Association of periconceptional folate supplements and FOLR1 and FOLR2 gene polymorphisms with risk of congenital heart disease in offspring: A hospital-based case-control study / 中南大学学报(医学版)

OBJECTIVES@#Maternal periconceptional folic acid supplement is by far the most effective primary prevention strategy to reduce the incidence of congenital heart disease (CHD) in offspring. It was revealed that the underlying mechanisms are complex, including a combination of genetic and environmental factors. The purpose of this study is to investigate the association between periconceptional folic acid supplement, the genetic polymorphisms of maternal folic acid receptor 1 gene (FOLR1) and folic acid receptor 2 gene (FOLR2) and the impact of their interaction on the risk of CHD in offspring, and to provide epidemiological evidence for individualized folic acid dosing in hygienic counseling.@*METHODS@#A case-control study on 569 mothers of CHD infants and 652 mothers of health controls was performed. The interesting points were periconceptional folate supplements, single nucleotide polymorphisms (SNPs) of maternal FOLR1 gene and FOLR2 gene.@*RESULTS@#Mothers who took folate in the periconceptional period were observed a decreased risk of CHD [adjusted odds ratio (aOR)=0.58, 95% CI 0.35 to 0.95]. Our study also found that polymorphisms of maternal FOLR1 gene at rs2071010 (G/A vs G/G: aOR=0.67, 95% CI 0.47 to 0.96) and FOLR2 gene at rs514933 (T/C vs T/T: aOR=0.60, 95% CI 0.43 to 0.84; C/C vs T/T: aOR=0.55, 95% CI 0.33 to 0.90; the dominant model: T/C+ C/C vs T/T: aOR=0.59, 95% CI 0.43 to 0.81; and the addictive model: C/C vs T/C vs T/T: aOR=0.70, 95% CI 0.56 to 0.88) were significantly associated with lower risk of CHD [all P<0.05, false discovery rate P value (FDR_P)<0.1]. Besides, significant interaction between periconceptional folate supplements and rs2071010 G→A (aOR=0.59, 95% CI 0.41-0.86) and rs514933 T→C (aOR=0.52, 95% CI 0.37 to 0.74) on CHD risk were observed (all P<0.05, FDR_P<0.1).@*CONCLUSIONS@#Periconceptional folate supplements, polymorphisms of FOLR1 gene and FOLR2 gene and their interactions are significantly associated with risk of CHD. However, more studies in different ethnic populations with a larger sample and prospective designs are required to confirm our findings.

Changes of folate receptor -α protein expression in human gliomas and its clinical relevance / 中华外科杂志

<p><b>OBJECTIVE</b>To study the expression level of folate receptor α (FR-α) in glioma tissue and its clinical significance.</p><p><b>METHODS</b>Forty-eight human glioma specimens were collected from patients who underwent surgery from March 2012 to March 2013. These specimens were as follows:12 cases of glioblastoma (WHO IV), 6 cases of astrocytoma of each malignancy grade(WHO II, III), 6 cases of oligodendroastrocytoma of each malignancy grade (WHO II, III), 6 cases of oligodendroglioma of each malignancy grade (WHO II, III ). In addition, 6 cases of normal brain tissue resected from brain traumatic patients were taken as negative control, and one case of placental tissue (had got the consent of the parents and their families) was taken as positive control. The expression level of FR-α in tumor tissues was evaluated by Western blot analysis. The results of Western blot analysis were analyzed by t-test. The expression level of FR-α and Ki-67 in tumor tissues was evaluated immunohistochemistry, the results were analyzed by Kruskal-Wallis test and Nemenyi test. The correlation between the expression level of FR-α and cell proliferation index Ki-67 was analyzed by Pearson correlation analysis.</p><p><b>RESULTS</b>Western blot analysis showed that the FR-α was not expressed in normal brain tissue and oligodendroglioma tissue, but highly expressed in astrocytoma, oligodendroastrocytoma and gliomablastoma. The expression level in WHO III astrocytoma was significantly higher than in WHO II (t = 4.497, P < 0.05). FR-α was also highly expressed in oligodendroastrocytoma and its expression level in WHO III was also significantly higher than in the WHO II (t = 2.876, P < 0.05). Foremore, immunohistochemistry analysis also showed that FR-α was not expressed in oligodendroglioma, but expressed in astrocytoma, oligodendroastrocytoma and gliomablastoma. The positive rate of FR-α of WHO III was significantly higher than the WHO II astrocytoma(57.8% ± 2.2% vs. 45.7% ± 2.3%,χ(2) = 3.871, P = 0.034). In oligodendroastrocytoma, the positive rate of FR-α of WHO III was significantly higher than the WHO II(56.5% ± 5.4% vs. 37.1% ± 5.2%,χ(2) = 4.454, P = 0.021). Moreover, the expression level of FR-α in gliomablastoma was highest in all histological types of gliomas, the positive rate of FR-α was up to 65.0% ± 4.5%. Pearson correlation analysis showed that the positive rate of FR-α was positively correlated with Ki-67 index (r = 0.903, P < 0.05).</p><p><b>CONCLUSIONS</b>FR-α is expressed in astrocytoma, oligodendroastrocytoma and glioblastoma, and the expression level of FR-α is positively correlated with malignancy grade and Ki-67 index. Therefore, FR-α may be applied as a special target for diagnosis and treatment of glioma.</p>

Synthesis and bioactivity of the folate receptor targeted gamma-cyclodextrin-folate inclusion-coated CdSe/ZnS quantum dots / 药学学报

The gamma-cyclodextrin-folate (gamma-CD/FA) inclusion-coated CdSe/ZnS quantum dots (QDs) with folate-receptor (FR) targeted were synthesized by simple and convenient sonochemical method. The products were studied using Fourier transform infrared (FTIR), proton nuclear magnetic resonance (1H NMR), utraviolet-visible spectrometry (UV-vis), fluorescence spectrum and transmission electron micrographs (TEM). The results showed that the gamma-CD/FA-coated CdSe/ZnS QDs not only have good monodispersity and smaller size, but also have good optical performance, such as higher quantum yield (QY) and a long fluorescence lifetime. The cytotoxicity experiments showed that the gamma-CD/FA-coated CdSe/ZnS QDs have lower cytotoxicity and could more effectively enter cancer cells with FR over-expression. The QDs with 4-5 nm in diameter were relatively easy to enter the cell and to be removed through kidneys, so it is more suitable for biomedical applications for bioprobes and bioimaging.

Construction and identification of lentiviral vector carrying FOLR1 gene / 生物医学工程学杂志

Through this research a lentiviral vector expressing the gene of folate-binding protein-1 (FOLR1) was constructed and the corrsponding expression products were identified. Firstly, full-length of the FORL1 gene was amplified by PCR and cloned into the plasmid pWPI. Then it was further confirmed by PCR and sequencing. Secondly, after the recombinant pWPI and its helper plasmid co-transfected the virus packaging 293T cells, SKOV3 cells were infected with the virus particles and sorted by flow cytometry. Thirdly, the FOLR1 gene was detected by RT-PCR and its protein expression was detected by Western blot. Finally, the recombinant expression vector was successfully constructed, and lentiviruses were successfully packaged by the 293T cells. A great quantity of green fluorescent cells could be seen after the SKOV3 cells were effectively infected with the lentiviruses carrying the FOLR1 gene. The sorting could be done and detected by cytometrying the FORL1 gene and its stable expression by the two methods above, which laid experimental foundation for exploring its biological function in ovarian cancers.

Effect of paternal folate deficiency on placental folate content and folate receptor alpha expression in rats

We investigated the effect of paternal folate status on folate content and expression of the folate transporter folate receptor alpha (FRalpha) in rat placental tissues. Rats were mated after males were fed a diet containing 0 mg of folic acid/kg of diet (paternal folate-deficient, PD) or 8 mg folic acid/kg of diet (paternal folate-supplemented, PS) for 4 weeks. At 20 days of gestation, the litter size, placental weight, and fetal weight were measured, and placental folate content (n = 8/group) and expression of FRalpha (n = 10/group) were analyzed by microbiological assay and Western blot analysis, respectively. Although there was no difference observed in litter size or fetal weight, but significant reduction (10%) in the weight of the placenta was observed in the PD group compared to that in the PS group. In the PD group, placental folate content was significantly lower (by 35%), whereas FRalpha expression was higher (by 130%) compared to the PS group. Our results suggest that paternal folate status plays a critical role in regulating placental folate metabolism and transport.

Expression of folate receptor alpha in ovarian epithelial tumors / 中华病理学杂志

<p><b>OBJECTIVE</b>to investigate the expression of folate receptor(FR)α in ovarian epithelial tumors and its clinopathological significance.</p><p><b>METHODS</b>tissue microarrays (TMAs) were constructed from 86 epithelial ovarian cancers and 29 borderline ovarian tumors, followed by the FRα expression evaluation by immunohistochemistry. FRα mRNA expression was investigated by quantitative real-time PCR using fresh-frozen tissues from 40 cases of ovarian carcinoma and 14 cases of borderline tumor. FRα expression levels in ovarian tumors were also analyzed in correlation with tumor morphology, pathogenesis and FIGO stage.</p><p><b>RESULTS</b>FRα expression was detected in 40 of 86 (46.5%) of ovarian cancers, with the highest rate of expression observed in serous carcinomas (62.7%, 32/51) compared with that of the other cancer types (P = 0.000). Depending on pathogenesis type, FRα expressions in type II ovarian carcinomas were significantly higher than those in type I ovarian carcinomas (P = 0.001). Ovarian carcinomas had a tendency to express higher FRα than the borderline tumors (46.5% vs 27.6%), although statistically not significant (P = 0.074). FRα expressions in ovarian carcinomas showed no correlation with the FIGO stage (P = 0.498). However, real-time PCR showed that FRα mRNA levels were significantly higher in ovarian carcinomas compared with that of the borderline tumors (P = 0.000) and also higher in serous ovarian borderline tumors compared with mucinous type (P = 0.007).</p><p><b>CONCLUSION</b>higher level of FRα expression occurs frequently in ovarian epithelial tumors, especially in carcinomas and ovarian serous tumors.</p>

Role of folate receptor 1 in paclitaxel-resistance of nasopharyngeal carcinoma cells / 中华耳鼻咽喉头颈外科杂志

<p><b>OBJECTIVE</b>To provide experimental evidence for the folate receptor 1 (FOLR1) mediated targeted cancer therapy and resistance reversal, the FOLR1 expression differences in nasopharyngeal carcinoma cells (CNE-1) and immortalized normal nasopharyngeal cells (NP69) and the correlation between FOLR1 expression and paclitaxel resistance index in nasopharyngeal carcinoma were investigated.</p><p><b>METHODS</b>The expressions of FOLR1 in CNE-1, CNE-1/Taxol (paclitaxel-resistance cells) and NP69 was detected by cDNA microarray, reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot and immunocytochemistry. Proliferation inhibition rates of CNE-1 and CNE-1/Taxol cells were measured by colony formation assay after treated by short interfering RNA (siRNA) of FOLR1.</p><p><b>RESULTS</b>The expressions of FOLR1 gene in CNE-1/Taxol cells and CNE-1 cells were 2636.0 and 176.0, respectively. The expression of FOLR1 was not detected in the NP69 by semi-quantative RT-PCR and Western blot. The high expression of FOLR1 in CNE-1/Taxol was verified by semi-quantative RT-PCR, and its expression level was positively correlated to the degree of drug-resistance (r(2) = 0.8719). The results were also validated by Western blot and immunocytochemistry. The sensitivity of CNE-1/Taxol to paclitaxel significantly increased after inhibition of FOLR1 gene expression by siRNA, and its IC(50) value was decreased by 59.6% (t = 6.92, P < 0.01).</p><p><b>CONCLUSIONS</b>The expression of FOLR1 is closely related to the occurrence of NPC and Taxol resistance. FOLR1 gene may be one of the important target molecules in NPC treatment and reversion of the paclitaxel-resistance in NPC.</p>