prostaglandin-d2 and Body-Weight

Prostaglandin D2 (PGD2) is the most abundant prostaglandin in the brain, but its involvement in brain damage caused by type 2 diabetes (T2D) has not been reported. In the present study, we found that increased PGD2 content is related to the inhibition of autophagy, which aggravates brain damage in T2D, and may be involved in the imbalanced expression of the corresponding PGD2 receptors DP1 and DP2. We demonstrated that DP2 inhibited autophagy and promotedT2D-induced brain damage by activating the PI3K/AKT/mTOR pathway, whereas DP1enhanced autophagy and amelioratedT2D brain damage by activating the cAMP/PKA pathway. In a T2D rat model, DP1 expression was decreased, and DP2 expression was increased; therefore, the imbalance in PGD2-DPs may be involved in T2D brain damage through the regulation of autophagy. However, there have been no reports on whether PKA can directly inhibit mTOR. The PKA catalytic subunit (PKA-C) has three subtypes (α, β and γ), and γ is not expressed in the brain. Subsequently, we suggested that PKA could directly interact with mTOR through PKA-C(α) and PKA-C(β). Our results suggest that the imbalance in PGD2-DPs is related to changes in autophagy levels in T2D brain damage, and PGD2 is involved in T2D brain damage by promoting autophagy via DP1-PKA/mTOR and inhibiting autophagy via DP2-PI3K/AKT/mTOR.

Topics: Animals; Autophagy; Blood Glucose; Body Weight; Brain Injuries; Cholesterol; Diabetes Mellitus, Type 2; Insulin; Learning; Memory; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Triglycerides

To overcome negative adverse effects and improve therapeutic index of dexamethasone (Dex) in rheumatoid arthritis (RA), we developed a novel sustained release formulation-intra-articular injectable dexamethasone-loaded thermosensitive hydrogel (DLTH) with chitosan-glycerin-borax as carrier for the remission of inflammation and pain. The focus of this article is to explore both anti-inflammatory and pain-relieving effects of DLTH joint injection in bovine type-II collagen-induced arthritis (CIA) rats.. Wistar rats were randomized into three groups, including the normal group (n=6), the model group (n=6) and the DLTH group (n=10). Joint injection of DLTH (1mg/kg Dex per rat) was injected on day 12 in the DLTH group twice a week for three weeks. Clinical signs of body weight, paw swelling and arthritis scores, histologic analysis, hind paw mechanical withdrawal threshold (MWT), plantar pressure pain threshold (PPT) were taken into consideration. Serum contents of IL-17A, prostaglandin E2 (PGE2), prostacyclin 2 (PGI2) and prostaglandin D2 (PGD2), real-time polymerase chain reaction (PCR) analysis of inflammatory factors and pain-related mediators in synovium and dorsal root ganglia (DRG), Western blotting of NF-κB in synovium were all evaluated.. Paw swelling, arthritis scores and joint inflammation destruction were all attenuated in the DLTH-treated group. Results showed that DLTH not only down-regulated serum IL-17A, but also mRNA levels of inflammatory factors and NGF, and key proteins contents of the NF-κB pathway in synovium. Increases of MWT and PPT in DLTH-treated rats elucidated pain-reducing effects of DLTH. Elevated serum PGD2 levels and declines of serum PGE2 and PGI2, and inflammatory and pain-related genes in DRGs in the DLTH group were also recorded.. These data elucidated that DLTH joint injection impeded synovial inflammation processes through down-regulating transcription activity of NF-κB pathway, and intra-articular DLTH may aid in the regulation of RA pain through regulating inflammation and pain conduction process.

Topics: Animals; Anti-Inflammatory Agents; Arthritis, Experimental; Body Weight; Dexamethasone; Dinoprostone; Edema; Ganglia, Spinal; Hydrogels; Inflammation; Interleukin-17; Male; NF-kappa B; Pain; Pain Threshold; Prostaglandin D2; Rats; Rats, Wistar; Synovial Membrane

Krüppel-like factor (KLF) 5, which initiates vascular smooth muscle cell (VSMC) proliferation, also participates in Angiotensin (Ang) II-induced vascular remodeling. The protective effect of rosiglitazone on vascular remodeling may be due to their impact on VSMC proliferation. However, the underlying mechanisms involved remain unclear. This study was designed to investigate whether the antiproliferation effects of rosiglitazone are mediated by regulating Ang II/KLF5 response. We found that, in aortas of Ang II-infused rats, vascular remodeling and KLF5 expression were markedly increased, and its target gene cyclin D1 was overexpressed. Co-treatment with rosiglitazone diminished these changes. In growth-arrested VSMCs, PPAR-γ agonists (rosiglitazone and 15d-PGJ2) dose-dependently inhibited Ang II-induced cell proliferation and expression of KLF5 and cyclin D1. Moreover, these effects were attenuated by the PPAR-γ antagonists GW9662, bisphenol A diglycidyl ether and PPAR-γ specific siRNA. Furthermore, rosiglitazone inhibited Ang II-induced phosphorylation of protein kinase C (PKC) ζ and extracellular signal-regulated kinase (ERK) 1/2 and activation of early growth response protein (Egr). In conclusion, in Ang II-stimulated VSMCs, rosiglitazone might have an antiproliferative effect through mechanisms that include reducing KLF5 expression, and a crosstalk between PPAR-γ and PKCζ/ERK1/2/Egr may be involved in. These findings not only provide a previously unrecognized mechanism by which PPAR-γ agonists inhibit VSMC proliferation, but also document a novel evidence for the beneficial vascular effect of PPAR-γ activation.

Topics: Angiotensin II; Anilides; Animals; Blood Pressure; Body Weight; Cell Proliferation; Cells, Cultured; Cyclin D1; Gene Expression Regulation; Hypoglycemic Agents; Kruppel-Like Transcription Factors; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Muscle, Smooth, Vascular; Phosphorylation; PPAR gamma; Prostaglandin D2; Protein Kinase C; Rats; Rats, Sprague-Dawley; Rosiglitazone; Signal Transduction; Thiazolidinediones

15-deoxy-Δ¹²,¹⁴ prostaglandin J₂ (15d-PGJ₂) is a ligand of peroxisome proliferator-activated receptor γ (PPARγ) having diverse effects such as the differentiation of adipocytes and atherosclerotic lesion formation. 15d-PGJ₂ can also regulate the expression of inflammatory mediators on immune cells independent of PPARγ. We investigated the antiatherogenic effect of 15d-PGJ₂.. We fed apolipoprotein (apo) E-deficient female mice a Western-type diet from 8 to 16 wk of age and administered 1 mg/kg/day 15d-PGJ₂ intraperitoneally. We measured atherosclerotic lesions at the aortic root, and examined the expression of macrophage and inflammatory atherosclerotic molecules by immunohistochemical and real-time PCR in the lesion.. Atherosclerotic lesion formation was reduced in apo E-null mice treated with 15d-PGJ₂, as compared to in the controls. Immunohistochemical and real-time PCR analyses showed that the expression of MCP-1, TNF-α, and MMP-9 in atherosclerotic lesions was significantly decreased in 15d-PGJ₂ treated mice. The 15d-PGJ₂ also reduced the expression of macrophages and RelA mRNA in atherosclerotic lesions.. This is the first report 15d-PGJ₂, a natural PPARγ agonist, can improve atherosclerotic lesions in vivo. 15d-PGJ₂ may be a beneficial therapeutic agent for atherosclerosis.

Topics: Animals; Aorta, Thoracic; Apolipoproteins E; Body Weight; Female; Gene Expression Regulation; Gene Knockout Techniques; Lipids; Mice; Mice, Inbred C57BL; Mice, Knockout; Plaque, Atherosclerotic; Prostaglandin D2; Sinus of Valsalva

Lipocalin-type prostaglandin (PG) D synthase is expressed in adipose tissues and involved in the regulation of glucose tolerance and atherosclerosis in type 2 diabetes. However, the physiological roles of PGD(2) in adipogenesis in vivo are not clear, as lipocalin-type prostaglandin D synthase can also act as a transporter for lipophilic molecules, such as retinoids. We generated transgenic (TG) mice overexpressing human hematopoietic PGDS (H-PGDS) and investigated the in vivo functions of PGD(2) in adipogenesis. PGD(2) production in white adipose tissue of H-PGDS TG mice was increased approximately seven-fold as compared with that in wild-type (WT) mice. With a high-fat diet, H-PGDS TG mice gained more body weight than WT mice. Serum leptin and insulin levels were increased in H-PGDS TG mice, and the triglyceride level was decreased by about 50% as compared with WT mice. Furthermore, in the white adipose tissue of H-PGDS TG mice, transcription levels of peroxisome proliferator-activated receptor gamma, fatty acid binding protein 4 and lipoprotein lipase were increased approximately two-fold to five-fold as compared with those of WT mice. Finally, H-PGDS TG mice showed clear hypoglycemia after insulin clamp. These results indicate that TG mice overexpressing H-PGDS abundantly produced PGD(2) in adipose tissues, resulting in pronounced adipogenesis and increased insulin sensitivity. The present study provides the first evidence that PGD(2) participates in the differentiation of adipocytes and in insulin sensitivity in vivo, and the H-PGDS TG mice could constitute a novel model mouse for diabetes studies.

Topics: Adipocytes; Adipogenesis; Animals; Blood Glucose; Body Weight; Cell Differentiation; Diabetes Mellitus, Experimental; Dietary Fats; Female; Humans; Male; Mice; Mice, Transgenic; Obesity; Prostaglandin D2; Up-Regulation

Mast cell number and reactivity were shown to be down-regulated under diabetic conditions. Since the balance between globular and filamentous actin plays a pivotal role in the activity of secretory cells, we investigated whether an imbalance in that system could underlie the hyporesponsiveness of mast cells in diabetes. The apoptotic state was also evaluated. By means of rhodamine/phalloidine staining of F-actin, we noted that diabetic mast cells exhibited an increase in fluorescence intensity and reduction in cellular size, when compared with cells from normal animals, in parallel with elevation in the percentage of cells developing apoptosis. The levels of Bax, a pro-apoptotic member of Bcl-2 family, appeared increased at baseline in mast cells from diabetic rats compared with normal cells. These phenomena correlated with reduction in histamine and PGD2 release following antigen challenge in vitro. The steroid antagonist RU 486 abolished the reduction of histamine secretion from diabetic mast cells. We conclude that hyporesponsiveness of mast cells noted in diabetes may be accounted for by reduction in actin filament plasticity, in clear association with the rise in the percentage of cells undergoing apoptosis. In addition, the refractoriness of diabetic mast cells to antigen in vitro seems to be dependent on glucocorticoids.

Topics: Abortifacient Agents; Actins; Adrenalectomy; Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Blood Glucose; Blotting, Western; Body Weight; Cell Separation; Depsipeptides; Diabetes Mellitus, Experimental; Flow Cytometry; Glucocorticoids; Histamine Release; Male; Mast Cells; Microscopy, Fluorescence; Mifepristone; Prostaglandin D2; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Wistar

Colitis involves immune cell-mediated tissue injuries, but the contribution of epithelial cells remains largely unclear. Vanin-1 is an epithelial ectoenzyme with a pantetheinase activity that provides cysteamine/cystamine to tissue. Using the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-colitis model we show here that Vanin-1 deficiency protects from colitis. This protection is reversible by administration of cystamine or bisphenol A diglycidyl ether, a peroxisome proliferator-activated receptor (PPAR)gamma antagonist. We further demonstrate that Vanin-1, by antagonizing PPARgamma, licenses the production of inflammatory mediators by intestinal epithelial cells. We propose that Vanin-1 is an epithelial sensor of stress that exerts a dominant control over innate immune responses in tissue. Thus, the Vanin-1/pantetheinase activity might be a new target for therapeutic intervention in inflammatory bowel disease.

Topics: Active Transport, Cell Nucleus; Amidohydrolases; Animals; Benzhydryl Compounds; Body Weight; Cell Adhesion Molecules; Cell Line; Cell Nucleus; Chemokine CCL2; Chemokine CXCL2; Chemokines; Colitis; Colon; Cyclooxygenase 2; Cystamine; Cytokines; Epithelial Cells; Epoxy Compounds; Gene Expression Regulation; GPI-Linked Proteins; Interleukin-1beta; Mice; Mice, Inbred BALB C; Mice, Knockout; Mice, SCID; PPAR gamma; Prostaglandin D2; Survival Analysis; Trinitrobenzenesulfonic Acid

In this study, we investigated thyroid hormones, thyroid stimulating hormone (TSH), prostaglandin D(2) (PGD(2)) and prostaglandin E(2) (PGE(2)) levels in rapid-eye-movement (REM) sleep-deprived rats compared with controls. The aim of the present study was to detect the effect of REM sleep deprivation (RSD) especially on hypothalamic prostaglandin levels. Twenty-seven male rats were randomly assigned in three groups as dry cage control, yoked control, and RSD. RSD rats were sleep deprived for 10 consecutive days. At the end of 10th day all rats were sacrificed for measurement. Our results indicated that total triiodothyronine (T(3)) and thyroxine (T(4)) decreased in the RSD group while there was no change in TSH. We also measured hypothalamic PGD(2) and PGE(2) levels, but we could not find any significant change between groups.

Topics: Animals; Body Weight; Dinoprostone; Hypothalamus; Male; Prostaglandin D2; Prostaglandins; Rats; Rats, Sprague-Dawley; Sleep Deprivation; Sleep, REM; Temperature; Thyroid Hormones; Thyroxine; Time Factors; Triiodothyronine

Peroxisome proliferator-activated receptor (PPAR) gamma is a nuclear receptor known to regulate adipogenesis. Deletion of the PPARgamma gene in the mouse results in death by embryonic day 10.0 (E10.0) due to the failure of establishment of a labyrinth layer in the placenta, which suggests that PPARgamma is involved in trophoblast differentiation. To define PPARgamma function further in placental development, the expression and localization of the PPARgamma gene in the rat placenta was investigated. RT-PCR analysis shows the presence of PPARgamma mRNA in the placenta of day 11 of pregnancy (d11). The expression level is higher at d13 and then later decreased. Immunohistochemistry detects both PPARgamma and its putative intrinsic ligand, 15-deoxy-Delta(12,14)-prostaglandin J(2), in the trophoblast of layer I which lined the maternal sinus. Oral administration of troglitazone, an agonist of PPARgamma, to pregnant rats between d9 and d11 increases the expression level of PPARgamma in the placenta and reduces the mortality of the fetuses by half. These results suggest that PPARgamma is required not only for trophoblast differentiation but also trophoblast maturation to establish maternal-fetal transport.

Topics: Administration, Oral; Animals; Body Weight; Cell Differentiation; Chromans; DNA; Ear, Inner; Female; Gene Deletion; Gene Expression Regulation, Developmental; Immunohistochemistry; Ligands; Maternal Exposure; Maternal-Fetal Exchange; Microscopy, Fluorescence; Placenta; Pregnancy; Pregnancy, Animal; Prostaglandin D2; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Reverse Transcriptase Polymerase Chain Reaction; RNA; RNA, Messenger; Thiazolidinediones; Time Factors; Transcription Factors; Troglitazone; Trophoblasts

Hematopoietic prostaglandin D synthase (PGDS) is a key enzyme to produce prostaglandin (PG) D and J series. These PGs are involved in inflammation and immune system. The PGDS complementary DNA (cDNA)-expressing retrovirally transfected fibroblasts were introduced in vivo, and effect of the expression on lung injury induced by bleomycin was investigated in mice. Intravenous injection of PGDS cDNA-expressing fibroblasts significantly reduced lung edema, leukocyte infiltration in bronchoalveolar lavage (BAL) fluid, and pulmonary collagen content at 4 wk after instillation of bleomycin. Survival rate in mice instilled with the PGDS-expressing fibroblasts was higher than that in mice that received the mock transfection. Administration of 15-deoxy-Delta 12,14-PGJ2, which is a nonenzymatic metabolite of PGD2, also attenuated the lung injury, suggesting mediation of PGs produced by PGDS for the attenuation. Introduction of PGDS cDNA-expressing fibroblasts suppressed expression of basic fibroblast growth factor, connective tissue growth factor, and collagen messenger RNAs in the lungs, as well as the levels of total proteins and hemoglobin in BAL fluid. These data suggest that the suppressive effect of PGDS on the lung injury could be partly mediated by edema formation and inhibition of genes involved in the fibrotic change.

Topics: Animals; Bleomycin; Body Weight; Bronchoalveolar Lavage Fluid; Cells, Cultured; Collagen; Cyclooxygenase Inhibitors; Fibroblasts; Gene Transfer Techniques; Growth Substances; Humans; In Situ Hybridization; Intramolecular Oxidoreductases; Lipocalins; Lung; Male; Mice; Mice, Inbred C57BL; Prostaglandin D2; Retroviridae; Survival Rate

Biochemical assessment of liver damage during ethanol-induced stress was done by measuring the activities of serum enzymes, viz., aspartate transaminase (AST) and alkaline phosphatase (ALP), which were significantly elevated in rats fed ethanol. Ethanol administration for a period of 60 days modifies the fatty acid composition, and the analysis of fatty acids showed that there was a significant increase in the concentrations of palmitic acid (16:0), stearic acid (18:0), and oleic acid (18:1) in liver, kidney, and brain, whereas the concentrations of palmitoleic (16:1) and arachidonic acid (20:4) were significantly decreased. The breakdown products of arachidonic acids (20:4), prostaglandins, were elevated. The antioxidants curcumin and N-acetylcysteine (NAC) decreased the activities of serum AST and ALP. Curcumin and NAC decreased the concentrations of fatty acids, viz., palmitic, stearic, and oleic acid, whereas arachidonic acid and palmitoleic acid were elevated. The prostaglandin concentrations were also decreased after curcumin and N-acetylcysteine treatment. Thus the present investigation shows that curcumin and N-acetylcysteine prevent the fatty acid changes produced by ethanol and also reduce the inflammatory response of ethanol by reducing the level of prostaglandins.

Topics: Acetylcysteine; Alprostadil; Animals; Antioxidants; Arachidonic Acid; Body Weight; Brain; Central Nervous System Depressants; Curcumin; Dinoprost; Dinoprostone; Enzyme Inhibitors; Ethanol; Fatty Acids; Kidney; Liver; Male; Phospholipids; Prostaglandin D2; Rats; Rats, Wistar

Prostaglandin E2 (PGE2) plays an important role in the maintenance of oral mucosal integrity. In this study, we characterized PGE2 receptor binding in the buccal mucosa of Syrian hamster and assessed the effect of nicotine (NC) and benzo (a) pyrene (BP), the two major ingredients in cigarette smoke, on this receptor. Adult male animals were treated for 4 weeks by apical swabbing of the buccal pouch with corn oil (control, C), 1 mM NC, BP, or NC + BP in corn oil, twice a day, 5 days a week. The results obtained with the untreated group revealed the presence of a specific PGE2 receptor consisting of two binding sites (high affinity with Kd = 1.52 nM and Bmax = 37 fmol/mg protein and low affinity with Kd = 813 nM and Bmax = 1.29 pmol/mg protein). The treatment with NC, BP, and NC + BP caused a significant decrease in PGE2 receptor binding (specific binding: 10.20 +/- 0.42, 6.84 +/- 1.32**, 6.58 +/- 0.67** and 5.88 +/- 1.03** fmol/mg protein; C, NC, BP, and NC+BP, respectively; Mean +/- SD, n = 5, **p < 0.01). The data suggest that decreased receptor binding for PGE2 in the buccal mucosa may be the cause for the adverse effect of cigarette smoke on the health of oral mucosa.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Topical; Animals; Benzo(a)pyrene; Binding, Competitive; Body Weight; Cheek; Cricetinae; Dinoprostone; Epoprostenol; Male; Mesocricetus; Mouth Mucosa; Nicotine; Organ Size; Prostaglandin D2; Receptors, Prostaglandin E

We investigated the effects of prostaglandins (PG) E1, I2 and D2 on the pulmonary vascular bed of newborn rats subjected to chronic hypoxia. Forty seven newborn rats were exposed to chronic hypoxia (10% oxygen) for 23 days and divided into five groups which received PGE1 (N = 10), PGI2 (N = 9), PGD2 (N = 11), placebo (N = 9) or served as controls (N = 8). The PG's were administered by implanting slow release subcutaneous pellets delivering an average daily dose of 1 microgram. Thirteen newborn rats in room air received either placebo or served as controls. All rats were killed after 23 days and heart-lung preparations were perfusion fixed with glutaraldehyde. Appropriate blocks were processed for quantitative morphometry of the pulmonary parenchyma, arteries and arterioles. For analysis the pulmonary vessels were grouped by external diameter, i.e. 30-50 mu and 50-100 mu. External diameter/lumen diameter, an index of medial smooth muscle mass, was 1.39 +/- 0.02 in room air controls, this index of medial muscle mass was significantly increased (p less than 0.01) to 1.53 +/- 0.03 in hypoxic controls and the PGD2 and PGI2 groups. However, the PGE1 group did not have medial hypertrophy evidenced by a medial muscle mass index of 1.34 +/- 0.04, similar to room air controls. These findings suggest that PGE1 may prevent the development of medial hypertrophy that occurs in chronic hypoxia.

Topics: Alprostadil; Animals; Animals, Newborn; Arterioles; Body Weight; Chronic Disease; Epoprostenol; Female; Hematocrit; Hypoxia; Lung; Prostaglandin D2; Prostaglandins D; Pulmonary Artery; Pulmonary Veins; Rats; Rats, Inbred Strains; Vasodilator Agents