In Silico Analysis of the Molecular-Level Impact of SMPD1 Variants on Niemann-Pick Disease Severity

Sphingomyelin phosphodiesterase (SMPD1) is a key enzyme in the sphingolipid metabolism. Genetic SMPD1 variants have been related to the Niemann-Pick lysosomal storage disorder, which has different degrees of phenotypic severity ranging from severe symptomatology involving the central nervous system (type A) to milder ones (type B). They have also been linked to neurodegenerative disorders such as Parkinson and Alzheimer. In this paper, we leveraged structural, evolutionary and stability information on SMPD1 to predict and analyze the impact of variants at the molecular level. We developed the SMPD1-ZooM algorithm, which is able to predict with good accuracy whether variants cause Niemann-Pick disease and its phenotypic severity; the predictor is freely available for download. We performed a large-scale analysis of all possible SMPD1 variants, which led us to identify protein regions that are either robust or fragile with respect to amino acid variations, and show the importance of aromatic-involving interactions in SMPD1 function and stability. Our study also revealed a good correlation between SMPD1-ZooM scores and in vitro loss of SMPD1 activity. The understanding of the molecular effects of SMPD1 variants is of crucial importance to improve genetic screening of SMPD1-related disorders and to develop personalized treatments that restore SMPD1 functionality.     

基于乙酰胆碱酯酶和氧化应激研究海胆酮对阿尔茨海默症的作用机制

海胆酮是一种酮式类胡萝卜素，主要从海胆及藻类等海洋生物中提取。本文研究海胆酮对乙酰胆碱酯酶（acetylcholinesterase，AChE）的抑制作用，应用酶动力学、荧光光谱、圆二色光谱和分子对接技术研究海胆酮对AChE的抑制机理，并用淀粉样β蛋白片段25～35（amyloid beta-peptide 25-35，Aβ25-35）诱导大鼠肾上腺嗜铬细胞瘤细胞（PC12细胞）建立阿尔茨海默症（Alzheimer’s disease，AD）模型，研究海胆酮对AD细胞模型氧化应激损伤的作用。结果表明，海胆酮有很强的AChE抑制活性，其半抑制质量浓度为（16.29±0.97）μg/mL，抑制常数Ki为3.82 μg/mL，表现为竞争性抑制；海胆酮可诱导AChE二级结构改变，更容易与AChE活性中心氨基酸Ser200、His440、Trp84和Tyr121结合，阻碍底物碘代硫代乙酰胆碱（acetylthiocholine iodide，ATCI）与酶结合，从而引起酶活力降低。海胆酮能有效抑制Aβ25-35诱导PC12细胞的AChE活力，降低丙二醛含量，增加超氧化物歧化酶、过氧化氢酶和谷胱甘肽过氧化物酶活力，减轻Aβ25-35诱导的PC12细胞氧化应激损伤。本研究基于AChE和氧化应激阐明了海胆酮对AD的潜在作用机制，为海胆酮在功能食品、生物医药等领域的应用提供了数据支持和理论根据。     

Ocular conditions and dry eye due to traditional and new forms of smoking: A review

Addiction to cigarette smoking has high prevalence rates recorded worldwide. Smoking has been linked to several life-threatening systemic conditions such as cancer, heart attack and stroke, in addition to a range of ocular pathologies. In recent years, electronic cigarettes (EC) have emerged as alternatives to smoking. ECs are nicotine delivery devices which produce an aerosol by heating, rather than combusting, a liquid which contains nicotine, flavours and preservatives. This review focuses on the association of traditional and new forms of smoking with dry eye disease, contact lens wear and four other common ocular diseases: cataract, age-related macular degeneration, glaucoma and Graves’ ophthalmopathy. It is concluded that smoking and vaping appear as a risk factor for the aforementioned ocular conditions. An evidence-based, clear link between cigarette smoking, or EC vaping and ocular problems is yet to be discovered.     

Clinical Characteristics and Outcomes of Type 2 Diabetes Patients Infected with COVID-19: A Retrospective Study

Diabetes and its related metabolic disorders have been reported as the leading comorbidities in patients with coronavirus disease 2019 (COVID-19). This clinical study aims to investigate the clinical features, radiographic and laboratory tests, complications, treatments, and clinical outcomes in COVID-19 patients with or without diabetes. This retrospective study included 208 hospitalized patients (≥ 45 years old) with laboratory-confirmed COVID-19 during the period between 12 January and 25 March 2020. Information from the medical record, including clinical features, radiographic and laboratory tests, complications, treatments, and clinical outcomes, were extracted for the analysis. 96 (46.2%) patients had comorbidity with type 2 diabetes. In COVID-19 patients with type 2 diabetes, the coexistence of hypertension (58.3% vs 31.2%), coronary heart disease (17.1% vs 8.0%), and chronic kidney diseases (6.2% vs 0%) was significantly higher than in COVID-19 patients without type 2 diabetes. The frequency and degree of abnormalities in computed tomography (CT) chest scans in COVID-19 patients with type 2 diabetes were markedly increased, including ground-glass opacity (85.6% vs 64.9%, P < 0.001) and bilateral patchy shadowing (76.7% vs 37.8%, P < 0.001). In addition, the levels of blood glucose (7.23 mmol·L⁻¹ (interquartile range (IQR): 5.80–9.29) vs 5.46 mmol·L⁻¹ (IQR: 5.00–6.46)), blood low-density lipoprotein cholesterol (LDL-C) (2.21 mmol·L⁻¹ (IQR: 1.67–2.76) vs 1.75 mmol·L⁻¹ (IQR: 1.27–2.01)), and systolic pressure (130 mmHg (IQR: 120–142) vs 122 mmHg (IQR: 110–137)) (1 mmHg = 133.3 Pa) in COVID-19 patients with diabetes were significantly higher than in patients without diabetes (P < 0.001). The coexistence of type 2 diabetes and other metabolic disorders is common in patients with COVID-19, which may potentiate the morbidity and aggravate COVID-19 progression. Optimal management of the metabolic hemostasis of glucose and lipids is the key to ensuring better clinical outcomes. Increased clinical vigilance is warranted for COVID-19 patients with diabetes and other metabolic diseases that are fundamental and chronic conditions.     

红外热成像在乳腺疾病检测的应用研究

乳腺疾病已严重危害女性身心健康,其中乳腺癌更位居全球范围内女性癌症发病率和死亡率首位,因此乳腺癌的早期发现意义重大。传统结构影像学早期检测疾病具有一定局限性,而红外热成像作为功能成像技术可为乳腺癌的早期筛查提供有效线索。因此本文主要就红外热成像在乳腺疾病的早期检测及预后评估的应用价值进行综述。     

In Silico Analysis and Experimental Validation of Active Compounds from Cichorium intybus L. Ameliorating Liver Injury

This study aimed at investigating the possible mechanisms of hepatic protective activity of Cichorium intybus L. (chicory) in acute liver injury. Pathological observation, reactive oxygen species (ROS) detection and measurements of biochemical indexes on mouse models proved hepatic protective effect of Cichorium intybus L. Identification of active compounds in Cichorium intybus L. was executed through several methods including ultra performance liquid chromatography/time of flight mass spectrometry (UPLC-TOF-MS). Similarity ensemble approach (SEA) docking, molecular modeling, molecular docking, and molecular dynamics (MD) simulation were applied in this study to explore possible mechanisms of the hepato-protective potential of Cichorium intybus L. We then analyzed the chemical composition of Cichorium intybus L., and found their key targets. Furthermore, in vitro cytological examination and western blot were used for validating the efficacy of the selected compounds. In silico analysis and western blot together demonstrated that selected compound 10 in Cichorium intybus L. targeted Akt-1 in hepatocytes. Besides, compound 13 targeted both caspase-1 and Akt-1. These small compounds may ameliorate liver injury by acting on their targets, which are related to apoptosis or autophagy. The conclusions above may shed light on the complex molecular mechanisms of Cichorium intybus L. acting on hepatocytes and ameliorating liver injury.     

Role of Post-translational Modifications in Alzheimer's Disease

The global burden of Alzheimer's disease (AD) is growing. Valiant efforts to develop clinical candidates for treatment have continuously met with failure. Currently available palliative treatments are temporary and there is a constant need to search for reliable disease pathways, biomarkers and drug targets for developing diagnostic and therapeutic tools to address the unmet medical needs of AD. Challenges in drug-discovery efforts raise further questions about the strategies of current conventional diagnosis; drug design; and understanding of disease pathways, biomarkers and targets. In this context, post-translational modifications (PTMs) regulate protein trafficking, function and degradation, and their in-depth study plays a significant role in the identification of novel biomarkers and drug targets. Aberrant PTMs of disease-relevant proteins could trigger pathological pathways, leading to disease progression. Advancements in proteomics enable the generation of patterns or signatures of such modifications, and thus, provide a versatile platform to develop biomarkers based on PTMs. In addition, understanding and targeting the aberrant PTMs of various proteins provide viable avenues for addressing AD drug-discovery challenges. This review highlights numerous PTMs of proteins relevant to AD and provides an overview of their adverse effects on the protein structure, function and aggregation propensity that contribute to the disease pathology. A critical discussion offers suggestions of methods to develop PTM signatures and interfere with aberrant PTMs to develop viable diagnostic and therapeutic interventions in AD.