scholarly journals Lung on a Chip Development from Off-Stoichiometry Thiol–Ene Polymer

Micromachines ◽  
2021 ◽  
Vol 12 (5) ◽  
pp. 546
Author(s):  
Roberts Rimsa ◽  
Artis Galvanovskis ◽  
Janis Plume ◽  
Felikss Rumnieks ◽  
Karlis Grindulis ◽  
...  
Keyword(s):  
Small Molecule ◽  
Light Transmission ◽  
Umbilical Vein ◽  
Drug Repurposing ◽  
In Vitro Models ◽  
Enzymatic Reactions ◽  
Promising Alternative ◽  
Prototype Development ◽  
Alternative Material

Current in vitro models have significant limitations for new respiratory disease research and rapid drug repurposing. Lung on a chip (LOAC) technology offers a potential solution to these problems. However, these devices typically are fabricated from polydimethylsiloxane (PDMS), which has small hydrophobic molecule absorption, which hinders the application of this technology in drug repurposing for respiratory diseases. Off-stoichiometry thiol–ene (OSTE) is a promising alternative material class to PDMS. Therefore, this study aimed to test OSTE as an alternative material for LOAC prototype development and compare it to PDMS. We tested OSTE material for light transmission, small molecule absorption, inhibition of enzymatic reactions, membrane particle, and fluorescent dye absorption. Next, we microfabricated LOAC devices from PDMS and OSTE, functionalized with human umbilical vein endothelial cell (HUVEC) and A549 cell lines, and analyzed them with immunofluorescence. We demonstrated that compared to PDMS, OSTE has similar absorption of membrane particles and effect on enzymatic reactions, significantly lower small molecule absorption, and lower light transmission. Consequently, the immunofluorescence of OSTE LOAC was significantly impaired by OSTE optical properties. In conclusion, OSTE is a promising material for LOAC, but optical issues should be addressed in future LOAC prototypes to benefit from the material properties.

Construction of lux-based promoter-reporter platforms in Mycobacterium bovis BCG for screening of drug repurposing small-molecule compounds as new anti-tuberculosis drugs

2021 ◽  
Author(s):  
Li Zhu ◽  
Annie Wing-tung Lee ◽  
Kelvin Ka-Lok WU ◽  
Peng GAO ◽  
Kingsley King-Gee Tam ◽  
...  
Keyword(s):  
Small Molecule ◽  
Drug Repurposing ◽  
Virulence Gene ◽  
Multidrug Resistant ◽  
Rapid Screening ◽  
Human Macrophage ◽  
Tuberculosis Complex ◽  
Low Cytotoxicity ◽  
Screening Platform

The emergence of multidrug-resistant strains and hyper-virulent strains of Mycobacterium tuberculosis are big therapeutic challenges for tuberculosis (TB) control. Repurposing bioactive small-molecule compounds has recently become a new therapeutic approach against TB. This study aimed to construct a rapid screening system to identify novel anti-TB agents from a library of small-molecule compounds. In this study, a total of 320 small-molecule compounds were used to screen for their ability to suppress the expression of a key virulence gene, phoP, of M. tuberculosis complex using luminescence (lux)-based promoter-reporter platforms. The minimum inhibitory and bactericidal concentrations on drug-resistant M. tuberculosis and cytotoxicity to human macrophage were determined. RNA-sequencing (RNA-seq) was conducted to determine the drug mechanisms of the selected compounds as novel antibiotics or anti-virulent agents against the M. tuberculosis complex. Six compounds displayed bactericidal activity against M. bovis BCG, in which Ebselen demonstrated the lowest cytotoxicity to macrophage and was considered as a potential antibiotic for TB. Another ten compounds did not inhibit the in vitro growth of the M. tuberculosis complex but down-regulated the expression of phoP specifically. Of them, ST-193 and ST-193 (hydrochloride) showed low cytotoxicity and could dysregulate the entire phoP-associated gene network, and thus identified as potential anti-virulence agents for M. tuberculosis. This study provides a rapid screening platform coupled with a systematic validation and eventually suggested one potential antibiotic and two anti-virulence agents for M. tuberculosis infections.

scholarly journals Covalent inhibitors of EGFR family protein kinases induce degradation of human Tribbles 2 (TRIB2) pseudokinase in cancer cells

2018 ◽  
Vol 11 (549) ◽  
pp. eaat7951 ◽  
Author(s):  
Daniel M. Foulkes ◽  
Dominic P. Byrne ◽  
Wayland Yeung ◽  
Safal Shrestha ◽  
Fiona P. Bailey ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Small Molecule ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Drug Repurposing ◽  
Protein Kinase Inhibitors ◽  
Cellular Mechanisms ◽  
Cellular Analysis

A major challenge associated with biochemical and cellular analysis of pseudokinases is a lack of target-validated small-molecule compounds with which to probe function. Tribbles 2 (TRIB2) is a cancer-associated pseudokinase with a diverse interactome, including the canonical AKT signaling module. There is substantial evidence that human TRIB2 promotes survival and drug resistance in solid tumors and blood cancers and therefore is of interest as a therapeutic target. The unusual TRIB2 pseudokinase domain contains a unique cysteine-rich C-helix and interacts with a conserved peptide motif in its own carboxyl-terminal tail, which also supports its interaction with E3 ubiquitin ligases. We found that TRIB2 is a target of previously described small-molecule protein kinase inhibitors, which were originally designed to inhibit the canonical kinase domains of epidermal growth factor receptor tyrosine kinase family members. Using a thermal shift assay, we discovered TRIB2-binding compounds within the Published Kinase Inhibitor Set (PKIS) and used a drug repurposing approach to classify compounds that either stabilized or destabilized TRIB2 in vitro. TRIB2 destabilizing agents, including the covalent drug afatinib, led to rapid TRIB2 degradation in human AML cancer cells, eliciting tractable effects on signaling and survival. Our data reveal new drug leads for the development of TRIB2-degrading compounds, which will also be invaluable for unraveling the cellular mechanisms of TRIB2-based signaling. Our study highlights that small molecule–induced protein down-regulation through drug “off-targets” might be relevant for other inhibitors that serendipitously target pseudokinases.

Repurposing Drugs to Combat Drug Resistance in Leprosy: A Review of Opportunities

2021 ◽  
Vol 25 ◽  
Author(s):  
Mukul Sharma ◽  
Pushpendra Singh
Keyword(s):  
Synergistic Effects ◽  
Drug Repurposing ◽  
New Drugs ◽  
Resistance Testing ◽  
Promising Alternative ◽  
Drug Molecules ◽  
Conventional Drug ◽  
Repurposed Drugs ◽  
Multiple Drugs

: Leprosy is caused by extremely slow-growing and uncultivated mycobacterial pathogens, namely Mycobacterium leprae and M. lepromatosis. Nearly 95% of the new cases of leprosy recorded globally are found in India, Brazil, and 20 other priority countries [WHO, 2019], of which nearly two-thirds of the cases are reported in India alone. Currently, leprosy is treated with dapsone, rifampicin, and clofazimine, also known as multi-drug therapy [MDT], as per the recommendations of WHO since 1981. Still, the number of new leprosy cases recorded globally has remained constant in the last one-decade ,and resistance to multiple drugs has been documented in various parts of the world, even though relapses are rare in patients treated with MDT. Antimicrobial resistance testing against M. leprae or the evaluation of the anti-leprosy activity of new drugs remains a challenge as leprosy bacilli do not grow in vitro. Besides, developing a new drug against leprosy through the conventional drug development process is not economically attractive or viable for pharma companies. Therefore, a promising alternative is the repurposing of existing drugs/approved medications or their derivatives for assessing their anti-leprosy potential. It is an efficient method to identify novel medicinal and therapeutic properties of approved drug molecules. Any combinatorial chemotherapy that combines these repurposed drugs with the existing first-line [MDT] and second-line drugs could improve the bactericidal and synergistic effects against these notorious bacteria and can help in achieving the much-cherished goal of “leprosy-free world”. This review highlights novel opportunities for drug repurposing to combat resistance to current therapeutic approaches.

scholarly journals Endothelialized silicone aneurysm models for in vitro evaluation of flow diverters

2020 ◽  
pp. neurintsurg-2020-016859
Author(s):  
Alyssa McCulloch ◽  
Ashley Turcott ◽  
Gabriella Graham ◽  
Sergey Frenklakh ◽  
Kristen O'Halloran Cardinal
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Umbilical Vein ◽  
Flow Diverter ◽  
In Vitro Models ◽  
Cell Coverage ◽  
Platelet Endothelial Cell Adhesion ◽  
Umbilical Vein Endothelial Cells ◽  
Over Time

ObjectiveThe goal of this work was to endothelialize silicone aneurysm tubes for use as in vitro models for evaluating endothelial cell interactions with neurovascular devices. The first objective was to establish consistent and confluent endothelial cell linings and to evaluate the silicone vessels over time. The second objective was to use these silicone vessels for flow diverter implantation and assessment.MethodsSilicone aneurysm tubes were coated with fibronectin and placed into individual bioreactor systems. Human umbilical vein endothelial cells were deposited within tubes to create silicone vessels, then cultivated on a peristaltic pump and harvested at 2, 5, 7, or 10 days to evaluate the endothelial cell lining. A subset of silicone aneurysm vessels was used for flow diverter implantation, and evaluated for cell coverage over device struts at 3 or 7 days after deployment.ResultsSilicone vessels maintained confluent, PECAM-1 (platelet endothelial cell adhesion molecule 1) positive endothelial cell linings over time. These vessels facilitated and withstood flow diverter implantation, with robust cell linings disclosed after device deployment. Additionally, the endothelial cells responded to implanted devices through coverage of the flow diverter struts with increased cell coverage over the aneurysm seen at 7 days after deployment as compared with 3 days.ConclusionsSilicone aneurysm models can be endothelialized and successfully maintained in vitro over time. Furthermore, these silicone vessels can be used for flow diverter implantation and assessment.

scholarly journals Investigation of the Synergistic Effect of Brown Sugar, Longan, Ginger, and Jujube (Brown Sugar Longan Ginger Tea) on Antioxidation and Anti-Inflammation in In Vitro Models

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Ping Lin ◽  
Kai-Wen Kan ◽  
Jia-Haur Chen ◽  
Yung-Kai Lin ◽  
Yung-Hao Lin ◽  
...  
Keyword(s):  
Synergistic Effect ◽  
Umbilical Vein ◽  
In Vitro Models ◽  
Mitochondrial Activity ◽  
Brown Sugar ◽  
Nonalcoholic Fatty Liver ◽  
Beneficial Effects ◽  
Positive Effects ◽  
Anti Inflammation

This research unveils the synergistic effect of brown sugar, longan, ginger, and jujube on the beneficial effects of antioxidation and anti-inflammation. Longan, ginger, and jujube are ubiquitous herbs in traditional Chinese medicine (TCM) and are frequently used in folk remedies. Longan and ginger have been reported to be beneficial for antioxidation, anti-inflammation, ant-obesity, and nonalcoholic fatty liver disease (NAFLD) improvements. However, the potential scientific and medical benefits of their combination Brown Sugar Longan Ginger Tea (BSLGT), a popular drink in Chinese cultures, are elusive. Through the in vitro methodologies, we discovered that BSLGT could significantly improve the mitochondrial activity, antioxidant capacity, lipid content, and inflammatory response in human hepatocytes. In addition, BSLGT also exerted positive effects on the downregulation of atherosclerosis-associated, vasoconstrictor, and thrombosis-related gene expression in human umbilical vein endothelial cells. In short, our experimental results successfully revealed that the antioxidative and anti-inflammatory effects of BSLGT may have the potential to improve liver metabolism and cardiovascular inflammation although solid evidence requires further investigation.

scholarly journals In Silico Analysis of Sea Urchin Pigments as Potential Therapeutic Agents Against SARS-CoV-2: Main Protease (Mpro) as a Target.

2020 ◽  
Author(s):  
Tamara Rubilar ◽  
Elena Susana Barbieri ◽  
Ayelén Gázquez ◽  
Marisa Avaro ◽  
Mercedes Vera-Piombo ◽  
...  
Keyword(s):  
Sea Urchin ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
In Silico Analysis ◽  
Promising Alternative ◽  
In Silico Docking ◽  
Main Protease

The SARS-CoV-2 outbreak has spread rapidly and globally generating a new coronavirus disease (COVID-19) since December 2019 that turned into a pandemic. Effective drugs are urgently needed and drug repurposing strategies offer a promising alternative to dramatically shorten the process of traditional de novo development. Based on their antiviral uses, the potential affinity of sea urchin pigments to bind main protease (Mpro) of SARS-CoV-2 was evaluated in silico. Docking analysis was used to test the potential of these sea urchin pigments as therapeutic and antiviral agents. All pigment compounds presented high molecular affinity to Mpro protein. However, the 1,4-naphtoquinones polihydroxilate (Spinochrome A and Echinochrome A) showed high affinity to bind around the Mpro´s pocket target by interfering with proper folding of the protein mainly through an H-bond with Glu166 residue. This interaction represents a potential blockage of this protease´s activity. All these results provide novel information regarding the uses of sea urchin pigments as antiviral drugs and suggest the need for further in vitro and in vivo analysis to expand all therapeutic uses against SARS-CoV-2. <br>

scholarly journals Hypoxia-preconditioned adipose-derived stem cells combined with scaffold promote urethral reconstruction by up-regulation of angiogenesis and glycolysis

2020 ◽  
Author(s):  
Xiang Wan ◽  
Min-kai Xie ◽  
Huan Xu ◽  
Zi-wei Wei ◽  
Hai-jun Yao ◽  
...  
Keyword(s):  
Stem Cells ◽  
Umbilical Vein ◽  
Urethral Reconstruction ◽  
Therapeutic Effects ◽  
Adipose Derived Stem Cells ◽  
Promising Alternative ◽  
Hypoxia Preconditioning ◽  
Novel Scaffold

Abstract Rationale: Tissue engineering is a promising alternative for urethral reconstruction, and adipose-derived stem cells (ADSCs) are widely used as seeding cells. Hypoxia preconditioning can significantly enhance the therapeutic effects of ADSCs. The low oxygen tension of postoperative wound healing is inevitable and may facilitate the nutritional function of ADSCs. This study aimed to investigate if hypoxia preconditioned ADSCs, compared to normxia preconditioned ADSCs, combined with scaffold could better promote urethral reconstruction and exploring the underlying mechanism.Methods: In vitro, paracrine cytokines and secretomes that were secreted by hypoxia- or normoxia-preconditioned ADSCs were added to cultures of human umbilical vein endothelial cells (HUVECs) to measure their functions. In vivo, hypoxia- or normoxia-preconditioned ADSCs were seeded on a porous nanofibrous scaffold for urethral repair on a defect model in rabbits.Results: The in vitro results showed that hypoxia could enhance the secretion of VEGFA by ADSCs, and hypoxia-preconditioned ADSCs could enhance the viability, proliferation, migration, angiogenesis and glycolysis of HUVECs (p < 0.05). After silencing VEGFA, angiogenesis and glycolysis were significantly inhibited (p < 0.05). The in vivo results showed that compared to normoxia-preconditioned ADSCs, hypoxia-preconditioned ADSCs combined with scaffolds led to a larger urethral lumen diameter, preserved urethral morphology and enhanced angiogenesis (p < 0.05). Conclusions: Hypoxia preconditioning of ADSCs combined with scaffold could better promote urethral reconstruction by upregulating angiogenesis and glycolysis. Hypoxia-preconditioned ADSCs combined with novel scaffold may provide a promising alternative treatment for urethral reconstruction.

scholarly journals In Silico Analysis of Sea Urchin Pigments as Potential Therapeutic Agents Against SARS-CoV-2: Main Protease (Mpro) as a Target.

2020 ◽  
Author(s):  
Tamara Rubilar ◽  
Elena Susana Barbieri ◽  
Ayelén Gázquez ◽  
Marisa Avaro ◽  
Mercedes Vera-Piombo ◽  
...  
Keyword(s):  
Sea Urchin ◽  
In Silico ◽  
De Novo ◽  
Drug Repurposing ◽  
In Silico Analysis ◽  
Promising Alternative ◽  
In Silico Docking ◽  
Main Protease

The SARS-CoV-2 outbreak has spread rapidly and globally generating a new coronavirus disease (COVID-19) since December 2019 that turned into a pandemic. Effective drugs are urgently needed and drug repurposing strategies offer a promising alternative to dramatically shorten the process of traditional de novo development. Based on their antiviral uses, the potential affinity of sea urchin pigments to bind main protease (Mpro) of SARS-CoV-2 was evaluated in silico. Docking analysis was used to test the potential of these sea urchin pigments as therapeutic and antiviral agents. All pigment compounds presented high molecular affinity to Mpro protein. However, the 1,4-naphtoquinones polihydroxilate (Spinochrome A and Echinochrome A) showed high affinity to bind around the Mpro´s pocket target by interfering with proper folding of the protein mainly through an H-bond with Glu166 residue. This interaction represents a potential blockage of this protease´s activity. All these results provide novel information regarding the uses of sea urchin pigments as antiviral drugs and suggest the need for further in vitro and in vivo analysis to expand all therapeutic uses against SARS-CoV-2. <br>

scholarly journals Korean Propolis Suppresses Angiogenesis through Inhibition of Tube Formation and Endothelial Cell Proliferation

2014 ◽  
Vol 9 (4) ◽  
pp. 1934578X1400900 ◽  
Author(s):  
Seon-Il Park ◽  
Toshiro Ohta ◽  
Shigenori Kumazawa ◽  
Mira Jun ◽  
Mok-Ryeon Ahn
Keyword(s):  
Umbilical Vein ◽  
Chorioallantoic Membrane ◽  
Tube Formation ◽  
In Vitro Models ◽  
Endothelial Cell Proliferation ◽  
Dependent Manner ◽  
Concentration Dependent Manner ◽  
Korean Propolis

Propolis, a sticky material that honeybees collect from living plants, has been used for its pharmaceutical properties since ancient times. In this study, we examined the effects of ethanol extracts of Korean propolis (EEKP) from various geographic regions on the inhibition of angiogenesis, both in vitro and in vivo. The effects of EEKP were tested on in vitro models of angiogenesis, that is, tube formation and proliferation of human umbilical vein endothelial cells (HUVECs). All EEKP samples exhibited significant inhibitory effects on tube formation of HUVECs in a concentration-dependent manner (6.25-25 μg/mL). In addition, two EEKP samples, prepared from Uijeongbu and Pyoseon propolis, significantly suppressed the proliferation of HUVECs in a concentration-dependent manner (3.13-25 μg/mL). Furthermore, in an in vivo angiogenesis assay using the chick embryo chorioallantoic membrane (CAM) system, we found that the two EEKP samples significantly reduced the number of newly formed vessels. These results indicate that Korean propolis may have potential applications in the prevention and treatment of angiogenesis-related diseases such as cancer.

Sign in / Sign up

Export Citation Format

Share Document