Publications
58 results found
Wiegman CH, Adcock IM, Rothaul A, et al., 2015, THE SELECTIVE PAN-JANUS KINASE (JAK) INHIBITOR VR588 DEMONSTRATES POTENT ANTI-INFLAMMATORY ACTIVITY IN A MURINE CHRONIC HOUSE DUST MITE (HDM) MODEL OF ASTHMA, 20th ISAM Congress, Publisher: Mary Ann Liebert, Pages: A22-A23, ISSN: 1941-2711
Rationale: Janus kinases have a key role in cytokine signalling inasthma. VR588 is a potent, balanced and selective pan-JAK inhibitor.This study investigates the pharmacokinetics (PK) of inhaled VR588and its in-vivo efficacy in an asthma model.A-22 POSTER ABSTRACTSMethods: Murine lung and plasma VR588 PK were measured for 24hours following intranasal (i.n) delivery (1.5 to 50 mg/kg; n¼6 per group).HDM extract (25 lg) was given i.n 5 days/week for 3 weeks with i.nVR588 doses (1.5 to 7.5 mg/kg) given 1 hour prior; another group receivedi.n VR588 7.5 mg/kg during only the last week of HDM exposure(n¼8). Oral tofacitinib (T)(15 mg/kg) and i.n fluticasone propionate(FP)(1.5 mg/kg) were controls. Airway hyperresponsiveness (AHR) wasassessed 24 hours after the last HDM; bronchoalveolar lavage fluid (BAL)was assessed for differential cell count, STAT activation and cytokines.Results: VR588 i.n rapidly (5 mins) achieved dose related lunglevels which stayed at relevant levels for 24 hours; plasma levels were1000-fold less. VR588 resulted in significant AHR reduction, at leastequal to FP. All VR588 doses significantly reduced BAL total cellcount with some doses inhibiting cell differentials. VR588 attenuatedcytokine release (IL-4, IL-5, IL-17) compared with saline control andactivation of STAT 3 at 24 hrs comparable to FP and T.Conclusions: VR588 i.n has a PK profile suited to inhaled delivery.Attenuation of HDM inflammation suggests that inhaled VR588 mayrepresent a novel treatment for asthma.
Seiffert J, Hussain F, Wiegman C, et al., 2015, Pulmonary Toxicity of Instilled Silver Nanoparticles: Influence of Size, Coating and Rat Strain, PLOS ONE, Vol: 10, ISSN: 1932-6203
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- Citations: 79
Zhang P, Li F, Wiegman CH, et al., 2015, Inhibitory Effect of Hydrogen Sulfide on Ozone-Induced Airway Inflammation, Oxidative Stress, and Bronchial Hyperresponsiveness, AMERICAN JOURNAL OF RESPIRATORY CELL AND MOLECULAR BIOLOGY, Vol: 52, Pages: 129-137, ISSN: 1044-1549
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- Citations: 33
Wiegman CH, Russell KE, Seiffert J, et al., 2015, The Selective Pan-Janus Kinase (jak) Inhibitor Vr588 Demonstrates Potent Anti-Inflammatory Activity In A Murine Chronic House Dust Mite (hdm) Model Of Asthma, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
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- Citations: 6
Haji G, Weigman C, Patel M, et al., 2014, Mitochondrial membrane potential in the airway and skeletal muscle compartments of smokers with and without COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Michaeloudes C, Wiegman C, Kirkham P, et al., 2014, Mitochondrial reactive oxygen species (ROS) mediate proliferation and cytokine release in airway smooth muscle cells of patients with COPD, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Wiegman CH, Li F, Clarke CJ, et al., 2014, A comprehensive analysis of oxidative stress in the ozone-induced lung inflammation mouse model, CLINICAL SCIENCE, Vol: 126, Pages: 425-440, ISSN: 0143-5221
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- Citations: 52
Haji G, Wiegman C, Patel M, et al., 2013, MITOCHONDRIAL DYSFUNCTION IN MUSCLE AND AIRWAY COMPARTMENTS IN COPD: PRELIMINARY FINDINGS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A161-A162, ISSN: 0040-6376
Li F, Wiegman C, Seiffert JM, et al., 2013, Effects of N-acetylcysteine in ozone-induced chronic obstructive pulmonary disease model, PLOS One, Vol: 8, ISSN: 1932-6203
Seiffert J, Weigman C, Feng L, et al., 2013, Determinants of inflammatory and functional toxicity of silver nanospheres in rat lung, EUROPEAN RESPIRATORY JOURNAL, Vol: 42, ISSN: 0903-1936
Michaeloudes C, Narang P, Wiegman CHC, et al., 2013, Effect of oxidative stress on mitochondrial function in airway smooth muscle (ASM) cells from COPD patients, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Pinart M, Zhang M, Li F, et al., 2013, IL-17A Modulates Oxidant Stress-Induced Airway Hyperresponsiveness but Not Emphysema, PLOS ONE, Vol: 8, ISSN: 1932-6203
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- Citations: 29
Li F, Wiegman C, Seiffert J, et al., 2012, Effects of N-acetylcysteine on airway inflammation, airway hyperresponsiveness and abnormal lung function in chronic ozone-induced COPD model, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Durham AL, Wiegman C, Adcock IM, 2011, Epigenetics of asthma, Vol: 1810, Pages: 1103-1109, ISSN: 0304-4165
Wiegman CH, Moriceau NOJ, Paul-Clark MJ, et al., 2010, Effect Of Short-term (3 Day) Cigarette Smoke-exposure In Mice On Histone Deacetylase (HDAC)2 And Hypoxia Inducible Factor (HIF)-1α Function, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 181, ISSN: 1073-449X
Sun X, Burden J, Wiegman C, et al., 2004, Sorting motifs in the intracellular domain of the low density lipoprotein (LDL) receptor interact with a novel domain of sorting nexin-17, 74th Congress of the European-Atherosclerosis-Society, Publisher: ELSEVIER SCI IRELAND LTD, Pages: 78-78, ISSN: 1567-5688
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- Citations: 13
Wiegman CH, Bandsma RHJ, Ouwens M, et al., 2003, Hepatic VLDL production in <i>ob</i>/<i>ob</i> mice is not stimulated by massive de novo lipogenesis but is less sensitive to the suppressive effects of insulin, DIABETES, Vol: 52, Pages: 1081-1089, ISSN: 0012-1797
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- Citations: 72
Gustafson LA, Kuipers F, Wiegman C, et al., 2002, Clofibrate improves glucose tolerance in fat-fed rats but decreases hepatic glucose consumption capacity., Journal of Hepatology
BACKGROUND/AIMS: High-fat (HF) diets cause glucose intolerance. Fibrates improve glucose tolerance. We have tried to obtain information on possible hepatic mechanisms contributing to this effect.METHODS: Rats were fed a HF diet, isocaloric with the control diet, for 3 weeks without or with clofibrate. Several parameters related to liver glucose and glycogen metabolism were measured.RESULTS: Clofibrate prevented the induction of glucose intolerance by 3 weeks HF feeding. Improved glucose tolerance by clofibrate was not due to increases in glucose phosphorylation or glycolysis in the liver, since both the HF diet and clofibrate suppressed glucokinase and pyruvate kinase activities with no effect on glucose 6-phosphatase. Clofibrate decreased glycogen storage in both control and HF rats. Clofibrate, with and without HF feeding, inhibited weight gain during the experimental period. Body temperature was significantly elevated by clofibrate, indicative of an increased basal metabolic rate. The capacity of liver mitochondria to oxidize long-chain fatty acids increased by clofibrate treatment. Mitochondria did not show uncoupling.CONCLUSIONS: Clofibrate does not improve glucose tolerance by improving hepatic glucose or glycogen metabolism. Peripheral glucose oxidation may be facilitated by increased energy dissipation.
Gustafson LA, Kuipers F, Wiegman C, et al., 2002, Clofibrate improves glucose tolerance in fat-fed rats but decreases hepatic glucose consumption capacity, Journal of Hepatology, Vol: 37, Pages: 425-431
Background/Aims: High-fat (HF) diets cause glucose intolerance. Fibrates improve glucose tolerance. We have tried to obtain information on possible hepatic mechanisms contributing to this effect.Methods: Rats were fed a HF diet, isocaloric with the control diet, for 3 weeks without or with clofibrate. Several parameters related to liver glucose and glycogen metabolism were measured.Results: Clofibrate prevented the induction of glucose intolerance by 3 weeks HF feeding. Improved glucose tolerance by clofibrate was not due to increases in glucose phosphorylation or glycolysis in the liver, since both the HF diet and clofibrate suppressed glucokinase and pyruvate kinase activities with no effect on glucose 6-phosphatase. Clofibrate decreased glycogen storage in both control and HF rats. Clofibrate, with and without HF feeding, inhibited weight gain during the experimental period. Body temperature was significantly elevated by clofibrate, indicative of an increased basal metabolic rate. The capacity of liver mitochondria to oxidize long-chain fatty acids increased by clofibrate treatment. Mitochondria did not show uncoupling.Conclusions: Clofibrate does not improve glucose tolerance by improving hepatic glucose or glycogen metabolism. Peripheral glucose oxidation may be facilitated by increased energy dissipation.
Wiegman CH, Van Dijk TH, Romijn JA, et al., 2002, High fat feeding in rats abolishes the ability of insulin to suppress <i>de novo</i> synthesis of glucose-6-phosphate, DIABETES, Vol: 51, Pages: A333-A333, ISSN: 0012-1797
Bandsma RHJ, Wiegman CH, Herling AW, et al., 2001, Acute inhibition of glucose-6-phosphate translocator activity leads to increased de novo lipogenesis and development of hepatic steatosis without affecting VLDL production in rats, DIABETES, Vol: 50, Pages: 2591-2597, ISSN: 0012-1797
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- Citations: 53
van Dijk TH, van der Sluijs FH, Wiegman CH, et al., 2001, Acute inhibition of hepatic glucose-6-phosphatase does not affect gluconeogenesis but directs gluconeogenic flux toward glycogen in fasted rats - A pharmacological study with the chlorogenic acid derivative S4048, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 276, Pages: 25727-25735, ISSN: 0021-9258
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- Citations: 76
Wiegman CH, Havinga R, Sauerwein HP, et al., 2001, Less effective suppression of hepatic very low density lipoprotein (VLDL) production by insulin in rats fed a high-fat diet, DIABETES, Vol: 50, Pages: A324-A324, ISSN: 0012-1797
Bandsma RHJ, Wiegman CH, Herling AW, et al., 2001, Acute Inhibition of Glucose-6-Phosphate Translocator Activity Leads to Increased de Novo Lipogenesis and Development of Hepatic Steatosis Without Affecting VLDL Production in Rats, Diabetes, Vol: 50, Pages: 2591-2597, ISSN: 0012-1797
Glucose-6-phosphatase (G6Pase) is a key enzyme in hepatic glucose metabolism. Altered G6Pase activity in glycogen storage disease and diabetic states is associated with disturbances in lipid metabolism. We studied the effects of acute inhibition of G6Pase activity on hepatic lipid metabolism in nonanesthetized rats. Rats were infused with an inhibitor of the glucose-6-phosphate (G6P) translocator (S4048, 30 mg · kg-1 · h-1) for 8 h. Simultaneously, [1-13C]acetate was administered for determination of de novo lipogenesis and fractional cholesterol synthesis rates by mass isotopomer distribution analysis. In a separate group of rats, Triton WR 1339 was injected for determination of hepatic VLDL-triglyceride production. S4048 infusion significantly decreased plasma glucose (-11%) and insulin (-48%) levels and increased hepatic G6P (201%) and glycogen (182%) contents. Hepatic triglyceride contents increased from 5.8 ± 1.4 μmol/g liver in controls to 20.6 ± 5.5 μmol/g liver in 84048-treated animals. De novo lipogenesis was increased > 10-fold in 84048-treated rats, without changes in cholesterol synthesis rates. Hepatic mRNA levels of acetyl-CoA carboxylase and fatty acid synthase were markedly induced. Plasma triglyceride levels increased fourfold, but no differences in plasma cholesterol levels were seen. Surprisingly, hepatic VLDL-triglyceride secretion was not increased in 84048-treated rats. These studies demonstrate that inhibition of the G6Pase system leads to acute stimulation of fat synthesis and development of hepatic steatosis, without affecting hepatic cholesterol synthesis and VLDL secretion. The results emphasize the strong interactions that exist between hepatic carbohydrate and fat metabolism.
Benthem L, Keizer K, Wiegman CH, et al., 2000, Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation, AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, Vol: 279, Pages: E1286-E1293, ISSN: 0193-1849
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- Citations: 63
Wiegman CH, Bandsma RHJ, Herling AW, et al., 2000, Acute inhibition of glucose-6-phosphatase by S4048 leads to increased de novo lipogenesis and development of fatty liver without affecting VLDL production in rats, DIABETES, Vol: 49, Pages: A291-A291, ISSN: 0012-1797
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- Citations: 1
Van Dijk TH, Wiegman C, Gustafson LA, et al., 2000, Acute inhibition of glucose-6-phosphatase by S4038 increases glycogen synthesis from gluconeogenic precursors and from glucose in fasted rat, Publisher: AMER DIABETES ASSOC, Pages: A291-A291, ISSN: 0012-1797
Benthem L, Keizer K, Wiegman CH, et al., 2000, Excess portal venous long-chain fatty acids induce syndrome X via HPA axis and sympathetic activation, American Journal of Physiology - Endocrinology and Metabolism, Vol: 279, ISSN: 0193-1849
We tested the hypothesis that excessive portal venous supply of long-chain fatty acids to the liver contributes to the development of insulin resistance via activation of the hypothalamus-pituitary-adrenal axis (HPA axis) and sympathetic system. Rats received an intraportal infusion of the long-chain fatty acid oleate (150 nmol/min, 24 h), the medium-chain fatty acid caprylate, or the solvent. Corticosterone (Cort) and norepinephrine (NE) were measured as indexes for HPA axis and sympathetic activity, respectively. Insulin sensitivity was assessed by means of an intravenous glucose tolerance test (IVGTT). Oleate infusion induced increases in plasma Cort (Δ = 13.5 ± 3.6 μg/dl; P < 0.05) and NE (Δ = 235 ± 76 ng/l; P < 0.05), whereas caprylate and solvent had no effect. The area under the insulin response curve to the IVGTT was larger in the oleate-treated group than in the caprylate and solvent groups (area = 220 ± 35 vs. 112 ± 13 and 106 ± 8, respectively, P < 0.05). The area under the glucose response curves was comparable [area = 121 ± 13 (oleate) vs. 135 ± 20 (caprylate) and 96 ± 11 (solvent)]. The results are consistent with the concept that increased portal free fatty acid is involved in the induction of visceral obesity-related insulin resistance via activation of the HPA axis and sympathetic system.
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