The Hippo–YAP pathway regulates the proliferation of alveolar epithelial progenitors after acute lung injury

Regeneration of pulmonary epithelial cells plays an important role in the recovery of acute lung injury (ALI), which is defined by pulmonary epithelial cell death. However, the mechanism of the regenerative capacity of alveolar epithelial cells is unknown. Using a lung injury mouse model induced by hemorrhagic shock and lipopolysaccharide, a protein mass spectrometry‐based high‐throughput screening and linage tracing technology to mark alveolar epithelial type 2 cells (AEC2s), we analyzed the mechanism of alveolar epithelial cells proliferation. We demonstrated that the expression of Hippo‐yes‐associated protein 1 (YAP1) key proteins were highly consistent with the regularity of the proliferation of alveolar epithelial type 2 cells after ALI. Furthermore, the results showed that YAP1+ cells in lung tissue after ALI were mainly Sftpc lineage‐labeled AEC2s. An in vitro proliferation assay of AEC2s demonstrated that AEC2 proliferation was significantly inhibited by both YAP1 small interfering RNA and Hippo inhibitor. These findings revealed that YAP functioned as a key regulator to promote AEC2s proliferation, with the Hippo signaling pathway playing a pivotal role in this process.     

MicroRNA-363-3p/sphingosine-1-phosphate receptor 1 axis inhibits sepsis-induced acute lung injury via the inactivation of nuclear factor kappa-B ligand signaling

Infection-associated inflammation and coagulation are critical pathologies in sepsis-induced acute lung injury (ALI). This study aimed to investigate the effects of microRNA-363-3p (miR-363-3p) on sepsis-induced ALI and explore the underlying mechanisms. A cecal ligation and puncture-induced septic mouse model was established. The results of this study suggested that miR-363-3p was highly expressed in lung tissues of septic mice. Knockdown of miR-363-3p attenuated sepsis-induced histopathological damage, the inflammation response and oxidative stress in lung tissues. Furthermore, knockdown of miR-363-3p reduced the formation of platelet-derived microparticles and thrombin generation in blood samples of septic mice. Downregulation of miR-363-3p suppressed sphingosine-1-phosphate receptor 1 (S1PR1) expression in lung tissues and subsequently inactivated the nuclear factor kappa-B ligand (NF-κB) signaling. A luciferase reporter assay confirmed that miR-363-3p directly targeted the 3’-untranslated region of the mouse S1pr1 mRNA. Collectively, our study suggests that inactivation of NF-κB signaling is involved in the miR-363-3p/S1PR1 axis-mediated protective effect on septic ALI.     

益生菌对调节脑梗死后大鼠运动功能的机制研究

探讨在脑梗死后康复期使用益生菌治疗促进大鼠运动功能恢复的机制。

成年雄性SPF级7～8周龄Wistar大鼠,体重200～250 g,共35只。25只大鼠颅内注射内皮素制作脑缺血模型,模型制作后5只大鼠死亡,剩余20只大鼠按照随机数表法分为缺血组（ISC组）和缺血+益生菌组（ISC+PB组）,每组10只。另外10只大鼠作为假手术组（SHAM组）。SHAM组大鼠仅使用生理盐水按照上述造模流程进行。各组均喂食普通大鼠饲料。ISC+PB组大鼠第7天开始使用益生菌VSL#3溶液进行灌胃,0.25 mL/(只•d)。采用原位末端转移酶标记（TdT-mediated dUTP nick-end labeling,TUNEL）凋亡试剂盒检测凋亡细胞。采用蛋白质免疫印迹法检测各组大鼠海马与梗死周边皮层脑源性神经营养因子（brain derived neurotrophic factor,BDNF）的蛋白水平变化。使用梯形平衡木测试大鼠的肢体运动功能。

ISC组大鼠TUNEL阳性细胞数量较SHAM组显著增多（t=3.278,P=0.016）,ISC+PB组大鼠的TUNEL阳性细胞数量低于ISC组（t=2.721,P=0.037）。ISC组大鼠海马与梗死周边BDNF蛋白表达水平高于SHAM组（t=2.012,P=0.032）,ISC+PB组大鼠海马与梗死周边皮层BDNF水平较ISC组进一步提高（t=1.892,P=0.021）。梯形平衡木行走实验显示ISC组大鼠产生明显的运动功能损伤（t=3.425,P=0.041）,而ISC+PB组错误率低于ISC组（t=4.131,P=0.024）。

脑梗死后益生菌通过调控BDNF水平,抑制细胞凋亡,改善运动功能。

     

Direct targeting of sEH with alisol B alleviated the apoptosis,inflammation, and oxidative stress in cisplatin-induced acute kidney injury

Acute kidney injury (AKI) is a pathological condition characterized by a rapid decrease in glomerular filtration rate and nitrogenous waste accumulation during hemodynamic regulation. Alisol B, from Alisma orientale, displays anti-tumor, anti-complement, and anti-inflammatory effects. However, its effect and action mechanism on AKI is still unclear. Herein, alisol B significantly attenuated cisplatin (Cis)-induced renal tubular apoptosis through decreasing expressions levels of cleaved-caspase 3 and cleaved-PARP and the ratio of Bax/Bcl-2 depended on the p53 pathway. Alisol B also alleviated Cis-induced inflammatory response (e.g. the increase of ICAM-1, MCP-1, COX-2, iNOS, IL-6, and TNF-α) and oxidative stress (e.g. the decrease of SOD and GSH, the decrease of HO-1, GCLC, GCLM, and NQO-1) through the NF-κB and Nrf2 pathways. In a target fishing experiment, alisol B bound to soluble epoxide hydrolase (sEH) as a direct cellular target through the hydrogen bond with Gln384, which was further supported by inhibition kinetics and surface plasmon resonance (equilibrium dissociation constant, K_D = 1.32 μM). Notably, alisol B enhanced levels of epoxyeicosatrienoic acids and decreased levels of dihydroxyeicosatrienoic acids, indicating that alisol B reduced the sEH activity in vivo. In addition, sEH genetic deletion alleviated Cis-induced AKI and abolished the protective effect of alisol B in Cis-induced AKI as well. These findings indicated that alisol B targeted sEH to alleviate Cis-induced AKI via GSK3β-mediated p53, NF-κB, and Nrf2 signaling pathways and could be used as a potential therapeutic agent in the treatment of AKI.     

Associations of serum high-sensitivity C-reactive protein and prealbumin with coronary vessels stenosis determined by coronary angiography and heart failure in patients with myocardial infarction

BackgroundTo explore the associations of serum high-sensitivity C-reactive protein (hs-CRP) and prealbumin (PAB) with the number of diseased coronary vessels, degree of stenosis and heart failure in patients with myocardial infarction (MI).MethodsA total of 39 MI patients treated in the Cardiology were selected as the observation group, and another 41 patients with normal results of coronary angiography during the same period were selected as the control group. The general data of patients were recorded in detail, the content of serum hs-CRP and PAB in the peripheral blood was detected, and the number of diseased coronary vessels and the degree of stenosis were detected via coronary angiography.ResultsCompared with those in control group, the blood pressure and heart rate significantly rose, the content of indexes related to the severity of MI were significantly increased, the content of hs-CRP was significantly increased, and the content of PAB was significantly decreased in observation group. Hs-CRP was positively correlated with the number of diseased coronary vessels, degree of stenosis and heart failure in patients, but PAB was negatively correlated with the above factors. The survival rate of MI patients with high content of hs-CRP was obviously lower than that of patients with low content of hsCRPConclusionsSerum hs-CRP and PAB are closely associated with the number of diseased coronary vessels, degree of stenosis and heart failure in MI patients.     

Experimental diabetes exacerbates autophagic flux impairment during myocardial I/R injury through calpain‐mediated cleavage of Atg5/LAMP2

To explore the role of autophagic flux in the increased susceptibility of the experimental diabetic heart to ischaemia‐reperfusion (I/R) injury, we established STZ‐induced diabetic mice and performed I/R. In vitro, neonatal mouse cardiomyocytes were subjected to high glucose and hypoxia/reoxygenation challenge to mimic diabetic I/R injury. We found that experimental diabetes aggravated I/R‐induced injury than compared with nondiabetic mice. Autophagic flux was impaired in I/R hearts, and the impairment was exacerbated in diabetic mice subjected to I/R with defective autophagosome formation and clearance. Calpains, calcium‐dependent thiol proteases, were upregulated and highly activated after I/R of diabetes, while calpain inhibition attenuated cardiac function and cell death and partially restored autophagic flux. The expression levels of Atg5 and LAMP2, two crucial autophagy‐related proteins, were significantly degraded in diabetic I/R hearts, alterations that were associated with calpain activation and could be reversed by calpain inhibition. Co‐overexpression of Atg5 and LAMP2 reduced myocardial injury and normalized autophagic flux. In conclusion, experimental diabetes exacerbates autophagic flux impairment of cardiomyocytes under I/R stress, resulting in worse I/R‐induced injury. Calpain activation and cleavage of Atg5 and LAMP2 at least partially account for the deterioration of autophagic flux impairment.     

Laying low: Rugged lowland rainforest preferred by feral cats in the Australian Wet Tropics

Invasive mesopredators are responsible for the decline of many species of native mammals worldwide. Feral cats have been causally linked to multiple extinctions of Australian mammals since European colonization. While feral cats are found throughout Australia, most research has been undertaken in arid habitats, thus there is a limited understanding of feral cat distribution, abundance, and ecology in Australian tropical rainforests. We carried out camera‐trapping surveys at 108 locations across seven study sites, spanning 200 km in the Australian Wet Tropics. Single‐species occupancy analysis was implemented to investigate how environmental factors influence feral cat distribution. Feral cats were detected at a rate of 5.09 photographs/100 days, 11 times higher than previously recorded in the Australian Wet Tropics. The main environmental factors influencing feral cat occupancy were a positive association with terrain ruggedness, a negative association with elevation, and a higher affinity for rainforest than eucalypt forest. These findings were consistent with other studies on feral cat ecology but differed from similar surveys in Australia. Increasingly harsh and consistently wet weather conditions at higher elevations, and improved shelter in topographically complex habitats may drive cat preference for lowland rainforest. Feral cats were positively associated with roads, supporting the theory that roads facilitate access and colonization of feral cats within more remote parts of the rainforest. Higher elevation rainforests with no roads could act as refugia for native prey species within the critical weight range. Regular monitoring of existing roads should be implemented to monitor feral cats, and new linear infrastructure should be limited to prevent encroachment into these areas. This is pertinent as climate change modeling suggests that habitats at higher elevations will become similar to lower elevations, potentially making the environment more suitable for feral cat populations.     

急性心肌梗死合并肺部感染患者多药耐药菌分布特征及心肌酶谱指标与炎性因子的关系分析

目的:分析急性心肌梗死合并肺部感染患者多药耐药菌分布特征及炎性因子与心肌酶谱指标的关系。方法:选择2015年2月~2018年10月期间中国人民解放军联勤保障部队第940医院收治的67例急性心肌梗死合并肺部感染患者作为感染组,选取同期收治的60例单纯急性心肌梗死患者作为未感染组,分析感染组多药耐药菌的分布及其耐药性,比较两组炎性因子与心肌酶谱指标水平,采用Pearson相关性分析感染组患者炎性因子与心肌酶谱指标的相关性。结果:67例患者痰培养标本中共分离出136株病原菌,其中有64株属于多药耐药菌,多药耐药菌中革兰阴性菌38株,占59.37%,革兰阳性菌26株,占40.63%。其中主要革兰阴性菌对哌拉西林/舒巴坦、头孢哌酮/舒巴坦、阿米卡星、美罗培南、亚胺培南等较为敏感,主要革兰阳性菌对替考拉宁、万古霉素、利福平等较为敏感。感染组患者白细胞介素-6(IL-6)、乳酸脱氢酶(LDH)、促血管生成素-2(Ang-2)、肌酸激酶(CK)、肿瘤坏死因子-α(TNF-α)、谷草转氨酶(AST)、肌酸激酶同工酶(CKMB)水平均高于未感染组患者(P0.05)。经Pearson相关性分析可得,感染组患者血清IL-6、Ang-2、TNF-α水平与AST、LDH、CK、CK-MB水平均呈正相关(P0.05)。结论:急性心肌梗死合并肺部感染患者心肌酶谱与炎性因子水平关系密切,有助于判断患者病情严重程度,且急性心肌梗死合并肺部感染患者多药耐药现象较为严重,临床应针对病原菌合理选取抗菌药物。     

腔隙性脑梗死伴脑白质病变患者血清miR-146a和NSE水平与MoCA评分的关系研究

摘要 目的：研究腔隙性脑梗死（LI）伴脑白质病变（WML）患者血清miR-146a和神经元特异性烯纯化酶（NSE）水平与蒙特利尔认知评估量表（MoCA）评分的关系。方法：纳入我院从2017年3月～2019年3月收治的LI伴WML患者108例进行研究,记作LI伴WML组。另取同期收治的单纯WML患者与单纯LI患者各100例,分别记作WML组与LI组,再取同期于我院进行体检的健康人员100例作为对照组。比较四组人员的血清miR-146a和NSE水平、MoCA评分,并作相关性分析。结果：LI伴WML组、WML组、LI组血清miR-146a相对表达量均低于对照组,而LI伴WML组血清miR-146a相对表达量又显著低于WML组、LI组（均P＜0.05）;LI伴WML组、WML组、LI组血清NSE水平均显著高于对照组,且LI伴WML组血清NSE水平均显著高于WML组、LI组（均P＜0.05）。LI伴WML组MoCA总分显著低于WML组与LI组,且WML组与LI组MoCA总分显著低于对照组（均P＜0.05）。经Pearson相关性分析可得：LI伴WML组患者血清miR-146a相对表达量与MoCA总分呈正相关关系（P＜0.05）,而血清NSE水平与MoCA总分呈负相关关系（P＜0.05）。结论：LI伴WML患者的血清miR-146a水平存在明显低表达,而NSE水平存在明显高表达,并与MoCA评分相关,两者可能在认知功能损伤的发生、发展过程中起着至关重要的作用。     

静脉溶栓时机对急性ST段抬高型心肌梗死患者溶栓效果及主要不良心脏事件发生率的影响

目的:探讨静脉溶栓时机对急性ST段抬高型心肌梗死患者溶栓效果及主要不良心脏事件发生率的影响。方法:将2016年1月至2017年12月我院接诊的314例急性ST段抬高型心肌梗死患者纳入本研究,按照溶栓治疗时间不同分为A组(发病至溶栓时间6 h)172例、B组(发病至溶栓时间为6～12 h)102例和C组(发病至溶栓时间12 h)40例,比较三组患者溶栓效果、溶栓后ST段回落情况以及住院期间主要不良心脏事件发生情况。结果:A组患者梗死冠脉溶通率、溶栓后ST段回落幅度高于B组和C组,且B组高于C组,差异均有统计学意义(P0.05)。A组患者治疗后ST段回落最大幅度所需时间、住院期间主要不良心脏事件总发生率低于B组和C组,且B组低于C组,差异均有统计学意义(P0.05)。结论:急性ST段抬高型心肌梗死患者发病后6 h内静脉溶栓治疗梗死冠脉溶通率更高、ST段回落效果更好,可降低住院期间主要不良心脏事件发生风险。