Design, synthesis, and ex vivo evaluation of a selective inhibitor for retinaldehyde dehydrogenase enzymes

The vitamin A metabolite retinoic acid (RA) plays a fundamental role in cellular functions by activating nuclear receptors. Retinaldehyde dehydrogenase-II (RALDH2) creates localized RA gradients needed for proper embryonic development, but very little is known regarding its regulated expression in adults. Using a human ex vivo model of aller-gic inflammation by coincubating IgE receptor–activated mast cells (MCs) with blood basophils, we observed prominent induction of a protein that was identified as RALDH2 by mass spectroscopy. RALDH2 was selectively induced in basophils by MC-derived interleukin-3 (IL-3) involving PI3-kinase and NF-κB pathways. Importantly, neither constitutive nor inducible RALDH2 expression was detectable in any other human myeloid or lymphoid leukocyte, including dendritic cells. RA generated by RALDH2 in basophils modulates IL-3–induced gene expression in an autocrine manner, providing positive (CD25) as well as negative (granzyme B) regulation. It also acts in a paracrine fashion on T-helper cells promoting the expression of CD38 and α4/β7 integrins. Furthermore, RA derived from IL-3–activated basophils provides a novel mechanism of Th2 polarization. Thus, RA must be viewed as a tightly controlled basophil-derived mediator with a high potential for regulating diverse functions of immune and resident cells in allergic diseases and other Th2-type immune responses.

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In Vivo and Ex Vivo Evaluation of 1,3-Thiazolidine-2,4-Dione Derivatives as Euglycemic Agents

PPAR Research ◽

10.1155/2021/5100531 ◽

2021 ◽

Vol 2021 ◽

pp. 1-11

Author(s):

Diana Alemán-González-Duhart ◽

Samuel Álvarez-Almazán ◽

Miguel Valdes ◽

Feliciano Tamay-Cach ◽

Jessica Elena Mendieta-Wejebe

Keyword(s):

Antioxidant Activity ◽

Ex Vivo ◽

Peroxisome Proliferator ◽

Oral Toxicity ◽

Peroxisome Proliferator Activated Receptor ◽

Tissue Samples ◽

Design Synthesis ◽

Antioxidant Agents ◽

Male Wistar Rats

Thiazolidinediones (TZDs), used to treat type 2 diabetes mellitus, act as full agonists of the peroxisome proliferator-activated receptor gamma. Unfortunately, they produce adverse effects, including weight gain, hepatic toxicity, and heart failure. Our group previously reported the design, synthesis, in silico evaluation, and acute oral toxicity test of two TZD derivatives, compounds 40 (C40) and 81 (C81), characterized as category 5 and 4, respectively, under the Globally Harmonized System. The aim of this study was to determine whether C40, C81, and a new compound, C4, act as euglycemic and antioxidant agents in male Wistar rats with streptozotocin-induced diabetes. The animals were randomly divided into six groups ( n = 7 ): the control, those with diabetes and untreated, and those with diabetes and treated with pioglitazone, C40, C81, or C4 (daily for 21 days). At the end of the experiment, tissue samples were collected to quantify the level of glucose, insulin, triglycerides, total cholesterol, and liver enzymes, as well as enzymatic and nonenzymatic antioxidant activity. C4, without a hypoglycemic effect, displayed the best antioxidant activity. Whereas C81 could only attenuate the elevated level of blood glucose, C40 generated euglycemia by the end of the treatment. All compounds produced a significant decrease in triglycerides.

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Design, synthesis and evaluation of (R)-3-(7-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-5-azaspiro[2.4]heptan-5-yl)-3-oxopropanenitrile as a JAK1-selective inhibitor

MedChemComm ◽

10.1039/c7md00568g ◽

2018 ◽

Vol 9 (3) ◽

pp. 477-489 ◽

Cited By ~ 1

Author(s):

Chieyeon Chough ◽

Sunmin Lee ◽

Misuk Joung ◽

Jaemin Lee ◽

Jong Hoon Kim ◽

...

Keyword(s):

Selective Inhibitor ◽

Selectivity Index ◽

Design Synthesis

We discovered a new JAK1-selective inhibitor with a selectivity index of 48 and identified its efficacy in CIA and AIA models.

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Positive allosteric modulators (PAMs) of the group II metabotropic glutamate receptors: Design, synthesis, and evaluation as ex-vivo tool compounds

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2021.128342 ◽

2021 ◽

Vol 50 ◽

pp. 128342

Author(s):

Yousuke Yamada ◽

Kristen Gilliland ◽

Zixiu Xiang ◽

Daniel Haymer ◽

Katherine E. Crocker ◽

...

Keyword(s):

Glutamate Receptors ◽

Metabotropic Glutamate Receptors ◽

Ex Vivo ◽

Allosteric Modulators ◽

Design Synthesis ◽

Metabotropic Glutamate ◽

Positive Allosteric Modulators ◽

Group Ii

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Design, Synthesis, Computational, and Preclinical Evaluation of natTi/45Ti-Labeled Urea-Based Glutamate PSMA Ligand

Molecules ◽

10.3390/molecules25051104 ◽

2020 ◽

Vol 25 (5) ◽

pp. 1104 ◽

Cited By ~ 2

Author(s):

Kristina Søborg Pedersen ◽

Christina Baun ◽

Karin Michaelsen Nielsen ◽

Helge Thisgaard ◽

Andreas Ingemann Jensen ◽

...

Keyword(s):

Computer Aided Design ◽

Ex Vivo ◽

Design Synthesis ◽

Psma Ligand ◽

Pet Tracer ◽

Positron Emission ◽

Tumor Accumulation ◽

Aided Design

Despite promising anti-cancer properties in vitro, all titanium-based pharmaceuticals have failed in vivo. Likewise, no target-specific positron emission tomography (PET) tracer based on the radionuclide 45Ti has been developed, notwithstanding its excellent PET imaging properties. In this contribution, we present liquid–liquid extraction (LLE) in flow-based recovery and the purification of 45Ti, computer-aided design, and the synthesis of a salan-natTi/45Ti-chelidamic acid (CA)-prostate-specific membrane antigen (PSMA) ligand containing the Glu-urea-Lys pharmacophore. The compound showed compromised serum stability, however, no visible PET signal from the PC3+ tumor was seen, while the ex vivo biodistribution measured the tumor accumulation at 1.1% ID/g. The in vivo instability was rationalized in terms of competitive citrate binding followed by Fe(III) transchelation. The strategy to improve the in vivo stability by implementing a unimolecular ligand design is presented.

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