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1.
Curr Drug Targets ; 20(8): 879-890, 2019.
Article in English | MEDLINE | ID: mdl-30556500

ABSTRACT

Newer classes of medications have been proven useful in glycemic control in type 2 diabetes (T2D), but many do not appear capable to slow down the progressive loss of ß-cell function, or to improve population-level glycemic control. Positive energy balance, e.g. surplus energy intake over expenditure, is at the core for developing metabolic syndrome and T2D. Currently available glycemic control drugs come to the market based on their 1-2 years risk-benefit profiles, but most of them do not correct positive energy balance and lose efficacy in the long-term. This denouement is destined by a positive energy balance of T2D. There is continuous endeavor/investment in new drugs for T2D. In this review, we compared the effects of commonly used oral hypoglycemic agents on energy balance and discussed several novel therapeutic targets/approaches for T2D that could potentially correct positive energy balance: changing the composition of intestinal host-microbiota to alleviate excess caloric consumption, controlling chylomicron uptake into intestinal lacteals to reduce excessive caloric intake, and activating pyruvate kinase M2 (PKM2) to ameliorate glucose metabolism and increase energy expenditure. We further reviewed how nicotine affects body weight and ameliorates positive energy balance, and ways to encourage people to adopt a more healthy lifestyle by exercising more and/or decreasing caloric intake. These potential targets/approaches may hopefully correct positive energy balance, delay disease progression, reverse some pathophysiological changes, and eventually prevent and/or cure the disease. Drug development strategies applying new insights into T2D process and therapeutic index to correct positive energy balance need to be seriously considered.


Subject(s)
Diabetes Mellitus, Type 2/drug therapy , Hypoglycemic Agents/pharmacology , Administration, Oral , Blood Glucose/drug effects , Diabetes Mellitus, Type 2/metabolism , Drug Development , Energy Metabolism/drug effects , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/chemistry , Microbiota/drug effects
2.
J Appl Toxicol ; 38(6): 790-800, 2018 06.
Article in English | MEDLINE | ID: mdl-29369373

ABSTRACT

Over a decade ago, use of tyrosine kinase inhibitors (TKIs) for the treatment of malignancies was found to cause left ventricular dysfunction, a finding that was unexpected and not well predicted by standard preclinical studies. Subsequently, several preclinical approaches were proposed to address this issue. Over the last 5 years, several approaches for preclinical evaluation of cardiac function using isolated perfused hearts, engineered heart tissue and human-induced pluripotent stem cell-derived cardiac myocytes have been shown to be relatively predictive of the cardiotoxic potential of TKIs. Further, preclinical studies submitted for regulatory review for recently approved KIs have demonstrated various forms of KI-induced cardiotoxicity. Thus, early identification and assessment of cardiotoxicity in the preclinical setting is now possible. Given that kinases are involved in diverse cellular processes common to both normal and tumor cells, KI-induced toxicity, particularly in the heart, appears difficult to avoid. To develop drugs with fewer adverse effects, better efficacy and safety assessments, such as pharmacological separation of targets for cancer from heart, and/or wider separation of the drug concentrations for antitumor activity from cardiac toxicity, may be helpful. Additional preclinical approaches for assessing drug efficacy and toxicity in parallel may include use of animal cancer models and a 3D integrated in vitro model of perfused tumor and heart tissues. Minimizing and predicting potential KI-induced cardiotoxicity is still an important regulatory challenge, and better preclinical approaches may help achieve this goal.


Subject(s)
Antineoplastic Agents/adverse effects , Drug Design , Drug Evaluation, Preclinical , Heart Diseases/chemically induced , Myocytes, Cardiac/drug effects , Neoplasms/drug therapy , Protein Kinase Inhibitors/adverse effects , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Cardiotoxicity , Diffusion of Innovation , Drug Evaluation, Preclinical/history , Drug Evaluation, Preclinical/trends , Forecasting , Heart Diseases/enzymology , Heart Diseases/pathology , Heart Diseases/physiopathology , History, 20th Century , History, 21st Century , Humans , Molecular Targeted Therapy/adverse effects , Myocytes, Cardiac/enzymology , Myocytes, Cardiac/pathology , Neoplasms/enzymology , Protein-Tyrosine Kinases/metabolism , Risk Assessment , Risk Factors , Signal Transduction/drug effects
3.
Toxicol Pathol ; 45(3): 381-388, 2017 04.
Article in English | MEDLINE | ID: mdl-28421966

ABSTRACT

Drug-induced valvular heart disease (VHD) is a serious side effect linked to long-term treatment with 5-hydroxytryptamine (serotonin) receptor 2B (5-HT2B) agonists. Safety assessment for off-target pharmacodynamic activity is a common approach used to screen drugs for this undesired property. Such studies include in vitro assays to determine whether the drug is a 5-HT2B agonist, a necessary pharmacological property for development of VHD. Measures of in vitro binding affinity (IC50, Ki) or cellular functional activity (EC50) are often compared to maximum therapeutic free plasma drug levels ( fCmax) from which safety margins (SMs) can be derived. However, there is no clear consensus on what constitutes an appropriate SM under various therapeutic conditions of use. The strengths and limitations of SM determinations and current risk assessment methodology are reviewed and evaluated. It is concluded that the use of SMs based on Ki values, or those relative to serotonin (5-HT), appears to be a better predictor than the use of EC50 or EC50/human fCmax values for determining whether known 5-HT2B agonists have resulted in VHD. It is hoped that such a discussion will improve efforts to reduce this preventable serious drug-induced toxicity from occurring and lead to more informed risk assessment strategies.


Subject(s)
Disease Models, Animal , Drug Evaluation, Preclinical , Heart Valve Diseases/chemically induced , Risk Assessment , Serotonin 5-HT2 Receptor Agonists/toxicity , Animals , Cell Line , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/standards , Government Regulation , Heart Valve Diseases/metabolism , Humans , In Vitro Techniques , Protein Binding , Receptors, Serotonin, 5-HT2/metabolism , Risk Assessment/legislation & jurisprudence , Risk Assessment/methods , Serotonin 5-HT2 Receptor Agonists/pharmacokinetics
5.
J Appl Toxicol ; 32(12): 945-51, 2012 Dec.
Article in English | MEDLINE | ID: mdl-22961481

ABSTRACT

Although therapies targeted to inhibit the activity of certain tyrosine kinases (TK) have helped advance cancer therapy in recent years, reports of cardiac toxicity following treatment with tyrosine kinase inhibitors (TKIs) were unexpected and not well predicted by preclinical studies. Such clinical findings exposed gaps in current preclinical drug testing for predicting the development of cardiac toxicities in humans. These gaps included a lack of a comprehensive TKI mechanism of action determination and appropriate cardiac functional evaluation. New preclinical approaches are suggested to address these issues. In addition to tyrosine kinase inhibition, other factors that may play a role in drug-induced cardiac effects should be assessed, such as unintended secondary targets of TKIs, toxic drug metabolites and drug accumulation in the heart. Both on-target and off-target toxic effects of TKIs on cultured cardiac myocytes have now been shown to be detectable, providing a rationale for using cardiomyocytes as a screening tool to study potential TKI-mediated cardiotoxicity. Incorporating isolated perfused heart methodology to chronic/subchronic rodent studies or including echocardiography in chronic large animal toxicity studies may improve the detection of changes in cardiac function over current methods, and they may eventually become a routine tool for screening drugs with suspected cardiotoxic potential. Further, assessing drug toxicity and efficacy together in an animal model of disease is highly informative for candidate drug selection, and should be encouraged to assess specific safety endpoints, such as cardiovascular function. Together, these approaches will help better close the gaps between preclinical testing and clinical outcomes.


Subject(s)
Clinical Trials as Topic/methods , Drug Evaluation, Preclinical/methods , Drugs, Investigational/adverse effects , Heart Diseases/chemically induced , Protein Kinase Inhibitors/adverse effects , Protein-Tyrosine Kinases/antagonists & inhibitors , Animals , Clinical Trials as Topic/standards , Congresses as Topic , Drug Evaluation, Preclinical/standards , Drugs, Investigational/therapeutic use , Heart Diseases/enzymology , Humans , Protein Kinase Inhibitors/therapeutic use
6.
Ups J Med Sci ; 114(4): 206-13, 2009.
Article in English | MEDLINE | ID: mdl-19961266

ABSTRACT

BACKGROUND: The interest in n-3 polyunsaturated fatty acids (PUFAs) has expanded significantly in the last few years, due to their many positive effects described. Consequently, the interest in fish oil supplementation has also increased, and many different types of fish oil supplements can be found on the market. Also, it is well known that these types of fatty acids are very easily oxidized, and that stability among supplements varies greatly. AIMS OF THE STUDY: In this pilot study we investigated the effects of two different types of natural fish oils containing different amounts of the n-3 PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) and antioxidants on plasma and brain fatty acids, blood lipids, vitamin E, and in vivo lipid peroxidation, as well as brain nitric oxide synthase (NOS) activity, an enzyme which has been shown to be important for memory and learning ability. METHODS: Sprague-Dawley rats were divided into four groups and fed regular rat chow pellets enriched with 5% (w/w) of butter (control group), a natural fish oil (17.4% EPA and 11.7% DHA, referred to as EPA-rich), and a natural fish oil rich in DHA (7.7% EPA and 28.0% DHA, referred to as DHA-rich). Both of the fish oils were stabilized by a commercial antioxidant protection system (Pufanox) at production. The fourth group received the same DHA-rich oil, but without Pufanox stabilization (referred to as unstable). As an index of stability of the oils, their peroxide values were repeatedly measured during 9 weeks. The dietary treatments continued until sacrifice, after 10 days. RESULTS: Stability of the oils varied greatly. It took the two stabilized oils 9 weeks to reach the same peroxide value as the unstable oil reached after only a few days. Both the stabilized EPA- and DHA-rich diets lowered the triacylglycerols and total cholesterol compared to control (-45%, P < 0.05 and -54%, P < 0.001; -31%, P < 0.05 and -25%, P < 0.01) and so did the unstable oil, but less efficiently. Only the unstable oil increased in vivo lipid peroxidation significantly compared to control (+40%, P < 0.001). Most of the fatty acids in the plasma phospholipids were significantly affected by both the EPA- and DHA-rich diets compared to control, reflecting their specific fatty acid pattern. The unstable oil diet resulted in smaller changes, especially in n-3 PUFAs. In the brain phospholipids the changes were less pronounced, and only the diet enriched with the stabilized DHA-rich oil resulted in a significantly greater incorporation of DHA (+13%, P < 0.01), as well as total n-3 PUFAs (+13%, P < 0.01) compared to control. Only the stabilized DHA-rich oil increased the brain NOS activity (+33%, P < 0.01). CONCLUSIONS: Both the EPA- and DHA-rich diets affected the blood lipids in a similarly positive manner, and they both had a large impact on plasma phospholipid fatty acids. It was only the unstable oil that increased in vivo lipid peroxidation. However, the intake of DHA was more important than that of EPA for brain phospholipid DHA enrichment and brain NOS activity, and the stability of the fish oil was also important for these effects.


Subject(s)
Brain/drug effects , Brain/metabolism , Dietary Fats, Unsaturated/analysis , Dietary Fats, Unsaturated/pharmacology , Fatty Acids/blood , Fatty Acids/metabolism , Fish Oils/chemistry , Fish Oils/pharmacology , Nitric Oxide Synthase/metabolism , Animals , Antioxidants/analysis , Antioxidants/pharmacology , Docosahexaenoic Acids/analysis , Docosahexaenoic Acids/pharmacology , Drug Stability , Eicosapentaenoic Acid/analysis , Eicosapentaenoic Acid/pharmacology , Lipid Peroxidation/drug effects , Lipoproteins/blood , Lipoproteins/chemistry , Male , Nitric Oxide Synthase Type I , Phospholipids/blood , Phospholipids/chemistry , Rats , Rats, Sprague-Dawley
7.
BMC Pharmacol ; 8: 7, 2008 May 12.
Article in English | MEDLINE | ID: mdl-18474108

ABSTRACT

BACKGROUND: Glucocorticoids down-regulate cytokine synthesis and suppress inflammatory responses. The glucocorticoid receptor (GR) antagonist RU486 may exacerbate the inflammatory response, and concerns over this exacerbation have limited the development and clinical use of GR antagonists in the treatment of diabetes and depression. We investigated the effects of RU486 on serum cytokines in db/db mice and on lipopolysaccharide (LPS)-induced circulating TNFalpha levels in both normal AKR mice and diet-induced obese (DIO) C57BL/6 mice. RESULTS: Chronic treatment of db/db mice with RU486 dose-dependently decreased blood glucose, increased serum corticosterone and ACTH, but did not affect serum MCP-1 and IL-6 levels. LPS dose-dependently increased serum TNFalpha in both AKR and C57BL/6 DIO mice, along with increased circulating corticosterone and ACTH. Pretreatment of the mice with RU486 dose-dependently suppressed the LPS induced increases in serum TNFalpha and further increased serum corticosterone. CONCLUSION: RU486 at doses that were efficacious in lowering blood glucose did not exacerbate cytokine release in these three mouse models. RU486 actually suppressed the lower dose LPS-mediated TNFalpha release, possibly due to the increased release of glucocorticoids.


Subject(s)
Diabetes Mellitus, Type 2/blood , Hormone Antagonists/pharmacology , Hypoglycemic Agents/pharmacology , Mifepristone/pharmacology , Obesity/blood , Receptors, Glucocorticoid/antagonists & inhibitors , Adrenocorticotropic Hormone/blood , Animals , Blood Glucose/analysis , Chemokine CCL2/blood , Corticosterone/blood , Corticosterone/immunology , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/genetics , Disease Models, Animal , Gene Expression Regulation, Enzymologic , Glucose-6-Phosphatase/genetics , Interleukin-6/blood , Interleukin-6/immunology , Lipopolysaccharides/immunology , Liver/drug effects , Liver/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Mutant Strains , Obesity/drug therapy , Obesity/genetics , Protein Serine-Threonine Kinases/genetics , Receptors, Leptin/genetics , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/immunology
8.
Cardiovasc Res ; 74(2): 235-43, 2007 May 01.
Article in English | MEDLINE | ID: mdl-17331484

ABSTRACT

Myocardial ischemia-reperfusion (IR) injury is associated with structural alterations involving both the necrotic and the non-necrotic myocardium. These changes are referred to as myocardial remodeling. In addition to the loss of critical cardiomyocyte mass through cell death, there are further structural alterations associated with scarring, as well as changes in a family of endogenous enzymes, the matrix metalloproteases (MMP), which cause loss of myocardial extracellular matrix (ECM) [Janssens S, Lijnen HR. What has been learned about cardiovascular effects of matrix metalloproteinases from mouse models. Cardiovasc Res 2006;69:585-594., Wainwright CL. Matrix metalloproteinases, oxidative stress and the acute response to acute myocardial ischaemia and reperfusion. Curr Opin Pharmacol 2004;4:132-138.]. The chemokine TGFbeta1, which has wide-ranging effects upon cells and tissues, is showing promise as a useful drug/agent for the limitation of IR injury. Coupled with the identification of TGFbeta1 as a therapeutic agent for IR treatment are investigations into its mode of delivery to the patient. Gene therapy utilizing delivery by viral vectors is just one of many possible ways to deliver TGFbeta1 for IR treatment. In this review we discuss the mechanisms of action of TGFbeta1 and how it might be delivered successfully to patients under risk of or who are actively undergoing acute IR injury.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Myocardial Reperfusion Injury/drug therapy , Transforming Growth Factor beta1/therapeutic use , Genetic Therapy/methods , Humans , Microspheres , Myocardial Ischemia/drug therapy , Myocardial Ischemia/immunology , Myocardial Ischemia/pathology , Myocardial Reperfusion Injury/immunology , Myocardial Reperfusion Injury/pathology , Nanotechnology , Ventricular Remodeling
9.
Biochem Biophys Res Commun ; 341(1): 209-17, 2006 Mar 03.
Article in English | MEDLINE | ID: mdl-16414018

ABSTRACT

The current study examined the relationship between skeletal muscle levels of adiponectin and parameters of insulin sensitivity. A high fat/sucrose diet (HFD) for 20 weeks resulted in significant increases in body weight, serum insulin, triglycerides (TG), and free fatty acids (FFA) (all p < 0.01). Interestingly, this diet leads to a slight increase in serum adiponectin, but significant decreases in gastrocnemius muscle and white adipose adiponectin (all p < 0.05). HFD for 4 weeks also resulted in a significant decrease in muscle adiponectin, which correlated with serum insulin, TG, and FFA (all p < 0.05). Treatment of the 4-week HFD rats with a PPARgamma agonist GI262570 ameliorated the diet-induced hyperinsulinemia and dyslipidemia, and effectively restored muscle adiponectin (all p < 0.05). This study demonstrated that HFD-induced hyperinsulinemia and dyslipidemia appeared without changes in serum adiponectin, but were associated with decreased tissue adiponectin. This provides the first evidence for a connection between tissue adiponectin and diet-induced hyperinsulinemia and dyslipidemia.


Subject(s)
Adiponectin/metabolism , Dietary Fats/metabolism , Dietary Sucrose/metabolism , Insulin Resistance/physiology , Muscle, Skeletal/metabolism , PPAR gamma/antagonists & inhibitors , PPAR gamma/metabolism , Animals , Dose-Response Relationship, Drug , Male , Oxazoles/administration & dosage , Rats , Rats, Sprague-Dawley , Tyrosine/administration & dosage , Tyrosine/analogs & derivatives
10.
Biochem Biophys Res Commun ; 334(1): 176-82, 2005 Aug 19.
Article in English | MEDLINE | ID: mdl-15993383

ABSTRACT

We investigated the effect of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists on serum vascular endothelial growth factor (VEGF) in diet-induced insulin resistant SD rats and ZDF rats. SD rats fed a high fat/sucrose diet showed increases in serum insulin and VEGF (both p < 0.01). Treatment with a PPARgamma agonist GI262570 normalized the diet-elevated insulin and VEGF (both p < 0.01). There was a positive correlation between serum insulin and VEGF (p < 0.05) in SD rats. ZDF rats had higher serum glucose, insulin, and VEGF than Zucker lean rats (all p < 0.01). Treatment of ZDF rats with PPARgamma agonist pioglitazone decreased serum glucose and VEGF (both p <0.01). There was a positive correlation between glucose and VEGF in ZDF rats (p < 0.05). In 3T3-L1 adipocytes, GI262570 did not affect insulin-stimulated VEGF secretion. These studies demonstrated that hyperinsulinemia in SD rats and hyperglycemia in ZDF rats were associated with increased serum VEGF; PPARgamma agonists normalized serum insulin, glucose, and VEGF, but did not affect VEGF secretion in vitro.


Subject(s)
Adipocytes/metabolism , Diabetes Mellitus, Experimental/blood , Insulin Resistance , Insulin/blood , Oxazoles/administration & dosage , PPAR gamma/agonists , PPAR gamma/metabolism , Tyrosine/analogs & derivatives , Vascular Endothelial Growth Factor A/blood , 3T3-L1 Cells , Adipocytes/drug effects , Animals , Diet , Dose-Response Relationship, Drug , Male , Mice , Rats , Rats, Sprague-Dawley , Rats, Zucker , Tyrosine/administration & dosage
11.
J Pharmacol Exp Ther ; 312(2): 718-25, 2005 Feb.
Article in English | MEDLINE | ID: mdl-15475592

ABSTRACT

Peroxisome proliferator-activated receptor-gamma (PPARgamma) agonists have been shown to have significant therapeutic benefits such as desirable glycemic control in type 2 diabetic patients; however, these agents may cause fluid retention in susceptible individuals. Since PPARgamma is expressed selectively in distal nephron epithelium, we studied the mechanism of PPARgamma agonist-induced fluid retention using male Sprague-Dawley rats treated with either vehicle or GI262570 (farglitazar), a potent PPARgamma agonist. GI262570 (20 mg/kg/day) induced a plasma volume expansion. The plasma volume expansion was accompanied by a small but significant decrease in plasma potassium concentration. Small but significant increases in plasma sodium and chloride concentrations were also observed. These changes in serum electrolytes suggested an activation of the renal mineralocorticoid response system; however, GI262570-treated rats had lower plasma levels of aldosterone compared with vehicle-treated controls. mRNA levels for a group of genes involved in distal nephron sodium and water absorption are changed in the kidney medulla with GI262570 treatment. In addition, due to a possible rebound effect on epithelial sodium channel (ENaC) activity, a low dose of amiloride did not prevent GI262570-induced fluid retention. On the contrary, the rebound effect after amiloride treatment potentiated GI262570-induced plasma volume expansion. This is at least partially due to a synergistic effect of GI262570 and the rebound from amiloride treatment on ENaCalpha expression. In summary, our current data suggest that GI262570 can increase water and sodium reabsorption in distal nephron by stimulating the ENaC and Na,K-ATPase system. This may be an important mechanism for PPARgamma agonist-induced fluid retention.


Subject(s)
Electrolytes/metabolism , Kidney Tubules, Distal/metabolism , Nephrons/metabolism , Oxazoles/pharmacology , PPAR gamma/agonists , Tyrosine/analogs & derivatives , Tyrosine/pharmacology , Water/metabolism , Actins/biosynthesis , Aldosterone/blood , Amiloride/pharmacology , Animals , Blood Volume/drug effects , Diuretics/pharmacology , Epithelial Cells/drug effects , Epithelial Cells/metabolism , Epithelial Sodium Channels , Gene Expression/drug effects , Kidney Medulla/drug effects , Kidney Medulla/metabolism , Kidney Tubules, Distal/cytology , Kidney Tubules, Distal/drug effects , Male , Nephrons/cytology , Nephrons/drug effects , RNA/biosynthesis , RNA/isolation & purification , Rats , Rats, Sprague-Dawley , Reverse Transcriptase Polymerase Chain Reaction , Sodium/metabolism , Sodium Channels/biosynthesis , Sodium Channels/genetics
12.
BMC Pharmacol ; 4: 23, 2004 Oct 18.
Article in English | MEDLINE | ID: mdl-15491498

ABSTRACT

BACKGROUND: PPARgamma agonists ameliorate insulin resistance and dyslipidemia in type 2 diabetic patients. Adiponectin possesses insulin sensitizing properties, and predicts insulin sensitivity of both glucose and lipid metabolism. In diet-induced insulin resistant rats and ZDF rats, the current studies determined the correlation between PPARgamma agonist-upregulated fatty acid binding protein(FABP3) mRNA in adipose tissue and PPARgamma agonist-elevated serum adiponectin, and the correlation between PPARgamma agonist-elevated serum adiponectin and PPARgamma agonist-mediated efficacy in insulin sensitization and lipid lowering. RESULTS: Parallel groups of SD rats were fed a high fat/sucrose (HF) diet for 4 weeks. These rats were orally treated for the later 2 weeks with vehicle, either PPARgamma agonist GI262570 (0.2-100 mg/kg, Q.D.), or GW347845 (3 mg/kg, B.I.D). Rats on HF diet showed significant increases in postprandial serum triglycerides, free fatty acids (FFA), insulin, and area under curve (AUC) of serum insulin during an oral glucose tolerance test, but showed no change in serum glucose, adiponectin, and glucose AUC. Treatment with GI262570 dose-dependently upregulated adipose FABP3 mRNA, and increased serum adiponectin. There was a position correlation between adipose FABP3 mRNA and serum adiponectin (r = 0.7350, p < 0.01). GI262570 dose-dependently decreased the diet-induced elevations in triglycerides, FFA, insulin, and insulin AUC. Treatment with GW347845 had similar effects on serum adiponectin and the diet-induced elevations. There were negative correlations for adiponectin versus triglycerides, FFA, insulin, and insulin AUC (For GI262570, r = -0.7486, -0.4581, -0.4379, and -0.3258 respectively, all p < 0.05. For GW347845, r = -0.6370, -0.6877, -0.5512, and -0.3812 respectively, all p < 0.05). In ZDF rats treated with PPARgamma agonists pioglitazone (3-30 mg/kg, B.I.D.) or GW347845 (3 mg/kg, B.I.D.), there were also negative correlations for serum adiponectin versus glucose, triglycerides, FFA (for pioglitazone, r = -0.7005, -0.8603, and -0.9288 respectively; for GW347845, r = -0.9721, -0.8483, and -0.9453 respectively, all p < 0.01). CONCLUSIONS: This study demonstrated that (a) PPARgamma agonists improved insulin sensitivity and ameliorated dyslipidemia in HF fed rats and ZDF rats, which were correlated with serum adiponectin; (b) Serum adiponectin was positively correlated with adipose FABP3 mRNA in GI262570-treated rats. These data suggest that serum adiponectin can serve as a biomarker for both in vivo PPARgamma activation and PPARgamma agonist-induced efficacy on insulin resistance and dyslipidemia in rats.


Subject(s)
Insulin/physiology , Intercellular Signaling Peptides and Proteins/blood , Lipids/blood , PPAR gamma/agonists , PPAR gamma/metabolism , Adiponectin , Animals , Biomarkers/blood , Carrier Proteins/metabolism , Diabetes Mellitus/metabolism , Fatty Acid-Binding Proteins , Insulin/blood , Insulin Resistance/physiology , Male , Obesity/metabolism , Oxazoles/pharmacology , Pioglitazone , Rats , Rats, Sprague-Dawley , Rats, Zucker , Thiazolidinediones/pharmacology , Tyrosine/analogs & derivatives , Tyrosine/pharmacology
13.
Circ Res ; 95(5): 506-14, 2004 Sep 03.
Article in English | MEDLINE | ID: mdl-15256482

ABSTRACT

Human CYP2J2 is abundant in heart and active in the biosynthesis of epoxyeicosatrienoic acids (EETs); however, the functional role of this P450 and its eicosanoid products in the heart remains unknown. Transgenic mice with cardiomyocyte-specific overexpression of CYP2J2 were generated. CYP2J2 transgenic (Tr) mice have normal heart anatomy and basal contractile function. CYP2J2 Tr hearts have improved recovery of left ventricular developed pressure (LVDP) compared with wild-type (WT) hearts after 20 minutes ischemia and 40 minutes reperfusion. Perfusion with the selective P450 epoxygenase inhibitor N-methylsulphonyl-6-(2-proparglyloxyphenyl)hexanamide (MS-PPOH) for 20 minutes before ischemia results in reduced postischemic LVDP recovery in WT hearts and abolishes the improved postischemic LVDP recovery in CYP2J2 Tr hearts. Perfusion with the ATP-sensitive K(+) channel (K(ATP)) inhibitor glibenclamide (GLIB) or the mitochondrial K(ATP) (mitoK(ATP)) inhibitor 5-hydroxydecanoate (5-HD) for 20 minutes before ischemia abolishes the cardioprotective effects of CYP2J2 overexpression. Flavoprotein fluorescence, a marker of mitoK(ATP) activity, is higher in cardiomyocytes from CYP2J2 Tr versus WT mice. Moreover, CYP2J2-derived EETs (1 to 5 micromol/L) increase flavoprotein fluorescence in WT cardiomyocytes. CYP2J2 Tr mice exhibit increased expression of phospho-p42/p44 mitogen-activated protein kinase (MAPK) after ischemia, and addition of the p42/p44 MAPK kinase (MEK) inhibitor PD98059 during reperfusion abolishes the cardioprotective effects of CYP2J2 overexpression. Together, these data suggest that CYP2J2-derived metabolites are cardioprotective after ischemia, and the mechanism for this cardioprotection involves activation of mitoK(ATP) and p42/p44 MAPK.


Subject(s)
Cytochrome P-450 Enzyme System/physiology , MAP Kinase Signaling System , Membrane Proteins/physiology , Myocardial Reperfusion Injury/enzymology , Myocardial Reperfusion Injury/physiopathology , Oxygenases/physiology , Potassium Channels/physiology , Animals , Cytochrome P-450 CYP2J2 , Cytochrome P-450 Enzyme System/genetics , Fatty Acids/metabolism , Flavoproteins/chemistry , Fluorescence , Heart/anatomy & histology , Heart/physiopathology , Humans , In Vitro Techniques , Mice , Mice, Transgenic , Mitogen-Activated Protein Kinase 1/physiology , Mitogen-Activated Protein Kinase 3/physiology , Myocardial Reperfusion Injury/metabolism , Myocardium/enzymology , Oxygenases/genetics , Potassium Channel Blockers/pharmacology , Ventricular Function, Left , Ventricular Pressure/drug effects
14.
Zhonghua Wai Ke Za Zhi ; 42(22): 1384-8, 2004 Nov 22.
Article in Chinese | MEDLINE | ID: mdl-15634410

ABSTRACT

OBJECTIVE: To improve the diagnosis and treatment of hypoglossal neurilemmoma (HGN). METHODS: The data of 10 patients with HGN were retrospectively reviewed, 5 of 10 patients (early group) had been reported previously. A comparison of treatment strategy between early and latter group was made. RESULTS: Typical hemiatrophy of the tongue presented in all 10 patients, hypoglossal canal could be showed in the bone window of CT, which, however, might not confirm the existence of tumor if it is very small. MRI was the optical choice for diagnosis. Among the early 5 cases with HGN which were all of dumbbell type, the intracranial part and the extracranial part of the tumor in 2 cases were removed by stages, 3 cases were operated via the far-lateral approach, of which 1 was via trans-condylar approach and 2 were via trans-supracondylar approach; the 5 tumors were removed subtotally except 1 totally; CSF leakage and intra-cranial infection after operation occurred in 1 case; the rating of Karnofsky Prognosis Scale was good in 4 cases and dead in 1 case. However, among the latter 5 cases, 4 cases including 2 of dumbbell type, 1 of intra-cranial type and 1 of intracanal type were operated via the modified far-lateral approach, of which 1 was via trans-condylar approach and 3 were via trans-supracondylar approach; and the tumor of extracranial type in the last case was resected twice via transcervical approach, being removed subtotally in the first operation followed by total removal with the aid of neuronavigation and neuroendoscopy in the second operation when it failed to react to the treatment of gamma knife; the 5 tumors were removed totally except 1 subtotally.; all postoperative courses were uneventful.; follow up was performed successfully in 4 cases, the rating of Karnofsky Prognosis Scale was excellent in 3 cases and fair in 1 case. The outcomes of the latter 5 cases resected via modified approach were better than those of the early 5 cases. CONCLUSION: HGN is extremely rare and it is difficult to treat it. To achieve a good operative outcome, it is very important to design the approach individually based on its location and size and operate mini-invasively and resect tumor totally as possible as can in the primary stage.


Subject(s)
Cranial Nerve Neoplasms , Hypoglossal Nerve Diseases , Neurilemmoma , Adult , Cranial Nerve Neoplasms/diagnosis , Cranial Nerve Neoplasms/surgery , Female , Humans , Hypoglossal Nerve Diseases/diagnosis , Hypoglossal Nerve Diseases/surgery , Magnetic Resonance Imaging , Male , Neurilemmoma/diagnosis , Neurilemmoma/surgery , Retrospective Studies , Skull Base/diagnostic imaging , Tomography, X-Ray Computed
15.
J Cardiovasc Pharmacol ; 42(3): 436-41, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12960690

ABSTRACT

PPARgamma agonists ameliorate insulin resistance and lower blood pressure. Volume expansion/edema has been observed in susceptible patients treated with these agents. Alterations of renal hemodynamics affect renal tubular reabsorption, and thus may contribute to volume expansion. This study seeks to determine whether volume expansion caused by a PPARgamma agonist, GI262570, is related to changes in glomerular filtration rate, effective renal plasma flow, or renal filtration fraction. Chronically catheter-implanted conscious rats were studied to determine the effects on glomerular filtration rate, effective renal plasma flow, and renal filtration fraction after 1, 4, and 10 days of GI262570 treatment (8 mg/kg, p.o., B.I.D.). Elevated adipose mRNA of PPARgamma target genes confirmed PPARgamma activation in GI262570-treated rats. GI262570 treatment for 10 days decreased hematocrit, hemoglobin, and serum albumin (all P < 0.05), indicating volume expansion, but did not alter glomerular filtration rate, effective renal plasma flow, or renal filtration fraction. However, nitrate + nitrite was significantly higher in plasma and hind limb muscle of GI262570-treated rats (both P < 0.05). This study demonstrated that treatment with PPARgamma agonist GI262570 resulted in volume expansion and increased nitric oxide, but did not affect glomerular filtration rate, effective renal plasma flow, or renal filtration fraction, indicating PPARgamma agonist-induced volume expansion is not related to changes in renal filtration fraction, and increased nitric oxide may contribute to the PPARgamma agonist-induced blood-pressure lowering.


Subject(s)
Glomerular Filtration Rate/drug effects , Hypoglycemic Agents/pharmacology , Nitric Oxide/metabolism , Oxazoles , Receptors, Cytoplasmic and Nuclear/agonists , Renal Plasma Flow, Effective/drug effects , Transcription Factors/agonists , Animals , Male , Nitrates/blood , Nitric Oxide/blood , Nitrites/blood , Rats , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear/genetics , Transcription Factors/genetics , Tyrosine/analogs & derivatives
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