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The high incidence of type 2 diabetes, the low rate of compliance, and the complex mechanism of vascular disease caused by diabetes make its complications increase year by year. Our study aimed to investigate the clinical characteristics of lower extremity vascular diseases in type 2 diabetes and evaluate the long-term efficacy of vascular intervention for these diseases.From 2007 to 2014, 362 patients who underwent vascular intervention in our hospital due to lower extremity vascular diseases in type 2 diabetes were followed up for 5 years and their clinical characteristics were analyzed in this retrospective study.Compared with those before treatment, the values of blood pressure, fasting blood glucose, glycated hemoglobin (HbA1c), total cholesterol (TC), triglyceride Ester (TG), and low density lipoprotein-cholesterol (LDL-C) of patients were significantly lower 5 years after intervention (P 0.01). We found that the levels of fibrinogen, blood glucose, HbA1c, TC, TG, LDL-C, and small dense low-density lipoprotein (sdLDL) in the vascular restenosis group were significantly higher than those in the vascular patency group (P 0.001), whereas the level of HDL-C in the vascular restenosis group was significantly lower compared with the vascular patency group.Vascular intervention can significantly improve a series of biochemical indicators in patients with lower extremity vascular diseases caused by type 2 diabetes. Postoperative restenosis may be related to hypertension, duration of diabetes, rate of inferior knee disease, fibrinogen, and sdLDL. Good survival and limb salvage were achieved in the patients in this series with interventions and medical treatment provided by endocrinologists.背景: 2型糖尿病的高发病率、低依从性以及由糖尿病引起的血管疾病的复杂机制使其并发症逐年增加。本研究旨在探讨2型糖尿病合并下肢血管病变临床特点及下肢血管介入治疗的远期疗效和临床意义。 方法: 对2007-2014年间因糖尿病下肢血管病变于我院行下肢血管病变介入治疗的362例患者进行5年疗效随访, 并对其临床特点进行分析。 结果: 与治疗前相比，患者的血压、空腹血糖、糖化血红蛋白(HbA1c)、总胆固醇(TC)、三酰甘油(TG)和低密度脂蛋白胆固醇(LDL-C)在干预5年后明显降低(P0.01)。与血管通畅组相比，血管再狭窄组患者的纤维蛋白原、血糖、HbA1c、TC、TG、LDL-C和小而密低密度脂蛋白(sdLDL)水平较高，而HDL-C水平较低。 结论: 血管介入治疗可以显着改善由2型糖尿病引起的下肢血管疾病患者的一系列生化指标。术后再狭窄可能与高血压、糖尿病持续时间、膝下疾病发生率、纤维蛋白原和sdLDL有关。通过内分泌科医师治疗和干预下，该系列患者获得了良好的生存和肢体挽救。.

Spread along nerve fiber bundles is one of the most important modes of glioma invasion; however, the current guidelines for radiotherapy target areas recommend a 1–2-cm margin in all directions from the tumor border based on pretreatment imaging findings. In this article, we analyzed the relationship between edema and nerve fiber bundles in 60 glioma patients and aimed to clarify the effect of including edema on delineation of the target volume.

Aims/Introduction. The present study estimated the cost-effectiveness of bariatric surgery versus medication therapy for the management of recently diagnosed type 2 diabetes mellitus (T2DM) in obese patients from a Chinese health insurance payer perspective. Materials and Methods. A Markov model was established to compare the 40-year time costs and quality-adjusted life-years (QALYs) between bariatric surgery and medication therapy. The health-care costs in the bariatric surgery group, proportion of patients in each group with remission of diabetes, and state transition probabilities were calculated based on observed resource utilization from the hospital information system (HIS). The corresponding costs in the medication therapy group were derived from the medical insurance database. QALYs were estimated from previous literature. Costs and outcomes were discounted 5% annually. Results. In the base case analysis, bariatric surgery was more effective and less costly than medication therapy. Over a 40-year time horizon, the mean discounted costs were 86,366.55 RMB per surgical therapy patient and 113,235.94 CNY per medication therapy patient. The surgical and medication therapy patients lived 13.46 and 10.95 discounted QALYs, respectively. Bariatric surgery was associated with a mean health-care savings of 26,869.39 CNY and 2.51 additional QALYs per patient compared to medication therapy. Uncertainty around the parameter values was tested comprehensively in sensitivity analyses, and the results were robust. Conclusions. Bariatric surgery is a dominant intervention over a 40-year time horizon, which leads to significant cost savings to the health insurance payer and increases in health benefits for the management of recently diagnosed T2DM in obese patients in China.

Long noncoding RNAs (lncRNAs) are a group of noncoding RNAs whose nucleotides are longer than 200 bp. Previous studies have shown that they play an important regulatory role in many developmental processes and biological pathways. However, the contributions of lncRNAs to placental development are largely unknown. Here, our study aimed to investigate the lncRNA expression signatures in placental development by performing a microarray lncRNA screen. Placental samples were obtained from pregnant C57BL/6 female mice at three key developmental time points (embryonic day E7.5, E13.5, and E19.5). Microarrays were used to analyze the differential expression of lncRNAs during placental development. In addition to the genomic imprinting region and the dynamic DNA methylation status during placental development, we screened imprinted lncRNAs whose expression was controlled by DNA methylation during placental development. We found that the imprinted lncRNA Rian may play an important role during placental development. Its homologous sequence lncRNA MEG8 (RIAN) was abnormally highly expressed in human spontaneous abortion villi. Upregulation of MEG8 expression in trophoblast cell lines decreased cell proliferation and invasion, whereas downregulation of MEG8 expression had the opposite effect. Furthermore, DNA methylation results showed that the methylation of the MEG8 promoter region was increased in spontaneous abortion villi. There was dynamic spatiotemporal expression of imprinted lncRNAs during placental development. The imprinted lncRNA MEG8 is involved in the regulation of early trophoblast cell function. Promoter methylation abnormalities can cause trophoblastic cell defects, which may be one of the factors that occurs in early unexplained spontaneous abortion.

Objective Distinguishing recurrence and pseudoprogression is a major challenge in the clinical practice of treatment for high-grade gliomas (HGGs). The neutrophil-lymphocyte ratio (NLR) has been reported to be closely related to survival in HGGs. We aimed to assess the predictive value of NLR in the differential diagnosis of recurrence and pseudoprogression. Materials and Methods A total of 135 patients with histologically confirmed HGGs were studied. All patients underwent focal radiotherapy and concomitant temozolomide (TMZ), followed by 6 cycles of TMZ if MRI showed no progressive enlargement of contrast-enhancing lesions. MRI evaluation was taken 4 weeks after concurrent chemoradiotherapy and then every 2 months later. NLR was calculated at 4 time points of preoperation, before concurrent RT-TMZ (pretreatment), 4 weeks following completion of RT-TMZ, and MRI showed lesion enlarged or treatment completed. Results In 135 patients, 47 (34.8%) were found to be pseudoprogression (PsPD), and 28 (20.7%) were early disease progression (ePD). The mean pretreatment and post-treatment NLR were 4.2±2.1 and 5.1±3.5, respectively. The median overall survival in the PsPD group (25.2 months) was significantly longer than in the ePD (15.4 months) and no progression group (nPD) (21.6 months) (p

PurposeTo find an optimal model to predict venous thromboembolism specially for glioblastoma by a prospective research.Methods Patients with newly histologically confirmed glioblastoma multiform (GBM) were recruited for this study. Status of IDH1, PTEN, P53, BRAF, MGMT and TERT were determined using genetic sequencing through polymerase chain reaction (PCR). Amplification of EGFR was established through fluorescence in situ hybridization (FISH). Competing-risks regression model was performed to calculate the risk of VTE. Clinical and laboratory parameters that were independently predicted risk of VTE were used to develop a risk assessment model (RAM).Results145 patients with GBM were included in the present analysis. A total of 48/145 patients (33.1%) developed VTE, all 48 patients were found to be IDH1wt . D-dimer, ECOG score and EGFR staus were sugggested to be significantly associtaed with the VTE risk in multivariable analysis. High ECOG score (>2), high D-dimer (>1.6 μg/mL) and EGFR amplification were used as the strongest independent predictors of increased risk of VTE. The cumulative incidence of VTE was 17.2% for patients with score 0 (n =29), 23.6% for patients with score 1 (n =55 ) and 63.8% for patients with score 2 (n = 35) or score 3 (n = 12) by application of a RAM .Conclusion GBM patients with IDH1 mutation were at very low risk of VTE. In IDHwt patients, by applying a VTE risk assessment model, we could identify patients with a very high and low risk of VTE.

The microbiota in the human body play critical roles in many physiological and pathological processes. However, the diversity and dynamics of the female genital tract (FGT) microbiota have not been fully unveiled. In this study, we characterized the microbiome variations in reproductive-aged Chinese women, and we revealed that the cervicovaginal microbiota were dominated by Lactobacillus. Overall, the composition of microbiota in the uterine cavity was more diverse than that in the vagina and cervix. A positive correlation between Lactobacillus iners and Lactobacillus crispatus was observed in both the vagina and the cervix, suggesting that these two species might have a symbiotic relationship in the cervicovaginal microbiota. Moreover, we, for the first time, stratified the reproductive-aged Chinese women into subgroups, based on their microbiome profiles. Furthermore, we identified the bacteria whose abundance changed in the uterine cavity of infertile patients when compared with healthy controls, such as L. iners and L. crispatus. Functionally, the metabolism-related pathways, neurotrophin signaling pathway, and adipocytokine signaling pathway were predominantly dysregulated in the uterine cavity of infertile patients. In conclusion, we characterized a comprehensive microbial landscape in FGT, as well as their functional roles in female infertility of the Chinese population.

Background: Coronavirus disease 2019 (COVID-19), a newly erupted respiratory infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has swept across the most of countries. The laboratory characteristics of COVID-patients accompanied with cancer and the risk factors for disease progression and survival of this particular population were few reported. Methods: We enrolled 585 confirmed COVID-19 patients admitted to our hospitals with measured interleukin-6 level on admission. Laboratory tests and outcome were extracted from electronic medical records. Data was divided to cancer group and non-cancer group to explorer the risk factors of progression and survival.Findings: A total of 44 patients with different cancer type (cancer group) and 541 patients without cancer (non-cancer group) were included. Cancer group had significant higher levels of NEUT, NLR, IL-6, and CRP than non-cancer group, but lymphocyte count and ALB were lower. Cancer group showed significantly higher progression rate (42·1% vs 22·5%) and mortality (27·27% vs 11·91%) than non-cancer group. Elevated IL-6 and CRP were the risk factors associated with progression among moderate patients and death in-hospital (all pInterpretation: IL-6, CRP, NEUT, and NLR were elevated in COVID-19 patients with cancer, with lower level of LYMP and ALB. IL-6 and CRP were positively correlated with progression and poor outcome in patients without cancer. As one of combined diseases, despite malignancy history did not directly affect the prognosis of COVID-19, but it could play a role in the poorer outcome through release of IL-6 and CRP.

Recent studies have revealed significant roles of neurotransmitters and gut microbiota along the gut-brain axis in Parkinson's disease (PD); however, the potential mechanisms remain poorly understood. In the current study, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced characteristic PD neurobehavior changes accompanied by increased α-synuclein, apoptotic protein Bim, and cleaved caspase-3 and decreased expression of tyrosine hydroxylase (TH). Meanwhile, the tryptophan (Trp) and tyrosine (Tyr) neurotransmitter metabolites involving kynurenine (KYN), serotonin (5-HT), and dopamine (DA) pathways were significantly changed in serum. Furthermore, the step-limited enzymes, which are responsible for the key metabolic pathways of these neurotransmitters, were obviously dysregulated. The 16S rRNA gene sequence results indicated that the abundance and diversity of the microbiota were obviously decreased in MPTP-treated mice, the presence of Ruminococcus, Parabacteroides and Parasutterella genera were obviously increased, while Coriobacteriaceae, Flavonifractor, Lachnospiraceae, Lactobacillaceae, and Rikenellaceae abundance was markedly decreased. The connectivity between the gut microbiota and neurotransmitter metabolism revealed that the gut microbiota dysbiosis was associated with disturbance of the DA, KYN, and 5-HT metabolic pathways. Therefore, our results provide evidence that gut-microbiota-brain axis disturbance may play an important role in PD development and targeting this axis might provide a promising therapeutic strategy for PD.

Background Primary disease influenced the prognosis of coronavirus disease 2019 (COVID-19), but the clinical characters of patients accompanied with tumor were few reported. Methods We enrolled 528 COVID-19 patients. Date of laboratory tests and outcome were divided to corresponding groups to compare the risk factors of disease severity, progression and survival. Results The disease severity at hospitalization, progression rate (51.43% vs 54.42%) and mortality (19.51% vs 11.91%) were equal between tumor and non-tumor group. In both groups, lymphopenia was negatively related to the severity grading (OR = 0.019 and 0.168 separately), NLR was positively correlated with the poor outcome (OR = 1.371 and 1.155 separately), and CRP was relevant to the disease progression and survival (OR = 1.334 and 1.303 separately). Conclusions Malignancy history may have no marked effect on the severity and prognosis of COVID-19. Lymphopenia, NLR and CRP levels could be regarded as indicators to determine severe cases, and predict progression and survival.

Vitamin D deficiency can lead to high blood pressure. Polymorphisms in the vitamin D hydroxylase gene have been associated with serum vitamin D levels in some Western countries. The aim of this study was to investigate whether polymorphisms of hydroxylase genes in the vitamin D metabolic pathway contribute to hypertension by affecting serum vitamin D status in a Han Chinese population. We selected four single nucleotide polymorphisms (SNPs; rs1993116 and rs10741657 of CYP2R1; rs4809957 and rs6068816 of CYP24A1) for genotyping in 525 control subjects and 324 hypertensive patients, and detected vitamin D levels in blood in subsets of these groups. The results showed that rs1993116 and rs10741657 were associated with a reduced risk of hypertension. The odds ratios, 95% confidence intervals, and p values from the adjusted additive and dominant models were 0.788 (0.644-0.963, p = 0.02) and 0.719 (0.545-0.949, p = 0.02) for rs1993116 and 0.805 (0.66-0.983, p = 0.033) and 0.733 (0.556-0.966, p = 0.028) for rs10741657. A protective effect of CYP2R1 with regard to hypertension was also found in males and non-smokers. The TT genotypes of rs1993116 and rs10741657 were associated with significantly lower systolic blood pressure in treated hypertensive patients (both p = 0.002). No association with hypertension was found for the two SNPs of CYP24A1, and no difference in vitamin D level was found among the three genotypes of the four SNPs. Our results suggest that CYP2R1 polymorphisms are associated with a reduced risk of hypertension independent of the vitamin D level in the Han Chinese population.

Laparoscopic unwinding of adnexal torsion has been proposed for decades. However, this technique is still controversial regarding the concern of thromboembolic events. We present two cases of conservative laparoscopic management of adnexal torsion. In the first case, a 16-year-old adolescent with serous cystadenoma was successfully managed by untwisting and cystectomy. We followed up this patient for 17 years with regular re-examinations in our hospital. To the best of our knowledge, this is the longest follow-up reported of this condition. In the second case, a 32-year-old infertile woman who received oocyte retrieval 3 days before being admitted to hospital was referred to hospital with right ovarian torsion. We treated her successfully based on our long-term follow-up experience, and she is now asymptomatic and in her 7th month of pregnancy.

Gender dysphoria (GD) is characterized by an incongruence between the gender assigned at birth and the gender with which one identifies. The biological mechanisms of GD are unclear. While common genetic variants are associated with GD, positive findings have not always been replicated. To explore the role of rare variants in GD susceptibility within the Han Chinese population, whole-genome sequencing of 9 Han female-to-male transsexuals (FtMs) and whole-exome sequencing of 4 Han male-to-female transsexuals (MtFs) were analyzed using a pathway burden analysis in which variants are first collapsed at the gene level and then by Gene Ontology terms. Novel nonsynonymous variants in ion transport genes were significantly enriched in FtMs (P- value, 2.41E-10; Fold enrichment, 2.8) and MtFs (P- value, 1.04E-04; Fold enrichment, 2.3). Gene burden analysis comparing 13 GD cases and 100 controls implicated RYR3, with three heterozygous damaging mutations in unrelated FtMs and zero in controls (P = 0.001). Importantly, protein structure modeling of the RYR3 mutations indicated that the R1518H mutation made a large structural change in the RYR3 protein. Overall, our results provide information about the genetic basis of GD.

BACKGROUND The CYP17A1 gene has been identified to associate with hypertension in Chinese population. However, the association between CYP17A1 polymorphisms and hypertension-related factors is unclear. The present study aimed to investigate the relation between CYP17A1 single nucleotide polymorphisms (SNPs) and serum lipid profiles. METHODS In total, 1350 participants were included in the study. Six SNPs in or near CYP17A1 gene were genotyped in a Han Chinese population in two stages. RESULTS There was a statistically significant association of rs1004467 (adjusted odds ratio = 0.783, 95% confidence interval = 0.667-0.919, p

Background The functional aspects of mast cell-microglia interactions are important in neuroinflammation. Our previous studies have demonstrated that mast cell degranulation can directly induce microglia activation. However, the role of mast cells in Lipopolysaccharide (LPS)-induced microglia activation, neuroinflammation and cognitive impairment has not been clarified. Methods This study investigated the interaction between brain microglia and mast cells in vivo through site-directed injection of cromolyn into rat right hypothalamus using stereotaxic techniques. Cognitive function was subsequently assessed using trace fear conditioning and Y maze tests. Mast cells in rat brain were stained with toluidine blue and counted using Cell D software. Microglia activation was assessed by Iba1 immunohistochemistry both in rat brain and in mast cell-deficient KitW-sh/W-sh mice. Receptor expression in rat microglia was determined using flow cytometry analysis. Cytokine levels in rat brain tissue and cell supernatant were measured using high-throughput ELISA. Western blotting was used to analyze Cell signaling proteins. Results In this study, intraperitoneal injection of 1 mg/kg LPS induced mast cell activation in hypothalamus and cognitive dysfunction in rats, and that this process can be repressed by the mast cell stabilizer cromolyn (200 μg). Meanwhile, in mice, LPS IP injection induced significant microglia activation 24 h later in the hypothalamus of wild-type (WT) mice, but had little effect in KitW-sh/W-sh mice. The stabilization of mast cells in rats inhibited LPS-induced microglia activation, inflammatory factors release, and the activation of MAPK, AKT, and NF-κB signaling pathways. We also found that LPS selectively provokes upregulation of H1R, H4R, PAR2, and TLR4, but downregulation of H2R and H3R, in ipsilateral hypothalamus microglia; these effects were partially inhibited by cromolyn. In addition, LPS was also found to induce activation of P815 cells in vitro, consistent with findings from in vivo experiments. These activated P815 cells also induced cytokine release from microglia, which was mediated by the MAPK signaling pathway. Conclusion Taken together, our results demonstrate that stabilization of mast cells can inhibit LPS-induced neuroinflammation and memory impairment, suggesting a novel treatment strategy for neuroinflammation-related diseases.

Background Type 1 diabetes (T1DM) severely threatens human health, and the dysfunction of insulin-secreting β cells in islets is related to the reduced PDX-1 expression. It has been reported that long non-coding RNA MALAT1 regulates β cell function, while the potential mechanism is unclear. Methods Islets were isolated from non-obese diabetic (NOD) mice and wild type (WT) mice. Mouse islets and β cell line (Min6) were stimulated by IL-1β. The expression of MALAT1 was determined using real-time PCR, while the PDX-1 protein expression was determined using western blotting. ChIP-qPCR was carried out to determine the histone acetylation of the PDX-1 promoter. Results In NOD islets and IL-1β-stimulated Min6 cells, the expression of MALAT1 was increased, while the mRNA and protein levels of PDX-1 were decreased at an age/time-dependent manner. Overexpressing MALAT1 suppressed the H3 histone acetylation of the PDX-1 promoter, inhibiting both mRNA and protein expressions of PDX-1. Knocking down MALAT1 restored the decrease of the histone acetylation of the PDX-1 promoter, as well as the PDX-1 expression, which was reduced by IL-1β stimulation. Under high glucose stimulation, the overexpression of PDX-1 alone restored the insulin secretion which was inhibited by the simultaneous overexpression of MALAT1 and PDX-1. Under high glucose and IL-1β stimulation, the simultaneous knockdown of MALAT1 and PDX-1 reduced the enhancement of the insulin secretion which was raised by knocking down MALAT1 alone. Conclusion MALAT1 induces the dysfunction of β cells via reducing the H3 histone acetylation of the PDX-1 promoter and subsequently inhibiting the expression of PDX-1, thus suppressing the insulin secretion.

Background The goal of this study was to determine if vitamin D receptor (VDR) gene polymorphisms underlie susceptibility to dyslipidemia in a Chinese Han population. Methods Three tag single nucleotide polymorphisms (SNPs) (rs11574129, rs2228570, and rs739837) were genotyped using TaqMan assays to determine VDR SNP associations with dyslipidemia. We genotyped 877 cases of dyslipidemia from a normotensive, non-diabetes mellitus population and 1822 non-dyslipidemia subjects in a stage I study. In a follow-up stage II study, we included a larger sample of 3124 controls and 1679 cases with dyslipidemia. Finally, we explored the potential molecular mechanism for the SNP associations using molecular modeling analysis. Results We found a significant association between SNP rs2228570 and dyslipidemia in the additive (adjusted odds ratio (OR) = 1.255, 95% Confidence Interval (CI) = (1.118–1.409), P

Background and objective Parkinson's disease (PD) is the second most common age-related neurodegenerative disorder after Alzheimer's disease. The aim of this work was to determine whether the differences of serum miRNAs profiling could distinguish PD patients from healthy individuals. Methods We collected serum samples from 106 sporadic PD patients and 91 age/gender-matched healthy controls. Serum miRNAs were analysed by Solexa sequencing followed by a qRT-PCR examination. The qRT-PCR assay, which was divided into two phases, was used to validate the expression of miRNAs screened by Solexa sequencing. Receiver operating characteristic (ROC) curve analysis and clustering analysis were performed to determine the diagnostic usefulness of the selected miRNAs for PD. Results In this study, we generated a profile of 5 serum miRNAs: miR-195 was up-regulated, and miR-185, miR-15b, miR-221 and miR-181a were down-regulated. Conclusion This group of five miRNAs can precisely distinguish PD patients from health individuals and may be used as a potential serum-based biomarker for the diagnosis of PD.

Objective: To explore the effect of the environmental toxicants polycyclic aromatic hydrocarbons (PAH) on the ovary. Methods: Female mice of child-bearing age were randomized to a control group and three PAH exposure groups at a dose of 0.1 μg/mL, 1 μg/mL or 10 μg/mL. The ovary was removed using aseptic technique, cultured in vitro for 10 days, and HE stained to observe structural change by light microscopy. Ovarian granulosa cell apoptosis was detected by immunohistochemistry, and the number of ovarian follicles undergoing atresia was counted. Western blot was carried out to detect the expression of apoptosisrelated proteins (Caspase3,Caspase9, bax and bcl-2). Then we detected if these damages can be prevented by 740Y-P, an activator of PI3K/Akt pathway. Results: The number of ovarian follicles in the three PAH groups was significantly lower than that in the control group (P

The CYP17A1 gene, which encodes17α-hydroxylase and 17,20-lyase, has been identified as a common hypertension susceptibility locus in a European population. However, the association between CYP17A1 polymorphisms and hypertension is unclear in the Chinese population as well as in the role of serum 25(OH) D levels. Six single nucleotide polymorphisms (SNPs) in CYP17A1 were genotyped in two stages in a Han Chinese population, and the serum 25(OH) D levels were measured. Analysis in stage 1 showed that the rs1004467 minor G-allele and rs11191548 minor C-allele in CYP17A1 were significantly associated with a decreased risk of hypertension and higher serum 25(OH) D levels (all P

Estrogen regulates a wide variety of nonreproductive functions in the central nervous system. Cortical neurons contain a diverse range of voltage-gated ion channels, including calcium (Ca(2+)) channels, and Ca(2+) channels play an important role in the regulation of action potential generation and neuronal excitability. In this study, the effect of estradiol (E2) on high-voltage-activated (HVA) Ca(2+) channels in cultured rat cortical neurons was examined.We used the whole-cell patch-clamp technique to measure the HVA Ca(2+) channels.We found that HVA Ca(2+) channel currents was inhibited by 17β-E2 in a rapid, reversible and concentration-dependent manner. Moreover, 17β-E2 shifted the steady-state inactivation curve in the hyperpolarizing direction without changing the activation curve. We also found that the inhibitory effects of 17β-E2 on Ca(2+) currents were unaffected by the estrogen receptor (ER) antagonist ICI 182780; however, the protein kinase C (PKC) inhibitor rottlerin and protein kinase A (PKA) inhibitor H-89 blocked the 17β-E2-induced inhibition of Ca(2+) currents.E2 inhibited HVA Ca(2+) currents via PKC and PKA-dependent signaling pathway in cortical neurons, and the effects of BPA were independent of classical ER.

Estrogen has multiple actions in the brain to modulate homeostasis, synaptic plasticity, neuroprotection and pain sensitivity. Previous studies have demonstrated that estradiol may affect the ion channel function. The role of voltage-gated sodium channels in the transmission of nociceptive and neuropathic pain messages is well-established. Herein, we report the effects of estradiol (E2) on TTX-sensitive (TTX-S) and TTX-resistant (TTX-R) Na(+) currents, using a conventional whole-cell patch clamp technique from acutely isolated mouse dorsal root ganglion neurons. We found that the extracellularly 17β-E2 inhibited TTX-S Na(+) currents and TTX-R Na(+) currents; the effects were rapid, reversible and in a concentration-dependent manner. Moreover, 17β-E2 did not significantly affect the activation curve for Na(+) channel, and shifted the steady-state inactivation curve for TTX-S and TTX-R Na(+) channels in the hyperpolarizing direction. We also found that the membrane impermeable E2-BSA was as efficacious as 17β-E2, whereas 17α-E2 had no effect. Blockers of PKC (GÖ-6983) and PKA (H-89) abrogated these acute effects of 17β-E2. In conclusion, E2 inhibited voltage-gated Na(+) channels in mouse DRG neurons through a membrane ER-activated PKC-PKA signaling pathway. Through the modulation of voltage-gated sodium currents, estradiol could affect cell excitability, firing properties.

Corticospinal neurons (CSNs) represent the direct cortical outputs to the spinal cord and play important roles in motor control across different species. However, their organizational principle remains unclear. By using a retrograde labeling system, we defined the requirement of CSNs in the execution of a skilled forelimb food-pellet retrieval task in mice. In vivo imaging of CSN activity during performance revealed the sequential activation of topographically ordered functional ensembles with moderate local mixing. Region-specific manipulations indicate that CSNs from caudal or rostral forelimb area control reaching or grasping, respectively, and both are required in the transitional pronation step. These region-specific CSNs terminate in different spinal levels and locations, therefore preferentially connecting with the premotor neurons of muscles engaged in different steps of the task. Together, our findings suggest that spatially defined groups of CSNs encode different movement modules, providing a logic for parallel-ordered corticospinal circuits to orchestrate multistep motor skills.

The therapeutic effect of transplantation of human umbilical cord blood cell-derived mononuclear cells (HUCMNCs) on treating in-stent restenosis (ISR) after endovascular interventional therapy (EIT) was evaluated in preclinical rabbit model of type 2 diabetes mellitus (T2DM)-related peripheral artery disease (PAD). HUCMNCs were transplanted to T2DM rabbits subjected to femoral artery occlusion surgery and received EIT. Serum concentration of soluble vascular endothelial cadherin (VE-cad) and plasma concentration of lipoprotein-associated phospholipase A2 (Lp-PLA2) were determined with enzyme-linked immunosorbent assay before and after the transplantation. The injury and the recovery of right femoral artery at stenting site were evaluated with Hematoxylin and Eosin (HE) staining. HUCMNCs purified from umbilical cord blood were 100% CD45+ and 96.5% CD34− with round or oval morphology and adherent growth pattern. The soluble VE-cad and Lp-PLA2 were significantly attenuated after HUCMNC transplantation. The intimal area and the ratio between intimal area and medium film area in the dilated occlusion site were also dramatically decreased 4 weeks after receiving HUCMNCs. HUCMNC transplantation is effective in protecting vascular endothelial function and preventing ISR after EIT in T2DM rabbits suffering from PAD.

Estrogen receptors (ERα and ERβ) mediate the neuroprotection of estrogens against MPTP-induced striatal dopamine (DA) depletion. Pain is an important and distressing symptom in Parkinson's disease (PD). Voltage-gated sodium channels in sensory neurons are involved in the development of neuropathic pain. In this study, MPTP caused changes in nociception and alterations of gene expression of voltage-gated sodium channels in dorsal root ganglion (DRG) neurons in ER knockout (ERKO) mice were investigated. We found that administration of MPTP (11 mg/kg) to WT mice led to an extensive depletion of DA and its two metabolites, αERKO mice were observed to be more susceptible to MPTP toxicity than βERKO or WT mice. In addition, we found that the mRNA levels of TTX-S and TTX-R sodium channel subtypes were differentially affected in MPTP-treated WT animals. The MPTP-induced up-regulation of Nav1.1 and Nav1.9, down-regulation of Nav1.6 in DRG neurons may be through ERβ, up-regulation of Nav1.7 and down-regulation of Nav1.8 are dependent on both ERα and ERβ. Therefore, the MPTP-induced alterations of gene expression of sodium channels in DRG neurons could be an important mechanism to affect excitability and nociceptive thresholds, and the ERs appear to play a role in nociception in PD.

Bisphenol A (BPA), an estrogenic compound, is contained in cans, polycarbonate bottles, and some dental sealants. Exposure to BPA might have potential toxicological effects on the nervous system. Previous studies have demonstrated that BPA may affect ion channel function, but the effects of BPA on voltage-gated sodium channels are unknown. Herein, we report the effects of BPA on TTX-sensitive (TTX-S) and TTX-resistant (TTX-R) Na+ currents, using a conventional whole-cell patch clamp technique from acutely isolated mouse dorsal root ganglion neurons. BPA inhibited TTX-S Na+ currents and TTX-R Na+ currents, the effects of BPA were rapid, reversible and in a concentration-dependent manner. Moreover, BPA could shift the voltage-gated activation curve for TTX-S Na+ channel in the hyperpolarizing direction without changing that for TTX-R Na+ channel; shift the steady-state inactivation curve for TTX-S Na+ channel in the depolarizing direction without changing that for TTX-R Na+ channel; and lengthen the time course of recovery from inactivation for both TTX-S Na+ current and TTX-R Na+ current. We also found that PKC inhibitor GÖ-6983 and PKA inhibitor H-89 blocked the BPA-induced inhibition of Na+ currents. Considering its complex modulatory effects on voltage-gated sodium channels, BPA might have potential toxicological effects on the nervous system and lead to a change in excitability of nociceptive afferent fibers.

A genome-wide approach found significant association of two at-risk haplotypes (HapA, HapB) in the ALOX5AP gene with myocardial infarction and stroke. To date, it is still controversial whether ALOX5AP gene polymorphisms are risk factors for stroke. The aim of the present study is to investigate the association between the ALOX5AP gene polymorphism and the risk for stroke in Eastern Chinese Han population with a haplotype-based analysis. We conducted a comprehensive association study of 507 stroke patients and 510 healthy controls to assess the association between the ALOX5AP tagging single-nucleotide polymorphisms (tSNPs) and stroke risk. Genotyping was performed using the PCR-RFLP assay. In the single-locus analysis, we found that the rs9579646 AG genotype was associated with a marginally decreased risk for stroke (adjusted odds ratio, 0.65; 95% confidence interval, 0.45-0.96), compared with the AA genotype. Haplotype-based association analysis of block 2 involving rs10507391 and rs12429692 revealed that the decreased risk of stroke was significantly associated with haplotype AA (OR, 0.66; 95% CI, 0.46-0.95). These results suggested that the genetic variants in ALOX5AP might modulate the risk of stroke in Eastern Chinese Han population. The frequencies of single-marker alleles and haplotypes showed remarkable differences from those in other populations.

RAD51 plays a key role in homologous recombination repair of double-stranded DNA breaks which may cause chromosomal breaks and genomic instability. We performed a meta-analysis of 9 epidemiological studies involving 13,241 cases and 13,203 controls that examined the association between RAD51 135G>C polymorphism and breast cancer. No significant association of RAD51 135G>C polymorphism with breast cancer was found in overall and European populations. However, after the studies which did not fulfill Hardy–Weinberg equilibrium were excluded, we observed an overall significant increased breast cancer risk (for the recessive model CC vs. GG/CG: OR = 1.35, 95% CI = 1.05–1.74, P heterogeneity = 0.06). In summary, our meta-analysis suggested the RAD51 135G>C polymorphism may contribute to breast cancer susceptibility.

The Catechol-O-methyltransferase (COMT) plays an important role in the development of breast cancer. Many previous epidemiologic studies explored the association of COMT Val158Met polymorphism with breast cancer susceptibility. However, the results were inconsistent. We therefore performed a meta-analysis of 26 published studies including 16,693 breast cancer patients and 18,261 healthy controls. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of the association of the COMT Val158Met polymorphism with breast cancer risk. No significant association was found in all genetic models in overall, Asian, European populations. After the studies whose genotype frequencies in the controls did not fulfill Hardy–Weinberg equilibrium were excluded, we found a borderline significant decreased breast cancer risk among Europeans (for the recessive model LL versus HH/HL: OR = 0.90, 95% CI = 0.90–1.00, P heterogeneity = 0.33). There was no between-study heterogeneity. In conclusion, COMT Val158Met polymorphism may be a low-penetrant risk factor for breast cancer development in European population.

Resveratrol has been reported to protect several types of cells against beta-amyloid peptide (Abeta) toxicity by scavenging reactive oxygen species (ROS) and inactivating caspase-3. However, other studies found that long-term treatment with resveratrol inhibited cells by inducing ROS generation and activating caspase-3. In the current report, a 48-h incubation of resveratrol at the concentrations of 5 and 10 microM significantly attenuated the viability of PC12 cells and a 12-h pre-incubation of resveratrol did not protect PC12 cells against Abeta exposure (even further inhibited PC12 cells at the concentrations of 10 microM) by acting as a pro-oxidant. Due to the lipophilicity of resveratrol, resveratrol-loaded polymeric micelles basing on amphiphilic block copolymer were developed. Then, the effects of resveratrol-loaded polymeric micelles on the viability and Abeta protection of PC12 cells were investigated. At the equivalent concentrations of 5 and 10 microM resveratrol, a 48-h incubation of resveratrol-loaded nanoparticles did not show toxicity to cells, while 12-h pre-incubation of resveratrol-loaded nanoparticles protected PC12 cells from Abeta-induced damage in a dose dependent manner (1-10 microM) by attenuating intracellular oxidative stress and caspase-3 activity. Further investigations are absolutely needed to evaluate the feasibility and advantages of in vivo applications of resveratrol-loaded nanoparticles.

Aim To investigate the role of CCL5 secreted by tumor associated macrophages (TAMs) in gastric cancer, and to explore how CCL5/CCR5 axis modulates phenotypes of gastric cancer cells. Methods Expression of CCL5 and TAM surface marker CD68 in gastric cancer tissues was examined using SP immunohistochemistry. Serum CCL5 levels of patients were assessed using ELISA. Cross-analyses of CCL5 and CD68 expression with clinicopathological data were done. Correlation between CCL5 and CD68 in gastric cancer tissues was also studied. In vitro functional characterization of CCL5 in gastric cancer was done in co-culture of AGS and THP-1 derived macrophages using MTS assay, plate clone formation assay, and transwell experiment. Expression of chemokines and its receptors were detected by RT-PCR, while Stat3 phosphorylation and downstream target proteins were studied using western blot. Results CCL5 and CD68 were both highly expressed in tissues gastric cancer, of which the expressions were positively correlated with each other, and of clinical importance, were associated with the depth of invasion, lymph node metastasis, TNM staging and tumor differentiation. Serum CCL5 was also elevated in patients with gastric cancer comparing to healthy volunteers. Co-culture of AGS cells with THP-1 derived macrophages increased cell proliferation, clone forming ability as well as migration of AGS cells. Migration of AGS cells across transwell membrane was also enhanced by increasing exogenous CCL5. Meanwhile, mRNA expression of CCL5, MMP2, MMP9, and CCR5 was also highly expressed in the cells. Stat3 signaling as reflected by its phosphorylation was also increased in AGS cells upon co-culture with THP-1 derived macrophages. Conclusion CCL5 secreted by TAMs may promote the proliferation, invasion and metastasis of gastric cancer cells, in which Stat3 signaling pathway is likely to play an important role. The correlation of CCL5 with clinicopathological parameters suggested CCL5 holds promise as important molecular marker of gastric cancer staging and disease progression.

We investigated the effect of vitamin D receptor (VDR) gene polymorphism on the risk of type 2 diabetes mellitus (T2DM) in a Chinese Han population.Three tagSNPs (rs11574129, rs2228570 and rs739837) were genotyped using TaqMan assays in a case-control study including 669 cases with T2DM, 1084 individuals with impaired fasting glucose (IFG) and 1,961 controls with normal fasting glucose. Multiple logistic regression was applied to analyze the association of SNPs and the risk of diabetes by adjusting for covariates including age, sex, body mass index (BMI) and smoking. General linear model (GLM) was applied to compare fasting blood glucose levels between genotypes and adjusted for confounding factors.The results showed that rs739837 was significantly associated with increased risk of T2DM in additive model (OR = 1.166, 95% CI 1.017-1.337, p = 0.028) and dominant (OR = 1.166, 95% CI 1.017-1.337, p = 0.002) model. Stratified analysis showed that rs739837 and rs2228570 were, respectively, correlated with T2DM in females and males. Significant associations were found between three SNPs and T2DM in the population55 years of age. SNPs (rs739837, rs11574129) showed significant associations with T2DM in the smoking population. Quantitative trait analysis indicated that the CC group of rs2228570 has lower fasting glucose than TT/TC genotype group in controls.This study provides further evidence that rs739837 in the VDR gene is associated with increased risk of T2DM in a Chinese Han population.

Over the last decades, increasing knowledge about the genetic architecture of Parkinson's disease(PD) has provided novel insights into the pathogenesis of the disorder. Recently, several studies in different populations have found a strong association between idiopathic PD and the single-nucleotide polymorphism (SNP) rs356219, which is located in the 3'UTR of the SNCA gene. In this study, we aimed to verify these findings and to explore further the nature of the association in a subset of Chinese Han PD patients.Four hundred and three unrelated patients with sporadic PD and 315 healthy ethnically matched control subjects were recruited consecutively for the study. Patients and normal controls were genotyped for SNCA rs356219 variant by ligase detection reaction (LDR).A statistically significant difference was found in the frequencies of the single alleles of rs356219 (χ(2) = 12.986,P = 0.002) between PD patients and normal subjects. The distribution of AG genotypes was different between patients and controls (χ(2) = 13.243, P0.001). The OR for subjects with the variant genotypes (AG and GG) was 1.88 (95%CI = 1.27-2.78, P = 0.001). The frequencies of the homozygous genotype for this variant was 42.2% (170 patients), which was significantly higher than that in controls (32.4%, P0.001).The results suggested that SNCA rs356219 variant might have an increased risk of susceptibility to PD in a Chinese Han population. Further studies are needed to replicate the association that we found.

AIMS: Glioblastoma (GBM) is the most lethal of all human tumors. Ionizing radiation (IR), as a major therapeutic modality, induces multiple types of DNA lesions in cells, therefore causes cell death. However, IR could also affect neighboring unirradiated cells, inducing Bystander Effects as chromosomal aberrations, increased proliferation, etc. Intercellular communication through the release of different components is involved in the mechanism. GBM cells release different soluble factors as well as tumor microvesicles (TMVs) to modify the phenotype of neighboring cells, thus participating in the tumor progression. The present study was designed to investigate in vitro the impact of IR on the communication between tumor cells and endothelial cells in the tumor microenvironment via soluble factors and TMVs. MATERIALS AND METHODS: Two GBM cell lines (T98G, U87) were grown and sham-irradiated (0Gy) or irradiated (2 or 10Gy) using a Clinac iX linear accelerator. Cell culture media (CM) were collected. Filtrate (containing only soluble factors) and TMVs were separated with successive centrifugations and Pierce concentrator. Cell viability was assessed by cell counting using trypan blue. TMVs quantifications were performed by flow cytometry. The effect of CM/Filtrate/TMVs on the global behavior (proliferation, adhesion) of bystander tumor cells or HUVEC was investigated using the xCELLigence system (ACEA). RESULTS: As expected, irradiation caused a loss of cell number in U87 and T98G: 20% at 2Gy and 60% at 10Gy 48h post-IR as compared to untreated cells. Both CM and Filtrate collected from sham-irradiated tumor cells induced a 50% reduction of bystander tumor cells proliferation, while CM and Filtrate recovered from 10Gy-irradiated cells had different influence on the proliferation: herein, the inhibitory properties of CM were less marked than those of Filtrate. The discordant effects between CM and Filtrate led us to investigate the role of TMVs. When quantified using flow cytometry, two-fold more TMVs were found in 10Gy-irradiated T98G as compared to untreated cells 48h post-IR, while in U87 this stimulation of release was observed at 2h. TMVs were shown to induce a 2-fold increase of HUVEC cell index. Interestingly after 10Gy-irradiation, TMVs from both cell lines slightly also favored both bystander tumor cells and HUVEC proliferation. CONCLUSION: IR inhibits GBM cells proliferation. IR stimulates TMVs release by GBM cells in a time- and line-dependent manner. IR facilitates tumor progression by stimulating the proliferation of bystander tumor cells as well as favoring tumor angiogenesis via TMVs.

Background and Purpose— Leptomeningeal artery abnormalities in Cerebral Autosomal–Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) have not been extensively characterized. We quantified substructure and diameter of leptomeningeal arteries in CADASIL compared with age-matched controls and the very old; in addition, we characterized intimal thickening in CADASIL using immunohistochemistry. Methods— Frontal and temporal cortex of 6 genetically proven CADASIL brains (average age, 66 years), 6 controls without symptoms of cerebrovascular disease, and 6 very old brains (average age, 89 years) were examined for leptomeningeal artery intimal, medial, and adventitial thickness; inner diameter; and sclerotic index and for smooth muscle markers. Results— The intima of CADASIL arteries was thickened 5-fold compared with controls and the very aged ( P P P Conclusions— Principle changes of leptomeningeal arteries in CADASIL include intimal thickening and medial thinning, but not luminal narrowing. Smooth muscle–like cells participate in neointimal thickening of CADASIL arteries.

Circadian mechanisms play an important role in the regulation of sleep. A circadian clock-controlled gene, Tef, has been suggested to be associated with depressive symptoms, restless legs syndrome, and slow wave sleep in patients with sleep disorders. The present study sought to explore the association between Tef and sleep disturbances in patients with Parkinson's disease (PD).Three hundred and ninety-two unrelated patients with PD were recruited for this study. All of them completed the PD Sleep Scale (PDSS) and other clinical and demographic assessments. rs738499, a single nucleotide polymorphism of the Tef gene, was genotyped by polymerase chain reaction-restriction fragment length polymorphism.Mean total PDSS scores were 111.5 (standard deviation [SD] 23.0) in the TT genotype and 122.2 (SD 18.2) in the TG+GG genotypes (P0.01). Significant differences were found between genotypes (TT vs TG+GG) for 14 item scores (all P0.05). Total and item scores displayed negative associations with the TT genotype (all P0.05) except Item 2 (P=0.178). Linear regression adjusted for gender, duration, depression and disease severity showed that the polymorphism could explain 0.9% of the variance in PDSS scores.These preliminary results suggest that the TT genotype in Tef rs738499 is associated with sleep disturbances in PD. Depression and disease severity are the main contributors to these findings, but rs738499 itself is an independent risk factor.

Recent evidence indicated that the PRKCH gene was a susceptibility gene for lacunar infarction in a Japanese population. The aim of the present study was to explore the association of the gene with lacunar infarction in a population of Chinese Han ancestry. A total of 280 consecutive lacunar infarction patients and 306 unrelated population-based controls that had been matched for age and sex were examined using a case-control design. Two single nucleotide polymorphisms (SNPs) of PRKCH gene (rs3783799 and rs2230500) were genotyped with ligase detection reaction (LDR) and multiplex polymerase chain reaction (PCR). Linkage disequilibrium (LD) and haplotype analysis were also investigated between these two groups. Overall alleles and genotype frequencies were similar between cases and controls. No significant association was detected with the gene polymorphisms mentioned above and lacunar infarction; no significant difference was found with haplotype analysis between these two groups. None of the two SNPs showed significant association with lacunar infarction in the whole subjects before and after adjustment for conventional stroke risk factors (hypertension, diabetes mellitus, and hypercholesterolemia). The frequencies of PRKCH differed largely from those in the Japanese population. The present study suggests that variants in the PRKCH gene are not the risk factors for lacunar infarction in individuals from a small population of Chinese Han ancestry. Population differences in alleles and haplotype frequencies as well as LD structure may contribute to the observed differences between populations.

Parkinson's disease (PD) is a common neurodegenerative disorder with genetic risk factors. Semaphorin 5A (SEMA5A) was recognized as a risk factor for PD through high resolution whole genome association study by Maraganore et al. We used polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay to check two single nucleotide polymorphisms (SNPs) within SEMA5A in 340 PD patients and 222 PD free cases of Chinese Han ancestry and tested by gene sequencing. We found that the SEMA5A variant genotype (allele) of rs7702187 and rs3798097 had no association with the risk of PD in our sample. The AC haplotype was associated with a significant increased risk of PD and the AT haplotype showed an associated decreased risk of PD compared with the most common haplotype TC. Our findings suggested that haplotypes of SEMA5A may be involved in PD risk in the Chinese Han population.

Background and Objective: Previous genetic studies in Parkinson's disease (PD) have provided conclusive evidence for association of genes with strong biological rationale for PD. Recently several studies in different populations have found a strong association between idiopathic PD and the single-nucleotide polymorphism (SNP) rs2736990, located within an intron of the α-synuclein (SNCA) gene. In this study, we aimed to verify these findings and to explore the characteristic of the association in a subset of Chinese Han PD patients. Materials and Methods: A total of 515 unrelated patients with sporadic PD and 450 healthy ethnically matched control subjects were recruited consecutively for the study. Patients and healthy controls were genotyped for SNCA rs2736990 variant by polymerase chain reaction - ligase detection reaction. Results: Our data showed a significant association between the rs2736990 polymorphism and PD, the frequency of the allele C in PD patients was significantly higher than that in controls (P = 0.017, OR = 1.26, 95% confident intervals (CI) =1.04-1.51). The distribution of C > T genotypes was different between patients and controls (P = 0.027). Furthermore, allele C of SNP rs2736990 in early-onset PD was significantly more frequent than that in healthy controls (P = 0.007, odds ratio = 1.60, 95% CI = 1.13-2.26). Conclusions: Our study demonstrated that SNCA rs2736990 C > T polymorphism was associated with susceptibility to PD in Chinese Han population. Further studies are needed to replicate the association we found.