Background::Activation of microglia and astrocytes has been observed in Alzheimer’s disease (AD). Transglutaminase 2 (TG2) is reported to be activated in AD and involved in cell proliferation, differentiation, and inflammation. Moreover, amyloid β (Aβ) aggregation is detected as a characteristic pathology in the AD brain, and is known to be a substrate of TG2. All-trans retinoic acid (ATRA) can modify cell proliferation and differentiation, and is reported to have therapeutic effects on AD pathology.Objective::We aimed to assess the effects of ATRA in microglia and astrocytes on TG2 expression and glial functions.Methods::After treatment with ATRA, TG2 expression and TG activity were assayed in both murine microglia BV-2 cells and cultured rat brain astrocytes. Endocytosis activity in BV-2 cells and Aβ aggregation by astrocytes conditioned medium were also assessed.Results::In both BV-2 cells and cultured astrocytes, ATRA increased TG2 expression and TG activity. The increase was blocked by AGN194310, an RA receptor antagonist. ATRA enhanced the endocytosis activity in BV-2 cells, and the addition of AGN194310 reversed it. The addition of cystamine, a competitive TG inhibitor, also reduced ATRA-enhanced endocytosis activity. On the other hand, Aβ aggregation was potentiated by ATRA-treated astrocytes conditioned medium compared to control astrocytes conditioned medium.Conclusion::These results suggest that ATRA increased TG2 expression and TG activity via RA receptor in microglia and astrocytes. ATRA-enhanced TGs might be involved in phagocytosis and Aβ aggregation. Adequate control of TGs expression and function in microglia and astrocytes can be an important factor in AD pathology.

21 May 2021·The Journal of Organic ChemistryQ2 · CHEMISTRY

From Propargylic Alcohols to Substituted Thiochromenes: gem-Disubstituent Effect in Intramolecular Alkyne Iodo/hydroarylation

Q2 · CHEMISTRY

Article

Author: Suárez, Anisley ; Suárez-Pantiga, Samuel ; Fernández-Rodríguez, Manuel Ángel ; Martínez-Lara, Fernando ; Sanz, Roberto ; Velasco, Noelia

This work describes the 6-endo-dig cyclization of S-aryl propargyl sulfides to afford 2H-thiochromenes. The substitution at the propargylic position plays a crucial role in allowing intramolecular silver-catalyzed alkyne hydroarylation and N-iodosuccinimide-promoted iodoarylation. Additionally, a PTSA-catalyzed thiolation reaction of propargylic alcohols was developed to synthesize the required tertiary S-aryl propargyl ethers. The applicability of merging these two methods is demonstrated by synthesizing the retinoic acid receptor antagonist AGN194310.

01 Feb 2017·Archivum Immunologiae et Therapiae ExperimentalisQ4 · MEDICINE

Antagonizing Retinoic Acid Receptors Increases Myeloid Cell Production by Cultured Human Hematopoietic Stem Cells

Q4 · MEDICINE

Article

Author: Brown, Geoffrey ; Marcinkowska, Ewa ; Marchwicka, Aleksandra ; Cunningham, Alan ; Toellner, Kai-Michael

Activities of the retinoic acid receptor (RAR)α and RARγ are important to hematopoiesis. Here, we have investigated the effects of receptor selective agonists and antagonists on the primitive human hematopoietic cell lines KG1 and NB-4 and purified normal human hematopoietic stem cells (HSCs). Agonizing RARα (by AGN195183) was effective in driving neutrophil differentiation of NB-4 cells and this agonist synergized with a low amount (10 nM) of 1α,25-dihydroxyvitamin D₃ to drive monocyte differentiation of NB-4 and KG1 cells. Treatment of cultures of human HSCs (supplemented with stem cell factor ± interleukin 3) with an antagonist of all RARs (AGN194310) or of RARα (AGN196996) prolonged the lifespan of cultures, up to 55 days, and increased the production of neutrophils and monocytes. Slowing down of cell differentiation was not observed, and instead, hematopoietic stem and progenitor cells had expanded in number. Antagonism of RARγ (by AGN205728) did not affect cultures of HSCs. Studies of CV-1 and LNCaP cells transfected with RAR expression vectors and a reporter vector revealed that RARγ and RARβ are activated by sub-nM all-trans retinoic acid (EC₅₀-0.3 nM): ~50-fold more is required for activation of RARα (EC₅₀-16 nM). These findings further support the notion that the balance of expression and activity of RARα and RARγ are important to hematopoietic stem and progenitor cell expansion and differentiation.

100 Deals associated with IRX-4310

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Indication	Highest Phase	Country/Location	Organization	Date
Dermatitis, Atopic	Phase 3	GB	Allergan Ltd. (Ireland)	-
Neutropenia	Phase 3	US	Io Therapeutics, Inc.	-
Neutropenia	Phase 3	-	Allergan Ltd. (Ireland)	-
Neutropenia	Phase 3	US	Io Therapeutics, Inc.	-
Neutropenia	Phase 3	-	Allergan Ltd. (Ireland)	-
Psoriasis	Phase 3	GB	Allergan Ltd. (Ireland)	-
Xerostomia	Phase 3	-	Allergan Ltd. (Ireland)	-
Xerostomia	Phase 3	US	-	-
Acne Vulgaris	Preclinical	GB	Allergan Ltd. (Ireland)	-
Psoriasis	Preclinical	US	Allergan Ltd. (Ireland)	-

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