scholarly journals Evolutionary Origin of Insulin-Degrading Enzyme and Its Subcellular Localization and Secretion Mechanism: A Study in Microglial Cells

Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 227
Author(s):  
Miriam Corraliza-Gómez ◽  
Concepción Lillo ◽  
Irene Cózar-Castellano ◽  
Eduardo Arranz ◽  
Diego Sanchez ◽  
...  
Keyword(s):  
Subcellular Localization ◽  
Phylogenetic Analyses ◽  
In Silico Analysis ◽  
Insulin Degrading Enzyme ◽  
Degrading Enzyme ◽  
Raft Domains ◽  
The Brain ◽  
Silico Analysis

The insulin-degrading enzyme (IDE) is a zinc-dependent metalloendopeptidase that belongs to the M16A metalloprotease family. IDE is markedly expressed in the brain, where it is particularly relevant due to its in vitro amyloid beta (Aβ)-degrading activity. The subcellular localization of IDE, a paramount aspect to understand how this enzyme can perform its proteolytic functions in vivo, remains highly controversial. In this work, we addressed IDE subcellular localization from an evolutionary perspective. Phylogenetic analyses based on protein sequence and gene and protein structure were performed. An in silico analysis of IDE signal peptide suggests an evolutionary shift in IDE exportation at the prokaryote/eukaryote divide. Subcellular localization experiments in microglia revealed that IDE is mostly cytosolic. Furthermore, IDE associates to membranes by their cytoplasmatic side and further partitions between raft and non-raft domains. When stimulated, microglia change into a secretory active state, produces numerous multivesicular bodies and IDE associates with their membranes. The subsequent inward budding of such membranes internalizes IDE in intraluminal vesicles, which later allows IDE to be exported outside the cells in small extracellular vesicles. We further demonstrate that such an IDE exportation mechanism is regulated by stimuli relevant for microglia in physiological conditions and upon aging and neurodegeneration.

Investigation of indole functionalized pyrazoles and oxadiazoles as anti-inflammatory agents: synthesis, in-vivo, in-vitro and in-silico analysis

2021 ◽  
pp. 105068
Author(s):  
Devendra Kumar ◽  
Ravi Ranjan Kumar ◽  
Shelly Pathania ◽  
Pankaj Kumar Singh ◽  
Sourav Kalra ◽  
...  
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Anti Inflammatory ◽  
Silico Analysis

In-Silico Analysis to Identify Potent Quinoline Analogues Against Multi-Targets of SARS-CoV-2

2021 ◽  
Vol 6 (4) ◽  
pp. 25-37
Author(s):  
Shahanas Naisam ◽  
Viji V.S. ◽  
Suvanish Kumar ◽  
Nidhin Sreekumar
Keyword(s):  
Interaction Analysis ◽  
In Silico Analysis ◽  
Preventive Treatment ◽  
Drug Molecule ◽  
Current Outbreak ◽  
In Vivo Analysis ◽  
Effective Drugs ◽  
Silico Analysis

In the current outbreak of COVID-19, various studies have been conducted all over the world to develop effective drugs against the virus. Recent studies have shown that hydroxychloroquine, chloroquine (antimalarial drugs), isoflavones, flavonoids, etc. have potent antiviral properties, and few have been proven as effective drugs for the preventive treatment of COVID-19. But their exact action against SARS-CoV-2 is still unknown. The strategy of this study is the virtual screening of quinoline analogues, design new ligand molecules, perform molecular interaction analysis, their MD validation against multi targets (Spike-ACE2, TMPRSS2, and Spike Protein) of SARS-CoV-2, and to suggest the most promising and effective drug molecule. Hydroxychloroquine and chloroquine were considered as the reference molecules in this study. A ligand N-[4-(3-Benzylideneazetidine-1-carbonyl)phenyl]quinoline-8-sulfonamide interacting with TMPRSS2 shows better interaction among the list even after MD validation. Further in-vitro and in-vivo analysis of this study is needed for future validation.

scholarly journals Predicting In Vivo Responses to Biomaterials via Combined In Vitro and In Silico Analysis

2015 ◽  
Vol 21 (2) ◽  
pp. 148-159 ◽  
Author(s):  
Matthew T. Wolf ◽  
Yoram Vodovotz ◽  
Stephen Tottey ◽  
Bryan N. Brown ◽  
Stephen F. Badylak
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Silico Analysis

Ouabain-induced Seizures in Rats: Regional and Subcellular Localization of 3H-Ouabain Associated with Na+–K+-ATPase in Brain

1972 ◽  
Vol 50 (8) ◽  
pp. 888-896 ◽  
Author(s):  
J. Donaldson ◽  
J. L. Minnich ◽  
A. Barbeau
Keyword(s):  
Subcellular Localization ◽  
Regional Distribution ◽  
Subcellular Fractionation ◽  
Synaptosomal Membrane ◽  
Intraventricular Injections ◽  
The Brain

Previous observations on clonic and tonic seizures in rats induced by intraventricular injections of ouabain, Zn2+, or Cu2+ have been expanded and confirmed. Tritiated ouabain was injected intraventricularly to rats and its regional distribution studied in the brain. The hippocampus and hypothalamus were found to be the regions with highest accumulation of radioactivity. This was supported by the in vitro finding that synaptosomes from both these regions demonstrate the highest uptake of the labelled ouabain. Subcellular fractionation experiments following in vivo injection of 3H-ouabain revealed that maximal radioactivity is associated with synaptosomal membrane fractions rich in Na+–K+-ATPase.

In Vitro, In Vivo and In Silico Analysis of the Anticancer and Estrogen-like Activity of Guava Leaf Extracts

2014 ◽  
Vol 21 (20) ◽  
pp. 2322-2330 ◽  
Author(s):  
L.Y. Rizzo ◽  
G.B. Longato ◽  
A.LT.G. Ruiz ◽  
S.V. Tinti ◽  
A. Possenti ◽  
...  
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Leaf Extracts ◽  
Guava Leaf ◽  
Silico Analysis

scholarly journals In vivo, in vitro, and in silico analysis of methylation of the HIV-1 provirus

Methods ◽  
2011 ◽  
Vol 53 (1) ◽  
pp. 47-53 ◽  
Author(s):  
Leonard Chávez ◽  
Steven Kauder ◽  
Eric Verdin
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Silico Analysis ◽  
Hiv 1

scholarly journals Ginsenoside F1 Protects the Brain against Amyloid Beta-Induced Toxicity by Regulating IDE and NEP

Life ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 58
Author(s):  
Yee-Jin Yun ◽  
Bong-Hwan Park ◽  
Jingang Hou ◽  
Jung-Pyo Oh ◽  
Jin-Hee Han ◽  
...  
Keyword(s):  
Amyloid Beta ◽  
Neuronal Cell ◽  
Insulin Degrading Enzyme ◽  
Human Neuroblastoma ◽  
Aβ Aggregation ◽  
Neuronal Cell Lines ◽  
The Brain

Ginsenoside F1, the metabolite of Rg1, is one of the most important constituents of Panax ginseng. Although the effects of ginsenosides on amyloid beta (Aβ) aggregation in the brain are known, the role of ginsenoside F1 remains unclear. Here, we investigated the protective effect of ginsenoside F1 against Aβ aggregation in vivo and in vitro. Treatment with 2.5 μM ginsenoside F1 reduced Aβ-induced cytotoxicity by decreasing Aβ aggregation in mouse neuroblastoma neuro-2a (N2a) and human neuroblastoma SH-SY5Y neuronal cell lines. Western blotting, real-time PCR, and siRNA analysis revealed an increased level of insulin-degrading enzyme (IDE) and neprilysin (NEP). Furthermore, liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis confirmed that ginsenoside F1 could pass the blood–brain barrier within 2 h after administration. Immunostaining results indicate that ginsenoside F1 reduces Aβ plaques in the hippocampus of APPswe/PSEN1dE9 (APP/PS1) double-transgenic Alzheimer’s disease (AD) mice. Consistently, increased levels of IDE and NEP protein and mRNA were observed after the 8-week administration of 10 mg/kg/d ginsenoside F1. These data indicate that ginsenoside F1 is a promising therapeutic candidate for AD.

scholarly journals Target related in silico analysis of Bergenin and tuberculosis management

Biomedicine ◽  
2021 ◽  
Vol 40 (4) ◽  
pp. 474-481
Author(s):  
Virupaksha A. Bastikar ◽  
Alpana Bastikar ◽  
Pramodkumar P. Gupta ◽  
Sandeep R. Pai ◽  
Santosh S. Chhajed
Keyword(s):  
Protein Interactions ◽  
In Silico ◽  
Biological Process ◽  
In Silico Analysis ◽  
Enrichment Analysis ◽  
Binding Mode ◽  
Health Concern ◽  
Silico Analysis

Introduction and Aim: Tuberculosis (TB) is a global health concern, claiming two million lives every year. Although an oldest known human infectious disease, researcher is falling short of giving out an effective and reliable vaccine or therapy. The current antimycobacterial drugs include Isoniazid, Ethambutol, Rifampicin and Pyrazinemamide available in market, but most of these are known to have certain adverse effects. Hence there is an increase in demand for natural products with anti-tuberculosis activity with no or limited side effects. Indian traditional systems of medicine have a plethora of promising plants for treatment of tuberculosis, of which Bergenin is the most well established and extensively used compound. The main aim of this research was to investigate the role of Bergenin as an anti-tuberculosis agent with the help of in-silico analysis and protein interaction studies. Materials and Methods: In the present study 04 known 3-dimensional crystallized anti-tubercular drug target is considered and retrieved from PDB. Drug Isoniazid, Ethambutol, Rifampicin, Pyrazineamide and phytochemical Bergenin were retrieved, sketched and geometrically optimized. Molecular docking is carried to understand the binding mode and its core interactions. ADMET properties were calculated in assessment of the toxicity. Protein-protein interactions and enrichment analysis is carried out to understand the biological process involved with rpsA protein. Results: In the present study other than Rifampicin, Bergenin reported with better binding energy and similar pharmacophoric interaction pattern as compared to all the 04 indigenous inhibitors. The PPI network and enrichment analysis predicts the plausible biological process involved with rpsA protein and can be further targeted in treatment of tuberculosis. Conclusion: The results showed that Bergenin was better than and competent with the existing drugs and can be used as an anti-tuberculosis agent if studied in-vitro and in-vivo for its activity.

scholarly journals A Report on Multi-Target Anti-Inflammatory Properties of Phytoconstituents from Monochoria hastata (Family: Pontederiaceae)

Molecules ◽  
2021 ◽  
Vol 26 (23) ◽  
pp. 7397
Author(s):  
Md Mazedul Haq ◽  
Md Arifur Rahman Chowdhury ◽  
Hilal Tayara ◽  
Ibrahim Abdelbaky ◽  
Md Shariful Islam ◽  
...  
Keyword(s):  
In Silico ◽  
In Silico Analysis ◽  
Control Group ◽  
Dependent Manner ◽  
In Vivo Experiments ◽  
Microbial Infections ◽  
Anti Inflammatory ◽  
Silico Analysis

This study aims to investigate the potential analgesic properties of the crude extract of Monochoria hastata (MH) leaves using in vivo experiments and in silico analysis. The extract, in a dose-dependent manner, exhibited a moderate analgesic property (~54% pain inhibition in acetic acid-induced writhing test), which is significant (** p < 0.001) as compared to the control group. The complex inflammatory mechanism involves diverse pathways and they are inter-connected. Therefore, multiple inflammatory modulator proteins were selected as the target for in silico analysis. Computational analysis suggests that all the selected targets had different degrees of interaction with the phytochemicals from the extract. Rutin (RU), protocatechuic acid (PA), vanillic acid (VA), and ferulic acid (FA) could regulate multiple targets with a robust efficiency. None of the compounds showed selectivity to Cyclooxygenase-2 (COX-2). However, regulation of COX and lipoxygenase (LOX) cascade by PA can reduce non-steroidal analgesic drugs (NSAIDs)-related side effects, including asthma. RU showed robust regulation of cytokine-mediated pathways like RAS/MAPK and PI3K/NF-kB by inhibition of EGFR and IKBα (IKK), which may prevent multi-organ failure due to cytokine storm in several microbial infections, for example, SARS-CoV-2. Further investigation, using in vivo and in vitro experiments, can be conducted to develop multi-target anti-inflammatory drugs using the isolated compounds from the extract.

Effect of pH and inhibitors on beta-amyloid fibril assembly

1996 ◽  
Vol 54 ◽  
pp. 752-753
Author(s):  
Beverly E. Maleeff ◽  
Timothy K. Hart ◽  
Stephen J. Wood ◽  
Ronald Wetzel
Keyword(s):  
Amyloid Fibril ◽  
Peptide Fragment ◽  
Hydrophobic Peptides ◽  
Amyloid Fibril Formation ◽  
Effects Of Ph ◽  
Severity Of The Disease ◽  
Kinetics Of ◽  
The Brain

Alzheimer's disease is characterized post-mortem in part by abnormal extracellular neuritic plaques found in brain tissue. There appears to be a correlation between the severity of Alzheimer's dementia in vivo and the number of plaques found in particular areas of the brain. These plaques are known to be the deposition sites of fibrils of the protein β-amyloid. It is thought that if the assembly of these plaques could be inhibited, the severity of the disease would be decreased. The peptide fragment Aβ, a precursor of the p-amyloid protein, has a 40 amino acid sequence, and has been shown to be toxic to neuronal cells in culture after an aging process of several days. This toxicity corresponds to the kinetics of in vitro amyloid fibril formation. In this study, we report the biochemical and ultrastructural effects of pH and the inhibitory agent hexadecyl-N-methylpiperidinium (HMP) bromide, one of a class of ionic micellar detergents known to be capable of solubilizing hydrophobic peptides, on the in vitro assembly of the peptide fragment Aβ.

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