scholarly journals Functional Group-Dependent Induction of Astrocytogenesis and Neurogenesis by Flavone Derivatives

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 812 ◽  
Author(s):  
Ha-Rim Lee ◽  
Jin Mi Kang ◽  
Young Min Kim ◽  
Sagang Kim ◽  
Jihyae Ann ◽  
...  
Keyword(s):  
Methoxy Group ◽  
Structural Changes ◽  
Cell Types ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Wide Range ◽  
Methoxy Flavone ◽  
Astrocytic Differentiation ◽  
Multiple Cell ◽  
Flavone Derivatives

Neural stem cells (NSCs) differentiate into multiple cell types, including neurons, astrocytes, and oligodendrocytes, and provide an excellent platform to screen drugs against neurodegenerative diseases. Flavonoids exert a wide range of biological functions on several cell types and affect the fate of NSCs. In the present study, we investigated whether the structure-activity relationships of flavone derivatives influence NSC differentiation. As previously reported, we observed that PD98059 (2′-amino-3′-methoxy-flavone), compound 2 (3′-methoxy-flavone) induced astrocytogenesis. In the present study, we showed that compound 3 (2′-hydroxy-3′-methoxy-flavone), containing a 3′-methoxy group, and a non-bulky group at C2′ and C4′, induced astrocytogenesis through JAK-STAT3 signaling pathway. However, compound 1 and 7–12 without the methoxy group did not show such effects. Interestingly, the compounds 4 (2′,3′-dimethoxyflavone), 5 (2′-N-phenylacetamido-3′-methoxy-flavone), and 6 (3′,4′-dimethoxyflavone) containing 3′-methoxy could not promote astrocytic differentiation, suggesting that both the methoxy groups at C3′ and non-bulky group at C2′ and C4′ are required for the induction of astrocytogenesis. Notably, compound 6 promoted neuronal differentiation, whereas its 4′-demethoxylated analog, compound 2, repressed neurogenesis, suggesting an essential role of the methoxy group at C4′ in neurogenesis. These findings revealed that subtle structural changes of flavone derivatives have pronounced effects on NSC differentiation and can guide to design and develop novel flavone chemicals targeting NSCs fate regulation.

scholarly journals Computer-aided prediction of inhibitors against STAT3 for managing COVID-19 associate cytokine storm

2021 ◽  
Author(s):  
Anjali Dhall ◽  
Sumeet Patiyal ◽  
Neelam Sharma ◽  
Naorem Leimarembi Devi ◽  
Gajendra P. S. Raghava
Keyword(s):  
Prediction Models ◽  
Validation Dataset ◽  
Cytokine Storm ◽  
Hybrid Features ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Wide Range ◽  
Proinflammatory Responses ◽  
Highly Correlated ◽  
Approved Drugs

Abstract It has been shown in the past that levels of cytokines, including interleukin 6 (IL6), is highly correlated with the disease severity of COVID-19 patients. IL6 mediated activation of STAT3 is responsible to proliferate proinflammatory responses that leads to promotion of cytokine storm. Thus, STAT3 inhibitors may play a crucial role in managing pathogenesis of COVID-19. This paper describes a method developed for predicting inhibitors against the IL6-mediated STAT3 signaling pathway. The dataset used for training, testing, and evaluation of models contains small-molecule based 1564 STAT3 inhibitors and 1671 non-inhibitors. Analysis of data indicates that rings and aromatic groups are significantly abundant in STAT3 inhibitors compared to non-inhibitors. In order to build models, we generate a wide range of descriptors for each chemical compound. Firstly, we developed models using 2-D and 3-D descriptors and achieved maximum AUC 0.84 and 0.73, respectively. Secondly, fingerprints (FP) are used to build prediction models and achieved 0.86 AUC and accuracy of 78.70% on validation dataset. Finally, models were developed using hybrid features or descriptors, achieve a maximum of 0.87 AUC on the validation dataset. We used our best model to identify STAT3 inhibitors in FDA-approved drugs and found few drugs (e.g., Tamoxifen, and Perindopril) that can be used to manage COVID-19 associated cytokine storm. A webserver “STAT3In” (https://webs.iiitd.edu.in/raghava/stat3in/ ) has been developed to predict and design STAT3 inhibitors.

scholarly journals A versatile automated high-throughput drug screening platform for zebrafish embryos

2020 ◽  
Author(s):  
Alexandra Lubin ◽  
Jason Otterstrom ◽  
Yvette Hoade ◽  
Ivana Bjedov ◽  
Eleanor Stead ◽  
...  
Keyword(s):  
High Throughput ◽  
Drug Screening ◽  
Imaging System ◽  
Cell Types ◽  
Wide Range ◽  
Stem And Progenitor Cells ◽  
Multiple Cell ◽  
Flexible Imaging ◽  
Automated Screening ◽  
Screening Platform

AbstractZebrafish provide a unique opportunity for drug screening in living animals, with the fast developing, transparent embryos allowing for relatively high throughput, microscopy-based screens. However, the limited availability of rapid, flexible imaging and analysis platforms has limited the use of zebrafish in drug screens. We have developed a easy-to-use, customisable automated screening procedure suitable for high-throughput phenotype-based screens of live zebrafish. We utilised the WiScan®Hermes High Content Imaging System to rapidly acquire brightfield and fluorescent images of embryos, and the WiSoft®Athena Zebrafish Application for analysis, which harnesses an Artificial Intelligence-driven algorithm to automatically detect fish in brightfield images, identify anatomical structures, partition the animal into regions, and exclusively select the desired side-oriented fish. Our initial validation combined structural analysis with fluorescence images to enumerate GFP-tagged haematopoietic stem and progenitor cells in the tails of embryos, which correlated with manual counts. We further validated this system to assess the effects of genetic mutations and x-ray irradiation in high content using a wide range of assays. Further, we performed simultaneous analysis of multiple cell types using dual fluorophores in high throughput. In summary, we demonstrate a broadly applicable and rapidly customisable platform for high content screening in zebrafish.

scholarly journals Heterodimer-heterotetramer formation mediates enhanced sensor activity in a biophysical model for BMP signaling

2021 ◽  
Vol 17 (9) ◽  
pp. e1009422
Author(s):  
M. Shahriar Karim ◽  
Aasakiran Madamanchi ◽  
James A. Dutko ◽  
Mary C. Mullins ◽  
David M. Umulis
Keyword(s):  
Distinct Type ◽  
Cell Types ◽  
Bmp Signaling ◽  
Biophysical Model ◽  
Transmembrane Receptors ◽  
Bmp Receptors ◽  
Morphogenetic Protein ◽  
Wide Range ◽  
Multiple Cell ◽  
Organismal Development

Numerous stages of organismal development rely on the cellular interpretation of gradients of secreted morphogens including members of the Bone Morphogenetic Protein (BMP) family through transmembrane receptors. Early gradients of BMPs drive dorsal/ventral patterning throughout the animal kingdom in both vertebrates and invertebrates. Growing evidence in Drosophila, zebrafish, murine and other systems suggests that BMP ligand heterodimers are the primary BMP signaling ligand, even in systems in which mixtures of BMP homodimers and heterodimers are present. Signaling by heterodimers occurs through a hetero-tetrameric receptor complex comprising of two distinct type one BMP receptors and two type II receptors. To understand the system dynamics and determine whether kinetic assembly of heterodimer-heterotetramer BMP complexes is favored, as compared to other plausible BMP ligand-receptor configurations, we developed a kinetic model for BMP tetramer formation based on current measurements for binding rates and affinities. We find that contrary to a common hypothesis, heterodimer-heterotetramer formation is not kinetically favored over the formation of homodimer-tetramer complexes under physiological conditions of receptor and ligand concentrations and therefore other mechanisms, potentially including differential kinase activities of the formed heterotetramer complexes, must be the cause of heterodimer-heterotetramer signaling primacy. Further, although BMP complex assembly favors homodimer and homomeric complex formation over a wide range of parameters, ignoring these signals and instead relying on the heterodimer improves the range of morphogen interpretation in a broad set of conditions, suggesting a performance advantage for heterodimer signaling in patterning multiple cell types in a gradient.

scholarly journals The IκB Kinase Inhibitor ACHP Targets the STAT3 Signaling Pathway in Human Non-Small Cell Lung Carcinoma Cells

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 875 ◽  
Author(s):  
Jong Hyun Lee ◽  
Chakrabhavi Dhananjaya Mohan ◽  
Salundi Basappa ◽  
Shobith Rangappa ◽  
Arunachalam Chinnathambi ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Cell Lines ◽  
Inhibitory Activity ◽  
Small Cell ◽  
Nsclc Cell ◽  
Small Cell Lung ◽  
Cell Lung Carcinoma ◽  
Stat3 Signaling ◽  
Stat3 Signaling Pathway ◽  
Wide Range

STAT3 is an oncogenic transcription factor that regulates the expression of genes which are involved in malignant transformation. Aberrant activation of STAT3 has been observed in a wide range of human malignancies and its role in negative prognosis is well-documented. In this report, we performed high-throughput virtual screening in search of STAT3 signaling inhibitors using a cheminformatics platform and identified 2-Amino-6-[2-(Cyclopropylmethoxy)-6-Hydroxyphenyl]-4-Piperidin-4-yl Nicotinonitrile (ACHP) as the inhibitor of the STAT3 signaling pathway. The predicted hit was evaluated in non-small cell lung cancer (NSCLC) cell lines for its STAT3 inhibitory activity. In vitro experiments suggested that ACHP decreased the cell viability and inhibited the phosphorylation of STAT3 on Tyr705 of NSCLC cells. In addition, ACHP imparted inhibitory activity on the constitutive activation of upstream protein tyrosine kinases, including JAK1, JAK2, and Src. ACHP decreased the nuclear translocation of STAT3 and downregulated its DNA binding ability. Apoptosis was evidenced by cleavage of caspase-3 and PARP with the subsequent decline in antiapoptotic proteins, including Bcl-2, Bcl-xl, and survivin. Overall, we report that ACHP can act as a potent STAT3 signaling inhibitor in NSCLC cell lines.

scholarly journals Antitumoral Activities of Curcumin and Recent Advances to ImProve Its Oral Bioavailability

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1476
Author(s):  
Marta Claudia Nocito ◽  
Arianna De Luca ◽  
Francesca Prestia ◽  
Paola Avena ◽  
Davide La Padula ◽  
...  
Keyword(s):  
Curcuma Longa ◽  
Cell Types ◽  
In Vivo Studies ◽  
Beneficial Effects ◽  
Bioactive Component ◽  
Wide Range ◽  
Multiple Cell ◽  
Cycle Regulation ◽  
Cell Signaling Pathways

Curcumin, a main bioactive component of the Curcuma longa L. rhizome, is a phenolic compound that exerts a wide range of beneficial effects, acting as an antimicrobial, antioxidant, anti-inflammatory and anticancer agent. This review summarizes recent data on curcumin’s ability to interfere with the multiple cell signaling pathways involved in cell cycle regulation, apoptosis and the migration of several cancer cell types. However, although curcumin displays anticancer potential, its clinical application is limited by its low absorption, rapid metabolism and poor bioavailability. To overcome these limitations, several curcumin-based derivatives/analogues and different drug delivery approaches have been developed. Here, we also report the anticancer mechanisms and pharmacokinetic characteristics of some derivatives/analogues and the delivery systems used. These strategies, although encouraging, require additional in vivo studies to support curcumin clinical applications.

scholarly journals Exosomes: A Key Piece in Asthmatic Inflammation

2021 ◽  
Vol 22 (2) ◽  
pp. 963
Author(s):  
José A. Cañas ◽  
José M. Rodrigo-Muñoz ◽  
Marta Gil-Martínez ◽  
Beatriz Sastre ◽  
Victoria del Pozo
Keyword(s):  
Cell Types ◽  
Donor Cells ◽  
Wide Range ◽  
Spherical Structures ◽  
Multiple Cell ◽  
Extracellular Microenvironment ◽  
Almost All ◽  
Multiple Cells ◽  
Different Sources

Asthma is a chronic disease of the airways that has an important inflammatory component. Multiple cells are implicated in asthma pathogenesis (lymphocytes, eosinophils, mast cells, basophils, neutrophils), releasing a wide variety of cytokines. These cells can exert their inflammatory functions throughout extracellular vesicles (EVs), which are small vesicles released by donor cells into the extracellular microenvironment that can be taken up by recipient cells. Depending on their size, EVs can be classified as microvesicles, exosomes, or apoptotic bodies. EVs are heterogeneous spherical structures secreted by almost all cell types. One of their main functions is to act as transporters of a wide range of molecules, such as proteins, lipids, and microRNAs (miRNAs), which are single-stranded RNAs of approximately 22 nucleotides in length. Therefore, exosomes could influence several physiological and pathological processes, including those involved in asthma. They can be detected in multiple cell types and biofluids, providing a wealth of information about the processes that take account in a pathological scenario. This review thus summarizes the most recent insights concerning the role of exosomes from different sources (several cell populations and biofluids) in one of the most prevalent respiratory diseases, asthma.

scholarly journals A versatile, automated and high-throughput drug screening platform for zebrafish embryos

Biology Open ◽  
2021 ◽  
Author(s):  
Alexandra Lubin ◽  
Jason Otterstrom ◽  
Yvette Hoade ◽  
Ivana Bjedov ◽  
Eleanor Stead ◽  
...  
Keyword(s):  
High Throughput ◽  
Drug Screening ◽  
Imaging System ◽  
Cell Types ◽  
Wide Range ◽  
Stem And Progenitor Cells ◽  
Multiple Cell ◽  
Flexible Imaging ◽  
Automated Screening ◽  
Screening Platform

Zebrafish provide a unique opportunity for drug screening in living animals, with the fast developing, transparent embryos allowing for relatively high-throughput, microscopy-based screens. However, the limited availability of rapid, flexible imaging and analysis platforms has limited the use of zebrafish in drug screens. We have developed an easy-to-use, customisable automated screening procedure suitable for high-throughput phenotype-based screens of live zebrafish. We utilised the WiScan® Hermes High Content Imaging System to rapidly acquire brightfield and fluorescent images of embryos, and the WiSoft® Athena Zebrafish Application for analysis, which harnesses an Artificial Intelligence-driven algorithm to automatically detect fish in brightfield images, identify anatomical structures, partition the animal into regions, and exclusively select the desired side-oriented fish. Our initial validation combined structural analysis with fluorescence images to enumerate GFP-tagged haematopoietic stem and progenitor cells in the tails of embryos, which correlated with manual counts. We further validated this system to assess the effects of genetic mutations and x-ray irradiation in high content using a wide range of assays. Further, we performed simultaneous analysis of multiple cell types using dual fluorophores in high throughput. In summary, we demonstrate a broadly applicable and rapidly customisable platform for high-content screening in zebrafish.

Nucleocytoplasmic shuttling: a common theme in mechanotransduction

2014 ◽  
Vol 42 (3) ◽  
pp. 645-649 ◽  
Author(s):  
Amir S. Sharili ◽  
John T. Connelly
Keyword(s):  
Serum Response Factor ◽  
Nuclear Translocation ◽  
Mammary Epithelial Cells ◽  
Cell Types ◽  
Common Element ◽  
Specific Gene ◽  
Binding Motif ◽  
Nucleocytoplasmic Shuttling ◽  
Wide Range ◽  
Multiple Cell

Cells sense their mechanical and physical environment through diverse mechanisms, and these interactions specify a wide range of responses including growth, survival, migration and differentiation. Although much work has focused on dissecting the adhesive and structural components of the cell responsible for transducing external mechanical forces into biochemical signalling cascades, only recently have studies begun to examine how mechanical signals are transmitted to the nucleus and activate specific gene expression programmes. One necessary step in these processes is the transport of signalling molecules from the cytoplasm to the nucleus. The SRF (serum-response factor) and YAP (Yes-associated protein)/TAZ (transcriptional co-activator with PDZ-binding motif) pathways are known mediators of this process in multiple cell types, including mesenchymal stem cells, keratinocytes, mammary epithelial cells and smooth muscle cells. In addition, recent evidence suggests a potential role for β-catenin and Smad signalling in mechanotransduction, but further mechanistic studies are needed to prove this hypothesis. As a model system, the epidermis of the skin is one tissue in which nucleocytoplasmic shuttling mediates cellular mechanosensing and is essential for tissue development, homoeostasis and repair. We propose that nuclear translocation is a common element of mechanotransduction conserved across multiple cell types and tissues.

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