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1.
JACC Adv ; 2(10): 100696, 2023 Dec.
Article in English | MEDLINE | ID: mdl-38938482

ABSTRACT

Background: Lipid-lowering therapy (LLT) is a central aspect of the treatment of patients with coronary artery disease (CAD), and the benefits of LLT accrue over time. However, there are limited real-world data on longitudinal lipid control in patients with premature CAD. Objectives: The purpose of this study was to assess longitudinal attainment of guideline-recommended lipid goals and outcomes in a contemporary cohort of patients with premature CAD. Methods: We enrolled males younger than 50 years and females younger than 55 years with coronary stenosis of >50% and examined achievement of lipid goals, LLT characteristics, and cardiovascular outcomes (major adverse cardiovascular event [MACE]). Results: Of 476 patients who presented with acute coronary syndrome (ST-elevation myocardial infarction, non-ST-segment elevation myocardial infarction, unstable angina) (68%), stable angina (28%), or other symptoms, 73.2% achieved low-density lipoprotein cholesterol (LDL-C) <1.8 mmol/L on at least 1 occasion, but only 27.3% consistently stayed in the target range for 3 years after diagnosis. Although 73.9% of patients received high-intensity LLT at the time of diagnosis, only 43.5% had good adherence over the following 3 years. In multivariable analysis, 1 mmol/L increase in time-weighted average exposure to LDL-C, but not the lowest achieved LDL-C, was associated with a higher risk of MACE, hazard ratio 2.02 (95% CI: 1.48-2.76), when adjusted for sex, age, hypertension, diabetes, and smoking. Conclusions: We found low rates of longitudinal lipid target achievement in patients with premature CAD. Cumulative LDL-C exposure, but not lowest achieved LDL-C, was associated with risk of MACE. This highlights the critical importance of longitudinal control of lipids levels and identifies opportunities to improve LLT and maximize the time-dependent benefits of lipid-lowering.

2.
Sci Rep ; 10(1): 13136, 2020 08 04.
Article in English | MEDLINE | ID: mdl-32753679

ABSTRACT

Endothelial dysfunction has been shown to play an important role in the pathogenesis of glomerular damage during diabetic kidney disease (DKD). As such, a better understanding of the molecular mechanisms involved in glomerular endothelial dysfunctions could provide novel therapeutic strategies for the prevention of DKD. We have previously shown that Alk1/BMP9 signaling plays an important function to maintain vascular integrity in diabetic animals. As such, we evaluated the effects of Alk1 suppression on glomerular endothelial function in diabetic mice. In the present study, we used mice with conditional heterozygote deletion of Alk1 in the endothelium (Alk1ΔEC) to evaluate the role of Alk1 on kidney function during STZ-induced diabetes. DKD was investigated in diabetic control and Alk1ΔEC mice euthanized eight weeks after the onset of diabetes. We showed that Alk1 expression is reduced in the glomeruli of human DKD patients. While renal function was not altered in Alk1ΔEC non-diabetic mice, we showed that Alk1 haploinsufficiency in the glomerular endothelium leads to microalbuminuria, thickening of the glomerular basement membrane, glomerular apoptosis and podocyte loss in diabetic mice. These data suggest that Alk1 is important for the proper function of glomerular endothelial cells and that decreased Alk1 combined with chronic hyperglycemia can impair renal function.


Subject(s)
Activin Receptors, Type II/metabolism , Albuminuria/metabolism , Diabetes Mellitus, Experimental/metabolism , Diabetic Nephropathies/metabolism , Haploinsufficiency , Signal Transduction , Activin Receptors, Type II/genetics , Albuminuria/genetics , Albuminuria/pathology , Animals , Diabetes Mellitus, Experimental/genetics , Diabetes Mellitus, Experimental/pathology , Diabetic Nephropathies/genetics , Diabetic Nephropathies/pathology , Endothelial Cells/metabolism , Endothelial Cells/pathology , Female , Humans , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Male , Mice , Mice, Transgenic
3.
Sci Rep ; 10(1): 12778, 2020 07 29.
Article in English | MEDLINE | ID: mdl-32728158

ABSTRACT

Non-alcoholic Fatty Liver Disease (NAFLD) is the most common form of liver disease and is associated with metabolic dysregulation. Although G protein-coupled receptor 84 (GPR84) has been associated with inflammation, its role in metabolic regulation remains elusive. The aim of our study was to evaluate the potential of PBI-4547 for the treatment of NAFLD and to validate the role of its main target receptor, GPR84. We report that PBI-4547 is a fatty acid mimetic, acting concomitantly as a GPR84 antagonist and GPR40/GPR120 agonist. In a mouse model of diet-induced obesity, PBI-4547 treatment improved metabolic dysregulation, reduced hepatic steatosis, ballooning and NAFLD score. PBI-4547 stimulated fatty acid oxidation and induced gene expression of mitochondrial uncoupling proteins in the liver. Liver metabolomics revealed that PBI-4547 improved metabolic dysregulation induced by a high-fat diet regimen. In Gpr84-/- mice, PBI-4547 treatment failed to improve various key NAFLD-associated parameters, as was observed in wildtype littermates. Taken together, these results highlight a detrimental role for the GPR84 receptor in the context of meta-inflammation and suggest that GPR84 antagonism via PBI-4547 may reflect a novel treatment approach for NAFLD and its related complications.


Subject(s)
Acetates/pharmacology , Fatty Acids/pharmacology , Non-alcoholic Fatty Liver Disease/drug therapy , Non-alcoholic Fatty Liver Disease/metabolism , Receptors, G-Protein-Coupled/metabolism , Animals , Binding, Competitive , Biosensing Techniques , Cholesterol/metabolism , Disease Models, Animal , Disease Progression , Drug Discovery , Female , Glucose/metabolism , Glucose Tolerance Test , HEK293 Cells , Homeostasis , Humans , Ligands , Magnetic Resonance Spectroscopy , Male , Metabolomics , Mice , Mitochondria/metabolism , Obesity/metabolism , Oxygen/metabolism , Plasmids/metabolism , Protein Binding
4.
Sci Rep ; 9(1): 15901, 2019 11 04.
Article in English | MEDLINE | ID: mdl-31685846

ABSTRACT

Cardiovascular disease (CVD) remains the leading cause of death in chronic kidney disease (CKD) patients despite treatment of traditional risk factors, suggesting that non-traditional CVD risk factors are involved. Trimethylamine-N-oxide (TMAO) correlates with atherosclerosis burden in CKD patients and may be a non-traditional CVD risk factor. Serum TMAO concentrations are significantly increased in CKD patients, which may be due in part to increased hepatic flavin monooxygenase (FMO)-mediated TMAO formation. The objective of this work was to elucidate the mechanism of increased FMO activity in CKD. In this study, FMO enzyme activity experiments were conducted in vitro with liver microsomes isolated from experimental CKD and control rats. Trimethylamine was used as a probe substrate to assess FMO activity. The FMO activator octylamine and human uremic serum were evaluated. FMO gene and protein expression were also determined. FMO-mediated TMAO formation was increased in CKD versus control. Although gene and protein expression of FMO were not changed, metabolic activation elicited by octylamine and human uremic serum increased FMO-mediated TMAO formation. The findings suggest that metabolic activation of FMO-mediated TMAO formation is a novel mechanism that contributes to increased TMAO formation in CKD and represents a therapeutic target to reduce TMAO exposure and CVD.


Subject(s)
Methylamines/metabolism , Mixed Function Oxygenases/metabolism , Renal Insufficiency, Chronic/pathology , Activation, Metabolic , Animals , Blood Urea Nitrogen , Creatinine/blood , Cytochrome P-450 CYP1A2/genetics , Cytochrome P-450 CYP1A2/metabolism , Disease Models, Animal , Kinetics , Male , Rats , Rats, Sprague-Dawley , Renal Insufficiency, Chronic/metabolism , Substrate Specificity
5.
Clin Sci (Lond) ; 133(14): 1587-1602, 2019 07 31.
Article in English | MEDLINE | ID: mdl-31308217

ABSTRACT

PBI-4050 (3-pentylbenzenacetic acid sodium salt), a novel first-in-class orally active compound that has completed clinical Phases Ib and II in subjects with chronic kidney disease (CKD) and metabolic syndrome respectively, exerts antifibrotic effects in several organs via a novel mechanism of action, partly through activation of the G protein receptor 40 (GPR40) receptor. Here we evaluate the effects of PBI-4050 in both WT and Gpr40-/- mice on adenine-induced tubulointerstitial injury, anemia and activation of the unfolded protein response (UPR) pathway. Adenine-induced CKD was achieved in 8-week-old C57BL/6 mice fed a diet supplemented with 0.25% adenine. After 1 week, PBI-4050 or vehicle was administered daily by oral-gavage for 3 weeks. Gpr40-/- mice were also subjected to adenine-feeding, with or without PBI-4050 treatment. PBI-4050 improved renal function and urine concentrating ability. Anemia was present in adenine-fed mice, while PBI-4050 blunted these effects and led to significantly higher plasma erythropoietin (EPO) levels. Adenine-induced renal fibrosis, endoplasmic reticulum (ER) stress and apoptosis were significantly decreased by PBI-4050. In parallel, Gpr40-/- mice were more susceptible to adenine-induced fibrosis, renal function impairment, anemia and ER stress compared with WT mice. Importantly, PBI-4050 treatment in Gpr40-/- mice failed to reduce renal injury in this model. Taken together, PBI-4050 prevented adenine-induced renal injury while these beneficial effects were lost upon Gpr40 deletion. These data reinforce PBI-4050's use as a renoprotective therapy and identify GPR40 as a crucial mediator of its beneficial effects.


Subject(s)
Acetates/administration & dosage , Adenine/adverse effects , Kidney Diseases/drug therapy , Kidney/injuries , Receptors, G-Protein-Coupled/metabolism , Animals , Disease Models, Animal , Endoplasmic Reticulum Stress/drug effects , Humans , Kidney/drug effects , Kidney/metabolism , Kidney Diseases/etiology , Kidney Diseases/genetics , Kidney Diseases/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Receptors, G-Protein-Coupled/genetics
6.
J Acquir Immune Defic Syndr ; 82(3): 257-264, 2019 11 01.
Article in English | MEDLINE | ID: mdl-31356468

ABSTRACT

BACKGROUND: Little is known about risk compensation among female sex workers (FSW) on HIV pre-exposure prophylaxis (PrEP), and self-report of sexual behaviors is subject to bias. SETTING: Prospective observational PrEP demonstration study conducted among FSW in Cotonou, Benin. METHODS: Over a period of 24 months, we assessed and compared trends in unprotected sex as measured by self-report (last 2 or 14 days), by detection of sexually transmitted infections (STIs), and by vaginal detection of prostate-specific antigen and Y-chromosomal DNA, 2 biomarkers of semen exposure in the last 2 or 14 days, respectively. Trends were assessed and compared using a log-binomial regression that was simultaneously fit for all unprotected sex measures. RESULTS: Of 255 participants, 120 (47.1%) completed their follow-up. Prevalence of STI decreased from 15.8% (95% confidence interval: 11.8% to 21.0%) at baseline to 2.1% (95% confidence interval: 0.4% to 10.2%) at 24 months of follow-up (P-trend = 0.04). However, we observed no trend in self-report of unprotected sex in the last 2 (P = 0.42) or 14 days (P = 0.49), nor in prostate-specific antigen (P = 0.53) or Y chromosomal DNA (P = 0.25) over the same period. We observed no statistically significant difference between trends in self-report of unprotected sex and trends in biomarkers of semen exposure in the last 2 days (P = 0.14) or in the last 14 days (P = 0.29). CONCLUSIONS: We observed no evidence of risk compensation, and a decrease in STI among FSW on PrEP. PrEP intervention may be an opportunity to control STI among FSW. Future studies should assess risk compensation with biomarkers of semen exposure when possible.


Subject(s)
HIV Infections/prevention & control , Pre-Exposure Prophylaxis , Safe Sex , Sex Workers , Adolescent , Adult , Benin , Biomarkers , DNA/analysis , Female , Genes, Y-Linked , Humans , Prospective Studies , Prostate-Specific Antigen , Self Report , Sexual Behavior , Sexually Transmitted Diseases/diagnosis , Sexually Transmitted Diseases/epidemiology , Sexually Transmitted Diseases/prevention & control , Unsafe Sex/statistics & numerical data , Young Adult
7.
PLoS One ; 14(7): e0220326, 2019.
Article in English | MEDLINE | ID: mdl-31344101

ABSTRACT

OBJECTIVES: Because self-report of sexual behaviours is prone to biases, biomarkers of recent semen exposure are increasingly used to assess unprotected sex. We aimed to present a novel nested polymerase chain reaction (PCR) assay targeting testis-specific protein Y-encoded (TSPY) genes and to compare its performance in detecting recent semen exposure with that of four other assays. METHODS: Forty-five vaginal samples were selected at baseline of a prospective observational demonstration study of early antiretroviral treatment and pre-exposure prophylaxis among female sex workers in Benin. Semen exposure was assessed with: a rapid prostate-specific antigen (PSA) detection assay, a quantitative PCR targeting the sex-determining region (SRY) gene, a standard PCR targeting SRY, a standard PCR targeting TSPY, and a nested PCR targeting TSPY (n-TSPY). Because we had hypothesized that n-TSPY would be the most sensitive of the five assays while remaining specific, and as our results suggested that it was the case, sensitivity and specificity were calculated for each assay in comparison with n-TSPY. RESULTS: The n-TSPY could detect male DNA at concentration 16 and 64 times lower compared to s-TSPY and s-SRY, respectively. Among the 45 vaginal samples, prevalences of semen exposure according to the different assays varied from 22.2% (95%CI: 11.2%-37.1%) to 70.5% (95%CI: 54.8%-83.2%), with the highest prevalence measured with n-TSPY. The n-TSPY products were of expected size and we observed no false-positive in female DNA controls. The assay that offered the second best performance in detecting semen exposure was the PSA rapid test, with a sensitivity of 61.3% and a specificity of 100% compared to n-TSPY. CONCLUSIONS: Compared to n-TSPY, all other PCR assays had poor performance to detect semen exposure. The n-TSPY is an accessible assay that may have great utility in assessing semen exposure in studies where many factors are expected to accelerate biomarkers' clearance.


Subject(s)
Cell Cycle Proteins/genetics , Occupational Exposure/analysis , Polymerase Chain Reaction/methods , Semen Analysis/methods , Unsafe Sex , Benin , Biomarkers/analysis , Biomarkers/metabolism , Body Fluids/metabolism , Cell Cycle Proteins/analysis , Feasibility Studies , Female , Humans , Male , Multigene Family/genetics , Predictive Value of Tests , Semen/cytology , Semen/metabolism , Sensitivity and Specificity , Sex Workers , Sexual Behavior/physiology , Vagina/cytology , Vagina/metabolism
8.
Open Forum Infect Dis ; 6(2): ofz010, 2019 Feb.
Article in English | MEDLINE | ID: mdl-30746385

ABSTRACT

BACKGROUND: Self-reported unprotected sex validity is questionable and is thought to decline with longer recall periods. We used biomarkers of semen to validate self-reported unprotected sex and to compare underreporting of unprotected sex between 2 recall periods among female sex workers (FSW). METHODS: At baseline of an early antiretroviral therapy and pre-exposure prophylaxis demonstration study conducted among FSW in Cotonou, Benin, unprotected sex was assessed with retrospective questionnaires, and with vaginal detection of prostate-specific antigen (PSA) and Y-chromosomal deoxyribonucleic acid (Yc-DNA). Underreporting in the last 2 or 14 days was defined as having reported no unprotected sex in the recall period while testing positive for PSA or Yc-DNA, respectively. Log-binomial regression was used to compare underreporting over the 2 recall periods. RESULTS: Unprotected sex prevalence among 334 participants was 25.8% (50.3%) according to self-report in the last 2 (or 14) days, 32.0% according to PSA, and 44.3% according to Yc-DNA. The proportion of participants underreporting unprotected sex was similar when considering the last 2 (18.9%) or 14 days (21.0%; proportion ratio = 0.90; 95% confidence interval, 0.72-1.13). Among the 107 participants who tested positive for PSA, 19 (17.8%) tested negative for Yc-DNA. CONCLUSIONS: Underreporting of unprotected sex was high among FSW but did not seem to be influenced by the recall period length. Reasons for discrepancies between PSA and Yc-DNA detection, where women tested positive for PSA but negative for Yc-DNA, should be further investigated.

9.
J Pharmacol Exp Ther ; 367(1): 71-81, 2018 10.
Article in English | MEDLINE | ID: mdl-30093459

ABSTRACT

Hepatic fibrosis is a major cause of morbidity and mortality for which there is currently no effective therapy. We previously showed that 2-(3-pentylphenyl)acetic acid (PBI-4050) is a dual G protein-coupled receptor GPR40 agonist/GPR84 antagonist that exerts antifibrotic, anti-inflammatory, and antiproliferative action. We evaluated PBI-4050 for the treatment of liver fibrosis in vivo and elucidated its mechanism of action on human hepatic stellate cells (HSCs). The antifibrotic effect of PBI-4050 was evaluated in carbon tetrachloride (CCl4)- and bile duct ligation-induced liver fibrosis rodent models. Treatment with PBI-4050 suppressed CCl4-induced serum aspartate aminotransferase levels, inflammatory marker nitric oxide synthase, epithelial to mesenchymal transition transcription factor Snail, and multiple profibrotic factors. PBI-4050 also decreased GPR84 mRNA expression in CCl4-induced injury, while restoring peroxisome proliferator-activated receptor γ (PPARγ) to the control level. Collagen deposition and α-smooth muscle actin (α-SMA) protein levels were also attenuated by PBI-4050 treatment in the bile duct ligation rat model. Transforming growth factor-ß-activated primary HSCs were used to examine the effect of PBI-4050 and its mechanism of action in vitro. PBI-4050 inhibited HSC proliferation by arresting cells in the G0/G1 cycle phase. Subsequent analysis demonstrated that PBI-4050 signals through a reduction of intracellular ATP levels, activation of liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK), and blockade of mammalian target of rapamycin (mTOR), resulting in reduced protein and mRNA levels of α-SMA and connective tissue growth factor and restored PPARγ mRNA expression. Our findings suggest that PBI-4050 may exert antifibrotic activity in the liver through a novel mechanism of action involving modulation of intracellular ATP levels and the LKB1/AMPK/mTOR pathway in stellate cells, and PBI-4050 may be a promising agent for treating liver fibrosis.


Subject(s)
AMP-Activated Protein Kinases/metabolism , Adenosine Triphosphate/metabolism , Anti-Inflammatory Agents/pharmacology , Hepatic Stellate Cells/metabolism , Liver Cirrhosis/drug therapy , Protein Serine-Threonine Kinases/metabolism , TOR Serine-Threonine Kinases/metabolism , AMP-Activated Protein Kinase Kinases , Animals , Carbon Tetrachloride/pharmacology , Gene Expression Regulation/drug effects , Hepatic Stellate Cells/drug effects , Humans , Liver/drug effects , Liver/metabolism , Liver Cirrhosis/metabolism , Liver Cirrhosis, Experimental/chemically induced , Liver Cirrhosis, Experimental/drug therapy , Liver Cirrhosis, Experimental/metabolism , Male , Mice , Mice, Inbred C57BL , PPAR gamma/metabolism , RNA, Messenger/metabolism , Rats , Rats, Wistar , Signal Transduction/drug effects
10.
Am J Pathol ; 188(5): 1132-1148, 2018 05.
Article in English | MEDLINE | ID: mdl-29454750

ABSTRACT

Numerous clinical conditions can lead to organ fibrosis and functional failure. There is a great need for therapies that could effectively target pathophysiological pathways involved in fibrosis. GPR40 and GPR84 are G protein-coupled receptors with free fatty acid ligands and are associated with metabolic and inflammatory disorders. Although GPR40 and GPR84 are involved in diverse physiological processes, no evidence has demonstrated the relevance of GPR40 and GPR84 in fibrosis pathways. Using PBI-4050 (3-pentylbenzeneacetic acid sodium salt), a synthetic analog of a medium-chain fatty acid that displays agonist and antagonist ligand affinity toward GPR40 and GPR84, respectively, we uncovered an antifibrotic pathway involving these receptors. In experiments using Gpr40- and Gpr84-knockout mice in models of kidney fibrosis (unilateral ureteral obstruction, long-term post-acute ischemic injury, and adenine-induced chronic kidney disease), we found that GPR40 is protective and GPR84 is deleterious in these diseases. Moreover, through binding to GPR40 and GPR84, PBI-4050 significantly attenuated fibrosis in many injury contexts, as evidenced by the antifibrotic activity observed in kidney, liver, heart, lung, pancreas, and skin fibrosis models. Therefore, GPR40 and GPR84 may represent promising molecular targets in fibrosis pathways. We conclude that PBI-4050 is a first-in-class compound that may be effective for managing inflammatory and fibrosis-related diseases.


Subject(s)
Kidney Diseases/pathology , Receptors, G-Protein-Coupled/metabolism , Renal Insufficiency, Chronic/pathology , Animals , Fibrosis/genetics , Fibrosis/metabolism , Fibrosis/pathology , Kidney Diseases/genetics , Kidney Diseases/metabolism , Mice , Mice, Knockout , Receptors, G-Protein-Coupled/genetics , Renal Insufficiency, Chronic/genetics , Renal Insufficiency, Chronic/metabolism
11.
J Surg Oncol ; 117(6): 1318-1322, 2018 May.
Article in English | MEDLINE | ID: mdl-29355970

ABSTRACT

BACKGROUND AND OBJECTIVES: Pemetrexed is an appealing agent to use for cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). However, the optimal method of pemetrexed delivery still remains undefined. Using a murine model, we compared the use of open and closed abdomen techniques on the absorption of intraperitoneal (IP) pemetrexed in different compartments. METHODS: Eleven Sprague-Dawley rats were submitted to a fixed dose of IP pemetrexed (1000 mg/m2 ) at a perfusion temperature of 40°C during 25 min according to two techniques: open and closed. At the end of perfusion, samples in different compartments were harvested and the concentrations of pemetrexed were measured by high performance liquid chromatography. RESULTS: Absorption of IP pemetrexed in portal and systemic blood was significantly higher using the open compared to the closed abdomen technique (93.17 vs 52.50 µg/mL, P < 0.001) and (76.26 vs 51.65 µg/mL, P < 0.001), respectively. No difference was found between the two techniques on the peritoneal tissue concentration of pemetrexed (18.07 vs 19.17 µg/g, P = 0.51). CONCLUSION: Peritoneal absorption of pemetrexed is not modified by the use of either technique. However, systemic concentrations of pemetrexed increased using the open technique, suggesting it could increase systemic toxicity.


Subject(s)
Abdominal Cavity , Antineoplastic Agents/administration & dosage , Disease Models, Animal , Drug Delivery Systems , Pemetrexed/administration & dosage , Peritoneal Neoplasms/drug therapy , Animals , Male , Rats , Rats, Sprague-Dawley
12.
PLoS One ; 12(5): e0176650, 2017.
Article in English | MEDLINE | ID: mdl-28459862

ABSTRACT

Chronic kidney disease is associated with homeostatic imbalances such as insulin resistance. However, the underlying mechanisms leading to these imbalances and whether they promote the development of type 2 diabetes is unknown. The effect of chronic kidney disease on insulin resistance was studied on two different rat strains. First, in a 5/6th nephrectomised Sprague-Dawley rat model of chronic kidney disease, we observed a correlation between the severity of chronic kidney disease and hyperglycemia as evaluated by serum fructosamine levels (p<0.0001). Further, glucose tolerance tests indicated an increase of 25% in glycemia in chronic kidney disease rats (p<0.0001) as compared to controls whereas insulin levels remained unchanged. We also observed modulation of glucose transporters expression in several tissues such as the liver (decrease of ≈40%, p≤0.01) and muscles (decrease of ≈29%, p≤0.05). Despite a significant reduction of ≈37% in insulin-dependent glucose uptake in the muscles of chronic kidney disease rats (p<0.0001), the development of type 2 diabetes was never observed. Second, in a rat model of metabolic syndrome (Zucker Leprfa/fa), chronic kidney disease caused a 50% increased fasting hyperglycemia (p<0.0001) and an exacerbated glycemic response (p<0.0001) during glucose challenge. Similar modulations of glucose transporters expression and glucose uptake were observed in the two models. However, 30% (p<0.05) of chronic kidney disease Zucker rats developed characteristics of type 2 diabetes. Thus, our results suggest that downregulation of GLUT4 in skeletal muscle may be associated with insulin resistance in chronic kidney disease and could lead to type 2 diabetes in predisposed animals.


Subject(s)
Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Type 2/metabolism , Insulin Resistance/physiology , Renal Insufficiency, Chronic/metabolism , Animals , Disease Progression , Glucose/metabolism , Glucose Transporter Type 4/metabolism , Glycosuria/metabolism , Liver/metabolism , Male , Muscle, Skeletal/metabolism , Nephrectomy , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Rats, Zucker , Risk , Sodium-Glucose Transport Proteins/metabolism , Tissue Culture Techniques
13.
Biomark Insights ; 11: 91-4, 2016.
Article in English | MEDLINE | ID: mdl-27398022

ABSTRACT

OBJECTIVE: The aim of our study is to describe the changes in urinary and serum levels of novel biomarkers after gadolinium contrast administration in patients with normal renal function. METHODS: We measured four biomarkers in 28 volunteers: interleukin-18 (IL-18), N-acetyl-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin, and cystatin C. Urinary and serum samples were collected at 0, 3, and 24 hours following gadolinium administration. RESULTS: Baseline serum creatinine was 57.8 ± 34.5 µmol/L and remained stable. Urinary IL-18 levels increased significantly at three hours (10.7 vs. 7.3 ng/mg creatinine; P < 0.05). Similarly, urinary NAG levels increased significantly at three hours (3.9 vs. 2.2 IU/mg creatinine; P < 0.001). For both these markers, the difference was no longer significant at 24 hours. No statistically significant differences were observed for urinary and serum neutrophil gelatinase-associated lipocalin levels and for serum cystatin C levels. CONCLUSIONS: Urinary IL-18 and NAG levels increased transiently after administration of gadolinium-based contrast agents in patients with normal renal function.

14.
Surg Oncol ; 25(4): 435-440, 2016 Dec.
Article in English | MEDLINE | ID: mdl-27251757

ABSTRACT

BACKGROUND: Pemetrexed is a systemic chemotherapeutic agent used in the treatment of malignant mesothelioma. This drug represents a potentially promising intraperitoneal (IP) agent to use for hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of peritoneal mesothelioma. However, this has yet to be supported by preclinical studies. Therefore, we aimed to study the effect of pemetrexed dose and perfusion temperature on the resultant pemetrexed concentration in 3 different compartments (systemic circulation, portal circulation and peritoneal tissues) using a murine model. METHODS: Under general anesthesia, 29 Sprague-Dawley rats were submitted to 3 different doses of IP pemetrexed (500, 1000 and 1500 mg/m2) combined with 3 different perfusion temperatures (37, 40 and 43 °C) for a total duration of 25 min. At the end of perfusion, samples in different compartments (systemic circulation, portal circulation and peritoneum) were harvested and concentrations of pemetrexed were measured using high performance liquid chromatography. RESULTS: With increasing dose of IP pemetrexed, higher concentrations were measured in the 3 compartments tested. In peritoneal cells, the difference between IP doses of 500 and 1000 mg/m2 (2.03 vs. 19.17 µg/g, p < 0.001) was greater than the difference between 1000 and 1500 mg/m2 (19.17 vs. 22.80 µg/g, p = 0.027). When the perfusion temperature increased, we observed a proportional rise of pemetrexed concentration in both the portal and systemic compartments; while in the peritoneal cells, the pemetrexed concentration increased up to 40 °C, after which it plateaued. CONCLUSION: Both heat and increasing doses of IP pemetrexed enhance peritoneal cell concentration of pemetrexed. However, for temperatures above 40 °C, pemetrexed concentration reached a plateau in peritoneal cells. Systemic and portal concentrations increased proportionally with both increasing temperatures and IP doses. We believe these results should be taken into consideration for the design of an eventual clinical study in humans.


Subject(s)
Antineoplastic Agents/pharmacokinetics , Pemetrexed/pharmacokinetics , Peritoneum/drug effects , Peritoneum/metabolism , Animals , Antineoplastic Agents/administration & dosage , Hot Temperature , Injections, Intraperitoneal , Male , Models, Animal , Pemetrexed/administration & dosage , Rats , Rats, Sprague-Dawley , Tissue Distribution
15.
Int J Hyperthermia ; 32(6): 643-7, 2016 09.
Article in English | MEDLINE | ID: mdl-27270101

ABSTRACT

BACKGROUND: The use of electrocautery devices is associated with complications such as perforation or fistulisation when used near intestinal structures. This is likely due to its effect on vascularisation of the bowel wall. To test this hypothesis we established a murine model to quantify the effect of electrocautery injury on the intestinal microvascularisation. METHODS: Sprague-Dawley rats were subjected to five electrocautery injuries on the small bowel in coagulation mode (30 W intensity) and in cut mode (40 W, 80 W and 200 W intensities) for durations of 1, 2 and 5 s. 5 mg/kg of fluorescein was injected intravenously, the injured bowel segments harvested and the rat sacrificed. The segments were analysed to measure the fluorescence of injured bowel compared to adjacent unharmed tissue. RESULTS: A significant decrease in bowel wall microvascularisation occurred with increasing intensity (coag 30 W/cut 40 W versus cut 200 W 1 s: p < 0.05) and duration of electrocautery injury (cut 40 W 1/2 s versus 5 s: p < 0.05). There was a 40% perforation rate when decreased bowel wall microvascularisation was 25% or more. Despite similar electrocautery injury, a significantly greater microvascularisation decrease was observed in jejunum compared to ileum (p < 0.05). CONCLUSION: We successfully established a murine model to quantify the decrease of bowel wall microvascularisation associated with electrocautery use. Unsurprisingly, the decrease in microvascularisation is greater with higher intensity and duration of electrocautery and is associated with more perforations in the experimental model. The jejunum seems more vulnerable to electrocautery injury than the ileum. These observations support caution when using electrocautery devices near intestinal structures.


Subject(s)
Electrocoagulation/adverse effects , Ileum/blood supply , Ileum/surgery , Jejunum/blood supply , Jejunum/surgery , Animals , Male , Microvessels , Rats, Sprague-Dawley
16.
Drug Metab Dispos ; 44(8): 1174-9, 2016 08.
Article in English | MEDLINE | ID: mdl-27271372

ABSTRACT

Chronic renal failure (CRF) impedes renal excretion of drugs and their metabolism by reducing the expression of liver cytochrome P450 (P450). Uremic serum contains factors, such as parathyroid hormone (PTH), that decrease liver P450s. The P450s are also involved in the metabolism of xenobiotics in the brain. This study investigates: 1) the effects of CRF on rat brain P450, 2) the role of PTH in the downregulation of brain P450s in CRF rats, and 3) the effects of PTH on P450s in astrocytes. Protein and mRNA expression of P450s were assessed in the brain of CRF and control (CTL) rats, as well as from CTL or CRF rats that underwent parathyroidectomy (PTX) 1 week before nephrectomy. CYP3A activity was measured using 3-[(3, 4-difluorobenzyl) oxy]-5, 5-dimethyl-4-[4-methylsulfonyl) phenyl] furan-2(5H)-1 metabolism in brain microsomal preparation. CYP3A protein expression was assessed in primary cultured astrocytes incubated with serum obtained from CRF or CTL rats or with PTH. Significant downregulations (≥40%) of CYP1A, CYP2C11, and CYP3A proteins were observed in microsomes from CRF rat brains. CYP3A activity reduction was also observed. CYP3A expression and activity were unaffected in PTX-pretreated CRF rats. Serum of PTX-treated CRF rats had no impact on CYP3A levels in astrocytes compared with that of untreated CRF rats. Finally, PTH addition to normal calf serum induced a reduction in CYP3A protein similar to CRF serum, suggesting that CRF-induced hyperparathyroidism is associated with a significant decrease in P450 drug-metabolizing enzymes in the brain, which may have implications in drug response.


Subject(s)
Brain/enzymology , Cytochrome P-450 Enzyme System/metabolism , Kidney Failure, Chronic/enzymology , Animals , Aryl Hydrocarbon Hydroxylases/genetics , Aryl Hydrocarbon Hydroxylases/metabolism , Astrocytes/enzymology , Cells, Cultured , Cytochrome P-450 CYP1A1/genetics , Cytochrome P-450 CYP1A1/metabolism , Cytochrome P-450 CYP2E1/genetics , Cytochrome P-450 CYP2E1/metabolism , Cytochrome P-450 CYP3A/genetics , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 Enzyme System/genetics , Cytochrome P450 Family 2/genetics , Cytochrome P450 Family 2/metabolism , Disease Models, Animal , Gene Expression Regulation, Enzymologic , Kidney Failure, Chronic/genetics , Male , Nephrectomy , Parathyroid Hormone/metabolism , Parathyroidectomy , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Steroid 16-alpha-Hydroxylase/genetics , Steroid 16-alpha-Hydroxylase/metabolism
17.
Oxid Med Cell Longev ; 2016: 8627384, 2016.
Article in English | MEDLINE | ID: mdl-26989455

ABSTRACT

We studied the age-dependent regulation of the expression of the antioxidant enzyme manganese superoxide dismutase (MnSOD encoded by Sod2) through promoter methylation. C57Bl/6 mice were either (i) sedentary (SED), (ii) treated with the antioxidant catechin (CAT), or (iii) voluntarily exercised (EX) from weaning (1-month old; mo) to 9 mo. Then, all mice aged sedentarily and were untreated until 12 mo. Sod2 promoter methylation was similar in all groups in 9 mo but decreased (p < 0.05) in 12 mo SED mice only, which was associated with an increased (p < 0.05) transcriptional activity in vitro. At all ages, femoral artery endothelial function was maintained; this was due to an increased (p < 0.05) contribution of eNOS-derived NO in 12 mo SED mice only. CAT and EX prevented these changes in age-related endothelial function. Thus, a ROS-dependent epigenetic positive regulation of Sod2 gene expression likely represents a defense mechanism prolonging eNOS function in aging mouse femoral arteries.


Subject(s)
Aging/metabolism , DNA Methylation , Femoral Artery/enzymology , Promoter Regions, Genetic , Superoxide Dismutase/biosynthesis , Transcription, Genetic , Aging/drug effects , Aging/genetics , Animals , Catechin/pharmacology , Mice , Nitric Oxide/genetics , Nitric Oxide/metabolism , Nitric Oxide Synthase Type III/biosynthesis , Nitric Oxide Synthase Type III/genetics , Physical Conditioning, Animal , Superoxide Dismutase/genetics
18.
J Chromatogr Sci ; 54(4): 554-60, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26657732

ABSTRACT

A simple and rapid liquid chromatographic-tandem mass spectrometric method has been developed and validated for the enantiospecific determination of R- and S-warfarin in human urine. Warfarin enantiomers were extracted from urine using methyl tert-butyl ether. Chromatographic separation of warfarin enantiomers and the internal standard d5-warfarin was achieved using a Astec Chirobiotic V column with gradient mobile phase at a flow rate of 400 µL/min over 10 min. Detection was performed on a TSQ Quantum Ultra triple quadrupole mass spectrometer equipped with a heated electrospray ionization source. Analytes were detected in negative ionization mode using selected reaction monitoring. Calibration curves were linear with a correlation coefficient of ≥0.996 for both enantiomers over a concentration range of 5-500 ng/mL. The intra- and interday accuracy and precision for both analytes were within ±9.0%. Excellent extraction efficiency and negligible matrix effects were observed. The applicability of the method was demonstrated by successful measurement of warfarin enantiomers in urine of patients with kidney disease. The method is simple, accurate and reproducible and is currently being used to support warfarin pharmacokinetic studies.


Subject(s)
Anticoagulants/urine , Chromatography, High Pressure Liquid/methods , Tandem Mass Spectrometry/methods , Warfarin/urine , Calibration , Humans , Reproducibility of Results , Spectrometry, Mass, Electrospray Ionization , Stereoisomerism , Warfarin/chemistry
19.
Drug Metab Dispos ; 43(12): 1960-5, 2015 Dec.
Article in English | MEDLINE | ID: mdl-26438628

ABSTRACT

1-Aminobenzotriazole (ABT) is regularly used in vivo as a nonspecific and irreversible cytochrome P450 inhibitor to elucidate the role of metabolism on the pharmacokinetic profile of xenobiotics. However, few reports have considered the recent findings that ABT can alter drug absorption or have investigated the possible differential inhibition of ABT on intestinal and hepatic metabolism. To address these uncertainties, pharmacokinetic studies under well controlled and defined ABT pretreatment conditions (50 mg/kg, 1 hour ABT i.v. and 16 hours ABT p.o.) were conducted prior to the oral administration of metoprolol, a permeable P450 probe that undergoes extensive intestinal and hepatic metabolism. The pharmacokinetic profile of metoprolol was affected differently by the two ABT pretreatments. An increase in area under the curve of 16-fold with ABT p.o. and 6.5-fold with ABT i.v. was observed compared with control. Based on in vitro studies, this difference could not be attributed to a differential inhibition of intestinal and hepatic metabolism. In the ABT i.v. pretreatment group, the increase in area under the curve was also associated with a prolonged time at maximal concentration (24-fold versus control), suggesting a delay in absorption. This was further confirmed by the administration of a charcoal meal, which resulted in a 7-fold increase in stomach weights in the 1-hour ABT pretreated groups compared with the untreated or 16-hour ABT pretreated rats. Based on these results, we recommend pretreating rats with ABT p.o. 16 hours before the administration of a test compound to preserve the inhibitory effect on intestinal and hepatic metabolism and avoid the confounding effect on drug absorption.


Subject(s)
Metoprolol/metabolism , Triazoles/metabolism , Animals , Drug Interactions/physiology , Gastric Emptying/drug effects , Gastric Emptying/physiology , Male , Metoprolol/chemistry , Metoprolol/pharmacology , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Rats , Rats, Sprague-Dawley , Triazoles/chemistry , Triazoles/pharmacology
20.
Nephrol Ther ; 11(3): 144-51, 2015 Jun.
Article in French | MEDLINE | ID: mdl-25861715

ABSTRACT

The prevalence and incidence of chronic kidney disease (CKD) has steadily increased over the past two decades attributed to an important raise of cases of diabetes, hypertension and obesity, leading risk factors of renal failure. CKD is known to impair drug disposition of non-renally eliminated medications that may lead to unintended toxicity or lower therapeutic effect despite dose adjustment according to glomerular filtration rate (GFR). Modulation of metabolism enzymes (cytochrome P450, phase II) and drug transporters in various organs (intestines, liver, kidneys and brain) are being held responsible for altered pharmacokinetics where uremic toxins, inflammatory cytokines and parathyroid hormone, common factors present in CKD, may be considered possible culprits. This review gives a thorough summary of the recent preclinical, clinical studies and Food and Drug Administration (FDA) guidelines and allows a current understanding of drug absorption, distribution, metabolism and excretion in CKD.


Subject(s)
Renal Insufficiency, Chronic/drug therapy , Renal Insufficiency, Chronic/metabolism , Renal Insufficiency/drug therapy , Renal Insufficiency/metabolism , Glomerular Filtration Rate , Humans , Organ Specificity , Pharmaceutical Preparations , Pharmacokinetics , Renal Insufficiency/pathology , Renal Insufficiency, Chronic/pathology
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