Randomized, Double-blind, Placebo-controlled, Parallel Groups, Multicenter Pivotal Study Assessing the Efficacy and Safety of 15 mg Twice a Day (BID) of SER150 in Well-controlled Type 2 Diabetic Patients With Diabetic Kidney Disease and Albuminuria in Treatment With an Angiotensin Converting Enzyme Inhibitor or an Angiotensin Receptor Antagonist

This study is to assess the efficacy and safety of SER150 administered for 24 weeks as a 15 mg twice a day BID dose (except on Day 168 15 mg QD) in participants with type 2 diabetes (T2D) and albuminuria in treatment with either an angiotensin converting enzyme inhibitor (ACEi) or an angiotensin receptor antagonist (ARB).

Start Date18 Aug 2021

Sponsor / Collaborator

Serodus ASA

JPRN-UMIN000041528 / Completed

Safety evaluation of excessive intake of ONO-SR/AST-SOYPC for healthy adults. - Safety evaluation of excessive intake of ONO-SR/AST-SOYPC

Start Date01 Sep 2020

Sponsor / Collaborator

TTC CO LTD (Tokyo)

JPRN-UMIN000041538 / Completed

Safety evaluation of excessive intake of ONO-SR/AST-DA for healthy adults. - Safety evaluation of excessive intake of ONO-SR/AST-DA.

Start Date01 Sep 2020

Sponsor / Collaborator

TTC CO LTD (Tokyo)

100 Clinical Results associated with Prostanoid receptor x TXA2 synthase

100 Translational Medicine associated with Prostanoid receptor x TXA2 synthase

0 Patents (Medical) associated with Prostanoid receptor x TXA2 synthase

147

Literatures (Medical) associated with Prostanoid receptor x TXA2 synthase

01 Sep 2022·American Journal of Respiratory and Critical Care Medicine

Thromboxane–Prostanoid Receptor Signaling Drives Persistent Fibroblast Activation in Pulmonary Fibrosis

Article

Author: Kropski, Jonathan A. ; Gutor, Sergey ; Han, Wei ; Banovich, Nicholas E. ; Tada, Yuji ; Blackwell, Timothy S. ; Gokey, Jason J. ; Polosukhin, Vasiliy V. ; Winters, Nichelle I. ; Freeman, Michael L. ; Camarata, Jane E. ; Sherrill, Taylor P. ; Young, Lisa R. ; Sabusap, Carleen ; West, James D. ; Carrier, Erica J. ; Chen, Jingyuan ; Tanjore, Harikrishna ; Chen, Xinping ; Suzuki, Toshio ; Rathinasabapathy, Anandharajan ; Gulleman, Peter

Rationale: Although persistent fibroblast activation is a hallmark of idiopathic pulmonary fibrosis (IPF), mechanisms regulating persistent fibroblast activation in the lungs have not been fully elucidated. Objectives: On the basis of our observation that lung fibroblasts express TBXA2R (thromboxane-prostanoid receptor) during fibrosis, we investigated the role of TBXA2R signaling in fibrotic remodeling. Methods: We identified TBXA2R expression in lungs of patients with IPF and mice and studied primary mouse and human lung fibroblasts to determine the impact of TBXA2R signaling on fibroblast activation. We used TBXA2R-deficient mice and small-molecule inhibitors to investigate TBXA2R signaling in preclinical lung fibrosis models. Measurements and Main Results: TBXA2R expression was upregulated in fibroblasts in the lungs of patients with IPF and in mouse lungs during experimental lung fibrosis. Genetic deletion of TBXA2R, but not inhibition of thromboxane synthase, protected mice from bleomycin-induced lung fibrosis, thereby suggesting that an alternative ligand activates profibrotic TBXA2R signaling. In contrast to thromboxane, F2-isoprostanes, which are nonenzymatic products of arachidonic acid induced by reactive oxygen species, were persistently elevated during fibrosis. F2-isoprostanes induced TBXA2R signaling in fibroblasts and mediated a myofibroblast activation profile due, at least in part, to potentiation of TGF-β (transforming growth factor-β) signaling. In vivo treatment with the TBXA2R antagonist ifetroban reduced profibrotic signaling in the lungs, protected mice from lung fibrosis in three preclinical models (bleomycin, Hermansky-Pudlak mice, and radiation-induced fibrosis), and markedly enhanced fibrotic resolution after bleomycin treatment. Conclusions: TBXA2R links oxidative stress to fibroblast activation during lung fibrosis. TBXA2R antagonists could have utility in treating pulmonary fibrosis.

01 Apr 2021·YAKUGAKU ZASSHIQ4 · MEDICINE

Activation Mechanism of Prostanoid Receptors —X-ray Crystallography of EP3 Receptor—

Q4 · MEDICINE

Review

Author: Morimoto, Kazushi

Prostanoids [prostaglandins (PGs) and thromboxanes (TXs)] are a series of bioactive lipid metabolites that function in an autacoid manner via activation of cognate G protein-coupled receptors (GPCRs). The nine subtypes of prostanoid receptors (DP1, DP2, EP1, EP2, EP3, EP4, FP, IP, TP) are involved in a wide range of functions, including inflammation, immune response, reproduction, and homeostasis of the intestinal mucosa and cardiovascular system. Among the prostanoid receptors, the structure of antagonist-bound DP2, which belongs to the chemoattractant receptor family, was previously determined. However, the mechanisms of prostanoid recognition and receptor activation remained elusive. To address this issue, we determined the crystal structures of antagonist-bound EP4 and PGE₂-bound EP3. The EP3-PGE₂ complex exhibits an active-like conformation, including outward movement of the cytoplasmic end of transmembrane (TM) 6 relative to the cytoplasmic end of TM6 of the EP4 complex. The carboxyl moiety of PGE₂ is recognized through three hydrogen bonds formed by highly conserved residues: Y114^_2.65, T206^{Extracelluar loop 2 (ECL2)}, and R333^7.40 (superscripts denote Ballesteros-Weinstein numbering). In addition, the ω-chain of PGE₂ orients toward TM6, which appears to contribute to receptor activation. The structure reveals important insights into the activation mechanism of prostanoid receptors and provides a molecular basis for the binding modes of endogenous ligands. These findings should facilitate the development of subtype-selective and non-PG-like ligands.

01 Apr 2021·British Journal of DermatologyQ1 · MEDICINE

An additional drug repurposing study for hidradenitis suppurativa/acne inversa

Q1 · MEDICINE

Letter

Author: Readhead, B. ; Dudley, J.T. ; Zouboulis, C.C.

Current transcriptome and proteome studies have identified differentially regulated genes and proteins in hidradenitis suppurativa/acne inversa (HS), both in entire involved skin and in involved skin apocrine glands.In this report, we provide addnl. information obtained by further anal. of our data using mol. drug information available through chemogenomic studies.Raw microarray profiles from our own previous studies downloaded from Gene Expression Omnibus (GSE137141) and (GSE144801) were used in this study.The data for anal. originated from whole lesional skin (LS) and nonlesional skin (NLS) of 28 European patients [20 female, eight male; aged 35.0 (10.2) years] with active HS Hurley stage II-III and healthy skin (CS) of 12 matched controls [aged 37.1 (13.2) years].The comparison of LS vs. NLS revealed several new drug target genes, namely ABAT, ADH1C, ADIRF, ADRA1A, ANDR, CFD, CHRM1, CLEC3B, CP3A4, DACB, DRD1, DRD5, GABBR1, GBP6, GBRA6, GBRR1, GCR, GPD1, GRIA1, GRM4, HRH1, IF4H, KRT6B, LPA, MCR, MRCA, MRCB, OPRD, OPRM, PA24A, PBPC, PLAT, PLG, PRKAB1, PTGS1, PTGS2, RPL38, SLC6A4, TA2R, TBXA2R, THAS, TLR2 and UTS2, in addition to the ones detected as HS biomarkers in our previous study, namely DEFB4A/ DEFB4B, GJB2, KRT6A, KRT16, MMP1, MMP9, PI3, S100A7A, S100A8, S100A9, S100A12, SERPINB3, SERPINB4 and SPRR3.Therefore, repurposing drugs may become future targets of investigator-initiated studies supported from peer-reviewed public funding sources.

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