scholarly journals Phenotypic Screening of Molecular Docking Enriched Chemical Libraries from Targets Identified in Ischemic Stroke Genome Data by Network-Based Method

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Xiaojiang Peng ◽  
Dao-jin Xue
Keyword(s):  
Ischemic Stroke ◽  
Molecular Docking ◽  
Cardiovascular Diseases ◽  
Disease Progression ◽  
Screening Method ◽  
The Body ◽  
Signal Pathways ◽  
Enriched Library ◽  
Phenotypic Screening ◽  
Sequencing Data

Cerebral ischemia (IS) is one of the main cardiovascular diseases threatening life and disability. Like most cardiovascular events, the disease progression of is affects a variety of signaling pathways and changes multiple overexpressed genes in the body. The use of new therapeutic agents to interfere with the disease progression of cardiovascular diseases (such as is) can be achieved by selectively regulating small molecules of the target set of different signal pathways, also known as selective multipharmacology. Phenotypic screening can be an effective method to solve this problem, but the lack of targeted methods for ischemic stroke limits its impact. Here, we aim to identify IS-specific targets by RNA sequencing data with a network-based approach. Molecular docking approach was applied to screen over 210,000 molecules from SPECS compound library. Screening of this enriched library resulted in 605 candidates that led to several potent active hits. The novelty analysis suggested that the structure scaffolds of the compounds were dissimilar to existing IKKB inhibitors, and further biological test result confirmed two identified compounds represented novel IKKB inhibitors. Further, docking exploration with IKKB (PDB id: 4KIK) showed that the three selective compounds were stable inside the binding pocket of IKKB which shared a homology of compound-protein interactions in comparison with the bioactive inhibitor of CHEMBL1762621. Our screening method is expected to produce selective multidrug lead compounds for the development of treatments for complex diseases, such as ischemic stroke.

scholarly journals Could Lipoxins Represent a New Standard in Ischemic Stroke Treatment?

2021 ◽  
Vol 22 (8) ◽  
pp. 4207
Author(s):  
Nikola Tułowiecka ◽  
Dariusz Kotlęga ◽  
Andrzej Bohatyrewicz ◽  
Małgorzata Szczuko
Keyword(s):  
Ischemic Stroke ◽  
Cardiovascular Diseases ◽  
Blood Brain Barrier ◽  
Inflammatory Cytokines ◽  
The Body ◽  
Brain Barrier ◽  
Lipoxin A4 ◽  
Stroke Treatment ◽  
Blood Brain ◽  
Anti Inflammatory

Introduction: Cardiovascular diseases including stroke are one of the most common causes of death. Their main cause is atherosclerosis and chronic inflammation in the body. An ischemic stroke may occur as a result of the rupture of unstable atherosclerotic plaque. Cardiovascular diseases are associated with uncontrolled inflammation. The inflammatory reaction produces chemical mediators that stimulate the resolution of inflammation. One of these mediators is lipoxins—pro-resolving mediators that are derived from the omega-6 fatty acid family, promoting inflammation relief and supporting tissue regeneration. Aim: The aim of the study was to review the available literature on the therapeutic potential of lipoxins in the context of ischemic stroke. Material and Methods: Articles published up to 31 January 2021 were included in the review. The literature was searched on the basis of PubMed and Embase in terms of the entries: ‘stroke and lipoxin’ and ‘stroke and atherosclerosis’, resulting in over 110 articles in total. Studies that were not in full-text English, letters to the editor, and conference abstracts were excluded. Results: In animal studies, the injection/administration of lipoxin A4 improved the integrity of the blood–brain barrier (BBB), decreased the volume of damage caused by ischemic stroke, and decreased brain edema. In addition, lipoxin A4 inhibited the infiltration of neutrophils and the production of cytokines and pro-inflammatory chemokines, such as interleukin (Il-1β, Il-6, Il-8) and tumor necrosis factor-α (TNF-α). The beneficial effects were also observed after introducing the administration of lipoxin A4 analog—BML-111. BML-111 significantly reduces the size of a stroke and protects the cerebral cortex, possibly by reducing the permeability of the blood–brain barrier. Moreover, more potent than lipoxin A4, it has an anti-inflammatory effect by inhibiting the production of pro-inflammatory cytokines and increasing the amount of anti-inflammatory cytokines. Conclusions: Lipoxins and their analogues may find application in reducing damage caused by stroke and improving the prognosis of patients after ischemic stroke.

Effect of age on outcome in patients with cerebral stroke

2020 ◽  
pp. 41-45
Author(s):  
G. R. Kuchava ◽  
E. V. Eliseev ◽  
B. V. Silaev ◽  
D. A. Doroshenko ◽  
Yu. N. Fedulaev
Keyword(s):  
Ischemic Stroke ◽  
Neurological Deficit ◽  
Neurological Status ◽  
Statistical Correlation ◽  
Multiple Organ ◽  
The Body ◽  
Social Adaptation ◽  
Cerebral Stroke ◽  
Septic Complications ◽  
Risk Of Death

The aim of the study was to assess the course and outcome of cerebral infarction, depending on the age factor and duration of stay in the neuroblock. Materials and methods: a dynamic observation of 494 patients, men and women, aged 38–84 years with acute ischemic stroke of hemispheric localization, which were divided into the three groups depending on age, was performed. Group 1 – younger than 60 years old, group 2–60–70 years old, group 3 – older than 60 years. All patients underwent standard therapy, according to the recommendations for the treatment of ischemic stroke. The patients underwent comprehensive clinical and instrumental monitoring, which included assessment of somatic and neurological status according to the NIH‑NINDS scales at 1st, 3rd, 10th days and at discharge or death; assessment of the level of social adaptation according to the Bartel scale on 1st, 3rd, 10th days and at discharge, clinical and biochemical blood tests, computed tomography of the brain. Assessment of the quality of therapy was carried out according to specially developed maps using methods of statistical correlation analysis. Results: the most pronounced positive dynamics of neurological status was in the 1st group of patients. The regression of neurological deficit in the 2nd group was worse. The minimal dynamics of neurological deficit was in the 3rd group of patients with cerebral stroke. Most often, the death of patients with cerebral stroke occurred from the development of multiple organ disorders. Conclusions: patients over 70 years of age have the greatest risk of death, due to: a decrease in the reactivity of the body, the presence of initially severe concomitant somatic pathology in patients with admission to hospital; accession of secondary somatic and purulent‑septic complications.

scholarly journals TRAIL and Cardiovascular Disease—A Risk Factor or Risk Marker: A Systematic Review

2021 ◽  
Vol 10 (6) ◽  
pp. 1252
Author(s):  
Katarzyna Kakareko ◽  
Alicja Rydzewska-Rosołowska ◽  
Edyta Zbroch ◽  
Tomasz Hryszko
Keyword(s):  
Systematic Review ◽  
Risk Factor ◽  
Ischemic Stroke ◽  
Cardiovascular Diseases ◽  
Animal Studies ◽  
Gestational Hypertension ◽  
Cochrane Library ◽  
Major Adverse Cardiovascular Events ◽  
Risk Marker ◽  
Artery Disease

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a pro-apoptotic protein showing broad biological functions. Data from animal studies indicate that TRAIL may possibly contribute to the pathophysiology of cardiomyopathy, atherosclerosis, ischemic stroke and abdominal aortic aneurysm. It has been also suggested that TRAIL might be useful in cardiovascular risk stratification. This systematic review aimed to evaluate whether TRAIL is a risk factor or risk marker in cardiovascular diseases (CVDs) focusing on major adverse cardiovascular events. Two databases (PubMed and Cochrane Library) were searched until December 2020 without a year limit in accordance to the PRISMA guidelines. A total of 63 eligible original studies were identified and included in our systematic review. Studies suggest an important role of TRAIL in disorders such as heart failure, myocardial infarction, atrial fibrillation, ischemic stroke, peripheral artery disease, and pulmonary and gestational hypertension. Most evidence associates reduced TRAIL levels and increased TRAIL-R2 concentration with all-cause mortality in patients with CVDs. It is, however, unclear whether low TRAIL levels should be considered as a risk factor rather than a risk marker of CVDs. Further studies are needed to better define the association of TRAIL with cardiovascular diseases.

scholarly journals Computational Study on Selective PDE9 Inhibitors on PDE9-Mg/Mg, PDE9-Zn/Mg, and PDE9-Zn/Zn Systems

Biomolecules ◽  
2021 ◽  
Vol 11 (5) ◽  
pp. 709
Author(s):  
Dakshinamurthy Sivakumar ◽  
Sathish-Kumar Mudedla ◽  
Seonghun Jang ◽  
Hyunjun Kim ◽  
Hyunjin Park ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Erectile Dysfunction ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Cardiovascular Diseases ◽  
Neurodegenerative Disorders ◽  
Computational Study ◽  
Dynamics Simulation ◽  
Interaction Patterns

PDE9 inhibitors have been studied to validate their potential to treat diabetes, neurodegenerative disorders, cardiovascular diseases, and erectile dysfunction. In this report, we have selected highly potent previously reported selective PDE9 inhibitors BAY73-6691R, BAY73-6691S, 28r, 28s, 3r, 3s, PF-0447943, PF-4181366, and 4r to elucidate the differences in their interaction patterns in the presence of different metal systems such as Zn/Mg, Mg/Mg, and Zn/Zn. The initial complexes were generated by molecular docking followed by molecular dynamics simulation for 100 ns in triplicate for each system to understand the interactions’ stability. The results were carefully analyzed, focusing on the ligands’ non-bonded interactions with PDE9 in different metal systems.

scholarly journals Functional profiling of COVID-19 respiratory tract microbiomes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Niina Haiminen ◽  
Filippo Utro ◽  
Ed Seabolt ◽  
Laxmi Parida
Keyword(s):  
Respiratory Tract ◽  
Carbohydrate Metabolism ◽  
Lower Respiratory Tract ◽  
Viral Infections ◽  
Lavage Fluid ◽  
Degradation Pathway ◽  
Community Acquired Pneumonia ◽  
The Body ◽  
Sequencing Data ◽  
Functional Profiling

AbstractIn response to the ongoing global pandemic, characterizing the molecular-level host interactions of the new coronavirus SARS-CoV-2 responsible for COVID-19 has been at the center of unprecedented scientific focus. However, when the virus enters the body it also interacts with the micro-organisms already inhabiting the host. Understanding the virus-host-microbiome interactions can yield additional insights into the biological processes perturbed by viral invasion. Alterations in the gut microbiome species and metabolites have been noted during respiratory viral infections, possibly impacting the lungs via gut-lung microbiome crosstalk. To better characterize microbial functions in the lower respiratory tract during COVID-19 infection, we carry out a functional analysis of previously published metatranscriptome sequencing data of bronchoalveolar lavage fluid from eight COVID-19 cases, twenty-five community-acquired pneumonia patients, and twenty healthy controls. The functional profiles resulting from comparing the sequences against annotated microbial protein domains clearly separate the cohorts. By examining the associated metabolic pathways, distinguishing functional signatures in COVID-19 respiratory tract microbiomes are identified, including decreased potential for lipid metabolism and glycan biosynthesis and metabolism pathways, and increased potential for carbohydrate metabolism pathways. The results include overlap between previous studies on COVID-19 microbiomes, including decrease in the glycosaminoglycan degradation pathway and increase in carbohydrate metabolism. The results also suggest novel connections to consider, possibly specific to the lower respiratory tract microbiome, calling for further research on microbial functions and host-microbiome interactions during SARS-CoV-2 infection.

scholarly journals PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases

2021 ◽  
Vol 22 (15) ◽  
pp. 8298
Author(s):  
Hugo Christian Monroy-Ramirez ◽  
Marina Galicia-Moreno ◽  
Ana Sandoval-Rodriguez ◽  
Alejandra Meza-Rios ◽  
Arturo Santos ◽  
...  
Keyword(s):  
Liver Diseases ◽  
Metabolic Regulation ◽  
Structural Changes ◽  
Critical Role ◽  
The Body ◽  
Molecular Characteristics ◽  
Signal Pathways ◽  
Virus Infections ◽  
Physiological Processes ◽  
Hepatic Level

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.

scholarly journals Cardiovascular risks awareness in coaches and amateur athletes

2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
A Markovich ◽  
O Mironova
Keyword(s):  
Physical Activity ◽  
Cardiovascular Diseases ◽  
Heart Attack ◽  
Conflicts Of Interest ◽  
The Body ◽  
Treadmill Test ◽  
Cardiovascular Risks ◽  
Sports Cardiology ◽  
Long Distance ◽  
Endurance Sport

Abstract Funding Acknowledgements Type of funding sources: None. Background Regular physical activity is an important component of therapy for most сardiovascular diseases and is associated with reduced cardiovascular and all-cause mortality. The promotion of the physical activity and regular exercise is an important preventive measure that affects the prognosis. Purpose To assess the awareness of the prevalence of cardiovascular disease in exercising population and its influence on the safety of the patients and healthy adults among coaches and people actively engaged in sports activities. Methods An open non-randomized observation was conducted. The questionnaire created by our team included 45 questions about cardiovascular diseases and sport. 111 athletes and coaches aged from 19 to 46 were enrolled in the study. 61,5% (68) are men and 38,5% (42) of the respondents are women. 30,3% (33) of the respondents are coaches. 45,5% (15) of them have over 5 years of coaching experience. 44% (48) of all respondents prefer endurance sport, 25,7% (28) train strength exercise. 63,6% (70) train 3-8 hours per week, 12,7% (14 [7 women and 7 men]) train more than 8 hours each week. Results 18,5% (20 [6 women and 14 men]) think that ECG is enough for screening for cardiovascular diseases. 20% (4) of them are coaches. Only 69,5% (77) of all respondents know about treadmill test. And 41,6% (32/77) of them know about the necessary screening for arrhythmogenic condition. 13% (10/77) of them train more than 8 hours per week. And only 27,3% (21/77) of people who know about treadmill test, passed it themselves. Also 21,6% (24) of all respondents think that any episode of arrhythmia is the  contraindication for any sport. But 96,4% (107) of the respondents know that it is necessary to regularly screen the cardiovascular system, even in the absence of complaints. 9% (10) of the interviewed think that diet is not important for people with cardiovascular diseases. And 18,9% (21) of the respondents don’t know about the effect of electrolytes on the body and the work of the heart muscle. Only 53,2% (59 [21 women and 38 men]) of the respondents trust the doctors more than coaches or themselves. And this is one of the reasons why it is necessary to talk about the basic principles of sports cardiology not only to doctors. 8,1% (9) of the respondents have never heard about any cases of sudden death of an athlete during training or at competitions due to «heart problems». 63,6% (21) of the coaches would not train a person who has suffered a heart attack. 71,8% (56) of the sportsmen would like to return to training after a heart attack. Conclusions Despite the fact that most people prefer a sedentary lifestyle, high-intensity fitness and long-distance endurance sport is getting more popular. Our survey proves the relatively low level of education about the underlying health conditions and possible risks associated with sports not only among  athletes but  professional coaches as well. There are no conflicts of interest to declare.

scholarly journals Molecular mechanism underlying the hypolipidemic effect of Shanmei Capsule based on network pharmacology and molecular docking

2021 ◽  
Vol 29 ◽  
pp. 239-256
Author(s):  
Qian Wang ◽  
Lijing Du ◽  
Jiana Hong ◽  
Zhenlin Chen ◽  
Huijian Liu ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Signaling Pathway ◽  
Molecular Mechanism ◽  
Kegg Pathway ◽  
Network Pharmacology ◽  
Pathway Enrichment Analysis ◽  
Signal Pathways ◽  
Hypolipidemic Effect ◽  
Active Ingredients ◽  
Pathway Enrichment

BACKGROUND: Shanmei Capsule is a famous preparation in China. However, the related mechanism of Shanmei Capsule against hyperlipidemia has yet to be revealed. OBJECTIVE: To elucidate underlying mechanism of Shanmei Capsule against hyperlipidemia through network pharmacology approach and molecular docking. METHODS: Active ingredients, targets of Shanmei Capsule as well as targets for hyperlipidemia were screened based on database. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed via Database for Annotation, Visualization, and Integrated Discovery (DAVID) 6.8 database. Ingredient-target-disease-pathway network was visualized utilizing Cytoscape software and molecular docking was performed by Autodock Vina. RESULTS: Seventeen active ingredients in Shanmei Capsule were screened out with a closely connection with 34 hyperlipidemia-related targets. GO analysis revealed 40 biological processes, 5 cellular components and 29 molecular functions. A total of 15 signal pathways were enriched by KEGG pathway enrichment analysis. The docking results indicated that the binding activities of key ingredients for PPAR-α are equivalent to that of the positive drug lifibrate. CONCLUSIONS: The possible molecular mechanism mainly involved PPAR signaling pathway, Bile secretion and TNF signaling pathway via acting on MAPK8, PPARγ, MMP9, PPARα, FABP4 and NOS2 targets.

scholarly journals Association between Serum Concentration of Carotenoid and Visceral Fat

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 912
Author(s):  
Mai Matsumoto ◽  
Hiroyuki Suganuma ◽  
Naoki Ozato ◽  
Sunao Shimizu ◽  
Mitsuhiro Katashima ◽  
...  
Keyword(s):  
Cardiovascular Diseases ◽  
Visceral Fat ◽  
Fruits And Vegetables ◽  
Beta Carotene ◽  
The Body ◽  
Healthy Individuals ◽  
Health Checkup ◽  
Visceral Fat Area ◽  
The Relationship ◽  
Aomori Prefecture

Consumption of fruits and vegetables rich in carotenoids has been widely reported to prevent cardiovascular diseases. However, the relationship between serum carotenoid concentrations and visceral fat area (VFA), which is considered a better predictor of cardiovascular diseases than the body-mass index (BMI) and waist circumference, remains unclear. Therefore, we examined the relationship in healthy individuals in their 20s or older, stratified by sex and age, to compare the relationship between serum carotenoid concentrations and VFA and BMI. The study was conducted on 805 people, the residents in Hirosaki city, Aomori prefecture, who underwent a health checkup. An inverse relationship between serum carotenoid concentrations and VFA and BMI was observed only in women. In addition, the results were independent of the intake of dietary fiber, which is mainly supplied from vegetables as well as carotenoids. This suggests that consumption of a diet rich in carotenoids (especially lutein and beta-carotene) is associated with lower VFA, which is a good predictor of cardiovascular disease, especially in women. This study is the first to comprehensively evaluate the association between serum carotenoid levels and VFA in healthy individuals.

scholarly journals Saturated Fat Consumption and Risk of Coronary Heart Disease and Ischemic Stroke: A Science Update

2017 ◽  
Vol 70 (1) ◽  
pp. 26-33 ◽  
Author(s):  
Joyce A. Nettleton ◽  
Ingeborg A. Brouwer ◽  
Johanna M. Geleijnse ◽  
Gerard Hornstra
Keyword(s):  
Coronary Heart Disease ◽  
Heart Disease ◽  
Ischemic Stroke ◽  
Saturated Fat ◽  
The Body ◽  
Epidemiological Methods ◽  
Risk Markers ◽  
Fat Consumption ◽  
Chd Risk ◽  
Important Health

At a workshop to update the science linking saturated fatty acid (SAFA) consumption with the risk of coronary heart disease (CHD) and ischemic stroke, invited participants presented data on the consumption and bioavailability of SAFA and their functions in the body and food technology. Epidemiological methods and outcomes were related to the association between SAFA consumption and disease events and mortality. Participants reviewed the effects of SAFA on CHD, causal risk factors, and surrogate risk markers. Higher intakes of SAFA were not associated with higher risks of CHD or stroke apparently, but studies did not take macronutrient replacement into account. Replacing SAFA by cis-polyunsaturated fatty acids was associated with significant CHD risk reduction, which was confirmed by randomized controlled trials. SAFA reduction had little direct effect on stroke risk. Cohort studies suggest that the food matrix and source of SAFA have important health effects.

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