gw-1929 and Inflammation

Topics: Animals; Diabetes Mellitus; Drug Design; Humans; Hyperlipidemias; Hypertension; Inflammation; Ligands; Models, Molecular; Neoplasms; Nuclear Proteins; Obesity; Receptors, Cytoplasmic and Nuclear; Transcription Factors

Diabetic cardiomyopathy (DCM) is a kind of disease caused by metabolic disorders and microangiopathy. The main pathophysiological changes of DCM include fibrosis, myocardial cell apoptosis and autonomic neuropathy. Therefore, treatment aimed at these processes may benefit patients with DCM. We designed an experiment with the peroxisome proliferator-activated receptor-gamma (PPARγ) agonist GW 1929 to detect whether the activation of PPARγ could alleviate the degree of DCM. To further detect the mechanism of PPARγ in DCM, we used the PPARγ antagonist GW 9662 and ERK antagonist PD 098059 both in vitro and in vivo and found that PPARγ functioned by inhibiting ERK. We also performed Western blot, PCR, ELISA, immunohistochemistry, TUNEL assay, Sirius red staining and gelatin zymography to investigate inflammation, apoptosis, MMP activity and epithelial-to-mesenchymal transition (EMT). The results showed that the activation of PPARγ inhibited these reactions and inhibiting ERK also simulated this phenomenon. In conclusion, these results demonstrated that PPARγ activation in the diabetic myocardium of mice reduces myocardial fibrosis via regulation of the TGF-β/ERK pathway and EMT.

Topics: Animals; Benzophenones; Diabetic Cardiomyopathies; Epithelial-Mesenchymal Transition; Fibrosis; Inflammation; Male; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Myocardium; Peroxisome Proliferator-Activated Receptors; PPAR gamma; Signal Transduction; Transforming Growth Factor beta; Tyrosine

PGlyRPs recognize bacterial peptidoglycan and function in antibacterial innate immunity. Focusing on the interference between nutrition and recognition pattern proteins, free fatty acids (FFA) of dietary and bacterial sources may exert their immunological response through modulating the expression level of the PGlyRPs in enterocytes. PGlyRP3 was the only PGlyRPs member expressed in Caco2 cells. In silico analysis showed that the promoter of PGlyRP3 has some PPRE regions that, as tested by EMSA, bind physically to the PPARγ-RXRα complex. PGlyRP3 gene expression was induced by PPARγ ligands including GW1929 and some FFA. Overexpression of PGlyRP3 in Caco2 cells down regulated the expression of the inflammatory cytokines IL-8, IL-12 and TNF-α, while its silencing increased the expression of these cytokines. FFA that induced the PGlyRP3 inhibited the tested cytokines. Silencing of PGlyRP3 gene caused the same FFA to increase the cytokine gene expression. A negative regulation of NF-κB pathway, including up-regulation of Iκβ-α and down regulation of NF-κB and COX-2, is involved in the anti-inflammatory effects of PGlyRP3. In conclusion, PPARγ mediates a modulation of PGlyRP3 gene expression, which is involved in inhibiting inflammation through negative regulation of NF-κB pathway.

Topics: Benzophenones; Caco-2 Cells; Carrier Proteins; Cytokines; Fatty Acids; Gene Expression Regulation; Humans; Inflammation; NF-kappa B; PPAR gamma; Promoter Regions, Genetic; Retinoid X Receptor alpha; Signal Transduction; Tyrosine

PPARγ agonist; 2-(Benzoylphenyl)-O-[2-(methyl-2-pyridinylamino) ethyl]-L-tyrosine (GW1929) in focal cerebral ischemic-reperfusion (IR) injury in rats. Focal cerebral IR injury resulted significant brain infarction and neurological deficits in rats. A significant increase in various inflammatory mediators like COX-2, iNOS, MMP-9, TNFα and IL-6 and massive apoptotic DNA fragmentation was also observed in the IR challenged brains. GW1929 treatment significantly attenuated the neurological damage in focal cerebral IR injury. Neuroprotective effects of GW1929 were found to be associated with significant reduction in the COX-2, iNOS, MMP-9, TNFα and IL-6 levels. Together, we have also evaluated the effects of Pioglitazone, a clinically available thiazolidinedione PPARγ agonist, against focal cerebral IR injury. Like GW1929, Pioglitazone also showed beneficial effects in cerebral IR injury associated neurological damage but at the higher dose as compared to GW1929. Neuroprotective effects of PPARγ agonists were found to be associated with significant reduction in TUNEL positive cells in IR challenged brain. In summary, these results suggested the neuroprotective potential of PPARγ agonists in cerebral IR injury and these effects may be attributed to their anti-inflammatory and anti-apoptotic potential.

Topics: Animals; Apoptosis; Benzophenones; Brain Ischemia; Enzyme-Linked Immunosorbent Assay; Immunohistochemistry; In Situ Nick-End Labeling; Inflammation; Male; Neuroprotective Agents; PPAR gamma; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Tyrosine

Th1 cytokines promote monocyte differentiation into proatherogenic M1 macrophages, while Th2 cytokines lead to an "alternative" anti-inflammatory M2 macrophage phenotype. Here we show that in human atherosclerotic lesions, the expression of M2 markers and PPARgamma, a nuclear receptor controlling macrophage inflammation, correlate positively. Moreover, PPARgamma activation primes primary human monocytes into M2 differentiation, resulting in a more pronounced anti-inflammatory activity in M1 macrophages. However, PPARgamma activation does not influence M2 marker expression in resting or M1 macrophages, nor does PPARgamma agonist treatment influence the expression of M2 markers in atherosclerotic lesions, indicating that only native monocytes can be primed by PPARgamma activation to an enhanced M2 phenotype. Furthermore, PPARgamma activation significantly increases expression of the M2 marker MR in circulating peripheral blood mononuclear cells. These data demonstrate that PPARgamma activation skews human monocytes toward an anti-inflammatory M2 phenotype.

Topics: Benzophenones; Biomarkers; Blood Cells; Carotid Artery Diseases; Cell Differentiation; Cells, Cultured; Foam Cells; Humans; Inflammation; Macrophages; Monocytes; Paracrine Communication; Phenotype; PPAR gamma; Stem Cells; Tyrosine