Fisetin for COVID-19 in skilled nursing facilities: Senolytic trials in the COVID era

The burden of senescent cells (SnCs), which do not divide but are metabolically active and resistant to death by apoptosis, is increased in older adults and those with chronic diseases. These individuals are also at the greatest risk for morbidity and mortality from SARS-CoV-2 infection. SARS-CoV-2 complications include cytokine storm and multiorgan failure mediated by the same factors as often produced by SnCs through their senescence-associated secretory phenotype (SASP). The SASP can be amplified by infection-related pathogen-associated molecular profile factors. Senolytic agents, such as Fisetin, selectively eliminate SnCs and delay, prevent, or alleviate multiple disorders in aged experimental animals and animal models of human chronic diseases, including obesity, diabetes, and respiratory diseases. Senolytics are now in clinical trials for multiple conditions linked to SnCs, including frailty; obesity/diabetes; osteoporosis; and cardiovascular, kidney, and lung diseases, which are also risk factors for SARS-CoV-2 morbidity and mortality. A clinical trial is underway to test if senolytics decrease SARS-CoV-2 progression and morbidity in hospitalized older adults. We describe here a National Institutes of Health-funded, multicenter, placebo-controlled clinical trial of Fisetin for older adult skilled nursing facility (SNF) residents who have been, or become, SARS-CoV-2 rtPCR-positive, including the rationale for targeting fundamental aging mechanisms in such patients. We consider logistic challenges of conducting trials in long-term care settings in the SARS-CoV-2 era, including restricted access, consent procedures, methods for obtaining biospecimens and clinical data, staffing, investigational product administration issues, and potential solutions for these challenges. We propose developing a national network of SNFs engaged in interventional clinical trials.     

Potential involvement of cellular ageing in the pathogenesis of arthritis

Recently, attention has been drawn to the involvement of cellular ageing in the pathogenesis of bone and joint diseases. We reviewed the mechanism underlying degeneration of bone and cartilage tissues, from a viewpoint of the senescence of cells composing the joints. We demonstrated not only the mechanism controlling ageing but also the development of new methods of treatment and prophylactic measures for diseases affecting bone and joint tissues in the future.     

脑钠肽在先天性心脏病临床评估中的应用潜力

脑钠肽是心室肌细胞在室壁牵张力刺激下分泌的一类肽类激素,因其反映心室前后负荷及收缩、舒张功能的敏感性与无创性,广泛用于各种心血管疾病研究中。现主要针对血浆脑钠肽水平在先天性心脏病的早期诊断、危险性分层和预后评估等方面的应用潜力作一概述。     

Melatonin protects chronic kidney disease mesenchymal stem cells against senescence via PrPC‐dependent enhancement of the mitochondrial function

Although mesenchymal stem cell (MSC)‐based therapy is a treatment strategy for ischemic diseases associated with chronic kidney disease (CKD), MSCs of CKD patients undergo accelerated senescence, with decreased viability and proliferation upon uremic toxin exposure, inhibiting their utility as a potent stem cell source for transplantation therapy. We investigated the effects of melatonin administration in protecting against cell senescence and decreased viability induced by pathophysiological conditions near the engraftment site. MSCs harvested from CKD mouse models were treated with H₂O₂ to induce oxidative stress. CKD‐derived MSCs exhibited greater oxidative stress‐induced senescence than normal‐mMSCs, while melatonin protected CKD‐mMSCs from H₂O₂ and associated excessive senescence. The latter was mediated by PrP^C‐dependent mitochondrial functional enhancement; melatonin upregulated PrP^C, which bound PINK1, thus promoting mitochondrial dynamics and metabolism. In vivo, melatonin‐treated CKD‐mMSCs survived longer, with increased secretion of angiogenic cytokines in ischemic disease engraftment sites. CKD‐mMSCs are more susceptible to H₂O₂‐induced senescence than normal‐mMSCs, and melatonin administration protects CKD‐mMSCs from excessive senescence by upregulating PrP^C and enhancing mitochondrial function. Melatonin showed favorable therapeutic effects by successfully protecting CKD‐mMSCs from related ischemic conditions, thereby enhancing angiogenesis and survival. These results elucidate the mechanism underlying senescence inhibition by melatonin in stem cell‐based therapies using mouse‐derived CKD‐mMSCs.     

Therapeutic Effects of SRT2104 on Lung Injury in Rats with Emphysema via Reduction of Type II Alveolar Epithelial Cell Senescence

Abstract

Chronic obstructive pulmonary disease (COPD) is one of the most prevalent and severe diseases worldwide with high societal and health care costs. The pathogenesis of COPD is very complicated, and no curative treatment is available. Cellular senescence promotes the development of COPD. Type II alveolar epithelial cells (AECII) play a momentous role in lung tissue repair and maintenance of alveolar homeostasis. Sirtuin 1 (SIRT1), an antiaging molecule involved in the response to chronic inflammation and oxidative stress, regulates many pathophysiological changes including stress resistance, apoptosis, inflammation, and cellular senescence. This study aimed to investigate whether the pharmacological SIRT1 activator SRT2104 protects against AECII senescence in rats with emphysema. Our findings confirmed that SRT2104 administration reduced the pathological characteristics of emphysema and improved lung function parameters, including pulmonary resistance, pulmonary dynamic compliance, and peak expiratory flow. Moreover, SRT2104 treatment upregulated the expression of surfactant proteins A and C, SIRT1, and forkhead box O 3a (FoxO3a), decreased senescence-associated-β-galactosidase (SA-β-gal) activity, increased SIRT1 deacetylase activity, and downregulated the levels of p53 and p21. Therefore, SRT2104 administration protected against AECII senescence in rats with emphysema via SIRT1/FoxO3a and SIRT1/p53 signaling pathways and may provide a novel potential therapeutic strategy for COPD.     

miRNAs as Potential Biomarkers for Viral Hepatitis B and C

Around 257 million people are living with hepatitis B virus (HBV) chronic infection and 71 million with hepatitis C virus (HCV) chronic infection. Both HBV and HCV infections can lead to liver complications such as cirrhosis and hepatocellular carcinoma (HCC). To take care of these chronically infected patients, one strategy is to diagnose the early stage of fibrosis in order to treat them as soon as possible to decrease the risk of HCC development. microRNAs (or miRNAs) are small non-coding RNAs which regulate many cellular processes in metazoans. Their expressions were frequently modulated by up- or down-regulation during fibrosis progression. In the serum of patients with HBV chronic infection (CHB), miR-122 and miR-185 expressions are increased, while miR-29, -143, -21 and miR-223 expressions are decreased during fibrosis progression. In the serum of patients with HCV chronic infection (CHC), miR-143 and miR-223 expressions are increased, while miR-122 expression is decreased during fibrosis progression. This review aims to summarize current knowledge of principal miRNAs modulation involved in fibrosis progression during chronic hepatitis B/C infections. Furthermore, we also discuss the potential use of miRNAs as non-invasive biomarkers to diagnose fibrosis with the intention of prioritizing patients with advanced fibrosis for treatment and surveillance.     

C反应蛋白在AECOPD的意义

目的探讨C反应蛋白（CRP）在慢性阻塞性肺疾病急性加重期（AECOPD）变化的意义及临床应用价值。方法检测152例AECOPD患者及88名COPD缓解期患者CRP、白细胞计数（WBC）、中性粒细胞计数百分比（N）、血沉（ESR）,疾培养及X线胸片,同时对152例AECOPD患者给予抗感染治疗,并比较这些指标治疗前后的变化。结果AECOPD患者血清CRP水平显著高于COPD稳定期患者（P〈0．01）,而在AECOPD患者死亡组血清CRP水平又显著高于存活组（P〈0．001）。结论CRP升高不仅可以提示COPD的急性加重,极度升高又提示COPD患者病情严重并且可能预后不良。CRP在AECOPD是一个良好的观察指标,可反映抗生素的即时疗效,比WBC,ESR更迅速且敏感。     

Melatonin suppresses doxorubicin‐induced premature senescence of A549 lung cancer cells by ameliorating mitochondrial dysfunction

Abstract: Melatonin is an indolamine that is synthesized in the pineal gland and shows a wide range of physiological functions. Although the anti‐aging properties of melatonin have been reported in a senescence‐accelerated mouse model, whether melatonin modulates cellular senescence has not been determined. In this study, we examined the effect of melatonin on anticancer drug‐induced cellular premature senescence. We found that the doxorubicin (DOX)‐induced senescence of A549 human lung cancer cells and IMR90 normal lung cells was substantially inhibited by cotreatment with melatonin in a dose‐dependent manner. Mechanistically, the DOX‐induced G2/M phase cell cycle arrest and the decrease in cyclinB and cdc2 expression were not affected by melatonin. However, the DOX‐induced increase in intracellular levels of ROS, which is necessary for premature senescence, was completely abolished upon melatonin cotreatment. In addition, the reduction in mitochondrial membrane potential that occurs upon DOX treatment was inhibited by melatonin. An aberrant increase in mitochondrial respiration was also significantly suppressed by melatonin, indicating that melatonin ameliorates the mitochondrial dysfunction induced by DOX treatment. The treatment of A549 cells with luzindole, a potent inhibitor of melatonin receptors, failed to prevent the effects of melatonin treatment on mitochondrial functions and premature senescence in cells also treated with DOX; this suggests that melatonin suppresses DOX‐induced senescence in a melatonin receptor‐independent manner. Together, these results reveal that melatonin has an inhibitory effect of melatonin on premature senescence at the cellular level and that melatonin protects A549 cells from DOX‐induced senescence. Thus, melatonin might have the therapeutic potential to prevent the side effects of anticancer drug therapy.     

COPD急性加重期血清C反应蛋白与前白蛋白检测的临床意义

目的 探讨慢性阻塞性肺疾病(COPD)患者急性加重期C反应蛋白(CRP)和前白蛋白检测的临床意义.方法 检测56例COPD急性加重期患者治疗前后血浆CRP和前白蛋白水平,同时选择54例正常健康体检者作为正常对照组,对上述检测结果进行比较和分析.结果 COPD急性加重期CRP水平明显升高,治疗后明显下降,且均大于正常对照组表达水平,组间比较差异有统计学意义(P＜0.05);COPD急性加重期前白蛋白水平明显下降,治疗后明显上升,且均小于正常对照组,组间比较差异有统计学意义(P＜O.05).结论 CRP和前白蛋白是反映COPD急性加重期感染和疗效判断的敏感指标.     

Re-expression of senescent markers in deinduced reversibly immortalized cells

We have developed a simian virus 40 (SV40) T-antigen immortalized human cell line, 1MR90-D305.2H4 (IDH4), in which the expression of T-antigen is controlled by the mouse mammary tumor virus (MMTV) promoter and thus regulated by steroids such as dexamethasone. Studies on the regulation of proliferation by T-antigen led to the formulation of a two-stage model for human cell immortalization, in which a mortality stage 1 mechanism (M1) was the target of T-antigen action, and an independent mortality stage 2 mechanism (M2) produced crisis and prevented T-antigen from directly immortalizing cells. Rarely, a cell expressing T-antigen escaped crisis (e.g., M2) and was capable of indefinite proliferation. This model predicted that the deinduction of T-antigen in IDH4 cells would lead to the reexpression of the M1 mechanism, and thus a reexpression of the senescent phenotype. Our study confirms the prediction that, in the absence of steroids, IDH4 cells express a variety of morphological and biochemical markers characteristic of normal senescent human fibroblasts.     

糖皮质激素对痰嗜酸性粒细胞阳性COPD患者的疗效评价

目的论证痰检嗜酸粒细胞阳性的COPD患者是否预示吸入糖皮质激素的临床和功能反应较好。方法60例痰检嗜酸粒细胞阳性的AECOPD患者随机分为治疗组(28例)及对照组(32例),治疗组应用糖皮质激素及常规治疗,对照组应用糖皮质激素(静脉予甲基强的松龙40 mg/d×0～3天后即停用)及常规治疗,共6个月。常规治疗包括:控制性氧疗,抗感染,化痰,止咳,应用支气管舒张剂等。治疗前及治疗后10天、30天测FEV1、FEV1占预计值百分比、FEV1/FVC,统计6个月内首次COPD严重急性发作时间和COPD急性加重发生率。结果治疗组FEV1、FEV1占预计值百分比、FEV1/FVC均有明显提高,两组之间差异有显著性(P0.05),治疗组首次COPD严重急性发作时间(98.21±36.35天)较对照组(63.54±25.62)明显延长(P0.05),治疗组的COPD急性加重发生率34.5%明显少于对照组48.6%。结论痰检嗜酸粒细胞阳性患者预示吸入糖皮质激素的临床和功能反应较好,痰检嗜酸粒细胞阳性是临床COPD患者应用糖皮质激素的指标,值得临床推广应用。     

Biology of extracellular vesicles secreted from senescent cells as senescence‐associated secretory phenotype factors

The increase of the morbidity rate in age‐related diseases, such as cancer, Alzheimer’s disease, arteriosclerosis and pulmonary fibrosis, has become a profound social problem. Recent reports have pointed out that senescent cells accumulated in the body with aging might cause these aged‐related pathologies. Cellular senescence is known as an irreversible cell cycle arrest induced by various stresses, and can function as an important tumor suppression mechanism to exclude the premalignant cells. In contrast, senescent cells provoke the phenomenon, termed the senescence‐associated secretory phenotype, which causes the secretion of various inflammatory proteins, and it is at risk of facilitating chronic inflammation and oncogenic transformation to surrounding cells. We have previously reported that senescent cells secrete not only inflammatory proteins, but also extracellular vesicles (EV). EV include various cellular components, such as proteins, lipids and nucleic acids, which are proven to be important factors for cell‐to‐cell communication. Recent evidence suggests that EV secreted from senescent cells might contribute to tumorigenesis and age‐associated pathologies as new senescence‐associated secretory phenotype factors. In addition, we also showed that the EV secretion pathway is one of the essential defense mechanisms to maintain cellular homeostasis by excretion of intercellular toxic substances into extracellular space. Herein, this review shows the biological functions of EV secreted from senescent cells. Geriatr Gerontol Int 2020; ??: ??–?? .     

静息能量消耗测定在老年慢病人群中的应用

人体每日能量消耗的精确测定有助于个体化营养治疗方案的制定,防止出现营养过剩或营养不良,使营养治疗受益最大化。影响静息能量消耗的因素有很多,如体型与机体构成、性别、年龄、疾病、环境条件等,本文主要对静息能量消耗测定在不同慢病时期老年人群中的临床应用加以综述。     

慢性阻塞性肺疾病急性发作与低钠血症的关系

目的探讨慢性阻塞性肺疾病（COPD）急性发作患者发生低钠血症的病因及治疗的重要性。方法70例COPD住院患者,其中ICU患者加例,普通病房患者50例,观察其血钠情况,可能发生低血钠的原因及酸碱失衡的情况,并分析其中的关系。结果COPD急性发作的ICU患者低钠血症发生率明显高于普通病房,与病情严重程度存在明显的相关性。结论低钠血症病因复杂,与疾病的发展程度及医源性因素有关,在综合治疗原发病的基础上,应定期检测血电解质并给予及时处理,以降低死亡率。     

重症慢性呼吸道疾病合并侵袭性肺曲霉病的临床特点

目的 总结重症慢性呼吸道疾病(CRD)合并侵袭性肺曲霉病(IPA)的临床特点,为早期诊断和治疗提供依据.方法 分析2004年10月至2007年2月在北京朝阳医院呼吸科重症监护室(RICU)住院的149例痰或BALF分离出曲霉的CRD患者资料.以SPSS 10.0统计软件进行数据处理,所有计量资料以均数±标准差表示,计数资料以例数表示.计量资料采用t检验,计数资料采用X2检验.结果 149例CRD患者中共收集16例IPA病例(COPD 11例,COPD合并支气管哮喘4例,支气管扩张症1例),其中3例确诊,10例临床诊断,3例拟诊.12例在人RICU前使用过大量糖皮质激素,15例使用广谱抗生素.15例临床表现为严重气道痉挛,9例行无创通气失败,14例因严重呼吸衰竭而需有创机械通气.12例X线胸片可见明显渗出影.外周血白细胞及中性粒细胞比例在疾病后期迅速增高;早期气管镜检查可见气道黏膜充血、水肿、糜烂,气道痉挛,痰液黏稠,后期气道黏膜可出现伪膜;早期真菌病原学检查阳性率低(2/12),后期阳性率高(10/12);早期治疗的患者存活率高(4/4),晚期治疗效果差(11/12),由呼吸衰竭迅速进展为多脏器衰竭是最主要的死亡原因.结论 CRD合并IPA并不少见,预后差.根据临床特点进行早期诊断及经验性治疗可改善患者的预后.     

The impact of novel coronavirus COVID-19 on noncommunicable disease patients and health systems: a review

Coronavirus disease 2019 (COVID-19) is an ongoing global pandemic affecting all levels of health systems. This includes the care of patients with noncommunicable diseases (NCDs) who bear a disproportionate burden of both COVID-19 itself and the public health measures enacted to combat it. In this review, we summarize major COVID-19-related considerations for NCD patients and their care providers, focusing on cardiovascular, pulmonary, renal, haematologic, oncologic, traumatic, obstetric/gynaecologic, operative, psychiatric, rheumatologic/immunologic, neurologic, gastrointestinal, ophthalmologic and endocrine disorders. Additionally, we offer a general framework for categorizing the pandemic’s disruptions by disease-specific factors, direct health system factors and indirect health system factors. We also provide references to major NCD medical specialty professional society statements and guidelines on COVID-19. COVID-19 and its control policies have already resulted in major disruptions to the screening, treatment and surveillance of NCD patients. In addition, it differentially impacts those with pre-existing NCDs and may lead to de novo NCD sequelae. Likely, there will be long-term effects from this pandemic that will continue to affect practitioners and patients in this field for years to come.     

老年多器官衰竭发病危险因素的临床分析

目的探讨老年多器官衰竭(MOFE)发病的危险因素。方法入选2013年1月至2016年2月期间上海交通大学附属瑞金医院卢湾分院老年科、重症监护病房、心血管内科、神经内科及消化内科收治住院的老年患者656例,依据是否发生MOFE分为两组:MOFE组(n=280)和非MOFE组(n=376)。收集患者的临床资料,了解发病前患者慢性基础疾病的情况。通过逐步logistic回归分析筛选MOFE发病的独立危险因素。结果 MOFE发病前患者一般均存在≥2种慢性疾病。慢性心功能不全、慢性呼吸衰竭、脑血管疾病、肾功能不全和糖尿病是影响MOFE发病的独立危险因素。结论慢性基础疾病是发生MOFE的重要病理基础,对于存在危险因素的老年患者,应加强对相关慢性疾病的治疗,积极保护和改善各脏器功能,从而降低MOFE的发生率和病死率。     

丙型肝炎病毒慢性感染相关的系统性自身免疫病分析

目的描述和分析丙型肝炎病毒(HCV)慢性感染相关系统性自身免疫病(SAD)患者的临床表现、实验室检查特征、治疗及预后。方法对1989年至2009年北京协和医院收治的12例HCV慢性感染相关SAD患者的临床表现、实验室检查特征及治疗情况进行统计和分析。结果 12例患者在发现慢性HCV感染后发生SAD,其中5例系统性红斑狼疮(SLE)、2例冷球蛋白血症、1例显微镜下多血管炎(MPA)、1例结节性多动脉炎(PAN)、1例系统性硬化(SSc)、1例类风湿关节炎(RA)合并多发性肌炎(PM)、1例皮肌炎(DM)。男女比例为1:11,发现慢性HCV感染时平均年龄为39.8岁(18～62岁),SAD平均发病年龄为41.5岁(23～62岁)。所有患者都符合相应SAD的分类标准,最常见临床表现为血液系统受累(83.3%)和皮肤受累(66.7%),最常见实验室检查特征为抗核抗体(ANA)阳性(83.3%),红细胞沉降率增快(83.3%)和低补体血症(75.0%)。对5例SLE患者进行亚组分析显示,其临床表现和实验室检查结果与一般SLE患者差异无显著性。此外,12例伴发SAD的慢性HCV感染者中,11例(91.7%)丙氨酸转氨酶(ALT)水平正常,ALT正常率显著高于慢性HCV感染患者的平均水平(P<0.01)。SAD的治疗,除1例患者拒绝治疗自行出院外,其余11例患者采用糖皮质激素联合免疫抑制剂治疗均可有效控制SAD。慢性HCV感染的治疗,1例治疗前ALT水平升高患者拒绝干扰素联合利巴韦林抗病毒治疗,剩余11例ALT水平正常患者中3例接受治疗,其中1例由于干扰素使用后白细胞数下降而停用,余2例均获得了持续病毒学应答(SVR)。接受抗病毒治疗的3例患者中,有2例因SAD活动再次入院治疗;未接受抗病毒治疗的9例患者有3例因SAD活动再次入院(P>0.05)。结论 HCV慢性感染相关的SAD在临床表现及实验室检查特征上与未合并HCV慢性感染时相比无差异,使用糖皮质激素联合免疫抑制剂治疗仍安全有效。出现SAD的HCV慢性感染患者的肝炎表现较轻微,ALT大多处于正常范围,是否使用抗病毒治疗需根据个体情况确定。