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Combinational effect of angiotensin receptor blocker and folic acid therapy on uric acid and creatinine level in hyperhomocysteinemia-associated hypertension

Singh Y, Samuel VP, Dahiya S, Gupta G, Gillhotra R, Mishra A, et al.

Biotechnol Appl Biochem, 2019 Sep;66(5):715-719.
PMID: 31314127 DOI: 10.1002/bab.1799

Homocysteine [HSCH2 CH2 CH(NH2 )COOH] (Hcy) is a sulfur-containing amino acid of 135.18 Da of molecular weight, generated during conversion of methionine to cysteine. If there is a higher accumulation of Hcy in the blood, that is usually above 15 µmol/L, it leads to a condition referred to as hyperhomocysteinemia. A meta-analysis of observational study suggested an elevated concentration of Hcy in blood, which is termed as the risk factors leading to ischemic heart disease and stroke. Further experimental studies stated that Hcy can lead to an increase in the proliferation of vascular smooth muscle cells and functional impairment of endothelial cells. The analyses confirmed some of the predictors for Hcy presence, such as serum uric acid (UA), systolic blood pressure, and hematocrit. However, angiotensin-converting enzyme inhibitors angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) alone are inadequate for controlling UA and creatinine level, although the addition of folic acid may be beneficial in hypertensive patients who are known to have a high prevalence of elevated Hcy. We hypothesized that combination therapy with an ARB (olmesartan) and folic acid is a promising treatment for lowering the UA and creatinine level in hyperhomocysteinemia-associated hypertension.

Matched MeSH terms: Folic Acid/pharmacology*
l-5-Methyltetrahydrofolate Supplementation Increases Blood Folate Concentrations to a Greater Extent than Folic Acid Supplementation in Malaysian Women

Henderson AM, Aleliunas RE, Loh SP, Khor GL, Harvey-Leeson S, Glier MB, et al.

J Nutr, 2018 Jun 01;148(6):885-890.
PMID: 29878267 DOI: 10.1093/jn/nxy057

BACKGROUND: Folic acid fortification of grains is mandated in many countries to prevent neural tube defects. Concerns regarding excessive intakes of folic acid have been raised. A synthetic analog of the circulating form of folate, l-5-methyltetrahydrofolate (l-5-MTHF), may be a potential alternative.
OBJECTIVE: The objective of this study was to determine the effects of folic acid or l-5-MTHF supplementation on blood folate concentrations, methyl nutrient metabolites, and DNA methylation in women living in Malaysia, where there is no mandatory fortification policy.
METHODS: In a 12-wk, randomized, placebo-controlled intervention trial, healthy Malaysian women (n = 142, aged 20-45 y) were randomly assigned to receive 1 of the following supplements daily: 1 mg (2.27 μmol) folic acid, 1.13 mg (2.27 μmol) l-5-MTHF, or a placebo. The primary outcomes were plasma and RBC folate and vitamin B-12 concentrations. Secondary outcomes included plasma total homocysteine, total cysteine, methionine, betaine, and choline concentrations and monocyte long interspersed nuclear element-1 (LINE-1) methylation.
RESULTS: The folic acid and l-5-MTHF groups had higher (P folic acid group [RBC folate, 1498 ± 580 nmol/L; plasma folate, 40.1 nmol/L (24.9, 52.7 nmol/L)]. The folic acid and l-5-MTHF groups had 17% and 15%, respectively, lower (P folic acid and l-5-MTHF groups. No differences in plasma vitamin B-12, total cysteine, methionine, betaine, and choline and monocyte LINE-1 methylation were observed.
CONCLUSION: These findings suggest differential effects of l-5-MTHF compared with folic acid supplementation on blood folate concentrations but no differences on plasma total homocysteine lowering in Malaysian women. This trial was registered at clinicaltrials.gov as NCT01584050.

Matched MeSH terms: Folic Acid/pharmacology
Fulltext Factors influencing pregnancy planning of multi-ethnic Asian women with diabetes: A qualitative study

Z I I, C J N, P Y L, N H

PLoS One, 2020;15(12):e0242690.
PMID: 33270663 DOI: 10.1371/journal.pone.0242690

INTRODUCTION: Pregnancy planning varies among women with diabetes. Observing that the literature examining the factors affecting diabetic women's pregnancy intentions in multi-ethnic Asian populations is limited, we sought to explore these factors to give a better perspective on these women's pregnancy planning.
METHODS: This qualitative study used individual in-depth interviews to capture the views and experiences of non-pregnant diabetic women of reproductive age in four public health clinics in a southwestern state of peninsular Malaysia from May 2016 to February 2017. The participants were purposively sampled according to ethnicity and were interviewed using a semi-structured topic guide. Interviews were audio-recorded, and transcripts were analysed using thematic analysis.
RESULTS: From the 33 interviews that were analysed, four important factors influencing participants' decisions regarding pregnancy planning were identified. Participants' perception of poor pregnancy outcomes due to advanced age and medical condition was found to have an impact. However, despite these fears and negative relationships with doctors, personal, family and cultural influences supported by religious 'up to God' beliefs took centre stage in the pregnancy intention of some participants. Participants demonstrated a variety of understandings of pregnancy planning. They outlined some activities for pregnancy preparation, although many also reported limited engagement with pre-pregnancy care.
CONCLUSIONS: This study emphasised the known dilemma experienced by diabetic women considering their desire for an ideal family structure against their perceived pregnancy risks, heterogeneous religious beliefs and the impact of cultural demands on pregnancy intention. This study urges healthcare providers to increase their engagement with the women in pregnancy planning in a more personalised approach.

Matched MeSH terms: Folic Acid/pharmacology
In vivo tumor targeting and anti-tumor effects of 5-fluororacil loaded, folic acid targeted quantum dot system

Bwatanglang IB, Mohammad F, Yusof NA, Abdullah J, Alitheen NB, Hussein MZ, et al.

J Colloid Interface Sci, 2016 Oct 15;480:146-58.
PMID: 27428851 DOI: 10.1016/j.jcis.2016.07.011

In this study, we modulated the anti-cancer efficacy of 5-Fluorouracil (5-FU) using a carrier system with enhanced targeting efficacy towards folate receptors (FRs) expressing malignant tissues. The 5-FU drug was loaded onto Mn-ZnS quantum dots (QDs) encapsulated with chitosan (CS) biopolymer and conjugated with folic acid (FA) based on a simple wet chemical method. The formation of 5-FU drug loaded composite was confirmed using Fourier transform infrared spectroscopy (FTIR), thermo gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Furthermore, the in vivo biodistribution and tumor targeting specificity of the 5-FU@FACS-Mn:ZnS in the tumor-bearing mice was conducted based on the Zn(2+) tissue bioaccumulation using inductively coupled plasma (ICP) spectroscopy. In addition to the characterization, the in vitro release profile of 5-FU from the conjugates investigated under diffusion controlled method demonstrated a controlled release behaviour as compared against the release behaviour of free 5-FU drug. The as-synthesized 5-FU@FACS-Mn:ZnS nanoparticle (NP) systemically induced higher level of apoptosis in breast cancer cells in vitro as compared to cells treated with free 5-FU drug following both cell cycle and annexin assays, respectively. Also, the in vivo toxicity assessment of the 5-FU@FACS-Mn:ZnS NPs as compared to the control did not cause any significant increase in the activities of the liver and kidney function biomarkers, malondialdehyde (MDA) and nitric oxide (NO) levels. However, based on the FA-FRs chemistry, the 5-FU@FACS-Mn:ZnS NPs specifically accumulated in the tumor of the tumor-bearing mice and thus contributed to the smaller tumor size and less event of metastasis was observed in the lungs when compared to the tumor-bearing mice groups treated with the free 5-FU drug. In summary, the results demonstrated that the 5-FU@FACS-Mn:ZnS QDs exhibits selective anti-tumor effect in MDA-MB231 breast cancer cells in vitro and 4TI breast cancer cells in vivo, providing a blueprint for improving the 5-FU efficacy and tumor targeting specificity with limited systemic toxicity.

Matched MeSH terms: Folic Acid/pharmacology*
Fulltext Hyperhomocysteinemia causes ER stress and impaired autophagy that is reversed by Vitamin B supplementation

Tripathi M, Zhang CW, Singh BK, Sinha RA, Moe KT, DeSilva DA, et al.

Cell Death Dis, 2016 12 08;7(12):e2513.
PMID: 27929536 DOI: 10.1038/cddis.2016.374

Hyperhomocysteinemia (HHcy) is a well-known risk factor for stroke; however, its underlying molecular mechanism remains unclear. Using both mouse and cell culture models, we have provided evidence that impairment of autophagy has a central role in HHcy-induced cellular injury in the mouse brain. We observed accumulation of LC3B-II and p62 that was associated with increased MTOR signaling in human and mouse primary astrocyte cell cultures as well as a diet-induced mouse model of HHcy, HHcy decreased lysosomal membrane protein LAMP2, vacuolar ATPase (ATP6V0A2), and protease cathepsin D, suggesting that lysosomal dysfunction also contributed to the autophagic defect. Moreover, HHcy increased unfolded protein response. Interestingly, Vitamin B supplementation restored autophagic flux, alleviated ER stress, and reversed lysosomal dysfunction due to HHCy. Furthermore, the autophagy inducer, rapamycin was able to relieve ER stress and reverse lysosomal dysfunction caused by HHcy in vitro. Inhibition of autophagy by HHcy exacerbated cellular injury during oxygen and glucose deprivation and reperfusion (OGD/R), and oxidative stress. These effects were prevented by Vitamin B co-treatment, suggesting that it may be helpful in relieving detrimental effects of HHcy in ischemia/reperfusion or oxidative stress. Collectively, these findings show that Vitamin B therapy can reverse defects in cellular autophagy and ER stress due to HHcy; and thus may be a potential treatment to reduce ischemic damage caused by stroke in patients with HHcy.

Matched MeSH terms: Folic Acid/pharmacology
Fulltext Association between dietary folate intake and blood status of folate and homocysteine in Malaysian adults

Chew SC, Khor GL, Loh SP

J Nutr Sci Vitaminol (Tokyo), 2011;57(2):150-5.
PMID: 21697634 DOI: 10.3177/jnsv.57.150

Folate is of prime interest among investigators in nutrition due to its multiple roles in maintaining health, especially in preventing neural tube defects and reducing the risk of cardiovascular diseases. We investigated the effect of dietary folate intake on blood folate, vitamin B(12), vitamin B(6), and homocysteine status. One hundred subjects consisting of Chinese and Malay subjects volunteered to participate in this cross-sectional study. Dietary folate intake was assessed by 24-h dietary recall and a food-frequency questionnaire (FFQ). Serum and red blood cell folate were analyzed using a microbiological assay, while serum vitamin B(12) was determined by electrochemiluminescence immunoassay (ECLIA), and high-performance liquid chromatography (HPLC) was used for the determination of serum vitamin B(6) and homocysteine. The mean folate intake, serum folate, RBC folate, serum vitamin B(12), and B(6), were higher in female subjects, with the exception of serum homocysteine. The Chinese tended to have higher folate intake, serum folate, RBC folate, and vitamin B(12). A positive association was found between folate intake and serum folate while a negative association was found between folate intake and serum homocysteine. Stepwise linear regression of serum folate showed a significant positive coefficient for folate intake whilst a significant negative coefficient was found for serum homocysteine when controlling for age, gender, and ethnicity. In conclusion, high dietary folate intake helps to increase serum folate and to lower the homocysteine levels.

Matched MeSH terms: Folic Acid/pharmacology*