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Background: Alzheimer’s disease (AD) is a chronic and fatal neurodegenerative disease; accumulating evidence suggests that vitamin deficiency is associated with the risk of AD. However, studies attempting to elucidate the relationship between vitamins and AD varied widely. Objective: This study aimed to investigate the relationship between serum vitamin levels and AD in a cohort of the Chinese population. Methods: A total of 368 AD patients and 574 healthy controls were recruited in this study; serum vitamin A, B1, B6, B9, B12, C, D, and E were measured in all participants. Results: Compared with the controls, vitamin B2, B9, B12, D, and E were significantly reduced in AD patients. Lower levels of vitamin B2, B9, B12, D, and E were associated with the risk of AD. After adjusting for age and gender, low levels of vitamin B2, B9, and B12 were still related to the risk of AD. In addition, a negative correlation was determined between vitamin E concentration and Activity of Daily Living Scale score while no significant association was found between serum vitamins and age at onset, disease duration, Mini-Mental State Examination, and Neuropsychiatric Inventory Questionnaire score. Conclusion: We conclude that lower vitamin B2, B9, B12, D, and E might be associated with the risk of AD, especially vitamin B2, B9, and B12. And lower vitamin E might be related to severe ability impairment of daily activities.

Background The zinc finger protein 587B (ZNF587B) is a novel cisplatin-sensitive gene that was identified in our previous research by using a genome-scale CRISPR-Cas9 knockout library in ovarian cancer (OC) cell lines. ZNF587B belongs to the C2H2-type zinc finger protein (ZFP) family. Many ZFP protein could inhibit tumor development and malignancy. However, the function of ZNF587B remains unknown. Methods Quantitative PCR (qPCR) was utilized to compare ZNF587B mRNA expression levels in OC and normal ovarian cell lines. The small interfering RNA (siRNA) and full-length ZNF587B eukaryotic expression plasmid were constructed and transfected into OC cells later. Colony formation, 5-ethynyl-2'-deoxyuridine (EdU) assay, transwell assay, and xenograft experiment were conducted to evaluate the effect of ZNF587B on OC cells. Results ZNF587B was downregulated by approximately 43% and 17% in the OC cell lines SKOV3 and A2780, respectively, compared with that in the normal ovarian cell line IOSE80. Overexpression of ZNF587B reduced cell proliferation, colony formation, migration, and invasion, which could be reversed by knockdown of ZNF587B via siRNA. Xenograft experiments also confirmed that ZNF587B could suppress tumor growth. Survival data of OC patients in the SurvExpress database showed that with respect to overall survival, low-risk patients grouped by the prognostic index had a higher expression of ZNF587B and a better prognosis than high-risk group (HR = 1.77, 95% CI: 0.55-0.70, p = 0.023). Moreover, overexpression of ZNF587B promoted OC cells apoptosis when pretreated with cisplatin. Conclusion ZNF587B is a novel potential tumor suppressor of OC and may be a therapeutic target for OC.

Aim: The present study aimed to assess the association between IGF2/H19 genetic variants and susceptibility to platinum-based chemotherapy in epithelial ovarian cancer (EOC). Methods: A total of 43 platinum-resistant (PR) and 138 platinum-sensitive (PS) EOC patients were recruited in our study. 21 polymorphisms in IGF2/H19 locus were genotyped by Sequenom MassARRAY assay. Results: The frequencies of GG genotype in both rs3842761(C/G) and rs4244809(A/G) were significantly lower in PR group compared with those in PS group (9.76 vs 23.36%, p = 0.049; 9.76 vs 26.09%, p = 0.045; respectively). Compared with the AA genotype, rs4244809 GG genotype was associated with significantly reduced risk of platinum resistance (adjusted OR: 0.30; 95% CI: 0.10–0.91; p = 0.033). Further stratified analyses revealed that the SNPs of rs3842761 and rs4244809 were greatly related to PR risk in FIGO stage III–IV (rs3842761GG/CC+CG: adjusted OR: 0.15; 95% CI: 0.02–1.21; rs4244809 GG/AA+AG: adjusted OR: 0.24; 95% CI: 0.07–0.84; respectively) and serous adenocarcinoma subgroups (rs3842761 GG/CC+CG: adjusted OR: 0.21; 95% CI: 0.05–0.94; rs4244809 GG/AA+AG: adjusted OR: 0.19; 95% CI: 0.04–0.5; respectively), while rs7924316 polymorphism was associated with reduced risk of PR in serous adenocarcinoma subgroup as analyzed by a recessive model (rs7924316 GG/TT+TG: adjusted OR: 0.22; 95% CI: 0.05–0.98). In addition, both TCT haplotypes of rs3741206/rs3842761/rs7924316 and TC haplotype of rs3741206/rs3842761 were associated with elevated risk of PR (for the TCT haplotype of rs3741206/rs3842761/rs7924316: p = 0.049; OR: 1.69; 95% CI: 1.00–2.87; for the TC haplotype of rs3741206/rs3842761: p = 0.044; OR: 1.71; 95% CI: 1.01–2.88). Conclusion: These results suggest that polymorphisms in IGF2/H19 gene locus are associated with PR risk in EOC.

Objective Early detection of platinum resistance for ovarian cancer treatment remains challenging. This study aims to develop a machine learning model incorporating genomic data such as Single-Nucleotide Polymorphisms (SNPs) of Human Sulfatase 1 (SULF1) with a CT radiomic model based on pre-treatment CT images, to predict platinum resistance for ovarian cancer (OC) treatment. Methods A cohort of 102 patients with pathologically confirmed OC was retrospectively enrolled into this study from January 2006 to February 2018. All patients had platinum-based chemotherapy after maximal cyto-reductive surgery. This cohort was separated into two groups according to treatment response, i.e., the group with platinum-resistant disease (PR group) and the group with platinum-sensitive disease (PS group). We genotyped 12 SNPs of SULF1 for all OC patients using Mass Array Method. Radiomic features, SNP data and clinicopathological data of the 102 patients were used to build the differentiation models. The study participants were divided into two cohorts: the training cohort (n = 71) and the validation cohort (n = 31). Feature selection and predictive modeling were performed using least absolute shrinkage and selection operator (LASSO), Random Forest Classifier and Support Vector Machine methods. Model performance for predicting platinum resistance was assessed with respect to its calibration, discrimination, and clinical application. Results For prediction of platinum resistance, the approach combining the radiomics, clinicopathological data and SNP data demonstrated higher classification efficiency, with an AUC value of 0.993 (95 % CI: 0.83 to 0.98) in the training cohort and 0.967 (95 % CI: 0.83 to 0.98) in validation cohort, than the performance with only the SNPs of SULF1 model (AUC: training, 0.843 [95 %CI: 0.738-0.948]; validation, 0.815 [0.601-1.000]), or with only the radiomic model (AUC: training, 0.874 [95 %CI: 0.789-0.960]; validation, 0.832 [95 %CI: 0.687-0.976]). This integrated approach also showed good calibration and favorable clinical utility. Conclusions A predictive model combining pretreatment CT radiomics with genomic data such as SNPs of SULF1 could potentially help to predict platinum resistance in ovarian cancer treatment.

The D2 dopamine receptor (Drd2) is implicated in several brain disorders such as schizophrenia, Parkinson’s disease, and drug addiction. Drd2 is also the primary target of both antipsychotics and Parkinson’s disease medications. Although the expression pattern of Drd2 is relatively well known in mouse brain, the temporal and spatial distribution of Drd2 is lesser clear in rat brain due to the lack of Drd2 reporter rat lines. Here, we used CRISPR/Cas9 techniques to generate two knockin rat lines: Drd2::Cre and Rosa26::loxp-stop-loxp-tdTomato. By crossing these two lines, we produced Drd2 reporter rats expressing the fluorescence protein tdTomato under the control of the endogenous Drd2 promoter. Using fluorescence imaging and unbiased stereology, we revealed the cellular expression pattern of Drd2 in adult and postnatal rat forebrain. Strikingly, the Drd2 expression pattern differs between Drd2 reporter rats and Drd2 reporter mice generated by BAC transgene in prefrontal cortex and hippocampus. These results provide fundamental information needed for the study of Drd2 function in rat forebrain. The Drd2::Cre rats generated here may represent a useful tool to study the function of neuronal populations expressing Drd2.

In this study, a series of new flavones (2-phenyl-chromone), 2-naphthyl chromone, 2-anthryl-chromone, or 2-biphenyl-chromone derivatives containing 6 or 7-substituted tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results indicated that the alteration of aromatic ring connecting to chromone scaffold brings about a significant impact on biological activity. Compared with flavones, the inhibitory activity of 2-naphthyl chromone, 2-anthryl-chromone derivatives against AChE significantly decreased, while that of 2-biphenyl chromone derivatives with 7-substituted tertiary amine side chain is better than relative flavones derivatives. For all new synthesized compounds, the position of tertiary amine side chain obviously influenced the activity of inhibiting AChE. The results above provide great worthy information for the further development of new AChE inhibitors. Among the newly synthesized compounds, compound 5a is potent in AChE inhibition (IC50 = 1.29 ± 0.10 μmol/L) with high selectivity for AChE over BChE (selectivity ratio: 27.96). An enzyme kinetic study of compound 5a suggests that it produces a mixed-type inhibitory effect against AChE.

Based on our recent investigations on chalcone derivatives as AChE inhibitors, a series of ferulic acid (FA) tertiary amine derivatives similar to chalcone compounds were designed and synthesized. The results of bioactivity evaluation revealed that most of new synthesized compounds had comparable or more potent AChE inhibitory activity than the control drug Rivastigmine. The alteration of carbon chain linking tertiary amine groups and ferulic acid scaffold markedly influenced the inhibition activity against AChE. Among them the inhibitory activity of compound 6d (IC50: 0.71 ± 0.09 μmol/L) and 6e (IC50: 1.11 ± 0.17 μmol/L) was equal to 15-fold and 9-fold than that of Rivastigmine against AChE (IC50: 10.54 ± 0.86 μmol/L), respectively. Moreover, compound 6d shows the highest selectivity for AChE over butyrylcholinesterase(BuChE) (ratio: 18.3). The kinetic study suggested that compound 6d revealed a mixed-type inhibition against AChE. The result of molecular docking showed that compound 6d combines to AChE with three amino acid sites(Trp84, Tyr334 and Trp279), while combines to BuChE with two amino acid sites (Tyr67 and Gly66) in enzyme domains, respectively. Compound 6d might act as a potential agent for the treatment of Alzheimer's diseases (AD).

Gene-gene (GXG) and gene-environment (GXE) interactions play important roles in pharmacogenetics study. Simultaneously incorporating multiple single nucleotide polymorphisms (SNPs) and clinical factors is needed to explore the association of their interactions with drug response and toxicity phenotypes. We genotyped 504 SNPs in a total of 490 Chinese non-small cell lung cancer (NSCLC) patients, and the correlation of GXG and GXE interactions with platinum-based chemotherapeutic efficacy and safety were analyzed. In this data descriptor, we shared our data set which could help others to reuse them. All kinds of file types needed for GXG and GXE analysis were supplied. The process of genotyping and data analysis was also introduced step by step. Machine-accessible metadata file describing the reported data (ISA-Tab format)

In this study, a series of new fluorine or chlorine-substituted cinnamic acid derivatives that contain tertiary amine side chain were designed, synthesized, and evaluated in acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibition. The results show that almost all the derivatives containing tertiary amine side chain (compounds 4a-9d) exhibit moderate or potent activity in AChE inhibition. By contrast, their parent compounds (compounds 3a-3f) in the absence of tertiary amine moitery exhibit poor inhibitory activity against AChE. For the compounds containing pyrroline or piperidine side chain, the bioactivity in AChE inhibition is much intense than those containing N,N-diethylamino side chain. The chlorine or fluorine substituted position produces a significant effect on the bioactivity and selectivity in AChE inhibition. Most of the compounds that contain para-substituted fluorine or chlorine exhibit potent activity against AChE and poor activity against BChE, while ortho-substituted analogs show the opposite effect. It is worth noticing that the compounds containing N,N-diethylamino side chain are exceptions to this pattern. Among the newly synthesized compounds, compounds 6d are the most potent in AChE inhibition (IC50 = 1.11 ± 0.08 μmol/L) with high selectivity for AChE over BChE (selectivity ratio: 46.58). An enzyme kinetic study of compounds 6d suggests it produces a mixed-type inhibitory effect in AChE.

Radiation therapy is important for the comprehensive treatment of intracranial tumors. However, the molecular mechanisms underlying the pathogenesis of delayed cognitive dysfunction are not well-defined and effective treatments or prevention measures remain insufficient. In the present study, 60 adult male Wistar rats were randomly divided into three groups, which included a control, whole brain radiotherapy (WBRT) (single dose of 30 Gy of WBRT) and nimodipine (single dose of 30 Gy of WBRT followed by nimodipine injection intraperitoneally) groups. The rats were sacrificed 7 days or 3 months following irradiation. At 3 months, the Morris water maze test was used to assess spatial learning and memory function in rats. The results demonstrated that the WBRT group demonstrated a significantly impaired cognitive performance, decreased numbers of hippocampal Cornu Ammonis (CA)1 neurons and upregulated expression of caspase-3 in the dentate gyrus compared with those in the control and nimodipine groups. Reverse transcription-quantitative polymerase chain reaction analysis demonstrated that the WBRT group exhibited increased ratio of B-cell lymphoma 2 (Bcl-2)-associated X protein (Bax)/Bcl-2 compared with that in control and nimodipine groups on day 7 following irradiation. However, the WBRT group exhibited decreased levels of brain-derived neurotrophic factor (BDNF) compared with that in control and nimodipine groups at 3 months following brain irradiation. The levels of growth-associated protein 43 and amyloid precursor protein between the nimodipine group and WBRT group were not statistically significant. The present study demonstrated that neuron apoptosis may lead to delayed cognitive deficits in the hippocampus, in response to radiotherapy. The cognitive impairment may be alleviated in response to a calcium antagonist nimodipine. The molecular mechanisms involved in nimodipine-mediated protection against cognitive decline may involve the regulation of Bax/Bcl-2 and BDNF in the hippocampus.

The copper transportersitalicCTR1/italic,italicCTR2/italic,italicATP7A/italic, anditalicATP7B/italicregulate intracellular concentration of platinum by mediating its uptake and efflux in cells. We sought to explore the effect of genetic polymorphisms initalicCTR1/italic,italicCTR2/italic,italicATP7A/italic, anditalicATP7B/italicon platinum resistance in patients suffering from epithelial ovarian cancer (EOC). A total of 152 Chinese EOC patients were enrolled in this study, all of whom underwent adjuvant chemotherapy using platinum and taxane after maximal debulking surgery. In total, 11 single-nucleotide polymorphisms (SNPs) initalicCTR1, CTR2, ATP7A/italic, anditalicATP7B/italicwere genotyped in these patients. TheitalicCTR1/italicrs10981694 polymorphism was observed to be associated with carboplatin resistance, while patients with the rs10981694 G allele showed a significantly higher rate of carboplatin resistance (OR = 4.00, 95% CI 1.309 - 12.23, p 0.01). In addition, we found thatitalicATP7A/italicrs2227291 was associated with cisplatin resistance and that carriers of the C allele were more sensitive to cisplatin (OR = 0.40, 95% CI: 0.17 - 0.94, p = 0.03). Our findings suggest that theitalicCTR1/italicanditalicATP7A/italicgenetic polymorphisms could affect platinum resistance. TheitalicCTR1/italicanditalicATP7A/italicgenes might be considered a predictive marker for carboplatin and cisplatin resistance, respectively. .

Astrocytes play critical roles in neural circuit formation and function. Recent studies have revealed several secreted and contact-mediated signals from astrocytes which are essential for neurite outgrowth and synapse formation. However, the mechanisms underlying the regulation of dendritic branching by astrocytes remain elusive. Phospholipase D1 (PLD1), which catalyzes the hydrolysis of phosphatidylcholine (PC) to generate phosphatidic acid (PA) and choline, has been implicated in the regulation of neurite outgrowth. Here we showed that knockdown of PLD1 selectively in astrocytes reduced dendritic branching of neurons in neuron-glia mixed culture. Further studies from sandwich-like cocultures and astrocyte conditioned medium suggested that astrocyte PLD1 regulated dendritic branching through secreted signals. We later demonstrated that PA was the key mediator for astrocyte PLD1 to regulate dendritic branching. Moreover, PA itself was sufficient to promote dendritic branching of neurons. Lastly, we showed that PA could activate protein kinase A (PKA) in neurons and promote dendritic branching through PKA signaling. Taken together, our results demonstrate that astrocyte PLD1 and its lipid product PA are essential regulators of dendritic branching in neurons. These results may provide new insight into mechanisms underlying how astrocytes regulate dendrite growth of neurons.

Hypermethylation of specific gene promoters is an important mechanism of carcinogenesis. A high frequency of promoter methylation of PAX1 and ZNF582 genes has been detected in cervical cancer. In the present study, we investigated the methylation status of PAX1 and ZNF582 genes in esophageal squamous cell carcinoma (ESCC) tissues. Tumor and paracancerous tissues were obtained from 14 ESCC patients. Genomic DNA was extracted from both tumor and paracancerous tissues, and the concentration of DNA were determined. DNA methylation analysis of PAX1 and ZNF582 genes was carried out using quantitative methylation-specific PCR. To assess the diagnostic performance of the two methylated genes for cancer detection, receiver operating characteristic (ROC) curves were generated. Sensitivities and specificities were tested at cut-offs obtained from the ROC curves. The methylation levels of both PAX1 and ZNF582 genes were significantly higher in tumor tissues compared to non-tumor paracancerous tissues. The methylation rates of PAX1 and ZNF582 in ESCC tumor and paracancerous tissues were 100% and 21.4% (p = 0.006), 85.7% and 0% (p < 0.001), respectively. The sensitivities and specificities of PAX1 and ZNF582 methylation for the detection of cancer were 100% and 85.7%, and 78.6% and 100%, respectively. The DNA methylation levels and frequencies of PAX1 and ZNF582 genes were markedly higher in ESCC tumor tissues compared to those in paracancerous tissues. Moreover, the conclusions were verified by using The Cancer Genome Atlas (TCGA) datasets. DNA methylation status of these two genes showed a relatively good sensitivity and specificity for the detection of ESCC tumors. This data suggests that DNA methylation testing holds a great promise for ESCC screening and warrants further prospective population-based studies.