Importance Of The Field: PPARgamma full agonists (pioglitazone and rosiglitazone) are the mainstay drugs for the treatment of type 2 diabetes; however, mechanism-based side effects have limited their full therapeutic potential. In recent years, much progress has been achieved in the discovery and development of selective PPARgamma modulators (SPPARgammaMs) as safer alternatives to PPARgamma full agonists.
Areas Covered In This Review: This review focuses on the preclinical and clinical data of all the SPPARgammaMs discovered so far, retrieved by searching PubMed, Prous Integrity database and company news updates from 1999 to date.
What The Reader Will Gain: Here we thoroughly discuss SPPARgammaMs' mode of action, briefly examine new ways to identify superior SPPARgammaMs, and finally, compare and contrast the pharmacological and safety profile of various agents.
Take Home Message: The preclinical and clinical findings clearly suggest that selective PPARgamma modulators have the potential to become the next generation of PPARgamma agonists: effective insulin sensitizers with a superior safety profile to that of PPARgamma full agonists.
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Human T9 cells rely on PPAR-γ-mediated cystine uptake to prevent lipid peroxidation and bioenergetic failure.
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Department of Dermatology, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland. Electronic address:
T9 cells are implicated in allergic skin inflammation and depend on the transcription factor PPAR-γ for full effector function. In this study, we uncovered a role for PPAR-γ in the amino acid metabolism of human T9 cells. In in-vitro-primed T9 cells, PPAR-γ expression positively correlated with the expression of SLC7A8, which encodes LAT2, a transporter of large neutral amino acids, including cystine.
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November 2024
MOE Key Laboratory for Nonequilibrium Synthesis and Modulation of Condensed Matter, School of Physics, Xi'an Jiaotong University, Xi'an 710049, China.
Peroxisome proliferator-activated receptor γ (PPAR), a nuclear receptor involved in metabolic processes, inflammation, and energy balance, represents a promising therapeutic target for cardiovascular diseases. Danshensu Bingpian Zhi (DBZ), a chiral compound derived from traditional Chinese medicine, exhibits potential as a PPAR agonist. Using an ensemble-based docking approach, molecular dynamics (MD) simulations, and the molecular mechanics generalized born surface area (MM/GBSA) methods, we explored the binding modes and energetics of DBZ stereoisomers with the PPAR ligand-binding domain (LBD).
View Article and Find Full Text PDFIdentification of Novel PPARγ Partial Agonists Based on Virtual Screening Strategy: In Silico and In Vitro Experimental Validation.
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School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China.
Thiazolidinediones (TZDs) including rosiglitazone and pioglitazone function as peroxisome proliferator-activated receptor gamma (PPARγ) full agonists, which have been known as a class to be among the most effective drugs for the treatment of type 2 diabetes mellitus (T2DM). However, side effects of TZDs such as fluid retention and weight gain are associated with their full agonistic activities toward PPARγ induced by the AF-2 helix-involved "locked" mechanism. Thereby, this study aimed to obtain novel PPARγ partial agonists without direct interaction with the AF-2 helix.
View Article and Find Full Text PDFAgonists of the Nuclear Receptor PPARγ Can Produce Biased Signaling.
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Biochemistry and Biophysics Graduate Program (M.L.R., T.S.H.), Department of Biomedical and Pharmaceutical Sciences (M.D.N., T.S.H.), and Pharmaceutical Sciences and Drug Design Graduate Program (A.H.V., T.S.H.), University of Montana, Missoula, Montana
Biased signaling and ligand bias, often termed functional selectivity or selective nuclear receptor modulation, have been reported for nuclear receptor partial agonists over the past 20 years. Whether signaling differences produced by partial agonists result from less intense modulation, off-target effects, or biased signaling remains unclear. A commonly postulated mechanism for biased signaling is coactivator favoritism, where agonists induce different coactivator recruitment profiles.
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Int J Med Sci
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Department of Plastic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
Adipocytes play a crucial role in tissue regeneration, contributing to the restoration of damaged areas and modulating the inflammatory milieu. The modulation of gene expression through chemically modified PPARγ mRNA (PPARγ-modRNA) introduces a sophisticated approach to precisely control adipogenic processes. This study aims to explore the adipogenic potential of the PPARγ-modRNA in 3T3-L1 preadipocytes and its role in wound healing.
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