Betaine alleviates cognitive impairment induced by homocysteine through attenuating NLRP3-mediated microglial pyroptosis in an m6A-YTHDF2-dependent manner.

Dementia, with homocysteine (Hcy) as an important risk factor, is a severe public health problem in the aging society. Betaine serves as a methyl donor and plays an important role in reducing Hcy. However, the effects and mechanisms of betaine on Hcy-induced cognitive impairment remain unclear. Firstly, SD rats were injected with Hcy (400 µg/kg) through vena caudalis, and betaine (2.5 % w/v) was supplemented via drinking water for 14 days. Betaine supplementation could attenuate Hcy-induced cognitive impairment in the Y maze and novel object recognition tests by repairing brain injury. Meanwhile, microglial activation was observed to be inhibited by betaine supplementation using immunofluorescence and sholl analysis. Secondly, HMC3 cells were treated with betaine, which was found to decrease the ROS level, ameliorate cell membrane rupture, reduce the release of LDH, IL-18 and IL-1ß, and attenuate the damage of microglia to neurons. Mechanistically, betaine alleviates cognitive impairment by inhibiting microglial pyroptosis via reducing the expressions of NLRP3, ASC, pro-caspase-1, cleaved-caspase-1, GSDMD, GSDMD-N, IL-18 and IL-1ß. Betaine treatment can increase SAM/SAH ratio, confirming its enhancement on methylation capacity. Furthermore, betaine treatment was found to enhance N6-methyladenosine (m6A) modification of NLRP3 mRNA, and reduced the NLRP3 mRNA stability through increasing the expression of the m6A reader YTH N6-methyladenosine RNA binding protein 2 (YTHDF2). Finally, silencing YTHDF2 could reverse the inhibitory effect of betaine on pyroptosis. Our data demonstrated that betaine attenuated Hcy-induced cognitive impairment by suppressing microglia pyroptosis via inhibiting the NLRP3/caspase-1/GSDMD pathway in an m6A-YTHDF2-dependent manner.

Folate deficiency promotes cervical squamous carcinoma SiHa cells progression by targeting miR-375/FZD4/ß-catenin signaling.

Epidemiological studies suggest an association between folate deficiency (FD) and cervical squamous cell carcinoma (SCC) progression. However, the underlying mechanism is unclear. Our study showed that FD-driven downregulation of miR-375 promoted proliferation of SCC SiHa cells and progression of xenograft tumors developed from SiHa; however, the exact mechanism of this process remained unclear. The current study aimed to elucidate the underlying mechanisms by which FD promotes the progression of SiHa cells by downregulating miR-375 expression. The results showed that miR-375 acted as a suppressor of SCC and inhibited the proliferation, migration, and invasion of SiHa cells. The FZD4 gene was identified as a target gene of miR-375, which can reverse the anti-onco effect of miR-375 and promote the proliferation and migration of SiHa cells. Furthermore, the regulatory effects of miR-375 and FZD4 on SiHa cells may be achieved by activating the ß-catenin signaling pathway. Moreover, FD may regulate the expression of miR-375 by regulating its DNA methylation level in the promoter region. In conclusion, our study reveals that FD regulates the miR-375/FZD4 axis by increasing the methylation of the miR-375 promoter, thereby activating ß-catenin signaling to promote SiHa cells progression. This study may provide new insights into the role of folic acid in the prevention and treatment of SCC.

Reinvestigation of 2-acetylthiazole formation pathways in the Maillard reaction.

2-Acetylthiazole possesses a nutty, cereal-like and popcorn-like aroma and a low odor threshold, and this compound has been identified in some processed foods, while the formation pathway of 2-acetylthiazole has not been clearly elucidated. Here, a model reaction of d-glucose and l-cysteine was constructed to investigate the formation pathway of 2-acetylthiazole. l-Cysteine, d-glucose and the corresponding intermediates, namely, dicarbonyl compounds (DCs), were involved in the formation of 2-acetylthiazole and detected by high-performance liquid chromatography with tandem mass spectrometry (HPLC-MS/MS), high-performance ion chromatography (HPIC) and HPLC, respectively. The carbon module labeling (CAMOLA) technique revealed that the C-4 and C-5 of 2-acetylthiazole were derived from the carbons of glucose. The potential of glyoxal, which is degraded by glucose, to form 2-acetylthiazole was revealed for the first time. A novel route to form 2-acetylthiazole by the reaction of glyoxal and methylglyoxal produced by d-glucose with H2S and NH3 produced by l-cysteine was proposed.

Loss of MED12 Induces Tumor Dormancy in Human Epithelial Ovarian Cancer via Downregulation of EGFR.

A high rate of disease relapse makes epithelial ovarian cancer (EOC) the leading cause of death among all gynecologic malignancies. These relapses are often due to tumor dormancy. Here we identify the RNA polymerase II transcriptional mediator subunit 12 (MED12) as an important molecular regulator of tumor dormancy. MED12 knockout (KO) induced dormancy of EOC cells in vitro and in vivo, and microarray analysis showed that MED12 KO decreased expression of EGFR. Restoration of EGFR expression in MED12 KO cells restored proliferation. Additionally, MED12 bound to the promoter of EGFR, and correlation studies showed that MED12 expression positively correlated with EGFR expression in EOC patient samples. Clinical data demonstrated that chemotherapy-resistant patients expressed lower levels of MED12 compared with responsive patients. Overall, our data show that MED12 plays an important role in regulating dormancy of EOC through regulation of EGFR.Significance: MED12 is identified as a novel, important regulator of tumor dormancy in human ovarian cancer. Cancer Res; 78(13); 3532-43. ©2018 AACR.

Unconjugated Bilirubin Is a Novel Prognostic Biomarker for Nasopharyngeal Carcinoma and Inhibits Its Metastasis via Antioxidation Activity.

Distant metastasis is the most common cause of treatment failure and mortality in nasopharyngeal carcinoma (NPC) patients. Thus, it is important to understand the mechanism of NPC metastasis and identify reliable prognostic factors. In this study, we investigated the prognostic value of unconjugated bilirubin (UCB), which was previously considered a byproduct of heme catabolism, in NPC patients and examined the effects of UCB on NPC metastasis. The receiver operating characteristic analysis-generated UCB cutoff point for DMFS was 9.7 µmol/L. We found that higher UCB levels were significantly associated with favorable distant metastasis-free survival (DMFS, 93.3% vs. 84.2%, P < 0.001) in NPC patients and was an independent predictor for DMFS (HR, 0.416; 95% confidence interval, 0.280-0.618; P < 0.001). We next found that UCB treatment impaired the invasion capability of NPC cells and potently inhibited lung metastasis of NPC cells in nude mice. Further investigation showed that UCB inhibited reactive oxygen species production, which is involved in the repression of ERK1/2 activation and matrix metalloproteinase-2 (MMP-2) expression. Moreover, lower levels of ERK1/2 phosphorylation and MMP-2 expression were observed in the NPC lung metastases of nude mice administered UCB. Taken together, our results indicate that UCB is a significantly favorable factor for DMFS in NPC patients and may play an important role in NPC chemoprevention.

Serum apolipoprotein A-I is a novel prognostic indicator for non-metastatic nasopharyngeal carcinoma.

BACKGROUND: We investigated the value of pretreatment serum apolipoprotein A-I (ApoA-I) in complementing TNM staging in the prognosis of non-metastatic nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: We retrospectively reviewed 1196 newly diagnosed patients with non-metastatic NPC. Disease-specific survival (DSS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) rates were compared according to serum ApoA-I level. Multivariate analysis was performed to assess the prognostic value of serum ApoA-I. RESULTS: The 5-year DSS, DMFS, and LRFS rates for patients with elevated or decreased serum ApoA-I were 81.3% versus 69.3% (P < 0.001), 83.4% versus 67.4% (P < 0.001), and 80.9% versus 67.3% (P < 0.001), respectively. ApoA-I ≥ 1.025 g/L was an independent prognostic factor for superior DSS, DMFS, and LRFS in multivariate analysis. After stratification by clinical stage, serum ApoA-I remained a clinically and statistically significant predictor of prognosis. CONCLUSION: Our data suggest that the level of ApoA-I at diagnosis is a novel independent prognostic marker that could complement clinical staging for risk definition in non-metastatic NPC.

Obstetrical disease spectrum in China: an epidemiological study of 111,767 cases in 2011.

BACKGROUND: No national research on maternal and fetal complications and outcomes has been carried out in the mainland of China in recent years. This study was to provide a scientific basis for better control of obstetrical and neonatal diseases and better allocation of medical resources by analyzing the epidemiological characteristics of obstetrical diseases in the mainland of China. METHODS: Hospitalized obstetrical cases from 19 tertiary and 20 secondary hospitals in 14 provinces (nationally representative) during the period January 1, 2011 to December 31, 2011 were randomly selected. The general condition, pregnancy complications, and perinatal outcomes of the patients were studied. RESULTS: The top five medical and surgical complications of pregnant women in the mainland of China were anemia (6.34%), uterine fibroids (2.69%), thyroid disease (1.11%), thrombocytopenia (0.59%), and heart disease (0.59%). The incidences of premature rupture of membranes (PROM), preterm birth, prolonged pregnancy, hypertensive disorders complicating pregnancy (HDCP), multiple pregnancy, intrahepatic cholestasis of pregnancy (ICP), placenta previa, placental abruption, postpartum hemorrhage, and amniotic fluid embolism were 15.27%, 7.04%, 6.71%, 5.35%, 1.57%, 1.22%, 1.14%, 0.54%, 3.26% and 0.06%, respectively. The incidences of anemia and prolonged pregnancy were significantly lower in tertiary than secondary hospitals (P < 0.001), whereas the incidence of uterine fibroids, thyroid diseases, thrombocytopenia, heart disease, PROM, preterm birth, HDCP, multiple pregnancy, ICP, placenta previa, and placental abruption were significantly higher in tertiary than secondary hospitals (P < 0.001). The cesarean section (CS) rate was 54.77%. The newborn sex ratio was 119:100, and 1.03% of the neonates were malformed. The percentages of low birth weight and fetal macrosomia in full-term babies were 2.10% and 7.09%, respectively. CONCLUSIONS: The incidence of some obstetrical diseases is still high in the mainland of China. The CS rate is much higher than World Health Organization recommendations, in which CS delivery by maternal request (CDMR) accounted for a large proportion. The government should propose solutions to reduce CS rate, especially the rate of CDMR. Most obstetrical complications have higher incidence in tertiary hospitals compared with secondary hospitals. It is important to manage the health of pregnant women systematically, especially those with high-risk factors.

Design of a prognostic score model for nasopharyngeal carcinoma.

BACKGROUND: The purpose of this analysis was to create a prognostic score model for newly diagnosed nasopharyngeal carcinoma (NPC) which has not been created before. METHODS: We retrospectively reviewed the medical records of 419 patients with newly diagnosed, nondisseminated, and biopsy proven NPC. RESULTS: Independent prognostic factors included age >45, stage III/IV, antienzyme rate of Epstein-Barr virus DNase-specific neutralizing antibody (AER) >58%, and absolute neutrophil count (ANC) >4.7 × 10(9) /L. Four prognostic groups based on prognostic score model were obtained: low-risk group (total score = 0-2); low-intermediate-risk group (total score = 3-4); high-intermediate-risk group (total score = 5-6); and high-risk group (total score = 7). CONCLUSION: Our proposed prognostic score model was a useful tool for improving the prognostic assessment of patients with NPC, stratifying patients into different risk groups that call for different treatments, and comparing clinical trials.

Percutaneous coronary intervention compared with coronary artery bypass graft in coronary artery disease patients with chronic kidney disease: a systematic review and meta-analysis.

Previous reports of percutaneous coronary intervention versus coronary artery bypass graft outcomes in coronary artery disease patients with chronic kidney disease (CKD) were inconsistent. We evaluated the optimal revascularization strategy for CKD patients. We searched Pub Med, EMBASE, and the Cochrane Central Register of Controlled Trials and scanned the references of relevant articles and reviews. All studies that compared relevant clinical outcomes between percutaneous coronary intervention and coronary artery bypass graft in CKD patients were selected. We defined short-term and long-term all-cause mortality as primary outcome, and long-term incidences of myocardial infarction and revascularization as secondary outcomes. A total of 2235 citations were retrieved, and 31 studies involving 99,054 patients, with 55,383 receiving percutaneous coronary intervention and 43,671 receiving coronary artery bypass graft, were included. In subgroup analyses of dialysis patients receiving percutaneous coronary intervention with stents versus coronary artery bypass graft, CKD patients with multivessel coronary disease, and CKD patients receiving drug-eluting stent versus coronary artery bypass graft, the pooled outcomes revealed that percutaneous coronary intervention possessed lower short-term mortality, but higher late revascularization risk. No significant differences in long-term mortality were observed between the two strategies in these subgroup analyses. In conclusion, in some specific clinical circumstances, CKD patients receiving percutaneous coronary intervention possessed lower short-term all-cause mortality, but higher long-term revascularization risk, than coronary artery bypass graft; long-term all-cause mortality was not different between the two strategies.

The impact of smoking on clinical efficacy and pharmacodynamic effects of clopidogrel: a systematic review and meta-analysis.

CONTEXT: Previous findings regarding the relationship between smoking and clopidogrel effects were considerably discrepant. OBJECTIVE: To assess the impact of smoking on clinical and pharmacodynamic response to clopidogrel. DATA SOURCES: Medline, EMBASE and the Cochrane Library through January 2013 were searched. Reference lists of pertinent literatures and abstracts of major cardiovascular conferences were screened. STUDY SELECTION: Clinical and laboratory studies, which reported major adverse cardiovascular events and on-clopidogrel platelet reactivity categorised by smoking status respectively, were selected. DATA EXTRACTION: Descriptive and quantitative data were extracted. The main analyses were performed under a random-effects model. For clinical studies, HR estimates were synthesised according to smoking status; for laboratory studies, standardised mean difference (SMD) of on-clopidogrel platelet reactivity and OR for high on-clopidogrel platelet reactivity were pooled. Heterogeneity was quantified by computing I(2) statistic. RESULTS: Of the 1869 citations retrieved, seven clinical studies and 12 laboratory studies involving 111 132 patients with established cardiovascular disease and 6658 patients with acute coronary syndrome and/or stent deployment, respectively, were included for meta-analysis. Pooled clinical results showed that an intensified antiplatelet regimen involving clopidogrel was associated with 10% reduced risk for major adverse cardiovascular events among non-current smokers (HR 0.90; 95% CI 0.85 to 0.96), while this clinical benefit was enhanced by 2.9-fold among current smokers (HR 0.71; 95% CI 0.62 to 0.80). Pooled analysis of laboratory studies revealed that current smokers had significantly lower on-clopidogrel platelet reactivity (SMD -0.30; 95% CI -0.46 to -0.15) but, notably, there was considerable inter-study heterogeneity (I(2) 76.2%; p=0.000). The analysis based on four studies (n=1423) suggested a significantly lower odds of high on-clopidogrel platelet reactivity among current smokers than those among never smokers (OR 0.33; 95% CI 0.22 to 0.43). CONCLUSIONS: Smoking appears to positively modify the relative clinical efficacy and pharmacodynamic effects of clopidogrel.

[Management of burn wounds with Hippophae rhamnoides oil].

OBJECTIVE: To observe the therapeutic effects of Hippophae rhamnoides oil, a preparation of traditional Chinese herbal medicine derived from the fruits of sea buckthorn, on the wounds in burn patients. METHODS: Hippophae rhamnoides oil dressing was applied on the burn wounds as an inner dressing and covered by disinfecting dressing. The oil dressing was changed every other day until wound healing. RESULTS: Totally 151 burned patients received the treatment with Hippophae rhamnoides oil dressing, which obviously alleviated the swelling and effusion of the wounds and relieved the pains. Compared with the control patients (treated with vaseline gauze), patients receiving the dressing showed more obvious exudation reduction, pain relief, and faster epithelial cell growth and wound healing, with statistically significant difference between the two groups. CONCLUSION: As a valuable plant oil with wide uses in medicine, Hippophae rhamnoides oil for external application has definite effects on the healing of burn wounds.