Therapeutic efficacy of novel memantine nitrate MN‐08 in animal models of Alzheimer’s disease

Alzheimer''s disease (AD) is a leading cause of dementia in elderly individuals and therapeutic options for AD are very limited. Over‐activation of N‐methyl‐D‐aspartate (NMDA) receptors, amyloid β (Aβ) aggregation, a decrease in cerebral blood flow (CBF), and downstream pathological events play important roles in the disease progression of AD. In the present study, MN‐08, a novel memantine nitrate, was found to inhibit Aβ accumulation, prevent neuronal and dendritic spine loss, and consequently attenuate cognitive deficits in 2‐month‐old APP/PS1 transgenic mice (for a 6‐month preventative course) and in the 8‐month‐old triple‐transgenic (3×Tg‐AD) mice (for a 4‐month therapeutic course). In vitro, MN‐08 could bind to and antagonize NMDA receptors, inhibit the calcium influx, and reverse the dysregulations of ERK and PI3K/Akt/GSK3β pathway, subsequently preventing glutamate‐induced neuronal loss. In addition, MN‐08 had favorable pharmacokinetics, blood‐brain barrier penetration, and safety profiles in rats and beagle dogs. These findings suggest that the novel memantine nitrate MN‐08 may be a useful therapeutic agent for AD.     

PLCγ1 inhibition-driven autophagy of IL-1β-treated chondrocyte confers cartilage protection against osteoarthritis,involving AMPK,Erk and Akt

Previous studies identified the involvement of phosphoinositide-specific phospholipase C (PLC) γ1 in some events of chondrocytes. This study aims to investigate whether and how PLCγ1 modulates autophagy to execute its role in osteoarthritis (OA) progression. Rat normal or human OA chondrocytes were pretreated with IL-1β for mimicking or sustaining OA pathological condition. Using Western blotting, immunoprecipitation, qPCR, immunofluorescence and Dimethylmethylene blue assays, and ELISA and transmission electron microscope techniques, we found that PLCγ1 inhibitor U73122 enhanced Collagen II, Aggrecan and GAG levels, accompanied with increased LC3B-II/I ratio and decreased P62 expression level, whereas autophagy inhibitor Chloroquine partially diminished its effect. Meanwhile, U73122 dissociated Beclin1 from Beclin1-IP3R-Bcl-2 complex and blocked mTOR/ULK1 axis, in which the crosstalk between PLCγ1, AMPK, Erk and Akt were involved. Additionally, by haematoxylin and eosin, Safranin O/Fast green, and immunohistochemistry staining, we observed that intra-articular injection of Ad-shPLCγ1-1/2 significantly enhanced Collagen and Aggrecan levels, accompanied with increased LC3B and decreased P62 levels in a rat OA model induced by anterior cruciate ligament transection and medial meniscus resection. Consequently, PLCγ1 inhibition-driven autophagy conferred cartilage protection against OA through promoting ECM synthesis in OA chondrocytes in vivo and in vitro, involving the crosstalk between PLCγ1, AMPK, Erk and Akt.     

ARL4C might serve as a prognostic factor and a novel therapeutic target for gastric cancer: bioinformatics analyses and biological experiments

The ADP-ribosylation factor-like proteins (ARLs) have been proved to regulate the malignant phenotypes of several cancers. However, the exact role of ARLs in gastric cancer (GC) remains elusive. In this study, we systematically investigate the expression status, interactive relations, potential pathways, genetic variations and clinical values of ARLs in GC. We find that ARLs are significantly dysregulated in GC and involved in various cancer-related pathways. Subsequently, machine learning models identify ARL4C as one of the two most significant clinical indicators among ARLs for GC. Furthermore, ARL4C silencing remarkably inhibits the growth and metastasis of GC cells both in vitro and in vivo. Moreover, enrichment analysis indicates that ARL4C is highly correlated with TGF-β1 signalling. Correspondingly, TGF-β1 treatment dramatically increases ARL4C expression and ARL4C knockdown inhibits the phosphorylation level of Smads, downstream factors of TGF-β1. Meanwhile, the coexpression of ARL4C and TGF-β1 worsens the prognosis of GC patients. Our work comprehensively demonstrates the crucial role of ARLs in the carcinogenesis of GC and the specific mechanisms underlying the GC-promoting effects of TGF-β1. More importantly, we uncover the great promise of ARL4C-targeted therapy in improving the efficacy of TGF-β1 inhibitors for GC patients.     

PRPF6 promotes androgen receptor/androgen receptor-variant 7 actions in castration-resistant prostate cancer cells

Androgen receptor (AR) and its variants play vital roles in development and progression of prostate cancer. To clarify the mechanisms involved in the enhancement of their actions would be crucial for understanding the process in prostate cancer and castration-resistant prostate cancer transformation. Here, we provided the evidence to show that pre-mRNA processing factor 6 (PRPF6) acts as a key regulator for action of both AR full length (AR-FL) and AR variant 7 (AR-V7), thereby participating in the enhancement of AR-FL and AR-V7-induced transactivation in prostate cancer. In addition, PRPF6 is recruited to cis-regulatory elements in AR target genes and associates with JMJD1A to enhance AR-induced transactivation. PRPF6 also promotes expression of AR-FL and AR-V7. Moreover, PRPF6 depletion reduces tumor growth in prostate cancer-derived cell lines and results in significant suppression of xenograft tumors even under castration condition in mouse model. Furthermore, PRPF6 is obviously highly expressed in human prostate cancer samples. Collectively, our results suggest PRPF6 is involved in enhancement of oncogenic AR signaling, which support a previously unknown role of PRPF6 during progression of prostate cancer and castration-resistant prostate cancers.     

基于流式细胞术和K-mer分析的银缕梅属(Parrotia C.A.Mey.)植物基因组大小测定

金缕梅科(Hamamelidaceae)银缕梅属(Parrotia C.A.Mey.)仅包含银缕梅(Parrotia subaequalis(H.T.Chang)R.M.Hao&H.T.Wei)和波斯铁木(Parrotia persica(DC.)C.A.Mey.)两种落叶阔叶乔木,其中银缕梅是我国华东地区特有的Ⅰ级濒危珍稀保护植物,属东亚第三纪孑遗成分;其姊妹种波斯铁木则间断分布于伊朗北部,属北极第三纪孑遗植物类群。本研究首次利用流式细胞术和K-mer分析方法对银缕梅属两姊妹种的基因组大小进行了测定,建立和优化了以萝卜(Raphanus sativus L.‘Saxa’)为内标、WPB(Woody plant buffer)为细胞核解离液的两种植物单倍体基因组的DNA含量(DNA C值)流式测定的适宜体系,旨在为金缕梅科银缕梅属植物的全基因组测序、基因组学研究、种质资源开发和利用以及物种保育等提供前期基础数据参考;同时也可为金缕梅科其他属、种的基因组大小测定提供借鉴。主要研究结果如下:(1)通过流式测定银缕梅基因组大小约为971.45±13.91 Mb,波斯铁木基因组大小约为890.52±24.69 Mb;(2)K-mer分析估测银缕梅基因组大小为951.70 Mb,杂合率为1.740%,重复序列比例为77.50%;波斯铁木基因组大小为858.50 Mb,杂合率为0.695%,重复序列占74.30%;(3)银缕梅属于高杂合和高重复基因组,波斯铁木则属于微杂合和高重复基因组。本研究的结果为银缕梅属植物后续基于DNA三代高通量测序技术的全基因组测序、组装及去冗余处理等工作提供了重要的数据参考。     

芽胞杆菌治疗幽门螺杆菌感染疗效的Meta分析

目的评价芽胞杆菌(Bacillus)联合根除标准疗法治疗幽门螺杆菌(H.pylori)感染的有效性。方法收集关于芽胞杆菌联合治疗H.pylori感染的随机对照试验(RCT),检索时限为建库至2020年5月;对符合纳入标准的研究进行偏倚风险评价及Meta分析。结果最终纳入14个RCT。Meta分析结果显示芽胞杆菌联合治疗能提高H.pylori根除率(ITT分析:RR=1.13,95%CI:1.08~1.18,P0.001;PP分析:RR=1.13,95%CI:1.09~1.17,P0.001),降低不良反应发生率(RR=0.42,95%CI:0.35~0.50,P0.001)。根据亚组分析结果,芽胞杆菌联合H.pylori两种常规治疗方案[三联疗法(RR=1.22,95%CI:1.10~1.36,P=0.003),铋剂四联疗法(RR=1.11,95%CI:1.07~1.15,P0.001)]以及芽胞杆菌联合H.pylori常规治疗的两种疗程[10 d(RR=1.14,95%CI:1.04~1.24,P=0.006),14 d(RR=1.14,95%CI:1.07~1.21,P0.001)]均提高H.pylori根除率;而亚组分析芽胞杆菌种类中,地衣芽胞杆菌差异有统计学意义(RR=1.14,95%CI:1.10~1.19,P0.001),凝结芽胞杆菌与蜡样芽胞杆菌需扩大样本量进一步统计分析。结论芽胞杆菌联合疗法能有利于提高H.pylori根除率,并降低总不良反应的发生,相对于标准疗法有一定的意义。     

多囊卵巢综合征患者与健康人群肠道菌群差异性分析

目的比较多囊卵巢综合征(PCOS)患者与健康人群间肠道菌群的差异,为后续研究提供参考。方法采用16S rDNA扩增子测序法对30例PCOS患者(PCOS组)和20例健康人(健康组)粪便标本中菌群结构进行分析,并比较两组之间的区别。结果与健康组相比,PCOS组患者肠道菌群α多样性降低。PCOS组患者肠道厚壁菌门(Firmicutes)、放线菌门(Actinobacteria)丰度高于健康组,拟杆菌门(Bacteroidetes)丰度低于健康组(均P0.05)。两组对象肠道梭菌门(Clostridia)、放线菌门(Actinobacteria)丰度差异无统计学意义(均P0.05)。PCOS组患者肠道变形杆菌纲(Proteobacteria)、芽胞杆菌纲(Bacilli)、红椿杆菌纲(Coriobacteriia)丰度高于健康组,拟杆菌纲(Bacteroidia)丰度低于健康组(均P0.05)。PCOS组患者肠道布劳特菌属(Blautia)、霍氏真杆菌属(Eubacterium_hallii_group)、阴沟杆菌属(Agathobacter)丰度高于健康组,拟杆菌属(Bacteroides)、粪杆菌属(Faecalibacterium)丰度低于健康组(均P0.05)。两组对象肠道双歧杆菌属(Bifidobacterium)、埃希菌-志贺菌属(Escherichia-Shigella)丰度差异无统计学意义(均P0.05)。结论 PCOS患者存在肠道菌群失调情况,但其是否是PCOS发展的潜在致病因素需要进一步研究。     

环境因子对海南岛野生兰科植物物种组成与分布格局的影响

海南岛是中国兰科植物物种丰富度较高的地区, 了解环境因子对海南岛野生兰科植物物种组成和分布格局的影响, 对于该地区野生兰科植物的保护管理和相关研究具有重要指导意义。基于海南岛野生兰科植物调查分布样方的植被类型、海拔、坡向、坡度、年平均气温、年降水量的数据, 采用典范相关分析探索了环境因子对物种组成的影响, 并计算各个环境因子对物种组成的总效应与净效应, 同时分析了6个环境因子对野生兰科植物分布格局的影响。结果表明, 所选的6个环境因子共解释了海南岛野生兰科植物组成变异的3.7%; 植被类型、海拔、年平均气温、年降水量、坡向、坡度这6个环境因子的总效应与净效应均达显著水平, 但其解释率依次减小。所选的6个环境因子对海南岛野生兰科植物的分布均有影响, 野生兰科植物在海南岛主要分布在中海拔段、5°-35°的坡度范围、阴坡与半阴坡、年平均气温较低且年降水量较高的环境, 并且于原生植被中分布最多。     

The mechanism and prevention of mitochondrial injury after exercise

Journal of Physiology and Biochemistry - With the development of society, physical activity has come to be an effective means by which people pursue good health to improve the quality of life....     

卵巢早衰患者血清抑制素B、抗苗勒管激素及性激素水平与子宫动脉血流参数的相关性研究

目的:探讨卵巢早衰(POF)患者血清抑制素B(INHB)、抗苗勒管激素(AMH)及性激素水平与子宫动脉血流参数的相关性。方法:选择2018年5月至2020年5月期间我院收治的126例POF患者(POF组)和同期于我院进行体检的85例健康女性志愿者(对照组)。检测所有研究对象血清INHB、AMH以及促黄体生成素(LH)、促卵泡激素(FSH)、雌二醇(E2)水平,经阴道多普勒超声检测子宫动脉血流参数[收缩期峰值流速(PSV)、舒张末期流速(EDV),血流阻力指数(RI)、搏动指数(PI)]。Pearson相关性分析POF患者血清INHB、AMH、LH、FSH、E2水平与PSV、EDV、RI、PI的相关性。结果:POF组血清INHB、AMH、E2水平、PSV、EDV低于对照组(P<0.05),LH、FSH水平、RI、PI高于对照组(P<0.05)。Pearson相关性分析结果显示POF患者血清INHB、AMH、E2水平与PSV、EDV呈正相关(P<0.05),与RI、PI呈负相关(P<0.05),LH、FSH与PSV、EDV呈负相关(P<0.05),与RI、PI呈正相关(P<0.05)。结论:POF患者血清INHB、AMH、E2水平降低,LH、FSH水平升高,血清INHB、AMH和性激素与子宫动脉血流受限有关。