Combination Of Rosiglitazone Research Articles

Low-Dose Combination Therapy With Rosiglitazone And Metformin to Prevent Type 2 Diabetes Mellitus (CANOE Trial): A Double-Blind Randomized Controlled Study

Several drug regimens have demonstrated effectiveness in reducing the development of type 2 diabetes mellitus in patients with impaired glucose tolerance (IGT). Their adoption has been slow because of concern with adverse effects and long-term safety. Monotherapy with the thiazolidinedione rosiglitazone effectively reduces the risk of type 2 diabetes, but recommended maximum doses are associated with an increased risk of adverse outcomes, including, weight gain and increased risk of congestive heart failure. Metformin, a commonly used oral hypoglycaemic, is also effective therapy for type 2 diabetes; its use has been associated with substantial gastrointestinal side effects, even at submaximum doses. The Canadian Normoglycemia Outcomes Evaluation trial was a double-blind, randomized controlled study that investigated whether combination therapy with half the maximum dose of rosiglitazone and metformin would prevent type 2 diabetes in patients with IGT. A total of 207 patients with IGT were randomly assigned to receive twice daily a combination of rosiglitazone 2 mg and metformin 500 mg (n = 103) or a matching placebo (n = 104) for a median of 3.9 years. All patients and investigators were masked as to treatment allocation. The primary study outcome was the development of new onset type 2 diabetes diagnosed either by 2 fasting plasma glucose values of ≥7.0 mmol/L or an oral glucose tolerance test. Complete vital status was available for 96% (198/207) of the participants. Compliance was similar in the 2 groups: 78% of the treatment group and 81% in the placebo group (P = 0.60). Significantly fewer patients in the treatment group (n = 14 [14%]) than in the placebo group (n = 41 [39%]) developed incident diabetes (P < 0.0001). The relative risk reduction was 66%, with a 95% confidence interval (CI) of 41 to 80. Based on the absolute relative risk of 26% (95% CI, 14–37), the number needed to treat was calculated to be 4 (95% CI, 2.70–7.14). By the end of the study, a significantly greater proportion of patients in the treatment group than in the placebo had regressed to normal glucose tolerance (treatment group: 79.6% vs. placebo: 53.1%, P = 0.0002). Moreover, by the study end, insulin sensitivity had decreased by a greater extent in the placebo group (median, −1.24; interquartile range [IQR], −2.38 to −0.08) compared to the treatment group which had remained unchanged (median, −0.39; IQR, −1.30 to 0.84; P = 0.0006 between groups). There was no significant change in β-cell function (measured by the insulin secretion-sensitivity index-2) between groups (placebo: median, −252.3; IQR, −382.2 to −58.0 vs. treatment group: median, −221.8; IQR, −330.4 to −87.8; P = 0.28 between groups). More diarrhea was noted among patients in the treatment group than those in the placebo (16% vs. 6%, P = 0.025). These findings demonstrate that combining half the maximum dose of rosiglitazone with metformin is effective in preventing type 2 diabetes in patients with IGT and appears to be safe, with few clinically relevant adverse events.

Treatment of type 2 diabetes: New clinical studies and effects of GLP-1 on macrovascular complications

Various publications in 2009 showed that the treatment of type 2 diabetic (T2D) patients with macrovascular complications is still a controversial subject, whether with regard to the use of glitazones, to the best management strategy for T2D patients with stable coronary artery disease or to the use of incretin mimetic drugs in patients with heart disease. The Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycemia in Diabetes study (RECORD) compared cardiovascular morbidity-mortality outcomes in patients taking rosiglitazone in combination with metformin or sulfonylurea versus metformin with sulfonylurea. The results showed that rosiglitazone was not inferior to the metformin-sulfonylurea combination in terms of mortality and cardiovascular hospitalization, but caution must be used when interpreting the results, as the event rate was low. The BARI 2D study (Bypass Angioplasty Revascularization Investigation 2 Diabetes) is a cardiovascular morbidity-mortality trial with the goal of determining the best strategy for blood glucose control and revascularization in T2D patients with stable coronary artery disease. The results of this trial showed that early revascularization is not clearly beneficial, except in a subgroup of patients in whom surgical revascularization is indicated. The use of GLP-1 analogs (Glucagon-Like Peptide-1) in the acute phase of myocardial ischemia in animal models provided promising results. Some clinical studies also suggest an improvement in cardiovascular risk factors with these treatments. Results from morbidity-mortality studies are needed to better assess the long-term efficiency of these new drugs.

A systems biology approach to identify effective cocktail drugs.

BackgroundComplex diseases, such as Type 2 Diabetes, are generally caused by multiple factors, which hamper effective drug discovery. To combat these diseases, combination regimens or combination drugs provide an alternative way, and are becoming the standard of treatment for complex diseases. However, most of existing combination drugs are developed based on clinical experience or test-and-trial strategy, which are not only time consuming but also expensive.ResultsIn this paper, we presented a novel network-based systems biology approach to identify effective drug combinations by exploiting high throughput data. We assumed that a subnetwork or pathway will be affected in the networked cellular system after a drug is administrated. Therefore, the affected subnetwork can be used to assess the drug's overall effect, and thereby help to identify effective drug combinations by comparing the subnetworks affected by individual drugs with that by the combination drug. In this work, we first constructed a molecular interaction network by integrating protein interactions, protein-DNA interactions, and signaling pathways. A new model was then developed to detect subnetworks affected by drugs. Furthermore, we proposed a new score to evaluate the overall effect of one drug by taking into account both efficacy and side-effects. As a pilot study we applied the proposed method to identify effective combinations of drugs used to treat Type 2 Diabetes. Our method detected the combination of Metformin and Rosiglitazone, which is actually Avandamet, a drug that has been successfully used to treat Type 2 Diabetes.ConclusionsThe results on real biological data demonstrate the effectiveness and efficiency of the proposed method, which can not only detect effective cocktail combination of drugs in an accurate manner but also significantly reduce expensive and tedious trial-and-error experiments.

Insights on distinct pathways of thiazolidinediones (PPARγ ligand)‐promoted apoptosis in TRAIL‐sensitive or ‐resistant malignant urothelial cells

Thiazolidinediones, including rosiglitazone and troglitazone, are insulin-sensitizing drugs and high-affinity ligands for the peroxisome proliferator-activated receptor gamma (PPARgamma). Apart from their antidiabetic activity, these molecules possess antitumor properties. We investigated their potential apoptotic effects on RT4 (derived from a well-differentiated Grade I papillary tumor) and T24 (derived from an undifferentiated Grade III carcinoma) bladder cancer cells. Rosiglitazone induced G2/M or G0/G1 phase cell cycle arrest in RT4 and T24 cells, respectively. Only troglitazone triggered apoptosis via extrinsic and intrinsic pathways in both cell lines. Interestingly, rosiglitazone amplified TRAIL-induced apoptosis in TRAIL-sensitive RT4 cells or let TRAIL-resistant T24 cells to respond to TRAIL. Thiazolidinediones acted through PPARgamma activation-independent mechanisms. The underlying mechanisms involved for the first time in cancer cells the upregulation of soluble and/or membrane-bound TRAIL. This was associated with increased cell surface death receptor 5 expression and c-FLIP and survivin downregulation, mediated in part through proteasome-dependent degradation in troglitazone-promoted cell death. Therefore, the combination of rosiglitazone and TRAIL could be clinically relevant as chemopreventive or therapeutic agents for the treatment of TRAIL-resistant high-grade urothelial cancers.

Benefits of fixed-doses combination for type 2 diabetes

With consideration of optimizing treatment of type 2 diabetes,early combination therapy has been deeply explored, with fixed-doses combination therapy as a available preparation for easier administration. Avandamet ( rosiglitazone maleate and metformin HC1) is widely used in clinical treatment, providing comprehensive and sustained long-term efficacy and confirmed safety with lower hypoglycemia risk, and also high convenience and compliance. Combination of rosiglitazone and metformin improves the dual core defects of type 2 diabetes, targeting FPG and PPG reduction through decreasing hepatic glucose output, and improving peripheral insulin resistance, especially increasing skeletal muscle's utilization of glucose respectively. Large-scale clinical trials gave more confidence to Avandamet. Recently, RECORD study indicated that rosiglitazone in combination with metformin achieved long-term antihyperglycemic efficacy in 5 years period, superior to sulphanylureas plus metformin. Additionally, lower risk of hypoglycemia is another benefit of Avandamet. In conclusion,early use of Avandamet can yield much more benefits than monotherapy and late administration, in consistent with implication of evidence-based trial, guideline, and clinical experiences. Key words: Metformin; Rosiglitazone; Fasting blood glucose; Postprandial blood glucose; Insulin resistence; Hypoglycemia

Prognosis of Pulmonary Arterial Hypertension

The study of rare diseases is limited by just that, their infrequency. Pulmonary arterial hypertension (PAH), for example, has a prevalence of 15 cases per million.1 Although there has been an explosion in knowledge of and therapies for this life-threatening disease over the past decade, most of our insight is based on small studies. The first therapy that was approved by the Food and Drug Administration in 1995, intravenous epoprostenol, was based on the results of an 81-patient trial.2 The most recently approved therapy, inhaled treprostinil, in 2009, was based on the results of a 235-patient trial.3 Similarly, our understanding of the natural history of this disease is based on small observational series. Articles see pp 156 and 164 To further our comprehension of rare diseases, we often turn to “registries,” constructed as multicenter cohorts of patients who have the disease with longitudinal follow-up. Despite the inherent limitations of their observational and uncontrolled nature, which also represent strengths, these cohorts are useful to describe and compare patient characteristics, practice patterns, and outcomes. Observations from such registries can generate hypotheses that subsequently form the basis of further studies. Lastly, such cohorts facilitate the study of the prognostic profile of the disease via the derivation and validation of clinical prediction tools. In this issue of Circulation , data from the 2 of the most important present-day registries in PAH give us the opportunity to better understand the prognosis of PAH, its determinants, and outcomes in the current treatment era. Humbert and colleagues4 share data from the French National Registry, in which 354 consecutive idiopathic, heritable, and anorexigen-associated patients with PAH were enrolled from October 2002 to October 2003. They report 1-, 2-, and 3-year survival rates of 82.9%, 67.1%, and 58.2%, respectively. Sadly, despite the many advances in …

The combination of sirolimus and rosiglitazone produces a renoprotective effect on diabetic kidney disease in rats

Aims Peroxisome proliferator-activated receptor-γ (PPAR-γ) agonists and mammalian target of rapamycin (mTOR) inhibitors share mechanisms concerning cell growth and reduction of extracellular matrix accumulation. The purpose of this study was to evaluate the potential synergistic effect of this combination on diabetic kidney disease in rats. Main methods Diabetes was induced by streptozotocin in 42 male Sprague–Dawley rats. Sixteen weeks after diabetes induction, animals were divided into four groups: diabetic animals without intervention (D), diabetic animals with administration of sirolimus (D + SRL), diabetic animals with administration of rosiglitazone (D + RGT), and diabetic animals with administration of sirolimus and rosiglitazone (D + SRL + RGT). Key findings At a 30-day follow up, diabetic rats showed higher kidney weight, mean glomerular volume, mesangial expansion and albuminuria compared with non-diabetic rats. mTOR downstream proteins, p-T389-S6K and p-T37/46-4EBP1, were higher in diabetic than non-diabetic kidneys, whereas p-S473-AKT was not, suggesting that hyperglycemia mainly activated the mTORC1 pathway in vivo. Moreover, the catalytic subunit of protein phosphatase 2A (PP2Ac) was down-regulated in the diabetic kidney. Sirolimus inhibited the mTORC1 pathway, while the PPAR-γ agonist rosiglitazone enhanced PP2Ac and reduced p70S6K. Both drugs were associated with a reduction in albuminuria, renal enlargement and mesangial expansion, but without any improvement in glycemic control. Sirolimus and rosiglitazone in combination down-regulated the mTORC1 pathway and over-activated PP2Ac in diabetic kidney. This effect may account for the synergistic reduction of renal hypertrophy, albuminuria and renal TGF-β1 observed in diabetic rats treated with SRL + RGT. Significance The combination of sirolimus and rosiglitazone is renoprotective with respect to diabetic nephropathy.

Paradoxical Severe Decrease in High-Density Lipoprotein Cholesterol Due to Rosiglitazone-Fenofibrate Interaction

To determine whether the marked decrease in high-density lipoprotein cholesterol (HDL-C) occasionally associated with combination fibrate-thiazolidinedione therapy results from interaction between the 2 drugs or is solely the result of fibrate administration, a previously recognized cause. We prospectively followed the clinical course of 2 patients receiving fenofibrate and rosiglitazone and reviewed the relevant literature, searching PubMed for reports describing striking reductions in HDL-C associated with fibrate administration alone and in conjunction with rosiglitazone and statins. Additional references were obtained from the bibliography of each identified article. Each of the 2 patients demonstrated a Drug Interaction Probability Score score of 9, indicating a highly probable likelihood of interaction. Critical review of all reported cases of concurrent fenofibrate-rosiglitazone-associated decreases in HDL-C failed to show conclusive evidence that the HDL-C decrease could be due to an interaction between the 2 drugs as opposed to either drug being given alone. In at least some patients who experience marked HDL-C decrease when given a combination of fenofibrate and rosiglitazone, this severe adverse effect is the result of a drug interaction between the 2 pharmaceutical agents and is not reproduced by the administration of either drug singly.

Regulation of Adipogenesis by Natural and Synthetic REV-ERB Ligands

The nuclear hormone receptor, REV-ERB, plays an essential role in adipogenesis. Rev-erbalpha expression is induced in 3T3-L1 cells during adipogenesis, and overexpression of this receptor leads to expression of adipogenic genes. We recently demonstrated that the porphyrin heme functions as a ligand for REV-ERB, and binding of heme is required for the receptor's activity. We therefore hypothesized that REV-ERB ligands may play a role in regulation of adipogenesis. We detected an increase intracellular heme levels during 3T3-L1 adipogenesis that correlated with induction of aminolevulinic acid synthase 1 (Alas1) expression, the rate-limiting enzyme in heme biosynthesis. If the increase in Alas1 expression was blocked, adipogenesis was severely attenuated, indicating that induction of expression of Alas1 and the increase in heme synthesis is critical for differentiation. Inhibition of heme synthesis during adipogenesis leads to decreased recruitment of nuclear receptor corepressor to the promoter of a REV-ERB target gene, suggesting alteration of REV-ERB activity. Treatment of 3T3-L1 cells with a synthetic REV-ERB ligand, SR6452, resulted in induction of adipocyte differentiation to a similar extent as treatment with the peroxisomal proliferator-activated receptor-gamma agonist, rosiglitazone. Combination of SR6452 and rosiglitazone had an additive effect on stimulation of adipocyte differentiation. These results suggest that heme, functioning as a REV-ERB ligand, is an important signaling molecule for induction of adipogenesis. Moreover, synthetic small molecule ligands for REV-ERB are effective modulators of adipogenesis and may be useful for treatment of metabolic diseases.

Abstract 5391: Rosiglitazone and Gemcitabine combination therapy limits tumor progression and prolongs survival in pancreatic adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer related mortality with a dismal 2-5% 5-year survival rate because clinically apparent disease is usually detected late in disease progression and lacks effective therapies. The current ‘standard of care’ for pancreatic cancer patients is Gemcitabine, a deoxycytidine analog, which has been shown to increase quality of life and the median survival of patients by a few weeks. Although Gemcitabine therapy limits pancreatic tumor progression, PDA is often insensitive to chemotherapeutic agents, limiting their success and underlining the need for additional therapies which would enhance the efficacy of current treatments. We investigated combinations of Gemcitabine with drugs that target both the growing tumor and the immunosuppressive inflammatory microenvironment. Inflammation accompanies tumor progression in pancreatic cancer which can support tumor cell survival and growth directly, enhance tumor cell resistance to Gemcitabine and limit anti-tumor immune responses through induction of immunosuppressive mechanisms. Rosiglitazone Maleate, an FDA-approved drug for the treatment of type II diabetes, targets the PPARγ receptor, a major modulator of the inflammatory response. Rosiglitazone has been shown to limit tumor growth through effects on angiogenesis, differentiation and apoptosis. Additionally, some evidence suggests that PPARγ may regulate multi-drug resistance and may therefore limit tumor chemoresistance. We found that Rosiglitazone enhanced the efficacy of Gemcitabine by reducing tumor proliferation, limiting invasiveness, and enhancing tumor cell apoptosis in vitro. Therapeutic combination of Rosiglitazone and Gemcitabine was evaluated in subcutaneous and orthotopic models of pancreatic cancer, and revealed that the combination significantly reduced tumor progression and metastasis, enhanced tumor cell apoptosis in vivo and significantly extended overall survival compared to Gemcitabine alone. Together these results provide pre-clinical data in support of combining Rosiglitazone and Gemcitabine as a clinical therapy for pancreatic adenocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5391.

The low dose combination of fenofibrate and rosiglitazone halts the progression of diabetes-induced experimental nephropathy

The present study investigated the combined effect of low doses of fenofibrate (PPAR-alpha agonist) and rosiglitazone (PPAR-gamma agonist) in diabetes-induced experimental nephropathy. Rats were administered streptozotocin (55 mg/kg i.p., once) to induce experimental diabetes mellitus. The development of diabetic nephropathy was assessed biochemically and histologically. In addition, the lipid profile and renal oxidative stress were assessed. The single administration of streptozotocin produced diabetes, which induced the renal oxidative stress, altered the lipid profile, and subsequently produced nephropathy in 8 weeks by elevating serum creatinine, blood urea nitrogen, proteinuria, and inducing glomerular damage. Treatment with low dose fenofibrate (30 mg/kg/day p.o.) normalizes the altered lipid profile in diabetic rats, whereas the low dose rosiglitazone (1mg/kg/day p.o.) treatment has no effect on lipid alteration in diabetic rats. Treatment with low dose rosiglitazone partially reduced the elevated glucose level in diabetic rats, whereas fenofibrate treatment has no effect on it. The low dose combination of fenofibrate and rosiglitazone was more effective in attenuating the diabetes-induced nephropathy and renal oxidative stress as compared to treatment with either drug alone or lisinopril (1mg/kg/day p.o., employed as a standard agent). It may be concluded that diabetes-induced oxidative stress and lipid alterations may be responsible for the induction of nephropathy in diabetic rats. The concurrent administration of fenofibrate and rosiglitazone at low doses may have prevented the development of diabetes-induced nephropathy by reducing the lipid alteration, decreasing the renal oxidative stress and certainly providing the direct nephroprotective action.

Site-specific modulation of white adipose tissue lipid metabolism by oleoyl-estrone and/or rosiglitazone in overweight rats

In spite of their shared decrease of insulin resistance, oleoyl-estrone [OE], and rosiglitazone show diverging effects on body fat mass and distribution. In this study, we studied whether their effects on white adipose tissue [WAT] were due to a shared or synergistic mechanism of action. Combined effects of OE and rosiglitazone 10-day treatment on WAT lipid, cell mass/number, and the expression of key lipid metabolism and regulatory agents were studied using an adult male overweight rat model. OE decreased WAT cell mass and lipids, parameters not changed by rosiglitazone. The effects of OE and--specially--rosiglitazone were more marked in small-cell WAT (i.e., mesenteric and subcutaneous sites) than in larger cell WAT (retroperitoneal and perigonadal). OE decreased the expressions in WAT of lipogenic enzymes, lipoprotein lipase, PPARs, and SREBP1c, effects symmetrically reversed by rosiglitazone. OE showed no effects on hormone-sensitive lipase expression, which was increased by rosiglitazone. OE strongly inhibited WAT lipogenesis, leaving lipolysis unchanged, thus unbalancing (and helping mobilize) WAT lipid stores. Rosiglitazone acted practically only on small-cell WAT sites, where it favored lipogenesis, but also stimulated lipolysis, which resulted in limited changes in lipid stores. Combination of OE and rosiglitazone induced less fat loss than OE alone.

Influence of combination of Rosiglitazone wtih Metformin/Glimepiride onErythropoeitic and germinal cell damages in male diabetic rats

Monotherapy of oral hypoglycemics in chronic diabetes rarely maintain the optimum glycemic control and is considered themajor cause for late onset complications. In this study combination of rosiglitazone (Rosi-0.2 mg/kg) with metformin (Met-50 mg/kg) or glimepiride (Gmp – 0.2 mg/kg) orally once daily for 4 weeks was tested against type 2 diabetes mellitus(T2DM) induced by nicotinamide (NA-230 mg/kg, i.p) and streptozotocin (STZ-65 mg/kg, i.p) in male Wistar rats. Resultsindicated that experimental T2DM significantly (P<0.001) increased micronucleated erythrocytes, sperm shape abnormalityand decreased the P/N (polychromatic: normochromatic erythrocytes) ratio, sperm count and weight of testis along with anincrease in the oxidative stress and blood glucose level compared to normal animals. Administration of Rosi+Metsignificantly (P<0.05) reduced the population of micronucleated erythrocytes, sperm shape abnormality, hyperglycemiabesides improving the sperm count and antioxidant defense system in the diabetic rats. However, Rosi+Gmp activity wasrestricted to only the antidiabetic effect. The observations suggest that Rosi+Met reduced the somatic and germinal celldamages in the diabetic animals owing to the antioxidant property.

Acute exposure to rosiglitazone does not affect glucose transport in intact human skeletal muscle

Thiazolidinediones (TZDs) such as rosiglitazone are widely used as antidiabetic drugs. Animal studies suggest that TZDs may have direct metabolic actions in skeletal muscle. Here, we examined if acute exposure to rosiglitazone stimulates glucose transport rate and affects proximal insulin signaling in isolated skeletal muscle strips from nondiabetic men. Open muscle biopsies were obtained from musculus vastus lateralis from 15 nondiabetic men (50 ± 3 years old, 26.9 ± 1.1 kg/m 2). Skeletal muscle strips were isolated and exposed to rosiglitazone (1 or 10 μmol/L), 5-aminoimidazole-4-carboxamide 1- β- d-ribonucleoside (1 mmol/L), insulin (120 nmol/L), or a combination of insulin (120 nmol/L) and rosiglitazone (10 μmol/L) in vitro for 1 hour. Glucose transport was analyzed by accumulation of intracellular 3- O-methyl [ 3H] glucose; phosphorylation of Akt-Ser 473 and Akt-Thr 308 and phosphorylation of acetyl coenzyme A carboxylase β were determined using phosphospecific antibodies. 5-Aminoimidazole-4-carboxamide 1- β- d-ribonucleoside and insulin increased glucose transport rate 1.5-fold ( P < .05) and 1.7-fold ( P < .01) in isolated muscle strips, respectively. Exposure to rosiglitazone transiently increased phosphorylation of acetyl coenzyme A carboxylase β, with a maximum effect at 15 minutes and return to baseline at 60 minutes. However, rosiglitazone did not affect basal or insulin-stimulated glucose transport rate, or phosphorylation of Akt-Ser 473 or Akt-Thr 308 in isolated muscle strips. In conclusion, acute exposure to rosiglitazone does not affect glucose transport in human skeletal muscle.

PPARα and PPARγ are co‐expressed, functional and show positive interactions in the rat urinary bladder urothelium

Some dual-acting PPARalpha + gamma agonists cause cancer in the rat urinary bladder, in some cases overrepresented in males, by a mechanism suggested to involve chronic stimulation of PPARalpha and PPARgamma, i.e. exaggerated pharmacology. By western blotting, we found that the rat urinary bladder urothelium expressed PPARalpha at higher levels than the liver and heart, and comparable to kidney. Urothelial expression of PPARgamma was above that of fat, heart, skeletal muscle and kidney. Male rats exhibited a higher PPARalpha/PPARgamma expression balance in the bladder urothelium than did female rats. Rats were treated by gastric gavage with rosiglitazone (PPARgamma agonist), fenofibrate (PPARalpha agonist) or a combination of rosiglitazone and fenofibrate for 7 days. In the urothelium, the transcription factor Egr-1 was induced to significantly higher levels in rats co-administered rosiglitazone and fenofibrate than in rats administered either rosiglitazone or fenofibrate alone. Egr-1 was also induced in the heart and liver of rats treated with fenofibrate, but a positive interaction between rosiglitazone and fenofibrate with regards to Egr-1 induction was only seen in the urothelium. Thus, in the rat urinary bladder urothelium, PPARalpha and PPARgamma were expressed at high levels, were functional and exhibited positive interactions. Interestingly, fenofibrate induced the peroxisome membrane protein PMP70 not only in liver, but also in the bladder urothelium, opening the possibility that oxidative stress may contribute to rat urothelial carcinogenesis by dual-acting PPARalpha + gamma agonists.

All‐trans retinoic acid can intensify the growth inhibition and differentiation induction effect of rosiglitazone on multiple myeloma cells

Activation of PPARgamma by its ligands has shown potential anti-neoplastic effects in solid tumors. In this study, we investigate the effects of rosiglitazone (RGZ) alone as well as in combination with all trans-retinoic acid (ATRA) on human myeloma cell lines and try to address its potential mechanism. U266, RPMI-8226 and primary myeloma cells from patients were treated with different concentrations of RGZ in the presence or absence of ATRA and various biological responses were studied by the methods of [3H] thymidine incorporation, MTT, cell cycle analysis, Annexin V-PI staining, Wright-Giemsa staining, CD49e expression assay, light chain protein detection, RT-PCR and caspase-3 activity assay. We report that exposure to RGZ induced proliferation inhibition and viability reduction in a dose-dependent manner in both U266 and RPMI-8226 cells. A similar exposure to RGZ also induced cell cycle arrest and cell apoptosis of myeloma cells. A combination of RGZ with ATRA enhanced the effects of RGZ and induced cell cycle arrest and apoptosis more profoundly in both cell lines. RGZ treated cells displayed morphological characteristics of cell differentiation, and more evident signs of differentiation were observed when combined with ATRA. These changes were confirmed by the detection of CD49e expression and light chain protein secretion. Similar cell apoptosis and differentiation were observed when primary CD138+ myeloma cells were treated with RGZ and ATRA. The mRNA expressions of FLIP, XIAP and survivin were detected in both cell lines and the levels decreased significantly after culture with RGZ. The addition of ATRA in culture medium made these changes more apparently. Caspase-3 activity was increased upon exposure to RGZ in both U266 and RPMI-8226 cells while combination of RGZ and ATRA brought out more effective activation of caspase-3. Similar apoptosis and cell differentiation induced by RGZ and ATRA can also be observed in primary CD138+ cells from myeloma patients. Concomitant RXRalpha activation by ATRA enhanced the inhibitory effects of RGZ on myeloma cell proliferation, cell cycle, apoptosis and differentiation. Combination of RGZ and ATRA may be a useful therapy for human multiple myeloma.

Role of histone deacetylase in inhibiting invasion of human gastric carcinoma cell line SGC-7901 by PPAR gamma-mediated pathway

Histone deacetylase (HDAC) can attenuate the function of peroxisome proliferator-activated receptor gamma (PPARgamma) to drive adipocyte differentiation. PPARgamma activation is confirmed to inhibit the development and metastasis of a variety of malignant cells. This study was to investigate the role of HDAC in inhibiting the invasion of human gastric carcinoma SGC-7901 cells through PPARgamma-mediated pathway, and explore potential mechanism. SGC-7901 cells were treated with different concentrations of Trichostatin A (TSA) and Rosiglitazone (ROZ) respectively to select the best combination through assessing cell proliferation by MTT assay. Then cells were randomly divided into control group, TSA group, ROZ group, and combination group. Cell proliferation was detected by MTT assay after 48 h; cell invasion was detected by Boyden chamber invasion test. The mRNA levels of PPARgamma and matrix metalloproteinase-2 (MMP-2) were assessed by reverse transcription-polymerase chain reaction (RT-PCR), and the protein level of MMP-2 was evaluated by Western blot. Both TSA and ROZ inhibited the proliferation of SGC-7901 cells in a dose-dependent manner. A combination of 20 nmol/L TSA and 5 mumol/L ROZ synergistically inhibited the invasion of SGC-7901 cells (q=1.41). ROZ down-regulated the mRNA and protein expression of MMP-2. TSA and ROZ in combination reduced MMP-2 expression more obviously than ROZ alone. TSA up-regulated the expression of PPARgamma mRNA. HDAC suppresses the activation of PPARgamma through a series of molecular mechanisms. The activity of ROZ in inhibiting invasion of human gastric carcinoma cells can be enhanced after the activity of HDAC is inhibited by TSA.

Effects of rosiglitazone and aspirin on experimental model of induced type 2 diabetes in rats: focus on insulin resistance and inflammatory markers

Both insulin resistance and decreased insulin secretion are major features of the pathophysiology of type 2 diabetes. Inflammatory pathways are found to be critical in mechanisms underlying insulin resistance, which is a major determinant of increased risk of cardiovascular complications in type 2 diabetes, and so, it is a potential therapeutic target. Thiazolidinediones (e.g., rosiglitazone) act primarily as insulin sensitizers and were discovered to have anti-inflammatory effects leading to reevaluation of their potential use in treatment of diabetes. Acetyl salicylic acid (aspirin), which is currently recommended for cardiovascular disease (CVD) or even CVD risk factors, is shown to ameliorate diabetic process. This work aimed to study correlation between homeostasis model assessment estimate of insulin resistance (HOMA-IR) with serum levels of inflammatory markers tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), C-reactive protein (CRP), and free fatty acids (FFAs) in experimental model of induced type 2 diabetes in rats, with evaluation of effects of rosiglitazone and aspirin (low or high dose), alone or in combination. There is significant elevation of insulin resistance and serum levels of fasting glucose, insulin, TNF-α, IL-6, CRP, and FFAs in the diabetic group when compared to the normal group, with positive significant correlation between levels of each of TNF-α, IL-6, CRP, and FFAs with insulin resistance (HOMA-IR). Administration of rosiglitazone, low-dose aspirin, or high-dose aspirin to diabetic rats caused nonsignificant lowering in insulin level with significant reduction of levels of other parameters when compared to the diabetic group. Also, there is no significant difference in the measured parameters between diabetic rats administered a combination of rosiglitazone with high-dose aspirin and those administered a combination of rosiglitazone with low-dose aspirin. It was concluded that aspirin and rosiglitazone offer unique approaches for treatment of type 2 diabetes due to their insulin-sensitizing and anti-inflammatory properties, and their combination was found to provide augmented beneficial effects. Also, in view of the potential dose-dependent adverse effects of aspirin, with no achievement of further benefit by high dose in this study, it is strongly recommended to use low-dose aspirin as a safe and effective medication for diabetes.

Inhibition of COX-2 and activation of peroxisome proliferator-activated receptor γ synergistically inhibits proliferation and induces apoptosis of human pancreatic carcinoma cells

Although inhibition of cyclooxygenase-2 (COX-2) or activation of peroxisome proliferators-activated receptor γ (PPAR-γ) leads to growth inhibition in malignancies, the synergistic anti-tumor effects of combination of COX-2 inhibitor (NS-398) and PPAR-γ agonist (rosiglitazone) on the human pancreatic cancer cells remains unknown. Here, we evaluated the effects of NS-398 and/or rosiglitazone on the cell proliferation and apoptosis in a pancreatic cancer cell line, SW1990. NS-398 and rosiglitazone decreased cell proliferation in a dose- and time-dependent manner. Proliferating cell nuclear antigen (PCNA) labeling index significantly decreased in the cells treated with either NS-398 or rosiglitazone. Both NS-398 and rosiglitazone alone induced apoptotic cell death of SW1990. The combination of NS-398 and rosiglitazone exerted synergistic effects on proliferation inhibition, and apoptosis induction in SW1990 cells, with down-regulation of Bcl-2 and up-regulation of Bax expression. Our results indicate that simultaneous targeting of COX-2 and PPAR-γ inhibits pancreatic cancer development more effectively than targeting each molecule alone.

Combination thiazolidinedione and fibrate effect on high-density lipoprotein cholesterol (HDL-C) concentration in a Veterans Affairs patient population

Type 2 diabetes mellitus (T2DM) is a coronary heart disease (CHD) risk equivalent warranting aggressive management of dyslipidemia and tight glycemic control. Recent reports demonstrate a paradoxic decrease in high-density lipoprotein cholesterol (HDL-C) with thiazolidinedione (TZD) and fibrate combination therapy. Evaluate change in HDL-C from start of combination therapy to 1 year and assess the proportion, characteristics, and regimens of patients who developed a ≥20% decrease in HDL-C from baseline. Patients with T2DM treated concurrently with a combination of TZD and fibrate were identified through retrospective query from a Veterans Affairs medical center database. HDL-C was recorded for 1 year after patients started combination therapy. Logistic regression analysis was performed to determine any predictors of HDL-C change. A total of 322 patients were included in the analysis. There was no significant differences in mean ± standard deviation HDL-C from baseline to end point (36.8 ± 8.5 to 40.3 ± 11.8 mg/dL; P = 0.097). There was a subset of patients identified (13%; n = 43) on combination therapy who experienced a ≥20% reduction in HDL-C. Of these patients, a decrease in HDL-C was more likely to occur with fenofibrate-based regimens (odds ratio 3.08, 95% confidence interval 1.22 to 7.75; P = 0.018). There was a trend toward more of these patients in this subset to have the combination of rosiglitazone and fenofibrate in their profiles (odds ratio 2.82, 95% confidence interval 0.98 to 8.0; P = 0.064). Our study demonstrated that a subset of patients with T2DM experienced a paradoxic decrease in HDL-C when taking a fibrate and TZD combination.