**3.1. Antioxidant drugs in cardiovascular risk status and roll of red blood cell antioxidant defense capacity**

## *3.1.1. Probucol*

Probucol has modest lipid-lowering properties. It was used for the treatment of hypercholesterolemia until more tolerable and effective cholesterol-lowering treatments, such as the HMG Co-A reductase inhibitors, or "statins," became available. Probucol lowers the level of cholesterol in the bloodstream by increasing the rate of LDL catabolism. Additionally, probucol may inhibit cholesterol synthesis and delay cholesterol absorption in [86]. Another possible mechanism of action of probucol is inhibition of ABCA1-mediated cholesterol efflux without influencing scavenger receptor class B type I–mediated efflux (ABCA1 = ATP-binding cassette transporter - member 1 of human transporter sub-family ABCA, also known as the cholesterol efflux regulatory protein is a protein which in humans is encoded by the ABCA1 gene). The inhibition of ABCA1 translocation to the plasma membrane may in part explain the reported in vivo high-density lipoprotein–lowering action of probucol in [89].

Probucol is a powerful antioxidant which inhibits the oxidation of cholesterol in LDLs; this slows the formation of foam cells, which contribute to atherosclerotic plaques.

The major mechanism by which probucol lowers LDL levels relates not to changes in the cellular mechanisms for LDL uptake or to changes in LDL production but rather to intrinsic changes in the structure and metabolism of the plasma LDL in [87]. It has been postulated that the oxidative modification of LDL might contribute to atherogenesis by facilitating lipid accumulation in macrophages (foam cells) and by inhibiting macrophage motility. LDL resists oxidative modification, however, when probucol is added to in vitro incubations or when the LDL itself is isolated from probucol-treated patients in [88]. Under the treatment with probucol xanthomatous lesions disappear which that suggest a facilitation of cholesterol transferred from tissues to the excretion or catabolic pathways. Compared with other hipolipemiants, probucol is a non hepatotoxic drug and induces a decrease of lithogenic index of bile.

In recent studies was shown that probucol protect against diabetes-associated and adriamycin-induced cardiomyopathy by enhancing the endogenous antioxidant system including glutathione peroxidase, catalase and superoxide dismutase [90].

## *3.1.2. The HMG Co-A reductase inhibitors, or "statins"*

54 Blood Cell – An Overview of Studies in Hematology

**antioxidant defense capacity** 

system.

*3.1.1. Probucol* 

action of probucol in [89].

lithogenic index of bile.

Another element involved in the function of necessary enzyme for cellular protection is selenium. Selenium functions primarily as an activator of enzymes necessary for cellular protection from oxidative damage and maintenance of normal redox potentials. A primary role of selenium in erythrocytes appears to be the activation of the enzyme glutathione peroxidase whereby glutathione (the critical tripeptide antioxidant/antitoxin for all cells) reacts with oxygen radicals. Importantly, selenium catalyzes glutathione reductase, an

Specify participation of erythrocyte enzymatic system as adaptive mechanism to different pathological processes and specify how nutritional deficiencies and oxidative drugs can interfere these systems introduces the chapter on pharmacology of erythrocyte antioxidant

**3.1. Antioxidant drugs in cardiovascular risk status and roll of red blood cell** 

Probucol has modest lipid-lowering properties. It was used for the treatment of hypercholesterolemia until more tolerable and effective cholesterol-lowering treatments, such as the HMG Co-A reductase inhibitors, or "statins," became available. Probucol lowers the level of cholesterol in the bloodstream by increasing the rate of LDL catabolism. Additionally, probucol may inhibit cholesterol synthesis and delay cholesterol absorption in [86]. Another possible mechanism of action of probucol is inhibition of ABCA1-mediated cholesterol efflux without influencing scavenger receptor class B type I–mediated efflux (ABCA1 = ATP-binding cassette transporter - member 1 of human transporter sub-family ABCA, also known as the cholesterol efflux regulatory protein is a protein which in humans is encoded by the ABCA1 gene). The inhibition of ABCA1 translocation to the plasma membrane may in part explain the reported in vivo high-density lipoprotein–lowering

Probucol is a powerful antioxidant which inhibits the oxidation of cholesterol in LDLs; this

The major mechanism by which probucol lowers LDL levels relates not to changes in the cellular mechanisms for LDL uptake or to changes in LDL production but rather to intrinsic changes in the structure and metabolism of the plasma LDL in [87]. It has been postulated that the oxidative modification of LDL might contribute to atherogenesis by facilitating lipid accumulation in macrophages (foam cells) and by inhibiting macrophage motility. LDL resists oxidative modification, however, when probucol is added to in vitro incubations or when the LDL itself is isolated from probucol-treated patients in [88]. Under the treatment with probucol xanthomatous lesions disappear which that suggest a facilitation of cholesterol transferred from tissues to the excretion or catabolic pathways. Compared with other hipolipemiants, probucol is a non hepatotoxic drug and induces a decrease of

slows the formation of foam cells, which contribute to atherosclerotic plaques.

enzyme that maintains the glutathione in its reduced or active form [85].

Specific for hypercholesterolemia status is the high production of free oxygen radicals. These can impair the endothelial function because destroying of nitric oxide (NO) and secondary affecting its beneficial and protective effects on the vessel wall. Most of the other cholesterol-lowering therapies present, also, antioxidant effects. There are two way improving antioxidant defence system in hypercolesterolemiant patients: either increasing the activities of CuZn-SOD and GSH-Px or preventing the production of the superoxide radicals*.*

Malone dialdehyde (MDA), more than cholesterol plasma level, is considered a marker of patients with increased risk of coronary heart disease, because MDA is a marker of lipid peroxidation. In individuals who smoke or who have diabetes are particularly prone to oxidative stress that can lead to the formation of oxidized LDL (oxLDL). Oxidatively modified LDL is considered to be highly atherogenic and can be considered a biochemical risk marker for coronary heart disease. Oxidative modification of LDL increases their ability to bind to the extracellular matrix, increasing its retention within the intima and accumulation of oxLDL in macrophages, so, it contributes to the formation of an atherosclerotic lesion.

The oxLDL accumulation within macrophages promotes the chemotaxis of monocytes into the vessel wall and initiates the various pro-inflammatory effects by different scavenger receptor pathways: CD36 class B scavenger receptors from human macrophages (activates nuclear factor kB that regulates the expression of many pro-inflammatory genes), class A scavenger receptors (modify macrophage activation), lectin-like oxidized LDL receptor - LOX-1 (the expression of endothelial cell adhesion molecule). On the other hands, the accumulation of inflammatory cells can further increase the levels of oxidative stress. Oxidative stress inactivates nitric oxide (NO) and inhibits its synthesis by endothelial nitric oxide synthase (eNOS). On this way, the vasoprotectant effect of NO (anti-inflammatory, anti-platelets, antioxidant and vasodilator) is affected [92].

Statins inhibit 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase the rate-limiting enzyme in the mevalonate pathway through which cells synthesizes cholesterol. On this way, the "statins" increase the resistance of LDL to oxidation. Statins may also exert effects beyond cholesterol lowering. These "pleiotropic" vascular effects of statins are involved in restoring or improving endothelial function: by increasing the bioavailability of nitric oxide, promoting reendothelialization, reducing oxidative stress, and inhibiting inflammatory responses.

Other effects of statins that explain their involving in preserving normal vascular function and blood flow are: inhibition of the uptake and generation of Ox-LDL*,* decreasing the

vascular and endothelial superoxide anion formation by inhibition of NADH oxidases via Rho-dependent mechanisms and preserving the relative levels of vitamin E, vitamin C and endogenous antioxidants (such as, ubiquinone and glutathione) in LDL particles*.* All these mechanisms explain a dual action of statins on oxidative stress, not only decreasing oxidants but also restoring antioxidants [92]. Statins reduce both extracellular LDL oxidation (by reducing substrate availability) and intracellular oxidative stress (by cholesterolindependent effects on NO and, indirectly, by reducing Ox-LDL) [91].

Homocysteine in Red Blood Cells Metabolism – Pharmacological Approaches 57

Very few data concerning the fibrates are available. In hypercholesterolemic patients, it has been shown that bezafibrate is more active than pravastatin in reducing the susceptibility of LDL oxidation [104]. Moreover, in diabetics, De Leeuw and Van Gaal have found that fenofibrate, but not pravastatin or simvastatin, can reduce the oxidizibility of LDL and of

Beta adrenergic blocking agents have also been shown to have beneficial effect on atherosclerosis. Several mechanisms of action have been suggested including an antioxidant action. All β-blockers have in vitro antioxidant activity which appears to be related to their degree of lipophilicity. In patients with CHD, Croft and coworkers showed that, while the lag time in patients with CHD is not significantly different from controls, in patients with CHD who are taking β-blockers, the lag time is higher than that observed in patients who are not taking β-blockers in [106]. When LDL are oxidized in vitro by copper or by macrophages, carvedilol, the most lipophilic β -blocker appears more potent than pindolol,

ACE inhibitors have been shown to have a beneficial effect in atherosclerosis. They reduce the progression of the disease in animals. These beneficial effects of ACE inhibitors have been related to an antioxidant activity against LDL oxidation that has been demonstrated. In vitro, the lag time was found to be clearly increased by the presence of captopril at concentrations close to those that can be achieved therapeutically with large doses. A similar effect is observed with *N*-acetylcysteine which contains like captopril, a sulfhydryl group. Quinapril, which lacks the sulfhydryl group, had no antioxidant activity [108]. In vivo, Aviram and coworkers have shown that the propensity of LDL to oxidation is increased in patients with hypertension and is positively correlated with the blood pressure. Giving captopril or enalapril for 3 weeks decreases the oxidizibility of LDL. That suggests that the sulfhydryl group, which is absent in enalapril, does not have any influence on the resistance of LDL oxidation [109]. Actually, the same group gave data suggesting that the antioxidant activity might be related to the decreased production of angiotensin-II (A-II) as A-II appears

All calcium channel blocker are potent antioxidants in vitro and this property is probably related to their interaction with the lipid bilayer of the membranes. Lacidipine has the highest degree of interaction with the membrane Lacidipine inhibits the LDL oxidation

labetolol, atenolol and propranolol and this is confirmed in vivo [107].

*3.1.5. Angiotensin-converting enzyme (ACE) inhibitors* 

to increase the LDL oxidation by macrophages [110].

*3.1.6. Calcium channel blocker* 

produced by several oxidants. [111].

*3.1.3. Fenofibrate* 

VLDL [105].

*3.1.4. Beta-adrenergic blockers* 

Statins themselves may be able to reduce levels of superoxide radicals, an effect that can only partially be explained by a reduction in LDL cholesterol. Rosuvastatin has been reported to reduce markers of oxidative stress in ApoE (−/−) mice [93] while fluvastatin treatment has been shown to decrease superoxide radical generation and to reduce the susceptibility of LDL to oxidation in cholesterol-fed rabbits [95, 96].

Atorvastatin has been demonstrated to inhibit angiotensin II-induced superoxide formation by NADPH oxidase in isolated rat vascular smooth muscle cells [96] and in rats in vivo [97]. In addition, statins have been shown to reduce NADPH-dependent superoxide formation by a monocyte-derived cell line in culture [98].

Another beneficial effect of statins is potentiation the synthesis of tetrahydrobiopterin, which may prevent the uncoupling of eNOS and shift the balance away from NOSgenerated superoxide production to the generation of NO [99]. Statins may also be influence the endogenous antioxidants other than NO. Atorvastatin has been shown to increase paraoxonase activity and reduce the enhanced cellular uptake of oxLDL of monocytes differentiating into macrophages [100]. Long-term treatment with HMG-CoA reductase inhibitors (statins) appears to upregulate the expression and the activity of the vascular endothelial NO synthase (eNOS) pathway and increases nitric oxide availability, resulting in not only a downregulation of oxidative enzymes but also a direct scavenging of superoxide anion. As oxygen radical production is increased in various clinical settings such as hypercholesterolaemia, diabetes and hypertension, this statin-induced eNOS upregulation may play a foremost role in the vascular protective effects of these drugs. [119]. Moreover, sustained nitroglycerin (NTG) treatment is associated with an increased bioavailability of superoxide anion, likely playing a major role in the development of nitrate tolerance. The triggering events leading to this redox imbalance remain controversial as several cellular enzyme systems have been shown to be impaired by sustained in vivo exposure to NTG, including membrane bound oxidases in [121] endothelial NOS in [122] and arginine transporters [123].

Other effects than hipocholesterolemic of statins was described. Lovastatin or simvastatin has been shown to have anti-inflammatory properties. They reduce monocyte adhesion to endothelial cells, cytokine expression and MCP-1 production [101-103]. By limiting the influx of inflammatory cells statins may reduce the release of superoxide radicals and the oxidative modification of LDL. On this way statins increases the resistance of LDL to oxidation. Macrophage growth stimulated by oxLDL can also be inhibited by statins [92]

#### *3.1.3. Fenofibrate*

56 Blood Cell – An Overview of Studies in Hematology

vascular and endothelial superoxide anion formation by inhibition of NADH oxidases via Rho-dependent mechanisms and preserving the relative levels of vitamin E, vitamin C and endogenous antioxidants (such as, ubiquinone and glutathione) in LDL particles*.* All these mechanisms explain a dual action of statins on oxidative stress, not only decreasing oxidants but also restoring antioxidants [92]. Statins reduce both extracellular LDL oxidation (by reducing substrate availability) and intracellular oxidative stress (by cholesterol-

Statins themselves may be able to reduce levels of superoxide radicals, an effect that can only partially be explained by a reduction in LDL cholesterol. Rosuvastatin has been reported to reduce markers of oxidative stress in ApoE (−/−) mice [93] while fluvastatin treatment has been shown to decrease superoxide radical generation and to reduce the

Atorvastatin has been demonstrated to inhibit angiotensin II-induced superoxide formation by NADPH oxidase in isolated rat vascular smooth muscle cells [96] and in rats in vivo [97]. In addition, statins have been shown to reduce NADPH-dependent superoxide formation

Another beneficial effect of statins is potentiation the synthesis of tetrahydrobiopterin, which may prevent the uncoupling of eNOS and shift the balance away from NOSgenerated superoxide production to the generation of NO [99]. Statins may also be influence the endogenous antioxidants other than NO. Atorvastatin has been shown to increase paraoxonase activity and reduce the enhanced cellular uptake of oxLDL of monocytes differentiating into macrophages [100]. Long-term treatment with HMG-CoA reductase inhibitors (statins) appears to upregulate the expression and the activity of the vascular endothelial NO synthase (eNOS) pathway and increases nitric oxide availability, resulting in not only a downregulation of oxidative enzymes but also a direct scavenging of superoxide anion. As oxygen radical production is increased in various clinical settings such as hypercholesterolaemia, diabetes and hypertension, this statin-induced eNOS upregulation may play a foremost role in the vascular protective effects of these drugs. [119]. Moreover, sustained nitroglycerin (NTG) treatment is associated with an increased bioavailability of superoxide anion, likely playing a major role in the development of nitrate tolerance. The triggering events leading to this redox imbalance remain controversial as several cellular enzyme systems have been shown to be impaired by sustained in vivo exposure to NTG, including membrane bound oxidases in [121] endothelial NOS in [122] and arginine

Other effects than hipocholesterolemic of statins was described. Lovastatin or simvastatin has been shown to have anti-inflammatory properties. They reduce monocyte adhesion to endothelial cells, cytokine expression and MCP-1 production [101-103]. By limiting the influx of inflammatory cells statins may reduce the release of superoxide radicals and the oxidative modification of LDL. On this way statins increases the resistance of LDL to oxidation. Macrophage growth stimulated by oxLDL can also be inhibited by statins [92]

independent effects on NO and, indirectly, by reducing Ox-LDL) [91].

susceptibility of LDL to oxidation in cholesterol-fed rabbits [95, 96].

by a monocyte-derived cell line in culture [98].

transporters [123].

Very few data concerning the fibrates are available. In hypercholesterolemic patients, it has been shown that bezafibrate is more active than pravastatin in reducing the susceptibility of LDL oxidation [104]. Moreover, in diabetics, De Leeuw and Van Gaal have found that fenofibrate, but not pravastatin or simvastatin, can reduce the oxidizibility of LDL and of VLDL [105].

## *3.1.4. Beta-adrenergic blockers*

Beta adrenergic blocking agents have also been shown to have beneficial effect on atherosclerosis. Several mechanisms of action have been suggested including an antioxidant action. All β-blockers have in vitro antioxidant activity which appears to be related to their degree of lipophilicity. In patients with CHD, Croft and coworkers showed that, while the lag time in patients with CHD is not significantly different from controls, in patients with CHD who are taking β-blockers, the lag time is higher than that observed in patients who are not taking β-blockers in [106]. When LDL are oxidized in vitro by copper or by macrophages, carvedilol, the most lipophilic β -blocker appears more potent than pindolol, labetolol, atenolol and propranolol and this is confirmed in vivo [107].

#### *3.1.5. Angiotensin-converting enzyme (ACE) inhibitors*

ACE inhibitors have been shown to have a beneficial effect in atherosclerosis. They reduce the progression of the disease in animals. These beneficial effects of ACE inhibitors have been related to an antioxidant activity against LDL oxidation that has been demonstrated. In vitro, the lag time was found to be clearly increased by the presence of captopril at concentrations close to those that can be achieved therapeutically with large doses. A similar effect is observed with *N*-acetylcysteine which contains like captopril, a sulfhydryl group. Quinapril, which lacks the sulfhydryl group, had no antioxidant activity [108]. In vivo, Aviram and coworkers have shown that the propensity of LDL to oxidation is increased in patients with hypertension and is positively correlated with the blood pressure. Giving captopril or enalapril for 3 weeks decreases the oxidizibility of LDL. That suggests that the sulfhydryl group, which is absent in enalapril, does not have any influence on the resistance of LDL oxidation [109]. Actually, the same group gave data suggesting that the antioxidant activity might be related to the decreased production of angiotensin-II (A-II) as A-II appears to increase the LDL oxidation by macrophages [110].

#### *3.1.6. Calcium channel blocker*

All calcium channel blocker are potent antioxidants in vitro and this property is probably related to their interaction with the lipid bilayer of the membranes. Lacidipine has the highest degree of interaction with the membrane Lacidipine inhibits the LDL oxidation produced by several oxidants. [111].

#### *3.1.7. Metabolic medication - Trimetazidine*

Trimetazidine (TMZ) is the first in a new class of metabolic agents, available for clinical use. In conditions of hypoxia or induced ischemia, TMZ maintains homeostasis and cellular functions by selectively inhibiting 3-ketoacyl-CoA-thiolase [112]. As a consequence, fatty acid b-oxidation is reduced and glucose oxidation is stimulated, resulting in decreased cellular acidosis and higher ATP production [113, 114]. In humans, TMZ has been shown to increase the ischaemic threshold and to relieve angina pectoris in patients with coronary artery disease. These benefits have been observed without any change in heart rate, blood pressure, and rate-pressure product at rest, during submaximal and peak exercise in [115,116]. There is also demonstration that TMZ has antioxidant properties. During acute and chronic ischemia, TMZ reduces the loss of intracellular K+ induced by oxygen free radicals and also the membrane content of peroxidated lipids [117]. In vivo, pre-treatment with TMZ (40–60 mg per day for 7 days) significantly decreases membrane malondialdehyde (MDA) content of red blood cells incubated with superoxide dismutase inhibitor diethyldithiocarbamate [118]. In humans, plasma levels of MDA were decreased after pre-treatment with TMZ during coronary artery bypass surgery [118].

Homocysteine in Red Blood Cells Metabolism – Pharmacological Approaches 59

Our research study to which we referred at the references was supported by grant PNCDII Idei 1225/2007 sustained by Ministry of Education and Research National Authority for

[1] Rifkind JM, Nagababu E, Ramasamy LB. Redox Rep. Review hemoglobin redox

[3] David E. Metzler, Biochemistry. The Chemical Reaction of Living Cells, second edition,

[4] Michael Lieberman, Allan D. Marks, Colleen Smith, Marks'Essentials of Medical Biochemistry. A Clinical Approach.2007, edited by Lippincott Williams&Wilkins [5] T.McKee, J. McKee. Biochemistry: The Molecular Basis of Life. 2004. 3rd Ed *T McKee*, *J* 

[7] Hara P. Misra and Irwin Fridovici, The generation of superoxide radical during the autoxidation of hemoglobin, The Journal of Biological Chemistry, 1972, 247(21): 6960-

[8] Balagopalakrishna C . Manoharan PT, Abugo OO, Rifkind JM, Production of superoxide from hemoglobin-bound oxygen under hypoxic condition, Biochemistry, 1996, 35(20):

[9] Koppenol, W.H. (2001). "The Haber-Weiss cycle – 70 years later". *Redox Report* 6 (4): 229–

[10] Mwebi N.O., Fenton&Fenton-like reaction: the nature of oxidizing intermediates involved (dissertation submitted to the Faculty of the Graduate School of the University

[12] Bogdanova A. Y. and Nikinmaa M., J. Gen. Physiol., 2001,117,181-190, Groves J.T.,

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234.

## **4. Instead of conclusion**

Mechanism of action of homocysteine is far from being elucidated. The big number of studies on this subject was gathered a lot of evidences about the role of Hcy as a major cardiovascular risk factor. All studied diseases: nephropathies, neurodegenerative illnesses, osteoporosis, atherosclerosis seems to be tributary to this homocysteine effect. It is widely accepted that involvement of homocysteine in the pathogenesis of these diseases activates prooxidative mechanisms. Therefore, the initiation of therapy of drug with antioxidant properties in such pathologies is justified. Moreover, there is clinical evidence to support this point of view. Thus, although the clinicians question the value of trimetazidine in the treatment of myocardial ischemia or degenerative deafness. [124-128] there are the clinical trials and basic research that support the benefits of this antioxidant metabolic medication. Scientific arguments exist regarding the use of atorvastatin [129, 130] or nimodipine [131] therapy for antiischemic effects and prevention of vascular events.

#### **Author details**

Filip Cristiana and Zamosteanu Nina *Dept. Biochemistry. Univ.Med. Pharm. "Gr.T.Popa", Iasi, Romania* 

Albu Elena *Dept. Pharmacology. Univ.Med. Pharm. "Gr.T.Popa", Iasi, Romania* 

#### **5. Acknowledgement**

Our research study to which we referred at the references was supported by grant PNCDII Idei 1225/2007 sustained by Ministry of Education and Research National Authority for Scientific Research UEFISCSU

#### **6. References**

58 Blood Cell – An Overview of Studies in Hematology

**4. Instead of conclusion** 

events.

Albu Elena

**Author details** 

Filip Cristiana and Zamosteanu Nina

*Dept. Biochemistry. Univ.Med. Pharm. "Gr.T.Popa", Iasi, Romania* 

*Dept. Pharmacology. Univ.Med. Pharm. "Gr.T.Popa", Iasi, Romania* 

*3.1.7. Metabolic medication - Trimetazidine* 

Trimetazidine (TMZ) is the first in a new class of metabolic agents, available for clinical use. In conditions of hypoxia or induced ischemia, TMZ maintains homeostasis and cellular functions by selectively inhibiting 3-ketoacyl-CoA-thiolase [112]. As a consequence, fatty acid b-oxidation is reduced and glucose oxidation is stimulated, resulting in decreased cellular acidosis and higher ATP production [113, 114]. In humans, TMZ has been shown to increase the ischaemic threshold and to relieve angina pectoris in patients with coronary artery disease. These benefits have been observed without any change in heart rate, blood pressure, and rate-pressure product at rest, during submaximal and peak exercise in [115,116]. There is also demonstration that TMZ has antioxidant properties. During acute and chronic ischemia, TMZ reduces the loss of intracellular K+ induced by oxygen free radicals and also the membrane content of peroxidated lipids [117]. In vivo, pre-treatment with TMZ (40–60 mg per day for 7 days) significantly decreases membrane malondialdehyde (MDA) content of red blood cells incubated with superoxide dismutase inhibitor diethyldithiocarbamate [118]. In humans, plasma levels of MDA were decreased

after pre-treatment with TMZ during coronary artery bypass surgery [118].

Mechanism of action of homocysteine is far from being elucidated. The big number of studies on this subject was gathered a lot of evidences about the role of Hcy as a major cardiovascular risk factor. All studied diseases: nephropathies, neurodegenerative illnesses, osteoporosis, atherosclerosis seems to be tributary to this homocysteine effect. It is widely accepted that involvement of homocysteine in the pathogenesis of these diseases activates prooxidative mechanisms. Therefore, the initiation of therapy of drug with antioxidant properties in such pathologies is justified. Moreover, there is clinical evidence to support this point of view. Thus, although the clinicians question the value of trimetazidine in the treatment of myocardial ischemia or degenerative deafness. [124-128] there are the clinical trials and basic research that support the benefits of this antioxidant metabolic medication. Scientific arguments exist regarding the use of atorvastatin [129, 130] or nimodipine [131] therapy for antiischemic effects and prevention of vascular

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Homocysteine in Red Blood Cells Metabolism – Pharmacological Approaches 61

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**Chapter 4** 

© 2012 Shaikh and Bhartiya, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

© 2012 Shaikh and Bhartiya, licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

**Pluripotent Stem Cells** 

Ambreen Shaikh and Deepa Bhartiya

http://dx.doi.org/10.5772/48133

**1. Introduction** 

Additional information is available at the end of the chapter

cell types and for the repair of damaged tissues.

(Image: Hematopoiesis\_ (human) \_diagram.png by A. Rad)

**Figure 1.** Hematopoiesis in Bone Marrow

**in Bone Marrow and Cord Blood** 

In a short span of few years, the possibility that the human body contains cells that can repair and regenerate damaged and diseased tissue has become a reality. Adult stem cells have been isolated from numerous adult tissues, umbilical cord, and other non-embryonic sources, and have demonstrated a surprising ability for transformation into other tissue and
