scholarly journals Phenylethanoid glycosides as a possible COVID-19 protease inhibitor: a virtual screening approach

2021 ◽  
Author(s):  
Mario Bernardi ◽  
Mohammad Reza Ghaani ◽  
Omer Bayazeid
Keyword(s):  
Binding Site ◽  
Viral Entry ◽  
Inhibitory Effect ◽  
The Body ◽  
Dynamics Simulation ◽  
World Population ◽  
Phenylethanoid Glycosides ◽  
Natural Product Library ◽  
Kinase Inhibitory Activity ◽  
The Impact

Abstract From the beginning of pandemic more than 100 million people have been infected with a death rate higher than 2%. Indeed, the current exit strategy involving the spreading of vaccines must be combined with progress in effective treatments development. This scenario is sadly supported by the vaccine’s immune activation time and the inequalities in the global immunization schedule. Bringing the crises under control means providing the world population with accessible and impactful new therapeutics. We screened a natural product library that contains a unique collection of 2370 natural products into the binding site of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro). According to the docking score and to the interaction at the active site, three phenylethanoid glycosides (forsythiaside A, isoacteoside and verbascoside) were selected. In order to provide better insight into the atomistic interaction and test the impact of the three selected compounds at the binding site, we resorted to a half microsecond-long molecular dynamics simulation. As a result, we are showing that forsythiaside A is the most stable molecule and it is likely to possess the highest inhibitory effect against SARS-CoV-2 Mpro. Phenylethanoid glycosides also have been reported to have both protease and kinase activity. This kinase inhibitory activity is very beneficial in fighting viruses inside the body as kinases are required for viral entry, metabolism, and/or reproduction. The dual activity (kinase/protease) of phenylethanoid glycosides makes them very promising anit-COVID-19 agents.

scholarly journals Investigating crosstalk among PTMs provides novel insight into the structural basis underlying the differential effects of Nt17 PTMs on mutant Httex1 aggregation

2021 ◽  
Author(s):  
Anass Chiki ◽  
Zhidian Zhang ◽  
Kolla Rajasekhar ◽  
Luciano A. Abriata ◽  
Iman Rostami ◽  
...  
Keyword(s):  
Inhibitory Effect ◽  
Dynamics Simulation ◽  
Helical Conformation ◽  
Structural Basis ◽  
Similar Distribution ◽  
Post Translational Modifications ◽  
Differential Effects ◽  
The Impact ◽  
Insight Into

AbstractPost-translational modifications (PTMs) within the first 17 amino acids (Nt17) of the Huntingtin protein (Htt) have been shown to inhibit the aggregation and attenuate the toxicity of mutant Htt proteins in vitro and in various models of Huntington’s disease. Our group’s previous studies suggested that the Nt17 PTM code is a combinatorial code that involves a complex interplay between different PTMs. Here, we expand on these studies by investigating the effect of methionine 8 oxidation (oxM8) and crosstalk between this PTM and either lysine 6 acetylation (AcK6) or threonine 3 phosphorylation (pT3) on the aggregation of mutant Httex1. We show that M8 oxidation delays but does not inhibit the aggregation and has no effect on the final morphologies of mutant Httex1 aggregates. This delay in aggregation kinetics could be attributed to the transient accumulation of oligomeric aggregates, which disappear upon the formation of Httex1 oxM8 fibrils. Interestingly, the presence of both oxM8 and AcK6 resulted in dramatic inhibition of Httex1 fibrillization, whereas the presence of oxM8 did not influence the aggregation inhibitory effect of pT3. To gain insight into the structural basis underlying these proteins’ aggregation properties, we investigated the impact of each PTM and the combination of these PTMs on the conformational properties of the Nt17 peptide by circular dichroism spectroscopy and molecular dynamics simulation. These studies show that M8 oxidation decreases the helicity of the Nt17 in the presence or absence of PTMs and provides novel insight into the structural basis underlying the effects of different PTMs on mutant Httex1 aggregation. PTMs that lower the mutant Httex1 aggregation rate (oxM8, AcK6/oxM8, pT3, pT3/oxM8, and phosphorylation at Serine 13) result in stabilization and increased population of a short N-terminal helix (first eight residues) in Nt17 or decreased abundance of other helical forms, including long helix and short C-terminal helix. PTMs that did not alter the aggregation of mutant Httex1 exhibit a similar distribution of helical conformation as the unmodified peptides. These results show that the relative abundance of N- vs. C-terminal helical conformations and long helices, rather than the overall helicity of Nt17, better explains the effect of different Nt17 PTMs on mutant Httex1; thus, explaining the lack of correlation between the effect of PTMs on the overall helicity of Nt17 and mutant Httex1 aggregation in vitro. Taken together, our results provide novel structural insight into the differential effects of single PTMs and crosstalk between different PTMs in regulating mutant Httex1 aggregation.TOC Figure

scholarly journals Pathogenic Role of iNOs+ M1 Effector Macrophages in Fibromyalgia

2020 ◽  
Author(s):  
Vishwas Tripathi ◽  
Amaresh Mishra ◽  
Yamini Pathak ◽  
Aklank Jain ◽  
Hridayesh Prakash
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Neurodegenerative Disorder ◽  
Specific Treatment ◽  
The Body ◽  
World Population ◽  
Pain Models ◽  
Chronic Pain Conditions ◽  
Inflammatory Macrophages ◽  
The Impact

Fibromyalgia (FM) or Fibromyalgia Syndrome (FMS) is a neurodegenerative disorder causing musculoskeletal pain, tenderness, stiffness, fatigue, and sleep disorder in the body. It is one of the most common chronic pain conditions, affecting about 6% of the world population. Being refractory, till date, no specific treatment of this disease is available. Accumulating evidences over the last few decades indicate that proinflammatory macrophages, cytokines, & chemokines as the key players in this disease. Recent findings suggest activation of Microglial cells and associated pro-inflammatory signals as one of the major causes of chronic pain in patients suffering from fibromyalgia. Increased density of iNOs/CD68+ M1 effector macrophages has been associated with neuropathic pain models. In light of this, depletion of these pro-inflammatory macrophages has been shown to reduce sensitivity to neuropathic pain. On the other hand, modulating pattern of AGEs (Advanced Glycation End-Products) can also contribute to inactivation of macrophages. These findings strongly suggest that macrophages are critical in both inflammatory and neuropathic pain. Therefore, this chapter highlights the impact of macrophage plasticity in various immunopathological aspects of fibromyalgia.

The Impact of Shariah Governance and Corporate Governance on the Risk Management Practices: Evidence from Local and Foreign Islamic Banks in Malaysia

2018 ◽  
Vol 15 (2) ◽  
pp. 1-20
Author(s):  
Sabri Embi ◽  
Zurina Shafii
Keyword(s):  
Risk Management ◽  
Corporate Governance ◽  
Management Practices ◽  
Principal Component ◽  
T Test ◽  
The Body ◽  
Primary Data ◽  
Islamic Banks ◽  
Shariah Governance ◽  
The Impact

The purpose of this study is to examine the impact of Shariah governance and corporate governance (CG) on the risk management practices (RMPs) of local Islamic banks and foreign Islamic banks operating in Malaysia. The Shariah governance comprises the Shariah review (SR) and Shariah audit (SA) variables. The study also evaluates the level of RMPs, CG, SR, and SA between these two type of banks. With the aid of SPSS version 20, the items for RMPs, CG, SR, and SA were subjected to principal component analysis (PCA). From the PCA, one component or factor was extracted each for the CG, SR, and RMPs while another two factors were extracted for the SA. Primary data was collected using a self-administered survey questionnaire. The questionnaire covers four aspects ; CG, SR, SA, and RMPs. The data received from the 300 usable questionnaires were subjected to correlation and regression analyses as well as an independent t-test. The result of correlation analysis shows that all the four variables have large positive correlations with each other indicating a strong and significant relationship between them. From the regression analysis undertaken, CG, SR, and SA together explained 52.3 percent of the RMPs and CG emerged as the most influential variable that impacts the RMPs. The independent t-test carried out shows that there were significant differences in the CG and SA between the local and foreign Islamic banks. However, there were no significant differences between the two types of the bank in relation to SR and RMPs. The study has contributed to the body of knowledge and is beneficial to academicians, industry players, regulators, and other stakeholders.

Influence of DAFS-25+polizon composition on blood and functional state of liver of steers at fattening

2020 ◽  
pp. 15-18
Author(s):  
Inna R. Kilmetova ◽  
◽  
Igor A. Rodin ◽  
Nazira I. Khayrullina ◽  
Nikolay G. Fenchenko ◽  
...  
Keyword(s):  
Functional State ◽  
White Blood Cells ◽  
Live Weight ◽  
The Body ◽  
Farm Animals ◽  
Control Group ◽  
Standard Diet ◽  
The Impact ◽  
Experimental Group ◽  
Stimulation Of

Summary. The disbalanced feeding and the uneven distribution of micro- and macroelements in the environment leads to a trace element, in particular hypomelanosis. To accelerate the growth and preservation of young farm animals include in the diet of various biological additives and drugs, which include selenium. For stimulation of weight gain in the livestock industry, as well as for the prevention and treatment of pathological processes in addition to micro - and macrouse amino acids, primarily methionine. The aim of this work was to study the influence of composition of DAFS-25+Polizon on morpho-biochemical parameters of blood and functional state of the liver in fattening bulls of black-motley breed in the conditions of the Republic of Bashkortostan. Experiments using were conducted on bull-calves of black-motley breed of the properties in the properties age from 6 to 15 months. The first experimental group during the experiment was additionally given the composition of DAFS-25+Polizon at a dose of 2 mg/kg, the animals of the control group received a standard diet. To assess the impact of the composition DAFS-25+Polizon on metabolism cattle studied morphological and biochemical indicators of blood and conducted histological examination of the liver. It is established that the use of the composition of DAFS-25+Polizon at a dose of 2 mg/kg increases the number of erythrocytes and hemoglobin in the experimental group and reduces the amount of white blood cells. The serum content of total protein, phosphorus and calcium increases in the group of experimental animals. Microscopic examination of the liver revealed no changes in the structure of the organ and hepatocytes in the experimental group, whereas in the control group hemodynamic disorders and dystrophic changes in liver cells were observed. Thus, the use of the composition DAFS-25+Polizon at a dose of 2 mg/kg of live weight in fattening bulls black-and-white breed contributes to the increase of redox processes in the body, stimulation of metabolism, prevent the development of liver disorders of cellular mechanisms of metabolism, optimizes the structure of the liver, which generally provides higher productivity.

Comparative assessment of morphological mechanisms of maintaining structural liver homeostasis in the dynamics of exposure to coal-rock dust and sodium fluoride on the body

2020 ◽  
pp. 189-194
Author(s):  
M. S. Bugaeva ◽  
O. I. Bondarev ◽  
N. N. Mikhailova ◽  
L. G. Gorokhova
Keyword(s):  
Sodium Fluoride ◽  
Morphological Changes ◽  
The Body ◽  
System Level ◽  
Production Factor ◽  
Coal Rock ◽  
The Impact ◽  
Structural Homeostasis ◽  
Rock Dust

Introduction. The impact on the body of such factors of the production environment as coal-rock dust and fluorine compounds leads to certain shift s in strict indicators of homeostasis at the system level. Maintaining the relative constancy of the internal environment of the body is provided by the functional consistency of all organs and systems, the leading of which is the liver. Organ repair plays a crucial role in restoring the structure of genetic material and maintaining normal cell viability. When this mechanism is damaged, the compensatory capabilities of the organ are disrupted, homeostasis is disrupted at the cellular and organizational levels, and the development of the main pathological processes is noted.The aim of the study is to compare the morphological mechanisms of maintaining structural homeostasis of the liver in the dynamics of the impact on the body of coal-rock dust and sodium fluoride.Materials and methods. Experimental studies were conducted on adult white male laboratory rats. Features of morphological mechanisms for maintaining structural homeostasis of the liver in the dynamics of exposure to coal-rock dust and sodium fluoride were studied on experimental models of pneumoconiosis and fluoride intoxication. For histological examination in experimental animals, liver sampling was performed after 1, 3, 6, 9, 12 weeks of the experiment.Results. The specificity of morphological changes in the liver depending on the harmful production factor was revealed. It is shown that chronic exposure to coal-rock dust and sodium fluoride is characterized by the development of similar morphological changes in the liver and its vessels from the predominance of the initial compensatory-adaptive to pronounced violations of the stromal and parenchymal components. Long-term inhalation of coal-rock dust at 1–3 weeks of seeding triggers adaptive mechanisms in the liver in the form of increased functional activity of cells, formation of double-core hepatocytes, activation of immunocompetent cells and endotheliocytes, ensuring the preservation of the parenchyma and the general morphostructure of the organ until the 12th week of the experiment. Exposure to sodium fluoride leads to early disruption of liver compensatory mechanisms and the development of dystrophic changes in the parenchyma with the formation of necrosis foci as early as the 6th week of the experiment.Conclusions. The study of mechanisms for compensating the liver structure in conditions of long-term exposure to coal-rock dust and sodium fluoride, as well as processes that indicate their failure, and the timing of their occurrence, is of theoretical and practical importance for developing recommendations for the timely prevention and correction of pathological conditions developing in employees of the aluminum and coal industry.The authors declare no conflict of interests.

Experience in the use of double broncholytic therapy in occupational practice

2019 ◽  
pp. 303-307
Author(s):  
Elena A. Beigel ◽  
Natalya G. Kuptsova ◽  
Elena V. Katamanova ◽  
Oksana V. Ushakova ◽  
Oleg L. Lakhman
Keyword(s):  
Quality Of Life ◽  
Personal Data ◽  
The Body ◽  
Step Test ◽  
Aluminum Production ◽  
Chronic Obstructive ◽  
Body Plethysmography ◽  
Occupational Copd ◽  
The Impact

Introduction. Occupational chronic obstructive pulmonary disease (COPD) is one of the leading nosological forms of occupational respiratory disease. Numerous studies have shown high effectiveness of the combination of indacaterol/glycopyrronium (Ultibro®breezhaler®) on the impact on clinical and functional indicators in the treatment of COPD in General practice.The aim of the investigation the case of occupational COPD with the analysis of the dynamics of functional indicators, tolerance to physical load and evaluation of the quality of life of workers engaged in aluminum production by using combination of indacaterol/glycopyrronium.Materials and methods. The random sampling method included 20 men, workers of aluminum production, with the established diagnosis of professional COPD at the age of 40 to 60 years. The survey was conducted (Borg scale, medical Research Council scale (mMRC) and COPD Assessment Test (CAT). Functional methods of studies were conducted: spirometry, body plethysmography, electrocardiography (ECG) and the six-minute stepper test (6-MST).Results. Against the background of 8 weeks of therapy, the volume of forced exhalation for 1 minute (FEV1) increased by 14.7% and amounted to 67.90% of the due values, the forced vital capacity of the lungs (FVC) increased by 11.3% and amounted to 76.95% of the due. According to the body plethysmography (BPG) is set to decrease in residual lung volume on average by 13.4% and static hyperinflation, confirmed by the decrease in functional residual volume (FRV) of 18.8%. During the study period increased physical activity of patients. The average difference between the distance traveled in the six-minute step test before and after treatment was 58.8 m. The analysis of personal data showed that the quality of life of patients improved, the total score in the questionnaire CAT at the beginning of the study was 16.9 points, and after 8 weeks decreased by 63% and amounted to 10.7 points.Conclusions: The Results indicate a positive effect of combination therapy with indacaterol/glycopyrronium on the course and progression of occupational COPD.

Studying Abroad in Nepal: Assessing Impact

2003 ◽  
Vol 9 (1) ◽  
pp. 175-188 ◽  
Author(s):  
Patricia Farrell ◽  
Murari Suvedi
Keyword(s):  
Personal Development ◽  
Intellectual Development ◽  
Longitudinal Research ◽  
Adult Learning Theory ◽  
Academic Program ◽  
The Body ◽  
Study Abroad Programs ◽  
Studying Abroad ◽  
Perceived Impact ◽  
The Impact

The purpose of this study is to analyze the reported or perceived impact of studying in Nepal on student’s academic program, personal development and intellectual development. The study draws upon adult learning theory to analyze survey instrument data, interviews, and case studies to discern the impact of the program on college students and to contribute to the body of longitudinal research on U.S. study abroad programs.

Adrenergic and Cholinergic Uterine Innervation and the Impact on Reproduction in Aged Women

2020 ◽  
Vol 26 (3) ◽  
pp. 358-362 ◽  
Author(s):  
Ioannis P. Kosmas ◽  
Antonio Malvasi ◽  
Daniele Vergara ◽  
Ospan A. Mynbaev ◽  
Radmila Sparic ◽  
...  
Keyword(s):  
Negative Impact ◽  
Smooth Muscles ◽  
Nerve Fibers ◽  
The Body ◽  
Autonomous Nervous System ◽  
Childbearing Age ◽  
Assisted Reproductive Technique ◽  
Aged Patients ◽  
Post Menopause ◽  
The Impact

: In recent years, the development of Assisted Reproductive Technique, the egg and embryo donation changed substantially the role of the uterus in recent years. It provided a higher chance for a pregnancy even in women over 45 years or post-menopause. In fact, the number of aged patients and in peri/post-menopause in pregnancy is nowadays increasing, but it increases obstetrical and neonatal related problems. The human uterus is richly innervated and modified especially during pregnancy and labor, and it is endowed with different sensory, parasympathetic, sympathetic and peptidergic neurofibers. They are differently distributed in uterine fundus, body and cervix, and they are mainly observed in the stroma and around arterial vessel walls in the myometrial and endometrial layers. Many neurotransmitters playing important roles in reproductive physiology are released after stimulation by adrenergic or cholinergic nerve fibers (the so called sympathetic/parasympathetic co-transmission). Immunohistochemical study demonstrated the localization and quantitative distribution of neurofibers in the fundus, the body and cervix of young women of childbearing age. : Adrenergic and cholinergic effects of the autonomous nervous system are the most implicated in the uterine functionality. In such aged women, the Adrenergic and AChE neurofibers distribution in the fundus, body and cervix is progressively reduced by increasing age. Adrenergic and AChE neurotransmitters were closely associated with the uterine arteries and myometrial smooth muscles, and they reduced markedly by ageing. The Adrenergic and AChE neurofibers decreasing has a dramatical and negative impact on uterine physiology, as the reduction of pregnancy chance and uterine growth, and the increase of abortion risk and prematurity.

Unveiling the Structural Insights into the Selective Inhibition of Protein Kinase D1

2019 ◽  
Vol 25 (10) ◽  
pp. 1059-1074 ◽  
Author(s):  
Raju Dash ◽  
Md. Arifuzzaman ◽  
Sarmistha Mitra ◽  
Md. Abdul Hannan ◽  
Nurul Absar ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Dynamics Simulation ◽  
Protein Kinase ◽  
Binding Site ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Selective Inhibitors ◽  
Conserved Residues ◽  
Protein Kinase D1 ◽  
Binding Mechanisms

Background: Although protein kinase D1 (PKD1) has been proved to be an efficient target for anticancer drug development, lack of structural details and substrate binding mechanisms are the main obstacles for the development of selective inhibitors with therapeutic benefits. Objective: The present study described the in silico dynamics behaviors of PKD1 in binding with selective and non-selective inhibitors and revealed the critical binding site residues for the selective kinase inhibition. Methods: Here, the three dimensional model of PKD1 was initially constructed by homology modeling along with binding site characterization to explore the non-conserved residues. Subsequently, two known inhibitors were docked to the catalytic site and the detailed ligand binding mechanisms and post binding dyanmics were investigated by molecular dynamics simulation and binding free energy calculations. Results: According to the binding site analysis, PKD1 serves several non-conserved residues in the G-loop, hinge and catalytic subunits. Among them, the residues including Leu662, His663, and Asp665 from hinge region made polar interactions with selective PKD1 inhibitor in docking simulation, which were further validated by the molecular dynamics simulation. Both inhibitors strongly influenced the structural dynamics of PKD1 and their computed binding free energies were in accordance with experimental bioactivity data. Conclusion: The identified non-conserved residues likely to play critical role on molecular reorganization and inhibitor selectivity. Taken together, this study explained the molecular basis of PKD1 specific inhibition, which may help to design new selective inhibitors for better therapies to overcome cancer and PKD1 dysregulated disorders.

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