Effects of sildenafil on inflammatory injury of the lung in sodium taurocholate-induced severe acute pancreatitis rats

BackgroundInflammatory response and acute lung injury (ALI) occur in sodium taurocholate-induced severe acute pancreatitis (SAP). Because sildenafil has anti-inflammatory, anti-oxidant and immune-modulating effects, we investigated its effect on inflammatory and lung injury in sodium taurocholate-induced SAP-associated ALI rat lung.MethodsSodium taurocholate-induced SAP rats received sildenafil (100 mg/kg) or not and were compared to age-matched normal control animals. We evaluated inflammatory response by detecting the expression of inflammatory factors including IL-1β, IL-6 and TNF-α, and detected the level of lung injury through histopathological evaluation. Moreover, we also tested the protein expression of PCNA, P21, Bcl-2 and Bax in the lung.ResultsSildenafil administration rats had a low level of lung injury and inflammation. In addition, sildenafil significantly increased the expression of proliferation-related markers and decreased the expression of apoptosis-related markers in lung tissue.ConclusionsSildenafil administration may attenuate inflammation and lung injury by promoting proliferation and suppressing apoptosis in SAP rats.     

Cinnamaldehyde suppresses NLRP3 derived IL-1β via activating succinate/HIF-1 in rheumatoid arthritis rats

Cinnamaldehyde (CA) is an essential component of cinnamon (Cinnamomum cassia Presland), which is often used as a flavoring condiment in beverages, pastries, perfumes, etc. Cinnamon is also used as herbal medicine in China and Southeast Asia to treat rheumatoid arthritis. However, the molecular mechanism is unclear. In this study, we aim to investigate its anti-inflammatory effects against Rheumatoid arthritis (RA) using activated macrophages (Raw246.7) in vitro and adjuvant arthritis rats (AA) in vivo. The results demonstrated that CA significantly reduced synovial inflammation in AA rats, possibly due to suppression of the expressions of pro-inflammatory cytokines, especially the IL-1β. Further investigation found that CA also suppressed the activity of HIF-1α by inhibiting the accumulation of succinate in cytoplasm. As we know, the reduction of HIF-1α nucleation slows down IL-1β production, because HIF-1α activates the expression of NLRP3, which is involved in the assembly of inflammasome and processing of IL-1β. In addition, CA also inhibited the expression of the succinate receptor GPR91, which in turn inhibited the activation of HIF-1α. In conclusions, our results suggested that CA might be a potential therapeutic compound to relieve rheumatoid arthritis progress by suppressing IL-1β through modulating succinate/HIF-1α axis and inhibition of NLRP3.     

利用规律间隔成簇短回文重复序列/相关蛋白9系统敲减α2δ1对人肝癌细胞系Hep-12干性的影响

目的 通过规律间隔成簇短回文重复序列/相关蛋白9(CRISPR/Cas9)系统敲减人肝癌细胞系Hep12中电压依赖性钙离子通道 α2δ1的表达，观察α2δ1敲减后对肝癌细胞干性的影响。方法 设计3对靶向α2δ1的向导 (sgRNA)，长度为20 bp，构建到lenti CRISPRv2-puro载体上，然后在体外检测sgRNA切割活性，利用慢病毒包装系统包装含有sgRNA的重组质粒，将包装好的病毒感染Hep-12细胞，2 d后加入嘌呤霉素筛选。利用Western blotting验证α2δ1的敲减效果和干性相关基因的表达。通过成球实验检测其体外自我更新能力的变化。结果 测序结果显示，sgRNA成功插入载体质粒；体外切割实验显示，3条sgRNA均有切割活性；Western blotting结果显示，α2δ1基因的表达显著降低，干性相关基因B细胞特异性莫洛尼白血病病毒插入位点1(BMI1)和Nanog的表达显著被抑制；无血清培养基成球实验结果表明，敲减α2δ1导致Hep-12细胞的体外自我更新能力减弱。结论 利用CRISPR/Cas9技术成功构建敲除α2δ1基因的Hep-12细胞系；敲除α2δ1基因后能抑制Hep-12细胞肿瘤干细胞样特性。     

Increased activation of the fear neurocircuitry in children exposed to violence

Most studies investigating the effect of childhood trauma on the brain are retrospective and mainly focus on maltreatment, whereas different types of trauma exposure such as growing up in a violent neighborhood, as well as developmental stage, could have differential effects on brain structure and function. The current magnetic resonance imaging study assessed the effect of trauma exposure broadly and violence exposure more specifically, as well as developmental stage on the fear neurocircuitry in 8‐ to 14‐year‐old children and adolescents (N = 69). We observed reduced hippocampal and increased amygdala volume with increasing levels of trauma exposure. Second, higher levels of violence exposure were associated with increased activation in the amygdala, hippocampus, and ventromedial prefrontal cortex during emotional response inhibition. This association was specifically observed in children younger than 10 years. Finally, increased functional connectivity between the amygdala and brainstem was associated with higher levels of violence exposure. Based on the current findings, it could be hypothesized that trauma exposure during childhood results in structural changes that are associated with later risk for psychiatric disorders. At the same time, it could be postulated that growing up in an unsafe environment leads the brain to functionally adapt to this situation in a way that promotes survival, where the long‐term costs or consequences of these adaptations are largely unknown and an area for future investigations.     

Meta-analysis of the effects of transcranial direct current stimulation on inhibitory control

BackgroundInhibitory control refers to a central cognitive capacity involved in the interruption and correction of actions. Dysfunctions in these cognitive control processes have been identified as major maintaining mechanisms in a range of mental disorders such as ADHD, binge eating disorder, obesity, and addiction. Improving inhibitory control by transcranial direct current stimulation (tDCS) could ameliorate symptoms in a broad range of mental disorders.ObjectiveThe primary aim of this pre-registered meta-analysis was to investigate whether inhibitory control can be improved by tDCS in healthy and clinical samples. Additionally, several moderator variables were investigated.MethodsA comprehensive literature search was performed on PubMed/MEDLINE database, Web of Science, and Scopus. To achieve a homogenous sample, only studies that assessed inhibitory control in the go-/no-go (GNG) or stop-signal task (SST) were included, yielding a total of 75 effect sizes from 45 studies.ResultsResults of the meta-analysis indicate a small but significant overall effect of tDCS on inhibitory control (g = 0.21) which was moderated by target and return electrode placement as well as by the task. The small effect size was further reduced after correction for publication bias.ConclusionBased on the studies included, our meta-analytic approach substantiates previously observed differences between brain regions, i.e., involvement of the right inferior frontal gyrus (rIFG) vs. the right dorsolateral prefrontal cortex (rDLPFC) in inhibitory control. Results indicate a small moderating effect of tDCS on inhibitory control in single-session studies and highlight the relevance of technical and behavioral parameters.     

Clinical Significance of the Initial and Best Responses after Chemoembolization in the Treatment of Intermediate-Stage Hepatocellular Carcinoma with Preserved Liver Function

PurposeTo evaluate the clinical implications of initial and best responses during repeated transarterial chemoembolization procedures for hepatocellular carcinoma (HCC).Materials and MethodsThis study included 726 patients who received a diagnosis of intermediate-stage HCC with Child-Pugh class A liver function between 2007 and 2016, and who were treated with transarterial chemoembolization as the first-line treatment. Evaluation of treatment response was based on the modified response evaluation criteria in solid tumors. Overall survival (OS) was compared between response categories after implementation of landmark analysis.ResultsOf the 726 patients, an objective response (complete response [CR] or partial response [PR]) was observed as the initial response in 78.1% of patients. Regarding the best response during the transarterial chemoembolization series, 87.2% of patients were overall responders. The median OS of initial responders (n = 483) was not significantly different from that of subsequent responders at the 1-year landmark (stable disease [SD] after first transarterial chemoembolization but CR or PR after repeated transarterial chemoembolization; n = 61; 46.2 vs 40.1 months, respectively; P = .145). Likewise, the median OS of initial CR patients (n = 326) was not significantly different from that of the subsequent CR group (n = 126) at the 1-year landmark (PR or SD after first transarterial chemoembolization but CR after repeated transarterial chemoembolization; 53.4 vs 46.3 months, respectively; P = .455). Multivariate Cox analyses showed that the objective responses, the initial responses (hazard ratio [HR], 0.638; P = .001), and the best responses (HR, 0.304; P < .001) had the significant prognostic significance for OS.ConclusionsBoth the initial and best responses during repeated transarterial chemoembolization were significantly associated with OS in patients with intermediate-stage HCC and preserved liver function.     

疏肝化瘀益气法对肝纤维化大鼠HIF-1α、VEGF表达的影响

目的研究疏肝化瘀益气法干预肝纤维化大鼠模型过程中,对大鼠肝脏组织HIF-1α、VEGF表达的影响。方法采用无菌猪血清诱导大鼠肝纤维化模型。随机分为3组。空白组、模型组给予生理盐水灌胃;软肝散干预组自造模开始即给予软肝散生药水煎剂灌胃。采用HE染色和Masson染色观察肝组织纤维化程度,RT-PCR、Western bolt检测肝组织中HIF-1α、VEGF蛋白的表达情况。结果与模型组相比,软肝散干预组肝组织中HIF-1α、VEGF表达显著下调(P<0.05或P<0.01)。且随着干预给药时间的延长,其表达量逐渐降低。结论以疏肝化瘀益气法为指导的软肝散可以改善肝纤维化的病理改变,通过下调HIF-1α、VEGF表达,抑制HIF-1α、VEGF的过表达,调控HIF-1α/VEGF信号通路抑制肝组织纤维化进程,从而发挥抗纤维化的作用。     

Design,synthesis and pharmacological evaluation of 4-(3-chloro-4-(3-cyclopropylthioureido)-2-fluorophenoxy)-7-methoxyquinoline-6-carboxamide (WXFL-152): a novel triple angiokinase inhibitor for cancer therapy

Angiokinases, such as vascular endothelial-, fibroblast- and platelet-derived growth factor receptors (VEGFRs, FGFRs and PDGFRs) play crucial roles in tumor angiogenesis. Anti-angiogenesis therapy using multi-angiokinase inhibitor has achieved great success in recent years. In this study, we presented the design, synthesis, target identification, molecular mechanism, pharmacodynamics (PD) and pharmacokinetics (PK) research of a novel triple-angiokinase inhibitor WXFL-152. WXFL-152, identified from a series of 4-oxyquinoline derivatives based on a structure–activity relationship study, inhibited the proliferation of vascular endothelial cells (ECs) and pericytes by blocking the angiokinase signals VEGF/VEGFR2, FGF/FGFRs and PDGF/PDGFRβ simultaneously in vitro. Significant anticancer effects of WXFL-152 were confirmed in multiple preclinical tumor xenograft models, including a patient-derived tumor xenograft (PDX) model. Pharmacokinetic studies of WXFL-152 demonstrated high favourable bioavailability with single-dose and continuous multi-dose by oral administration in rats and beagles. In conclusion, WXFL-152, which is currently in phase Ib clinical trials, is a novel and effective triple-angiokinase inhibitor with clear PD and PK in tumor therapy.     

小剂量超短波对脊髓损伤功能恢复及对血清iNOS、TNF-α、VEGF、BDNF表达的影响

目的　探讨小剂量超短波对脊髓损伤患者功能恢复效果及对血清诱导型一氧化氮合酶（iNOS）、肿瘤坏死因子-α（TNF-α）、血管内皮生长因子（VEGF）、脑源性神经营养因子（BDNF）表达的影响。 方法　收集60例脊髓损伤患者，随机分为治疗组与对照组，每组30例。对照组给予基础康复治疗，治疗组加用小剂量超短波治疗，共治疗3个疗程。评估疗效并分析影响脊髓功能恢复的因素。 结果　治疗组总有效率高于对照组（P<0.05）；康复治疗后，治疗组ASIA量表运动功能、感觉功能评分高于对照组（P<0.05）；血清VEGF、BDNF表达含量高于对照组（P<0.05），iNOS、TNF-α表达含量低于对照组（P<0.05）；小剂量超短波治疗是脊髓损伤患者预后的保护因素（P<0.05）。 结论　小剂量超短波辅助治疗可明显促进患者脊髓功能恢复，其机制可能与下调血清iNOS、TNF-α表达，上调VEGF、BDNF表达有关。