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PubMed1999

Prediction of clearance, volume of distribution and half-life by allometric scaling and by use of plasma concentrations predicted from pharmacokinetic constants: a comparative study.

Pharmacokinetic parameters (clearance, CL, volume of distribution in the central compartment, VdC, and elimination half-life, t1/2beta) predicted by an empirical allometric approach have been compared with parameters predicted from plasma concentrations calculated by use of the pharmacokinetic constants A, B, alpha and beta, where A and B are the intercepts on the Y axis of the plot of plasma concentration against time and alpha and beta are the rate constants, both pairs of constants being for the distribution and elimination phases, respectively. The pharmacokinetic parameters of cefpiramide, actisomide, troglitazone, procaterol, moxalactam and ciprofloxacin were scaled from animal data obtained from the literature. Three methods were used to generate plots for the prediction of clearance in man: dependence of clearance on body weight (simple allometric equation); dependence of the product of clearance and maximum life-span potential (MLP) on body weight; and dependence of the product of clearance and brain weight on body weight. Plasma concentrations of the drugs were predicted in man by use of A, B, alpha and beta obtained from animal data. The predicted plasma concentrations were then used to calculate CL, VdC and t1/2beta. The pharmacokinetic parameters predicted by use of both approaches were compared with measured values. The results indicate that simple allometry did not predict clearance satisfactorily for actisomide, troglitazone, procaterol and ciprofloxacin. Use of MLP or the product of clearance and brain weight improved the prediction of clearance for these four drugs. Except for troglitazone, VdC and t1/2beta predicted for man by use of the allometric approach were comparable with measured values for the drugs studied. CL, VdC and t1/2beta predicted by use of pharmacokinetic constants were comparable with values predicted by simple allometry. Thus, if simple allometry failed to predict clearance of a drug, so did the pharmacokinetic constant approach (except for actisomide). The results of this study indicate that caution should be employed in interpreting plasma concentrations predicted for a drug in man by use of pharmacokinetic constants obtained in animals.

Animals↗
PubMed2006

What has prevented the expansion of insulin sensitisers?

The ability to improve insulin sensitivity with synthetic compounds was uncovered by empirical discoveries by Takeda in the late 1970s. The potential of a class of thiazolidinediones for the treatment of Type 2 diabetes, by decreasing glucose and triglycerides alongside lowering circulating insulin, was made public during the 1980s. As the first of the chemicals (pioglitazone, troglitazone and rosliglitazone) proceeded to clinical trials, these observations were soon extended to demonstrate a rich and complex pharmacology. The promise of this mode of action included prevention of diabetes as well as making a significant impact on the incidence and severity of the life-shortening consequences of the established disease. There are now two of these drugs on the market: pioglitazone and rosiglitazone, and they are being used to treat significant numbers of diabetic patients. However, the use of these drugs and development of future generations of successful candidates has not met the expectations that were held out in the early 1980s. This can be attributed to two major prevailing conditions. Troglitazone became the first thiazolidinedione to be approved as a result of delays in the development of pioglitazone. Unfortunately, troglitazone produced a unique idiosyncratic and sometimes fatal, hepatoxicity that necessitated its removal from the marketplace; second, there has been an incomplete understanding of the biochemical mechanism of action of these drugs that has slowed (and perhaps derailed) attempts to produce second-generation compounds. The latter issue is the subject of this editorial, which suggests that it is time to take a fresh look at the pharmacology of insulin sensitisers.

Diabetes Mellitus, Type 2↗
PubMed1997

Mechanisms and clinical effects of thiazolidinediones.

Studies of pioglitazone, troglitazone, BRL 49653 and other thiazolidinediones in preclinical animal models of non-insulin dependent diabetes mellitus (NIDDM) and obesity led to the observation that these compounds were effective in reducing hyperglycaemia and hyperlipidaemia. In these models, animals treated with thiazolidinediones had notable improvements in blood glucose levels, hepatic glucose output, peripheral insulin resistance, and serum lipid levels. Mechanistic studies indicate that thiazolidinediones act at many intracellular sites and can influence several processes to increase cell sensitivity to insulin. These include influence on insulin receptor kinase activity, control of insulin receptor phosphorylation, change in number of insulin receptors, quantity and activity of GLUT-4, modulation of tumour necrosis factor (TNF) activity, activation of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and alteration of hepatic glucose metabolism. Available data on pioglitazone and troglitazone from clinical studies support the efficacy and safety of this class of compounds in reducing hyperglycaemia, hypertriglyceridaemia and insulin resistance associated with NIDDM. Currently, only troglitazone is approved for use in the United States and only in combination with insulin. This new pharmacological class of drugs has great promise for the treatment of NIDDM and also as a valuable research tool to further the understanding of the mechanisms that underlie NIDDM and insulin resistance syndrome.

Journal Article↗
PubMed2006

Beyond peroxisome proliferator-activated receptor gamma signaling: the multi-facets of the antitumor effect of thiazolidinediones.

Certain members of the thiazolidinedione (TZD) family of the peroxisome proliferator-activated receptor gamma (PPARgamma) agonists, such as troglitazone and ciglitazone, exhibit antitumor activities; however, the underlying mechanism remains inconclusive. Substantial evidence suggests that the antiproliferative effect of these TZD members in cancer cells is independent of PPARgamma activation. To discern the role of PPARgamma in the antitumor effects of TZDs, we have synthesized PPARgamma-inactive TZD analogs which, although devoid of PPARgamma activity, retain the ability to induce apoptosis with a potency equal to that of their parental TZDs in cancer cell lines with varying PPARgamma expression status. Mechanistic studies from this and other laboratories have further suggested that troglitazone and ciglitazone mediate antiproliferative effects through a complexity of PPARgamma-independent mechanisms. Evidence indicates that troglitazone and ciglitazone block BH3 domain-mediated interactions between the anti apoptotic Bcl-2 (B-cell leukemia/lymphoma 2) members Bcl-2/Bcl-xL and proapoptotic Bcl-2 members. Moreover, these TZDs facilitate the degradation of cyclin D1 and caspase-8-related FADD-like IL-l-converting enzyme (FLICE)-inhibitory protein through proteasome-mediated proteolysis, and down-regulate the gene expression of prostate-specific antigen gene expression by inhibiting androgen activation of the androgen response elements in the promoter region. More importantly, dissociation of the effects of TZDs on apoptosis from their original pharmacological activity (i.e. PPARgamma activation) provides a molecular basis for the exploitation of these compounds to develop different types of molecularly targeted anticancer agents. These TZD-derived novel therapeutic agents, alone or in combination with other anticancer drugs, have translational relevance in fostering effective strategies for cancer treatment.

Antineoplastic Agents↗
PubMed1999

In vivo prevention of hyperglycemia also prevents glucotoxic effects on PDX-1 and insulin gene expression.

Chronic exposure of pancreatic islet beta-cell lines to supraphysiologic glucose concentrations causes defects in insulin gene expression and insulin secretion. To determine whether these in vitro phenomena have pathophysiologic relevance in vivo, we studied the Zucker diabetic fatty (ZDF) rat, an animal model of type 2 diabetes. The ZDF animals had relatively higher levels of glycemia and islet insulin mRNA at 6 weeks of age than age-matched Zucker lean control (ZLC) rats. As glycemia increased in 12- and 16-week-old ZDF rats, we observed decrements in glucose-induced insulin secretion during static incubations of pancreatic islets and in insulin mRNA levels, PDX-1 mRNA levels, and PDX-1 protein binding to the insulin promoter compared with age-matched ZLC rats and 6-week-old ZDF rats. To determine whether normalization of blood glucose levels would prevent these defects, ZDF rats were treated with troglitazone beginning at 6 weeks of age. Troglitazone prevented ZDF rats from becoming hyperglycemic and preserved glucose-induced insulin responses. Furthermore, troglitazone-treated ZDF animals had greater levels of insulin and PDX-1 mRNAs compared with untreated ZDF animals of the same ages at 12 and 16 weeks. Our results demonstrate that chronic and progressive hyperglycemia resulting from type 2 diabetes in ZDF rats is associated with loss of insulin and PDX-1 mRNAs and loss of glucose-stimulated insulin secretion. Prevention of hyperglycemia prevented the associated defects in insulin and PDX-1 gene expression and improved insulin secretion. These findings provide the first in vivo evidence that prevention of progressive hyperglycemia in a model of type 2 diabetes preserves insulin and PDX-1 gene expression.

Animals↗
PubMed1999

Promising new approaches.

Insulin resistance in liver and muscle tissue, together with beta-cell secretory defects, leads to overt type 2 diabetes mellitus. In the early stages of this progressive disorder, glycaemic control can be established through diet and exercise alone. Indeed, in some patients, marked weight reduction can lead to normalized fasting blood glucose. As a consequence, pharmacological approaches to weight loss have been investigated as a new option for the management of type 2 diabetes in obese patients. The serotonin- and noradrenaline-reuptake inhibitor sibutramine has emerged as the most promising agent in the treatment of obesity, although it appears to be less effective in diabetic patients than in non-diabetic patients. Other weight-reducing agents of potential benefit include noradrenergic anorexiants, orlistat, leptin, and beta3-agonists. Insulin and insulin secretagogues, the oldest available antidiabetic drugs, have been used to compensate for beta-cell secretory defects in patients with type 2 diabetes. Repaglinide, a new, fast-acting insulin secretagogue with a short duration of action, reduces postprandial hyperglycaemia when taken shortly before meals. Other novel antidiabetic agents are currently under development, including pramlintide (an amylin analogue) and glucagon-like peptide. Pramlintide slows gastric emptying and delays glucose absorption, and glucagon-like peptide is the most potent endogenous stimulator of glucose-induced insulin release. Recent advances in type 2 diabetes therapy have seen the development of the thiazolidinediones (troglitazone, rosiglitazone, and pioglitazone), which improve insulin resistance in patients whose diabetes is poorly controlled by diet and exercise therapy. Thiazolidinediones bind to peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and act through a process involving gene regulation at a transcriptional level. Troglitazone, the first approved drug in the class, has been shown to decrease plasma glucose levels as monotherapy but is more effective in combination with sulphonylureas, metformin, or insulin. However, despite its generally good safety profile, troglitazone has been associated with severe idiosyncratic hepatocellular injury. There have been more than 150 spontaneous reports of serious hepatic events, including at least 25 instances in which patients died or required a liver transplant. Rosiglitazone, the most potent thiazolidinedione, is still in clinical development, as is pioglitazone. To date, rosiglitazone has been shown to have no reported cases of idiosyncratic drug reactions leading to jaundice or liver failure and no clinically significant drug interactions with cytochrome P450 3A4-metabolized drugs such as nifedipine. Although the available data for pioglitazone are limited to the results of short-term studies, it is reported to be safe and well tolerated. Combination therapy is increasingly important in type 2 diabetes management following failure of monotherapy because complementary mechanisms of action of the different classes of oral agents demonstrate synergistic effects when used in combination. Oral agents may also be used as adjuncts to insulin for achieving glycaemic control.

Blood Glucose↗
PubMed2005

[Roles of PPARs in carcinogenesis].

Peroxisome proliferator activated receptors (PPARs) is known to be expressed in several cancers, but their roles on carcinogenesis has not been confirmed. PPARalpha and delta have not been defined whether as an accelerator or an inhibitor, but now PPARgamma is thought as an inhibitor on carcinogenesis. Therefore, we attempted to elucidate the role of PPARgamma in gastric carcinogenesis and explore the possibility of using PPARgamma ligand as chemopreventive agent for gastric cancer with PPARgamma knockout mice. The present study demonstrated that PPARgamma suppresses gastric carcinogenesis, the PPARgamma ligand troglitazone is a potential chemopreventive agent for gastric carcinogenesis, and troglitazone's chemopreventive effect is dependent on PPARgamma. Unfortunately, thiazolidinediones such as troglitazone has side effects, including edema at the high dose of administration. So we expect the development of new PPARgamma ligands, which are more selective and powerful for PPARgamma, to break through the difficulties of PPARgamma ligands' use clinically.

Animals↗
PubMed1997

High glucose-induced growth factor resistance in human fibroblasts can be reversed by antioxidants and protein kinase C-inhibitors.

We have studied the influence of high glucose on basal fibroblast proliferation, growth factor induced cellular proliferation and the effects of antioxidants, protein kinase C-inhibitors and troglitazone. Fibroblast cultures were obtained from five patients undergoing mammary reduction plastic surgery. A fluorometric method was used for determining total DNA in the cell samples, DNA content being proportional to cell number. D-Glucose at 15.5 mM and above was shown to inhibit fibroblast proliferation, and the cells were resistant to growth factors such as IGF-I and EGF at this glucose concentration. H7, bisindolylmaleimide IX, troglitazone, alpha-tocopherol acetate, Q10, ascorbic acid, beta-carotene, DMTU and selenite were all found to reverse the high glucose-induced growth factor resistance observed in human fibroblasts. We believe that these findings may be of value in the understanding and future treatment of wound healing in diabetic foot ulcers.

Antioxidants↗
PubMed2001

PPARgamma agonists inhibit cell growth and suppress the expression of cyclin D1 and EGF-like growth factors in ras-transformed rat intestinal epithelial cells.

Peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits the growth of several types of cancer cells. However, the mechanisms by which this occurs are poorly understood. The goal of the present study was to investigate the effects of PPARgamma on mutated ras-induced cell growth, activation of transcription factors and expression of genes associated with cellular transformation in rat intestinal epithelial cells. A human PPARgamma cDNA was introduced to the activated H-ras-transfected IEC-6 cells (IECras) and 1 clone (IECrasPR82) that stably expresses both activated ras and PPARgamma was obtained. Thiazolidinedione derivatives such as troglitazone and rosiglitazone, selective ligands for PPARgamma, inhibited the cellular growth of IECrasPR82 cells in a time-dependent manner and induced G1 cell cycle arrest. Treatment with troglitazone (20 microM) decreased the expression of cyclin D1, heparin-binding epidermal growth factor-like growth factor (HB-EGF) and amphiregulin and suppressed the promoter activities of cyclin D1 and HB-EGF. Furthermore, a luciferase assay and an electrophoretic mobility shift assay showed that thiazolidinedione derivatives suppressed the transcriptional activities of AP-1 and Ets, both of which play crucial roles in the expression of cyclin D1 and HB-EGF. These findings suggest that reduction of EGF-like growth factors and cyclin D1 through the suppression of AP-1 and Ets may be 1 mechanism whereby PPARgamma inhibits their growth.

Animals↗
PubMed2000

Peroxisome proliferator-activated receptor-gamma agonists increase vascular endothelial growth factor expression in human vascular smooth muscle cells.

Vascular endothelial growth factor (VEGF), expressed in a variety of mesenchymal cells including vascular smooth muscle cells (VSMC), is a potent mitogen for endothelial cells, and is used clinically applied for ischemic disease of peripheral vessels. To determine whether peroxisome proliferator-activated receptor gamma (PPARgamma) regulates VEGF production in VSMC, we examined VEGF secretion from VSMC treated with PPAR agonists. Troglitazone increased VEGF secretion in a time- and dose-dependent manner (261 +/- 35% with 25 mM of troglitazone for 24 h), and also increased levels of VEGF mRNA. VEGF secretion was also increased by other PPARgamma agonists, pioglitazone, LY171883, and 15d-PGJ2 (224 +/- 17.1%, 247 +/- 36.8% and 171 +/- 7.8%, respectively), but not the PPARgamma agonists bezafibrate and Wy14643 (85.2 +/- 1.5%, 94.6 +/- 3.2, respectively). Our findings suggest that thiazolidinediones might be useful for the therapeutic angiogenesis for ischemic artery disease.

Acetophenones↗
PubMed2005

Regulation of adiponectin receptor 1 in human hepatocytes by agonists of nuclear receptors.

The adiponectin receptors AdipoR1 and AdipoR2 have been identified to mediate the insulin-sensitizing effects of adiponectin. Although AdipoR2 was suggested to be the main receptor for this adipokine in hepatocytes, AdipoR1 protein is highly abundant in primary human hepatocytes and hepatocytic cell lines. Nuclear receptors are main regulators of lipid metabolism and activation of peroxisome proliferator-activated receptor alpha and gamma, retinoid X receptor (RXR), and liver X receptor (LXR) by specific ligands may influence AdipoR1 abundance. AdipoR1 protein is neither altered by RXR or LXR agonists nor by pioglitazone. In contrast, fenofibric acid reduces AdipoR1 whereas hepatotoxic troglitazone upregulates AdipoR1 protein in HepG2 cells. Taken together this work shows for the first time that AdipoR1 protein is expressed in human hepatocytes but that it is not a direct target gene of nuclear receptors. Elevated AdipoR1 induced by hepatotoxic troglitazone may indicate a role of this receptor in adiponectin-mediated beneficial effects in liver damage.

Adiponectin↗
PubMed2006

AMPK regulation of the growth of cultured human keratinocytes.

AMP kinase (AMPK) is a fuel sensing enzyme that responds to cellular energy depletion by increasing processes that generate ATP and inhibiting others that require ATP but are not acutely necessary for survival. In the present study, we examined the relationship between AMPK activation and the growth (proliferation) of cultured human keratinocytes and assessed whether the inhibition of keratinocyte growth by vitamin D involves AMPK activation. In addition, we explored whether the inhibition of keratinocyte proliferation as they approach confluence could be AMPK-related. Keratinocytes were incubated for 12 h with the AMPK activator, 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR). At concentrations of 10(-4) and 10(-3) M, AICAR inhibited keratinocyte growth by 50% and 95%, respectively, based on measurements of thymidine incorporation into DNA. It also increased AMPK and acetyl CoA carboxylase phosphorylation (P-AMPK and P-ACC) and decreased the concentration of malonyl CoA confirming that AMPK activation had occurred. Incubation with the thiazolidinedione, troglitazone (10(-6) M) caused similar alterations in P-AMPK, P-ACC, and cell growth. In contrast, the well known inhibition of keratinocyte growth by 1,25-dihydroxyvitamin D3 (10(-7) and 10(-6) M) was not associated with changes in P-AMPK or P-ACC. Like most cells, the growth of keratinocytes diminished as they approached confluence. Thus, it was of note that we found a progressive increase in P-AMPK (1.5- to 2-fold, p < 0.05) as keratinocytes grown in control medium went from 25% to 100% confluence. In conclusion, the data are consistent with the hypothesis that activation of AMPK acts as a signal to diminish the proliferation of cultured keratinocytes as they approach confluence. They also suggest that AMPK activators, such as AICAR and troglitazone, inhibit keratinocyte growth and that the inhibition of cell growth by 1,25-dihydroxyvitamin D3 is AMPK-independent.

AMP-Activated Protein Kinases↗
PubMed2006

Different roles of protein kinase C-betaI and -delta in the regulation of adipocyte differentiation.

Protein kinase C (PKC) is a member of serine/threonine protein kinase family that plays important roles in the control of vast variety of cellular functions. Nevertheless, the regulatory effect of PKC on adipogenesis remained not well understood. In this study, we investigated the effect of several PKC isoforms on the adipogenic conversion of 3T3-L1 preadipocytes induced by dexamethasone, isobutylmethylxanthine and insulin. Treatment of cells with broad-spectrum PKC inhibitor Rö318220 suppressed the adipogenesis. Gö6976, a selective inhibitor for PKC isoforms-alpha, -betaI and -mu, also inhibited the adipogenesis of cells. Pretreatment of cells with peroxisomal proliferator activated receptor-gamma (PPARgamma) agonist troglitazone abolished the inhibitory effect of Gö6976 on adipogenesis. The plasmic membrane translocation of PKC-betaI was observed at the first 2 days of differentiation. Whereas no translocation of PKC-alpha and -mu was observed. Overexpression of dominant negative PKC-betaI, but not wild-type PKC-betaI, blocked adipogenesis. This effect of dominant negative PKC-betaI can be reversed by troglitazone, suggesting that PKC-betaI is required for the initiation of adipogenesis. In addition, rottlerin, a specific inhibitor of PKC-delta, can reverse the suppression of adipogenesis mediated by 12-O-tetradecanoyl-phorbol-13-acetate, transforming growth factor-beta1, and epidermal growth factor. These data suggest that PKC-betaI is important in the induction of adipogenesis, while the PKC-delta has an inhibitory role for adipogenesis.

3T3-L1 Cells↗
PubMed2005

Pivotal role of peroxisome proliferator-activated receptor gamma (PPARgamma) in regulation of erythroid progenitor cell proliferation and differentiation.

OBJECTIVE: The aim of this study was to reveal the role of peroxisome proliferator-activated receptor gamma (PPARgamma) in erythropoiesis. METHODS: The effects of PPARgamma ligands on cellular proliferation and differentiation were investigated in erythroid colony-forming cells (ECFCs) purified from human peripheral blood. RESULTS: RT-PCR analysis revealed that PPARgamma mRNA is expressed in ECFCs. Synthetic PPARgamma ligands, troglitazone or pioglitazone, suppressed cellular proliferation without inducing apoptosis and delayed maturation of ECFCs, as determined by flow cytometry. The delay in erythroid maturation by troglitazone was confirmed by the down-regulation of gamma-globin, beta-globin and GATA-1 mRNA, and the maintenance of GATA-2 mRNA. CONCLUSIONS: Our results suggest that PPARgamma modulates the differentiation process of erythroid progenitor cells, and plays a crucial role in regulating the balance of hematopoiesis.

Antineoplastic Agents↗
PubMedDate not supplied

Anti-inflammatory effects of PPAR-gamma agonists directly correlate with PPAR-gamma expression during acute pancreatitis.

Peroxisome proliferator-activated receptors (PPARs) are ligand-inducible transcription factors that regulate cellular energy and lipid metabolism. PPAR-gamma agonists also have potent anti-inflammatory properties through down-regulation of early inflammatory response genes. The role of PPAR-gamma in acute pancreatitis has not been adequately examined. In this study, we determined the effect of PPAR-gamma agonists on the severity of pancreatitis and sought to correlate PPAR-gamma expression in pancreatic acinar cells and the severity of acute pancreatitis in vivo. Acute pancreatitis was induced in mice by hyperstimulation with the cholecystokinin analog, cerulein. PPAR-gamma agonists were administered by intraperitoneal injection 15-30 minutes before induction of pancreatitis (pretreatment) or at various times after induction of pancreatitis (treatment). Pancreata and serum were harvested over the course of 24 hours. Serum amylase activity and glucose levels were measured. Pancreata were used for histological evaluation as well as protein and mRNA analysis. Pretreatment of mice with the PPAR-gamma agonists 15-deoxy-Delta12, 14-prostaglandin J(2), or troglitazone significantly reduced the severity of pancreatitis in a dose-dependent manner. This reduction was indicated by reduced serum amylase activity and histological damage (leukocyte infiltration, vacuolization, and necrosis). Although cerulein decreased PPAR-gamma expression in the pancreas, pretreatment with agonists maintained PPAR-gamma expression early in acute pancreatitis. The expression of PPAR-gamma inversely correlated with pancreatitis severity and expression of the proinflammatory cytokines, interleukin-6, and tumor necrosis factor-alpha. Treatment with troglitazone after the induction of pancreatitis reduced serum amylase activity. The results suggest that PPAR-gamma plays a direct role in the inflammatory cascade during the early events of acute pancreatitis. Our data are the first to demonstrate that PPAR-gamma agonists represent a promising therapeutic strategy for acute pancreatitis.

Animals↗
PubMed2003

A novel peroxisome proliferator-activated receptor (PPAR)gamma agonist, NIP-222, reduces urinary albumin excretion in streptozotocin-diabetic mice independent of PPARgamma activation.

NIP-222 is a novel peroxisome proliferator-activated receptor (PPAR)gamma agonist. This study provides evidence that NIP-222 decreases urinary albumin excretion (UAE) in diabetic mice independent of its PPARgamma activation. We compared the effect of NIP-222 and another PPARgamma agonist, troglitazone, on UAE, plasma glucose level, blood pressure, and creatinine clearance (C(cr)) in streptozotocin (STZ)-induced diabetic mice. Treatment for 3 weeks with NIP-222 (30 mg/kg) was associated with a significant decrease in UAE without any change in blood pressure, creatinine clearance, or plasma glucose level. In contrast, UAE did not decrease in mice treated with troglitazone (300 mg/kg). These results indicate that NIP-222 has PPARgamma independent effects on UAE in diabetic mice and suggest that this agent may have potential to minimize the development and progression of diabetic nephropathy.

Albuminuria↗
PubMedDate not supplied

Effect of nuclear factor-kappa B inhibitors and peroxisome proliferator-activated receptor-gamma ligands on PTHrP release from human fetal membranes.

Parathyroid hormone-related protein (PTHrP) has been implicated in many processes during normal and pathological pregnancies. In the human fetal membranes, PTHrP exhibits cytokine-like actions. We have recently shown that inhibitors of the nuclear factor-kappa B (NF-kappaB) and activators of the peroxisome proliferator-activated receptor (PPAR)-gamma signalling pathways down-regulate cytokine release from human gestational tissues. Therefore, the aim of this study was to determine whether NF-kappaB and PPAR-gamma also regulate PTHrP release from human fetal membranes. Human amnion and choriodecidua explants were incubated in the absence (control) or presence of two known NF-kappaB inhibitors (1, 5 and 10 mM sulphasalazine (SASP) or 5, 10 and 15 mM N-acetyl-cysteine (NAC)), and two PPAR-gamma ligands (15 and 30 microM 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) or 15 and 30 microM troglitazone), under basal conditions. After 18 h incubation, the tissues were collected and NF-kappaB p65 DNA binding activity in nuclear extracts was assessed by ELISA, and the incubation medium was collected and the release of PTHrP was quantified by RIA. Treatment of amnion and choriodecidual tissues with SASP concentrations greater than 5 mM, 15 mM NAC, 30 microM 15d-PGJ(2) and 30 microM troglitazone significantly reduced the release of PTHrP (p < 0.05). This study demonstrates that PTHrP release from human fetal membranes is regulated by inhibitors of NF-kappaB, and ligands of PPAR-gamma.

Acetylcysteine↗
PubMed2004

Peroxisome proliferator-activated receptor gamma is expressed in hippocampal neurons and its activation prevents beta-amyloid neurodegeneration: role of Wnt signaling.

The molecular pathogenesis of Alzheimer's disease (AD) involves the participation of the amyloid-beta-peptide (A beta), which plays a critical role in the neurodegeneration that triggers the disease. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors, which are members of the nuclear receptor family. We report here that (1) PPAR gamma is present in rat hippocampal neurons in culture. (2) Activation of PPAR gamma by troglitazone and rosiglitazone protects rat hippocampal neurons against A beta-induced neurodegeneration, as shown by the 3-[4,5 -2yl]-2,5-diphenyltetrazolium bromide (MTT) reduction assay, immunofluorescence using an anti-heavy neurofilament antibody, and quantitative electron microscopy. (3) Hippocampal neurons treated with several PPAR gamma agonists, including troglitazone, rosiglitazone, and ciglitazone, prevent the excitotoxic A beta-induced rise in bulk-free Ca2+. (4) PPAR gamma activation results in the modulation of Wnt signaling components, including the inhibition of glycogen synthase kinase-3beta (GSK-3beta) and an increase of the cytoplasmic and nuclear beta-catenin levels. We conclude that the activation of PPAR gamma prevents A beta-induced neurodegeneration by a mechanism that may involve a cross talk between neuronal PPAR gamma and the Wnt signaling pathway. More important, the fact that the activation of PPAR gamma attenuated A beta-dependent neurodegeneration opens the possibility to fight AD from a new therapeutic perspective.

Amyloid beta-Peptides↗