Cardiac remodelling is characterized by abnormal changes in the function and morphological properties such as diameter, mass, normal diameter of cavities, heart shape, fibrosis, thickening of vessels and heart layers, cardiomyopathy, infiltration of inflammatory cells, and some others. These damages are associated with damage to systolic and diastolic abnormalities, damage to ventricular function, and vascular remodelling, which may lead to heart failure and death. Exposure of the heart to radiation or anti-cancer drugs including chemotherapy drugs such as doxorubicin, receptor tyrosine kinase inhibitors (RTKIs) such as imatinib, and immune checkpoint inhibitors (ICIs) can induce several abnormal changes in the heart structure and function through the induction of inflammation and fibrosis, vascular remodelling, hypertrophy, and some others. This review aims to explain the basic mechanisms behind cardiac remodelling following cancer therapy by different anti-cancer modalities.

以课程为基础,将线上的网络教学与线下的课堂授课有机结合,构建线上线下混合式教学模式是当前教学改革的重点.天然药物化学课程的主要内容是天然药物的结构、理化性质、提取纯化等内容,化学结构复杂,知识理论性强,学生较难理解.传统式教学较难激发学生学习兴趣,学生自主学习的意愿不强.为提高天然药物化学的教学效果,以蓝墨云班课为平台,开展线上线下混合式教学模式改革.结果表明,线上线下混合式教学模式可以激发学生的学习兴趣,提高学生自主学习的能力.

Histone deacetylase (HDAC) 2 plays a vital role in modifying histones to mediate inflammatory responses, while HDAC2 itself is commonly regulated by post-translational modifications. Small ubiquitin-related modifier (SUMO), as an important PTM factor, is involved in the regulation of multiple protein functions. Our previous studies have shown that carbocisteine (S-CMC) reversed cigarette smoke extract (CSE)-induced down-regulation of HDAC2 expression/activity in a thiol/GSH-dependent manner and enhanced sensitivity of steroid therapy. However, the mechanism by which S-CMC regulates HDAC2 is worth further exploring. Our study aimed to investigate the relationships between HDAC2 sumoylation and its deacetylase activity under oxidative stress and the molecular mechanism of S-CMC to regulate HDAC2 activity that mediates inflammatory responses in human bronchial epithelial cells. We found that modification of HDAC2 by SUMO1 and SUMO2/3 occurred in 16HBE cells under physiological conditions, and CSE induced SUMO1 modification of HDAC2 in a dose and time-dependent manner. K462 and K51 of HDAC2 were the two major modification sites of SUMO1, and the K51 site mediated deacetylation activity and function of HDAC2 on histone H4 that regulates IL-8 secretion. S-CMC inhibited CSE-induced SUMO1 modification of HDAC2 in the presence of thiol/GSH, increased HDAC activity, and decreased IL-8 expression. Our study may provide novel mechanistic explanation of S-CMC to ameliorate steroid sensitivity treatment in chronic obstructive pulmonary disease.

高职助产专业护用药理学教学改革通过增加与助产专业相关的药理学教学内容,突出助产专业特色,做到教学内容与临床助产岗位对接,创新教学方法和评价方法,融入护士执业资格考试真题,找准助产专业临床定位,突出学生能力培养,提高了助产专业学生岗位胜任力和就业竞争力.

SUMOylation is a significant post-translational modification (PTM) by the small ubiquitin-related modifier (SUMO). Increasing evidence shows SUMOylation regulates GPCR signaling; however, very few GPCRs have been shown to be SUMOylation targets to date. In this study, we identified M1 muscarinic acetylcholine receptor (M1 mAChR), a member of the GPCRs, as a new SUMO substrate. When the mAChR was activated by the agonist carbachol, the colocalization of the M1 mAChR and SUMO-1 protein markedly decreased in immunoprecipitation and immunofluorescence assays. SUMOylation of the M1 mAChR played an important role in increasing the ligand-binding affinity to M1 mAChR, signaling efficiencies, and receptor endocytosis. Through the site-directed mutagenesis approach, K327 was identified as the SUMOylation site of the M1 mAChR. Mutation of the consensus SUMOylation site of the M1 mAChR reduces not only the colocalization of SUMO-1, but also the ligand-binding affinity and signal transduction. The function of M1 mAChR was regulated by SUMOylation through the stabilization of active-state conformation revealed by molecular dynamics simulations. Our results provide evidence that M1 SUMOylation is an important PTM involved in regulation of the affinity for agonists and for activation of signaling pathways.-Xu, J., Tan, P., Li, H., Cui, Y., Qiu, Y., Wang, H., Zhang, X., Li, J., Zhu, L., Zhou, W., Chen, H. Direct SUMOylation of M1 muscarinic acetylcholine receptor increases its ligand-binding affinity and signal transduction.

At the present stage,moderate to severe depression and antidepressant tolerance in senile depression patients are very com-mon,and antidepressant drugs alone can not achieve the treatment effect. Many researchers at home and abroad combine antidepressant drugs with atypical antipsychotics for the treatment of senile depression,the clinical effect is significant. In order to promote the devel-opment of the treatment of senile depression and provide reference for clinical drug use,the situation of the combined use of drugs is re-viewed in this paper.

OBJECTIVE:To study the improvement effects of citalopram combined with huperzine A in aged depression model rats. METHODS:Aged rats were randomly divided into blank control group,model group,huperzine A group(0.3 mg/kg),citalo-pram group(5 mg/kg),and combination group(huperzine A 0.3 mg/kg+citalopram 5 mg/kg),10 in each group. Except for blank control group,rats in other groups received chronic unpredictable mild stress to reduce depression model. After modeling,rats were intragastrically administrated relevant drugs once a day,for 2 weeks. The depression,learning and memory behavior changes of rats in each group were observed by using open-field test,sucrose consumption test,tail suspension test,forced swimming test and Morris water maze test. RESULTS:Compared with blank control group,the horizontal crossing number,uprightness number,su-crose preference rate,crossing number in platform,percentages of target quadrant distance and time of rats in model group were ob-viously decreased (P<0.05 or P<0.01);immobility time of tail suspension and swimming,escape latency were obviously pro-longed(P<0.05 or P<0.01). Compared with model group,the depression-related indexes of rats in citalopram group and combina-tion group were obviously improved(P<0.05 or P<0.01),and combination group had better effects;the learning and memory-re-lated indexes in combination group were obviously improved(P<0.05 or P<0.01),only crossing time in platform in huperzine A group and citalopram group were obviously increased (P<0.05 or P<0.01),and other learning and memory-related indexes had no obvious changes(P>0.05). CONCLUSIONS:Citalopram combined with huperzine A can obviously improve the depression be-havior,learning and memory ability of aged rats with depression,showing better effects than citalopram alone.

目的 观察APP/PS1双转基因小鼠的认知功能及其海马组织小分子泛素样相关修饰物(SUMO)修饰水平的变化.方法 选取3月龄和16月龄的淀粉样前体蛋白/早老素(APP/PS1)双转基因小鼠及同月龄野生型小鼠,应用Morris水迷宫测试其认知功能,应用实时定量PCR和免疫组织化学技术检测其海马组织中的SUMO1,2,3和SUMO特异性蛋白酶(SENPs) SENP1,2,3的基因及蛋白表达情况.结果 与3月龄小鼠不同,16月龄APP/PS1双转基因小鼠的潜伏期延长,穿台次数、路程和时间百分比明显小于同月龄野生型小鼠,海马组织SUMO1,3基因的表达量明显低于野生型小鼠,而SENP1,3基因的表达量明显高于野生型小鼠.结论 APP/PS1双转基因小鼠的认知功能障碍可能与SUMO修饰水平下降有关.

AIMS:Muscarinic acetylcholine receptor agonist pilocarpine reduces intraocular pressure (IOP) of glaucoma mainly by stimulating ciliary muscle contraction and then increasing aqueous outflow. It is of our great interest to know whether pilocarpine has the additional properties of retinal neuroprotection independent of IOP lowering in vitro and in vivo models. METHODS:In rat primary retinal cultures, cell viability was measured using an MTT assay and the trypan blue exclusion method, respectively. Retinal ganglion cells (RGCs) were identified by immunofluorescence and quantified by flow cytometry. For the in vivo study, the retinal damage after retinal ischemia/reperfusion injury in rats was evaluated by histopathological study using hematoxylin and eosin staining, transmission electron microscopy, and immunohistochemical study on cleaved caspase-3, caspase-3, and ChAT. RESULTS:Pretreatment of pilocarpine attenuated glutamate-induced neurotoxicity of primary retinal neurons in a dose-dependent manner. Protection of pilocarpine in both retinal neurons and RGCs was largely abolished by the nonselective muscarinic receptor antagonist atropine and the M1-selective muscarinic receptor antagonist pirenzepine. After ischemia/reperfusion injury in retina, the inner retinal degeneration occurred including ganglion cell layer thinning and neuron lost, and the optic nerve underwent vacuolar changes. These degenerative changes were significantly lessened by topical application of 2% pilocarpine. In addition, the protective effect of pilocarpine on the ischemic rat retina was favorably reflected by downregulating the expression of activated apoptosis marker cleaved caspase-3 and caspase-3 and upregulating the expression of cholinergic cell marker ChAT. CONCLUSIONS:Taken together, this highlights pilocarpine through the activation of muscarinic receptors appear to afford significant protection against retinal neurons damage and optic nerve degeneration at clinically relevant concentrations. These data also further support muscarinic receptors as potential therapeutic neuroprotective targets in glaucoma.

Hypoxia-induced retinal ganglion cell (RGC) death has been proposed to be the critical event in the pathophysiology of glaucoma. Therefore, delaying or halting RGC degeneration, known as neuroprotection, is a novel and promising approach with potential clinical applications for treating glaucoma. In this study, we investigate hypoxia-induced cell death of RGCs and the underlying mechanisms of N-acetylcysteine (NAC) as a neuroprotectant. To establish a model for chemical hypoxia-induced cell death, RGC-5 cells were treated with the hypoxia mimetic cobalt chloride (CoCl2). Following CoCl2 exposure, significant levels of apoptotic and autophagic cell death were observed in RGC-5 cells, evidenced by lysosome dysfunction and autophagosome formation. Pretreating RGC-5 cells with NAC significantly counteracted the autophagic cell death. NAC-mediated neuroprotection was attributed to the direct scavenging of reactive oxygen species and was mediated by targeting the hypoxia-inducible factor-1α pathway via the BNIP3 and PI3K/Akt/mTOR pathways. These results provide insights into the degeneration of RGCs and present a potential clinical application for NAC as a neuroprotectant.