scholarly journals Aza-Reversine Promotes Reprogramming of Lung (MRC-5) and Differentiation of Mesenchymal Cells into Osteoblasts

Materials ◽  
2021 ◽  
Vol 14 (18) ◽  
pp. 5385
Author(s):  
Fani Tsitouroudi ◽  
Vasiliki Sarli ◽  
Dimitrios Poulcharidis ◽  
Maria Pitou ◽  
Alexandros Katranidis ◽  
...  
Keyword(s):  
Small Molecule ◽  
Fetal Lung ◽  
Mesenchymal Cells ◽  
Culture Conditions ◽  
Specific Cell ◽  
Induce Cell Cycle Arrest ◽  
Polymeric Surfaces ◽  
Wide Range ◽  
Activity Loss ◽  
Purine Ring

Reversine or 2-(4-morpholinoanilino)-N6-cyclohexyladenine was originally identified as a small organic molecule that induces dedifferentiation of lineage-committed mouse myoblasts, C2C12, and redirects them into lipocytes or osteoblasts under lineage-specific conditions (LISCs). Further, it was proven that this small molecule can induce cell cycle arrest and apoptosis and thus selectively lead cancer cells to cell death. Further studies demonstrated that reversine, and more specifically the C2 position of the purine ring, can tolerate a wide range of substitutions without activity loss. In this study, a piperazine analog of reversine, also known as aza-reversine, and a biotinylated derivative of aza-reversine were synthesized, and their potential medical applications were investigated by transforming the endoderm originates fetal lung cells (MRC-5) into the mesoderm originated osteoblasts and by differentiating mesenchymal cells into osteoblasts. Moreover, the reprogramming capacity of aza-reversine and biotinylated aza-reversine was investigated against MRC-5 cells and mesenchymal cells after the immobilization on PMMA/HEMA polymeric surfaces. The results showed that both aza-reversine and the biofunctionalized, biotinylated analog induced the reprogramming of MRC-5 cells to a more primitive, pluripotent state and can further transform them into osteoblasts under osteogenic culture conditions. These molecules also induced the differentiation of dental and adipose mesenchymal cells to osteoblasts. Thus, the possibility to load a small molecule with useful “information” for delivering that into specific cell targets opens new therapeutic personalized applications.

Synthesis of Elaborate Benzofuran-2-Carboxamide Derivatives Through a Combination of 8-Aminoquinoline Directed C–H Arylations and Transamidations

2019 ◽  
Author(s):  
Michael Oschmann ◽  
Linus Johansson Holm ◽  
Oscar Verho
Keyword(s):  
Small Molecule ◽  
High Efficiency ◽  
Synthetic Strategy ◽  
Small Molecule Screening ◽  
Physiological Properties ◽  
Wide Range ◽  
Directing Group ◽  
Synthetic Sequence

Benzofurans are everywhere in nature and they have been extensively studied by medicinal chemists over the years because of their chemotherapeutic and physiological properties. Herein, we describe a strategy that can be used to access elaborate benzo-2-carboxamide derivatives, which involves a synthetic sequence of 8-aminoquinoline directed C–H arylations followed by transamidations. For the directed C–H arylations, Pd catalysis was used to install a wide range of aryl and heteroaryl substituents at the C3 position of the benzofuran scaffold in high efficiency. Directing group cleavage and further diversification of the C3-arylated benzofuran products were then achieved in a single synthetic operation through the utilization of a two-step transamidation protocol. By bocylating the 8-aminoquinoline amide moiety of these products, it proved possible to activate them towards aminolysis with different amine nucleophiles. Interestingly, this aminolysis reaction was found to proceed efficiently without the need of any additional catalyst or additive. Given the high efficiency and modularity of this synthetic strategy, it constitute a very attractive approach for generating structurally-diverse collections of benzofuran derivatives for small molecule screening.

scholarly journals Glossary and tutorial of xenobiotic metabolism terms used during small molecule drug discovery and development (IUPAC Technical Report)

2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Paul Erhardt ◽  
Kenneth Bachmann ◽  
Donald Birkett ◽  
Michael Boberg ◽  
Nicholas Bodor ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Small Molecule ◽  
Chemical Structure ◽  
Early Stage ◽  
Xenobiotic Metabolism ◽  
Drug Discovery And Development ◽  
Small Molecule Drug ◽  
Technical Report ◽  
Wide Range ◽  
Draft Version

Abstract This project originated more than 15 years ago with the intent to produce a glossary of drug metabolism terms having definitions especially applicable for use by practicing medicinal chemists. A first-draft version underwent extensive beta-testing that, fortuitously, engaged international audiences in a wide range of disciplines involved in drug discovery and development. It became clear that the inclusion of information to enhance discussions among this mix of participants would be even more valuable. The present version retains a chemical structure theme while expanding tutorial comments that aim to bridge the various perspectives that may arise during interdisciplinary communications about a given term. This glossary is intended to be educational for early stage researchers, as well as useful for investigators at various levels who participate on today’s highly multidisciplinary, collaborative small molecule drug discovery teams.

scholarly journals Activation of the receptor tyrosine kinase RET improves long-term hematopoietic stem cell outgrowth and potency

Blood ◽  
2020 ◽  
Vol 136 (22) ◽  
pp. 2535-2547 ◽  
Author(s):  
W. Grey ◽  
R. Chauhan ◽  
M. Piganeau ◽  
H. Huerga Encabo ◽  
M. Garcia-Albornoz ◽  
...  
Keyword(s):  
Intracellular Signaling ◽  
Culture Conditions ◽  
Cellular Growth ◽  
Great Promise ◽  
Bone Marrow Niche ◽  
Hematopoietic Stem ◽  
Intracellular Signaling Pathway ◽  
Wide Range

Abstract Expansion of human hematopoietic stem cells (HSCs) is a rapidly advancing field showing great promise for clinical applications. Recent evidence has implicated the nervous system and glial family ligands (GFLs) as potential drivers of hematopoietic survival and self-renewal in the bone marrow niche; how to apply this process to HSC maintenance and expansion has yet to be explored. We show a role for the GFL receptor, RET, at the cell surface of HSCs in mediating sustained cellular growth, resistance to stress, and improved cell survival throughout in vitro expansion. HSCs treated with the key RET ligand/coreceptor complex, glial-derived neurotrophic factor and its coreceptor, exhibit improved progenitor function at primary transplantation and improved long-term HSC function at secondary transplantation. Finally, we show that RET drives a multifaceted intracellular signaling pathway, including key signaling intermediates protein kinase B, extracellular signal-regulated kinase 1/2, NF-κB, and p53, responsible for a wide range of cellular and genetic responses that improve cell growth and survival under culture conditions.

Elucidating Protein-protein Interactions Through Computational Approaches and Designing Small Molecule Inhibitors Against them for Various Diseases

2018 ◽  
Vol 18 (20) ◽  
pp. 1719-1736 ◽  
Author(s):  
Sharanya Sarkar ◽  
Khushboo Gulati ◽  
Manikyaprabhu Kairamkonda ◽  
Amit Mishra ◽  
Krishna Mohan Poluri
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
Computational Techniques ◽  
Protein Protein Interactions ◽  
Computational Tools ◽  
Computational Approaches ◽  
Protein Protein Interaction ◽  
Wide Range ◽  
Therapeutic Measures

Background: To carry out wide range of cellular functionalities, proteins often associate with one or more proteins in a phenomenon known as Protein-Protein Interaction (PPI). Experimental and computational approaches were applied on PPIs in order to determine the interacting partners, and also to understand how an abnormality in such interactions can become the principle cause of a disease. Objective: This review aims to elucidate the case studies where PPIs involved in various human diseases have been proven or validated with computational techniques, and also to elucidate how small molecule inhibitors of PPIs have been designed computationally to act as effective therapeutic measures against certain diseases. Results: Computational techniques to predict PPIs are emerging rapidly in the modern day. They not only help in predicting new PPIs, but also generate outputs that substantiate the experimentally determined results. Moreover, computation has aided in the designing of novel inhibitor molecules disrupting the PPIs. Some of them are already being tested in the clinical trials. Conclusion: This review delineated the classification of computational tools that are essential to investigate PPIs. Furthermore, the review shed light on how indispensable computational tools have become in the field of medicine to analyze the interaction networks and to design novel inhibitors efficiently against dreadful diseases in a shorter time span.

scholarly journals A new lead to NLRP3 inhibition

2017 ◽  
Vol 214 (11) ◽  
pp. 3147-3149 ◽  
Author(s):  
Mohamed Lamkanfi ◽  
Vishva M. Dixit
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitor ◽  
Therapeutic Benefit ◽  
Human Diseases ◽  
Molecule Inhibitor ◽  
Wide Range ◽  
Potential Therapeutic Benefit

The discovery of a small molecule inhibitor that targets the inflammasome sensor NLRP3 offers a new path for the development of selective inflammasome blockers with potential therapeutic benefit in a wide range of human diseases (in this issue, see Jiang et al., https://doi.org/10.1084/jem.20171419).

scholarly journals Deconstructing Gastrulation at the Single Cell Level

2021 ◽  
Author(s):  
Tomer Stern ◽  
Sebastian J Streichan ◽  
Stanislav Y Shvartsman ◽  
Eric F Wieschaus
Keyword(s):  
Large Scale ◽  
Drosophila Embryo ◽  
Cell Segmentation ◽  
Model Organisms ◽  
Specific Cell ◽  
Cell Behaviors ◽  
Animal Development ◽  
Wide Range ◽  
Cell Groups ◽  
Epithelial Sheets

Gastrulation movements in all animal embryos start with regulated deformations of patterned epithelial sheets. Current studies of gastrulation use a wide range of model organisms and emphasize either large-scale tissue processes or dynamics of individual cells and cell groups. Here we take a step towards bridging these complementary strategies and deconstruct early stages of gastrulation in the entire Drosophila embryo, where transcriptional patterns in the blastoderm give rise to region-specific cell behaviors. Our approach relies on an integrated computational framework for cell segmentation and tracking and on efficient algorithms for event detection. Our results reveal how thousands of cell shape changes, divisions, and intercalations drive large-scale deformations of the patterned blastoderm, setting the stage for systems-level dissection of a pivotal step in animal development.

scholarly journals Quantitative analysis of tumour spheroid structure

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Alexander P Browning ◽  
Jesse A Sharp ◽  
Ryan J Murphy ◽  
Gency Gunasingh ◽  
Brodie Lawson ◽  
...  
Keyword(s):  
Cell Lines ◽  
Tumour Microenvironment ◽  
Culture Conditions ◽  
Experimental Models ◽  
Seeding Density ◽  
Modelling Framework ◽  
Tumour Spheroid ◽  
Tumour Spheroids ◽  
Wide Range

Tumour spheroids are common in vitro experimental models of avascular tumour growth. Compared with traditional two-dimensional culture, tumour spheroids more closely mimic the avascular tumour microenvironment where spatial differences in nutrient availability strongly influence growth. We show that spheroids initiated using significantly different numbers of cells grow to similar limiting sizes, suggesting that avascular tumours have a limiting structure; in agreement with untested predictions of classical mathematical models of tumour spheroids. We develop a novel mathematical and statistical framework to study the structure of tumour spheroids seeded from cells transduced with fluorescent cell cycle indicators, enabling us to discriminate between arrested and cycling cells and identify an arrested region. Our analysis shows that transient spheroid structure is independent of initial spheroid size, and the limiting structure can be independent of seeding density. Standard experimental protocols compare spheroid size as a function of time; however, our analysis suggests that comparing spheroid structure as a function of overall size produces results that are relatively insensitive to variability in spheroid size. Our experimental observations are made using two melanoma cell lines, but our modelling framework applies across a wide range of spheroid culture conditions and cell lines.

scholarly journals Plasticity in Escherichia coli cell wall metabolism promotes fitness and mediates intrinsic antibiotic resistance across environmental conditions

2018 ◽  
Author(s):  
Elizabeth A Mueller ◽  
Petra Anne Levin
Keyword(s):  
Escherichia Coli ◽  
Cell Wall ◽  
Growth Parameter ◽  
Culture Conditions ◽  
Cell Wall Integrity ◽  
Bacterial Cells ◽  
Intrinsic Resistance ◽  
Wide Range ◽  
Peptidoglycan Cell Wall ◽  
Wide Ph Range

ABSTRACTAlthough the peptidoglycan cell wall is an essential structural and morphological feature of most bacterial cells, the extracytoplasmic enzymes involved in its synthesis are frequently dispensable under standard culture conditions. By modulating a single growth parameter—extracellular pH—we discovered a subset of these so-called “redundant” enzymes in Escherichia coli are required for maximal fitness across pH environments. Among these pH specialists are the class A penicillin binding proteins PBP1 a and PBP1 b; defects in these enzymes attenuate growth in alkaline and acidic conditions, respectively. Genetic, biochemical, and cytological studies demonstrate that synthase activity is required for cell wall integrity across a wide pH range, and differential activity across pH environments significantly alters intrinsic resistance to cell wall active antibiotics. Together, our findings reveal previously thought to be redundant enzymes are instead specialized for distinct environmental niches, thereby ensuring robust growth and cell wall integrity in a wide range of conditions.

Age-specific different immune responses due to capabilities of secreting primal immunoglobulins responding to unexperienced antigens

2021 ◽  
Author(s):  
JANGHO LEE ◽  
Kyoungshik Cho ◽  
Hyejin Kook ◽  
Suman Kang ◽  
Yunsung Lee ◽  
...  
Keyword(s):  
Stem Cells ◽  
Immune System ◽  
Defense Mechanism ◽  
Ex Vivo ◽  
Binding Capacity ◽  
Culture Conditions ◽  
Fetal Stem Cells ◽  
Self Defense ◽  
Wide Range ◽  
Ex Vivo Culture

Abstract Among numerous studies on COVID-19, we noted that the infection and mortality rates of SARS-CoV-2 increased with age and that fetuses known to be particularly susceptible to infection were better protected despite various mutations. Hence, we established the hypothesis that a new immune system exists that forms before birth and decreases with aging. To prove this, we analyzed the components from early pregnancy fetal stem cells cultivated in various ex-vivo culture conditions simulating the environment during pregnancy. Resultingly, we confirmed that IgM, a natural antibody produced only in early B-1 cells, immunoglobulins including IgG3, which has a wide range of antigen-binding capacity and affinity, complement proteins, and antiviral proteins are induced. Our results suggest that fetal stem cells can form an independent immune system responding to unlearned antigens as a self-defense mechanism before establishing mature immune systems. Moreover, we propose the possibility of new solutions to cope with various infectious diseases based on the factors therein.

Embryonic and larval development of the caridean shrimp Palaemon argentinus (Decapoda, Caridea): effects of salinity and diet

Crustaceana ◽  
2021 ◽  
Vol 94 (1) ◽  
pp. 45-62
Author(s):  
Carolina Tropea ◽  
Liane Stumpf ◽  
Laura S. López Greco
Keyword(s):  
Larval Development ◽  
Artemia Salina ◽  
Culture Conditions ◽  
Nutritional Requirements ◽  
Larval Performance ◽  
Larval Rearing ◽  
Caridean Shrimp ◽  
Natural Habitats ◽  
Larval Stages ◽  
Wide Range

Abstract The caridean shrimp Palaemon argentinus is a species of commercial and ecological interest. Its numerous larval stages, the lack of knowledge on their nutritional requirements, and their ability to survive in a wide range of salinities raise questions on the optimum conditions for larval rearing in captivity. The present study was aimed at evaluating embryonic development under different salinities and larval development under different combinations of salinities and diet regimes, in order to define alternative, cheaper culture conditions. We tested salinities usually encountered by the species in natural habitats (0.1, 1 and 5 ppt) and a highly protein-inert diet (Tetracolor®) as a potential replacement for live food (nauplii of Artemia salina). The incubation period and fecundity were similar among salinity treatments. Overall, the number of survival days and percentage of zoeae that moulted two, three and four times were higher when embryogenesis occurred at 5 ppt and when larvae were exposed to 5 ppt. These results suggest that the conditions experienced by embryos affect the performance of the first larval stages, and probably reflect the lower energetic requirements of zoeae to osmoregulate as water and haemolymph osmolarity become closer. On the other hand, larval performance was better when fed A. salina nauplii than Tetracolor®. The latter may not cover the nutritional requirements of zoeae or may have low digestibility due to insufficient enzymes in the undeveloped larval digestive system. Based on the present results, we conclude that a salinity of 5 ppt combined with a diet consisting of Artemia sp. nauplii is optimal for larval culture at early stages.

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