Moderately high folic acid supplementation exacerbates experimentally induced liver fibrosis in rats

Under certain clinical circumstances, folic acid can have undesirable effects. We investigated the following: (i) the effects of moderately high folic acid supplementation on the course of liver impairment in CCl(4)-treated rats and (ii) the influence of folic acid supplements on the hepatic recovery following the interruption of the CCl(4)-induced toxic injury. Four experimental groups of rats were used: CCl(4)-treated rats (0.5 ml of CCl(4) twice a week i.p.) fed standard chow for up to 12 weeks (Group A); treated rats fed chow supplemented with 25 mg/kg folic acid from weeks 6 to 12 (Group B); treated rats fed a standard diet but with CCl(4) discontinued after 6 weeks to allow for tissue recovery over 4 weeks (Group C); rats as Group C but fed a diet supplemented with 25 mg/kg folic acid from weeks 6 to 10 (Group D). Liver and blood samples were obtained for biochemical, histological, and gene expression analyses. Animals that received the supplement had a higher content of collagen, activated stellate cells, and apoptotic parenchymal cells in biopsy tissue at weeks 8 and 10 of treatment and more extensive alterations in serum albumin and bilirubin concentrations (Group B vs. Group A). In some of the time periods analyzed, alterations were observed in the expression of genes related to apoptosis (B-cell leukemia/lymphoma 2, inhibitor of apoptosis 2) and to fibrosis (procollagen I, matrix metalloproteinase 7). In the recovery period (Groups C and D), folic acid administration was associated with increased hepatic inflammation and apoptosis and with a decrease in the tissue inhibitor of metalloproteinase-3 expression following 1 week of recovery. We conclude that folic acid administration aggravates the development of fibrosis in CCl(4)-treated rats. Follow-up studies are needed to determine whether folic acid treatment would be contraindicated in patients with chronic liver diseases.     

Synergistic effect of folic acid and vitamin B12 in ameliorating arsenic-induced oxidative damage in pancreatic tissue of rat

The efficacies of two nutritional factors, folic acid and vitamin B12, were assessed in this study against arsenic-induced islet cellular toxicity. Rats were divided into four groups consisting of five rats in each group: Group A, control; Group B, arsenic-treated; Group C, arsenic+folic acid; and Group D, arsenic+folic acid+vitamin B12. The dose of arsenic, folic acid and vitamin B12, respectively, was 3 mg, 36 microg and 0.63 microg kg(-1) body weight day(-1) for 30 days. Results showed that, compared to control group, there was a significant increase in the levels of nitric oxide (NO), malondialdehyde (MDA) and hydroxyl radical (OH-) formation in the pancreatic tissue of arsenic-treated rats, while the activity of antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT), and cellular content of antioxidant glutathione (GSH) were low in these animals. The serum level of tumor necrosis factor-alpha (TNF-alpha) and IL-6 was significantly high in these animals. Light microscopic examination showed a marked fall in the number of islet cells. Concomitant administration of either folic acid or folic acid and vitamin B12 with arsenic significantly restored all these parameters. Although folic acid alone could not restore the normal level of TNF-alpha and IL-6, combined folic acid and vitamin B12 could restore it. Folic acid and vitamin B12 combined also could recover islet cell count. These results suggest that folic acid+vitamin B12 are capable of reducing arsenic-induced cellular oxidative and inflammatory toxic changes. Thus, supplement with vitamin B12+folic acid may be predicted as a possible nutritional management strategy against arsenic-induced toxicity.     

The relationship between micronuclei in human lymphocytes and selected micronutrients in vegetarians and non-vegetarians

A vegetarian diet results in higher intake of vitamins and micronutrients, which - although providing antioxidant defence - may lead to deficiency in other micronutrients involved in DNA metabolism and stability (such as vitamins belonging to the B group). The principal difference among various vegetarian diets is the extent to which animal products are avoided. We have performed a pilot study to determine the relationship between the micronucleus frequency in lymphocytes and diet, and we compared the levels of Vitamins C and E, beta-carotene, B(12), folic acid, homocysteine and total antioxidant capacity in healthy vegetarians and non-vegetarians. The vegetarian group, consisting of 24 volunteers (13 women and 11 men), were matched for age and sex with 24 volunteers (12 women and 12 men) with a traditional dietary habit. Among the vegetarians were 13 lacto-ovo-vegetarians with average duration of vegetarian diet 10.8 years (ranging from 5 to 26 years) and 11 lacto-vegetarians with average duration of vegetarian diet 8.2 years (ranging from 3 to 15 years). Homocysteine, Vitamins C and E and beta-carotene levels in plasma were assayed by HPLC, and serum folate and Vitamin B(12) were determined with Elecsys Immunoassay tests. The total antioxidant capacity of plasma was estimated by measuring the ferric-reducing activity in a spectrophotometric assay. Micronuclei were measured in cytokinesis-blocked lymphocytes. Vegetarians had significantly higher levels of Vitamin C and beta-carotene (but not Vitamin E) in plasma compared with non-vegetarians (P<0.001). There were no significant differences in serum levels of folic acid and Vitamin B(12) between the monitored groups. Levels of folic acid in vegetarians correlated with length of vegetarianism (r=0.62, P=0.001, N=24). Vegetarians had elevated levels of homocysteine compared with non-vegetarians (P=0.007), as did vegetarian women compared with non-vegetarian women (P=0.031). We did not find any differences in total antioxidant capacity or in micronucleus frequency between the groups. Micronuclei correlated with age (r=0.62, P<0.001, N=48), women having higher frequencies than men. Multifactorial regression analysis showed significant effects of age, sex and total antioxidant capacity on micronucleus frequency (N=48, P<0.001).     

The role of folic acid and Vitamin B12 in genomic stability of human cells

Folic acid plays a critical role in the prevention of chromosome breakage and hypomethylation of DNA. This activity is compromised when Vitamin B12 (B12) concentration is low because methionine synthase activity is reduced, lowering the concentration of S-adenosyl methionine (SAM) which in turn may diminish DNA methylation and cause folate to become unavailable for the conversion of dUMP to dTMP. The most plausible explanation for the chromosome-breaking effect of low folate is excessive uracil misincorporation into DNA, a mutagenic lesion that leads to strand breaks in DNA during repair. Both in vitro and in vivo studies with human cells clearly show that folate deficiency causes expression of chromosomal fragile sites, chromosome breaks, excessive uracil in DNA, micronucleus formation and DNA hypomethylation. In vivo studies show that Vitamin B12 deficiency and elevated plasma homocysteine are significantly correlated with increased micronucleus formation. In vitro experiments indicate that genomic instability in human cells is minimised when folic acid concentration in culture medium is >227nmol/l. Intervention studies in humans show: (a) that DNA hypomethylation, chromosome breaks, uracil misincorporation and micronucleus formation are minimised when red cell folate concentration is >700nmol/l folate; and (b) micronucleus formation is minimised when plasma concentration of Vitamin B12 is >300pmol/l and plasma homocysteine is <7.5micromol/l. These concentrations are achievable at intake levels in excess of current RDIs i.e. more than 200-400microgram folic acid per day and more than 2microgram Vitamin B12 per day. A placebo-controlled study with a dose-response suggests that based on the micronucleus index in lymphocytes, an RDI level of 700microgram/day for folic acid and 7microgram/day for Vitamin B12 would be appropriate for genomic stability in young adults. Dietary intakes above the current RDI may be particularly important in those with extreme defects in the absorption and metabolism of these Vitamins, for which ageing is a contributing factor.     

Folic acid supplementation delays atherosclerotic lesion development in apoE-deficient mice

Folic acid is a vitamin that when used as a dietary supplementation can improve endothelial function. To assess the effect of folic acid on the development of atherosclerosis, male apolipoprotein E-deficient mice fed a standard chow diet received either water (control group) or an aqueous solution of folic acid that provided a dose of 75 microg/kg/day, for ten weeks. At the time of sacrifice, blood was drawn and the heart removed. The study measured plasma homocysteine, lipids, lipoproteins, low-density lipoprotein (LDL) oxidation, isoprostane, paraoxonase, and apolipoproteins, and aortic atherosclerotic areas. In folic acid-treated animals, total cholesterol, mainly carried in very low-density and low-density lipoproteins, increased significantly, and homocysteine, HDL cholesterol, paraoxonase, and triglyceride levels did not change significantly. Plasma isoprostane and apolipoprotein (apo) B levels decreased. The resistance of LDL to oxidization and plasma apoA-I and apoA-IV levels increased with a concomitant decrease in the area of atherosclerotic lesions. The administration of folic acid decreased atherosclerotic lesions independently of plasma homocysteine and cholesterol levels, but was associated with plasma levels of apolipoproteins A-I, A-IV and B, and decreased oxidative stress.     

Hyperglycinemia due to folate deficiency in rats: evidence for the lack of involvement of the hepatic glycine cleavage system

In addition to a well-recognized hyperhomocysteinemic state, folate deficiency also leads to profound hyperglycinemia. To further characterize the latter observation, two trials were conducted using a folate-deficient rat model to (1) determine the sensitivity of plasma glycine to folate repletion and (2) test the hypothesis that hyperglycinemia results from a reduced flux through the folate-dependent glycine cleavage system (GCS). Weanling male Sprague–Dawley rats were used, and they consumed an amino acid-defined diet with either 0 (FD) or 1 (FA) mg/kg of crystalline folic acid. In Trial 1, 30 rats consumed the FD diet for 28 days. Rats then consumed diets containing 0.1, 0.2, 0.3 or 0.4 mg/kg of folic acid for 14 days before termination. In Trial 2, 16 rats were allocated to receive either the FA (n=8) or FD (n=8) diet for 30 days before termination. Liver mitochondria were isolated and flux through the GCS (measured as ¹⁴CO₂ production from 1-¹⁴C-glycine) was determined. Plasma from blood collected at termination was analyzed for folate, homocysteine and glycine. In Trial 1, both homocysteine and glycine responded linearly to increased dietary folic acid (milligrams per kilogram) levels (P<.05). In Trial 2, plasma folate (FA=25.85 vs. FD=0.66; S.E.M.=1.4 μM), homocysteine (FA=11.1 vs. FD=55.3; S.E.M.=1.7 μM) and glycine (FA=564 vs. FD=1983; S.E.M.=114 μM) were significantly affected by folate deficiency (P<.0001). However, glycine flux through hepatic GCS was not affected by folate deficiency (P>.05). These results provide evidence that in a folate-deficient rat model, both homocysteine and glycine are sensitive to dietary folic acid levels; however, the observed hyperglycinemia does not appear to be related to a reduced flux through the hepatic GCS.     

Ω3-Polyunsaturated fatty acids prevent lipoperoxidation, modulate antioxidant enzymes, and reduce lipid content but do not alter glycogen metabolism in the livers of diabetic rats fed on a high fat thermolyzed diet

Ω3-Polyunsaturated fatty acids (Ω3-PUFAs) are known to act as hypolipidaemics, but the literature is unclear about the effects that Ω3-PUFAs have on oxidative stress in obese and diabetic patients. In this study, our aim was to investigate the effects of Ω3-PUFAs on oxidative stress, including antioxidant enzyme activity and hepatic lipid and glycogen metabolism in the livers of diabetic and non-diabetic rats fed on a high fat thermolyzed diet. Rats were divided into six groups: (1) the control group (C), (2) the control diabetic group (D), (3) the high fat thermolyzed diet group (HFTD), which were fed a diet that was enriched in fat that was heated for 60 min at 180°C, (4) the high fat thermolyzed diet diabetic group (D + HFTD), (5) the high fat thermolyzed diet + Ω3 polyunsaturated fatty acid group (HFTD + Ω3), and (6) the high fat thermolyzed diet + Ω3 polyunsaturated fatty acid diabetic group (D + HFTD + Ω3). The most important finding of this study was that Ω3-PUFAs are able to reduce triglycerides, non-esterified fatty acid, lipoperoxidation levels, advanced glycation end products, SOD/CAT enzymatic ratio, and CAT immunocontent and increase SOD2 levels in the livers of diabetic rats fed with a HFTD. However, Ω3-PUFAs did not alter the observed levels of protein damage, blood glucose, or glycogen metabolism in the liver. These findings suggest that Ω3-PUFAs may represent an important auxiliary adjuvant in combating some diseases like diabetes mellitus, insulin resistance, and non-alcoholic fatty liver disease.     

Effects of vitamin D supplementation on calcium balance and bone growth in young rats fed normal or low calcium diet

OBJECTIVE: We examined the effect of vitamin D supplementation on bone growth in young rats fed a normal or low calcium diet. METHODS: Fifty female Sprague-Dawley rats, 6 weeks of age, were randomized by stratified weight method into five groups with 10 rats in each group: baseline control, 0.5% (normal) or 0.1% (low) calcium diet, and 0.5 or 0.1% calcium diet + vitamin D (25 microg/100 g, food intake). Duration of the experiment was 10 weeks. RESULTS: Vitamin D supplementation stimulated intestinal calcium absorption and increased urinary calcium excretion in rats fed a low or normal calcium diet. Vitamin D supplementation prevented the reduction in periosteal bone gain but enhanced enlargement of the marrow cavity and reduced the maturation-related cancellous bone gain in rats fed a low calcium diet, and increased the maturation-related cancellous and cortical bone gains in rats fed a normal calcium diet. CONCLUSION: This study shows the differential effects of vitamin D supplementation on born growth in young rats fed a normal or low calcium diet.     

Folic acid supplementation inhibits NADPH oxidase-mediated superoxide anion production in the kidney

Hyperhomocysteinemia, a condition of elevated blood homocysteine (Hcy) levels, is a metabolic disease. It is a common clinical finding in patients with chronic kidney diseases and occurs almost uniformly in patients with end-stage renal disease. Hyperhomocysteinemia is also a risk factor for cardiovascular disease. Our recent studies indicate that hyperhomocysteinemia can lead to renal injury by inducing oxidative stress. Oxidative stress is one of the important mechanisms contributing to Hcy-induced tissue injury. Folic acid supplementation is regarded as a promising approach for prevention and treatment of cardiovascular disease associated with hyperhomocysteinemia due to its Hcy-lowering effect. However, its effect on the kidney is not clear. The aim of this study was to examine the effect of folic acid supplementation on Hcy-induced superoxide anion production via nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in the kidney during hyperhomocysteinemia. Hyperhomocysteinemia was induced in male Sprague-Dawley rats fed a high-methionine diet for 12 wk with or without folic acid supplementation. A group of rats fed a regular diet was used as control. There was a significant increase in levels of superoxide anions and lipid peroxides in kidneys isolated from hyperhomocysteinemic rats. Activation of NADPH oxidase was responsible for hyperhomocysteinemia-induced oxidative stress in the kidney. Folic acid supplementation effectively antagonized hyperhomocysteinemia-induced oxidative stress via its Hcy-lowering and Hcy-independent effect. In vitro study also showed that 5-methyltetrahydrofolate, an active form of folate, effectively reduced Hcy-induced superoxide anion production via NADPH oxidase. Xanthine oxidase activity was increased and superoxide dismutase (SOD) activity was decreased in the kidney of hyperhomocysteinemic rats, which might also contribute to an elevation of superoxide anion level in the kidney. Folic acid supplementation attenuated xanthine oxidase activity and restored SOD activity in the kidney of hyperhomocysteinemic rats. These results suggest that folic acid supplementation may offer renal protective effect against oxidative stress.     

High-Casein Diet Suppresses Guanidinoacetic Acid-Induced Hyperhomocysteinemia and Potentiates the Hypohomocysteinemic Effect of Serine in Rats

To determine the effect of dietary protein level on experimental hyperhomocysteinemia, rats were fed 10% casein (10C) and 40% casein (40C) diets with or without 0.5% guanidinoacetic acid (GAA) for 14 d. In addition, rats were fed 10C + 0.75% methionine (10CM) and 40C + 0.75% methionine (40CM) diets with or without 2.5% serine for 14 d to determine the relationship between the dietary protein level and intensity of the hypohomocysteinemic effect of serine. GAA supplementation markedly increased the plasma homocysteine concentration in rats fed with the 10C diet, whereas it did not increase the plasma homocysteine concentration in rats fed with the 40C diet. Although serine supplementation significantly suppressed the methionine-induced enhancement of plasma homocysteine concentration, the decreased plasma homocysteine concentration was significantly lower in rats fed with the 40CM diet than in rats fed with the 10CM diet. The hepatic cystathionine β-synthase and betaine-homocysteine S-methyltransferase activities were significantly higher in rats fed with the 40C or 40CM diet than in rats fed with the 10C or 10CM diet, irrespective of supplementation with GAA and serine. These results indicate that the high-casein diet was effective for both suppressing GAA-induced hyperhomocysteinemia and potentiating the hypohomocysteinemic effect of serine, probably through the enhanced activity of homocysteine-metabolizing enzymes.     

Effects of vitamin K2 administration on calcium balance and bone mass in young rats fed normal or low calcium diet

OBJECTIVE: The purpose of this study was to examine the effects of vitamin K2 administration on calcium balance and bone mass in young rats fed a normal or low calcium diet. METHODS: Forty female Sprague-Dawley rats, 6 weeks of age, were randomized by stratified weight method into four groups with 10 rats in each group: 0.5% (normal) calcium diet, 0.1% (low) calcium diet, 0.5% calcium diet + vitamin K2 (menatetrenone, 30 mg/100 g chow diet), and 0.1% calcium diet + vitamin K2. After 10 weeks of feeding, serum calcium and calciotropic hormone levels were measured, and intestinal calcium absorption and renal calcium reabsorption were evaluated. Bone histomorphometric analyses were performed on cortical bone of the tibial shaft and cancellous bone of the proximal tibia. RESULTS: Feeding a low calcium diet induced hypocalcemia, increased serum parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels with decreased serum 25-hydrovyvitamin D [25(OH)D] level, stimulated intestinal calcium absorption and renal calcium reabsorption, and reduced cortical bone mass as a result of decreased periosteal bone gain and enlarged marrow cavity, but did not significantly influence cancellous bone mass. Vitamin K2 administration in rats fed a low calcium diet stimulated renal calcium reabsorption, retarded the abnormal elevation of serum PTH level, increased cancellous bone mass, and retarded cortical bone loss, while vitamin K2 administration in rats fed a normal calcium diet stimulated intestinal calcium absorption by increasing serum 1,25(OH)2D level, and increased cortical bone mass. CONCLUSION: This study clearly shows the differential response of calcium balance and bone mass to vitamin K2 administration in rats fed a normal or low calcium diet.     

Investigation of the effects of folate deficiency on embryonic development through the establishment of a folate deficient mouse model

BACKGROUND: Folic acid (FA) has been shown to reduce the incidence of neural tube, craniofacial, and cardiovascular defects and low birth weight. The mechanism(s) by which the vitamin is effective, however, has not been determined. Therefore, a folic acid deficient mouse model was developed. METHODS: To create a folic acid deficiency, ICR female mice were placed on a diet containing no FA and including 1% succinyl sulfathiazole (SS) for 4 weeks before mating. Control mice were fed diets with either: 1) FA and 1% SS [+SS only diet]; 2) FA [normal diet]; or 3) a breeding diet. Dams and fetuses were examined during various days of gestation. RESULTS: Blood analysis showed that by gestational day 18, plasma folate concentrations in the -FA+SS fed dams decreased to 1.13 ng/ml, a concentration approximately 3% of that in breeding diet fed dams (33.24 ng/ml) and 8% of that in +SS only/normal fed dams (13.59 ng/ml). RBC folate levels showed a similar decrease, whereas homocysteine concentrations increased. Reproductive outcome in the -FA+SS fed dams was poor with increased fetal deaths, decreased fetal weight, and delays in palate and heart development. CONCLUSIONS: Female mice fed a folic acid deficient diet and 1% succinyl sulfathiazole exhibited many of the characteristics common to human folic acid deficiency, including decreased plasma and RBC folate, increased plasma homocysteine, and poor reproductive outcomes. Thus, an excellent model has been created to investigate the mechanism(s) underlying the origin of birth defects related to folic acid deficiency.     

Effect of folic acid deficiency upon lymphocyte subsets from lymphoid organs in mice.

1. Three groups of weanling C57BL/6 female mice were fed one of two folate-deficient diets (0 and 0.1 mg folic acid/kg diet) or a normal folate-containing diet (2 mg folic acid/kg diet) for 8 weeks. A control pair-fed group was introduced with the most severe folate-deficient diet. Seven mice were fed the 0 mg folic acid/kg diet for 8 weeks, then rehabilitated (R) on the 2 mg folic acid/kg diet for 10 days. 2. Mice fed 0 mg folic acid/kg diet were severely folate-deficient (SFD), whereas mice fed 0.1 mg folic acid/kg diet were moderately folate-deficient (MFD), as shown by their folate status parameters. 3. Thymus weight, thymocyte content and positive immature CD4+8+ cells were decreased in SFD mice compared to controls. These values were normalized after 10 days of rehabilitation. 4. Mesenteric lymph node cells were apparently not affected by folate deficiency. 5. The proportion of Thy-1+ splenocytes was mildly lower in SFD mice than in controls. In R mice, mean spleen weight and spleen cellularity were increased compared to the other groups, but the proportions of Thy-1+, CD4+8- and CD4-8+ cells were markedly lower than control values.     

Vitamin D ameliorates hepatic ischemic/reperfusion injury in rats

Vitamin D, most commonly associated with the growth and remodeling of bone, has been shown to ameliorate ischemia/reperfusion injury (IRI) in some tissues, yet its underlying mechanism remains elusive. This study was designed to examine the protective effect of vitamin D, if any, against hepatic IRI in rats and the underlying mechanism involved. Adult female Wistar rats were randomly divided into control, sham-operated (sham), ischemia/reperfusion (I/R), and ischemic-reperfused vitamin D-treated (vit D) groups. Rats in the I/R and vit D groups were subjected to partial (70 %) hepatic ischemia for 45 min, followed by 1 h of reperfusion. Vitamin D was given to rats orally in a dose of 500 IU/kg daily for 2 weeks before being subjected to I/R. Markers of liver damage, oxidative stress, inflammation and apoptosis were evaluated. Hepatic morphology was also examined. Vit D-treated rats had significantly lower serum levels of alanine aminotransferase, aspartate aminotransferase, and γ glutamyl transferase compared to rats in the I/R group. Also, vit D-treated rats showed a significant decrease in malondialdehyde, interleukin-1 beta, interleukin-6, tumor necrosis factor-α, nuclear factor κB, B cell leukemia/lymphoma 2-associated X protein, cytochrome c, and caspase-3 levels, with higher levels of glutathione peroxidase and B cell lymphoma 2 protein levels in liver tissues compared to I/R rats. Histological examination showed less damaged liver tissues with amelioration of apoptotic signs in the vit D group compared to the I/R group. In conclusion, vitamin D supplementation ameliorates hepatic IRI mostly by alleviating the inflammatory-apoptotic response mediated by the oxidative reperfusion injury insult.     

Effect of vitamin B12 and folate on biosynthesis of methionine from homocysteine in the nematode Caenorhabditis briggsae.

(i) Omission of L-methionine from the medium resulted in an 80% population reduction. Substitution of D,L-homocysteine corrected methionine deficiency in C. briggsae in the presence of supraoptimal vitamin B12 and folic acid. (ii) An absolute vitamin B12 requirement in C. briggsae developed in the medium containing homocysteine at the second subculture. Concentration of 6 ng/ml of vitamin B12 (at 100 ng/ml of folic acid) was sufficient to support maximum growth of C. briggsae in the medium containing homocysteine. (iii) It was found that either supraoptimal folic acid (2000 ng/ml) or supraoptimal vitamin B12 (3750 ng/ml), with homocysteine, supported very little population growth of C. briggsae. However, supraoptimal folic acid and supraoptimal vitamin B12 together supported a maximum population growth. Therefore, it was concluded that both vitamin B12 and folic acid were required for the biosynthesis of methionine from homocysteine. Studies also showed that the two vitamins spared each other for population growth in the medium containing homocysteine.     

Vascular endothelial dysfunction associated with elevated serum homocysteine levels in rat adjuvant arthritis: effect of vitamin E administration

We aimed to study the alterations in serum homocysteine levels and endothelium-dependent and -independent vascular relaxant responses in adjuvant-induced arthritis of the rat and to determine the effects of vitamin E administration on these changes. Arthritis was induced by a single intradermal injection of Freund's complete adjuvant into the paw. 26 days after the induction of arthritis, serum homocysteine levels and relaxant responses to acetylcholine and sodiumnitroprusside in thoracic aortas were evaluated. The relaxant responses to acetylcholine were decreased in aortas from arthritic rats, whereas the responses to sodiumnitroprusside were not significantly different when compared to the aortas from control rats. A significant increase was observed in serum homocysteine levels of the arthritic rats in comparison to those of controls. Vitamin E administration (100 mg/kg/day, i.m. for 26 days) to arthritic rats resulted in a significant increase in endothelium-dependent aortic responses to acetylcholine and a significant decrease in serum homocysteine levels with respect to the non-treated arthritic rats. However, in healthy rats, vitamin E treatment significantly decreased the acetylcholine-induced relaxant responses. We conclude that adjuvant-induced arthritis in the rat is associated with increased serum homocysteine levels and this is accompanied by a reduction in endothelium-dependent vascular responses in the thoracic aortas. Vitamin E treatment leads to normalization of the increased serum homocysteine levels and improves the endothelium-dependent relaxant responses in this experimental model.     

血清Hcy，叶酸和维生素B12在胃癌及其癌前疾病中的作用

目的:探讨血清同型半胱氨酸(Hcy)、叶酸以及维生素B12在胃癌及癌前疾病中的水平及临床意义。方法:收集2014年1月至2016年8月我院收治的100例胃癌患者(胃癌组),及100例胃良性病变患者包括41例胃炎、34例胃溃疡、25例胃息肉(癌前病变组),并于同期随机选择200例健康体检者为对照组,采用循环酶法测定三组的血清Hcy,电化学发光免疫分析法测定叶酸及维生素B12水平,并分析各指标与胃癌临床病理特征的关系。结果:胃癌组、癌前病变组血清Hcy水平均高于对照组,叶酸及维生素B12水平均低于对照组,并且胃癌组血清Hcy水平高于癌前病变组,叶酸及维生素B12水平低于癌前病变组,差异有统计学意义(P0.05)。Ⅲ+Ⅳ期胃癌患者Hcy水平高于Ⅰ+Ⅱ期,进展期患者Hcy水平高于早期,有淋巴结转移患者Hcy水平高于无转移者,差异有统计学意义(P0.05);Hcy表达与性别、年龄、病变位置以及分化程度无关,差异无统计学意义(P0.05)。叶酸、维生素B12的表达在胃癌患者中与各临床病理特征(性别、年龄、TNM分期、肿瘤浸润深度、病变位置、有无淋巴结转移、分化程度)无明显关系,差异无统计学意义(P0.05)。结论:血清Hcy在胃癌患者中呈高水平表达,而叶酸及维生素B12呈低水平表达,联合检测三种指标有助于早期区分胃癌及癌前病变,同时血清Hcy还可能参与了胃癌的发生发展过程。Hcy、叶酸及维生素B12可作为早期鉴别诊断胃癌及其癌前病变的重要指标。     

Increased Plasma Homocysteine Concentration in Rats from a Low Casein Diet

Rats were fed on a 10% casein (10C) diet, 30% casein (30C) diet, 10C+0.5% methionine diet, or 30C+0.5% methionine diet for 14 d to investigate the relationship between the dietary protein level and plasma homocysteine concentration. The plasma homocysteine concentration was significantly higher in the rats fed on the 10C diet than in the rats fed on the 30C diet, and this phenomenon persisted even under the condition of methionine supplementation. The activity of hepatic cystathionine β-synthase (CBS) was significantly lower in the rats fed on the 10% casein diets than in the rats fed on the 30% casein diets, irrespective of methionine supplementation. This is the first demonstration of a low-protein diet increasing the plasma homocysteine concentration in experimental animals. It is suggested that the decreased CBS activity might be associated, at least in part, with the hyperhomocysteinemia caused by the low-casein diet.     

Increased plasma homocysteine concentration in rats from a low casein diet

Rats were fed on a 10% casein (10C) diet, 30% casein (30C) diet, 10C+0.5% methionine diet, or 30C+0.5% methionine diet for 14 d to investigate the relationship between the dietary protein level and plasma homocysteine concentration. The plasma homocysteine concentration was significantly higher in the rats fed on the 10C diet than in the rats fed on the 30C diet, and this phenomenon persisted even under the condition of methionine supplementation. The activity of hepatic cystathionine beta-synthase (CBS) was significantly lower in the rats fed on the 10% casein diets than in the rats fed on the 30% casein diets, irrespective of methionine supplementation. This is the first demonstration of a low-protein diet increasing the plasma homocysteine concentration in experimental animals. It is suggested that the decreased CBS activity might be associated, at least in part, with the hyperhomocysteinemia caused by the low-casein diet.     

出血性卒中与MTHFR C677T基因多态性的相关性研究

摘要 目的：探讨与分析出血性卒中与亚甲基四氢叶酸还原酶（MTHFR）C677T基因多态性的相关性。方法：2020年2月到2021年4月选择在本地区诊治的H型高血压患者220例作为研究对象,检测所有患者的MTHFR C677T基因多态性状况,检测血清同型半胱氨酸、叶酸、维生素B12含量。随访判定患者的出血性卒中状况并进行相关性分析。结果：随访调查1年,220例患者中出现出血性卒中20例（出血性卒中组）,占比9.1 %。出血性卒中组的血清同型半胱氨酸含量明显高于非出血性卒中组,血清维生素B12、叶酸明显低于非出血性卒中组（P<0.05）。两组的MTHFR C677T基因型分布均符合Hardy-Weinberg遗传平衡,出血性卒中组的TT基因型、等位基因T占比分别为70.0 %、80.0 %,都显著高于非出血性卒中组的24.0 %、35.0 %（P<0.05）。Spearman相关系数分析显示H型高血压患者的血清同型半胱氨酸、叶酸、维生素B12含量、TT基因型、等位基因T都与出血性卒中存在相关性（P<0.05）。多元回归分析显示血清同型半胱氨酸、叶酸、维生素B12含量、TT基因型、等位基因T都为导致H型高血压患者出血性卒中发生的重要因素（P<0.05）。结论：H型高血压在随访过程中容易发生出血性卒中,也伴随有血清同型半胱氨酸、维生素B12、叶酸含量异常,MTHFR C677T的T基因型、等位基因T与出血性卒中存在相关性,也是导致出血性卒中发生的重要危险因素。