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Chemical structure of cholestyramine, which is associated with impairment folate and vitamin B12 absorption the molecule is too big
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Folate is vital for cell development and growth. It is involved in one-carbon transfer reactions essential for the synthesis of purines and pyrimidines. It also acts in conjunction with cobalamin (vitamin B12) as a fundamental cofactor in the remethylation cycle that converts homocysteine to methionine. A deficiency in folate or vitamin B12 can lea...
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Background/objectives:
This study investigates the predictors of serum cobalamin concentrations in community-dwelling older adults and the relationship between serum cobalamin and plasma homocysteine.
Subjects/methods:
Serum cobalamin and plasma homocysteine were measured by SimulTRAC-SNB radio assay and HPLC, respectively. Linear multiple regre...
Background
Serum folate is considered a biomarker of chronic enteropathy (CE) in dogs, but few studies have examined associations with markers of CE.
Hypothesis/Objectives
To evaluate serum folate concentrations in dogs with and without CE and associations with sample hemolysis and selected markers of CE. We hypothesized that hypofolatemia would b...
OBJECTIVE
Assess markers for pancreatic function and gastrointestinal malabsorption in African painted dogs ( Lycaon pictus ), including canine trypsin-like immunoreactivity (cTLI), canine pancreatic lipase immunoreactivity (cPLI), cobalamin, and folate at one North American facility.
ANIMALS
15 healthy African painted dogs held at one institution...
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Objective
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Citations
... Methotrexate (Fig. 20) is the first DHFR inhibitor that was obtained by the modification of folic acid, a natural substance, by substituting an amino group at position four of the pteridine ring and methylation of N10.FDA and EMA approved this drug for lymphoma, acute lymphoblastic leukemia, and osteosarcoma treatment in 1985 [12,65]. Some associated side effects are major toxicity of bone marrow, megaloblastic anaemia, fatigue, alopecia, lung infection, teratogenic effects, hepatotoxicity, and hypersensitivity [92][93][94]. ...
... The antiparasitic activity was tested against pneumocystis pneumonia in AIDS patients [12]. Some associated side effects are neutropenia, severe headache, fatigue, itching, hepatic and renal toxicity, anemia, myelosuppression, and teratogenic effects [94]. ...
... It is generally used as a trimethoprim-sulfamethoxazole combination. Some associated side effects are megaloblastic anemia, blood dyscrasias, aseptic meningitis, insomnia, teratogenic risk, neonatal hemolysis, uremia, and bone marrow hypoplasia [94,98]. ...
... Results from the International Surgical Outcomes Study (ISOS) showed 30.1% of adult elective inpatient surgery patients in 27 countries had preoperative anaemia (8). This result is comparable to the preoperative anaemia prevalence of 27.6% found in a large retrospective study of Chinese adult patients (9), 28.7% reported in a large prospective European cohort study of adult non-cardiac, non-obstetric, non-neurological surgery patients (10), and 47.8% seen in a large prospective observational study of adult non-cardiac, non-obstetric surgery patients across South Africa (11). Anaemia prevalence is increased in the elderly, in females, and in less wealthy regions (9,12). ...
... Intrinsic factor, produced in the stomach and required for absorption of vitamin B12 in the distal ileum of the small intestine, may be deficient due to autoimmune pathology or gastric achlorhydria associated with Helicobacter pylori infection or gastric resection/bypass surgeries (21,27). Nutritional deficiency of folic acid results from inadequate intake or malabsorption due to intestinal diseases, previous surgical resection or bypass of intestine, excessive alcohol consumption, or some medicines (e.g., phenytoin, carbamazepine, gabapentin) (21,28). ...
Roughly a third of surgical patients are found to have preoperative anaemia, with increased prevalence seen in children and the elderly, females, and residents of low-income regions. Perioperative anaemia is independently associated with poorer outcomes in surgery, which warrants a proactive approach to evaluation and management of anaemia. As allogeneic red blood cell (RBC) transfusion is associated with increased risk of infection and many comorbidities in patients, other modalities for treatment of anaemia and mitigation of blood loss should be employed. The appropriate approach to treatment of preoperative anaemia will depend on investigation of the patient’s underlying pathophysiology. The most common cause of preoperative anaemia is iron deficiency. Oral iron supplementation or intravenous (IV) iron, sometimes combined with erythropoiesis stimulating agents (ESAs), can effectively correct iron-deficiency anaemia prior to surgery. Techniques of intraoperative blood conservation, including intraoperative cell salvage and acute normovolemic hemodilution (ANH), along with hemostatic agents can reduce surgical blood loss and limit the need for allogeneic RBC transfusion. Effective care of the postoperative patient requires attention to limiting blood draws, optimizing nutrition, and judicious utilization of pharmacologic agents and blood component therapy. Increasing awareness of patient blood management as an overall approach and growing evidence of improved patient outcomes with blood conservation strategies will likely lead to increased adoption of best practices for management of perioperative anaemia.
... Methotrexate (Fig. 20) is the first DHFR inhibitor that was obtained by the modification of folic acid, a natural substance, by substituting an amino group at position four of the pteridine ring and methylation of N10.FDA and EMA approved this drug for lymphoma, acute lymphoblastic leukemia, and osteosarcoma treatment in 1985 [12,65]. Some associated side effects are major toxicity of bone marrow, megaloblastic anaemia, fatigue, alopecia, lung infection, teratogenic effects, hepatotoxicity, and hypersensitivity [92][93][94]. ...
... The antiparasitic activity was tested against pneumocystis pneumonia in AIDS patients [12]. Some associated side effects are neutropenia, severe headache, fatigue, itching, hepatic and renal toxicity, anemia, myelosuppression, and teratogenic effects [94]. ...
... It is generally used as a trimethoprim-sulfamethoxazole combination. Some associated side effects are megaloblastic anemia, blood dyscrasias, aseptic meningitis, insomnia, teratogenic risk, neonatal hemolysis, uremia, and bone marrow hypoplasia [94,98]. ...
Background:
Dihydrofolate reductase (DHFR) is an indispensable enzyme required for the survival of most prokaryotic and eukaryotic cells as it is involved in the biosynthesis of essential cellular components. DHFR has attracted a lot of attention as a molecular target for various diseases like cancer, bacterial infection, malaria, tuberculosis, dental caries, trypanosomiasis, leishmaniasis, fungal infection, influenza, Buruli ulcer, and respiratory illness. Various teams of researchers have reported different DHFR inhibitors to explore their therapeutic efficacy. Despite all the progress made, there is a strong need to find more novel leading structures, which may be used as better and safe DHFR inhibitors, especially against the microorganisms which are resistant to the developed drug candidates.
Objective:
This review aims to pay attention to recent development, particularly made in the past two decades and published in this field, and pay particular attention to promising DHFR inhibitors. Hence, an attempt has been made in this article to highlight the structure of dihydrofolate reductase, the mechanism of action of DHFR inhibitors, most recently reported DHFR inhibitors, diverse pharmacological applications of DHFR inhibitors, reported in-silico study data and recent patents based on DHFR inhibitors to comprehensively portray the current scenery for researchers interested in designing novel DHFR inhibitors.
Conclusion:
A critical review of recent studies revealed that most novel DHFR inhibitor compounds either synthetically or naturally derived are characterized by the presence of heterocyclic moieties in their structure. Non-classical antifolates like trimethoprim, pyrimethamine, and proguanil are considered excellent templates to design novel DHFR inhibitors, and most of them have substituted 2,4-diamino pyrimidine motifs. Targeting DHFR has massive potential to be investigated for newer therapeutic possibilities to treat various diseases of clinical importance.
... A 3-months postponed conception after cessation of MTX therapy is recommended due to the presence of active metabolites of MTX in tissue for several months as the median time of being undetected in red blood cells after discontinuation of consumption is 4 to 10 weeks (26,34). By inhibiting the DHFR enzyme, MTX disrupts the one-carbon metabolism, causing impairment of a number of folate-dependent reactions (35). Adequate folate supplementation is recommended to avoid side effects of MTX (36). ...
... Adequate folate supplementation is recommended to avoid side effects of MTX (36). Moreover, folate requirement is higher during pregnancy due to fast dividing maternal and embryonic tissues, and folate defi-ciency during the periconceptional period associates with susceptibility to a range of metabolic, genetic and nervous system disorders (35). Thus, all women in childbearing age are recommended to apply efficient types of contraception when taking MTX. ...
Objectives:
Methotrexate (MTX)is a folate antagonist that is administered in several conditions such as rheumatoid arthritis. Its use may associate with adverse effects presumably originating from folate deficiency. Although MTX side effects could be decreased by folate supplementation, the current guideline on folate administration is not precisely established, which could result in irreversible damage especially in high-risk groups like women in childbearing-age. Thus, this study aimed to investigate the in vitro rescuing effect of different folates including folic acid (FA), 5-methyltetrahydrofolate (MTHF) and folinic acid (5-Formyltetrahydrofolic acid, FTHF) on MTX-treated trophoblast cells.
Methods:
HTR-8/SVneo cells were stressed with a minimum effective dose of MTX and simultaneously treated with different concentrations of FA, MTHF or FTHF. The rescuing effect was assessed by MTT viability assay. The evaluation was completed by microscopic monitoring, apoptosis assessment and measuring LINE-1 DNA methylation.
Results:
The MTT viability assay showed no MTX-rescuing effect of FA, but a significant effect of FTHF or MTHF. Microscopic observations supported the results of the viability assay. Accordingly, apoptosis was reduced in MTHF or FTHF treatments, while FA has no effect on the apoptosis induced by MTX. The LINE-1 methylation was not affected by MTX treatment, and not significantly modified in folate supplemented cultures.
Conclusions:
Despite the general acceptance of administering FA to prevent adverse events of MTX therapy, our findings suggest that FA may not be optimal, and indicate FTHF or MTHF as a better choice. This study on trophoblast cells suggests that FTHF may be the optimal folate, particularly for women in childbearing-age.
... 7,8 Methionine is converted to homocysteine, which produces hydrogen sulfide (H 2 S). 9,10 H 2 S is physiologically produced from the homocysteine or cysteine by CSE (cystathionine γ-lyase), 11 CBS (cystathionine β-synthase), 12 and 3-MST (3-mercaptopyruvate sulfurtransferase) in the transsulfuration pathway during the homocysteine metabolism. 13 H 2 S has been shown to contribute to various physiological processes, such as regulation of blood pressure (BP) and clearance of reactive oxygen species, thereby having antihypertensive properties. ...
Hydrogen sulfide (H 2 S) is an endogenous gaseous antioxidant and antihypertensive molecule produced during the homocysteine metabolism. MsrA (methionine sulfoxide reductase A) enables the metabolism of homocysteine by reducing methionine sulfoxide to methionine. Although HDAC (histone deacetylase) inhibition has been reported to show blood pressure lowering effects, their effects on endogenous H 2 S production are largely unknown. Here, we assessed the relevance of MsrA in high-fat diet (HFD)-induced hypertension and the effect of HDAC inhibition on MsrA expression, H 2 S production, and hypertension. Male C57BL/6 mice were fed a normal diet or HFD. HFD increased blood pressure and activities of HDAC3 and 6 but downregulated MsrA in the mesenteric arteries and the serum H 2 S level. HFD upregulated 4 hydroxynonenal, TNF (tumor necrosis factor)-α, and IL (interleukin)-6, and vasocontractile proteins. The histone H3 acetylation of the MsrA promoter was decreased by HFD. In hypertensive HFD-fed mice, administration of the HDAC inhibitor CG200745 lowered blood pressure and increased serum H 2 S level. CG200745 increased acetylation of histone H3 and MsrA levels in the mesenteric arteries while downregulating oxidative stress, inflammation, and vasocontractile proteins. Silencing of MsrA in the vascular smooth muscle cells recapitulated HFD-induced in vivo hypertensive effects. CG200745 increased the histone H3 acetylation of the MsrA promoter, MsrA expression, and H 2 S production in vascular smooth muscle cells, supporting the in vivo results. Collectively, HFD-induced downregulation of MsrA plays a pivotal role in HFD-induced hypertension by reducing H 2 S levels. MsrA expression is epigenetically regulated by HDAC inhibitors, providing HDAC inhibitors as a therapeutic option and MsrA and H 2 S as novel therapeutic targets.
Graphic Abstract
An online graphic abstract is available for this article.
... Numerous medicines disturb folate metabolism by a variety of mechanisms-they inhibit different enzymes of the folate cycle, such as DHFR and MTHFR, impair folate and vitamin B 12 absorption, alter elimination of folate, induce liver enzymes, and act in numerous other ways. Examples of these medicines include trimethoprim, methotrexate, valproic acid, sulfasalazine, phenobarbital, phenytoin, and metformin [3]. ...
... Micronutrient folate (vitamin B 9 ) has a vital role in human health and disease and is essential for several crucial cellular processes, including DNA synthesis, amino acid interconversion, various methylation reactions, and consequently, for normal cell division and growth. Folate deficiency is associated with several congenital malformations, such as neural tube defects (NTDs), congenital heart defects, orofacial clefts, pregnancy-related complications, cardiovascular diseases, various psychiatric diseases, and cancer [1][2][3]. By contrast, excessive folate intake has also been associated with adverse health effects, such as increased risk for autism spectrum disorder and other negative neurocognitive Humans can obtain folate from food or food supplements, FA and 5-Me-THF. ...
... Currently, there are no recommendations for daily supplementation with 5-Me-THF, although it has some advantages over FA; 5-Me-THF, being an active form of folate, does not need enzymatic conversion to enter the folate cycle. As such, it could reduce the risk of lower conversion of FA to its active form, caused by medicines that inhibit enzyme DHFR, such as methotrexate, trimethoprim, triamterene, and sulfasalazine [3,10,30]. ...
Adequate levels of folates are essential for homeostasis of the organism, prevention of congenital malformations, and the salvage of predisposed disease states. They depend on genetic predisposition, and therefore, a pharmacogenetic approach to individualized supplementation or therapeutic intervention is necessary for an optimal outcome. The role of folates in vital cell processes was investigated by translational pharmacogenetics employing lymphoblastoid cell lines (LCLs). Depriving cells of folates led to reversible S-phase arrest. Since 5,10-methylenetetrahydrofolate reductase (MTHFR) is the key enzyme in the biosynthesis of an active folate form, we evaluated the relevance of polymorphisms in the MTHFR gene on intracellular levels of bioactive metabolite, the 5-methyltetrahydrofolate (5-Me-THF). LCLs (n = 35) were divided into low- and normal-MTHFR activity groups based on their genotype. They were cultured in the presence of folic acid (FA) or 5-Me-THF. Based on the cells' metabolic activity and intracellular 5-Me-THF levels, we conclude supplementation of FA is sufficient to maintain adequate folate level in the normal MTHFR activity group, while low MTHFR activity cells require 5-Me-THF to overcome the metabolic defects caused by polymorphisms in their MTHFR genes. This finding was supported by the determination of intracellular levels of 5-Me-THF in cell lysates by LC-MS/MS. FA supplementation resulted in a 2.5-fold increase in 5-Me-THF in cells with normal MTHFR activity, but there was no increase after FA supplementation in low MTHFR activity cells. However, when LCLs were exposed to 5-Me-THF, a 10-fold increase in intracellular levels of this metabolite was determined. These findings indicate that patients undergoing folate supplementation to counteract anti-folate therapies, or patients with increased folate demand, would benefit from pharmacogenetics-based therapy choices.
... 69 Folate deficiency leads to different disorders and diseases. 70 Among folate derivatives, 5-methyltetrahydrofolate (5-methyl THF) is found in circulation, and it acts as a co-substrate in the conversion of homocysteine to methionine (Figure 4) 71 . DNA mutations and strand breakage can also be the result of an increase in the replacement of uracil instead of thymidine. ...
... Antifolate medications have been used widely in cancer therapy to inhibit single-carbon metabolism, which is necessary for cell proliferation in cancerous tissue. 66,70 Other agents, such as chronic alcohol usage, 76 antacids, 77 and general anesthetics, 78 cause depletion or alteration in folate levels. ...
... These medications increase the elimination of folate. 70 The measurement of folate levels in the process of testing new therapeutic agents is considered a vital biomarker because of the essential role of folate in DNA biosynthesis and red blood cell synthesis. The depletion of folate levels increases the rate of cardiovascular and neuronal disorders. ...
Biomarkers are important parameters that are reliable, applicable, reproducible, and generally inexpensive. All biomarkers have a significant role in human health, especially mechanistic biomarkers, which are the most important for the prevention of toxic effects and diseases. They demonstrate the possibility of diagnosis, prognosis, recurrence, and spread of disease. Furthermore, they show the exposure levels to numerous chemical, biological, and physical agents. To date, the development and application of biomarkers require the knowledge of mechanisms underlying their production. Therefore, the present study focused on the possible mechanistic biomarkers.
... Because humans are unable to synthetize folates, they rely on dietary sources to achieve adequate folate levels. In addition, humans do not only depend on their folate intake, but are also influenced by genetic polymorphisms related to the folate pathway and homocysteine metabolism and a variety of environmental factors, such as alcohol consumption, smoking, and the use of medicines that interfere with the folate-homocysteine cycle, such as trimethoprim, methotrexate, valproic acid, sulfasalazine, etc., [10] [11][12] [13]. Because daily dietary intake of folates is generally lower than the dosage recommended by national health authorities [14], various folate supplements, such as folic acid (FA) and its derivatives-for example, 5-methyltetrahydrofolate (5-Me-THF)-are available and are also one of the most widely used food supplements. ...
Inadequate folate status is detrimental to human development. Deficiency has been implicated in congenital birth defects and cancer, whereas excess has been linked to various negative neurocognitive development outcomes. We developed a method for translational studies involving lymphoblastoid cell models for studying role of folates in vital cell processes. We describe a simple, sensitive, and fast liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of intracellular concentrations of clinically important metabolites of folate-homocysteine cycle; namely, folic acid (FA), 5-methyltetrahydrofolate (5-Me-THF), and homocysteine (Hcy). The method was validated for specificity, linearity, limits of quantification, repeatability, reproducibility, matrix effects, and stability. Method had a wide linear range between 0.341-71.053 ng Hcy/mg protein for Hcy, 0.004-0.526 ng FA/mg protein for FA and 0.003-0.526 ng 5-Me-THF/mg protein for 5-Me-THF. The method overcomes challenges associated with the quantification of endogenous molecules, poor stability, and extremely small amounts of the analytes. The method was successfully applied to evaluate the effects of FA and 5-Me-THF treatment of cells in vitro mimicking supplement therapy with various metabolically active species, and showed that 5-Me-THF is more effective than FA in increasing intracellular levels of the biologically active form of folate.
... Hcy, a sulfur-containing amino acid which is produced as an intermediate product as a result of demethylation during methionine metabolism [3,4], is a risk factor for cardiovascular disease [5,6]. In addition, some studies have also shown that Hcy is also associated with the development of malignant tumors [7,8]. ...
Background: The aim of the study was to evaluate the serum homocysteine (Hcy), vascular endothelial growth factor (VEGF) and transforming growth factor β1 (TGF-β1) dynamic change in colorectal cancer patients pre- and post-operation.
Material and methods: One hundred and eighteen CRC patients treated with surgery (CRC group) and 56 healthy controls (Control group) were included in this work. The serum Hcy, VEGF TGF-β1 were examined by enzymatic cycle and enzyme-linked immunosorbent assay (ELISA) of the two groups. We followed patients for 12 months and out of the 118 CRC patients, 14 patients had recurrent disease. Serum Hcy, VEGF and TGF-β1 were measured before and after surgery and repeated every 2 months.
Results Serum Hcy, VEGF and TGF-β1 were 16.20 ± 4.79 μmol/L, 492.36 ± 97.32 pg/ml, 29.23 ± 7.47 pg/ml for the CRC group and 8.98 ± 3.02 μmol/L, 315.21 ± 56.28 pg/ml, 7.69 ± 2.31 pg/ml for the control groups. Serum Hcy, VEGF and TGF-β1 was significantly (p<0.05) lower after surgery in both recurrent and nonrecurrent CRC patients (p<0.05). Interestingly, serum Hcy, VEGF and TGF-β1 gradually increased with time.
Conclusion Serum Hcy, VEGF and TGF-β1 levels are elevated in CRC patients and may correlated with the post-operative disease recurrence.
