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The hematocrit and MCV changes induced by folate deficiency in adult mice. Mice were fed either control or folatefree diet for 9 weeks. Blood cell counts were determined using an automated counter that was programmed for murine blood cells. All data are the means Ô 1 SEM of 10 mice. *P Ú .001 when comparing folate-deficient mice with control mice at the weeks shown.
Source publication
An in vitro model of folate-deficient erythropoiesis has been developed using proerythroblasts isolated from the spleens of Friend virus-infected mice fed an amino acid-based, folate-free diet. Control proerythroblasts were obtained from Friend virus-infected mice fed the same diet plus 2 mg folic acid/kg diet. Our previous studies showed that, aft...
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Citations
... Within hematopoietic tissues, this impairment results in increased death of immature erythroid cells leading to a decrease in the erythron or anemia. 175 Surviving erythroid cells are delayed in their maturation, which leads to a larger cell size (macrocytosis) and is reflected in an increase in the MCV. In addition, and depending on the cause, severity, and species, megaloblastic anemia will manifest with decreases in white blood cells or platelets with or without dysplastic changes (e.g., giant metamyelocytes, hypersegmented neutrophils). ...
... Vitamin B12 deficiency increases with aging [15] and has been associated with megaloblastic anemia and/or overt neurological complications [16]. Anemia in vitamin B12 deficiency is characterized by ineffective erythropoiesis caused by intramedullary apoptosis of megaloblastic erythroid precursors [17] and/or hemolysis because of shortened red cell survival [18]; increased plasma bilirubin and serum lactic dehydrogenase (LDH), with usually normal AST levels [19]; and higher iron, ferritin, and soluble transferrin receptor as a feature of a block in iron utilization [20][21][22]. ...
Background:
Vitamin B12 (cobalamin CBL) is a water-soluble vitamin required to form hematopoietic cells (red blood cells, white blood cells, and platelets). It is involved in the process of synthesizing DNA and myelin sheath. Deficiencies of vitamin B12 and/or folate can cause megaloblastic anemia (macrocytic anemia with other features due to impaired cell division). Pancytopenia is a less frequent exordium of severe vitamin B12 deficiency. Vitamin B12 deficiency can also cause neuropsychiatric findings. In addition to correcting the deficiency, an essential aspect of management is determining the underlying cause because the need for additional testing, the duration of therapy, and the route of administration may differ depending on the underlying cause.
Methods:
Here, we present a series of four patients hospitalized for megaloblastic anemia (MA) in pancytopenia. All patients diagnosed with MA were studied for a clinic-hematological and etiological profile.
Results:
All the patients presented with pancytopenia and megaloblastic anemia. Vitamin B12 deficiency was documented in 100% of cases. There was no correlation between the severity of anemia and deficiency of the vitamin. Overt clinical neuropathy was present in none of the cases of MA, while subclinical neuropathy was seen in one case. The etiology of vitamin B12 deficiency was pernicious anemia in two cases and low food intake in the remaining cases.
Conclusion:
This case study emphasizes the role of vitamin B12 deficiency as a leading cause of pancytopenia among adults.
... The connection between folate and erythroid differentiation was revealed in the 1940s when megaloblastic anemia was treated with folate supplementation 5 . Early studies that sought to understand the progression of folate-deficient anemia suggested DNA damage-induced apoptosis as the mechanism for reduced erythrocytic cell counts 6,7 . However, this suggested mechanism does not fully support the appearance of large, hemoglobin-rich, red blood cells that are characteristic of megaloblastic anemia. ...
... Megaloblastic anemia is characterized by the appearance of big, hemoglobinfilled, erythrocytes 38,39 . Early studies have suggested folate-deficient anemia is a result of DNA damage induced apoptosis 6,7 . It has been thought that the absence of folate decreases thymidylate synthesis and subsequently, the ratio of dTTP:dUTP. ...
All dividing cells require the essential vitamin folate. Hematopoietic cells harbor a unique sensitivity to folate deprivation, as implied by the development of folate-deficient anemia and the utility of anti-folate chemotherapy in blood cancer. To study this metabolic sensitivity, we applied mild folate depletion to human and mouse erythroid cell lines, as well as primary murine erythroid progenitors. We show that folate depletion induces early blockade of purine synthesis that is followed by enhanced heme metabolism, hemoglobin synthesis and erythroid differentiation. This finding is phenocopied by inhibition of folate metabolism using SHIN1, an inhibitor of the folate enzymes SHMT1/2. The metabolically-driven differentiation is rescued by supplementation of purine precursors, yet occurs independent of nucleotide sensing through mTORC1 and AMPK. Our work profiles the metabolic response to folate depletion in erythroid cells and suggest that premature differentiation of folate-deprived erythroid progenitor cells is a mechanistic etiology to folate-deficiency induced anemia.
... An increase in the reticulocyte count begins on days 3-5 and peaks on days 4-10 (Hillman, Adamson, & Burka, 1968). The new red cells come from newly formed normoblasts, and not from the old megaloblasts, most of which die before leaving the marrow (Koury, Horne, Brown, et al., 1997). Blood hemoglobin concentration becomes normal within 1-2 months. ...
Of the water-soluble vitamins, vitamin B12 (B12) has the lowest daily requirement. It also has several unique properties including a complex pathway for its absorption and assimilation requiring intact gastric and terminal small intestinal function, an enterohepatic pathway, and several dedicated binding proteins and chaperons. The many causes of B12 deficiency include malabsorption and defects in cellular delivery and uptake, as well as limited dietary intake. B12 is required as a cofactor for only two reactions in humans, the cytosolic methionine synthase reaction and the mitochondrial methymalonyl CoA mutase reaction. Disruption of either of these reactions gives rise to B12 deficiency. Although more common with advancing age, because of the higher prevalence of malabsorptive disorders in the elderly, B12 deficiency is widely distributed across all age groups particularly where food insecurity occurs. The consequences and severity of B12 deficiency are variable depending on the degree of deficiency and its duration. Major organ systems affected include the blood, bone marrow and nervous system. Megaloblastic anemia results from a defect in thymidine and therefore DNA synthesis in rapidly dividing cells. Nervous system involvement is varied, some of which results from defective myelin synthesis and repair. Cognitive impairment and psychosis may also occur. Diagnosis of B12 deficiency rests on clinical suspicion followed by laboratory testing, which consists of a panel of tests, that together provide clinically reliable predictive indices. B12 metabolism and deficiency is closely intertwined with folate, another B-vitamin. This chapter explores the various aspects of a unique and fascinating micronutrient.
... The heterogeneity among studies was estimated by I 2 score and Q test (12), and when the p-value of the heterogeneity was >0.1, the fixed-effect model was employed (13). Otherwise, the random-effect model was used (14). The publication bias was evaluated by Egger's test (15) and Begg's funnel plots (16). ...
... Impairments in genes and proteins involved in the production of sperm can be a source of infertility in men (4). Genes that are considered as risk factors for spermatogenesis include genes encoding protamines (5), telomere processing genes (6), genes involved in detoxification (7), and numerous other genes. However, an important group of these genes, which are considered serious spermatogenesis options, are folate metabolizing genes (8). ...
... In the case of the relationship between p53 and apoptosis, it is important to remember that p53 is initially maintained in the cytoplasm by binding to the murine double minute (MDM-2), a caspase substrate. The enzymatic action results in the release of p53, migrating to the nucleus, and activating the transcription of pro-apoptotic genes such as BAX25 [3][4][5][6][7][8][9][10][11]. ...
The pathogenesis of megaloblastic hemopathies (MH) is centered on the deficiency of vitamin B12 and folic acid with interruption of erythrocyte maturation. This study researched the participation of p53 and p21 in the pathophysiology of the disease. A retrospective study enrolled 95 patients with histopathologic diagnosis by biopsy or bone marrow clot (BMB/BMC), with clinical review and immunohistochemical study in tissue microarray (TMA) for p53 and p21, detailing their marking location. All patients had BMC and only 11 had BMB. The CMO was a differential of this study and it allowed an expanded sample. In the TMA, 63.7% (58/91) of the samples were immunopositive for p53; and 35.2% (31/88) were immunopositive for p21. Nuclear staining, divergent from the literature, was observed in 17.3% (10/58) among those p53+ and in 38.7% (12/31) among those p21+. The pattern of immunostaining showed non-significant differences (P=0.474) regarding morphologic and clinical aspects. The positivity for both may indicate an effective balance between apoptosis and anti-apoptotic action. Excessive inhibition of apoptosis would contribute to high global cellularity, but without functional maturation effectiveness. In conclusion, there is p21 and/or p53 immunoexpression in most cases of this study and there is no clear association between immunoexpression pattern and patient outcome. Unlike the literature, we also found a percentage of nuclear immunostaining, but the finding was not statistically significant. Combination of p21 and p53 results created different possibilities of pathologic interpretation for MH, reinforcing the importance of studies similar to this one.
... Normal excision and repair process of U-A incompatibility in DNA fails to correct the error due to persistent thymidine 5′-triphosphate deficiency. fragmentation, and apoptotic cell death [18,19]. ...
Introduction:
Peripheric blood derived stem cells are used in 75 % of allogeneic stem cell transplantations. Iron, vitamin B12 and folate involve in hematopoiesis. Therefore serum levels of iron, vitamin B12 and folat may effect stem cell mobilization. We aimed to analyze the effects of iron status, vitamin B12 and folate levels on peripheric blood stem cell mobilization in healthy donors.
Method:
The mobilization results of 218 allogeneic donors were analyzed retrospectively.
Results:
In 64 donors, serum ferritin level was <15 μg / L and transferrin saturation was <20 %. When we compared the donors with iron deficiency to the donors without iron deficiency, the number of collected CD34 + cell was significantly higher in donors without iron deficiency. We did not find any impact of serum vitamin B12 and folate level on CD34+ cells collected.
Conclusion:
Our study shows that serum ferritin and transferrin saturation have a greater effect on the amount of CD34+ cells collected from donors than serum vitamin B12 and folate levels. Consequently, when compliance tests of allogeneic donors are performed, the evaluation of vitamin B12 and folate levels is not necessary; whereas iron deficiency must be assessed and -if possible- corrected before apheresis is performed.
... The inadequacy of a number of folate-dependent proteins is hypthesized to participate significantly in the peri-conception period (Bliek et al. 2004). Folate insufficiency may also result in mutations due to the introduction of uracil instead of thymine into the DNA Koury et al. 1997). Chromosome instability and double-strand breaks may follow the inability to repair because of failure of removal of misincorporated uracil with subsequent apoptosis Koury et al. 1997). ...
... Folate insufficiency may also result in mutations due to the introduction of uracil instead of thymine into the DNA Koury et al. 1997). Chromosome instability and double-strand breaks may follow the inability to repair because of failure of removal of misincorporated uracil with subsequent apoptosis Koury et al. 1997). Formation and repair of DNA in addition to DNA methylation are critical in gametogenesis ,fertilization, and pregnancy (Jaroudi and SenGupta, 2007;Kiefer, 2007). ...
Background: Among the environmental factors, diet has received much attention because of growing bulk of data that discloses significant and substantial role for dietary elements, particularly, micronutrient in fertility pathophysiology. One of the major dietary elements that have been recently under focus is dietary folate. A number of vital cellular events, such as transfer RNA, synthesis of DNA, methionine and cysteine, require folate as an essential molecular participant. A number of previous studies have documented that folate supplementation can improve fertility outcome; whereas, other studies have denied such an association between folate supplementation and fertility outcomes. Aim of the study: to study a possible correlation between plasma and follicular fluid folate levels and the pregnancy rate in women enrolled in ICSI cycles. Patients and methods: The present study was done on 65 infertile couples who were chosen from those attended the High Institute of Infertility Diagnosis and Assisted Reproductive Technologies who were subjected to an intracytoplasmic sperm injection (ICSI) cycles. Their ages ranged from 18 to 42 years. Both primary and secondary types of infertility were involved, with heterogeneous causes. From each woman, venous blood sample and follicular fluid sample was obtained for folate concentration determination using ELISA technique. Results: The biochemical pregnancy rate was 32.3 %. There was significant association between plasma folate level and positive pregnancy outcome (P < 0.05), when comparing the pregnancy rate of deficient group, lower normal group and high group with that of normal group. The highest pregnancy rate was observed in women with normal plasma folate and it equals 56.7 %, therefore it was considered a reference group for purpose of comparison. Pregnancy rate of deficient folate group was significantly lower than that of normal folate group, 11.1 % versus 56.7 % (P = 0.043). In addition, pregnancy rate of lower normal folate group was significantly lower than that of normal folate group, 10.0 % versus 56.7 % (P = 0.028). Moreover, pregnancy rate of high folate group was significantly lower than that of normal group, 12.2 % versus 56.7 % (P = 0.004). Conclusion: Both high and low plasma folate are associated with low pregnancy rate; therefore, it should be recommended that serum folate should be monitored when prescribing folate to infertile women and that it should be discontinued once its level reaches the maximum normal plasma range.
... Folate deficiency has been established as a cause of megaloblastic anemia; both folate deficiency and megaloblastic anemia are associated with apoptosis. Folate deficient erythroblasts cultured in folate deficient medium demonstrated increased uracil misincorporation into DNA and increased p53 and p21 accumulation compared to control cells [95]. Patients with megaloblastic anemia often demonstrate primary folate deficiency or a secondary folate deficiency due to vitamin B12 deficiency, as well as increased p53 accumulation in bone marrow, compared to non-megaloblastic anemia controls [96]. ...
Genomic instability is implicated in the etiology of several deleterious health outcomes including megaloblastic anemia, neural tube defects, and neurodegeneration. Uracil misincorporation and its repair are known to cause genomic instability by inducing DNA strand breaks leading to apoptosis, but there is emerging evidence that uracil incorporation may also result in broader modifications of gene expression, including: changes in transcriptional stalling, strand break-mediated transcriptional upregulation, and direct promoter inhibition. The factors that influence uracil levels in DNA are cytosine deamination, de novo thymidylate (dTMP) biosynthesis, salvage dTMP biosynthesis, dUTPase, and DNA repair. There is evidence that the nuclear localization of the enzymes in these pathways in mammalian cells may modify and/or control the levels of uracil accumulation into nuclear DNA. Uracil sequencing technologies demonstrate that uracil in DNA is not distributed stochastically across the genome, but instead shows patterns of enrichment. Nuclear localization of the enzymes that modify uracil in DNA may serve to change these patterns of enrichment in a tissue-specific manner, and thereby signal the genome in response to metabolic and/or nutritional state of the cell.
