Abstract P422: Sanal Flow Choking Leads To Hemorrhagic Stroke And Other Neurological Disorders In Earth And Human Spaceflight

Background: Evidences are escalating on the diverse neurological disorders associated with COVID-19pandemic due to the nanoscale Sanal-flow-choking (PMC7267099) . The Sanal-flow-chokingoccurs at relatively high and low blood viscosity. Sanal-flow-choking leads to aneurysm andhemorrhagic-stroke and other neurological-disorders if the vessel geometry is having divergence,bifurcation, stenosis and/or occlusion regions (PMC7933821) . Nanoscale Sanal flow choking ismore susceptible at microgravity condition due to altered variations of blood viscosity, turbulenceand the blood pressure ratio (BPR). Astronauts/Cosmonauts experienced neurological disordersduring human spaceflight and thereafter. Methods: Closed-form analytical, in vitro and in silico studies have been carried out for establishing thephenomenon of Sanal-flow-choking. Biofluid/blood heat capacity ratio (BHCR) of various healthysubjects are estimated. Results: The closed-form analytical models reveal that the relatively high and low blood viscosity arerisk factors of Sanal-flow-choking. In vitro study shows that N2, O2, and CO2 gases arepredominant in fresh-blood samples of the healthy human-being and Guinea-pig at a temperaturerange of 37-40 0 C (98.6-104 0 F), which increases the risk of Sanal-flow-choking. In silico resultsshows the Sanal-flow-choking followed by shock-waves and pressure-overshoot in a simulatedartery with the divergence region. Conclusions: As the pressure of the nanoscale biofluid/non-continuum-flows rises, fluid viscosityincreases and average-mean-free-path diminishes and thus, the Knudsen number lowers headingto a zero-slip wall-boundary condition with the compressible flow regime, which increases the riskof Sanal-flow-choking and the shock wave generation causing asymptomatic cardiovasculardisease. Microgravity environment decreases plasma volume and increases the hematocritcompared with the situation on the earth surface, which increases the relative viscosity of bloodcausing an early Sanal-flow-choking. Herein we established that the disproportionate blood-thinning treatment increases the risk of the nanoscale Sanal-flow-choking due to the enhancedboundary-layer-blockage factor. The risk could be diminished by concurrently reducing theviscosity of biofluid/blood and flow-turbulence by increasing thermal-tolerance-level in terms ofBHCR and/or by decreasing the BPR through new drug discovery or using companion medicinewith the traditional blood thinners or other health care management. We recommend allastronauts/cosmonauts should wear ambulatory blood pressure and thermal level monitoringdevices similar to a wristwatch throughout the space travel for the diagnosis, prognosis andprevention of internal flow choking leading to asymptomatic cardiovascular disease includingneurological disorders.

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Very Low and High Blood Viscosity Are Risk Factors for Internal Flow Choking Causing Asymptomatic Cardiovascular Disease

10.21203/rs.3.rs-151850/v1 ◽

2021 ◽

Author(s):

SANAL KUMAR V R ◽

Shiv Kumar Choudhary ◽

Pradeep Kumar Radhakrishnan ◽

Bharath R.S. ◽

Nichith Chandrasekaran ◽

...

Keyword(s):

Shock Wave ◽

Cardiovascular Risk ◽

Guinea Pig ◽

Closed Form ◽

Blood Viscosity ◽

In Silico ◽

Thermal Tolerance ◽

Flow Choking ◽

Tolerance Level

Abstract BackgroundThe truly popular consequence of management with the blood-thinning-drug, causation of lower blood-viscosity (BV), is bleeding and very frequently asymptomatic-hemorrhage (AH) and the acute-heart-failure (AHF) happen without any preceding symptoms.ObjectivesOur aim was to develop an infallible closed-form analytical model for demonstrating the proof of the concept of the Sanal flow choking in cardiovascular system (CVS) causing AH and AHF by correlating the blood pressure ratio (BPR), biofluid/blood-heat-capacity-ratio(BHCR), blood viscosity(BV), stenosis (in terms of vessel cross-sectional area (VCA)) and ejection fraction(EF). For establishing the proof of the concept we were planned in vitro and in silico studies. MethodsThe closed-form-analytical-methodology is used herein to establish the proof of the concept of Sanal-flow-choking. In vitro method is invoked for the speciation analyses of blood samples of healthy subjects (human being/Guinea pig) for the BHCR estimation. In silico method is used for demonstrating the asymptomatic pressure-overshoot in an artery due to the Sanal flow choking and shock wave generation. ResultsThe closed-form analytical, in vitro and in silico results are presented herein to establish the proof of the concept of internal flow choking in CVS causing cardiovascular risk without prejudice to the percutaneous coronary intervention (PCI). The analytical models reveal that the relatively high and low BV are risk factors of AH and AHF. In vitro study shows that nitrogen(N2), oxygen(O2), carbon dioxide(CO2) and argon(Ar) gases are predominant in fresh-blood samples of the healthy human-being and Guinea-pig at a temperature range of 37-400 C (98.6-1040 F), which increases the risk of flow-choking leading to AH and AHF. The thermal-tolerance level in terms of BHCR of Guinea-pig is found higher than the human being. In silico results demonstrated the Sanal flow choking and shock wave generation in an artery with the divergent/bifurcation region. ConclusionsAn overdose of blood-thinning drug for reducing the blood-viscosity(BV) augments Reynolds number leading to high-turbulence and enhanced boundary-layer-blockage(BLB), which increases the chances of cavitation and the Sanal-flow-choking leading to the shock wave and pressure-overshoot causing memory effect (stroke history) in viscoelastic vessels. Designing the precise blood-thinning regimen is vital for attaining the desired therapeutic efficacy and negating undesirable flow-choking leading to AH and AHF. Herein we established that the disproportionate blood-thinning treatment increases the risk of the Sanal-flow-choking due to the enhanced BLB factor. The cardiovascular risk could be diminished by concurrently lessening the BV and flow turbulence by rising thermal-tolerance-level in terms of BHCR or by decreasing the BPR. Condensed AbstractHerein, we provide a proof of the concept to establish that such asymptomatic diseases are due to the boundary-layer-blockage (BLB) induced flow choking (Sanal-flow-choking) at a critical blood-pressure-ratio (BPR). When the pressure of the nanoscale-fluid increases, average-mean-free-path decreases and thus, the Knudsen number reduces leading to a no-slip boundary condition with compressible-viscous (CV) flow effect. Sanal-flow-choking is a CV flow effect creating a physical situation of the sonic-fluid-throat, at a critical BPR. We concluded that AH and AHF are transient-events due to flow-choking, and not an illness. The cardiovascular risk could be diminished by concurrently lessening the BV and flow turbulence by rising thermal-tolerance-level in terms of BHCR or by decreasing the BPR.

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Sanal Flow Choking Leads to Hemorrhagic Stroke and Other Neurological Disorders in Earth and Human Spaceflight

10.31219/osf.io/fp2q6 ◽

2021 ◽

Author(s):

SANALKUMAR V R

Keyword(s):

Blood Pressure ◽

Cardiovascular Disease ◽

Blood Viscosity ◽

Neurological Disorders ◽

Hemorrhagic Stroke ◽

Pressure Ratio ◽

Internal Flow ◽

Fluid Viscosity ◽

Human Spaceflight ◽

Flow Choking

Evidences are escalating on the diverse neurological disorders associated with COVID-19 pandemic due to the nanoscale Sanal flow choking (PMC7267099). The Sanal flow choking occurs at relatively high and low blood viscosity. Sanal flow choking leads to aneurysm, hemorrhagic-stroke and other neurological-disorders if the vessel geometry is having divergence, bifurcation, stenosis and/or occlusion regions (PMC7933821). Nanoscale Sanal flow choking is more susceptible at microgravity condition due to altered variations of blood viscosity, turbulence and the blood pressure ratio (BPR). Astronauts/Cosmonauts experienced neurological disorders during human spaceflight and thereafter. V.R.S.Kumar et al. (2021) reported that the asymptomatic episodes in the cardiovascular system are due to the internal flow choking (Biofluid/ Sanal flow choking) at a critical blood pressure ratio (BPR), which is regulated by the biofluid/blood heat capacity ratio (BHCR). As the pressure of the nanoscale biofluid / non-continuum-flows rises, fluid viscosity increases and average-mean-free-path diminishes and thus, the Knudsen number lowers heading to a zero-slip wall-boundary condition with the compressible flow regime, which increases the risk of Sanal flow choking and the shock wave generation causing asymptomatic cardiovascular disease. Microgravity environment decreases plasma volume and increases the hematocrit compared with the situation on the Earth surface, which increases the relative viscosity of blood causing an early Sanal flow choking. Herein, we established that the disproportionate blood-thinning treatment increases the risk of the nanoscale Sanal flow choking due to the enhanced boundary-layer-blockage factor. The risk could be diminished by concurrently reducing the viscosity of biofluid/ blood and flow-turbulence by increasing the thermal-tolerance-level in terms of BHCR and/or by decreasing the BPR through new drug discovery or using companion medicine with the traditional blood thinners or other health care management. We recommend all astronauts/cosmonauts should wear ambulatory blood pressure and thermal level monitoring devices similar to a wristwatch throughout the space travel for the diagnosis, prognosis and prevention of internal flow choking leading to asymptomatic cardiovascular disease including neurological disorders.

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Recent In Vitro and In Silico Advances in the Understanding of Intranasal Drug Delivery

Current Pharmaceutical Design ◽

10.2174/1381612826666201112143230 ◽

2020 ◽

Vol 26 ◽

Author(s):

John Chen ◽

Andrew Martin ◽

Warren H. Finlay

Keyword(s):

Drug Delivery ◽

In Silico ◽

Local Drug Delivery ◽

In Vivo Studies ◽

Intranasal Drug Delivery ◽

Nasal Sprays ◽

In Silico Studies ◽

Drug Delivery Devices

Background: Many drugs are delivered intranasally for local or systemic effect, typically in the form of droplets or aerosols. Because of the high cost of in vivo studies, drug developers and researchers often turn to in vitro or in silico testing when first evaluating the behavior and properties of intranasal drug delivery devices and formulations. Recent advances in manufacturing and computer technologies have allowed for increasingly realistic and sophisticated in vitro and in silico reconstructions of the human nasal airways. Objective: To perform a summary of advances in understanding of intranasal drug delivery based on recent in vitro and in silico studies. Conclusion: The turbinates are a common target for local drug delivery applications, and while nasal sprays are able to reach this region, there is currently no broad consensus across the in vitro and in silico literature concerning optimal parameters for device design, formulation properties and patient technique which would maximize turbinate deposition. Nebulizers are able to more easily target the turbinates, but come with the disadvantage of significant lung deposition. Targeting of the olfactory region of the nasal cavity has been explored for potential treatment of central nervous system conditions. Conventional intranasal devices, such as nasal sprays and nebulizers, deliver very little dose to the olfactory region. Recent progress in our understanding of intranasal delivery will be useful in the development of the next generation of intranasal drug delivery devices.

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In-silico Studies of Isolated Phytoalkaloid Against Lipoxygenase: Study Based on Possible Correlation

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207321666180220125406 ◽

2018 ◽

Vol 21 (3) ◽

pp. 215-221

Author(s):

Haroon Khan ◽

Muhammad Zafar ◽

Helena Den-Haan ◽

Horacio Perez-Sanchez ◽

Mohammad Amjad Kamal

Keyword(s):

In Silico ◽

Docking Studies ◽

In Vivo Studies ◽

In Vitro Assays ◽

Chronic Obstructive ◽

Lipoxygenase Inhibitors ◽

Lipoxygenase Inhibition ◽

In Silico Studies

Aim and Objective: Lipoxygenase (LOX) enzymes play an important role in the pathophysiology of several inflammatory and allergic diseases including bronchial asthma, allergic rhinitis, atopic dermatitis, allergic conjunctivitis, rheumatoid arthritis and chronic obstructive pulmonary disease. Inhibitors of the LOX are believed to be an ideal approach in the treatment of diseases caused by its over-expression. In this regard, several synthetic and natural agents are under investigation worldwide. Alkaloids are the most thoroughly investigated class of natural compounds with outstanding past in clinically useful drugs. In this article, we have discussed various alkaloids of plant origin that have already shown lipoxygenase inhibition in-vitro with possible correlation in in silico studies. Materials and Methods: Molecular docking studies were performed using MOE (Molecular Operating Environment) software. Among the ten reported LOX alkaloids inhibitors, derived from plant, compounds 4, 2, 3 and 1 showed excellent docking scores and receptor sensitivity. Result and Conclusion: These compounds already exhibited in vitro lipoxygenase inhibition and the MOE results strongly correlated with the experimental results. On the basis of these in vitro assays and computer aided results, we suggest that these compounds need further detail in vivo studies and clinical trial for the discovery of new more effective and safe lipoxygenase inhibitors. In conclusion, these results might be useful in the design of new and potential lipoxygenase (LOX) inhibitors.

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In Vitro, In Silico and Ex Vivo Studies of Dihydroartemisinin Derivatives as Antitubercular Agents

Current Topics in Medicinal Chemistry ◽

10.2174/1568026619666190305131425 ◽

2019 ◽

Vol 19 (8) ◽

pp. 633-644 ◽

Cited By ~ 1

Author(s):

Komal Kalani ◽

Sarfaraz Alam ◽

Vinita Chaturvedi ◽

Shyam Singh ◽

Feroz Khan ◽

...

Keyword(s):

Bone Marrow ◽

In Silico ◽

Ex Vivo ◽

Virulent Strain ◽

Infection Model ◽

Mouse Bone Marrow ◽

Significant Activity ◽

Macrophage Infection ◽

In Silico Studies

Introduction: As a part of our drug discovery program for anti-tubercular agents, dihydroartemisinin (DHA-1) was screened against Mtb H37Rv, which showed moderate anti-tubercular activity (>25.0 µg/mL). These results prompted us to carry out the chemical transformation of DHA-1 into various derivatives and study their antitubercular potential. Materials and Methods: DHA-1 was semi-synthetically converted into four new acyl derivatives (DHA-1A – DHA-1D) and in-vitro evaluated for their anti-tubercular potential against Mycobacterium tuberculosis H37Rv virulent strain. The derivatives, DHA-1C (12-O-(4-nitro) benzoyl; MIC 12.5 µg/mL) and DHA-1D (12-O-chloro acetyl; MIC 3.12µg/mL) showed significant activity against the pathogen. Results: In silico studies of the most active derivative (DHA-1D) showed interaction with ARG448 inhibiting the mycobacterium enzymes. Additionally, it showed no cytotoxicity towards the Vero C1008 cells and Mouse bone marrow derived macrophages. Conclusion: DHA-1D killed 62% intracellular M. tuberculosis in Mouse bone marrow macrophage infection model. To the best of our knowledge, this is the first-ever report on the antitubercular potential of dihydroartemisinin and its derivatives. Since dihydroartemisinin is widely used as an antimalarial drug; these results may be of great help in anti-tubercular drug development from a very common, inexpensive, and non-toxic natural product.

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Synthesis, In Vitro and In Silico Studies of Indolequinone Derivatives against Clinically Relevant Bacterial Pathogens

Current Topics in Medicinal Chemistry ◽

10.2174/1568026620666191223110518 ◽

2020 ◽

Vol 20 (3) ◽

pp. 192-208 ◽

Cited By ~ 1

Author(s):

Talita Odriane Custodio Leite ◽

Juliana Silva Novais ◽

Beatriz Lima Cosenza de Carvalho ◽

Vitor Francisco Ferreira ◽

Leonardo Alves Miceli ◽

...

Keyword(s):

In Silico ◽

Bacterial Infections ◽

Antimicrobial Agents ◽

Mass Spectrometry Analysis ◽

World Health ◽

Gram Negative Bacteria ◽

Gram Negative ◽

Dione Derivative ◽

In Silico Studies

Background: According to the World Health Organization, antimicrobial resistance is one of the most important public health threats of the 21st century. Therefore, there is an urgent need for the development of antimicrobial agents with new mechanism of action, especially those capable of evading known resistance mechanisms. Objective: We described the synthesis, in vitro antimicrobial evaluation, and in silico analysis of a series of 1H-indole-4,7-dione derivatives. Methods: The new series of 1H-indole-4,7-diones was prepared with good yield by using a copper(II)- mediated reaction between bromoquinone and β-enamino ketones bearing alkyl or phenyl groups attached to the nitrogen atom. The antimicrobial potential of indole derivatives was assessed. Molecular docking studies were also performed using AutoDock 4.2 for Windows. Characterization of all compounds was confirmed by one- and two-dimensional NMR techniques 1H and 13C NMR spectra [1H, 13C – APT, 1H x 1H – COSY, HSQC and HMBC], IR and mass spectrometry analysis. Results: Several indolequinone compounds showed effective antimicrobial profile against Grampositive (MIC = 16 µg.mL-1) and Gram-negative bacteria (MIC = 8 µg.mL-1) similar to antimicrobials current on the market. The 3-acetyl-1-(2,5-dimethylphenyl)-1H-indole-4,7-dione derivative exhibited an important effect against different biofilm stages formed by a serious hospital life-threatening resistant strain of Methicillin-Resistant Staphylococcus aureus (MRSA). A hemocompatibility profile analysis based on in vitro hemolysis assays revealed the low toxicity effects of this new series. Indeed, in silico studies showed a good pharmacokinetics and toxicological profiles for all indolequinone derivatives, reinforcing their feasibility to display a promising oral bioavailability. An elucidation of the promising indolequinone derivatives binding mode was achieved, showing interactions with important sites to biological activity of S. aureus DNA gyrase. These results highlighted 3-acetyl-1-(2-hydroxyethyl)-1Hindole- 4,7-dione derivative as broad-spectrum antimicrobial prototype to be further explored for treating bacterial infections. Conclusion: The highly substituted indolequinones were obtained in moderate to good yields. The pharmacological study indicated that these compounds should be exploited in the search for a leading substance in a project aimed at obtaining new antimicrobials effective against Gram-negative bacteria.

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Chalcones: As potent α-amylase enzyme inhibitors; synthesis, in vitro, and in silico studies

Medicinal Chemistry ◽

10.2174/1573406416666200611103039 ◽

2020 ◽

Vol 16 ◽

Author(s):

Mahboob Ali ◽

Momin Khan ◽

Khair Zaman ◽

Abdul Wadood ◽

Maryam Iqbal ◽

...

Keyword(s):

In Silico ◽

Enzyme Inhibitors ◽

Biological Activities ◽

Condensation Reaction ◽

Type Ii Diabetes Mellitus ◽

Spectroscopic Techniques ◽

Chalcone Derivatives ◽

In Silico Studies ◽

Wide Range

: Background: The inhibition of α-amylase enzyme is one of the best therapeutic approach for the management of type II diabetes mellitus. Chalcone possesses a wide range of biological activities. Objective: In the current study chalcone derivatives (1-17) were synthesized and evaluated their inhibitory potential against α-amylase enzyme. Method: For that purpose, a library of substituted (E)-1-(naphthalene-2-yl)-3-phenylprop-2-en-1-ones was synthesized by ClaisenSchmidt condensation reaction of 2-acetonaphthanone and substituted aryl benzaldehyde in the presence of base and characterized via different spectroscopic techniques such as EI-MS, HREI-MS, 1H-, and 13C-NMR. Results: Sixteen synthetic chalcones were evaluated for in vitro porcine pancreatic α-amylase inhibition. All the chalcones demonstrated good inhibitory activities in the range of IC50 = 1.25 ± 1.05 to 2.40 ± 0.09 μM as compared to the standard commercial drug acarbose (IC50 = 1.34 ± 0.3 μM). Conclusion: Chalcone derivatives (1-17) were synthesized, characterized, and evaluated for their α-amylase inhibition. SAR revealed that electron donating groups in the phenyl ring have more influence on enzyme inhibition. However, to insight the participation of different substituents in the chalcones on the binding interactions with the α-amylase enzyme, in silico (computer simulation) molecular modeling analyses were carried out.

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Design, Synthesis, In Vitro and In Silico Studies of Some Novel Thiazole-Dihyrofuran Derivatives as Aromatase Inhibitors

Bioorganic Chemistry ◽

10.1016/j.bioorg.2021.105123 ◽

2021 ◽

pp. 105123

Author(s):

Derya Osmaniye ◽

Şennur Görgülü ◽

Begum Nurpelin Saglik ◽

Serkan Levent ◽

Yusuf Ozkay ◽

...

Keyword(s):

Aromatase Inhibitors ◽

In Silico ◽

Design Synthesis ◽

In Silico Studies

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10-gingerol induces oxidative stress through HTR1A in cumulus cells: in-vitro and in-silico studies

Journal of Complementary and Integrative Medicine ◽

10.1515/jcim-2019-0042 ◽

2020 ◽

Vol 0 (0) ◽

Author(s):

Kiptiyah Kiptiyah ◽

Widodo Widodo ◽

Gatot Ciptadi ◽

Aulanni’am Aulanni’Am ◽

Mohammad A. Widodo ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Culture ◽

Superoxide Dismutase ◽

In Silico ◽

Cumulus Cell ◽

Cumulus Cells ◽

Sod Activity ◽

In Silico Studies ◽

Incubation Periods

AbstractBackgroundWe investigated whether 10-gingerol is able to induce oxidative stress in cumulus cells.MethodsFor the in-vitro research, we used a cumulus cell culture in M199, containing 10-gingerol in various concentrations (0, 12, 16, and 20 µM), and detected oxidative stress through superoxide dismutase (SOD) activity and malondialdehyde (MDA) concentrations, with incubation periods of 24, 48, 72, and 96 h. The obtained results were confirmed by in-silico studies.ResultsThe in-vitro data revealed that SOD activity and MDA concentration increased with increasing incubation periods: SOD activity at 0 µM (1.39 ± 0.24i), 12 µM (16.42 ± 0.35ab), 16 µM (17.28 ± 0.55ab), 20 µM (17.81 ± 0.12a), with a contribution of 71.1%. MDA concentration at 0 µM (17.82 ± 1.39 l), 12 µM (72.99 ± 0.31c), 16 µM (79.77 ± 4.19b), 20 µM (85.07 ± 2.57a), with a contribution of 73.1%. Based on this, the in-silico data uncovered that 10˗gingerol induces oxidative stress in cumulus cells by inhibiting HTR1A functions and inactivating GSK3B and AKT˗1.Conclusions10-gingerol induces oxidative stress in cumulus cells through enhancing SOD activity and MDA concentration by inhibiting HTR1A functions and inactivating GSK3B and AKT˗1.

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