In vitro effect of resistin on protein expression of peroxisome proliferator activated receptor (PPAR-γ) in cultured porcine ovarian follicles

In the present study, using real-time polymerase chain reaction and immunoblotting methods, we quantified the expression of peroxisome proliferator-activated receptor (PPAR) γ, PPARα and PPARβ in different sized ovarian follicles (small (SF), medium (MF) and large (LF) follicles) in prepubertal and adult pigs. In prepubertal pigs, PPARγ and PPARα expression was highest in LF; however, PPARβ expression did not differ among SF, MF and LF. In mature pigs, only protein expression of PPARγ and PPARα increased during ovarian follicle development. Following identification of very high levels of PPARγ expression in LF in prepubertal and adult pigs, using in vitro culture of ovarian follicles, we determined the effect of resistin at 0.1, 1 and 10 ng mL–1 on PPARγ mRNA and protein expression and the effect of rosiglitazone at 25 and 50 µM (a PPARγ agonist) on resistin mRNA and protein expression. Resistin increased PPARγ expression in ovarian follicles in both prepubertal and adult pigs, whereas rosiglitazone had an inhibitory effect on resistin expression. The role of PPARγ in regulating the effects of resistin on ovarian steroidogenesis was investigated using GW9662 (a PPARγ antagonist at dose of 1 μM). In these studies, GW9662 reversed the effect of resistin on steroid hormone secretion. The data suggest that there is local cooperation between resistin and PPARγ expression in the porcine ovary. Resistin significantly increased the expression of PPARγ, whereas PPARγ decreased resistin expression; thus, PPARγ is a new key regulator of resistin expression and function.

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Apple Flavonols Mitigate Adipocyte Inflammation and Promote Angiogenic Factors in LPS- and Cobalt Chloride-Stimulated Adipocytes, in Part by a Peroxisome Proliferator-Activated Receptor-γ-Dependent Mechanism

Nutrients ◽

10.3390/nu12051386 ◽

2020 ◽

Vol 12 (5) ◽

pp. 1386 ◽

Cited By ~ 1

Author(s):

Danyelle M. Liddle ◽

Meaghan E. Kavanagh ◽

Amanda J. Wright ◽

Lindsay E. Robinson

Keyword(s):

Mrna Expression ◽

Cobalt Chloride ◽

Nuclear Factor Κb ◽

Diglycidyl Ether ◽

Low Grade ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Anti Inflammatory

Adipose tissue (AT) expansion induces local hypoxia, a key contributor to the chronic low-grade inflammation that drives obesity-associated disease. Apple flavonols phloretin (PT) and phlorizin (PZ) are suggested anti-inflammatory molecules but their effectiveness in obese AT is inadequately understood. Using in vitro models designed to reproduce the obese AT microenvironment, 3T3-L1 adipocytes were cultured for 24 h with PT or PZ (100 μM) concurrent with the inflammatory stimulus lipopolysaccharide (LPS; 10 ng/mL) and/or the hypoxia mimetic cobalt chloride (CoCl2; 100 μM). Within each condition, PT was more potent than PZ and its effects were partially mediated by peroxisome proliferator-activated receptor (PPAR)-γ (p < 0.05), as tested using the PPAR-γ antagonist bisphenol A diglycidyl ether (BADGE). In LPS-, CoCl2-, or LPS + CoCl2-stimulated adipocytes, PT reduced mRNA expression and/or secreted protein levels of inflammatory and macrophage chemotactic adipokines, and increased that of anti-inflammatory and angiogenic adipokines, which was consistent with reduced mRNA expression of M1 polarization markers and increased M2 markers in RAW 264.7 macrophages cultured in media collected from LPS + CoCl2-simulated adipocytes (p < 0.05). Further, within LPS + CoCl2-stimulated adipocytes, PT reduced reactive oxygen species accumulation, nuclear factor-κB activation, and apoptotic protein expression (p < 0.05). Overall, apple flavonols attenuate critical aspects of the obese AT phenotype.

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Piperine Alleviates Doxorubicin-Induced Cardiotoxicity via Activating PPAR-γ in Mice

PPAR Research ◽

10.1155/2019/2601408 ◽

2019 ◽

Vol 2019 ◽

pp. 1-11 ◽

Cited By ~ 2

Author(s):

Jie Yan ◽

Si-Chi Xu ◽

Chun-Yan Kong ◽

Xiao-Yang Zhou ◽

Zhou-Yan Bian ◽

...

Keyword(s):

Oxidative Stress ◽

Cardiac Injury ◽

Inflammatory Factors ◽

Peroxisome Proliferator ◽

Protective Effects ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Myocardial Oxidative Stress

Background. Oxidative stress, inflammation and cardiac apoptosis were closely involved in doxorubicin (DOX)-induced cardiac injury. Piperine has been reported to suppress inflammatory response and pyroptosis in macrophages. However, whether piperine could protect the mice against DOX-related cardiac injury remain unclear. This study aimed to investigate whether piperine inhibited DOX-related cardiac injury in mice. Methods. To induce DOX-related acute cardiac injury, mice in DOX group were intraperitoneally injected with a single dose of DOX (15 mg/kg). To investigate the protective effects of piperine, mice were orally treated for 3 weeks with piperine (50 mg/kg, 18:00 every day) beginning two weeks before DOX injection. Results. Piperine treatment significantly alleviated DOX-induced cardiac injury, and improved cardiac function. Piperine also reduced myocardial oxidative stress, inflammation and apoptosis in mice with DOX injection. Piperine also improved cell viability, and reduced oxidative damage and inflammatory factors in cardiomyocytes. We also found that piperine activated peroxisome proliferator-activated receptor-γ (PPAR-γ), and the protective effects of piperine were abolished by the treatment of the PPAR-γ antagonist in vivo and in vitro. Conclusions. Piperine could suppress DOX-related cardiac injury via activation of PPAR-γ in mice.

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The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules

AJP Renal Physiology ◽

10.1152/ajprenal.00398.2012 ◽

2013 ◽

Vol 305 (2) ◽

pp. F143-F154 ◽

Cited By ~ 74

Author(s):

Harshini Mudaliar ◽

Carol Pollock ◽

Muralikrishna Gangadharan Komala ◽

Steven Chadban ◽

Huiling Wu ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Inflammatory Responses ◽

Proximal Tubules ◽

Peroxisome Proliferator ◽

Tlr2 Expression ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Diagnostic Threshold

Inflammatory responses are central to the pathogenesis of diabetic nephropathy. Toll-like receptors (TLRs) are ligand-activated membrane-bound receptors which induce inflammatory responses predominantly through the activation of NF-κB. TLR2 and 4 are present in proximal tubular cells and are activated by endogenous ligands upregulated in diabetic nephropathy, including high-mobility group box-1 (HMGB1) and fibronectin. Human proximal tubules were exposed to 5 mM (control), 11.2 mM (approximating the clinical diagnostic threshold for diabetes mellitus), and 30 mM (high) glucose for 72 h or 7 days. Cells were harvested for protein, mRNA, and nuclear extract to assess for TLR2, 4, and inflammatory markers. Glucose (11.2 mM) maximally increased TLR2 and 4 expression, HMGB1 release, and NF-κB activation with increased expression of cytokines. However, only TLR2 expression and subsequent NF-κB binding were sustained at 7 days. Recombinant HMGB1 induced NF-κB activation, which was prevented by both TLR2 silencing [small interfering (si)RNA] and TLR4 inhibition. Peroxisome proliferator-activated receptor-γ (PPAR-γ) transcription was reduced by exposure to 11.2 mM glucose with an increase observed at 30 mM glucose at 24 h. This may reflect a compensatory increase in PPAR-γ induced by exposure to 30 mM glucose, limiting the inflammatory response. Therefore, short-term moderate increases in glucose in vitro increase HMGB1, which mediates NF-κB activation through both TLR2 and 4. Furthermore, in vivo, streptozotocin-induced diabetic mice exhibited an increase in tubular TLR2 and HMGB1 expression. These results collectively suggest that TLR2 is likely to be the predominant long-term mediator of NF-κB activation in transducing inflammation in diabetic nephropathy.

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Stretch reduces nephrin expression via an angiotensin II-AT1-dependent mechanism in human podocytes: effect of rosiglitazone

AJP Renal Physiology ◽

10.1152/ajprenal.90423.2008 ◽

2010 ◽

Vol 298 (2) ◽

pp. F381-F390 ◽

Cited By ~ 40

Author(s):

Ilaria Miceli ◽

Davina Burt ◽

Elena Tarabra ◽

Giovanni Camussi ◽

Paolo Cavallo Perin ◽

...

Keyword(s):

Angiotensin Ii ◽

Protein Expression ◽

Slit Diaphragm ◽

Peroxisome Proliferator ◽

Glomerular Permeability ◽

Receptor System ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ ◽

Mrna And Protein Expression

Increased glomerular permeability to proteins is a characteristic feature of diabetic nephropathy (DN). The slit diaphragm is the major restriction site to protein filtration, and the loss of nephrin, a key component of the slit diaphragm, has been demonstrated in both human and experimental DN. Both systemic and glomerular hypertension are believed to be important in the pathogenesis of DN. Human immortalized podocytes were subjected to repeated stretch-relaxation cycles by mechanical deformation with the use of a stress unit (10% elongation, 60 cycles/min) in the presence or absence of candesartan (1 μM), PD-123319 (1 μM), and rosiglitazone (0.1 μM). Nephrin mRNA and protein expression were assessed using quantitative real-time PCR, immunoblotting, and immunofluorescence, and the protein expression of AT1 receptor and angiotensin II secretion were evaluated. Exposure to stretch induced a significant ∼50% decrease in both nephrin mRNA and protein expression. This effect was mediated by an angiotensin II-AT1 mechanism. Indeed, podocyte stretching induced both angiotensin II secretion and AT1 receptor overexpression, podocyte exposure to angiotensin II reduced nephrin protein expression, and both the AT-1 receptor antagonist candesartan and a specific anti-angiotensin II antibody completely abolished stretch-induced nephrin downregulation. Similar to candesartan, the peroxisome proliferator-activated receptor (PPAR)-γ agonist, rosiglitazone, also inhibited stretch-induced nephrin downregulation, suggesting interference with stretch-induced activation of the angiotensin II-AT1 receptor system. Accordingly, rosiglitazone did not alter stretch-induced angiotensin II secretion, but it prevented AT1 upregulation in response to stretch. These results suggest a role for hemodynamic stress in loss of nephrin expression and allude to a role of PPAR-γ agonists in the prevention of this loss.

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(–)-Epicatechin is associated with increased angiogenic and mitochondrial signalling in the hindlimb of rats selectively bred for innate low running capacity

Clinical Science ◽

10.1042/cs20120469 ◽

2013 ◽

Vol 124 (11) ◽

pp. 663-674 ◽

Cited By ~ 21

Author(s):

Maik Hüttemann ◽

Icksoo Lee ◽

Guy A. Perkins ◽

Steven L. Britton ◽

Lauren G. Koch ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Expression ◽

Mitogen Activated Protein Kinase ◽

Male Rats ◽

Control Group ◽

Peroxisome Proliferator ◽

In Vitro Experiments ◽

Peroxisome Proliferator Activated Receptor ◽

Mitogen Activated Protein

Alternative approaches to reduce congenital muscle dysfunction are needed in cases where the ability to exercise is limited. (−)-Epicatechin is found in cocoa and may stimulate capillarity and mitochondrial proliferation in skeletal muscle. A total of 21 male rats bred for LCR (low running capacity) from generation 28 were randomized into three groups: vehicle for 30 days (control); (−)-epicatechin for 30 days; and (−)-epicatechin for 30 days followed by 15 days without (−)-epicatechin. Groups 2 and 3 received 1.0 mg of (−)-epicatechin/kg of body mass twice daily, whereas water was given to the control group. The plantaris muscle was harvested for protein and morphometric analyses. In addition, in vitro experiments were conducted to examine the role of (−)-epicatechin on mitochondrial respiratory kinetics at different incubation periods. Treatment for 30 days with (−)-epicatechin increased capillarity (P<0.001) and was associated with increases in protein expression of VEGF (vascular endothelial growth factor)-A with a concomitant decrease in TSP-1 (thrombospondin-1) and its receptor, which remained after 15 days of (−)-epicatechin cessation. Analyses of the p38 MAPK (mitogen-activated protein kinase) signalling pathway indicated an associated increase in phosphorylation of MKK3/6 (MAPK kinase 3/6) and p38 and increased protein expression of MEF2A (myocyte enhancer factor 2A). In addition, we observed significant increases in protein expression of PGC-1α (peroxisome-proliferator-activated receptor γ co-activator 1α), PGC-1β, Tfam and cristae abundance. Interestingly, these increases associated with (−)-epicatechin treatment remained after 15 days of cessation. Lastly, in vitro experiments indicated that acute exposure of LCR muscle to (−)-epicatechin incubation was not sufficient to increase mitochondrial respiration. The results suggest that increases in skeletal muscle capillarity and mitochondrial biogenesis are associated with 30 days of (−)-epicatechin treatment and sustained for 15 days following cessation of treatment. Clinically, the use of this natural compound may have potential application in populations that experience muscle fatigue and are unable to perform endurance exercise.

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Telmisartan Protects Auditory Hair Cells from Gentamicin-Induced Toxicity in vitro

Audiology and Neurotology ◽

10.1159/000506796 ◽

2020 ◽

Vol 25 (6) ◽

pp. 297-308

Author(s):

Maurizio Cortada ◽

Eric Wei ◽

Neha Jain ◽

Soledad Levano ◽

Daniel Bodmer

Keyword(s):

Hair Cells ◽

Cell Types ◽

Protective Role ◽

Angiotensin Ii Receptor Blocker ◽

Peroxisome Proliferator ◽

Angiotensin Ii Receptor ◽

Peroxisome Proliferator Activated Receptor ◽

Auditory Hair Cells ◽

Ppar Γ

Background: Telmisartan is an angiotensin II receptor blocker that has pleiotropic effects and protective properties in different cell types. Moreover, telmisartan has also shown partial agonism on the peroxisome proliferator-activated receptor γ (PPAR-γ). Auditory hair cells (HCs) express PPAR-γ, and the protective role of PPAR-γ agonists on HCs has been shown. Objectives: The objective of this study was to investigate the effects of telmisartan on gentamicin-induced ototoxicity in vitro. Methods: Cochlear explants were exposed to gentamicin with or without telmisartan, and/or GW9662, an irreversible PPAR-γ antagonist. Results: Telmisartan protected auditory HCs against gentamicin-induced ototoxicity. GW9662 completely blocked this protective effect, suggesting that it was mediated by PPAR-γ signaling. Exposure to GW9662 or telmisartan alone was not toxic to auditory HCs. Conclusions: We found that telmisartan, via PPAR-γ signaling, protects auditory HCs from gentamicin-induced ototoxicity. Therefore, telmisartan could potentially be used in the future to prevent or treat sensorineural hearing loss.

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Pioglitazone, an Activator of Peroxisome Proliferator-Activated Receptor (PPAR-γ), Reduces the Expression of KB Nuclear Transcription Factor and Inhibits Apoptosis in Peripheral Blood Mononuclear Cells in Vitro

International Journal of Physiology and Pathophysiology ◽

10.1615/intjphyspathophys.v3.i4.90 ◽

2012 ◽

Vol 3 (4) ◽

pp. 371-377

Author(s):

N. I. Kutsenko ◽

L. E. Vesnina ◽

Igor P. Kaidashev

Keyword(s):

Transcription Factor ◽

Peripheral Blood Mononuclear Cells ◽

Mononuclear Cells ◽

Peroxisome Proliferator ◽

Peripheral Blood Mononuclear ◽

Peroxisome Proliferator Activated Receptor ◽

Nuclear Transcription Factor ◽

Ppar Γ ◽

Blood Mononuclear Cells

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Activation of peroxisome proliferator-activated receptor-γ contributes to the inhibitory effects of curcumin on rat hepatic stellate cell growth

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00474.2002 ◽

2003 ◽

Vol 285 (1) ◽

pp. G20-G30 ◽

Cited By ~ 147

Author(s):

Jianye Xu ◽

Yumei Fu ◽

Anping Chen

Keyword(s):

Gene Expression ◽

Liver Injury ◽

Hepatic Fibrosis ◽

Stellate Cell ◽

Healing Process ◽

Wound Healing Process ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Ppar Γ

Hepatic fibrogenesis occurs as a wound-healing process after many forms of chronic liver injury. Hepatic fibrosis ultimately leads to cirrhosis if not treated effectively. During liver injury, quiescent hepatic stellate cells (HSC), the most relevant cell type, become active and proliferative. Oxidative stress is a major and critical factor for HSC activation. Activation of peroxisome proliferator-activated receptor-γ (PPAR-γ) inhibits the proliferation of nonadipocytes. The level of PPAR-γ is dramatically diminished along with activation of HSC. Curcumin, the yellow pigment in curry, is a potent antioxidant. The aims of this study were to evaluate the effect of curcumin on HSC proliferation and to begin elucidating underlying mechanisms. It was hypothesized that curcumin might inhibit the proliferation of activated HSC by inducing PPAR-γ gene expression and reviving PPAR-γ activation. Our results indicated that curcumin significantly inhibited the proliferation of activated HSC and induced apoptosis in vitro. We demonstrated, for the first time, that curcumin dramatically induced the gene expression of PPAR-γ and activated PPAR-γ in activated HSC. Blocking its trans-activating activity by a PPAR-γ antagonist markedly abrogated the effects of curcumin on inhibition of cell proliferation. Our results provide a novel insight into mechanisms underlying the inhibition of activated HSC growth by curcumin. The characteristics of curcumin, including antioxidant potential, reduction of activated HSC growth, and no adverse health effects, make it a potential antifibrotic candidate for prevention and treatment of hepatic fibrosis.

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MBX-102/JNJ39659100, a Novel Peroxisome Proliferator-Activated Receptor-Ligand with Weak Transactivation Activity Retains Antidiabetic Properties in the Absence of Weight Gain and Edema

Molecular Endocrinology ◽

10.1210/me.2008-0473 ◽

2009 ◽

Vol 23 (7) ◽

pp. 975-988 ◽

Cited By ~ 65

Author(s):

Francine M. Gregoire ◽

Fang Zhang ◽

Holly J. Clarke ◽

Thomas A. Gustafson ◽

Dorothy D. Sears ◽

...

Keyword(s):

Target Genes ◽

Partial Agonist ◽

Oral Glucose ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Insulin Sensitizer ◽

Glucose Lowering ◽

Ppar Γ ◽

Primary Mouse

Abstract MBX-102/JNJ39659100 (MBX-102) is in clinical development as an oral glucose-lowering agent for the treatment of type 2 diabetes. MBX-102 is a nonthiazolidinedione (TZD) selective partial agonist of peroxisome proliferator-activated receptor (PPAR)-γ that is differentiated from the TZDs structurally, mechanistically, preclinically and clinically. In diabetic rodent models, MBX-102 has insulin-sensitizing and glucose-lowering properties comparable to TZDs without dose-dependent increases in body weight. In vitro, in contrast with full PPAR-γ agonist treatment, MBX-102 fails to drive human and murine adipocyte differentiation and selectively modulates the expression of a subset of PPAR-γ target genes in mature adipocytes. Moreover, MBX-102 does not inhibit osteoblastogenesis of murine mesenchymal cells. Compared with full PPAR-γ agonists, MBX-102 displays differential interactions with the PPAR-γ ligand binding domain and possesses reduced ability to recruit coactivators. Interestingly, in primary mouse macrophages, MBX-102 displays enhanced antiinflammatory properties compared with other PPAR-γ or α/γ agonists, suggesting that MBX-102 has more potent transrepression activity. In summary, MBX-102 is a selective PPAR-γ modulator with weak transactivation but robust transrepression activity. MBX-102 exhibits full therapeutic activity without the classical PPAR-γ side effects and may represent the next generation insulin sensitizer.

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