Multi-dimensional analysis identified rheumatoid arthritis-driving pathway in human T cell.

Objectives: Rheumatoid arthritis (RA) is an autoimmune disease accompanied by lymphocyte infiltration into joint synovium. While T cells are considered to be important for its pathogenesis, the features that are the most relevant to disease and how they change after treatment remain unclear. The aim of this study was to clarify the characteristics of T cells in RA, comprehensively.

Gene Signature-Based Approach Identified MEK1/2 as a Potential Target Associated With Relapse After Anti-TNFα Treatment for Crohn's Disease.

Background: Anti-tumor necrosis factor alpha (anti-TNFα) therapy has become the mainstay of therapy for Crohn's disease (CD). However, post-therapy, the recurrence rate is still high. The aim of this study was to dissect the molecular mechanism for recurrence of CD treated with anti-TNFα therapy and investigate novel therapeutic options that could induce complete remission.

A Novel LSD1 Inhibitor T-3775440 Disrupts GFI1B-Containing Complex Leading to Transdifferentiation and Impaired Growth of AML Cells.

Dysregulation of lysine (K)-specific demethylase 1A (LSD1), also known as KDM1A, has been implicated in the development of various cancers, including leukemia. Here, we describe the antileukemic activity and mechanism of action of T-3775440, a novel irreversible LSD1 inhibitor. Cell growth analysis of leukemia cell lines revealed that acute erythroid leukemia (AEL) and acute megakaryoblastic leukemia cells (AMKL) were highly sensitive to this compound.

Peroxisome proliferator-activated receptor gamma (PPARγ) has multiple binding points that accommodate ligands in various conformations: Structurally similar PPARγ partial agonists bind to PPARγ LBD in different conformations.

In the course of studies directed toward the creation of human peroxisome proliferator-activated receptor gamma (hPPARγ) partial agonists, we designed and synthesized benzylsulfonylaminocarbonyl derivative (3) by structural modification of our reported hPPARγ partial agonist 2. Co-crystallization of 3 with the hPPARγ ligand-binding domain (LBD) afforded a homodimeric complex in which one of the LBDs adopts a fully active structure without bound 3, while the other LBD exhibits a non-fully active structure containing one molecule of bound 3. Interestingly, 2 and 3 are structurally similar, but bind to hPPARγ LBD in distinct conformations, that is, the sulfonylaminocarbonyl moiety of bound 3 is directed at 180° away from that of bound 2.

Structural design and synthesis of arylalkynyl amide-type peroxisome proliferator-activated receptor γ (PPARγ)-selective antagonists based on the helix12-folding inhibition hypothesis.

Peroxisome proliferator-activated receptor γ (PPARγ) antagonists are candidates for treatment of type 2 diabetes, obesity and osteoporosis. However, few rational design strategies are currently available. Here, we utilized the helix12 (H12)-folding inhibition hypothesis, in combination with our previously determined X-ray crystal structure of PPARγ agonist MEKT-21 (6) complexed with the PPARγ ligand-binding domain, to design and develop a potent phenylalkynyl amide-type PPARγ antagonist 9i, focusing initially on pinpoint structural modification of the propanoic acid moiety of 6.

Hesperetin glucuronides induce adipocyte differentiation via activation and expression of peroxisome proliferator-activated receptor-γ.

In previous reports, hesperidin, a flavonoid glucoside from citrus fruit, is hydrolyzed to hesperetin, an aglycone of hesperidin, and converted to the hesperetin glucuronides (H7-OG and H3'-OG) in vivo and depresses blood glucose levels. But there are no reports on the activity of hesperetin glucuronides. To determine the activity of hesperetin glucuronides, H7-OG and H3'-OG were synthesized and peroxisome proliferator-activated receptor-γ (PPARγ) agonist activity was observed at 250 μM.

Molecular dynamics study-guided identification of cyclic amine structures as novel hydrophobic tail components of hPPARγ agonists.

We previously reported that a α-benzylphenylpropanoic acid-type hPPARγ-selective agonist with a piperidine ring as the hydrophobic tail part (3) exhibited sub-micromolar-order hPPARγ agonistic activity. In order to enhance the activity, we planned to carry out structural development based on information obtained from the X-ray crystal structure of hPPARγ ligand binding domain (LBD) complexed with 3. However, the shape and/or nature of the binding pocket surrounding the piperidine ring of 3 could not be precisely delineated because the structure of the omega loop of the LBD was poorly defined.

Potent protein glycation inhibition of plantagoside in Plantago major seeds.

Plantagoside (5,7,4',5'-tetrahydroxyflavanone-3'-O-glucoside) and its aglycone (5,7,3',4',5'-pentahydroxyflavanone), isolated from a 50% ethanol extract of Plantago major seeds (Plantaginaceae), were established to be potent inhibitors of the Maillard reaction. These compounds also inhibited the formation of advanced glycation end products in proteins in physiological conditions and inhibited protein cross-linking glycation. These results indicate that P.

Mechanism of peroxisome proliferator-activated receptor gamma (PPARγ) transactivation by hesperetin glucuronides is distinct from that by a thiazolidine-2,4-dione agent.

Hesperidin, a flavanone glycoside present abundantly in citrus fruits, is predominantly metabolized to hesperetin-7-O-β-D-glucuronide (H7-OG) and hesperetin-3'-O-β-D-glucuronide (H3'-OG), which exhibit partial agonistic activity towards peroxisome proliferator-activated receptor gamma (PPARγ). Here, in order to understand the mechanism(s) of action of PPARγ transactivation elicited by hesperetin glucuronides, we compared the transactivation activities of PPARγ (ligand-binding domain (LBD)) mutants by hesperetin glucuronides and troglitazone, a thiazolidine-2,4-dione class PPARγ full agonist. The assay results indicated that the mechanisms of activation of PPARγ by hesperetin glucuronides and by troglitazone are distinct, probably due to a difference in the binding sites of these compounds on the PPARγ LBD.

γ-Mangostin from Garcinia mangostana pericarps as a dual agonist that activates Both PPARα and PPARδ.

We tested the peroxisome proliferator-activated receptor (PPAR)δ agonistic activity of a Garcinia mangostana pericarp extract to develop a treatment for the metabolic syndrome, and demonstrated γ-mangostin to be an active compound on the basis of a luciferase reporter gene assay. γ-Mangostin induced the expression of the uncoupling protein-3 (UCP-3) gene which is related to energy expenditure and fat metabolism in L6 cells. We showed that γ-mangostin is a dual agonist that activates both PPARδ and PPARα.