INTRODUCTION:

Alzheimer disease (AD) is a neurodegenerative disorder in the central nervous system (CNS) resulting in the loss of memory and other cognitive skills that ultimately clinically results in severe dementia^1,2. Inside the brain of AD patients, proteins coagulate together to create structures called tangles and plaques concentrating around nerve cells. This results in weak connection between nerve cells leading to gradual death of nerve cells causing the loss of brain tissues³.

The main stage of pathogenesis in AD is the accumulation of amyloid β-peptide (Aβ), a neurotoxic proteolytic derivative of the amyloid precursor protein (APP)⁴. The generation of Aβ derivatives in several subcellular compartments, but a precept location is during the recycling and re-entry of amyloid precursor protein (APP) from the cell surface through the endocytic pathway^5,6,7. It is further reported that the inherited variants in the APP, apolipoprotein E (APOE), presenilin 1 (PS1) and presenilin 2 (PS2) genes are associated with accumulation of Aβ in the brain^8,9,10,11. The abnormal accumulation of Aβ and the sedimentation of neurofibrillary tangles in the brain of AD patients have been associated with a significant extent of oxidative damage¹². This indicates that AD patients will have higher oxidative stress and thus more susceptible to health problems caused by oxidative stress.

Oxidative Stress:

Oxidative stress is defined as an imbalance in output of free radicals and reactive metabolites (antioxidants)¹³. This imbalance can lead to the impairment of important cells and biomolecules affecting the functioning of whole body¹⁴. Free radicals are reactive molecules with free electrons that could impair the cell membrane fatty acids and proteins¹⁵. Further free radicals could be a predisposing factor for numerous health problems due to their effects on DNA damage and mutations¹⁶. Free radicals are generated endogenously in our body or exogenously as well, when exposed to different physiochemical conditions or pathological states. Even though a low or moderate ROS have a good physiochemical effect including the killing of invading pathogens, wound healing, and tissue renovation processes¹⁷. The disproportionate generation of ROS will badly affect the homeostasis causing oxidative tissue damage. The reverse impact of ROS can be limited by natural antioxidant pathways, but also can be stimulated by many oxidative stressors contributing to tissue damage¹⁸. ROS are produced in response to exogenous and endogenous agents including stress response. Disorder of normal cellular homeostasis by redox signalling gives a shone in an actual disease for every organ¹⁹. So, free radicals and antioxidants have become commonly used terms in modern discussions of disease mechanisms²⁰.

Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, NADPH oxidase isoforms (NOX), Peroxidases, lipoxygenases (LOXs), xanthine oxidase (XO), glucose oxidase, nitric oxide synthase, myeloperoxidase (MPO), and cyclooxygenases (COXs) are all enzymes that catalyse ROS-generating chemical reactions^21,22. Intracellular compartments including mitochondria, the endoplasmic reticulum, nuclei, peroxisomes, the cytosol, plasma membranes, and even extracellular spaces are capable of ROS generation^23,24. The mitochondrial electron transport chain is the major site of ROS production in most mammalian cells²⁵.

Oxidative Stress in AD:

It has been reported that the imbalance between the ROS and generation of free radicals can lead to pathogenesis inducing many neurodegenerative disorders including AD^26-28. Nerve cells seem to be especially vulnerable to attack by free radicals for various reasons including substantial deficiency in oxygen supply required for brain metabolism. Nerve cells membranes consist of a high proportion of polyunsaturated fatty acids with a lower glutathione concentration; an important natural antioxidant^29,30. Age as a main risk factor in AD is considerable due to the generation of free radicals especially produced by ROS over the years³¹. Aβ can interact with vascular endothelial cells to produce excess of free superoxide radicals that may lead produce oxidizing agents and scavenge the endothelium derived relaxing factor causing lipid peroxidation³². Many researchers showed increased lipid peroxidation in the brain of patient’s suffering from AD^33,34. Protein oxidation has also been reported in elderly people but it appears to be the most marked in AD patients³⁵. The increased oxidation of mitochondrial DNA and, to a lower extent, of nuclear DNA has been observed in the parietal cortex of patients suffering from AD³⁶.

Also nerve cells are quite sensitive to attacks by subversive free radicals³⁷. Growing evidence suggests that a significant role is played by zinc, iron and copper in aggregation of Aβ and neurodegeneration. These metals have catalytic activity that produces free radicals³⁸. Therefore oxidative stress results into several disorders including AD. As previously presented, an increased oxidative stress in the body can cause a harmful increase in ROS that may ultimately lead to countless physiological disorders including abnormal haematological parameters. Till date despite cognizance of the medical community to ever higher status, effect of oxidative stress on haematological parameters in AD patients has not be explored yet.

Role of Oxidative Stress in Abnormal Haematological Parameters:

Elevated levels of oxidative stress are linked to increased levels of ROS in tissues and in blood³⁹. ROS are derived from endogenous sources and their production is not neutralized by antioxidant defence mechanisms. Increased levels of ROS production lead to positive-feedback with inflammation related mechanism through pro-inflammatory cytokines trigger ROS production and by ROS induced expression of proinflammatorycytokines²⁴.Furthermore, ROS-induced apoptosis of skeletal muscle fibres is an important contributor to skeletal muscle fatigue and low exercise tolerance⁴⁰. High levels of ROS have been demonstrated in the venous blood of the cases that have high level of oxidative stress and are accompanied by high neutrophil superoxide anion generation⁴¹.

The presence of ROS in circulating blood leads to mitochondrial depolarization, which in turn leads to apoptosis of white blood cells (WBCs)⁴². Elevated WBC count has been shown to have a significant relationship with unfavourable lifestyles such as smoking, obesity, poor sleep, and unhealthy diet leading to contribute an increase level of stress then oxidative stress^43,44. Polymorphonuclear leukocytes (PMNL) are one of the major kinds of inflammatory cells⁴⁵. When the PMNL is activated, it releases reactive oxygen species including hydrogen peroxide contributing to endothelial damage diseases^{46, 47}. Oxidative stress can lead to general fatigue that may be a key determinant of low-grade inflammation as represented by increase neutrophil counts⁴². Oxidative stress can leads to endothelial dysfunction and initiate an acute phase inflammatory response involving the release of cytokines, acute phase proteins, and increase neutrophils, decrease monocytes lymphocytes, and increases neutrophil-lymphocyte ratio (NLR)⁴⁸. So, oxidative stress can lead to elevated total WBCs count in AD patients.

Red blood cells (RBCs) are constantly at risk from both exogenous and endogenous sources of ROS that can harm the RBC function⁴⁹. ROS are very interactive and many of the ROS released from macrophages, neutrophils, and endothelial cells into the plasma before they can be taken up by RBCs especially in the microcirculation being more close to the blood vessels^50,51. When the ROS entre into the RBC cytoplasm, they are mostly part neutralized by the cytosolic antioxidant system. Hydrogen peroxide attached to RBCs rapidly reacts with catalase being converted to oxygen without any oxidation of haemoglobin (Hb)⁴⁹. Slow autoxidation of Hb generates endogenous ROS with methaemoglobin production which does not have the ability to carry oxygen and superoxide production that rapidly dismutases to form hydrogen peroxide^52,53. The RBC cytosolic antioxidants neutralize the RBC bulk but the antioxidant system to neutralize the endogenous ROS is limited as the blood stream through the microcirculation when Hb becomes partially oxygenated⁵⁴. Partial oxygenation results in an Hb conformational change with certain unique properties. Thus there is a high increase in the rate of Hb autoxidation of partially oxygenated Hb^{53, 55}. The excess in the affinity of partially oxygenated Hb limits the efficiency of the antioxidant system for neutralizing the ROS formed at the membrane⁵⁶. This collection of un-neutralized ROS in the RBC leads to damage the RBC membrane impairing the flow of RBCs into the microcirculation and the transfer of oxygen to relevant tissues^57,58. In addition, recent studies indicated that the RBCs also contain nicotinamide adenine dinucleotide hydrogen (NADH) oxidases, which can generate endogenous ROS⁵⁹.

The RBC membrane band 3 is the control of integral trans-membrane protein. It has several crucial functions including the maintenance of anion homeostasis. Thus providing a link between the membrane and the cytoskeleton accountable for maintaining the cell shape, and providing for the reactions of cytosolic proteins with the membrane through the amino terminal region that emerges into the cytosol. This region of band 3 binds competitively to both; Hb and a quantity of glycolytic enzymes⁶⁰. The variations in Hb binding to band 3 is a function of the Hb oxygenation. Thus Hb oxygenation and Hb autoxidation results into glycolysis and ATP generation⁶¹. Oxidative damage to band 3 has been associated with RBC aging including the exposure of senescent specific neo-antigens that connect autologous IgG triggering RBC removal⁶². IgG binding has also been reported to be associated with band 3 clusters which is triggered by the binding of denatured oxidized Hb (haemichromes) to band 3^63,64,65. Caspase-3 activation, which involves oxidative stress, further cleaves the cytoplasmic end of band 3 affecting the communications of band 3 with cytosolic proteins as well as the linkage to ankyrin and the cytoskeleton, which also motivates PS exposure^66,67. The process of older cells formation is known as membrane micro-vesiculation⁶⁸. These changes affect the highly deformable biconcave shape maintenance which is necessary to pass through narrow pores, thus contributing to their removal from blood circulation. While cell shrinkage and vesiculation can be induced by different factors, some of which may not involve oxidative stress, however the shrinkage related with potassium leakage via the Gardos channel is triggered by oxidative stress⁶⁹. The damage of Ca-ATPase, which maintains a low intracellular concentration of free calcium ions⁷⁰, is accountable for the age induced increase in intracellular calcium and is resulted by the oxidative harm to ATPase^71,72. The increase in the intracellular calcium activates the Gardos channel which leads to potassium leakage from the cell resulting in cell shrinkage and damage^73,74. This increased intracellular calcium also activates calpain, transglutaminase-2 and some caspases that can degrade/crosslink cytoskeleton proteins⁷⁵. It also prevents phosphotyrosine phosphatase rising band 3 phosphorylation⁷⁶. The RBC lipid bilayer contains an asymmetric distribution of phospholipids with PS being maintained on the inner cover of the membrane by the rivalry between Scramblase (randomizes the allocation) and Flippase (internalizes the PS). In addition to the increase in Sphingomyelinase which increases ceramide, intracellular calcium increases has been linked to the exposure of PS and to the decrease of Flippase activity⁷⁷ triggering the interaction of RBCs with macrophages and eryptosis^{78, 79, 80}. So, oxidative stress resulting in AD patients plays a role in damaging the RBC membrane and impairing it, or accelerating the aging and death of the RBC.

The ROS aggressive effect has a tendency to the gastrointestinal (GI) tract. They are also bared to outside environment with immune cells presence and intestinal flora dietary factors, all prospect sources of ROS⁸¹. Two main enzymatic reactions produce ROS in the GI tract; the hypoxanthine (HX)/XO system and the NADPH oxidase system⁸². The GI tract has the largest concentration of XO in the body which along with various phagocytic cells and a great number of catalase-negative bacteria in the colon join to generate large amounts of oxygen (O₂⁻)⁸³. The excessive levels of ROS can lead to damage cellular proteins including cytoskeletal proteins and ultimately disrupting GI tract barrier resulting an increase in gut permeability which contributes to inflammation in a variety of GI tract diseases^{84, 85}. Therefore, oxidative stress resulting in AD patients can lead to GI disorders including malabsorption which leads to deficiency of important nutrients in the body including haematinic factors i.e., minerals and vitamins important to erythropoiesis.

Based on the above research reports, it can be argued that oxidative stress can be another cause of anaemia. However only two studies have been shown this relationship and discussed it in general. Therefore it can be suggested here the that more research investigations are needed to establish a more comprehensive evidences on the relationship of oxidative stress and anaemia (Table 1).

CONCLUSION:

It can be hypothesized from the available cited literature that there is a correlation between oxidative stress in AD patients and haematological parameters such as elevated WBCs count, especially neutrophils, as well as an increase chance of anaemia that leads to abnormal blood indicators according to the type of RBCs deficits. Therefore it is important to conduct deeper investigations in this topic to explore the relationship between oxidative stress and haematological parameters in general and specially with anaemia in AD patients.

ACKNOWLEDGEMENT:

We thank "Institute for Community Development and Quality of Life" at Universiti Sultan ZainalAbidin for assistance us, for comments that greatly improved the manuscript and for publish the manuscript.

CONFLICT OF INTEREST:

The authors declare no conflict of interest.

REFERENCES:

1. Alexopoulos GS, Chester JG. Outcomes of geriatric depression. Clin Geriatr Med. 1982; 8 (1): 363-376.

2. Bartus RT, Dean RL, Beer B, Lippa AS. The cholinergic hypothesis of geriatric memory dysfunction. Science. 1982; 217 (4558): 408-414.

3. Mattson MP. Pathways towards and away from Alzheimer’s disease. Nature. 2004;430:631–9.

4. Bayer TA, et al. Key factors in Alzheimer’s disease: beta-amyloid precursor protein processing, metabolism and intraneuronal transport. Brain Pathol. 2001;11:1–11.

5. Kinoshita A, et al. Demonstration by FRET of BACE interaction with the amyloid precursor protein at the cell surface and in early endosomes. J Cell Sci. 2003;116:3339–46.

6. Vetrivel KS, et al. Spatial segregation of gamma-secretase and substrates in distinct membrane domains. J Biol Chem. 2005;280:25892–25900.

7. Goate AM, et al. Segregation of a missense mutation in the amyloid precursor protein gene with Familial Alzheimer Disease. Nature. 1991;349:704–706.

8. Sherrington R, et al. Cloning of a gene bearing missense mutations in early onset familial Alzheimer’s disease. Nature. 1995;375:754–760.

9. Rogaev EI, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a novel gene on chromosome 1 related to the Alzheimer’s Disease type 3 gene. Nature. 1995;376:775–778.

10. Saunders A, et al. Association of Apoliprotein E allele e4 with the late-onset familial and sporadic Alzheimer Disease. Neurology. 1993;43:1467–1472.

11. Christen Y. Oxidative stress and Alzheimer disease. Am J ClinNutr. 2000; 71: 621S–629S.

12. Sharma RK, Pasqualotto FF, Nelson DR, Thomas Jr DR, Agarwal A. The reactive oxygen species—total antioxidant capacity score is a new measure of oxidative stress to predict male infertility. Hum. Reprod.1999; 14: 2801-2807.

13. Durackova Z. Some current insights into oxidative stress. Physiol. Res. 2010; 59: 459-469.

14. Cross CE, van der Vliet A, O'Neill CA, Louie S, Halliwell B. Oxidants, antioxidants, and respiratory tract lining fluids. Environmental Health Perspectives. 1994; 102(Suppl 10): 185.

15. Chicago Khansari N, ShakibaY, Mahmoudi M. Chronic inflammation and oxidative stress as a major cause of age-related diseases and cancer. Rec. Pat. Infl. Aller. dru. disc. 2009; 3: 73-80.

16. Wijk RV, Wijk E, Van PA, WiegantVA, Ives J,. Free radicals and low-level photon emission in human pathogenesis: State of the art. Indi. J. Exper. Bio. 2008; 46: 273-309‏.

17. Metcalfe NB, Alonso‐Alvarez C. Oxidative stress as a life‐history constraint: the role of reactive oxygen species in shaping phenotypes from conception to death. Func. Ecol. 2010; 24: 984-996.‏

18. Kim J, Park W. Oxidative stress response in Pseudomonas putida. App.Micr. Biot. 2014; 98: 6933-6946.

19. Lobo V, Patil A, PhatakA, Chandra N. Free radicals, antioxidants and functional foods: Impact on human health. Pharm. Rev. 2010; 4: 118-126.

20. Kulkarni AC, KuppusamyP, Parinandi N. Oxygen, the lead actor in the pathophysiologic drama: enactment of the trinity of normoxia, hypoxia, and hyperoxia in disease and therapy. Anti. Red. Sign. 2007; 9: 1717-1730.

21. Swindle EJ, Metcalfe D. The role of reactive oxygen species and nitric oxide in mast cell-dependent inflammatory processes. Immu. Rev. 2007; 217: 186-205.

22. Balaban RS, Nemoto S, Finkel T. Mitochondria, oxidants, aging. Cell. 2005; 120: 483-495.

23. Pritchard KA, Ackerman AW, Gross ER, Stepp DW, Shi Y, Fontana JT, Baker JE, Sessa WC. Heat shock protein 90 mediates the balance of nitric oxide and superoxide anion from endothelial nitric-oxide synthase. J. Biol. Chem. 2001; 276: 17621-17624.

24. Poyton RO, Castello PR, Ball KA, Woo DK, Pan N. Mitochondria and hypoxic signaling: a new view. Ann. New. York. Acad. Sci. 2009; 1177:48-56.

25. Hartman D. Free radical theory of aging: Alzheimer's disease pathogenesis.Age 1995;18:97–119.

26. Halliwell B, Gutteridge JMC. Free radicals in biology and medicine. Oxford, United Kingdom: Oxford University Press; 1989.

27. Packer L, Prilipko L, Christen Y, eds. Free radicals in the brain. Heidelberg, Germany: Springer-Verlag; 1992.

28. Uttara, B, Singh AV, Zamboni P, Mahajan RT. Oxidative stress and neurodegenerative diseases: a review of upstream and downstream antioxidant therapeutic options. Current neuropharmacology. 2009; 7 (1): 65-74.

29. Rahman, K. Studies on free radicals, antioxidants, and co-factors. Clinical interventions in aging. 2007; 2(2): 219.

30. Abdel Moneim A. Oxidant/antioxidant imbalance and the risk of Alzheimer's disease. Current Alzheimer Research. 2015; 12(4): 335-349.

31. Freeman LR, Keller JN. Oxidative stress and cerebral endothelial cells: regulation of the blood–brain-barrier and antioxidant based interventions. BiochimicaetBiophysicaActa (BBA)-Molecular Basis of Disease. 2012; 1822 (5): 822-829.

32. Bradley-Whitman MA, Lovell MA. Biomarkers of lipid peroxidation in Alzheimer disease (AD): an update. Archives of toxicology. 2015; 89 (7): 1035-1044.

33. Marcus DL, Thomas C, Rodriguez C, et al. Increased peroxidation and reduced antioxidant enzyme activity in Alzheimer's disease. Exp Neurol. 1998;150:40–4.

34. Wang X, Wang W, Li L, Perry G, Lee HG, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. BiochimicaetBiophysicaActa (BBA)-Molecular Basis of Disease. 2014; 1842 (8): 1240-1247.

35. De Souza-Pinto NC, Wilson DM, Stevnsner TV, Bohr VA. Mitochondrial DNA, base excision repair and neurodegeneration. DNA repair. 2008; 7 (7): 1098-1109.

36. Christen Y. Oxidative stress and Alzheimer disease. The American journal of clinical nutrition. 2000; 71 (2): 621s-629s.‏

37. Kozlowski H, Janicka-Klos A, Brasun J, Gaggelli E, Valensin D, Valensin G. Copper, iron, and zinc ions homeostasis and their role in neurodegenerative disorders (metal uptake, transport, distribution and regulation). CoordChem Rev. 2009; 253: 2665–2685.

38. Nita M, Grzybowski A. The role of the reactive oxygen species and oxidative stress in the pathomechanism of the age-related ocular diseases and other pathologies of the anterior and posterior eye segments in adults. Oxid. Med. Cell Long. 2016; 2016:23.

39. Powers SK, Ji LL, KavazisAN, Jackson MJ. Reactive oxygen species: impact on skeletal muscle. Comp. Phys. 2011; 1:941-969.

40. Mittal M, Siddiqui MR, Tran K, Reddy SP, Malik AB. Reactive oxygen species in inflammation and tissue injury. Anti. Red. Sign. 2014; 20: 1126-1167.

41. Nishitani N, Sakakibara H. Association of Psychological Stress Response of Fatigue with White Blood Cell Count in Male Daytime Workers. Indus. Heal. 2014; 52: 531-534.

42. Nakanishi N, Suzuki K, Tatara K. Association between lifestyle and white blood cell count: a study of Japanese male office workers. Occup. Med. 2003; 53: 135-137.

43. Nishitani N, Sakakibara H. Subjective poor sleep and white blood cell count in male Japanese workers. Indus. Heal. 2007; 45: 296-300.

44. Baggiolini M, Bretz U, Dewald B, Feigenson ME. The polymorphonuclear leukocyte. Inflam. Res. 1978; 8: 3-10.‏

45. Smedly LA, Tonnesen MG, Sandhaus RA, Haslett C, Guthrie LA, Johnston RJ, Henson PM, Worthen GS. Neutrophil-mediated injury to endothelial cells: enhancement by endotoxin and essential role of neutrophil elastase. J. Clin. Inves. 1986; 77:1233-1243.

46. Weiss SJ. Tissue destruction by neutrophils. N. Engl. J. Med. 1989; 320: 365-376.

47. Dhabhar FS, Malarkey WB, NeriandE, McEwen BS. Stress-induced redistribution of immune cells—From barracks to boulevards to battlefields: A tale of three hormones–Curt Richter Award Winner. Psychoneuroendocrinology. 2012; 37: 1345-1368.‏

48. Mohanty JG, Nagababu E, Rifkind JM. Red blood cell oxidative stress impairs oxygen delivery and induces red blood cell aging. Fron. Phys. 2014; 5:84.

49. Nagababu E, Rifkind JM. Formation of fluorescent heme degradation products during the oxidation of hemoglobin by hydrogen peroxide.Bioc.Bioph. Res. Comm. 1998; 247: 592-6.

50. Rifkind JM, AjmaniRS, Heim J. Impaired hemorheology in the aged associated with oxidative stress. Adv. Exp. Med. Biol. 1997; 428: 7-13.

51. Aoshiba K, Nakajima Y, Yasui S, TamaokiJ, Nagai A. Red blood cells inhibit apoptosis of human neutrophils. Blood. 1999; 93: 4006-4010.

52. Abugo O, Rifkind M. Oxidation of hemoglobin and the enhancement produced by nitrobluetetrazolium. J. Biol. Chem. 1994; 269: 24845-24853.

53. Pandey KB, RizviSI.Biomarkers of oxidative stress in red blood cells. Biom. P. Med. Fac. P. Uni. Olom. 2011; 155:131-136.

54. Balagopalakrishna C, Manoharan PT, AbugoOO, Rifkind JM. Production of superoxide from hemoglobin-bound oxygen under hypoxic conditions. Biochem. 1996; 35: 6393-6398.

55. Cao Z, Bell JB, Mohanty JG, NagababuE, Rifkind JM. Nitrite enhances RBC hypoxic ATP synthesis and the release of ATP into the vasculature: a new mechanism for nitrite-induced vasodilation. Am. J. Phys. Hea. Circ. Phys. 2009; 297: H1494–1503.

56. Nagababu E,Gulyani S, Earley CJ, Cutler RG, Mattson MP, Rifkind JM. Iron-deficiency anaemia enhances red blood cell oxidative stress. F. Rad. Res. 2008; 42:824-829.

57. Barodka VM, Nagababu E, Mohanty JM, Nyhan D, Berkowitz DE, Rifkind JM, Strouse JJ. New insights provided by a comparison of impaired deformability with erythrocyte oxidative stress for sickle cell disease. Blo. Cel. Molec. Dise. 2014; 52: 230-235.

58. George A, Pushkaran S, Konstantinidis DG, Koochaki S, Malik P, Mohandas N, Zheng Y, Joiner CH,Kalfa TA. Erythrocyte NADPH oxidase activity modulated by RacGTPases, PKC, and plasma cytokines contributes to oxidative stress in sickle cell disease. Blood. 2003; 121: 2099-2107.

59. Mohandas N, Gallagher PG. Red cell membrane: past, present, and future. Blood. 2008; 112: 3939-3948.

60. De Rosa M.C, Carelli AC, Galtieri A, Russo A, Giardina B. Allosteric properties of hemoglobin and the plasma membrane of the erythrocyte: new insights in gas transport and metabolic modulation. IUBMB Life. 2008; 60: 87-93.

61. Kay MM. Generation of senescent cell antigen on old cells initiates IgG binding to a neoantigen. Cel. Mol. Biol. 1993; 39: 131-153.

62. Low PS, Waugh SM, ZinkeK, Drenckhahn D. The role of hemoglobin denaturation and band 3 clustering in red blood cell aging. Science. 1985; 227: 531-533.

63. Rettig MP, Low PS, Gimm JA, Mohandas N, Wang J, Christian JA. Evaluation of biochemical changes during in vivo erythrocyte senescence in the dog. Blood. 1999; 93: 376-384.

64. Ferru E, Giger K, Pantaleo A, Campanella E, Grey J, Ritchie K, Vono R, TurriniF, Low PS. Regulation of membrane-cytoskeletal interactions by tyrosine phosphorylation of erythrocyte band 3. Blood. 2011; 117:5998–6006.

65. Mandal D, Baudin-Creuza V, Bhattacharyya A, Pathak S, Delaunay J, KunduM, Basu J. Caspase 3-mediated proteolysis of the N-terminal cytoplasmic domain of the human erythroid anion exchanger 1 (band 3). J. Biol. Chem. 2003; 278: 52551-52558.

66. Grey JL, KodippiliGC, Simon K. Low PS. Identification of contact sites between ankyrin and band 3 in the human erythrocyte membrane. Biochem. 2012; 51: 6838-6846.

67. Willekens FL, Were JM, Groenen-Dopp YA, Roerdinkholder-Stoelwinder B, de PB, Bosman GJ. Erythrocyte vesiculation: a self-protective mechanism? Br. J.Haem. 2008; 141:549-556.

68. Rifkind JM, Nagababu E. Hemoglobin redox reactions and red blood cell aging. Anti. Red. Sig. 2013; 18: 2274-2283.

69. Larsen FL, Katz S, Roufogalis BD. Calmodulin regulation of Ca2+transport in human erythrocytes. Biochem. J. 1981; 200: 185-191.

70. Samaja M,Rubinacci A, Motterlini R, De Pa, Portinaro N. Red cell aging and active calcium transport. Expe. Gero. 1990; 25: 279-286.

71. Kiefer CR, Snyder LM. Oxidation and erythrocyte senescence. Curr. Opin. Hema.2000; 7: 113-116.

72. Foller M, Kasinathan RS, Koka S, Lang C, Shumilina E, Birnbaumer L, Lang F, Huber SM. TRPC6 contributes to the Ca(2+)leak of human erythrocytes. Cell Phys. Bioch. 2008; 21: 183-192.

73. Brugnara C. Membrane transport of Na and K and cell dehydration in sickle erythrocytes. Experientia. 1993; 49: 100-109.

74. Redding GS, Record DM, Raess BU. Calcium-stressed erythrocyte membrane structure and function for assessing glipizide effects on transglutaminase activation. Proc. Soc. Exp. Biol. Med. 1991; 196: 76-82.

75. Zipser Y, Piade A, Barbul A, KorensteinR, Kosower NS. Ca2+promotes erythrocyte band 3 tyrosine phosphorylation via dissociation of phosphotyrosine phosphatase from band 3. Biochem. J. 2002; 368: 137-144.

76. Burger P, Kostova E, Bloem E, Hilarius-Stokman P, Meijer AB, van den Berg TK, Verhoeven AJ, de KorteD, van Bruggen R. Potassium leakage primes stored erythrocytes for phosphatidylserine exposure and shedding of pro-coagulant vesicles. Br. J.Haem. 2009; 160: 377-386.

77. Daleke DL. Regulation of phospholipid asymmetry in the erythrocyte membrane. Curr. Opin. Hema. 2008; 15: 191-195.

78. Foller M, Huber SM, Lang F. Erythrocyte programmed cell death. IUBMB Life. 2008; 60: 661-668.

79. Weiss E, Rees DC, Gibson JS. Role of calcium in phosphatidylserineexternalisation in red blood cells from sickle cell patients. Anemia. 2010; 2011:8.

80. Mureşan A, Suciu S, Mitrea DR, Alb C, Login C, Crişan D. Oxidative stress implications in experimental gastric ulcer induced by indomethacin. Bulletin of University of Agricultural Sciences and Veterinary Medicine Cluj-Napoca. Veter. Med. 2008; 65: 1843-5270.

81. Bhattacharyya A,Chattopadhyay R, Mitra S, Crowe SE. Oxidative stress: an essential factor in the pathogenesis of gastrointestinal mucosal diseases. Phys. Rev. 2014; 94: 329-354.‏

82. Mastroeni P, Immunity to systemic Salmonella infections. Curr. Mol. Med., 2010; 2:393-406.

83. Dasgupta SK, Abdel-Monem H,Guchhait P, Nagata S, Thiagarajan P. Role of lactadherin in the clearance of phosphatidylserine-expressing red blood cells. Transfusion. 2008; 48: 2370-2376.

84. Phull PS, Green CJ, Jacyna MR. A radical view of the stomach: the role of oxygen-derived free radicals and anti-oxidants in gastroduodenaldisease. Euro. J. Gast. Hepat. 1995; 7: 265-274.

85. Banan A, Choudhary S, Zhang Y, Fields JZ, Keshavarzian A. Ethanol-induced barrier dysfunction and its prevention by growth factors in human intestinal monolayers: evidence for oxidative and cytoskeletal mechanisms. J. Phar. Exp. Ther. 1999; 291: 1075-1085.

86. Hassan ZA, Chelebi NA, BazzazandAA, Bazzaz SA. Correlation of psychological stress to severity of anemia in Al-Haweejawomen.Euro. J. Phar. Med. Res. 2016; 3: 248-251.

87. Wei C, Zhou J, Li M, Huang X. Effects of psychological stress on serum iron and erythropoiesis. Int. J. Hem. 2008; 88: 52-56.

Received on 21.11.2017 Modified on 15.01.2018

Research J. Pharm. and Tech 2018; 11(9): 3881-3886.

DOI: 10.5958/0974-360X.2018.00711.4

Research sample	Source of oxidative stress	Results	Reference
Females aged 20-40 years old.	Stress caused bydeterioration in the quality of life due to general circumstances e.g. economical, political, civil war, recurrent pregnancy, and malnutrition.	Drop in both Hb and PCV indicates a mild symptomatic anaemia.	Hassan et al⁸⁶
Rats	Stress caused by special communication box system & electric foot-shock.	Serum iron and bone marrow iron showed the significant decrease compared with the controls, erythropoiesis was significantly inhibited, all the above led to anaemia.	Wei et al⁸⁷