In recent years, emphasis has shifted from preventing and treating chronic obstructive pulmonary disease (COPD) to early prevention, early treatment, and disease stabilization, with the main goal of improving patients’ quality of life and reducing the frequency of acute exacerbations. This review summarizes pharmacological therapies for stable COPD.
{"title":"Pharmacological therapy for stable chronic obstructive pulmonary disease","authors":"Ruirui Duan, Baicun Li, Ting Yang","doi":"10.1002/cdt3.65","DOIUrl":"10.1002/cdt3.65","url":null,"abstract":"<p>In recent years, emphasis has shifted from preventing and treating chronic obstructive pulmonary disease (COPD) to early prevention, early treatment, and disease stabilization, with the main goal of improving patients’ quality of life and reducing the frequency of acute exacerbations. This review summarizes pharmacological therapies for stable COPD.</p>","PeriodicalId":32096,"journal":{"name":"Chronic Diseases and Translational Medicine","volume":"9 2","pages":"82-89"},"PeriodicalIF":0.0,"publicationDate":"2023-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/95/4f/CDT3-9-82.PMC10249181.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9621259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease and the third leading cause of death worldwide. Developments in next-generation sequencing technology have improved microbiome analysis, which is increasingly recognized as an important component of disease management. Similar to the gut, the lung is a biosphere containing billions of microbial communities. The lung microbiome plays an important role in regulating and maintaining the host immune system. The microbiome composition, metabolites of microorganisms, and the interactions between the lung microbiome and the host immunity profoundly affect the occurrence, development, treatment, and prognosis of COPD. In this review, we drew comparisons between the lung microbiome of healthy individuals and that of patients with COPD. Furthermore, we summarize the intrinsic interactions between the host and the overall lung microbiome, focusing on the underlying mechanisms linking the microbiome to the host innate and adaptive immune response pathways. Finally, we discuss the possibility of using the microbiome as a biomarker to determine the stage and prognosis of COPD and the feasibility of developing a novel, safe, and effective therapeutic target.
{"title":"Interactions between the lung microbiome and host immunity in chronic obstructive pulmonary disease","authors":"Yixing Zhu, De Chang","doi":"10.1002/cdt3.66","DOIUrl":"10.1002/cdt3.66","url":null,"abstract":"<p>Chronic obstructive pulmonary disease (COPD) is a common chronic respiratory disease and the third leading cause of death worldwide. Developments in next-generation sequencing technology have improved microbiome analysis, which is increasingly recognized as an important component of disease management. Similar to the gut, the lung is a biosphere containing billions of microbial communities. The lung microbiome plays an important role in regulating and maintaining the host immune system. The microbiome composition, metabolites of microorganisms, and the interactions between the lung microbiome and the host immunity profoundly affect the occurrence, development, treatment, and prognosis of COPD. In this review, we drew comparisons between the lung microbiome of healthy individuals and that of patients with COPD. Furthermore, we summarize the intrinsic interactions between the host and the overall lung microbiome, focusing on the underlying mechanisms linking the microbiome to the host innate and adaptive immune response pathways. Finally, we discuss the possibility of using the microbiome as a biomarker to determine the stage and prognosis of COPD and the feasibility of developing a novel, safe, and effective therapeutic target.</p>","PeriodicalId":32096,"journal":{"name":"Chronic Diseases and Translational Medicine","volume":"9 2","pages":"104-121"},"PeriodicalIF":0.0,"publicationDate":"2023-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cdt3.66","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9674231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The amyloid hypothesis states that the buildup of ß-amyloid in the brain is the main factor for Alzheimer's disease (AD) pathogenesis. An imbalance between ß-amyloid production and ß-amyloid clearance causes the advanced stages of the disease, including the development of neurofibrillary tangles containing tau protein.1
Many medications that aim to reduce ß-amyloid in AD are not clinically effective. FDA has approved aducanumab, one of four anti-ß-amyloid antibodies that have been demonstrated to mediate the removal of amyloid plaque from the brains of AD patients. FDA accepted the decrease of amyloid plaque as a surrogate endpoint for aducanumab. But there is intense disagreement over the justification for approval and the scope of the clinical benefit provided by antiamyloid antibodies.2
One side effect of the antibodies is brain edema, effusion, and hemorrhages, so called amyloid-related imaging abnormalities (ARIA). ARIA occurs in aged squirrel monkeys as well as in humans.3
Lecanemab, an antiamyloid monoclonal antibody, was associated with edema or effusions in 12.4% of subjects, including three fatal brain hemorrhages; the placebo group had 1.7% brain edema.4-9 In the case of donanemab, another anti-amyloid monoclonal antibody, if edema or effusion occurred with the first three doses of the drug, the dosage was not increased.10
A serious clinical condition, brain edema is defined by a pathological swelling of the brain tissue brought on by an increase in the water content of the brain. In humans11 and in a mouse model, APOE isoform affects neurological prognosis following intracerebral hemorrhage. Poor functional outcome and more cerebral edema are linked to APOE4.12 Three SNPs of the ABCC8 gene, rs2283261, rs3819521, and rs2283258, are significantly associated with brain edema, measured by increased intracranial pressure and CT imaging. Haptoglobin type, Hp2 versus Hp1, may also influence brain edema.13
Aquaporins, a family of water channel proteins that have been found in animals, may provide an explanation for AD brain edema. Aquaporin-4 (AQP4), the most significant form of aquaporin in the central nervous system, mediates water homeostasis in healthy and pathological settings, such as severe brain injury.13, 14
Because brain edema has occurred during clinical trials of most anti-amyloid antibodies, we hypothesize that ß-amyloid might be an important element in brain water homeostasis. Removing ß-amyloid could cause brain edema and bleeding in some AD patients. To investigate this idea, we analyzed structures of aquaporin-4 and ß-amyloid from the RCSB protein data bank.
To help identify the brain regions where anti-amyloid antibodies may act, we used the Allen Brain Atlas and the H
淀粉样蛋白假说认为ß-淀粉样蛋白在大脑中的积聚是阿尔茨海默病(AD)发病的主要因素。ß-淀粉样蛋白产生和ß-淀粉样蛋白清除之间的不平衡导致疾病的晚期,包括含有tau蛋白的神经原纤维缠结的发展。许多旨在减少AD中ß-淀粉样蛋白的药物在临床上并不有效。FDA已经批准了aducanumab,这是四种抗-ß-淀粉样蛋白抗体之一,已被证明可以介导AD患者大脑中淀粉样蛋白斑块的清除。FDA接受淀粉样斑块的减少作为aducanumab的替代终点。但是对于批准的理由和抗淀粉样蛋白抗体提供的临床益处的范围存在激烈的分歧。抗体的一个副作用是脑水肿、积液和出血,即所谓的淀粉样蛋白相关成像异常(ARIA)。ARIA不仅发生在人类身上,也发生在年老的松鼠猴身上。3Lecanemab,一种抗淀粉样蛋白单克隆抗体,在12.4%的受试者中与水肿或积液相关,包括3例致命性脑出血;安慰剂组脑水肿率为1.7%。4-9在另一种抗淀粉样蛋白单克隆抗体donanemab的情况下,如果前三次剂量的药物出现水肿或积液,则不增加剂量。脑水肿是一种严重的临床状况,是由大脑含水量增加引起的脑组织的病理性肿胀。在人类和小鼠模型中,APOE亚型影响脑出血后的神经预后。ABCC8基因的三个snp rs2283261、rs3819521和rs2283258与脑水肿显著相关,通过颅内压升高和CT成像测量。触珠蛋白类型,Hp2与Hp1,也可能影响脑水肿。水通道蛋白是一种在动物体内发现的水通道蛋白家族,它可能是AD脑水肿的一种解释。水通道蛋白-4 (AQP4)是中枢神经系统中最重要的水通道蛋白形式,在健康和病理环境中介导水稳态,如严重脑损伤。13,14因为在大多数抗淀粉样蛋白抗体的临床试验中都发生过脑水肿,我们假设ß-淀粉样蛋白可能是脑水稳态的一个重要因素。去除ß-淀粉样蛋白会导致一些AD患者脑水肿和出血。为了研究这一观点,我们分析了RCSB蛋白质数据库中的水通道蛋白-4和ß-淀粉样蛋白的结构。为了帮助确定抗淀粉样蛋白抗体可能起作用的大脑区域,我们使用Allen brain Atlas和Human Protein Atlas来检测大脑中AQP4和APP(淀粉样蛋白前体蛋白)RNA的表达。15,16在PYMOL v 2.5.0软件上使用Super命令对两个蛋白序列进行Super比对。Super进行序列无关的基于结构的动态规划对齐(与align命令不同),然后进行一系列的优化循环,旨在通过消除具有高相对可变性的配对来改善拟合。对于序列相似度较低的蛋白质,Super命令比align命令更可靠。AQP4表达(Allen Brain Atlas)如图1所示。AQP4 RNA在多种脑区广泛而强烈地表达,包括AD发病的海马和海马旁区。图2为AQP4 RNA表达示意图。AQP4 RNA在人类和小鼠的多种脑区中都有强烈和广泛的表达(未显示)。供体为24岁男性黑人或非裔美国人(Allen Brain Atlas)。淀粉样蛋白前体蛋白(APP) RNA表达见图3。与AQP4一样,APP在整个大脑中强烈表达(Human Protein Atlas)。Pymol对29个排列的水通道蛋白-4和ß-淀粉样蛋白原子进行了5次循环计算,21个原子的原子位置的最终均方根偏差(RMSD)为0.300 Å(图4)。Pymol自动确定要计算的最佳循环数。RMSD值越低,表明验证的对准精度越高。RMSD值为1 Å或更小表示非常好的对齐。两个排列的分子水通道蛋白-4和ß-淀粉样蛋白如图5所示。21原子排列非常好。箭头表示水通道蛋白4外显子3上覆盖缬氨酸162的ß-淀粉样蛋白的异亮氨酸77。比对是比较相关蛋白质序列的有力方法。它们可以用来记录关于匹配序列的各种信息,例如共享的结构功能或共同的进化祖先。在过去的几十年里,蛋白质序列比对分析已经成为生物信息学分析研究的一个重要阶段。利用序列比对建立了大量蛋白质家族信息的蛋白质数据库。 我们的分析表明AQP4和ß-淀粉样蛋白可能具有共同的功能,包括维持脑水稳态和预防脑水肿。AQP4和APP在脑内表达的相似性(图2和3)支持了这一结论。最广泛的中枢神经系统水通道AQP4,常见于星形细胞端足。AQP4 RNA在人和小鼠的多种脑区均有广泛而强烈的表达。此外,整个小鼠大脑表现出显著的AQP4强度和星形胶质细胞端足的广泛免疫标记,这种模式代表了脉管系统和毛细血管壁。AQP4变异可能是AD血管源性水肿的危险因素。血管源性水肿是血管内皮细胞紧密连接破裂的直接结果,是由于血脑屏障完整性的破坏而产生的。由于来自脉管系统的液体和蛋白质穿透间隙,脑细胞外腔增大。血管源性水肿导致颅内压升高,脑血流量减少,脑疝,最终死亡。血管源性水肿可发生于外伤、动脉高血压、肿瘤释放的血管活性物质或内皮损伤物质,如花生四烯酸、兴奋性神经递质、类二十烷酸、缓激肽、组胺和自由基。血管源性水肿是抗淀粉样AD药物的常见副作用,可能是淀粉样蛋白从大脑中被清除的信号。一项AQP4外显子4的研究未发现突变。但在另一项研究中,在对363名创伤性脑损伤患者的临床、神经成像和遗传数据进行检查的研究中,在AQP4基因区域检测到7个标签单核苷酸多态性(snp)。标签SNP是位于基因组高度连锁不平衡区域的SNP,是单倍型SNP的一部分。两个标签snp, rs3763043,与精神分裂症相关,21和rs3875089,与脑出血相关,22与创伤性脑损伤后6个月评估的不良临床结果有关。23我们发现AQP4与ß-淀粉样蛋白密切相关,这可能表明ß-淀粉样蛋白与AQP4一样,在维持脑水稳态和预防脑水肿方面可能很重要。ß-淀粉样蛋白结构在哺乳动物进化过程中一直高度保守,表明一种或多种重要功能。例如,ß-amyloid具有抗菌作用,可能是对单纯疱疹型1.24的一种遗传防御。本研究的结果有两个值得注意的意义:(1)在抗淀粉样蛋白AD治疗前筛选AQP4多态性snp rs3763043、rs3875089和APOE4异构体,可以识别脑水肿出血高危患者。筛选ABCC8多态性和触珠蛋白形式也可能有价值。(2)在儿童中进行相同的筛查可以发现在某些运动中增加的创伤性脑损伤易感性:足球,曲棍球,篮球和棒球。APOE2、APOE4、AQP4和抗淀粉样蛋白抗体并不是AD血管源性水肿的唯一相关物质。治疗阿尔茨海默病的药物avagacestat是一种小分子γ -分泌酶抑制剂,可以降低ß-淀粉样蛋白水平,但也会引起血管源性水肿此外,在未接受任何治疗的AD患者中也发现无症状血管源性水肿因此,局灶性、局限性血管源性水肿可能是AD病理过程的一部分。由于APOE和ABCC8基因与脑水肿相关,因此评估这些蛋白结构与AQP4的对齐和其他相似之处是值得的。我们得出结论,ß-淀粉样蛋白可能参与脑水稳态和防止血管源性脑水肿。从AD患者体内去除ß-淀粉样蛋白可促进血管源性脑水肿和出血。筛选AQP4和ABCC8多态性、APOE2和APOE4亚型以及接触珠蛋白形式可以识别抗淀粉样蛋白治疗后脑水肿和出血的高危患者。进一步的研究是必要的。预印本发布https://doi.org/10.21203/rs.3.rs-2350250/v1Dr。Steven Lehrer和Peter H. Rhein
{"title":"Alignment of human aquaporin 4 and ß-amyloid proteins may indicate involvement of ß-amyloid in brain water homeostasis and prevention of brain edema","authors":"Steven Lehrer, Peter H. Rheinstein","doi":"10.1002/cdt3.64","DOIUrl":"10.1002/cdt3.64","url":null,"abstract":"<p>The amyloid hypothesis states that the buildup of ß-amyloid in the brain is the main factor for Alzheimer's disease (AD) pathogenesis. An imbalance between ß-amyloid production and ß-amyloid clearance causes the advanced stages of the disease, including the development of neurofibrillary tangles containing tau protein.<span><sup>1</sup></span></p><p>Many medications that aim to reduce ß-amyloid in AD are not clinically effective. FDA has approved aducanumab, one of four anti-ß-amyloid antibodies that have been demonstrated to mediate the removal of amyloid plaque from the brains of AD patients. FDA accepted the decrease of amyloid plaque as a surrogate endpoint for aducanumab. But there is intense disagreement over the justification for approval and the scope of the clinical benefit provided by antiamyloid antibodies.<span><sup>2</sup></span></p><p>One side effect of the antibodies is brain edema, effusion, and hemorrhages, so called amyloid-related imaging abnormalities (ARIA). ARIA occurs in aged squirrel monkeys as well as in humans.<span><sup>3</sup></span></p><p>Lecanemab, an antiamyloid monoclonal antibody, was associated with edema or effusions in 12.4% of subjects, including three fatal brain hemorrhages; the placebo group had 1.7% brain edema.<span><sup>4-9</sup></span> In the case of donanemab, another anti-amyloid monoclonal antibody, if edema or effusion occurred with the first three doses of the drug, the dosage was not increased.<span><sup>10</sup></span></p><p>A serious clinical condition, brain edema is defined by a pathological swelling of the brain tissue brought on by an increase in the water content of the brain. In humans<span><sup>11</sup></span> and in a mouse model, APOE isoform affects neurological prognosis following intracerebral hemorrhage. Poor functional outcome and more cerebral edema are linked to APOE4.<span><sup>12</sup></span> Three SNPs of the ABCC8 gene, rs2283261, rs3819521, and rs2283258, are significantly associated with brain edema, measured by increased intracranial pressure and CT imaging. Haptoglobin type, Hp2 versus Hp1, may also influence brain edema.<span><sup>13</sup></span></p><p>Aquaporins, a family of water channel proteins that have been found in animals, may provide an explanation for AD brain edema. Aquaporin-4 (AQP4), the most significant form of aquaporin in the central nervous system, mediates water homeostasis in healthy and pathological settings, such as severe brain injury.<span><sup>13, 14</sup></span></p><p>Because brain edema has occurred during clinical trials of most anti-amyloid antibodies, we hypothesize that ß-amyloid might be an important element in brain water homeostasis. Removing ß-amyloid could cause brain edema and bleeding in some AD patients. To investigate this idea, we analyzed structures of aquaporin-4 and ß-amyloid from the RCSB protein data bank.</p><p>To help identify the brain regions where anti-amyloid antibodies may act, we used the Allen Brain Atlas and the H","PeriodicalId":32096,"journal":{"name":"Chronic Diseases and Translational Medicine","volume":"9 2","pages":"177-181"},"PeriodicalIF":0.0,"publicationDate":"2023-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/09/4a/CDT3-9-177.PMC10249176.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9975942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Environmental factors, including chemical/physical pollutants, as well as lifestyle and psychological factors, contribute greatly to the pathways leading to cardiometabolic diseases with a heavy disease burden and economic loss. The concept of exposomes provides a novel paradigm for combining all exposure characteristics to evaluate disease risk. A solution-like exposome requires technological support to provide continuous data to monitor vital signs and detect abnormal fluctuations. Wearable devices allow people to conveniently monitor signals during their daily routines. These new technologies empower users to more actively prevent and manage cardiometabolic disease by reviewing risk factors of the disease, especially lifestyle factors, such as sleeping time, screen time, and mental health condition. Devices with multiple sensors can monitor electrocardiography data, oxygen saturation, intraocular pressure, respiratory rate, and heart rate to enhance the exposome study and provide precise suggestions for disease prevention and management.
{"title":"Application of wearable devices for monitoring cardiometabolic dysfunction under the exposome paradigm","authors":"Haodong Zhang, Lingming Hu, Pai Zheng, Guang Jia","doi":"10.1002/cdt3.67","DOIUrl":"10.1002/cdt3.67","url":null,"abstract":"<p>Environmental factors, including chemical/physical pollutants, as well as lifestyle and psychological factors, contribute greatly to the pathways leading to cardiometabolic diseases with a heavy disease burden and economic loss. The concept of exposomes provides a novel paradigm for combining all exposure characteristics to evaluate disease risk. A solution-like exposome requires technological support to provide continuous data to monitor vital signs and detect abnormal fluctuations. Wearable devices allow people to conveniently monitor signals during their daily routines. These new technologies empower users to more actively prevent and manage cardiometabolic disease by reviewing risk factors of the disease, especially lifestyle factors, such as sleeping time, screen time, and mental health condition. Devices with multiple sensors can monitor electrocardiography data, oxygen saturation, intraocular pressure, respiratory rate, and heart rate to enhance the exposome study and provide precise suggestions for disease prevention and management.</p>","PeriodicalId":32096,"journal":{"name":"Chronic Diseases and Translational Medicine","volume":"9 3","pages":"200-209"},"PeriodicalIF":0.0,"publicationDate":"2023-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b4/0f/CDT3-9-200.PMC10497849.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10271446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Guide for Authors","authors":"","doi":"10.1002/cdt3.61","DOIUrl":"10.1002/cdt3.61","url":null,"abstract":"","PeriodicalId":32096,"journal":{"name":"Chronic Diseases and Translational Medicine","volume":"9 1","pages":"63-69"},"PeriodicalIF":0.0,"publicationDate":"2023-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10011660/pdf/CDT3-9-63.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9492037","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}