Evaluating stability of human spine in static tasks: a combined in vivo-computational study

Background: N-{[3-(4-chlorophenyl)-4-oxo-3, 4-dihydroquinazolin-2-yl] methyl}, 2-[(2- isopropyl-5-methyl) 1-cyclohexylidene] hydrazinecarboxamide QS11 was designed by computational study. It possessed essential pharmacophoric features for anticonvulsant activity and showed good docking with iGluRs (Kainate) glutamate receptor. Methods: QSAR and ADMET screening results suggested that QS11 would possess good potency for anticonvulsant activity. QS11 was synthesised and evaluated for its anticonvulsant activity and neurotoxicity. QS11 showed protection in strychnine, thiosemicarbazide, 4-aminopyridine and scPTZ induced seizure models and MES seizure model. QS11 showed higher ED50, TD50 and PI values as compared to the standard drugs in both MES and scPTZ screen. A high safety profile (HD50/ED50 values) was noted and hypnosis, analgesia, and anaesthesia were only observed at higher doses. No considerable increase or decrease in the concentration of liver enzymes was observed. Optimized QS11 was subjected to preclinical (in-vivo) studies and the pharmacokinetic performance of the sample was investigated. The result revealed that the pharmacokinetic performance of QS11 achieved maximum plasma concentrations (Cmax) of 0.315 ± 0.011 µg/mL at Tmax of 2.0 ± 0.13 h, area under the curve (AUC0-∞) value 4.591 ± 0.163 µg/ml x h, elimination half-life (T1/2) 6.28 ± 0.71 h and elimination rate constant was found 0.110 ± 0.013 h-1. Results and Conclusion: Above evidences indicate that QS11 could serve as a lead for development of new antiepileptic drugs.

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Computational study for suppression of CD25/IL-2 interaction

Biological Chemistry ◽

10.1515/hsz-2020-0326 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Moein Dehbashi ◽

Zohreh Hojati ◽

Majid Motovali-bashi ◽

Mazdak Ganjalikhani-Hakemi ◽

Akihiro Shimosaka ◽

...

Keyword(s):

Small Molecules ◽

Cancer Progression ◽

Immune Escape ◽

De Novo ◽

Computational Study ◽

Treg Cells ◽

Homology Search ◽

Small Interfering Rnas

AbstractCancer recurrence presents a huge challenge in cancer patient management. Immune escape is a key mechanism of cancer progression and metastatic dissemination. CD25 is expressed in regulatory T (Treg) cells including tumor-infiltrating Treg cells (TI-Tregs). These cells specially activate and reinforce immune escape mechanism of cancers. The suppression of CD25/IL-2 interaction would be useful against Treg cells activation and ultimately immune escape of cancer. Here, software, web servers and databases were used, at which in silico designed small interfering RNAs (siRNAs), de novo designed peptides and virtual screened small molecules against CD25 were introduced for the prospect of eliminating cancer immune escape and obtaining successful treatment. We obtained siRNAs with low off-target effects. Further, small molecules based on the binding homology search in ligand and receptor similarity were introduced. Finally, the critical amino acids on CD25 were targeted by a de novo designed peptide with disulfide bond. Hence we introduced computational-based antagonists to lay a foundation for further in vitro and in vivo studies.

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Pharmacoinformatics and UPLC-QTOF/ESI-MS-Based Phytochemical Screening of Combretum indicum against Oxidative Stress and Alloxan-Induced Diabetes in Long–Evans Rats

Molecules ◽

10.3390/molecules26154634 ◽

2021 ◽

Vol 26 (15) ◽

pp. 4634

Author(s):

Md. Shaekh Forid ◽

Md. Atiar Rahman ◽

Mohd Fadhlizil Fasihi Mohd Aluwi ◽

Md. Nazim Uddin ◽

Tapashi Ghosh Roy ◽

...

Keyword(s):

Blood Glucose ◽

Immune Modulation ◽

Computational Study ◽

Density Lipoprotein ◽

Control Group ◽

Esi Ms ◽

Long Evans ◽

Antidiabetic Effects

This research investigated a UPLC-QTOF/ESI-MS-based phytochemical profiling of Combretum indicum leaf extract (CILEx), and explored its in vitro antioxidant and in vivo antidiabetic effects in a Long–Evans rat model. After a one-week intervention, the animals’ blood glucose, lipid profile, and pancreatic architectures were evaluated. UPLC-QTOF/ESI-MS fragmentation of CILEx and its eight docking-guided compounds were further dissected to evaluate their roles using bioinformatics-based network pharmacological tools. Results showed a very promising antioxidative effect of CILEx. Both doses of CILEx were found to significantly (p < 0.05) reduce blood glucose, low-density lipoprotein (LDL), and total cholesterol (TC), and increase high-density lipoprotein (HDL). Pancreatic tissue architectures were much improved compared to the diabetic control group. A computational approach revealed that schizonepetoside E, melianol, leucodelphinidin, and arbutin were highly suitable for further therapeutic assessment. Arbutin, in a Gene Ontology and PPI network study, evolved as the most prospective constituent for 203 target proteins of 48 KEGG pathways regulating immune modulation and insulin secretion to control diabetes. The fragmentation mechanisms of the compounds are consistent with the obtained effects for CILEx. Results show that the natural compounds from CILEx could exert potential antidiabetic effects through in vivo and computational study.

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Antioxidant Properties of Ergosterol and Its Role in Yeast Resistance to Oxidation

Antioxidants ◽

10.3390/antiox10071024 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1024

Author(s):

Sebastien Dupont ◽

Paul Fleurat-Lessard ◽

Richtier Gonçalves Cruz ◽

Céline Lafarge ◽

Cédric Grangeteau ◽

...

Keyword(s):

Computational Study ◽

Antioxidant Properties ◽

Beneficial Effects ◽

Tert Butyl Hydroperoxide ◽

Resistance To Oxidation ◽

Specific Accumulation ◽

The Subject

Although the functions and structural roles of sterols have been the subject of numerous studies, the reasons for the diversity of sterols in the different eukaryotic kingdoms remain unclear. It is thought that the specificity of sterols is linked to unidentified supplementary functions that could enable organisms to be better adapted to their environment. Ergosterol is accumulated by late branching fungi that encounter oxidative perturbations in their interfacial habitats. Here, we investigated the antioxidant properties of ergosterol using in vivo, in vitro, and in silico approaches. The results showed that ergosterol is involved in yeast resistance to tert-butyl hydroperoxide and protects lipids against oxidation in liposomes. A computational study based on quantum chemistry revealed that this protection could be related to its antioxidant properties operating through an electron transfer followed by a proton transfer mechanism. This study demonstrates the antioxidant role of ergosterol and proposes knowledge elements to explain the specific accumulation of this sterol in late branching fungi. Ergosterol, as a natural antioxidant molecule, could also play a role in the incompletely understood beneficial effects of some mushrooms on health.

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Diterpenes/Diterpenoids and Their Derivatives as Potential Bioactive Leads against Dengue Virus: A Computational and Network Pharmacology Study

Molecules ◽

10.3390/molecules26226821 ◽

2021 ◽

Vol 26 (22) ◽

pp. 6821

Author(s):

Rasel Ahmed Khan ◽

Rajib Hossain ◽

Abolghasem Siyadatpanah ◽

Khattab Al-Khafaji ◽

Abul Bashar Ripon Khalipha ◽

...

Keyword(s):

Dengue Virus ◽

Dengue Fever ◽

Computational Study ◽

Viral Proteins ◽

Network Pharmacology ◽

Binding Affinities ◽

Ns1 Protein ◽

Structural Protein ◽

E Protein

Dengue fever is a dangerous infectious endemic disease that affects over 100 nations worldwide, from Africa to the Western Pacific, and is caused by the dengue virus, which is transmitted to humans by an insect bite of Aedes aegypti. Millions of citizens have died as a result of dengue fever and dengue hemorrhagic fever across the globe. Envelope (E), serine protease (NS3), RNA-directed RNA polymerase (NS5), and non-structural protein 1 (NS1) are mostly required for cell proliferation and survival. Some of the diterpenoids and their derivatives produced by nature possess anti-dengue viral properties. The goal of the computational study was to scrutinize the effectiveness of diterpenoids and their derivatives against dengue viral proteins through in silico study. Methods: molecular docking was performed to analyze the binding affinity of compounds against four viral proteins: the envelope (E) protein, the NS1 protein, the NS3 protein, and the NS5 protein. Results: among the selected drug candidates, triptolide, stevioside, alepterolic acid, sphaeropsidin A, methyl dodovisate A, andrographolide, caesalacetal, and pyrimethamine have demonstrated moderate to good binding affinities (−8.0 to −9.4 kcal/mol) toward the selected proteins: E protein, NS3, NS5, and NS1 whereas pyrimethamine exerts −7.5, −6.3, −7.8, and −6.6 kcal/mol with viral proteins, respectively. Interestingly, the binding affinities of these lead compounds were better than those of an FDA-approved anti-viral medication (pyrimethamine), which is underused in dengue fever. Conclusion: we can conclude that diterpenoids can be considered as a possible anti-dengue medication option. However, in vivo investigation is recommended to back up the conclusions of this study.

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Computational Study on the Effects of Peripheral Vessel Network on Blood Flow in the Arterial Circle of Willis

ASME 2007 Summer Bioengineering Conference ◽

10.1115/sbc2007-176706 ◽

2007 ◽

Author(s):

Shigefumi Tokuda ◽

Takeshi Unemura ◽

Marie Oshima

Keyword(s):

Numerical Simulation ◽

Blood Flow ◽

Boundary Conditions ◽

Vascular System ◽

Computational Study ◽

Circulatory System ◽

Biological Data ◽

Patient Specific ◽

Peripheral Vessel

Cerebrovascular disorder such as subarachnoid hemorrhage (SAH) is 3rd position of the cause of death in Japan [1]. Its initiation and growth are reported to depend on hemodynamic factors, particularly on wall shear stress or blood pressure induced by blood flow. In order to investigate the information on the hemodynamic quantities in the cerebral vascular system, the authors have been developing a computational tool using patient-specific modeling and numerical simulation [2]. In order to achieve an in vivo simulation of living organisms, it is important to apply appropriate physiological conditions such as physical properties, models, and boundary conditions. Generally, the numerical simulation using a patient-specific model is conducted for a localized region near the research target. Although the analysis region is only a part of the circulatory system, the simulation has to include the effects from the entire circulatory system. Many studies have carried out to derive the boundary conditions to model in vivo environment [3–5]. However, it is not easy to obtain the biological data of cerebral arteries due to head capsule.

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Restitution and adaptation measurements for the estimate of short-term cardiac action potential memory: comparison of five human ventricular models

EP Europace ◽

10.1093/europace/euz205 ◽

2019 ◽

Vol 21 (10) ◽

pp. 1594-1602

Author(s):

Massimiliano Zaniboni ◽

Francesca Cacciani

Keyword(s):

Steady State ◽

Action Potential ◽

Short Term Memory ◽

Computational Study ◽

Numerical Models ◽

Cardiac Action Potential ◽

Short Term ◽

Term Memory ◽

Cardiac Action

Abstract Aims This computational study refines our recently published pacing protocol to measure short-term memory (STM) of cardiac action potential (AP), and apply it to five numerical models of human ventricular AP. Methods and results Several formulations of electrical restitution (ER) have been provided over the years, including standard, beat-to-beat, dynamic, steady-state, which make it difficult to compare results from different studies. We discuss here the notion of dynamic ER (dER) by relating it to its steady-state counterpart, and propose a pacing protocol based on dER to measure STM under periodically varying pacing cycle length (CL). Under high and highly variable-pacing rate, all models develop STM, which can be measured over the entire sequence by means of dER. Short-term memory can also be measured on a beat-to-beat basis by estimating action potential duration (APD) adaptation after clamping CL constant. We visualize STM as a phase shift between action potential (AP) parameters over consecutive cycles of CL oscillations, and show that delay between CL and APD oscillation is nearly constant (around 92 ms) in the five models, despite variability in their intrinsic AP properties. Conclusion dER, as we define it and together with other approaches described in the study, provides an univocal way to measure STM under extreme cardiac pacing conditions. Given the relevance of AP memory for repolarization dynamics and stability, STM should be considered, among other usual biomarkers, to validate and tune cardiac AP models. The possibility of extending the method to in vivo cellular and whole organ models can also be profitably explored.

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On the Stability Analysis of the Human Spine

Advances in Bioengineering ◽

10.1115/imece2003-43246 ◽

2003 ◽

Author(s):

M. El-Rich ◽

A. Shirazi-Adl

Keyword(s):

Stability Analysis ◽

Material Handling ◽

Muscle Activation ◽

The Body ◽

Abdominal Pressure ◽

Human Spine ◽

Manual Material Handling ◽

The Stability ◽

Force Relationship

The stability of the human spine in compression has attracted a considerable amount of attention in recent years. The passive ligamentous thoracolumbar and lumbar spines are known to exhibit large displacements or hypermobility (i.e., instability in an imperfect column) under compression loads <100N. Since such compression loads are only a small fraction of those supported by the spine even in regular daily activities, let aside the manual material handling tasks, the question arises as to how the spine is stablized in vivo? Various stabilizing mechanisms have been proposed and investigated; wrapping loading [Shirazi-Adl and Parnianpour, 2000], postural adaptations [Shirazi-Adl and parnianpor, 1999], intra-abdominal pressure [Cholewicki et al, 1999] and muscle activation/coactivation [Bergmark, 1989; Crisco and Panjabi, 1991]. In this work, a novel kinematics-based methad [Shirazi-Adl et al., 2002] is first applied to compute muscle forces and internal loads in standing postures under gravity with or without 200N loads held either on sides or close to the body in front. The stability of the system under given loads and prescribed postures is sudsequently examined using both linear bucking analysis based on the deformed configurations and nonlinear analysis while employing a liner stiffness-force relationship for muscules [Bergmark, 1989; Crico and Panjabi, 1991]. The relative accuracy of foregoing methods in stability analysis of some sample structures is also investigated. Moreover, the effect of co-activity on stability of the spine in neutral postures is studied.

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