29 cells. Nutrition;25:555–66. Shah, SJ, Sylvester, PW, 2005, Tocotrienol-induced cytotoxicity is unrelated to mitochondrial stress apoptotic signaling in neoplastic mammary epithelial cells. Biochem Cell Biol 2005;83:86–95. Takahashi, K, Loo, G, 2004, Disruption of mitochondria during tocotrienol-induced apoptosis in MDA-MB-231 human breast cancer cells. Biochem Pharmacol ;67:315–24. Sun, W, Xu, W, Liu H, Liu J, Wang Q, Zhou J, 2009, Gamma-Tocotrienol induces mitochondria-mediated apoptosis in human gastric adenocarcinoma SGC- 7901 cells. J Nutr Biochem 2009;20:276–84. Sylvester, PW, Shah, S, 2005, Intracellular mechanisms mediating tocotrienol-induced apoptosis in neoplastic mammary epithelial cells. Asia Pac J Clin Nutr ;14:366–73. Srivastava, JK, Gupta, S, 2006, Tocotrienol-rich fraction of palm oil induces cell cycle arrest and apoptosis selectively in human prostate cancer cells. Biochem Biophys Res Commun;346:447–53. Shibata, A, Nakagawa, K, Sookwong, P, Tsuduki, T, Tomita, S, Shirakawa, H, 2008, Tocotrienol inhibits secretion of angiogenic factors from human colorectal adenocarcinoma cells by suppressing hypoxia-inducible factor-1alpha. J Nutr ;138:2136–42. Miyazawa, T, Shibata, A, Nakagawa, K, Tsuzuki, T, 2008, Anti-angiogenic function of tocotrienol. Asia Pac J Clin Nutr;17(Suppl 1):253–6. Nakagawa, K, Eitsuka, T, Inokuchi, H, Miyazawa, T, 2004, DNA chip analysis of comprehensive food function: inhibition of angiogenesis and telomerase activity with unsaturated vitamin E, tocotrienol. Biofactors;21:5–10. Shibata, A, Nakagawa, K, Sookwong, P, Tsuduki, T, Oikawa, S, Miyazawa, T, 2010, delta- Tocotrienol suppresses VEGF induced angiogenesis whereas alpha-tocopherol does not. J Agric Food Chem;57:8696–704. Liu HK, Wang Q, Li Y, Sun WG, Liu JR, Yang YM, 2010, Inhibitory effects of gamma-tocotrienol on invasion and metastasis of human gastric adenocarcinoma SGC-7901 cells. J Nutr Biochem;21:206–13. Shirode, AB, Sylvester, PW, 2010, Synergistic anticancer effects of combined gammatocotrienol and celecoxib treatment are associated with suppression in Akt and NFkappaB signaling. Biomed Pharmacother ;64:327–32. Kuhad, A, Chopra K, 2009, Attenuation of diabetic nephropathy by tocotrienol: involvement of NFkB signaling pathway. Life Sci;84:296–301 Stuhlinger MC, et al, 2012, Endothelial dysfunction induced by hyperhomocyst(e)inemia: role of asymmetric dimethylarginine. Circulation; 108(8):933-938. Read More