Brain-Targeting Emodin Mitigates Ischemic Stroke via Inhibiting AQP4-Mediated Swelling and Neuroinflammation.

Failure to achieve target-specific delivery to ischemic brain sites has hampered the clinical efficacy of newly developed therapies for ischemic stroke. Emodin, an active ingredient isolated from traditional Chinese medicine, has been indicated to alleviate ischemic stroke; however, the underlying mechanism remains unclear. In this study, we aimed to achieve brain-targeted delivery of emodin to maximize its therapeutic efficacy and elucidate the mechanisms by which emodin alleviates ischemic stroke. A polyethylene glycol (PEG)/cyclic Arg-Gly-Asp (cRGD)-modified liposome was used to encapsulate emodin. TTC, HE, Nissl staining, and immunofluorescence staining were employed to evaluate the therapeutic efficacy of brain-targeting emodin in MCAO and OGD/R models. Inflammatory cytokine levels were determined using ELISA. Immunoprecipitation, immunoblotting, and RT-qPCR were utilized for clarifying the changes in key downstream signaling. Lentivirus-mediated gene restoration was employed to verify the core effector of emodin for relieving ischemic stroke. Encapsulating emodin in a PEG/cRGD-modified liposome enhanced its accumulation in the infarct region and substantially raised its therapeutic efficacy. Furthermore, we demonstrated that AQP4, the most abundant water transporter subunit expressed in astrocytes, plays a crucial role in mediating the mechanisms by which emodin inhibits astrocyte swelling, neuroinflammatory blood-brain barrier (BBB) breakdown in vivo and in vitro, and brain edema in general. Our study unveiled the critical target of emodin responsible for alleviating ischemic stroke and a localizable drug delivery vehicle in the therapeutic strategy for ischemic stroke and other brain injuries.

Periconceptional folic acid supplementation among women attending antenatal clinic in Anhui, China: data from a population-based cohort study.

OBJECTIVES: to examine the rate of periconceptional and optimal folic acid supplementation, and to characterise their patterns and determinants among antenatal women in central China. DESIGN: data from 4290 women in the Anhui Birth Defects and Child Development Cohort Study recruited between October 2008 and September 2009 were analysed. SETTING: seven Maternal and Child Health Centres of two cities (Hefei and Maanshan) in Anhui province of central China. PARTICIPANTS: women initiating prenatal care were included and asked to complete a structured questionnaire regarding folic acid supplementation. FINDINGS: sixty-eight per cent (2905/4290) of pregnant women reported taking folic acid supplementation periconceptionally (i.e. at some point before or during early pregnancy), and 32.8% (1405/4290) and 65.2% (2797/4290) had taken it before or during early pregnancy, respectively. However, only 16.1% (690/4290) used it optimally (i.e. regularly from four weeks before pregnancy throughout four weeks after pregnancy). Use of periconceptional folic acid was significantly associated with educational level, household income, registered residence, age, gestational age at recruitment, and planning of pregnancy. CONCLUSION: optimal folic acid supplementation was relatively low. IMPLICATIONS FOR PRACTICE: further efforts are needed to inform the population and promote the use of folic acid supplementation.

The polymorphisms of TS and MTHFR predict survival of gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy in Chinese population.

PURPOSE: The aim of this study was to investigate the association of the thymidylate synthase (TS) and methylenetetrahydrofolate reductase (MTHFR) polymorphisms with the clinical outcomes of gastric cancer patients treated with 5-FU-based adjuvant chemotherapy. METHODS: One-hundred and sixteen patients with gastric cancer were treated with 5-FU-based adjuvant chemotherapy. The TS (a 28-bp tandem repeat polymorphism in the TS enhancer region (TSER) and a 6 bp deletion/insertion polymorphism in the 3'-untranslated region) and MTHFR C677T polymorphisms were determined in blood samples from those patients using PCR and PCR-LDR (ligation detection reaction) method, respectively. RESULTS: The overall survival (OS) in patients with the TS ins6/ins6 genotype was significantly shorter than those in patients with the del6/del6 (P = 0.017) and ins6/del6 (P = 0.022) genotype. The relapse-free survival (RFS) and OS in patients with the MTHFR C/C genotype were significantly worse than those in patients with the T/T or C/T genotype (P = 0.043 and 0.040, respectively). Cox multivariate analysis also showed that patients with the TS ins6/ins6 genotype have worse OS than patients with the T/T or C/T genotype (HR = 2.437, P = 0.041), and the MTHFR C/C genotype was associated with shorter RFS (HR = 1.723, P = 0.031) and OS (HR = 1.681, P = 0.056). No significant association was found between the TSER polymorphism and the clinical outcomes (P > 0.05). CONCLUSION: The polymorphisms of TS 3'-UTR ins6/del6 and MTHFR C677T appear to be potential prognostic factors in gastric cancer patients treated with 5-FU-based adjuvant chemotherapy, which may allow identification of gastric cancer patients who will benefit from 5-FU chemotherapy.

Prognostic role of p53 codon 72 polymorphism in gastric cancer patients treated with fluorouracil-based adjuvant chemotherapy.

OBJECTIVE: The polymorphism of p53 codon 72 (Arg72Pro) has been suggested to play an important role in many cancers and may influence the response to chemotherapy. Our aim was to investigate the association of p53 Arg72Pro polymorphism with the clinical outcome of gastric cancer patients treated with 5-FU-based adjuvant chemotherapy. METHODS: The p53 codon 72 genotype was determined in blood samples from 110 Chinese patients with gastric cancer treated with 5-fluorouracil (5-FU)-based adjuvant chemotherapy, using polymerase chain reaction-ligation detection reaction (PCR-LDR) method. RESULTS: Kaplan-Meier survival analysis showed that gastric cancer patients with Pro/Pro genotype had shorter relapse-free survival (chi(2) = 10.632, P = 0.005) and overall survival (chi(2) = 7.104, P = 0.029) than patients with other genotypes. Cox multivariate analysis showed that Pro/Pro genotype was associated with statistically significant reduced relapse-free survival (adjusted OR = 3.049, 95% CI: 1.363-6.819, P = 0.007) and overall survival (adjusted OR = 2.581, 95% CI: 1.052-6.330, P = 0.038). CONCLUSION: These results suggested that p53 codon 72 polymorphism appears to be an independent prognostic factor in gastric cancer patients treated with 5-FU-based adjuvant chemotherapy.

Thymidylate synthase and thymidine phosphorylase gene expression as predictive parameters for the efficacy of 5-fluorouracil-based adjuvant chemotherapy for gastric cancer.

AIM: To investigate the prognostic role of thymidylate synthase (TS) and thymidine phosphorylase (TP) mRNA levels in T3 or T4 gastric cancer treated with 5-fluorouracil-based adjuvant chemotherapy. METHODS: Fifty-one patients with T3 or T4 gastric cancer received systemic 5-fluorouracil-based adjuvant chemotherapy, and intratumoral expression of TS and TP in 51 gastric cancer tissue samples was tested by real-time quantitative PCR. RESULTS: The median disease-free survival (DFS) time was 10.2 mo in the patients. There were no significant differences in DFS between the groups with high and low levels of TP. However, the group with low level of TS had a longer DFS (14.4 mo vs 8.3 mo, P = 0.017). The median overall survival (OS) time was 18.5 mo, and there were significant differences in OS between the groups with high and low levels of TS or TP (for TS, 17.0 mo vs 21.3 mo, P = 0.010; for TP, 16.6 mo vs 22.5 mo, P = 0.009). Moreover, the coupled low expression of these two genes was strongly associated with a longer survival time of patients as compared with that of a single gene. CONCLUSION: Expression of TS and TP mRNA is a useful predictive parameter for the survival of postoperative gastric cancer patients after 5-fluorouracil-based adjuvant chemotherapy.

[Study on the antihyperlipidemia effective constituent of Polygala fallax Hemsl].

OBJECTIVE: To study the antihyperlipidemia effective constituent of Polygala fallax Hemsl. METHOD: Column chromatographic techniques were employed for isolation and purification of chemical constituents of the plant and the structures were elucidated by IR, NMR and MS spectroscopy. RESULT: Four triterpenoid saponins were isolated and determined as 3-O-beta-D-glucopyranosyl-( 1--> 2) -beta-D-glucopyranosyl presenegenin 28-O-beta-D-xylopyranosyl-(1-->4 ) -alpha-L-rhamnopyranosyl-(1-->2 ) -beta-D-fucopyranosyl ester (I), 3-O-beta-D-glucopyranosyl-(1-->2) -beta-D-glucopyranosyl presenegenin 28-O-beta-D-xylopyranosyl-(1-->4) -alpha-L-rhamnopyranosyl-(1-->2) -(3-O-acetyl)-beta-D-fucopyranosyl ester (II), 3-O-beta-D-glucopyranosyl-(1-->2) -beta-D-glucopyranosyl presenegenin 28-O-beta-D-xylopyranosyl-(1-->4) -alpha-L-rhamnopyranosyl-(1-->2) -(4-O-acetyl) -beta-D-fucopyranosyl ester (II) and 3-O-beta-D-glucopyranosyl-(1--2) -beta-D-glucopyranosyl presenegenin 28-O-beta-D-xylopyranosyl-(1-->4 ) -alpha-L-rhamnopyranosyl-(1-->2 ) - (3,4-diacetyl) -beta-D-fucopyranosyl ester (IV). CONCLUSIONS: The effective constituents of Polygala fallax Hemsl. reduced blood lipid especially plasma TG markedly. The authors have studied the chemical constituents of effective constituent systematically for the first time.

[A new xanthone from Polygala aureocauda Dunn].

AIM: To study the chemical constituents of Polygala aureocauda Dunn.. METHODS: Chemical compounds were isolated by column chromatography and their structures were determined mainly by spectroscopic means (UV, IR, MS, 1HNMR, 13CNMR, HMQC, HMBC). RESULTS: Three compounds were isolated and identified as 3-hydroxy-1,4-dimethoxyxanthone (I), 1, 7-dihydroxy-2, 3-methylendioxyxanthone (II), 7-hydroxy-1-methoxy-2, 3-methylendioxyxanthone (III). CONCLUSION: Compounds I-III were isolated from Polygala aureocauda Dunn. for the first time, whereas compound I is a new xanthone.