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Hepatitis B virus (HBV) infection is a major health burden worldwide, and currently there is no cure. The persistence of HBV covalently closed circular DNA (cccDNA) is the major obstacle for antiviral trement. HBV core protein (HBc) has emerged as a promising antiviral target, as it plays important roles in critical steps of the viral life cycle. However, whether HBc could regulate HBV cccDNA transcription remains under debate. In this study, different approaches were used to address this question. In synthesized HBV cccDNA and HBVcircle transfection assays, lack of HBc showed no effect on transcription of HBV RNA as well as HBV surface antigen (HBsAg) production in a hepatoma cell line and primary human hepatocytes. Reconstitution of HBc did not alter the expression of cccDNA-derived HBV markers. Similar results were obtained from an in vivo mouse model harboring cccDNA. Chromatin immunoprecipitation (ChIP) or ChIP sequencing assays revealed transcription regulation of HBc-deficient cccDNA chromatin similar to that of wild-type cccDNA. Furthermore, treatment with capsid assembly modulators (CAMs) dramatically reduced extracellular HBV DNA but could not alter viral RNA and HBsAg. Our results demonstrate that HBc neither affects histone modifications and transcription factor binding of cccDNA nor directly influences cccDNA transcription. Although CAMs could reduce HBc binding to cccDNA, they do not suppress cccDNA transcriptional activity. Thus, therapeutics targeting capsid or HBc should not be expected to sufficiently reduce cccDNA transcription. IMPORTANCE Hepatitis B virus (HBV) core protein (HBc) has emerged as a promising antiviral target. However, whether HBc can regulate HBV covalently closed circular DNA (cccDNA) transcription remains elusive. This study illustrated that HBc has no effect on epigenetic regulation of cccDNA, and it does not participate in cccDNA transcription. Given that HBc is dispensable for cccDNA transcription, novel cccDNA-targeting therapeutics are needed for an HBV cure.

Klotho is a life extension factor that has the ability to regulate the function of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), whose dysfunction in the nucleus accumbens (NAc) underlies critical aspects of the pathophysiology of major depression. Here, we study the functional relevance of klotho in the pathogenesis of depression. A chronic social defeat stress paradigm, in which mice are categorized as either susceptible or unsusceptible based on their performance in a social interaction test, was used in this study. We found that the expression of klotho was largely decreased in the NAc of susceptible mice compared to control or unsusceptible mice. Genetic knockdown of klotho in the NAc induced behavioral alterations relevant to depression in naive mice, while overexpression of klotho produced an antidepressive effect in normal mice and ameliorated the behavioral responses to stress in susceptible mice. Molecularly, knockdown of klotho in the NAc resulted in selective decreases in total and synaptic GluN2B expression that were identical to those in susceptible mice. Elevation of klotho in the NAc reversed the reductions in GluN2B expressions and altered synaptic transmission and spine density in the NAc of susceptible mice. Furthermore, blockade of GluN2B with a specific antagonist abolished the beneficial effects of klotho elevation in susceptible mice. Collectively, we demonstrated that klotho in the NAc modulates behavioral responses to stress by regulating the function of GluN2B-containing NMDARs. These results reveal a novel role for klotho in the pathogenesis of depression, providing new insights into the molecular basis of major depression.

We aimed to investigate the prognostic role of genetic variants of VEGF in advanced NSCLC patients treated with platinum-based chemotherapy. A total of 196 patients with advanced NSCLC treated with first-line platinum-based chemotherapy were enrolled. We evaluated the relationship between VEGF polymorphisms and efficacy outcomes and chemotherapy toxicity. We found that rs699947, rs833061 and rs1005230 were in full linkage disequilibrium. Patients with CC genotype of rs833061 had a significant longer PFS than TT genotype (CC vs TT, HR = 1.67, 95%CI = 1.01-2.76, P = 0.043). Patients harbouring CC genotype had longer PFS compared with CT genotype (P0.001). Moreover, CC genotypes conferred a significantly increased PFS compared to CT and TT genotype in dominant model (CC vs CT + TT, HR = 1.95, 95%CI = 1.23-3.10, P = 0.005). Patients carrying TT genotype of rs833061 had improved both ORR (HR = 0.54, 95%CI = 0.30-0.98, P = 0.041) and DCR (HR = 0.37, 95%CI = 0.20-0.66, P = 0.001) than non-TT patients. Furthermore, no association was found between any rs833061 alleles and adverse events (P = 0.425), but patients carrying rs1570360 AA genotype were more likely to experience grade 3-4 toxicities (P = 0.004) (GG vs AA, HR = 3.16, 95%CI = 1.26-7.94, P = 0.015). In conclusion, the variant homozygote CC of rs833061 exhibited a better prognosis based on association analysis. The present study provides reference for the future study of platinum-based chemotherapy response and toxicity.

Context Diabetes has a bidirectional association with nonalcoholic fatty liver disease (NAFLD) and increases the risk of cirrhosis and related complications. Objective To investigate the association between visit-to-visit fasting glucose (FG) variability in early adulthood and NAFLD in middle age. Methods This prospective cohort study included 2467 Black and White adults aged 18 to 30 years at baseline (1985-1986) who were followed over 25 years in the Coronary Artery Risk Development in Young Adults Study. FG variability measures included coefficient of variation about the mean FG (CV-FG), the SD of FG (SD-FG), and the average real variability of FG (ARV-FG) across 25 years (year 0, 7, 10, 15, 20, and 25 examinations). NAFLD was defined as liver attenuation ≤ 40 Hounsfield units on computed tomography scan at year 25 examination after excluding other causes of hepatic steatosis. Results Of the 2467 participants, 241 (9.8%) had NAFLD at year 25. In multivariate analysis, the odds ratio for NAFLD was 2.80 (95% CI, 1.69-4.64; P trend Conclusion Greater visit-to-visit FG variability in early adulthood was associated with higher risk of NAFLD in middle age independent of mean FG level. FG variability may help identify individuals at high risk for NAFLD.

We aim to establish a predictive model for the evaluation of fecundity based on infertility-related factors.A total of 410 expectant couples who visited the First Affiliated Hospital of Xinjiang Medical University on January 1, 2017 and June 10, 2019 were included in this study. The 1-year follow-up was carried out to investigate the pregnancy of the female. They were divided into model group and test group, respectively. The basic information, life behavior and clinical indices were screened using the Logistics regression analysis and LASSO regression analysis. In addition, the multivariate logistic regression was used to establish the model for the prediction of fecundity risk.The risk factors for the predictive model included female age and occupational pressure, gynecological disease, anti-Müllerian hormone (AMH), follicle-stimulating hormone (FSH), fasting plasma glucose (FPG), depression, as well as male smoking. The area under the curve (AUC) for the model A and model B was 0.954 (0.931 ~ 0.978) and 0.955 (0.931 ~ 0.979), respectively. The AUC in the test group was 0.917 (0.869 ~ 0.965) and 0.921 (0.873 ~ 0.968). There were no statistical differences in the fitting value and measured values in the model group.We established a predictive model for the evaluation of fecundity, which showed a satisfactory accuracy and discriminatory power.

Introduction Patients whose solid tumors (ST) show leptomeningeal metastasis (LM) have very poor prognosis and short overall survival. The aim of this study was to evaluate the efficacy of first-line programed death-1(PD-1) monoclonal antibody (mAb) treatment in these patients. Methods We retrospectively evaluated patients diagnosed with LM from ST who were treated with first-line PD-1 mAb at our hospital between April 1 and November 30, 2019. We analyzed their clinicopathological characteristics and response to the treatment. Results We collected and analyzed data from 6 patients with different primary ST. 5 patients received PD-1 mAb combined with chemotherapy and/or anti-angiogenic drugs, while one received only PD-1 mAb. The median (range) number of treatment cycles was 5.5 (1-21). PD-1 mAb treatment did not cause neurotoxicity. The time period of first assessment varied from 21 to 65 days after treatment. Among 5 patients who got obvious symptoms relief, 4 patients persisted for > 3 months and even showed a reduction in the number of tumor cells in cerebrosprinal fluid. Ventriculoperitoneal (VP) shunt was used to treat hydrocephalus observed beneficial in 3 patients: 2 before and 1 after PD-1 mAb treatment. The median (range) follow-up time was 214 (57-460) days. 4 patients died. The overall survival ranged from 57 days to at least 460 days. 1 of the two alive patients continued to show no worsening of symptoms after 457 days. Conclusions Patients with LM from ST can benefit from first-line PD-1 mAb combined treatment without additional neurotoxicity. Further research is required to validate the safety and efficacy.

This study sought to investigate the association between blood pressure (BP) trajectories from early to middle adulthood and echocardiographic indices of structure and function in middle age.This prospective cohort study included 4717 black and white adults aged 18-30 years at baseline (1985-86) who were followed over 30 years in the Coronary Artery Risk Development in Young Adults (CARDIA) study. Trajectories of systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) from the Year 0 examination to Year 30 examination were identified using latent mixture modelling. Echocardiographic indices of myocardial structure, systolic function, and diastolic function were assessed at the Year 30 examination. Five distinct SBP trajectory groups were identified: low-stable [1110 participants (23.5%)], moderate-stable [2188 (46.4%)], high-stable [850 (18.0%)], moderate-increasing [416 (8.8%)], and high-increasing [153 (3.2%)]. After adjustment for clinical variables, a significant decreasing trend was observed from the high-increasing and moderate-increasing groups through to the low-stable group for left ventricular (LV) mass index [mean (SE): high-increasing, 112.3 (3.4); moderate-increasing, 99.3 (2.6); high-stable, 88.9 (2.5); moderate-stable, 86.1 (2.3); low-stable, 82.1 (2.4), P trend 0.01], as well as LV end-diastolic dimension, left atrial volume index, and E/e', while an increasing trend was apparent for LV longitudinal strain, E/A ratio, and average e' velocities. Results were generally consistent for trajectories of DBP and PP.Higher BP trajectories from early to middle adulthood were associated with worse indices of myocardial modelling and LV systolic and diastolic function at middle age.

Exosomes are critical mediators of intercellular communication. Exosomal circular RNAs (circRNAs) have been reported to play critical roles in the development of chemoresistance in various tumors, including gastric cancer. However, the role of exosomal circ_0063526 in cisplatin (CDDP) resistance of gastric cancer is still unclear. The expression of circ_0063526, microRNA-449a (miR-449a) and serine hydroxymethyltransferase 2 (SHMT2) mRNA was determined by quantitative real-time PCR (qRT-PCR). Cell viability was assessed by the Cell Counting Kit-8 assay. Cell migration and invasion were evaluated by the transwell assay and wound healing assay. Western blot assay was used to measure the protein expression of light Chain 3 (LC3) I/II, p62 and SHMT2. Exosomes were detected using transmission electron microscopy. The size distribution of exosomes was analyzed by nanoparticle tracking analysis. The interaction between miR-449a and circ_0063526 or SHMT2 was confirmed by a dual-luciferase reporter and RNA pull-down assays. Circ_0063526 expression was increased in gastric cancer tissues and cells and CDDP-resistant cells. Extracellular circ_0063526 could be packaged into exosomes and transmitted to sensitive cells, thus disseminating CDDP resistance. Knockdown of exosomal circ_0063526 inhibited CDDP resistance via suppressing migration, invasion and autophagy in gastric cancer cells. Moreover, circ_0063526 was identified as a molecular sponge of miR-449a to upregulate SHMT2 expression. Further, exosomal circ_0063526 regulated SHMT2 expression to enhance CDDP resistance of gastric cancer cells. Additionally, high expression of exosomal circ_0063526 in serum was associated with poor response to CDDP treatment in gastric cancer patients. Exosomal circ_0063526 facilitated CDDP resistance in gastric cancer via regulating the miR-449a/SHMT2 axis.

Epilepsy is a chronic brain disease with recurrent seizures. Autophagy plays a crucial role in the progression of epilepsy. This study aimed to explore the function and intrinsic mechanism of the long non-coding RNA (lncRNA) UCA1/miR-132-3p/ATG16L1 axis in epilepsy via regulation of autophagy.The expression of lncRNA UCA1, miR-132-3p and ATG16L1 was measured in serum from epileptic patients by quantitative RT-PCR. A SH-SY5Y cell model was further constructed using retinoic acid to investigate the UCA1/ miR-132-3p/ATG16L1 axis by quantitative RT-PCR, western blotting, fluorescence in situ hybridisation, RNA immunoprecipitation, chromatin immunoprecipitation, and a dual-luciferase reporter gene assay.In the serum of epileptic patients, the level of lncRNA UCA1 and ATG16L1 was reduced and miR-132-3p elevated, compared to controls. Similarly, in the SH-SY5Y cell model, the level of lncRNA UCA1 and ATG16L1 was reduced and miR-132-3p elevated in retinoic acid-treated cells; lncRNA UCA1 was mainly located in the cytoplasm. lncRNA UCA1 overexpression was shown to promote autophagic gene expression, which was reversed by miR-132-3p overexpression. Moreover, autophagic gene expression induced by miR-132-3p knockdown was reversed by ATG16L1 knockdown. Based on precipitation assays, lncRNA UCA1 and miR-132-3p were shown to form a complex with the transcription factor, EZH2, and miR-132-3p was shown to interact with ATG16L1 based on a luciferase assay. Finally, lncRNA UCA1 was shown to negatively regulate miR-132-3p expression, and miR-132-3p was shown to negatively regulate ATG16L1.In this cell model, lncRNA UCA1 promotes autophagic gene expression via epigenetic regulation mediated by ATG16L1 and miR-132-3p.

Leptomeningeal metastasis (LM) is a severe complication in non-small cell lung cancer (NSCLC) patients and the optimal treatment strategy remains challenged. This study aimed to investigate the treatment strategies and clinical outcomes in these patients.We retrospectively reviewed the data of 44 epidermal growth factor receptor tyrosine kinase inhibitor (EGFR) mutated NSCLC patients with LM between 2014 and 2020 at our institute. The patient characteristics, treatment approaches, LM progression free survival (LMThe median OSThe survival of NSCLC patients with LM has been improved in the target therapy era. Our study provided real-world clinical evidence that EGFR-mutated NSCLC patients who developed LM with T790M-positive would benefit from third generation EGFR-TKIs.

Honoured as the second genome in humans, the gut microbiota is involved in a constellation of physiological and pathological processes, including those related to the central nervous system. The communication between the gut microbiota and the brain is realized by a complex bidirectional connection, known as the "microbiota-gut-brain axis", via neuroendocrine, immunological, and direct neural mechanisms. Recent studies indicate that gut dysfunction/dysbiosis is presumably involved in the pathogenesis of and susceptibility to epilepsy. In addition, the reconstruction of the intestinal microbiome through, for example, faecal microbiota transplantation, probiotic intervention, and a ketogenic diet, has exhibited beneficial effects on drug-resistant epilepsy. The purposes of this review are to provide a brief overview of the microbiota–gut–brain axis and to synthesize what is known about the involvement of the gut microbiota in the pathogenesis and treatment of epilepsy, to bring new insight into the pathophysiology of epilepsy and to present a preliminary discussion of novel therapeutic options for epilepsy based on the gut microbiota.

Objective We described our initial experience of a new integrated oncology phamaceutical care practice to enhance the quality of pharmacy service and patient care in Huashan hospital. Data sources: A retrospective study was performed from August 2019 to September 2020. Patients were described as integrated pharmacy service group and routine care group. Medication adherence of patients in integrated pharmacy service group was recorded by the online management system. Patient satisfaction and the cumulative incidence of emergency room (ER) and outpatient visit were evaluated between two groups. Data summary: In total, 323 patients received the integrating oncology pharmacy service. The percentage of the patients missing administration every day was reduced from 29.7% to 0.3% within a 40-day monitoring and intervention period. There was a significant difference on patient satisfaction with pharmacy service in two groups ( P < 0.05). Fewer patients in the integrated pharmacy service group visited clinic and ER compared with routine care group (33.1% vs. 59.2%; P < 0.05). Conclusions As a new practice model, the integrated program is adopted to provide patient care and ongoing monitoring for cancer patients. The practice model delivers high continuity of care for cancer patients and improves communication and collaboration between healthcare professionals and oncology patients. The practice also provides the potential of developing hospital pharmaceutical service and optimizing disease prevention and treatment strategies.

Four pairs of cinnamoyl-β-triketone derivative enantiomers, (+)- and (-)-xanthostones A-D ((+)- and (-)-1-4), were isolated from Xanthostemon chrysanthus. Compounds 1 and 2 feature a new rearranged cinnamoyl-phloroglucinol scaffold fused with a cinnamyl-β-triketone framework. Compounds 1, 3, and 4 are the first examples of natural products with a peculiar phenethyl-pyranone acid unit. Their structures with absolute configurations were determined by spectroscopic data, X-ray diffraction analysis and electronic circular dichroism (ECD) calculation. Interestingly, these novel compounds showed a tautomeric behavior in solution, which was revealed by NMR spectroscopy and density functional theory calculation. A plausible biosynthetic pathway toward xanthostones A-D was proposed. Additionally, the anti-inflammatory and antibacterial activities of xanthostones A-D were evaluated.

Cognitive deficits are the core feature of schizophrenia and effective treatment strategies are still missing. Previous studies have reported that fisetin promotes long-term potentiation (LTP) and cognitive function in normal rodents and other model animals of neurological diseases. The aim of the present study was to assess the effect of fisetin on synaptic plasticity and cognitive deficits caused by a brief disruption of N-methyl-D-aspartate receptors (NMDARs) with dizocilpine (MK-801) during early development in rats. The cognitive performance was examined by the Morris water maze task and a fear conditioning test. Hippocampal synaptic plasticity was investigated by field potential recording. The expression of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) and cognition-related proteins were measured by Western blotting. We found that intraperitoneal administration of fisetin rescued hippocampus-dependent spatial and contextual fear memory in MK-801 rats. In parallel with these behavioral results, fisetin treatment in MK-801 rats reversed the impairment of hippocampal LTP. At the molecular level, fisetin treatment selectively increased the phosphorylation and surface expression of AMPA receptor subunit 1 (GluA1) in MK-801-treated rats. Moreover, fisetin restored the phosphorylation levels of calcium-calmodulin-dependent kinaseII (CaMKII), cAMP response element-binding protein (CREB) and the extracellular signal-regulated kinase (ERK1/2) in MK-801-treated rats. Collectively, our findings demonstrate that fisetin treatment can reverse the deficits of hippocampal synaptic plasticity and memory in a male rat model of schizophrenia by restoring the phosphorylation and surface expression of AMPAR GluA1 subunit, suggesting fisetin as a promising therapeutic candidate for schizophrenia-associated cognitive deficits.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have been confirmed as an effective therapy for advanced non-small cell lung cancer (NSCLC) patients with EGFR-positive. However, various adverse drug reactions (ADRs) are frequently occurred in patients treated with EGFR-TKIs. Genetic polymorphisms may predict EGFR-TKI-induced ADRs. We attempted to explored the potential association between the genetic polymorphisms of the JAK-STAT pathway and EGFR-TKIs related ADRs in non-small cell lung cancer (NSCLC) patients. In addition, we also researched the correlation between single nucleotide polymorphisms (SNPs) of Janus Kinase- Signal Transducer and Activator of Transcription (JAK-STAT) pathway and clinical survival outcomes of NSCLC patients treated with EGFR-TKIs.Methods: We recruited 162 Han Chinese patients with advanced non-small cell lung cancer. We analyzed the relationship between the adverse reactions of EGFR-TKIs and JAK-STAT signaling pathway by single factor and multi-factor logistic regression analysis. Kaplan–Meier test was used to evaluate the association of SNPs with progression-free survival of advanced NSCLC patients.Results: In the discovery group, we found the following: There were significantly associations between the severity of adverse drug reactions caused by EGFR-TKIs and rs1053023 (P=0.016), rs1053005 (P = 0.016) in STAT3, rs324011 (P= 0.019) in STAT6. Furthermore, patients with AA genotype had a prolonged progression-free survival (PFS) (P= 0.012) compared with AT and TT genotype of rs7043371. Besides, validation experiments showed that STAT3 rs1053023 (P=0.021), rs1053005 (P = 0.021), STAT6 rs324011 (P=0.002) were all significantly associated with the severity of ADRs induced by EGFR-TKIs by multivariable regression, which consistent with the study in the discovery group.Conclusions: STAT3 rs1053023, rs1053005 and STAT6 rs324011 might be potential predictors of the severity of ADRs in EGFR-TKIs treated NSCLC patients and their variants play important roles in predicting the adverse reactions of non-small cell lung cancer patients with EGFR-TKIs.

The drug-induced diverse response among patients is a severe problem for improving hemorheological character. However, there is no validated method for personalized therapy to the best of our knowledge. Here, we apply a gravity-driven deformability cytometry platform (GD-DCP) to profile the drug response of the red cell deformability (RCD) at the single-cell level using pentoxifylline (PTX) as a model drug, the effect of different concentrations of PTX (0, 2, 20, 200 μg mL

ObjectivesNon-small cell lung cancer (NSCLC) with Brain metastases (BM) is an advanced disease with poor prognosis and low survival rate. Our study evaluated the survival benefit of primary lung resection with mediastinal lymph node dissection in NSCLC patients with BM using Surveillance, Epidemiology, and End-result (SEER) databases.MethodsAll cases analyzed were from Surveillance, Epidemiology, and End Results database. The data of the patients with BM of NSCLC from 2010 to 2016 was retrospectively analyzed. Patients (N=203) patients who underwent radical surgical treatment for primary lung lesions and patients (N=15500) who did not undergo surgery were compared. We successfully analyzed patients using propensity score matching (PSM). Kaplan‐Meier and Cox‐ regression analyses were applied to assess prognosis.ResultsThe median survival in the surgery group was longer than in the control group (27 months vs 5 months; P < 0.001) in the overall sample, 21 months longer compared to the control group (27 months vs 6 months; P65 years, worse differentiation, squamous cell carcinoma, lymphatic metastasis, no systemic therapy. Subgroup analysis revealed that radical resection of the primary lung provided a survival benefit regardless of marital status, tumor size, tumor grade, tumor T stage, and mediastinal lymph node metastasis after PSM.ConclusionRadical resection of primary lung can improve the survival of NSCLC patients with BM. Male, age>65years, poorly differentiated tumor, tumor size>5cm, and mediastinal lymph node metastasis were factors for poor survival.

Background Changes in baseline resting heart rate (RHR) appear to predict new-onset hypertension (NOH). However, RHR is a dynamic anthropometric parameter; thus, the association between changes in RHR and NOH requires further investigation. Methods We studied 10 403 participants who were initially normotensive and who had at least one routine health examination at baseline and 1 year later during 2011-2016. We compared the RHR between the baseline and 1-year follow-up. We defined hypertension as SBP ≥140 mmHg or DBP ≥90 mmHg. Participants were divided into three groups: RHR decreased, RHR unchanged [from 0 to 10 beats per minute (bpm)], and RHR increased ≥10 bpm. Cox regression analysis was performed to calculate relative risk with 95% confidence intervals (CIs) for the association between NOH and RHR change. Results During a mean follow-up period of 2.42 years, 1173 (11.28%) participants developed hypertension. After adjusting for age, sex, SBP, DBP, RHR and other confounders obtained at baseline, and compared with participants with unchanged RHR, participants with decreased RHR had a 17% decreased risk of NOH (adjusted hazard ratio: 0.83, 95% CI 0.73-0.95), whereas subjects with RHR that increased ≥10 bpm had a 23% increased risk of NOH (adjusted hazard ratio: 1.23, 95% CI 1.04-1.46). Conclusion A 1-year increase in RHR for initially normotensive subjects is an independent risk factor for subsequent hypertension.

Microglial activation and phenotypic shift play vital roles in many neurological diseases. Runt-related transcription factor-1 (Runx1), which is localized on microglia, inhibits amoeboid microglial proliferation. Preliminary data have indicated that the interaction of Runx1 with the Notch1 pathway affects the hemogenic endothelial cell shift. However, little is known about the effect of Runx1 and the Notch1 signaling pathway on the phenotypic shift of microglia during neuroinflammation, especially in temporal lobe epilepsy (TLE). A mouse model of TLE induced by pilocarpine and the murine microglia cell line BV-2 were used in this study. The proportion of microglia was analyzed using flow cytometry. Western blot (WB) analysis and quantitative real-time polymerase chain reaction were used to analyze protein and gene transcript levels, respectively. Immunohistochemistry was used to show the distribution of Runx1. In the present study, we first found that in a male mouse model of TLE induced by pilocarpine, flow cytometry revealed a time-dependent M2-to-M1 microglial transition after status epilepticus. The dynamic expression patterns of Runx1 and the downstream Notch1/Jagged1/Hes5 signaling pathway molecules in the epileptic hippocampus were determined. Next, Runx1 knockdown by small interfering RNA in BV-2 cells strongly promoted an M2-to-M1 microglial phenotype shift and inhibited Notch1/Jagged1/Hes5 pathway expression. In conclusion, Runx1 may play a critical role in the M2-to-M1 microglial phenotype shift via the Notch1 signaling pathway during epileptogenesis in a TLE mouse model and in BV-2 cells.

SummaryAccumulating evidence suggests that a disruption of early brain development, in which insulin-like growth factor-2 (IGF-2) has a crucial role, may underlie the pathophysiology of schizophrenia. Our previous study has shown that decreased serum IGF-2 was correlated with the severity of psychopathology in patients with schizophrenia. Here we conducted a prospective observation trial to investigate the effects of atypical antipsychotics on serum IGF-2 level and its relationship with clinical improvements in schizophrenia patients. Thirty-one schizophrenia patients with acute exacerbation and 30 healthy individuals were recruited in this study. Psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) and serum IGF-2 levels were determined using ELISA. We found that schizophrenia patients with acute exacerbation had lower serum IGF-2 levels than control individuals at baseline (PPvs. 426.99±124.26 ng/mL; t =−5.044, Pr=−0.522, P=0.006). Collectively, our findings demonstrated changes of serum IGF-2 response to improvements of negative symptoms in schizophrenia patients treated with atypical antipsychotics, suggesting that serum IGF-2 might be a treatment biomarker for schizophrenia.

ObjectiveTo evaluate the association between serum galectin-3 and all-cause death (ACD) and cardiovascular death (CVD) in patients with chronic heart failure (CHF).MethodsThe PubMed and Embase databases and Clinical Trials Registry (www.clinicaltrials.gov) were searched for studies with data on serum galectin-3 and ACD and CVD in CHF patients. The hazard ratios (HRs) of ACD and CVD were calculated and presented with 95% CIs. HRs were pooled using fixed effects or random effects models when appropriate. Sensitivity analysis, meta-regression and subgroup analysis were applied to find the origin of heterogeneity. Visual inspection of Begg's funnel plot and Egger's test were performed to assess the possibility publication bias.ResultsPooled data included the results from 6,440 patients from 12 studies in the meta-analysis. Higher serum galectin-3 was associated with a higher risk of ACD (HR, 1.38; 95% CI, 1.14–1.67) and CVD (HR, 1.13; 95% CI, 1.02–1.25) in CHF patients. In the subgroup analyses, higher serum galectin-3 was associated with an increased risk of ACD in all subgroups. The pooled HR of the shorter follow-up group (1.78; 95% CI, 1.50–2.11) was significantly higher than the pooled HR of the longer follow-up group (1.15; 95% CI, 1.05–1.25). Sensitivity analysis of eliminating one study in each turn indicated that Koukoui et al.'s study had the largest influence on the risk of all-cause death. All-cause death publication bias was not detected (Pr>|z| = 0.35 for Begg's test and P>|t| = 0.15 for Egger's test).ConclusionsSerum galectin-3 has prognostic value of both all-cause death and cardiovascular death in CHF. Serum galectin-3 could be useful for risk classification in patients with CHF.Systematic Review Registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?RecordID=193399.

Klotho is a life extension factor that has an ability to regulate the function of GluN2B-containing N-methyl-D-aspartate receptors (NMDARs), whose dysfunction in the nucleus accumbens (NAc) underlies critical aspects of the pathophysiology of major depression. Here we study the functional relevance of klotho in the pathogenesis of depression. A chronic social defeat stress paradigm, where mice are either categorized as susceptible or unsusceptible group based on their performance in a social interaction test, was used in this study. We found that the expression of klotho was largely decreased in the NAc of susceptible mice when compared to control or unsusceptible group. Genetic knockdown of klotho in the NAc induced depressive-like behaviors in naive mice, while overexpression of klotho produced an antidepressive effect in normal mice and ameliorated the depressive-like behaviors in susceptible mice. Molecularly, knockdown of klotho in the NAc resulted in selective decreases of total and synaptic GluN2B expression that were identical to susceptible mice. Elevation of klotho in the NAc reversed the reductions of GluN2B expressions, as well as altered synaptic transmission and spine density in the NAc of susceptible mice. Furthermore, blockade of GluN2B with a specific antagonist abolished the beneficial effects of klotho elevation in susceptible mice. Collectively, we demonstrated that klotho in the NAc modulates depressive-like behaviors by regulating the function of GluN2B-containing NMDARs. These results reveal a novel role for klotho in the pathogenesis of depression, opening new insights into the molecular basis of major depression.

Background: Elevated blood pressure (BP) is a risk factor for cognitive impairment. Objective: We aim to explore the association between the duration of hypertension in early adulthood, with cognitive function in midlife. Furthermore, we investigate whether this asssociation is altered among participants with controlled BP. Methods: This prospective study included 2,718 adults aged 18–30 years without hypertension at baseline who participated in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Duration of hypertension was calculated based on repeat measurements of BP performed at 2, 5, 7, 10, 15, 20, and 25 years after baseline. Cognitive function was assessed at Year-25 using the Rey Auditory Verbal Learning Test (RAVLT), Digit Symbol Substitution Test (DSST), and Stroop test. Results: After multivariable adjustment, a longer hypertension duration was associated with worse verbal memory (RAVLT, p trend = 0.002) but not with processing speed (DSST, p trend = 0.112) and executive function (Stroop test, p trend = 0.975). Among subgroups of participants with controlled (BP

Accumulating evidence has suggested a dysfunction of synaptic plasticity in the pathophysiology of depression. Hydrogen sulfide (H2S), an endogenous gasotransmitter that regulates synaptic plasticity, has been demonstrated to contribute to depressive-like behaviors in rodents. The current study investigated the relationship between plasma H2S levels and the depressive symptoms in patients with depression. Forty-seven depressed patients and 51 healthy individuals were recruited in this study. The 17-item Hamilton Depression Rating Scale (HAMD-17) was used to evaluate depressive symptoms for all subjects and the reversed-phase high-performance liquid chromatography (RP-HPLC) was used to measure plasmaH2S levels. We found that plasma H2S levels were significantly lower in patients with depression relative to healthy individuals (P < 0.001). Compared with healthy controls (1.02 ± 0.34 μmol/L), the plasma H2S level significantly decreased in patients with mild depression (0.84 ± 0.28 μmol/L), with moderate depression (0.62 ± 0.21μmol/L), and with severe depression (0.38 ± 0.18 μmol/L). Correlation analysis revealed that plasma H2S levels were significantly negatively correlated with the HAMD-17 scores in patients (r = −0.484, P = 0.001). Multivariate linear regression analysis showed that plasma H2S was an independent contributor to the HAMD-17 score in patients (B = −0.360, t = −2.550, P = 0.015). Collectively, these results suggest that decreased H2S is involved in the pathophysiology of depression, and plasma H2S might be a potential indicator for depression severity.

Background and Aims: Central 5-hydroxytryptamine (5-HT) defects are responsible for the occurrence of sudden unexpected death in epilepsy (SUDEP). The DBA/1 mouse is an animal model of SUDEP since the mouse exhibits audiogenic seizure-induced respiratory arrest (S-IRA). The synthesis of central 5-HT is closely related to the gut microbiota. Moreover, emerging studies suggest a possible role for the microbiota in mitigating seizure likelihood. Based on this, we aimed to explore the effect of a high-tryptophan diet (HTD) on SUDEP as well as the synthesis and metabolism of central 5-HT. Furthermore, we investigated the involvement of the gut microbiota in this process.Methods: All DBA/1 mice were subjected to acoustic stimulation to induce seizures. Only those mice that exhibited S-IRA were randomly assigned to the normal diet (ND) group (n = 39) or HTD group (n = 53). After 1 month of dietary intervention, (1) S-IRA rates were evaluated, (2) the concentrations of 5-HT and its metabolite 5-hydroxyindoleacetic acid (5-HIAA) in the plasma and brain were determined by ultra-high-pressure liquid chromatography, and (3) the fecal flora biodiversity and species composition were analyzed by 16S rDNA microbiota profiling.Results: The S-IRA rate in DBA/1 mice was significantly reduced in the HTD group compared with that in the control group. HTD increased the levels of 5-HT and 5-HIAA in both the telencephalon and midbrain. HTD significantly elevated the species richness and diversity of the gut microbiota. Moreover, there was a significant difference in the gut microbiota composition between the two groups, and the intestinal flora was dominated by Proteobacteria and Actinobacteria after HTD.Conclusions: HTD is efficient in lowering S-IRA rates and elevating the central 5-HT level in DBA/1 mice. The gut microbiota was altered after HTD intervention. The significant increase in Proteobacteria and Actinobacteria may be related to the SUDEP-protective effect of HTD. Our findings shed light on a candidate choice of dietary prevention for SUDEP.

Background: Triglyceride-glucose (TyG) index and homeostasis model assessment-insulin resistance (HOMA-IR) are related to insulin resistance (IR). The aim of this study was to assess the association between triglyceride-glucose index / HOMA-IR within young adults and congestive heart failure (CHF), and to explore whether triglyceride-glucose index can replace HOMA-IR as a surrogate marker for insulin resistance in predicting the risk of CHF.Methods：A total of 4992 participants between the ages of 18 and 30 were enrolled from the Coronary Artery Risk Development in Young Adults (CARDIA) investigation (from 1985 to 1986 [year 0]). Cox proportional hazard regression analysis was conducted for assessing correlations between baseline TyG index / HOMA-IR and congestive heart failure events, together with Receiver Operating Characteristic (ROC) Curve employed for scrutinizing TyG index / HOMA-IR and he risk of CHF.Results: During the 31-year follow-up period, 64 (1.3%) out of the 4992 participants developed congestive heart failure. In multivariable Cox proportional hazards models, adjusted for confounding factors for CHF, increased risk of CHF was associated with per-unit increase in TyG index (hazard ratio [HR] 2.8; 95% confidence interval [CI], 1.7-4.7) and HOMA-IR (HR 1.2; 95%CI, 1.1-1.3). Kaplan-Meier curve analysis showed that participants in the TyG index and HOMA-IR index Q4 group had a higher risk of congestive heart failure than those in the Q1 group. The area under curve (AUC) for TyG index and HOMA-IR consisted of 0.67 (95% CI, 0.6-0.742) and 0.675 (95%CI, 0.604-0.746), respectively. There were no significant differences between TyG index and HOMA-IR for AUC (P = 0.986).Conclusions: TyG index and HOMA-IR are independent risk factors for CHF. The TyG index can replace HOMA-IR in young adulthood as a surrogate marker for IR to predict the risk of CHF.

Chronic heart failure (CHF) is a major public health burden and is associated with high morbidity, mortality, and cost. Recent studies demonstrated iron metabolism and myocardial energy metabolism were altered in CHF patients. In this study, we aimed to analyze the effects and correlations of iron metabolism on myocardial energy metabolism in CHF.One hundred and thirty patients with CHF [age: 66.2±11.5 years, males: 58.5% and New York Heart Association (NYHA) class (II/III/IV): 67/43/20] were included. Serum concentrations of ferritin, transferrin saturation (Tsat), and soluble transferrin receptor (sTfR) were quantified as the indexes of iron metabolism, and echocardiography was used to assess myocardial energy expenditure (MEE) levels. Iron deficiency (ID) was defined as ferritin100 or 100-300 µg/L with Tsat20%.Patients with CHF were divided into two groups based on iron status. The prevalence of ID in CHF was 36.9%, and increased with the severity of CHF, reaching 80.0% in those with NYHA class IV (NYHA class II/III/IV: 17.9% vs. 46.5% vs. 80.0%, P=0.000). The demographic characteristics [age, sex, body mass index (BMI), blood pressure, and heart rate] and hemoglobin (HGB) concentrations in two groups were similar (all P0.05). MEE was significantly higher in the ID group (92.7±23.0 vs. 65.6±20.8 cal/min, P=0.000), while NYHA classes II and III was significantly higher in the ID group (71.6±16.4 vs. 60.3±14.8 cal/min, P=0.022; 88.9±10.4 vs. 69.1±20.1 cal/min, P=0.000). In univariable linear regression models, the presence of ID, higher NYHA class, increased N-terminal pro-B-type natriuretic peptide (NT-proBNP), sTfR, left ventricular internal diastolic diameter (LVIDd), as well as reduced ferritin, Tsat levels, and lower left ventricular ejection fraction (LVEF) were associated with elevated MEE levels (all P0.05). In multivariable regression models, the presence of ID, reduced Tsat. and increased sTfR remained independent predictors of elevated MEE levels after adjustment for all variables that showed a significant association with MEE (all P0.05).The prevalence of ID is high in CHF and is associated with the severity of cardiac dysfunction. The presence of ID as well as reduced Tsat and increased sTfR concentrations are associated with elevated MEE levels in CHF.

Honoured as the second genome in humans, the gut microbiota is involved in a constellation of physiological and pathological processes, including those related to the central nervous system. The communication between the gut microbiota and the brain is realized by a complex bidirectional connection, known as the "microbiota-gut-brain axis", via neuroendocrine, immunological, and direct neural mechanisms. Recent studies indicate that gut dysfunction/dysbiosis is presumably involved in the pathogenesis of and susceptibility to epilepsy. In addition, the reconstruction of the intestinal microbiome through, for example, faecal microbiota transplantation, probiotic intervention, and a ketogenic diet, has exhibited beneficial effects on drug-resistant epilepsy. The purposes of this review are to provide a brief overview of the microbiota-gut-brain axis and to synthesize what is known about the involvement of the gut microbiota in the pathogenesis and treatment of epilepsy, to bring new insight into the pathophysiology of epilepsy and to present a preliminary discussion of novel therapeutic options for epilepsy based on the gut microbiota.

The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) lowered the diagnostic criteria for hypertension. We aimed to explore whether clustering of multiple risk factors are associated with the risk of new-onset hypertension defined by the 2017 ACC/AHA Hypertension Guideline. Subjects who attended ≥2 annual health examinations without baseline hypertension and cardiovascular disease were included. Hypertension was defined according to the 2017 ACC/AHA Hypertension Guideline. Seven predefined risk factors, including age, resting heart rate, overweight or obesity, dyslipidemia, hyperuricemia, impaired glucose regulation, and a poor estimated glomerular filtration rate, were analyzed. A composite, individual-level, cumulative score incorporating these seven risk factors (no = 0 point; yes = 1 point; total range of 0–7 points) was calculated. The association between the cumulative score and the risk of hypertension was analyzed using a Cox regression model. A total of 4424 (21.6%) of 20,190 subjects included had new-onset hypertension during a follow-up duration of 3.6 years. Compared with subjects with 0 points, the adjusted hazard ratios (95% confidence intervals) for the development of hypertension for those with 1, 2, 3, and ≥4 points were 1.21 (1.07–1.38), 1.34 (1.19–1.52), 1.44 (1.26–1.63), and 1.64 (1.44–1.87), respectively (P

Background Growing evidence indicates that high phosphoserine phosphatase (PSPH) expression is associated with tumor prognosis in many types of cancers. However, the role of PSPH in non-small cell lung cancer (NSCLC) is unclear. The purpose of this study was to investigate the clinical significance of PSPH in NSCLC. Methods One hundred forty-three patients with histologically confirmed NSCLC who underwent surgery were included. Quantitative real-time PCR and Western blot were used to assess PSPH expression in paired tumor and corresponding adjacent non-tumorous tissues. The role of PSPH in invasion and cell growth was investigated in vitro. Results Compared to adjacent normal lung tissues, PSPH messenger RNA and protein levels were significantly higher in NSCLC tissues, and the PSPH expression level was positively related to clinical stage, metastasis, and recurrence. High PSPH expression was predictive of poor overall survival. A549 cells transfected with small interfering-PSPH showed inhibited cell migration, invasion, and proliferation. We further demonstrated that PSPH might promote the invasive capabilities of NSCLC cells through the AKT/AMPK signaling pathway. Conclusion Our results indicate that PSPH may act as a putative oncogene in NSCLC, and may be a vital molecular marker for the metastasis and proliferation of NSCLC cells by regulating the AKT/AMPK signaling pathway.

Hyperuricemia is reportedly associated with poor outcome in acute heart failure (AHF). The association between changes in Uric acid (UA) levels with renal function change, diuretic doses, and mortality in patients with AHF were studied.Consecutive patients hospitalized with AHF were reviewed (n = 535). UA levels were measured at admission and either at discharge or on approximately the seventh day of admission. Patients with an UA change in the top tertile were defined as having an increase (UA-increase) and were compared to those outside the top tertile (non-UA-increase). The endpoint was all-cause mortality, with a mean follow-up duration of 22.2 months. Patients in the UA-increase group presented with greater creatine increase (P 0.001), and were administered a higher average daily dose of loop diuretic (P = 0.016) compared with the non-UA-increase group. In-hospital UA-increase was associated with higher risk of mortality even after adjusting for confounding variables including creatine change and diuretic dosage [harzard ratio (HR) 1.53, 95% confidence interval (CI) 1.02-2.30, P = 0.042]. In patients with hyperuricemia on admission, UA-increase was associated with increased mortality (adjusted HR 2.21, 95% CI 1.38-3.52, P = 0.001). Whereas, in those without admission hyperuricemia, UA-increase had no significant association with mortality.An increase in UA during in-hospital treatment is associated with an increase in creatine levels and daily diuretic dose. Mortality associated with increased UA is restricted to patients who already have hyperuricemia at admission. A combination of UA levels at admission and UA changes on serial assessment during hospitalization may be additional value in the risk stratification of AHF patients.

Background 2-oxoglutarate (2OG), an intermediate metabolite in the tricarboxylic acid cycle, has been found to associate with chronic heart failure (HF), but its effect on short-term adverse outcomes in patients with acute HF (AHF) is uncertain. Methods This prospective cohort study included 411 consecutive hospitalized patients with AHF. During hospitalization, fasting plasma samples were collected within the first 24 h of admission. Plasma 2OG levels were measured by hydrophilic interaction liquid chromatography-liquid chromatography tandem mass spectrometry (HILIC-LC/MS/MS). All participants were followed up for six months. Multiple logistic regression was used to determine the odds ratio (OR) and 95% confidence interval (CI) for primary outcomes. Results The AHF cohort consisted of HF with preserved ejection fraction (EF) (64.7%), mid-range EF (16.1%), and reduced EF (19.2%), the mean age was 65 (±13) years, and 65.2% were male. Participants were divided into two groups based on median 2OG levels (μg/ml): low group (

Epidermal growth factor receptor (EGFR) mutations are associated with leptomeningeal metastases (LM) of nonsmall cell lung cancer and sensitivity to tyrosine kinase inhibitor (TKI) treatment. Owing to the difficulty of obtaining carcinomatous meningeal tissue for analysis, cerebrospinal fluid (CSF) might be an alternative.To investigate the EGFR mutation detection in the CSF of lung adenocarcinoma patients with LM.Twenty-five lung adenocarcinoma patients with LM diagnosed by CSF cytology were retrospectively evaluated. The results of EGFR mutation detection in CSF, the treatment plan, and clinical outcome information were recorded.Nineteen patients had a known EGFR status in their primary tumors. Twenty patients received EGFR mutation analysis in CSF after LM diagnosis and 14 of them with a known EGFR mutation status of both primary tumors and CSF. Ten (71.4%) had the same EGFR gene status. In primary tumors, no T790M mutations were detected, whereas in CSF, 2 L858R cases and 1 19del case had T790M mutations at the same time. The detection rate of T790M mutations in CSF was 18.1% (2 of 11) in all cases with EGFR-sensitive mutations in the primary lesion.EGFR mutation detection in CSF of lung adenocarcinoma patients with LM might be an alternative when leptomeningeal biopsy cannot be applied and may help to guide TKI treatments.

Background: Central 5-hydroxytryptamine (5-HT) defects are responsible for the occurrence of audiogenic seizure-induced respiratory arrest (S-IRA) in DBA/1 mice, an animal model of sudden unexpected death in epilepsy (SUDEP). We aimed to explore the effect of a high tryptophan diet (HTD) on SUDEP and its possible mechanism involving 5-HT metabolism via gut microbiota.Methods: Primed animals were randomly assigned to the normal diet (ND) group or HTD group. Before and after diet interventions, 1) S-IRA rates were evaluated, 2) the concentrations of upstream-to-downstream 5-HT metabolites in the plasma and brain were detected by ultra-high-pressure liquid chromatography, and 3) the fecal flora biodiversity and species composition were analysed by 16S rDNA microbiota profiling. Second, antibiotics or probiotics combined with the HTD and S-IRA rates were reassessed.Results: The S-IRA rate in DBA/1 mice was significantly reduced in the HTD group compared with that in control. The HTD obviously increased the levels of tryptophan in the telencephalon and 5-HT and 5-hydroxyindoleacetic acid levels in both the telencephalon and midbrain. The HTD significantly increased the species richness and diversity of gut microbiota. Moreover, there was a significant difference in the gut microbiota composition between the HTD and ND groups. However, antibiotics or probiotics had no synergistic or antagonistic effects on S-IRA reduction mediated by the HTD.Conclusions: An HTD is efficient in lowering S-IRA rates in DBA/1 mice, possibly via modulation of 5-HT metabolism and gut microbiota. Our findings shed light on dietary prevention of SUDEP.

BACKGROUND: To explore the variations of the gross tumor volume (GTV) from different three-dimensional computed tomography (3DCT) scan modes and the consistency of internal target volume (ITV) between different 3DCT, cone-beam computed tomography (CBCT) and four-dimensional computed tomography (4DCT) scan, a study using a motion phantom simulating sinusoidal movement was conducted. METHODS: For three 3DCT scan modes: the GTV was contoured, and ITV(I) was generated on the basis of GTV with a 10-mm margin while ITV(II) and ITV(III) with a 0-mm margin on the motion direction. ITV(CBCT) and ITV(MIP) were contoured on the images of CBCT and maximum-intensity projection (MIP) reconstructed 4DCT images. The centroid position shifts of ITVs were analyzed. The volume consistency between ITV(I), ITV(II), ITV(III) and ITV(MIP) were evaluated by calculating the Dice similarity coefficient (Dsc) and the value of Δ Volume (ΔV). Furthermore, the 3DCT and CBCT images from 12 NSCLC patients were retrospectively collected, then the Dsc and ΔV were calculated. RESULTS: The mean ± standard deviation of centroid position of ITV(I), ITV(II) and ITV(III) were 2.3±4.7, 2.6±4.0, and 1.0±1.4 mm, respectively. The mean ± standard deviation of Dsc between ITV(I), ITV(II), ITV(III) and ITV(MIP) were 0.78±0.77, 0.86±0.1, and 0.94±0.05, respectively. The ΔV of ITV(I), ITV(II), ITV(III) were 29.67%, 17.22%, and 6.46%, respectively. The ITV from CBCT showed a deduction rate of 3.1–9.3% compared to 4DCT. For the patients, the mean Dsc andΔV between ITV(I) and ITV(CBCT) were 0.50 and 60.76%. CONCLUSIONS: The GTV acquired from 3DCT scan mode I possessed great deviation of centroid position and target volume. ITV on the basis of this GTV was significantly larger than ITV(MIP). A good similarity was showed between ITV(III) and ITV(MIP), 4DCT is still a golden standard for the ITV delineation, but in the absence of 4DCT, image from 3DCT scan mode III and KV-CBCT may be considered for ITV delineation with caution.

Schizophrenia is linked with abnormal neurodevelopment, on which growth differentiation factor 11 (GDF-11) has a great impact. However, a direct evidence linking GDF-11 to the pathophysiology of schizophrenia is still lacking. The current study aimed to investigate the relationship between plasma GDF-11 levels and both psychopathological symptoms and cognitive function in schizophrenia. Eighty-seven schizophrenia patients and 76 healthy controls were enrolled in the present study. The symptomatology of schizophrenia was evaluated using the Positive and Negative Syndrome Scale (PANSS). Cognitive function was assessed by Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) including twelve neurocognitive tests in five aspects of cognitive function. Plasma GDF-11 levels were determined by enzyme-linked immunosorbent assay (ELISA). We found that plasma levels of GDF-11 were significantly lower in schizophrenia patients relative to healthy controls. Correlation analysis showed significant negative correlations between the GDF-11 levels and the PANSS total score, the positive symptoms score, the negative symptoms score or the general score. Additionally, positive associations were observed between plasma GDF-11 levels and the visuospatial/constructional, attention, immediate memory, or delayed memory in patients. Partial correlation analysis showed that these correlations were still significant after adjusting for age, gender, education years, body mass index, duration of illness, and age of onset except for the visuospatial/constructional and attention index. Multiple regression analysis revealed that GDF-11 was an independent contributor to the immediate memory, delayed memory and RBANS total score in patients. Collectively, the correlations between plasma GDF-11 and psychopathological and cognitive symptoms suggest that abnormal GDF-11 signaling might contribute to schizophrenic psychopathology and cognitive impairments and GDF-11 could be a potential and promising biomarker for schizophrenia.

Aims Recent studies have shown that the choline-derived metabolite trimethylamine N-oxide (TMAO) is a biomarker that promotes cardiovascular disease through the induction of inflammation and stress. Inflammatory responses and stress are involved in the progression of calcified aortic valve disease (CAVD). Here, we examined whether TMAO induces the osteogenic differentiation of aortic valve interstitial cells (AVICs) through endoplasmic reticulum (ER) and mitochondrial stress pathways in vitro and in vivo. Methods and results Plasma TMAO levels were higher in patients with CAVD (n = 69) than in humans without CAVD (n = 263), as examined by liquid chromatography-tandem mass spectrometry. Western blot and staining probes showed that TMAO- induced an osteogenic response in human AVICs. Moreover, TMAO promoted ER stress, mitochondrial stress and NF-κB activation in vitro. Notably, the TMAO- mediated effects were reversed by the use of ER stress, mitochondrial stress and NF-κB activation inhibitors and siRNA. Mice treated with supplemental choline in a high fat diet had markedly increased TMAO levels and aortic valve thicknesses, which were reduced by 3,3-dimethyl-1-butanol (DMB, an inhibitor of trimethylamine formation) treatment. Conclusions Choline-derived TMAO promotes osteogenic differentiation through ER and mitochondrial stress pathways in vitro and aortic valve lesions in vivo. Translational perspective Trimethylamine-N-oxide (TMAO), a gut microbiota-generated metabolite, is associated with cardiovascular diseases. Here, we show that patients with calcified aortic valve disease (CAVD) have elevated circulating TMAO levels. TMAO induces osteogenic responses in human aortic valve interstitial cells via endoplasmic reticulum-mitochondrial stress in vitro and aggravates aortic valve lesions in mice. This may provide clues to the pathogenesis of CAVD and attractive potential targets for the prevention, diagnosis and treatment of this disease.

BACKGROUND: The recurrence and drug resistance of temporal lobe epilepsy (TLE) has been ceaselessly challenging scientists and epilepsy experts. There has been an accumulation of evidence linking the dysregulation of postsynaptic proteins etiology and the pathology of epilepsy. For example, NMDA receptors, AMPA receptors, and metabotropic glutamate receptors (mGluRs). Furthermore, our earlier proteomic analysis proved there to be differential expressions of cytoskeletons like microtubules among rat groups. These differential expressions were shown in TLE-spontaneous recurrent seizures (TLE-SRS), TLE without SRS (TLE-NSRS) and control groups. Therefore, we aimed to understand how the microtubule system of the hippocampal postsynaptic density (PSD) regulates the development of TLE. METHODS: In this study, a pilocarpine-induced Sprague-Dawley rat TLE model were used, and Western blot, Nissl staining, and the immunoelectron microscopic method were utilized to determine the dynamic change of microtubules (α- and β-tubulin) in PSD and the extent of hippocampal neuron loss respectively in acute SE, and latent and chronic (spontaneous seizures) periods. Animal models were then stereotactically treated using colchicine, a microtubule depolymerizer, and paclitaxel, a microtubule polymerization agent, after each animal’s acute SE period so as to further explore the function of PSD microtubules. RESULTS: Our study revealed 3 principal findings. One, both α- and β-tubulin were decreased from the 3(rd) to the 30(th) day (lowest at the 7(th) day) in the seizure group compared with the controls. Two, both α- and β-tubulin were found to be more downregulated in the TLE-SRS and the TLE-NSRS group than in the control group (especially in the TLE-SRS group). The same trend was also noticed for hippocampal neuron loss. Three, the paclitaxel lowered the chronic SRS rate and increased the expression of PSD β-tubulin in the hippocampus. CONCLUSIONS: Altogether, these results indicate that the microtubule system of PSD may play an essential role in the development and recurrence of epilepsy, and it may be used as a new target for the prevention and treatment of this refractory disease.

Heart failure (HF) is not uncommon among patients with hematologic malignancies (HM) undergoing hematopoietic stem cell transplantation (HSCT) and is associated with an increased mortality. Among HSCT patients without signs or symptoms of HF, groups with elevated and normal N-terminal probrain natriuretic peptide (NT-proBNP) levels have been poorly characterized in previous literature. Herein, we reviewed consecutive admissions for HM undergoing HSCT ( n = 301 ). Based on NT-proBNP levels and clinical signs or symptoms of HF at follow-up (one month after HSCT), patients were grouped into ENPH (elevated N T ‐ proBNP > 125 pg / mL , presence of HF symptoms or signs), ENAH (elevated N T ‐ proBNP > 125 pg / mL , absence of HF symptoms or signs), and NN (normal N T ‐ proBNP < 125 pg / mL ). ENPH, ENAH, and NN were observed in 22.9%, 54.5%, and 22.6% of patients, respectively. ENPH patients had a significantly higher baseline NT-proBNP level, followed by the ENAH and NN groups, respectively ( P < 0.001 ). Frequencies of HLA partially matched related donors, stem cell source (bone marrow+peripheral blood), and utilization of graft-versus-host disease prophylaxis regimens (ciclosporin+methotrexate+antithymocyte globulin±mycophenolate mofetil) were also the highest in the ENPH group, followed by ENAH and NN groups, respectively (all P < 0.05 ). Uric acid and hemoglobin levels, transplant type, and cyclophosphamide-based conditioning regimens utilized were similar between the ENAH and ENPH groups. We found that ENPH and ENAH are commonly observed in HM hospitalized for HSCT. Serum NT-proBNP levels may allow for earlier identification of HSCT patients at high risk of developing cardiac dysfunction.

Background and Objective: Recently, AMP-activated protein kinase (AMPK) signaling was confirmed to be intimately associated with atherosclerosis. Evidence indicates that genetic susceptibility play...

Cognitive impairments are a core feature of schizophrenia. Klotho is an anti-aging protein with demonstrated cognitive-enhancing effects on the brain. The purpose of this study was to investigate the differences in levels of plasma klotho between patients with schizophrenia and healthy controls, as well as the relationship between klotho level and cognitive function in patients. Forty patients with schizophrenia and 40 gender- and age-matched healthy individuals were recruited. Positive and Negative Syndrome Scale (PANSS) was used to assess the psychopathology of patients. A neuropsychological battery was performed to evaluate the cognitive function of participants. Plasma klotho was measured using enzyme-linked immunosorbent assay. We show that patients with schizophrenia performed worse in the neurocognitive tests than the healthy controls. The levels of plasma klotho were significantly higher in schizophrenia patients than in healthy controls (p < 0.001). In patients, plasma klotho levels were positively correlated with cognitive function with regard to attention (p = 0.010), working memory (p < 0.001), verbal memory (p = 0.044), executive function (p < 0.001), and composite cognitive score (p < 0.001). Stepwise linear regression analysis shows that executive function had the highest correlation with plasma klotho levels (β = 0.896, t = 8.290, p < 0.001). Collectively, these results indicate that anti-aging protein klotho may be implicated in the pathogenesis of schizophrenia, and increased klotho may act as a compensatory factor for the preservation of cognitive function in schizophrenia. Further studies are needed to investigate the dynamic changes of klotho and the mechanisms by which klotho modulates cognition in schizophrenia.

Background: Astrocytes are one of the most important types of neural cells in the central nervous system (CNS). Dysfunctional gap junction (GJ) communication could play an underlying role in epileptogenesis. Carbenoxolone (CBX) is a conventional chemical GJ blocker, and its target is connexin 43 (Cx43). Previous studies have shown that CBX can inhibit status epilepticus (SE) and spontaneous epileptic seizures (SESs). However, there is little information about the direct interaction between CBX and Cxs in temporal lobe epilepsy (TLE). Methods: The behavior of epileptic rats was observed. Moreover, micromorphological changes in the hippocampal cornu ammonis 1 (CA1) area of epileptic rats following CBX injection were determined through transmission electron microscopy (TEM). To illustrate the possible mechanism of these changes, the Western blot method was used. Results: After the injection of CBX, the seizure frequency, seizure duration, latency period to the first instance of SES, SESs behavioral score according to a scoring system developed by Veliskova and microstructures in the CA1 area were shown to be improved 60 days after SE by TEM. Furthermore, the dynamic expression patterns of Cx43 and Cx43 phosphorylated at Ser368 continuously declined after the injection of CBX until 60 days after SE. Conclusions: CBX may contribute to the improvement of GJ dysfunction during epileptogenesis in the hippocampal CA1 area in a TLE rat model.

Several studies show that even a level of urine albumin/creatinine ratio (UACR) within the normal range (below 30 mg/g) increases the risk of cardiovascular diseases. We speculate that mildly increased UACR is related to left ventricular hypertrophy (LVH) in patients with type 2 diabetes mellitus (T2DM). In this retrospective study, 317 patients with diabetes with normal UACR, of whom 62 had LVH, were included. The associations between UACR and laboratory indicators, as well as LVH, were examined using multivariate linear regression and logistic regression, respectively. The diagnostic efficiency and the optimal cutoff point of UACR for LVH were evaluated using the area under the receiver operating characteristic curve (AUC) and Youden index. Our results showed that patients with LVH had significantly higher UACR than those without LVH (P<0.001). The prevalence of LVH presented an upward trend with the elevation of UACR. UACR was independently and positively associated with hemoglobin A1c (P<0.001). UACR can differentiate LVH (AUC = 0.682, 95% CI (0.602–0.760),P<0.001). The optimal cutoff point determined with the Youden index was UACR = 10.2 mg/g. When categorized by this cutoff point, the odds ratio (OR) for LVH in patients in the higher UACR group (10.2–30 mg/g) was 3.104 (95% CI: 1.557–6.188,P=0.001) compared with patients in the lower UACR group (P=0.028). Overall, UACR below 30 mg/g is associated with LVH in patients with T2DM. The optimal cutoff value of UACR for identifying LVH in diabetes is 10 mg/g.

Background Schizophrenia is linked with abnormal brain neurodevelopment, on which IGF-2 (insulin-like growth factor-2) has a great impact. The purpose of this study was to assess the levels of serum IGF-2 and its binding proteins IGFBP-3 and IGFBP-7 in schizophrenia patients and the associations of these proteins with schizophrenia psychopathology and cognitive deficits. Methods Thirty-two schizophrenia patients and 30 healthy controls were recruited. The PANSS and a neurocognitive test battery were used to assess schizophrenic symptomatology and cognition, respectively. Serum IGF-2, IGFBP-3 and IGFBP-7 levels were determined using ELISA. Results The schizophrenia patients had a much lower content of serum IGF-2, IGFBP-3 and IGFBP-7 than controls. For the patients, IGF-2 levels were negatively correlated with the PANSS negative scores and positively associated with working memory, attention, and executive function. The correlations between IGF-2 and the PANSS negative scores, working memory or executive function were still significant after controlling for age, sex, education level, BMI, illness history and age of onset. No significant associations of IGFBP-3 or IGFBP-7 with the PANSS scores and cognitive function were observed in the patients. Conclusions Our study demonstrates that serum IGF-2 was significantly correlated with negative and cognitive symptoms in patients with schizophrenia, suggesting that altered IGF-2 signaling may be implicated in the psychopathology and cognitive deficits in schizophrenia.

BACKGROUND Cardiac rupture often occurs after acute myocardial infarction due to complex and unclear pathogenesis. This study investigated whether metformin increases the incidence of cardiac rupture after myocardial infarction through the AMPK-MTOR/PGC-1α signaling pathway. MATERIAL AND METHODS An acute myocardial infarction (MI) mouse model was established. A series of experiments involving RT-qPCR, Western blot, TUNEL staining, and Masson staining were performed in this study. RESULTS Myocardial infarction occurred, resulting in the cardiac rupture, and the expression level of PGC-1α increased in the cardiac myocardium. Meanwhile, the proportion of myocardial NT-PGC-1α/PGC-1α decreased. The expression level of myocardial PGC-1α in MI mice with cardiac rupture after MI was significantly higher than that in the mice without cardiac rupture, and the ratio of myocardial NT-PGC-1α/PGC-1α was low. In addition, increasing the dose of metformin significantly increased the incidence of cardiac rupture after myocardial infarction in MI mice. High-dose metformin caused cardiac rupture in MI mice. Moreover, high-dose metformin (Met 2.0 nM) reduces the proportion of NT-PGC-1α/PGC-1α in primary cardiomyocytes of SD mice (SD-NRVCs [Neonatal rat ventricular cardiomyocytes]), and its effect was inhibited by Compound C (AMPK inhibitor). Further, after 3 days of treatment with high-dose metformin in MI mice, myocardial fibrin synthesis decreased and fibrosis was significantly inhibited. Meanwhile, cardiomyocyte apoptosis increased significantly. With the increase in metformin concentration, the expression level of myocardial LC3b gradually increased in MI mice, suggesting that metformin enhances the autophagy of cardiomyocytes. CONCLUSIONS These results suggest that metformin increases cardiac rupture after myocardial infarction through the AMPK-MTOR/PGC-1α signaling pathway.