Decreased CNNM2 expression in prefrontal cortex affects sensorimotor gating function, cognition, dendritic spine morphogenesis and risk of schizophrenia.

Genome-wide association studies (GWASs) have reported multiple single nucleotide polymorphisms (SNPs) associated with schizophrenia, yet the underlying molecular mechanisms are largely unknown. In this study, we aimed to identify schizophrenia relevant genes showing alterations in mRNA and protein expression associated with risk SNPs at the 10q24.32-33 GWAS locus. We carried out the quantitative trait loci (QTL) and summary data-based Mendelian randomization (SMR) analyses, using the PsychENCODE dorsolateral prefrontal cortex (DLPFC) expression QTL (eQTL) database, as well as the ROSMAP and Banner DLPFC protein QTL (pQTL) datasets. The gene CNNM2 (encoding a magnesium transporter) at 10q24.32-33 was identified to be a robust schizophrenia risk gene, and was highly expressed in human neurons according to single cell RNA-seq (scRNA-seq) data. We further revealed that reduced Cnnm2 in the mPFC of mice led to impaired cognition and compromised sensorimotor gating function, and decreased Cnnm2 in primary cortical neurons altered dendritic spine morphogenesis, confirming the link between CNNM2 and endophenotypes of schizophrenia. Proteomics analyses showed that reduced Cnnm2 level changed expression of proteins associated with neuronal structure and function. Together, these results identify a robust gene in the pathogenesis of schizophrenia.

The prognostic value of baseline hematological parameters of peripheral blood in metastatic gastric cancer treated with apatinib.

Background: There is strong evidence that apatinib is effective in the treatment of third- or later-line advanced metastatic gastric cancer (mGC). Hematology prediction index is a convenient and cheap method to predict the prognosis of disease. However, the prognosis of baseline hematological parameters of peripheral blood, such as neutrophil-to-lymphocyte ratio (NLR), carbohydrate antigen 125 (CA125) and albumin (ALB) on mGC treated with apatinib have not been identified. Methods: We retrospectively analyzed mGC received apatinib between 1 January 2014 and 30 June 2021. Survival analyses were performed using the Kaplan-Meier method and Cox-proportional hazards model. Results: A total of 117 patients were included in this study. The cutoff value of NLR, CA125 and ALB was 2.25, 19.24 U/ml and 37.60 g/L, respectively. The disease control rates (DCR) in the high and low NLR groups were 52.94% and 73.47% (P=0.024); 48.28% and 74.58% (P=0.003) in high and low CA125 groups; 72.97% and 41.86% (P=0.001) in high and low ALB groups. By survival analysis, increasing NLR (P=0.003), CA125 (P<0.001) and decreasing ALB (P<0.001) predicted a shorter PFS after apatinib. NLR (P=0.015), CA125 (P=0.004) and ALB (P=0.005) were significantly predictors for PFS in mGC treated with aptinib. Conclusion: Increasing NLR, CA125 and decreasing ALB were associated with poorer clinical efficiency and prognosis after apatinib treatment.

Identification of a functional 339 bp Alu insertion polymorphism in the schizophrenia-associated locus at 10q24.32.

Genome-wide association studies (GWAS) have identified multiple single nucleotide polymorphisms (SNPs) or small indels robustly associated with schizophrenia; however, the functional risk variations remain largely unknown. We investigated the 10q24.32 locus and discovered a 339 bp Alu insertion polymorphism (rs71389983) in complete linkage disequilibrium (LD) with the schizophrenia GWAS risk variant rs7914558. The presence of the Alu insertion at rs71389983 strongly repressed transcriptional activities in in vitro luciferase assays. This polymorphism may be a target for future mechanistic research. Our study also underlines the importance and necessity of considering previously underestimated Alu polymorphisms in future genetic studies of schizophrenia.

Extraction of flavonoids from Chrysanthemum morifolium and antitumor activity in vitro.

The aim of the present study was to optimize flavonoid extraction from Chrysanthemum morifolium and to study the antitumor effects of flavonoids on human gastric cancer MKN45 cells in vitro. A single factor experiment was designed and the extraction process was optimized using an orthogonal test. MKN45 cells were treated with different concentrations of flavonoid from Chrysanthemum morifolium for 24 and 48 h and the inhibitory effect on the MKN45 cells was evaluated using an MTT assay. Following staining with Annexin V-fluorescein isothiocyanate/propidium iodide, flow cytometry was performed. The optimized flavonoid extraction conditions were as follows: Duration of ultrasonic treatment: 35 min; ethanol concentration: 75%; extraction temperature: 80°Cand liquid-to-solid ratio 25: 1. Under the above conditions, the extraction rate of flavonoids was 5.24%. When compared with a blank control group, flavonoids extracted from Chrysanthemum morifolium inhibited the proliferation of MKN45 cells in a dose- and time-dependent manner. Furthermore, in cell groups treated with low, moderate and high concentrations of flavonoid, it was observed that the proportion of apoptotic cells increased in a dose-dependent manner. The extraction process optimized by the orthogonal test achieved a high yield and satisfactory extraction efficiency. Additionally, the experiment demonstrated that flavonoids from Chrysanthemum morifolium inhibited the growth of MKN45 cells and induced their apoptosis. Thus, flavonoids from Chrysanthemum morifolium exerted antitumor effects on MKN45 cells, which may be exploited as a potential antitumor therapeutic for gastric cancer.

Expression of programmed death ligand-1 predicts poor outcome in nasopharyngeal carcinoma.

Programmed death ligand-1 (PD-L1) is a potentially important tumor immunotherapy target. However, whether PD-L1 expression is associated with survival in nasopharyngeal carcinoma (NPC) remains controversial. The aim of the present study was to investigate the association between PD-L1 expression and prognosis in NPC. The expression of PD-L1 was assessed in tumor specimens from 120 patients with NPC using immunohistochemistry. Staining was evaluated using the H-score method. The associations between PD-L1 expression and clinical characteristics and prognosis were analyzed. Overall, 78% of the patients had stage I-III and 22% had stage IV disease. The estimated 5-year overall survival (OS) and disease-free survival (DFS) rates for the entire cohort were 87.5 and 70.1%, respectively. PD-L1 expression was detected in 85 (71%) patients and was localized to the tumor cells. High tumor expression of PD-L1 (median H-score ≥5) was associated with significantly poorer OS (P=0.023) and DFS (P=0.002). Univariate analysis indicated that low PD-L1 expression was associated with better DFS compared with high PD-L1 expression (HR=0.163, 95% CI: 0.044-0.600, P=0.006 for DFS). Multivariate analysis revealed that T stage (HR=8.190, 95% CI: 1.355-18.152; P=0.023) and PD-L1 expression level (HR=0.124, 95% CI: 0.031-0.509; P=0.001) served as independent prognostic factors for DFS. In conclusion, tumor PD-L1 expression was found to be a significant prognostic factor in NPC, and high PD-L1 expression may be of prognostic value for recurrence and metastasis following conventional treatments.

Serum TGF-ß1 as a Biomarker for Type 2 Diabetic Nephropathy: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Abnormal expression of serum TGF-ß1 was found in patients with diabetic nephropathy. However, the association of TGF-ß1 with the risk of diabetic nephropathy remains unknown. The present study was undertaken to investigate whether such an association exists. METHODS: We searched the Chinese VIP, Wangfang, China National Knowledge Infrastructure, PubMed, Embase, and Google Scholar databases for relevant studies and extracted all eligible data. Stata12 software was used for statistical analysis. RESULTS: Nine reports met our criteria and were used for data extraction. There were 264 patients and 227 healthy controls from qualified reports in this meta-analysis. The results suggested that serum TGF-ß1 levels were significantly up-regulated in patients with diabetic nephropathy; the instrumental variable was 3.94 (95% confidence interval 3.20-4.68, p<0.01). CONCLUSIONS: Meta-analysis suggested that elevated serum TGF-ß level in patients with diabetes is associated with a high risk of nephropathy. Further studies are required to validate these observations.

Proanthocyanidin from grape seed extract inhibits airway inflammation and remodeling in a murine model of chronic asthma.

Asthma is characterized by airway inflammation and airway remodeling. Our previous study revealed that grape seed proanthocyanidin extract (GSPE) could inhibit asthmatic airway inflammation and airway hyper-responsiveness by down-regulation of inducible nitric oxide synthase in a murine model of acute asthma. The present study aimed to evaluate GSPE's effects on airway inflammation and airway remodeling in a chronic asthmatic model. BALB/c mice were sensitized with ovalbumin (OVA) and then were challenged three times a week for 8 weeks. Airway responsiveness was measured at 24 h after the last OVA challenge. HE staining, PAS staining, and Masson staining were used to observe any airway inflammation in the lung tissue, airway mucus secretion, and subepithelial fibrosis, respectively. The cytokines levels in the lavage fluid (BALF) in addition to the total serum immunoglobulin E (IgE) levels were detected by ELISA. Furthermore, lung collagen contents, α-smooth muscle actin (α-SMA), and transforming growth factor-ß1 (TGF-ß1) expression in the airway were assessed by hydroxyproline assay, immunohistochemistry, and Western blot analysis, respectively. GSPE administration significantly suppressed airway resistance as well as reduced the amount of inflammatory cells, especially the eosinophil count, in BALF. Additionally, the GSPE treatment markedly decreased interleukin (IL)-4, IL-13, and vascular endothelial growth factor (VEGF) levels in BALF in addition to the total serum IgE levels. A histological examination demonstrated that GSPE significantly ameliorated allergen-induced lung eosinophilic inflammation and decreased PAS-positive epithelial cells in the airway. The elevated hydroxyproline contents, lung α-SMA contents, and TGF-ß1 protein expression that were observed in the OVA mice were also inhibited by GSPE. In conclusion, GSPE could inhibit airway inflammation and airway remodeling in a murine model of chronic asthma, thus providing a potential treatment for asthma.

Study on the relationship between Chinese medicine constitutive susceptibility and diversity of syndrome in diabetic nephropathy.

OBJECTIVE: To explore the relationship between Chinese medicine (CM) constitutive susceptibility and syndrome diversity in diabetic nephropathy (DN). METHODS: Epidemiologic investigation on constitution adopting the "Constitution in Chinese Medicine Questionnaire" (CCMQ), and survey on syndrome type by CM syndrome scale (preliminary) were carried out in 180 DN patients. Cluster analysis on symptom items was used to determine the syndrome type, and canonical correlation analysis was used to analyze the relationship between patients' constitution and syndrome. RESULTS: Baseline levels in all enrolled patients were not different statistically. Cluster analysis showed 8 syndromes existed in DN patients, namely: I, qi-yin deficiency with qi-stagnancy type; II, yin-yang deficiency with heat-water-blood stasis type; III, qi-yin deficiency with dampness-heat type; IV, yin-yang deficiency with blood-stasis and heat type; V, qi-yin deficiency with stagnant heat type; VI, yin-yang deficiency with inner dampness-heat stagnancy type; VII, yin deficiency with heat stagnancy type; and VIII, Kidney (Shen)-Spleen (Pi) deficiency with stagnant heat type. Correlation analysis on the 8 syndromes and the 9 constitutions showed statistical significant correlations between syndrome III and dampness-heat constitution (P=0.0001); syndrome IV and blood-stasis constitution (P=0.0001); and syndrome VII and yin-deficiency constitution (P=0.0180). CONCLUSION: Certain relationship revealed between CM constitutions and syndrome types; constitution decides the disease genesis, its syndrome type and prognosis, as well as the change of syndromes.

Association of Chinese medicine constitution susceptibility to diabetic nephropathy and transforming growth factor-ß1 (T869C) gene polymorphism.

OBJECTIVE: To explore the association of Chinese medicine constitution susceptibility to diabetic nephropathy (DN) and transforming growth factor (TGF)-ß1 (T869C) gene polymorphism. METHODS: TGF-ß1 gene polymorphism detected with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was screened for 180 DN cases and 180 type 2 diabetic mellitus (T2DM) cases without combined DN. Patients with DN were surveyed epidemiologically with constitution in the Chinese medicine questionnaire (CCMQ). Binary logistic regression analysis was utilized to study the correlation between nine types of Chinese medicine constitution and TGF-ß1 (T869C) gene polymorphisms. RESULTS: The DN group has a higher frequency of TGF-ß1 (T869C) gene polymorphism than the T2DM group, and CC/CT genotypes than the T2DM group [CC, CT, TT (DN group): 88, 87, 5 (cases) versus (T2DM group) 71, 73, 36 (cases), P<0.05]. The phlegm-dampness constitution, damp-heat constitution, and blood stasis constitution have correlations with TGF-ß1 (T869C) gene polymorphism. CONCLUSION: Chinese medicine constitutions were associated with TGF-ß1 (T869C) gene polymorphism, a potential predictor of susceptibility to DN in T2DM patients.

[CT and MRI in diagnosis of avascular necrosis of the vertebral body].

OBJECTIVE: To evaluate the value of CT and MRI in the diagnosis of avascular necrosis of the vertebral body (ANV). METHODS: Twelve ANV patients were retrospectively analysed by their medical history, clinic manifestation, CT and MRI. Twelve AVN patients were treated with percutaneous vertebroplasty (PVP). The pain level of each patient was assessed, both before and after the procedure, using a visual analogue scale (VAS). RESULTS: All the patients had ANV in the thoracolumbar spine. The intravertebral vaccum phenomenon (VP), with gas or fluid-like collection, was seen on computed tomographic (CT) images and magnetic resonance images (MRI). In the early stages, the VP zone was characterized by fluid-like collection, and was low intensity on T1, high intensity on T2. In the latter stages, the margin of VP zone had sclerotic change on CT scan. VAS score decreased from preoperative (9.08 +/- 0.76) to (2.33 +/- 1.43) at 3 days after PVP. CONCLUSION: ANV must be considered as a possible diagnosis of VP secondary to osteoporotic vertebral fractures. Both CT and MRI could provide reliable diagnostic proof for ANV. PVP is proved to be an effective and safe procedure for the treatment of ANV, and could provid quick pain relief.

Grape seed proanthocyanidin extract attenuates airway inflammation and hyperresponsiveness in a murine model of asthma by downregulating inducible nitric oxide synthase.

Allergic asthma is characterized by hyperresponsiveness and inflammation of the airway with increased expression of inducible nitric oxide synthase (iNOS) and overproduction of nitric oxide (NO). Grape seed proanthocyanidin extract (GSPE) has been proved to have antioxidant, antitumor, anti-inflammatory, and other pharmacological effects. The purpose of this study was to examine the role of GSPE on airway inflammation and hyperresponsiveness in a mouse model of allergic asthma. BALB/c mice, sensitized and challenged with ovalbumin (OVA), were intraperitoneally injected with GSPE. Administration of GSPE remarkably suppressed airway resistance and reduced the total inflammatory cell and eosinophil counts in BALF. Treatment with GSPE significantly enhanced the interferon (IFN)- γ level and decreased interleukin (IL)-4 and IL-13 levels in BALF and total IgE levels in serum. GSPE also attenuated allergen-induced lung eosinophilic inflammation and mucus-producing goblet cells in the airway. The elevated iNOS expression observed in the OVA mice was significantly inhibited by GSPE. In conclusion, GSPE decreases the progression of airway inflammation and hyperresponsiveness by downregulating the iNOS expression, promising to have a potential in the treatment of allergic asthma.

The novel compound heterozygous mutations, V434del and W666X, in WFS1 gene causing the Wolfram syndrome in a Chinese family.

Wolfram syndrome (WFS), also known as DIDMOAD, is an infrequent cause of diabetes mellitus. WFS is an autosomal recessive neurodegenerative disease characterized by various clinical manifestations such as diabetes mellitus, optic atrophy, diabetes insipidus, deafness, neurological symptoms, renal tract abnormalities, psychiatric disorders, and gonadal disorders. The majority of patients with WFS carry the loss of function mutations in the WFS1 gene. The exons 2-8 of the WFS1 gene from one Chinese WFS patient were amplified by the polymerase chain reaction (PCR), subcloning techniques and direct sequence determination was applied to the amplified fragments. The compound heterozygous mutation of a 3-bp (GAC) deletion (V434del) and another compound heterozygous mutation (G-->N)(W666X) in exon 8 of WFS1 gene was identified in the patient. Other seventeen members of her family were investigated. Four cases with heterozygotes had been found through screening for the mutation V434del and five cases for the mutation W666X in the whole family. This is the first report of WFS with the mutation V434del and W666X in the WFS1 gene.