scholarly journals Therapeutic Effects of PPARαon Neuronal Death and Microvascular Impairment

PPAR Research ◽  
2015 ◽  
Vol 2015 ◽  
pp. 1-10 ◽  
Author(s):  
Elizabeth P. Moran ◽  
Jian-xing Ma
Keyword(s):  
Vascular Function ◽  
Target Genes ◽  
Microvascular Complications ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Nuclear Hormone Receptor ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Microvascular Impairment

Peroxisome-proliferator activated receptor-alpha (PPARα) is a broadly expressed nuclear hormone receptor and is a transcription factor for diverse target genes possessing a PPAR response element (PPRE) in the promoter region. The PPRE is highly conserved, and PPARs thus regulate transcription of an extensive array of target genes involved in energy metabolism, vascular function, oxidative stress, inflammation, and many other biological processes. PPARαhas potent protective effects against neuronal cell death and microvascular impairment, which have been attributed in part to its antioxidant and anti-inflammatory properties. Here we discuss PPARα’s effects in neurodegenerative and microvascular diseases and also recent clinical findings that identified therapeutic effects of a PPARαagonist in diabetic microvascular complications.

scholarly journals Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-δ gene

2014 ◽  
Vol 306 (7) ◽  
pp. H1001-H1010 ◽  
Author(s):  
Livius V. d'Uscio ◽  
Tongrong He ◽  
Anantha Vijay R. Santhanam ◽  
Li-Jung Tai ◽  
Ronald M. Evans ◽  
...  
Keyword(s):  
Vascular Function ◽  
Vascular Dysfunction ◽  
Vascular Endothelial Cell ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Superoxide Anion Production ◽  
No Donor ◽  
Peroxisome Proliferator Activated Receptor ◽  
Specific Deletion

Peroxisome proliferator-activated receptor (PPAR)-δ is a nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPAR-δ agonists exert vascular protective effects. The present study was designed to characterize vascular function in mice with genetic inactivation of PPAR-δ in the endothelium. Mice with vascular endothelial cell-specific deletion of the PPAR-δ gene (ePPARδ−/− mice) were generated using loxP/Cre technology. ePPARδ−/− mice were normotensive and did not display any sign of metabolic syndrome. Endothelium-dependent relaxations to ACh and endothelium-independent relaxations to the nitric oxide (NO) donor diethylammonium ( Z)-1-( N, N-diethylamino)diazen-1-ium-1,2-diolate were both significantly impaired in the aorta and carotid arteries of ePPARδ−/− mice ( P < 0.05). In ePPARδ−/− mouse aortas, phosphorylation of endothelial NO synthase at Ser1177 was significantly decreased ( P < 0.05). However, basal levels of cGMP were unexpectedly increased ( P < 0.05). Enzymatic activity of GTP-cyclohydrolase I and tetrahydrobiopterin levels were also enhanced in ePPARδ−/− mice ( P < 0.05). Most notably, endothelium-specific deletion of the PPAR-δ gene significantly decreased protein expressions of catalase and glutathione peroxidase 1 and resulted in increased levels of H2O2 in the aorta ( P < 0.05). In contrast, superoxide anion production was unaltered. Moreover, treatment with catalase prevented the endothelial dysfunction and elevation of cGMP detected in aortas of ePPARδ−/− mice. The findings suggest that increased levels of cGMP caused by H2O2 impair vasodilator reactivity to endogenous and exogenous NO. We speculate that chronic elevation of H2O2 predisposes PPAR-δ-deficient arteries to oxidative stress and vascular dysfunction.

scholarly journals Peroxisome Proliferator-Activated Receptors and Acute Lung Injury

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-8 ◽  
Author(s):  
Rosanna Di Paola ◽  
Salvatore Cuzzocrea
Keyword(s):  
Immune Responses ◽  
Metabolic Pathways ◽  
Target Genes ◽  
Inflammatory Diseases ◽  
Nuclear Hormone Receptor ◽  
Therapeutic Effects ◽  
Peroxisome Proliferator ◽  
Anti Inflammatory ◽  
Peroxisome Proliferator Activated Receptors ◽  
Ppar Ligands

Peroxisome proliferator-activated receptors are ligand-activated transcription factors belonging to the nuclear hormone receptor superfamily. PPARs regulate several metabolic pathways by binding to sequence-specific PPAR response elements in the promoter region of target genes, including lipid biosynthesis and glucose metabolism. Recently, PPARs and their respective ligands have been implicated as regulators of cellular inflammatory and immune responses. These molecules are thought to exert anti-inflammatory effects by negatively regulating the expression of proinflammatory genes. Several studies have demonstrated that PPAR ligands possess anti-inflammatory properties and that these properties may prove helpful in the treatment of inflammatory diseases of the lung. This review will outline the anti-inflammatory effects of PPARs and PPAR ligands and discuss their potential therapeutic effects in animal models of inflammatory lung disease.

scholarly journals New Target Genes for the Peroxisome Proliferator-Activated Receptor-γ(PPARγ) Antitumour Activity: Perspectives from the Insulin Receptor

PPAR Research ◽  
2009 ◽  
Vol 2009 ◽  
pp. 1-8 ◽  
Author(s):  
Daniela P. Foti ◽  
Francesco Paonessa ◽  
Eusebio Chiefari ◽  
Antonio Brunetti
Keyword(s):  
Insulin Receptor ◽  
Target Genes ◽  
Tumour Progression ◽  
Antitumour Activity ◽  
Peptide Hormone ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Preclinical Research ◽  
Peroxisome Proliferator Activated Receptor ◽  
Wide Range

The insulin receptor (IR) plays a crucial role in mediating the metabolic and proliferative functions triggered by the peptide hormone insulin. There is considerable evidence that abnormalities in both IR expression and function may account for malignant transformation and tumour progression in some human neoplasias, including breast cancer. PPARγis a ligand-activated, nuclear hormone receptor implicated in many pleiotropic biological functions related to cell survival and proliferation. In the last decade, PPARγagonists—besides their known action and clinical use as insulin sensitizers—have proved to display a wide range of antineoplastic effects in cells and tissues expressing PPARγ, leading to intensive preclinical research in oncology. PPARγand activators affect tumours by different mechanisms, involving cell proliferation and differentiation, apoptosis, antiinflammatory, and antiangiogenic effects. We recently provided evidence that PPARγand agonists inhibit IR by non canonical, DNA-independent mechanisms affecting IR gene transcription. We conclude that IR may be considered a new PPARγ“target” gene, supporting a potential use of PPARγagonists as antiproliferative agents in selected neoplastic tissues that overexpress the IR.

scholarly journals Protective effects of cyclohexenone long chain alcohols against the neuronal cell death due to calcium overloading

2000 ◽  
Vol 82 ◽  
pp. 178
Author(s):  
Mihoko Hirata ◽  
Remi Tsuchiya ◽  
Miyuki Ogawa ◽  
Nagisa Matsumoto ◽  
Masashi Yamada ◽  
...  
Keyword(s):  
Cell Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Protective Effects ◽  
Calcium Overloading ◽  
Long Chain

scholarly journals 1-O-Hexyl-2,3,5-Trimethylhydroquinone Ameliorates l-DOPA-Induced Cytotoxicity in PC12 Cells

Molecules ◽  
2019 ◽  
Vol 24 (5) ◽  
pp. 867 ◽  
Author(s):  
Hyun Park ◽  
Jong Kang ◽  
Myung Lee
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Pc12 Cells ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Mitogen Activated Protein Kinase ◽  
Protective Effects ◽  
Extracellular Signal ◽  
Dopaminergic Neuronal Cell ◽  
Mitogen Activated Protein

1-O-Hexyl-2,3,5-trimethylhydroquinone (HTHQ) has previously been found to have effective anti-oxidant and anti-lipid-peroxidative activity. We aimed to elucidate whether HTHQ can prevent dopaminergic neuronal cell death by investigating the effect on l-DOPA-induced cytotoxicity in PC12 cells. HTHQ protected from both l-DOPA-induced cell death and superoxide dismutase activity reduction. When assessing the effect of HTHQ on oxidative stress-related signaling pathways, HTHQ inhibited l-DOPA-induced phosphorylation of sustained extracellular signal-regulated kinases (ERK1/2), p38 mitogen-activated protein kinase (MAPK), and c-Jun N-terminal kinase (JNK1/2). HTHQ also normalized l-DOPA-reduced Bcl-2-associated death protein (Bad) phosphorylation and Bcl-2-associated X protein (Bax) expression, promoting cell survival. Taken together, HTHQ exhibits protective effects against l-DOPA-induced cell death through modulation of the ERK1/2-p38MAPK-JNK1/2-Bad-Bax signaling pathway in PC12 cells. These results suggest that HTHQ may show ameliorative effects against oxidative stress-induced dopaminergic neuronal cell death, although further studies in animal models of Parkinson’s disease are required to confirm this.

scholarly journals Peroxisome Proliferator-Activated Receptor γ Coactivator 1α Activates Vascular Endothelial Growth Factor That Protects Against Neuronal Cell Death Following Status Epilepticus through PI3K/AKT and MEK/ERK Signaling

2020 ◽  
Vol 21 (19) ◽  
pp. 7247
Author(s):  
Jyun-Bin Huang ◽  
Shih-Pin Hsu ◽  
Hsiu-Yung Pan ◽  
Shang-Der Chen ◽  
Shu-Fang Chen ◽  
...  
Keyword(s):  
Status Epilepticus ◽  
Protein Kinase ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mitogen Activated Protein ◽  
Hippocampal Ca3

Status epilepticus may cause molecular and cellular events, leading to hippocampal neuronal cell death. Peroxisome proliferator-activated receptor γ coactivator 1-α (PGC-1α) is an important regulator of vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2), also known as fetal liver kinase receptor 1 (Flk-1). Resveratrol is an activator of PGC-1α. It has been suggested to provide neuroprotective effects in epilepsy, stroke, and neurodegenerative diseases. In the present study, we used microinjection of kainic acid into the left hippocampal CA3 region in Sprague Dawley rats to induce bilateral prolonged seizure activity. Upregulating the PGC-1α pathway will increase VEGF/VEGFR2 (Flk-1) signaling and further activate some survival signaling that includes the mitogen activated protein kinase kinase (MEK)/mitogen activated protein kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathways and offer neuroprotection as a consequence of apoptosis in the hippocampal neurons following status epilepticus. Otherwise, downregulation of PGC-1α by siRNA against pgc-1α will inhibit VEGF/VEGFR2 (Flk-1) signaling and suppress pro-survival PI3K/AKT and MEK/ERK pathways that are also accompanied by hippocampal CA3 neuronal cell apoptosis. These results may indicate that the PGC-1α induced VEGF/VEGFR2 pathway may trigger the neuronal survival signaling, and the PI3K/AKT and MEK/ERK signaling pathways. Thus, the axis of PGC-1α/VEGF/VEGFR2 (Flk-1) and the triggering of downstream PI3K/AKT and MEK/ERK signaling could be considered an endogenous neuroprotective effect against apoptosis in the hippocampus following status epilepticus.

scholarly journals Peroxisome Proliferator-Activated Receptors: “Key” Regulators of Neuroinflammation after Traumatic Brain Injury

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-7 ◽  
Author(s):  
Philip F. Stahel ◽  
Wade R. Smith ◽  
Jay Bruchis ◽  
Craig H. Rabb
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuronal Cell Death ◽  
Synthetic Cannabinoids ◽  
Experimental Studies ◽  
Neuronal Cell ◽  
Peroxisome Proliferator ◽  
Therapeutic Concept ◽  
Anti Inflammatory ◽  
Peroxisome Proliferator Activated Receptors

Traumatic brain injury is characterized by neuroinflammatory pathological sequelae which contribute to brain edema and delayed neuronal cell death. Until present, no specific pharmacological compound has been found, which attenuates these pathophysiological events and improves the outcome after head injury. Recent experimental studies suggest that targeting peroxisome proliferator-activated receptors (PPARs) may represent a new anti-inflammatory therapeutic concept for traumatic brain injury. PPARs are “key” transcription factors which inhibit NFκBactivity and downstream transcription products, such as proinflammatory and proapoptotic cytokines. The present review outlines our current understanding of PPAR-mediated neuroprotective mechanisms in the injured brain and discusses potential future anti-inflammatory strategies for head-injured patients, with an emphasis on the putative beneficial combination therapy of synthetic cannabinoids (e.g., dexanabinol) with PPARαagonists (e.g., fenofibrate).

Protective effects of a selective L-type voltage-sensitive calcium channel blocker, S-312-d, on neuronal cell death

2004 ◽  
Vol 67 (6) ◽  
pp. 1153-1165 ◽  
Author(s):  
Tatsurou Yagami ◽  
Keiichi Ueda ◽  
Toshiyuki Sakaeda ◽  
Naohiro Itoh ◽  
Gaku Sakaguchi ◽  
...  
Keyword(s):  
Cell Death ◽  
Calcium Channel ◽  
Calcium Channel Blocker ◽  
Channel Blocker ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Protective Effects
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