scholarly journals Inside Cover: Sulfonylthiadiazoles with an Unusual Binding Mode as Partial Dual Peroxisome Proliferator-Activated Receptor (PPAR) γ/δ Agonists with High Potency and in vivo Efficacy (ChemMedChem 4/2011)

ChemMedChem ◽  
2011 ◽  
Vol 6 (4) ◽  
pp. 574-574
Author(s):  
Stefanie Keil ◽  
Hans Matter ◽  
Karl Schönafinger ◽  
Maike Glien ◽  
Magali Mathieu ◽  
...  
Keyword(s):  
Binding Mode ◽  
Peroxisome Proliferator ◽  
High Potency ◽  
Peroxisome Proliferator Activated Receptor ◽  
In Vivo Efficacy ◽  
Ppar Γ

Sulfonylthiadiazoles with an Unusual Binding Mode as Partial Dual Peroxisome Proliferator-Activated Receptor (PPAR) γ/δ Agonists with High Potency and in vivo Efficacy

ChemMedChem ◽  
2011 ◽  
Vol 6 (4) ◽  
pp. 633-653 ◽  
Author(s):  
Stefanie Keil ◽  
Hans Matter ◽  
Karl Schönafinger ◽  
Maike Glien ◽  
Magali Mathieu ◽  
...  
Keyword(s):  
Binding Mode ◽  
Peroxisome Proliferator ◽  
High Potency ◽  
Peroxisome Proliferator Activated Receptor ◽  
In Vivo Efficacy ◽  
Ppar Γ

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

PPAR Research ◽  
2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
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.

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

2013 ◽  
Vol 305 (2) ◽  
pp. F143-F154 ◽  
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.

α-Lipoic acid enhances endogenous peroxisome-proliferator-activated receptor-γ to ameliorate experimental autoimmune encephalomyelitis in mice

2013 ◽  
Vol 125 (7) ◽  
pp. 329-340 ◽  
Author(s):  
Kai-Chen Wang ◽  
Ching-Piao Tsai ◽  
Chao-Lin Lee ◽  
Shao-Yuan Chen ◽  
Gu-Jiun Lin ◽  
...  
Keyword(s):  
Experimental Autoimmune Encephalomyelitis ◽  
Lipoic Acid ◽  
Inflammatory Cells ◽  
Treg Cells ◽  
Peroxisome Proliferator ◽  
Autoimmune Encephalomyelitis ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Experimental Autoimmune

ALA (α-lipoic acid) is a natural, endogenous antioxidant that acts as a PPAR-γ (peroxisome-proliferator-activated receptor-γ) agonist to counteract oxidative stress. Thus far, the antioxidative and immunomodulatory effects of ALA on EAE (experimental autoimmune encephalomyelitis) are not well understood. In this study, we found that ALA restricts the infiltration of inflammatory cells into the CNS (central nervous system) in MOG (myelin oligodendrocyte glycoprotein)-EAE mice, thus reducing the disease severity. In addition, we revealed that ALA significantly suppresses the number and percentage of encephalitogenic Th1 and Th17 cells and increases splenic Treg-cells (regulatory T-cells). Strikingly, we further demonstrated that ALA induces endogenous PPAR-γ centrally and peripherally but has no effect on HO-1 (haem oxygenase 1). Together, these data suggest that ALA can up-regulate endogenous systemic and central PPAR-γ and enhance systemic Treg-cells to inhibit the inflammatory response and ameliorate MOG-EAE. In conclusion, our data provide the first evidence that ALA can augment the production of PPAR-γ in vivo and modulate adaptive immunity both centrally and peripherally in EAE and may reveal further antioxidative and immunomodulatory mechanisms for the application of ALA in human MS (multiple sclerosis).

scholarly journals Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-γ

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4250-4258 ◽  
Author(s):  
Raju C. Reddy ◽  
Venkata R. Narala ◽  
Venkateshwar G. Keshamouni ◽  
Jami E. Milam ◽  
Michael W. Newstead ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Human Pmns ◽  
Inflammatory Regulation

AbstractNeutrophils (polymorphonuclear leukocytes [PMNs]) are critical to the immune response, including clearance of infectious pathogens. Sepsis is associated with impaired PMN function, including chemotaxis. PMNs express peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear transcription factor involved in immune and inflammatory regulation. The role of PPAR-γ in PMN responses, however, is not well characterized. We report that freshly isolated human PMNs constitutively express PPAR-γ, which is up-regulated by the sepsis-induced cytokines TNF-α and IL-4. PMN chemotactic responses to formylmethionyl-leucyl-phenylalanine (fMLP) and IL-8 were dose-dependently inhibited by treatment with the PPAR-γ ligands troglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and by transfection of PMN-like HL-60 cells with a constitutively active PPAR-γ construct. Inhibition of chemotaxis by PPAR-γ ligands correlated with decreases in extracellular signal-regulated kinase-1 and -2 activation, actin polymerization, and adherence to a fibrinogen substrate. Furthermore, PMN expression of PPAR-γ was increased in sepsis patients and mice with either of 2 models of sepsis. Finally, treatment with the PPAR-γ antagonist GW9662 significantly reversed the inhibition of PMN chemotaxis and increased peritoneal PMN recruitment in murine sepsis. This study indicates that PPAR-γ activation is involved in PMN chemotactic responses in vitro and may play a role in the migration of these cells in vivo.

scholarly journals 15-keto-prostaglandin E2 activates host peroxisome proliferator-activated receptor gamma (PPAR-γ) to promote Cryptococcus neoformans growth during infection

2017 ◽  
Author(s):  
Robert J. Evans ◽  
Katherine Pline ◽  
Catherine A. Loynes ◽  
Sarah Needs ◽  
Maceler Aldrovandi ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Immune Surveillance ◽  
Fungal Growth ◽  
Prostaglandin E ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Opportunistic Fungal Pathogen

AbstractCryptococcus neoformans is one of the leading causes of invasive fungal infection in humans worldwide. C. neoformans uses macrophages as a proliferative niche to increase infective burden and avoid immune surveillance. However, the specific mechanisms by which C. neoformans manipulates host immunity to promote its growth during infection remain ill-defined. Here we demonstrate that eicosanoid lipid mediators manipulated and/or produced by C. neoformans play a key role in regulating pathogenesis. C. neoformans is known to secrete several eicosanoids that are highly similar to those found in vertebrate hosts. Using eicosanoid deficient cryptococcal mutants Δplb1 and Δlac1, we demonstrate that prostaglandin E2 is required by C. neoformans for proliferation within macrophages and in vivo during infection. Genetic and pharmacological disruption of host PGE2 synthesis is not required for promotion of cryptococcal growth by eicosanoid production. We find that PGE2 must be dehydrogenated into 15-keto-PGE2 to promote fungal growth, a finding that implicated the host nuclear receptor PPAR-γ. C. neoformans infection of macrophages activates host PPAR-γ and its inhibition is sufficient to abrogate the effect of 15-keto-PGE2 in promoting fungal growth during infection. Thus, we describe the first mechanism of reliance on pathogen-derived eicosanoids in fungal pathogenesis and the specific role of 15-keto-PGE2 and host PPAR-γ in cryptococcosis.Author SummaryCryptococcus neoformans is an opportunistic fungal pathogen that is responsible for significant numbers of deaths in the immunocompromised population worldwide. Here we address whether eicosanoids produced by C. neoformans manipulate host innate immune cells during infection. Cryptococcus neoformans produces several eicosanoids that are notable for their similarity to vertebrate eicosanoids, it is therefore possible that fungal-derived eicosanoids may provoke physiological effects in the host. Using a combination of in vitro and in vivo infection models we identify a specific eicosanoid species - prostaglandin E2 – that is required by C. neoformans for growth during infection. We subsequently show that prostaglandin E2 must be converted to 15-keto-prostaglandin E2 within the host before it has these effects. Furthermore, we find that prostaglandin E2/15-keto-prostaglandin E2 mediated virulence is via activation of host PPAR-γ – an intracellular eicosanoid receptor known to interact with 15-keto-PGE2.

scholarly journals Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1301
Author(s):  
Melissa L. D. Rayner ◽  
Jess Healy ◽  
James B. Phillips
Keyword(s):  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Neural Cells ◽  
Loss Of Function ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

The slow rate of neuronal regeneration that follows peripheral nerve repair results in poor recovery, particularly where reinnervation of muscles is delayed, leading to atrophy and permanent loss of function. There is a clear clinical need to develop drug treatments that can accelerate nerve regeneration safely, restoring connections before the target tissues deteriorate irreversibly. The identification that the Rho/Rho-associated kinase (ROCK) pathway acts to limit neuronal growth rate is a promising advancement towards the development of drugs. Targeting Rho or ROCK directly can act to suppress the activity of this pathway; however, the pathway can also be modulated through the activation of upstream receptors; one of particular interest being peroxisome proliferator-activated receptor gamma (PPAR-γ). The connection between the PPAR-γ receptor and the Rho/ROCK pathway is the suppression of the conversion of inactive guanosine diphosphate (GDP)-Rho to active guanosine triphosphate GTP-Rho, resulting in the suppression of Rho/ROCK activity. PPAR-γ is known for its role in cellular metabolism that leads to cell growth and differentiation. However, more recently there has been a growing interest in targeting PPAR-γ in peripheral nerve injury (PNI). The localisation and expression of PPAR-γ in neural cells following a PNI has been reported and further in vitro and in vivo studies have shown that delivering PPAR-γ agonists following injury promotes nerve regeneration, leading to improvements in functional recovery. This review explores the potential of repurposing PPAR-γ agonists to treat PNI and their prospective translation to the clinic.

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