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  1. Article ; Online: Selective peroxisome proliferator-activated receptor gamma (PPARgamma) modulation as a strategy for safer therapeutic PPARgamma activation.

    Higgins, Linda Slanec / Depaoli, Alex M

    The American journal of clinical nutrition

    2009  Volume 91, Issue 1, Page(s) 267S–272S

    Abstract: Peroxisome proliferator-activated receptor gamma (PPARgamma) is a clinically validated target for treatment of insulin resistance. PPARgamma activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in ... ...

    Abstract Peroxisome proliferator-activated receptor gamma (PPARgamma) is a clinically validated target for treatment of insulin resistance. PPARgamma activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in patients with type 2 diabetes without the concern for hypoglycemia or gastrointestinal toxicities associated with some other medications used to treat this disease. However, thiazolidinediones are linked to safety and tolerability issues such as weight gain, fluid retention, edema, congestive heart failure, and bone fracture. Distinctive properties of PPARgamma provide the opportunity for selective modulation of the receptor such that desirable therapeutic effects may be attained without the unwanted effects of full activation. PPARgamma is a nuclear receptor that forms a complex with coreceptor RXR and a cell type- and cell state-specific array of coregulators to control gene transcription. PPARgamma affinity for these components, and hence transcriptional response, is determined by the conformational changes induced by ligand binding within a complex pocket with multiple interaction points. This molecular mechanism thereby offers the opportunity for selective modulation. A desirable selective PPARgamma modulator profile would include high-affinity interaction with the PPARgamma-binding pocket in a manner that leads to retention of the insulin-sensitizing activity that is characteristic of full agonists as well as mitigation of the effects leading to increased adiposity, fluid retention, congestive heart failure, and bone fracture. Examples of endogenous and synthetic selective PPARgamma modulator (SPPARM) ligands have been identified. SPPARM drug candidates are being tested clinically and provide support for this strategy.
    MeSH term(s) Diabetes Mellitus, Type 2/diagnosis ; Diabetes Mellitus, Type 2/drug therapy ; Dipeptidyl-Peptidase IV Inhibitors/therapeutic use ; Gluconeogenesis/drug effects ; Gluconeogenesis/physiology ; Humans ; Hypoglycemia/prevention & control ; Hypoglycemic Agents/therapeutic use ; Incretins/therapeutic use ; Insulin Resistance/physiology ; PPAR gamma/agonists ; PPAR gamma/drug effects ; PPAR gamma/physiology ; PPAR gamma/therapeutic use ; Pioglitazone ; Quinolines/pharmacology ; Retinoid X Receptors/drug effects ; Retinoid X Receptors/physiology ; Rosiglitazone ; Sulfonamides/pharmacology ; Thiazolidinediones/therapeutic use
    Chemical Substances Dipeptidyl-Peptidase IV Inhibitors ; Hypoglycemic Agents ; INT 131 ; Incretins ; PPAR gamma ; Quinolines ; Retinoid X Receptors ; Sulfonamides ; Thiazolidinediones ; Rosiglitazone (05V02F2KDG) ; Pioglitazone (X4OV71U42S)
    Language English
    Publishing date 2009-11-11
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 280048-2
    ISSN 1938-3207 ; 0002-9165
    ISSN (online) 1938-3207
    ISSN 0002-9165
    DOI 10.3945/ajcn.2009.28449E
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article: Selective peroxisome proliferator-activated receptor γ (PPARγ) modulation as a strategy for safer therapeutic PPARγ activation

    Higgins, Linda Slanec / DePaoli, Alex M

    American journal of clinical nutrition AJN. 2010 Jan., v. 91, no. 1

    2010  

    Abstract: Peroxisome proliferator-activated receptor γ (PPARγ) is a clinically validated target for treatment of insulin resistance. PPARγ activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in patients ... ...

    Abstract Peroxisome proliferator-activated receptor γ (PPARγ) is a clinically validated target for treatment of insulin resistance. PPARγ activation by full agonists such as thiazolidinediones has shown potent and durable glucose-lowering activity in patients with type 2 diabetes without the concern for hypoglycemia or gastrointestinal toxicities associated with some other medications used to treat this disease. However, thiazolidinediones are linked to safety and tolerability issues such as weight gain, fluid retention, edema, congestive heart failure, and bone fracture. Distinctive properties of PPARγ provide the opportunity for selective modulation of the receptor such that desirable therapeutic effects may be attained without the unwanted effects of full activation. PPARγ is a nuclear receptor that forms a complex with coreceptor RXR and a cell type- and cell state-specific array of coregulators to control gene transcription. PPARγ affinity for these components, and hence transcriptional response, is determined by the conformational changes induced by ligand binding within a complex pocket with multiple interaction points. This molecular mechanism thereby offers the opportunity for selective modulation. A desirable selective PPARγ modulator profile would include high-affinity interaction with the PPARγ-binding pocket in a manner that leads to retention of the insulin-sensitizing activity that is characteristic of full agonists as well as mitigation of the effects leading to increased adiposity, fluid retention, congestive heart failure, and bone fracture. Examples of endogenous and synthetic selective PPARγ modulator (SPPARM) ligands have been identified. SPPARM drug candidates are being tested clinically and provide support for this strategy.
    Keywords insulin resistance ; noninsulin-dependent diabetes mellitus ; hypoglycemia ; adverse effects ; glucose ; humans ; drug therapy ; receptors ; toxicity
    Language English
    Dates of publication 2010-01
    Size p. 267S-272S.
    Publishing place American Society for Clinical Nutrition
    Document type Article
    Note In the supplement: Therapeutic advances for insulin resistance and diabetes / edited by George L. Blackburn.
    ZDB-ID 280048-2
    ISSN 1938-3207 ; 0002-9165
    ISSN (online) 1938-3207
    ISSN 0002-9165
    Database NAL-Catalogue (AGRICOLA)

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  3. Article: Transforming growth factor-beta receptor type 1 (TGFbetaRI) kinase activity but not p38 activation is required for TGFbetaRI-induced myofibroblast differentiation and profibrotic gene expression.

    Kapoun, Ann M / Gaspar, Nicholas J / Wang, Ying / Damm, Debby / Liu, Yu-Wang / O'young, Gilbert / Quon, Diana / Lam, Andrew / Munson, Kimberly / Tran, Thomas-Toan / Ma, Jing Ying / Murphy, Alison / Dugar, Sundeep / Chakravarty, Sarvajit / Protter, Andrew A / Wen, Fu-Qiang / Liu, Xiangde / Rennard, Stephen I / Higgins, Linda Slanec

    Molecular pharmacology

    2006  Volume 70, Issue 2, Page(s) 518–531

    Abstract: Transforming growth factor-beta (TGFbeta) is a major mediator of normal wound healing and of pathological conditions involving fibrosis, such as idiopathic pulmonary fibrosis. TGFbeta also stimulates the differentiation of myofibroblasts, a hallmark of ... ...

    Abstract Transforming growth factor-beta (TGFbeta) is a major mediator of normal wound healing and of pathological conditions involving fibrosis, such as idiopathic pulmonary fibrosis. TGFbeta also stimulates the differentiation of myofibroblasts, a hallmark of fibrotic diseases. In this study, we examined the underlying processes of TGFbetaRI kinase activity in myofibroblast conversion of human lung fibroblasts using specific inhibitors of TGFbetaRI (SD-208) and p38 mitogen-activated kinase (SD-282). We demonstrated that SD-208, but not SD-282, inhibited TGFbeta-induced SMAD signaling, myofibroblast transformation, and collagen gel contraction. Furthermore, we extended our findings to a rat bleomycin-induced lung fibrosis model, demonstrating a significant decrease in the number of myofibroblasts at fibroblastic foci in animals treated with SD-208 but not those treated with SD-282. SD-208 also reduced collagen deposition in this in vivo model. Microarray analysis of human lung fibroblasts identified molecular fingerprints of these processes and showed that SD-208 had global effects on reversing TGFbeta-induced genes involved in fibrosis, inflammation, cell proliferation, cytoskeletal organization, and apoptosis. These studies also revealed that although the p38 pathway may not be needed for appearance or disappearance of the myofibroblast, it can mediate a subset of inflammatory and fibrogenic events of the myofibroblast during the process of tissue repair and fibrosis. Our findings suggest that inhibitors such as SD-208 may be therapeutically useful in human interstitial lung diseases and pulmonary fibrosis.
    MeSH term(s) Activin Receptors, Type I/antagonists & inhibitors ; Activin Receptors, Type I/physiology ; Cell Differentiation ; Cells, Cultured ; Collagen/metabolism ; Connective Tissue Growth Factor ; Cytoskeleton/metabolism ; Fibroblasts/cytology ; Gene Expression Regulation ; Humans ; Immediate-Early Proteins/genetics ; Inflammation/metabolism ; Intercellular Signaling Peptides and Proteins/genetics ; Lung/drug effects ; Lung/metabolism ; MAP Kinase Signaling System ; Oligonucleotide Array Sequence Analysis ; Protein-Serine-Threonine Kinases/physiology ; Pteridines/pharmacology ; Pulmonary Fibrosis/drug therapy ; Pulmonary Fibrosis/etiology ; Receptor, Transforming Growth Factor-beta Type I ; Receptors, Transforming Growth Factor beta/antagonists & inhibitors ; Receptors, Transforming Growth Factor beta/physiology ; Reverse Transcriptase Polymerase Chain Reaction ; Signal Transduction/drug effects ; Smad Proteins/antagonists & inhibitors ; Smad Proteins/physiology ; Transforming Growth Factor beta/pharmacology ; Wound Healing ; p38 Mitogen-Activated Protein Kinases/physiology
    Chemical Substances CCN2 protein, human ; CCN2 protein, rat ; Immediate-Early Proteins ; Intercellular Signaling Peptides and Proteins ; Pteridines ; Receptors, Transforming Growth Factor beta ; SD-208 ; Smad Proteins ; Transforming Growth Factor beta ; Connective Tissue Growth Factor (139568-91-5) ; Collagen (9007-34-5) ; Protein-Serine-Threonine Kinases (EC 2.7.11.1) ; p38 Mitogen-Activated Protein Kinases (EC 2.7.11.24) ; Activin Receptors, Type I (EC 2.7.11.30) ; Receptor, Transforming Growth Factor-beta Type I (EC 2.7.11.30) ; Tgfbr1 protein, rat (EC 2.7.11.30)
    Language English
    Publishing date 2006-05-17
    Publishing country United States
    Document type Journal Article
    ZDB-ID 124034-1
    ISSN 1521-0111 ; 0026-895X
    ISSN (online) 1521-0111
    ISSN 0026-895X
    DOI 10.1124/mol.105.021600
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 525: Show issues Location:
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