Genetic aberrations in macroautophagy genes leading to diseases

The catabolic process of macroautophagy, through the rapid degradation of unwanted cellular components, is involved in a multitude of cellular and organismal functions that are essential to maintain homeostasis. Those functions include adaptation to starvation, cell development and differentiation, innate and adaptive immunity, tumor suppression, autophagic cell death, and maintenance of stem cell stemness. Not surprisingly, an impairment or block of macroautophagy can lead to severe pathologies. A still increasing number of reports, in particular, have revealed that mutations in the autophagy-related (ATG) genes, encoding the key players of macroautophagy, are either the cause or represent a risk factor for the development of several illnesses. The aim of this review is to provide a comprehensive overview of the diseases and disorders currently known that are or could be caused by mutations in core ATG proteins but also in the so-called autophagy receptors, which provide specificity to the process of macroautophagy. Our compendium underlines the medical relevance of this pathway and underscores the importance of the eventual development of therapeutic approaches aimed at modulating macroautophagy.     

Supplementation of grazing beef cows during gestation as a strategy to improve skeletal muscle development of the offspring

The appropriate supply of nutrients in pregnant cows has been associated with the optimal development of foetal tissues, performance of their progeny and their meat quality. The aim of this study was to evaluate supplementation effects of grazing cows in different stages of gestation on skeletal muscle development and performance of the progeny. Thereby, 27 Nellore cows were divided into three groups (n=9 for each group) and their progeny as follows: UNS, unsupplemented during gestation; MID, supplemented from 30 to 180 days of gestation; LATE, supplemented from 181 to 281 days of gestation. The percentage composition of the supplement provided for the matrices was the following: ground corn (26.25%), wheat bran (26.25%) and soya bean meal (47.5%). The supplement was formulated to contain 30% CP. Supplemented matrices received 150 kg of supplement (1 and 1.5 kg/day for cows in the MID and LATE groups, respectively). After birth, a biopsy was performed to obtain samples of skeletal muscle tissue from calves to determine number and size of muscle fibres and for messenger RNA (mRNA) expression analysis. The percentage composition of the supplement provided for the progeny was the following: ground corn grain (30%), wheat bran (30%), soya bean meal (35%) and molasses (5%). The supplement was formulated to contain 25% CP and offered in an amount of 6 g/kg BW. Performance of the progeny was monitored throughout the suckling period. Means were submitted to ANOVA and regression, and UNS, MID and LATE periods of supplementation were compared. Differences were considered at P<0.10. Birth weight, average daily gain and weaning weight of the offspring did not differ among treatments (P>0.10). Similarly, no differences were observed between calves for nutrient intake (P>0.10). However, greater subcutaneous fat thickness (P=0.006) was observed in the calves of LATE group. The ribeye area (P=0.077) was greater in calves born from supplemented compared with UNS cows. The supplementation of pregnant cows did not affect the muscle fibre size of their progeny (P=0.208). On the other hand, calves born from dams supplemented at mid-gestation had greater muscle fibre number (P=0.093) compared with calves from UNS group. Greater mRNA expression of peroxysome proliferator-activated receptor α (P=0.073) and fibroblast growth factor 2 (P=0.003) was observed in the calves born from MID cows. Although strategic supplementation did not affect the BW of offspring, it did cause changes in carcass traits, number of myofibres, and mRNA expression of a muscle hypertrophy and lipid oxidation markers in skeletal muscle of the offspring.     

Secretory phospholipase A2 in SARS-CoV-2 infection and multisystem inflammatory syndrome in children (MIS-C)

Secretory phospholipase 2 (sPLA2) acts as a mediator between proximal and distal events of the inflammatory cascade. Its role in SARS-CoV-2 infection is unknown, but could contribute to COVID-19 inflammasome activation and cellular damage. We present the first report of plasma sPLA2 levels in adults and children with COVID-19 compared with controls. Currently asymptomatic adults with a history of recent COVID-19 infection (≥4 weeks before) identified by SARS-CoV-2 IgG antibodies had sPLA2 levels similar to those who were seronegative (9 ± 6 vs.17 ± 28 ng/mL, P = 0.26). In contrast, children hospitalized with severe COVID-19 had significantly elevated sPLA2 compared with those with mild or asymptomatic SARS-CoV-2 infection (269 ± 137 vs. 2 ± 3 ng/mL, P = 0.01). Among children hospitalized with multisystem inflammatory syndrome in children (MIS-C), all had severe disease requiring pediatric intensive care unit (PICU) admission. sPLA2 levels were significantly higher in those with acute illness <10 days versus convalescent disease ≥10 days (540 ± 510 vs. 2 ± 1, P = 0.04). Thus, sPLA2 levels correlated with COVID-19 severity and acute MIS-C in children, implicating a role in inflammasome activation and disease pathogenesis. sPLA2 may be a useful biomarker to stratify risk and guide patient management for children with acute COVID-19 and MIS-C. Therapeutic compounds targeting sPLA2 and inflammasome activation warrant consideration.     

Down-regulation of miR-let-7e attenuates LPS-induced acute lung injury in mice via inhibiting pulmonary inflammation by targeting SCOS1/NF-κB pathway

Excessive pulmonary inflammatory response is critical in the development of acute lung injury (ALI). Previously, microRNAs (miRNAs) have been recognized as an important regulator of inflammation in various diseases. However, the effects and mechanisms of miRNAs on inflammatory response in ALI remain unclear. Herein, we tried to screen miRNAs in the processes of ALI and elucidate the potential mechanism. Using a microarray assay, microRNA let-7e (let-7e) was chose as our target for its reported suppressive roles in several inflammatory diseases. Down-regulation of let-7e by antagomiR-let-7e injection attenuated LPS-induced acute lung injury. We also found that antagomiR-let-7e could obviously improve the survival rate in ALI mice. Moreover, antagomiR-let-7e treatment reduced the production of proinflammatory cytokines (i.e., TNF-α, IL-1β and IL-6) in bronchoalveolar lavage fluid (BALF) of LPS-induced ALI mice. Luciferase reporter assays confirmed that suppressor of cytokine signaling 1 (SOCS1), a powerful attenuator of nuclear factor kappa B (NF-κB) signaling pathway, was directly targeted and suppressed by let-7e in RAW264.7 cells. In addition, it was further observed that SOCS1 was down-regulated, and inversely correlated with let-7e expression levels in lung tissues of ALI mice. Finally, down-regulation of let-7e suppressed the activation of NF-κB pathway, as evidenced by the reduction of p-IκBα, and nuclear p-p65 expressions in ALI mice. Collectively, our findings indicate that let-7e antagomir protects mice against LPS-induced lung injury via repressing the pulmonary inflammation though regulation of SOCS1/NF-κB pathway, and let-7e may act as a potential therapeutic target for ALI.     

盆底肌功能训练联合阴茎夹对前列腺增生术后患者尿失禁的临床应用分析

目的:分析盆底肌功能训练联合阴茎夹对前列腺增生术后患者尿失禁的临床应用效果。方法:选取我院2017年4月～2019年4月收治的72例前列腺增生术后尿失禁患者,随机分为对照组和观察组各36例,两组均予盆底肌功能训练,观察组加用阴茎夹控制排尿。对比两组术后尿失禁改善情况、排尿改善情况、国际尿失禁咨询委员会尿失禁问卷表简表(ICI-Q-SF)评分变化、压力性尿失禁分度评价及经济费用情况。结果:两组干预后20 d、干预后30 d、干预后90 d尿失禁发生率均较干预后10 d下降,观察组干预后10 d、干预后20 d、干预后30 d、干预后90 d尿失禁发生率均低于对照组,差异均有统计学意义(P0.05)。两组干预后90 d每日总尿量较干预前升高,每日总排尿次数、每日总漏尿次数均较干预前下降;观察组干预后90 d每日总尿量高于对照组,每日总排尿次数、每日总漏尿次数均低于对照组,差异均有统计学意义(P0.05)。两组干预后90d ICI-Q-SF评分均较干预前下降,且观察组干预后90d ICI-Q-SF评分低于对照组,差异均有统计学意义(P0.05)。观察组患者干预后压力性尿失禁临床治愈率高于对照组,差异有统计学意义(P0.05)。两组患者压力性尿失禁分度情况比较差异无统计学意义(P0.05)。观察组阴茎夹使用费用为(70.26±8.51)元,低于对照组的(388.71±26.44)元,差异有统计学意义(P0.05)。结论:在盆底肌功能训练的基础上联合阴茎夹能够有效改善前列腺增生术后患者尿失禁症状及生活质量,且有助于降低患者经济负担,值得临床推广应用。     

长链非编码RNA KCNQ1OT1影响脂多糖诱导的血管内皮细胞凋亡及其炎性因子表达的机制

该研究探讨了长链非编码RNA KCNQ1OT1对脂多糖(LPS)诱导的血管内皮细胞(VEC)凋亡和炎性因子表达的影响以及其可能机制.通过体外培养VEC,分别转染KCNQ1OT1过表达载体、miR-223抑制剂或共转染KCNQ1OT1过表达载体与miR-223模拟物后,用1.0mg/mLLPS干预24h,然后采用RT-q...     

肌萎缩侧索硬化患者血清SOD、GSH-Px、MIP-1α、VEGF水平与肌电图特征及病程的关系研究

摘要 目的：研究肌萎缩侧索硬化（ALS）患者血清超氧化物歧化酶（SOD）、谷胱甘肽过氧化物酶（GSH-Px）、巨噬细胞炎性蛋白-1α（MIP-1α）、血管内皮生长因子（VEGF）水平与肌电图特征及病程的关系。方法：将从2018年12月起直至2020年12月,我院收治的ALS患者86例纳入研究,记作病变组。另取同期90例于我院进行体检的健康人员作为对照组。检测并比较两组血清SOD、GSH-Px、MIP-1α、VEGF水平及肌电图特征。将所有病变组患者根据病程的差异分为病程较长组42例以及病程较短组44例,比较两组血清SOD、GSH-Px、MIP-1α、VEGF水平以及肌萎缩侧索硬化症功能评分量表（ALSFRS-r）评分。采用Pearson相关性分析ALS患者血清SOD、GSH-Px、MIP-1α、VEGF水平与肌电图特征及病程的关系。结果：病变组血清SOD、GSH-Px水平均低于对照组,而MIP-1α、VEGF水平均高于对照组（均P＜0.05）。病变组各项肌电图参数水平均低于对照组（均P＜0.05）。病程较长组血清SOD、GSH-Px水平以及ALSFRS-r评分均低于病程较短组,而MIP-1α、VEGF水平均高于病程较短组（均P＜0.05）。经Pearson相关性分析可得：ALS患者血清SOD、GSH-Px水平与肌电图各神经符合肌肉动作电位（CMAP）、ALSFRS-r评分均呈正相关,与病程呈负相关（均P＜0.05）;MIP-1α、VEGF水平则与肌电图各神经CMAP、ALSFRS-r评分均呈负相关,与病程呈正相关（均P＜0.05）。结论：ALS患者血清SOD、GSH-Px水平较低,MIP-1α、VEGF水平较高,且和肌电图特征以及病程密切相关,值得临床关注。     

纳米二氧化硅复合寒冷对A549细胞毒性及其炎性因子分泌的影响

目的:本研究旨在探讨纳米二氧化硅(Nano-SiO2)颗粒和寒冷复合对人肺腺癌上皮细胞A549细胞毒性及炎性因子分泌的影响。方法:本研究以A549细胞为实验对象,分别用10,50,100,200μg/ml Nano-SiO2颗粒对A549细胞染毒,以及分别在35℃,33℃,31℃条件下对A549细胞进行低温暴露,培养48 h后,观察细胞形态及测定细胞相对存活率。根据单因素分析结果,选出对A549细胞相对存活率有显著降低作用的Nano-SiO2剂量和温度的基础上,按照2×2析因设计实验,分为4组:①37℃对照组;②Nano-SiO2染毒组;③低温暴露组;④Nano-SiO2和低温复合组,不同条件下暴露48 h后,收集细胞上清液采用比色法检测LDH活性,以及ELISA法测定细胞因子白介素-6(IL-6)和白介素-8(IL-8)的水平,采用q RT-PCR法检测细胞IL-6和IL-8的基因表达水平。结果:100μg/ml Nano-SiO2组和31℃低温组能够显著降低A549细胞活性(P<0.01),在复合条件作用下对A549细胞活性抑制最为显著,且炎性因子IL-6和IL-8及m RN...