Quantitative DNA Methylation Analysis of DLGAP2 Gene Using Pyrosequencing in Schizophrenia With Tardive Dyskinesia: A Linear Mixed Model Approach

Tardive dyskinesia (TD) is a side effect of antipsychotic medications used to treat schizophrenia (SCZ) and other mental health disorders. No study has previously used pyrosequencing to quantify DNA methylation levels of the DLGAP2 gene; while the quantitative methylation levels among CpG sites within a gene may be correlated. To deal with the correlated measures among three CpG sites within the DLGAP2 gene, this study analyzed DNA methylation levels of the DLGAP2 gene using a linear mixed model (LMM) in a Chinese sample consisting of 35 SCZ patients with TD, 35 SCZ without TD (NTD) and 34 healthy controls (HCs) collected in Beijing, China. The initial analysis using the non-parametric Kruskal-Wallis test revealed that three groups (TD, NTD and HC) had significant differences in DNA methylation level for CpG site 2 (p = 0.0119). Furthermore, the average methylation levels among the three CpG sites showed strong correlations (all p values \u3c 0.0001). In addition, using the LMM, three groups had significant differences in methylation level (p = 0.0027); while TD, NTD and TD + NTD groups showed higher average methylation levels than the HC group (p = 0.0024, 0.0151, and 0.0007, respectively). In conclusion, the LMM can accommodate a covariance structure. The findings of this study provide first evidence of DNA methylation levels in DLGAP2 associated with SCZ with TD in Chinese population. However, TD just showed borderline significant differences to NTD in this study

Anti-Inflammatory ent-Kaurane Diterpenoids from Isodon serra

Ten new ent-kaurane diterpenoids, including two pairs of epimers 1/2 and 4/5 and a 6,7-seco-ent-kauranoid 10, were obtained from the aerial parts of Isodon serra. The structures of the new compounds were confirmed by extensive spectroscopic methods and electronic circular dichroism (ECD) data analysis. An anti-inflammatory assay was applied to evaluate their nitric oxide (NO) inhibitory activities by using LPS-stimulated BV-2 cells. Compounds 1 and 9 exhibited notable NO production inhibition with IC50 values of 15.6 and 7.3 μM, respectively. Moreover, the interactions of some bioactive diterpenoids with inducible nitric oxide synthase (iNOS) were explored by employing molecular docking studies.https://pubs.acs.org/journal/jnprdf2021-09-29hj2021Plant Production and Soil Scienc

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Quantitative DNA Methylation Analysis of DLGAP2 Gene using Pyrosequencing in Schizophrenia with Tardive Dyskinesia: A Linear Mixed Model Approach

Abstract Tardive dyskinesia (TD) is a side effect of antipsychotic medications used to treat schizophrenia (SCZ) and other mental health disorders. No study has previously used pyrosequencing to quantify DNA methylation levels of the DLGAP2 gene; while the quantitative methylation levels among CpG sites within a gene may be correlated. To deal with the correlated measures among three CpG sites within the DLGAP2 gene, this study analyzed DNA methylation levels of the DLGAP2 gene using a linear mixed model (LMM) in a Chinese sample consisting of 35 SCZ patients with TD, 35 SCZ without TD (NTD) and 34 healthy controls (HCs) collected in Beijing, China. The initial analysis using the non-parametric Kruskal-Wallis test revealed that three groups (TD, NTD and HC) had significant differences in DNA methylation level for CpG site 2 (p = 0.0119). Furthermore, the average methylation levels among the three CpG sites showed strong correlations (all p values < 0.0001). In addition, using the LMM, three groups had significant differences in methylation level (p = 0.0027); while TD, NTD and TD + NTD groups showed higher average methylation levels than the HC group (p = 0.0024, 0.0151, and 0.0007, respectively). In conclusion, the LMM can accommodate a covariance structure. The findings of this study provide first evidence of DNA methylation levels in DLGAP2 associated with SCZ with TD in Chinese population. However, TD just showed borderline significant differences to NTD in this study

High-Dose Betahistine Improves Cognitive Function in Patients With Schizophrenia: A Randomized Double-Blind Placebo-Controlled Trial

Background: There is currently no effective treatment for cognitive impairment associated with schizophrenia (CIAS). Recent studies have shown that increased histamine levels in the brain may help to improve CIAS symptoms. Betahistine is an H1-receptor agonist and H3-receptor antagonist. This study evaluated the effect of high-dose betahistine on cognitive function as well as its safety in Chinese Han patients with schizophrenia. Methods: This randomized double-blind, placebo-controlled trial enrolled 89 patients with schizophrenia who were randomly administered betahistine (72 mg/d) or placebo for 12 weeks. At baseline and at 4, 8, and 12 weeks after commencing the intervention, we measured changes in cognitive function and clinical symptoms using the MATRICS Consensus Cognitive Battery (MCCB) and Positive and Negative Syndrome Scale (PANSS), respectively. Furthermore, we used the Treatment Emergent Symptom Scale (TESS) to assess the adverse effects of the patients\u27 medications. Results: Compared to the placebo group, the betahistine group showed significant improvements in the MCCB composite score after 12 weeks of treatment (p = 0.003) as well as improvements in MCCB verbal learning (p = 0.02) and visual learning (p = 0.001) domain scores. However, there were no significant improvements in the PANSS total scores or subscores (p \u3e 0.05). Generally, high-dose betahistine treatment was considered safe in patients with schizophrenia. Conclusions: Additional use of high-dose betahistine can effectively improve cognitive function but not psychiatric symptoms in patients with schizophrenia. Betahistine (72 mg/d) is well tolerated by Chinese Han patients with schizophrenia. Trial Registration: chictr.org.cn, identifier: ChiCTR1900021078. http://www.chictr.org.cn/edit.aspx?pid=35484&htm=

Caseahomopene A, a ring-expanded homotriterpenoid from Casearia kurzii showing anti-inflammatory activities in vitro and in vivo

Caseahomopene A (1), a rare natural product with a ring-expanded homotriterpenoid skeleton, was isolated from the leaves of Casearia kurzii. The structure including the absolute configuration was determined by spectroscopic data and X-ray crystallography analysis. Compound 1 showed anti-inflammatory effects in vitro and in vivo using LPS-stimulated cell and zebrafish model. As a potential anti-inflammatory agent, the anti-inflammatory mechanism of 1 was also investigated.The National Key Research and Development Program of China, the National Natural Science Foundation of China, the Natural Science Foundation of Tianjin, China, Hundred Young Academic Leaders Program of Nankai University, and State Key Laboratory of Bioactive Substance and Function of Natural Medicines (Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College).http://www.elsevier.com/ locate/bmcl2021-05-01hj2021Plant Production and Soil Scienc

Obesity, altered oxidative stress, and clinical correlates in chronic schizophrenia patients

Abstract Antipsychotic pharmacotherapy is strongly obesogenic and is associated with increased oxidative stress in patients with schizophrenia. However, whether these changes reflect psychopathology, antipsychotic efficacy, or some other factor is not known. Our study aims to investigate the degree of oxidative stress in different BMI categories and to identify clinical symptomatology that may be paired with increased oxidative stress in a schizophrenia population. To this end, we performed a cross-sectional study and recruited 89 long-term inpatients with schizophrenia and collected the following variables: plasma malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), routine biochemical analysis, and psychopathology through the Positive and Negative Syndrome Scale (PANSS). The results indicate that the levels of the lipid peroxidation product, MDA, were significantly higher in the high BMI group than the low (normal) BMI group. As expected, high BMI was associated with an atherogenic lipid profile; however, it was also associated with fewer psychopathological symptoms. Multiple regression analysis found that MDA levels, the PANSS general psychopathology subscore, and triglyceride levels (all p < 0.05) were independent contributors to the BMI in patients. These results suggested that oxidative stress may play an important role in antipsychotic-induced weight gain. Further investigations using the longitudinal design in first-episode schizophrenia patients are needed to explore the beneficial effect of antioxidants on the abnormal lipid metabolism mediated by antipsychotic treatment

An Alternative Method of Endoscopic Intrasphenoidal Vidian Neurectomy

Objective To develop an easy surgical approach to facilitate clinical management. Study Design A novel transnasal endoscopic 3-step surgical method for vidian neurectomy was designed and tried in 91 cases with a mild-to-severe degree of allergic and nonallergic rhinitis refractory to routine medical therapy. Setting Endoscopic vidian neurectomy requires accurate localization of the vidian canal. However, it is not easy to localize during surgery because of its deep location and the complex anatomy of the pterygopalatine fossa. Subjects and Methods This technique consists of 3 steps, including transnasal endoscopic perforation of the anterior wall of the sphenoidal sinus as the first step and removal of the anterior wall until the exposure of the vidian canal in the junction between the anterior wall and the floor of the sphenoid sinus as the second step. The last step is the accurate resection and cauterization of the vidian nerve. In some cases in which the sphenoid sinus developed well with a big lateral space, an extended procedure of posterior ethmoidectomy was included to allow good exposure of the vidian canal. Results Using this technique, successful endoscopic vidian neurectomy in this series of patients was confirmed by both histology and Schirmer test, showing its distinct advantages of easy localization of the vidian canal and less risk of injury to the nerve and vessel bundles within the pterygopalatine fossa. Conclusion Taken together, this novel 3-step procedure of endoscopic vidian neurectomy plus an extended procedure guarantees good exposure of the vidian canal and therefore accurate vidian neurectomy