PPARα Agonist Suppresses Inflammation after Corneal Alkali Burn by Suppressing Proinflammatory Cytokines, MCP-1, and Nuclear Translocation of NF-κB

We investigated the effect of a peroxisome proliferator-activated receptor α (PPARα) agonist after corneal alkali injury. Fenofibrate 0.05% (PPARα agonist group) or vehicle (Vehicle group) was topically instilled onto the rat cornea after injury. Histological, immunohistochemical, and real-time reverse transcription PCR analyses were performed. PPARα-positive cells were observed among basal cells of the corneal epithelium in normal and alkali-burned corneas. The number of infiltrating neutrophils and macrophages at the corneal limbus was lower in the PPARα agonist group. Interleukin-1β (IL-1β), IL-6, IL-8, monocyte chemoattractant protein-1 (MCP-1), and vascular endothelial growth factor-An mRNA expression was suppressed in the PPARα agonist group compared to the Vehicle group. mRNA levels of nuclear factor kappa B (NF-κB) in corneal tissue were not different. However, NF-κB was expressed in the cytoplasm of basal cells in the PPARα agonist group and in the nucleus in the Vehicle group. MCP-1 was more weakly expressed in the PPARα agonist group. The PPARα agonist inhibited inflammation during the early phase after injury. Anti-inflammatory effects of the PPARα agonist included prevention of up-regulation of proinflammatory cytokines and MCP-1, and prevention of inflammatory cell infiltration into the injured cornea. Thus, a PPARα agonist may be a promising treatment for corneal injury.

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Allicin Alleviates Dextran Sodium Sulfate- (DSS-) Induced Ulcerative Colitis in BALB/c Mice

Oxidative Medicine and Cellular Longevity ◽

10.1155/2015/605208 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13 ◽

Cited By ~ 40

Author(s):

Ashok Kumar Pandurangan ◽

Salmiah Ismail ◽

Zeinab Saadatdoust ◽

Norhaizan Mohd. Esa

Keyword(s):

Body Weight ◽

Proinflammatory Cytokines ◽

Sodium Sulfate ◽

Nuclear Translocation ◽

Dextran Sodium Sulfate ◽

Nuclear Accumulation ◽

Mrna Levels ◽

Inhibitory Protein ◽

Reduced Body ◽

Enzymic Antioxidants

The objective of this study is to evaluate the effect of allicin (10 mg/kg body weight, orally) in an experimental murine model of UC by administering 2.5% dextran sodium sulfate (DSS) in drinking water to BALB/c mice. DSS-induced mice presented reduced body weight, which was improved by allicin administration. We noted increases in CD68 expression, myeloperoxidase (MPO) activities, and Malonaldehyde (MDA) and mRNA levels of proinflammatory cytokines, such astumor necrosis factor- (TNF-)α, interleukin- (IL-) 1β, IL-6, andIL-17, and decrease in the activities of enzymic antioxidants such as superoxide dismutase (SOD), Catalase (CAT), Glutathione reductase (GR), and Glutathione peroxidase (GPx) in DSS-induced mice. However, allicin treatment significantly decreased CD68, MPO, MDA, and proinflammatory cytokines and increased the enzymic antioxidants significantly (P<0.05). In addition, allicin was capable of reducing the activation and nuclear accumulation of signal transducer and activator of transcription 3 (STAT3), thereby preventing degradation of the inhibitory protein IκB and inducing inhibition of the nuclear translocation of nuclear factor (NF)-κB-p65 in the colonic mucosa. These findings suggest that allicin exerts clinically useful anti-inflammatory effects mediated through the suppression of the NF-κB and IL-6/p-STAT3Y705pathways.

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Hydroxytyrosol Modulates Adipocyte Gene and miRNA Expression Under Inflammatory Condition

Nutrients ◽

10.3390/nu11102493 ◽

2019 ◽

Vol 11 (10) ◽

pp. 2493 ◽

Cited By ~ 11

Author(s):

Egeria Scoditti ◽

Sara Carpi ◽

Marika Massaro ◽

Mariangela Pellegrino ◽

Beatrice Polini ◽

...

Keyword(s):

Gene Expression ◽

Glucose Transporter ◽

Matrix Metalloproteinase 2 ◽

Intercellular Adhesion Molecule ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Intercellular Adhesion Molecule 1 ◽

Plasminogen Activator Inhibitor 1 ◽

Monocyte Chemoattractant Protein 1 ◽

Tnf Α

Chronic inflammation of the adipose tissue (AT) is a major contributor to obesity-associated cardiometabolic complications. The olive oil polyphenol hydroxytyrosol (HT) contributes to Mediterranean diet cardiometabolic benefits through mechanisms still partially unknown. We investigated HT (1 and 10 μmol/L) effects on gene expression (mRNA and microRNA) related to inflammation induced by 10 ng/mL tumor necrosis factor (TNF)-α in human Simpson–Golabi–Behmel Syndrome (SGBS) adipocytes. At real-time PCR, HT significantly inhibited TNF-α-induced mRNA levels, of monocyte chemoattractant protein-1, C-X-C Motif Ligand-10, interleukin (IL)-1β, IL-6, vascular endothelial growth factor, plasminogen activator inhibitor-1, cyclooxygenase-2, macrophage colony-stimulating factor, matrix metalloproteinase-2, Cu/Zn superoxide dismutase-1, and glutathione peroxidase, as well as surface expression of intercellular adhesion molecule-1, and reverted the TNF-α-mediated inhibition of endothelial nitric oxide synthase, peroxisome proliferator-activated receptor coactivator-1α, and glucose transporter-4. We found similar effects in adipocytes stimulated by macrophage-conditioned media. Accordingly, HT significantly counteracted miR-155-5p, miR-34a-5p, and let-7c-5p expression in both cells and exosomes, and prevented NF-κB activation and production of reactive oxygen species. HT can therefore modulate adipocyte gene expression profile through mechanisms involving a reduction of oxidative stress and NF-κB inhibition. By such mechanisms, HT may blunt macrophage recruitment and improve AT inflammation, preventing the deregulation of pathways involved in obesity-related diseases.

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Polyunsaturated fatty acids stimulate hepatic UCP-2 expression via a PPARα-mediated pathway

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.281.6.e1197 ◽

2001 ◽

Vol 281 (6) ◽

pp. E1197-E1204 ◽

Cited By ~ 45

Author(s):

Michael B. Armstrong ◽

Howard C. Towle

Keyword(s):

Fatty Acids ◽

Arachidonic Acid ◽

Oleic Acid ◽

Polyunsaturated Fatty Acids ◽

Uncoupling Protein ◽

Protein S ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Pparα Agonist

The discovery of homologs of the brown fat uncoupling protein(s) (UCP) UCP-2 and UCP-3 revived the hypothesis of uncoupling protein involvement in the regulation of energy metabolism. Thus we hypothesized that UCP-2 would be regulated in the hepatocyte by fatty acids, which are known to control other energy-related metabolic processes. Treatment with 250 μM palmitic acid was without effect on UCP-2 expression, whereas 250 μM oleic acid exhibited a modest eightfold increase. Eicosapentaenoic acid (EPA), a polyunsaturated fatty acid, exerted a 50-fold upregulation of UCP-2 that was concentration dependent. This effect was seen within 12 h and was maximal by 36 h. Aspirin blocked the induction of UCP-2 by EPA, indicating involvement of the prostaglandin pathway. Hepatocytes treated with arachidonic acid, the immediate precursor to the prostaglandins, also exhibited an aspirin-inhibitable increase in UCP-2 levels, further supporting the involvement of prostaglandins in regulating hepatic UCP-2. The peroxisome proliferator-activated receptor-α (PPARα) agonist Wy-14643 stimulated UCP-2 mRNA levels as effectively as EPA. These data indicate that UCP-2 is upregulated by polyunsaturated fatty acids, potentially through a prostaglandin/PPARα-mediated pathway.

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A potent PPARα agonist stimulates mitochondrial fatty acid β-oxidation in liver and skeletal muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.280.2.e270 ◽

2001 ◽

Vol 280 (2) ◽

pp. E270-E279 ◽

Cited By ~ 123

Author(s):

Anne Minnich ◽

Nian Tian ◽

Lisa Byan ◽

Glenda Bilder

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Fatty Acid ◽

Biological Effects ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Mitochondrial Fatty Acid ◽

Cpt I ◽

Pparα Agonist

The proposed mechanism for the triglyceride (TG) lowering by fibrate drugs is via activation of the peroxisome proliferator-activated receptor-α (PPARα). Here we show that a PPARα agonist, ureido-fibrate-5 (UF-5), ∼200-fold more potent than fenofibric acid, exerts TG-lowering effects (37%) in fat-fed hamsters after 3 days at 30 mg/kg. In addition to lowering hepatic apolipoprotein C-III (apoC-III) gene expression by ∼60%, UF-5 induces hepatic mitochondrial carnitine palmitoyltransferase I (CPT I) expression. A 3-wk rising-dose treatment results in a greater TG-lowering effect (70%) at 15 mg/kg and a 2.3-fold elevation of muscle CPT I mRNA levels, as well as effects on hepatic gene expression. UF-5 also stimulated mitochondrial [3H]palmitate β-oxidation in vitro in human hepatic and skeletal muscle cells 2.7- and 1.6-fold, respectively, in a dose-related manner. These results suggest that, in addition to previously described effects of fibrates on apoC-III expression and on peroxisomal fatty acid (FA) β-oxidation, PPARα agonists stimulate mitochondrial FA β-oxidation in vivo in both liver and muscle. These observations suggest an important mechanism for the biological effects of PPARα agonists.

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Activation of Peroxisome Proliferator-Activated Receptor-Gamma by Glitazones Reduces the Expression and Release of Monocyte Chemoattractant Protein-1 in Human Mesothelial Cells

Mediators of Inflammation ◽

10.1155/2012/217696 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 6

Author(s):

Matthias Sauter ◽

Kathrin Kastenmüller ◽

Franziska Belling ◽

Markus Wörnle ◽

Roland Ladurner ◽

...

Keyword(s):

Primary Cultures ◽

Mesothelial Cells ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

Peroxisome Proliferator Activated Receptor ◽

Monocyte Chemoattractant Protein 1 ◽

Peritoneal Mesothelial Cells ◽

Monocyte Chemoattractant ◽

Monocyte Chemoattractant Protein ◽

Cytokines And Chemokines

Human peritoneal mesothelial cells (MC) play an important role in inflammatory processes of the peritoneal cavity by producing various cytokines and chemokines, such as monocyte chemoattractant protein-1 (MCP-1). The present study was designed to assess the effect of the peroxisome proliferator-activated receptor-gamma- (PPARγ-) activator rosiglitazone on the mesothelial MCP-1 expression and release. Primary cultures of MC were obtained from omental tissue. MCP-1 antigen concentrations were measured in the cell supernatant by ELISA and MCP-1 mRNA levels by real-time polymerase chain reaction. The presence of PPARγon MC was assayed in a Western Blot analysis. MC constitutively express PPARγ. Activation of this receptor via rosiglitazone (0,1–10 μmol/L) resulted in significantly reduced amounts of mesothelial MCP-1 release as well as MCP-1 mRNA. The use of the PPARγinhibitor GW-9662 could completely prevent the rosiglitazone effects. Rosiglitazone was also effective in reducing TNFα-induced enhanced secretion of MCP-1. Our findings indicate that glitazones are effective in reducing constitutive and TNFα-stimulated mesothelial MCP-1 mRNA expression and release.

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Extract of Wax Gourd Peel Prevents High-Fat Diet-Induced Hyperlipidemia in C57BL/6 Mice via the Inhibition of the PPARγPathway

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2013/342561 ◽

2013 ◽

Vol 2013 ◽

pp. 1-11 ◽

Cited By ~ 8

Author(s):

Ming Gu ◽

Shengjie Fan ◽

Gaigai Liu ◽

Lu Guo ◽

Xiaobo Ding ◽

...

Keyword(s):

Blood Glucose ◽

High Fat Diet ◽

Target Genes ◽

Metabolic Diseases ◽

Body Weight Gain ◽

Fasting Blood Glucose ◽

Peroxisome Proliferator ◽

Mrna Levels ◽

High Fat ◽

Wax Gourd

Wax gourd is a popular vegetable in East Asia. In traditional Chinese medicine, wax gourd peel is used to prevent and treat metabolic diseases such as hyperlipidemia, hyperglycemia, obesity, and cardiovascular disease. However, there is no experimental evidence to support these applications. Here, we examined the effect of the extract of wax gourd peel (EWGP) on metabolic disorders in diet-induced C57BL/6 obese mice. In the preventive experiment, EWGP blocked body weight gain and lowered serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-c), liver TG and TC contents, and fasting blood glucose in mice fed with a high-fat diet. In the therapeutic study, we induced obesity in the mice and treated with EWGP for two weeks. We found that EWGP treatment reduced serum and liver triglyceride (TG) contents and fasting blood glucose and improved glucose tolerance in the mice. Reporter assay and gene expression analysis showed that EWGP could inhibit peroxisome proliferator-activated receptorγ(PPARγ) transactivities and could decrease mRNA levels of PPARγand its target genes. We also found that HMG-CoA reductase (HMGCR) was downregulated in the mouse liver by EWGP. Our data suggest that EWGP lowers hyperlipidemia of C57BL/6 mice induced by high-fat diet via the inhibition of PPARγand HMGCR signaling.

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Gamma-Irradiated Cornea in Combat-related Ocular Trauma

Military Medicine ◽

10.1093/milmed/usaa479 ◽

2020 ◽

Author(s):

Brian M Davis ◽

Carson Clabeaux ◽

Anton Vlasov ◽

Paul Houghtaling

Keyword(s):

Ocular Trauma ◽

Cost Savings ◽

Corneal Tissue ◽

Significant Cost ◽

Visual Rehabilitation ◽

Military Health ◽

Corneal Injury ◽

Gamma Irradiated ◽

The Military ◽

Penetrating Ocular Trauma

ABSTRACT Corneal injury is a known risk for deployed troops worldwide. To the authors’ knowledge, there has been no reported use of gamma-irradiated corneas in the setting of severe corneal trauma. Our report highlights the case of a 36-year-old active duty solider who sustained bilateral penetrating ocular trauma from a nearby ordnance explosion. We propose that ocular surgeons should consider utilizing gamma-irradiated corneas in (1) a situation where the corneal tissue is so damaged that it would be challenging to accomplish an adequate repair while providing the opportunity for future visual rehabilitation and (2) remote and/or deployed environments where storage of fresh donor tissue is limited. The long shelf life of gamma-irradiated corneas reduces the need for specialized storage equipment and the need for continuous resupply, both potentially leading to significant cost savings for the Military Health System.

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Cellular effects of glycine and trehalose air-polishing powders on human gingival fibroblasts in vitro

Clinical Oral Investigations ◽

10.1007/s00784-021-04130-0 ◽

2021 ◽

Author(s):

Jens Weusmann ◽

James Deschner ◽

Jean-Claude Imber ◽

Anna Damanaki ◽

Natalia D. P. Leguizamón ◽

...

Keyword(s):

Wound Healing ◽

Cell Function ◽

Nuclear Translocation ◽

In Vitro Study ◽

Human Gingival Fibroblasts ◽

Mrna Levels ◽

Gingival Fibroblasts ◽

Air Polishing ◽

Wide Range

Abstract Objectives Air-polishing has been used in the treatment of periodontitis and gingivitis for years. The introduction of low-abrasive powders has enabled the use of air-polishing devices for subgingival therapy. Within the last decade, a wide range of different low-abrasive powders for subgingival use has been established. In this study, the effects of a glycine powder and a trehalose powder on human gingival fibroblasts (HGF) were investigated. Methods HGF were derived from three systemically and periodontally healthy donors. After 24 h and 48 h of incubation time, mRNA levels, and after 48 h, protein levels of TNFα, IL-8, CCL2, and VEGF were determined. In addition, NF-κB p65 nuclear translocation and in vitro wound healing were assessed. Statistical analysis was performed by ANOVA and post hoc Dunnett’s and Tukey’s tests (p < 0.05). Results Glycine powder significantly increased the expression of proinflammatory genes and showed exploitation of the NF-κB pathway, albeit trehalose powder hardly interfered with cell function and did not trigger the NF-κB pathway. In contrast to trehalose, glycine showed a significant inhibitory effect on the in vitro wound healing rate. Conclusion Subgingivally applicable powders for air-polishing devices can regulate cell viability and proliferation as well as cytokine expression. Our in vitro study suggests that the above powders may influence HGF via direct cell effects. Trehalose appears to be relatively inert compared to glycine powder.

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Protective Effects of PGC-1α Activators on Ischemic Stroke in a Rat Model of Photochemically Induced Thrombosis

Brain Sciences ◽

10.3390/brainsci11030325 ◽

2021 ◽

Vol 11 (3) ◽

pp. 325

Author(s):

Fatima M. Shakova ◽

Yuliya I. Kirova ◽

Denis N. Silachev ◽

Galina A. Romanova ◽

Sergey G. Morozov

Keyword(s):

Rat Model ◽

Nuclear Translocation ◽

Peroxisome Proliferator ◽

Protective Effects ◽

Protein Markers ◽

Peroxisome Proliferator Activated Receptor ◽

Pharmacological Agents ◽

Ischemic Brain ◽

Neuroprotective Therapy ◽

Dependent Protein

The pharmacological induction and activation of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), a key regulator of ischemic brain tolerance, is a promising direction in neuroprotective therapy. Pharmacological agents with known abilities to modulate cerebral PGC-1α are scarce. This study focused on the potential PGC-1α-modulating activity of Mexidol (2-ethyl-6-methyl-3-hydroxypyridine succinate) and Semax (ACTH(4–7) analog) in a rat model of photochemical-induced thrombosis (PT) in the prefrontal cortex. Mexidol (100 mg/kg) was administered intraperitoneally, and Semax (25 μg/kg) was administered intranasally, for 7 days each. The expression of PGC-1α and PGC-1α-dependent protein markers of mitochondriogenesis, angiogenesis, and synaptogenesis was measured in the penumbra via immunoblotting at Days 1, 3, 7, and 21 after PT. The nuclear content of PGC-1α was measured immunohistochemically. The suppression of PGC-1α expression was observed in the penumbra from 24 h to 21 days following PT and reflected decreases in both the number of neurons and PGC-1α expression in individual neurons. Administration of Mexidol or Semax was associated with preservation of the neuron number and neuronal expression of PGC-1α, stimulation of the nuclear translocation of PGC-1α, and increased contents of protein markers for PGC-1α activation. This study opens new prospects for the pharmacological modulation of PGC-1α in the ischemic brain.

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A Yes-Associated Protein (YAP) and Insulin-Like Growth Factor 1 Receptor (IGF-1R) Signaling Loop Is Involved in Sorafenib Resistance in Hepatocellular Carcinoma

Cancers ◽

10.3390/cancers13153812 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3812

Author(s):

Mai-Huong T. Ngo ◽

Sue-Wei Peng ◽

Yung-Che Kuo ◽

Chun-Yen Lin ◽

Ming-Heng Wu ◽

...

Keyword(s):

Nuclear Translocation ◽

Combination Index ◽

Specific Inhibitor ◽

In Vivo Model ◽

Mrna Levels ◽

Margin Distribution ◽

Related Proteins ◽

Emt Markers

The role of a YAP-IGF-1R signaling loop in HCC resistance to sorafenib remains unknown. Method: Sorafenib-resistant cells were generated by treating naïve cells (HepG2215 and Hep3B) with sorafenib. Different cancer cell lines from databases were analyzed through the ONCOMINE web server. BIOSTORM–LIHC patient tissues (46 nonresponders and 21 responders to sorafenib) were used to compare YAP mRNA levels. The HepG2215_R-derived xenograft in SCID mice was used as an in vivo model. HCC tissues from a patient with sorafenib failure were used to examine differences in YAP and IGF-R signaling. Results: Positive associations exist among the levels of YAP, IGF-1R, and EMT markers in HCC tissues and the levels of these proteins increased with sorafenib failure, with a trend of tumor-margin distribution in vivo. Blocking YAP downregulated IGF-1R signaling-related proteins, while IGF-1/2 treatment enhanced the nuclear translocation of YAP in HCC cells through PI3K-mTOR regulation. The combination of YAP-specific inhibitor verteporfin (VP) and sorafenib effectively decreased cell viability in a synergistic manner, evidenced by the combination index (CI). Conclusion: A YAP-IGF-1R signaling loop may play a role in HCC sorafenib resistance and could provide novel potential targets for combination therapy with sorafenib to overcome drug resistance in HCC.

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