fumarates and Body-Weight

Calcium salts of long-chain fatty acids (CSFA) from linseed oil have the potential to reduce methane (CH4) production from ruminants; however, there is little information on the effect of supplementary CSFA on rumen microbiome as well as CH4 production. The aim of the present study was to evaluate the effects of supplementary CSFA on ruminal fermentation, digestibility, CH4 production, and rumen microbiome in vitro. We compared five treatments: three CSFA concentrations-0% (CON), 2.25% (FAL) and 4.50% (FAH) on a dry matter (DM) basis-15 mM of fumarate (FUM), and 20 mg/kg DM of monensin (MON). The results showed that the proportions of propionate in FAL, FAH, FUM, and MON were increased, compared with CON (P < 0.05). Although DM and neutral detergent fiber expressed exclusive of residual ash (NDFom) digestibility decreased in FAL and FAH compared to those in CON (P < 0.05), DM digestibility-adjusted CH4 production in FAL and FAH was reduced by 38.2% and 63.0%, respectively, compared with that in CON (P < 0.05). The genera Ruminobacter, Succinivibrio, Succiniclasticum, Streptococcus, Selenomonas.1, and Megasphaera, which are related to propionate production, were increased (P < 0.05), while Methanobrevibacter and protozoa counts, which are associated with CH4 production, were decreased in FAH, compared with CON (P < 0.05). The results suggested that the inclusion of CSFA significantly changed the rumen microbiome, leading to the acceleration of propionate production and the reduction of CH4 production. In conclusion, although further in vivo study is needed to evaluate the reduction effect on rumen CH4 production, CSFA may be a promising candidate for reduction of CH4 emission from ruminants.

Topics: Animal Feed; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Calcium; Cluster Analysis; Detergents; Digestion; DNA, Bacterial; Fatty Acids; Fermentation; Fumarates; Gases; In Vitro Techniques; Linseed Oil; Megasphaera; Methane; Microbiota; Monensin; RNA, Ribosomal, 16S; Rumen; Salts; Selenomonas; Sheep; Silage; Streptococcus

Fumaric acid esters (FAE) have been used for over 30 years in the management of psoriasis. There have been a number of case reports linking the use of FAE with nephrotoxicity, including acute renal injury and Fanconi syndrome. However, one large multicentre retrospective trial showed no evidence of renal dysfunction with FAE.. The aim of this study was to determine the number of patients in our institution being treated with FAE who developed significant proteinuria or renal dysfunction.. This was a single-centre retrospective study assessing all patients on FAE who attended for follow-up during an 18-week period between February and June 2015. Demographics, comorbidities, duration and dose of treatment with FAE, proteinuria, renal function and other biochemical serum abnormalities were recorded.. One hundred and twenty-seven patients were included in the study. Eighty-two patients had proteinuria detected at some stage during treatment with FAE, and 18 of these had persistent proteinuria (positive in at least three consecutive specimens, 12 weeks apart). Six patients (five female) developed proximal tubular dysfunction (PTD). The risk factors for the development of PTD appear to be lower bodyweight (P = 0.03), higher dose per weight (P = 0.03) and longer duration of treatment (P = 0.03). Renal dysfunction improved on discontinuation or dose reduction in FAE.. Fumaric acid esters are frequently associated with transient or persistent proteinuria. Significant renal dysfunction is rare and usually reversible on dose reduction or discontinuation of FAE. This study highlights the importance of screening for proteinuria. Higher doses per weight of treatment and longer duration of FAE therapy are likely risk factors for PTD.

Topics: Adult; Aged; Aged, 80 and over; Body Weight; Creatinine; Cross-Sectional Studies; Dermatologic Agents; Fanconi Syndrome; Female; Fumarates; Glomerular Filtration Rate; Humans; Male; Middle Aged; Proteinuria; Psoriasis; Retrospective Studies; Risk Factors; Time Factors; Young Adult

Results of the very first experiments conducted to evaluate therapeutic potentials of a fumarate containing Fumaria indica extract and of fairly low daily oral doses of monomethyl fumarate for prevention of chronic unavoidable foot-shock stress-induced gastric ulcers, and possible involvement of diverse neuro-hormonal and oxidative process in their stress response desensitizing effects are reported and discussed in this article. Preventive effects of 21 daily oral 60, 120, and 240 mg/kg doses of a standardized 50 % methanolic F. indica extract (MFI) and 1.25, 2.50, and 5.00 mg/kg/day of pure monomethyl fumarate (MMF) were compared in rats subjected to one hour daily unavoidable foot-shocks. A pharmaceutically well-standardized Withania somnifera (WS) root extract was used as a reference herbal anti-stress agent in all experiments. Effects of the treatments on stress-induced alterations in body weight, adrenal and spleen weights, gastric ulcer and ulcer index, weight of glandular stomach, protective mucosal glycoprotein content, cellular proliferation, oxidative stress on stomach fundus, and brain tissues of male rats were quantified. Other parameters quantified were plasma corticosterone levels, brain monoamine levels, and expressions of the cytokines TNF-α, IL-10, and IL-1β in blood and brain of stressed and treated rats. Most but not every observed stress-induced anomalies were suppressed or completely prevented by both MFI and pure MMF treatments in dose-dependent manner. Qualitatively, the observed activity profiles of both of them were similar to those of WS dose tested. These results reveal that both MFI and MMF are potent gastro-protective agents against chronic unavoidable stress-induced ulcers and strongly suggest that they act as regulators or modulators of monoamine, corticosterone, and cytokine homeostasis.

Topics: Animals; Body Weight; Brain; Chronic Disease; Corticosterone; Cytokines; Fumarates; Fumaria; Male; Maleates; Methanol; Organ Size; Plant Extracts; Protective Agents; Rats; Real-Time Polymerase Chain Reaction; Stomach; Stomach Ulcer; Stress, Psychological

The current investigation, designed to investigate the role of rutin in two-kidney one-clip (2K1C) induced renovascular dysfunction associated with hypertension in rat.. The renovascular hypertension was developed by the application of vascular clip on left renal artery in rats; the right kidney was kept as such throughout the experimental protocol. The rutin (200 and 300 mg/kg; p.o.) and aliskiren (50mg/kg; p.o.) were administered for 9 consecutive days. The battery of pathophysiological tests i.e., systolic pressure, diastolic pressure and heart rate were performed to assess the anti-hypertensive effect of rutin. In addition, changes of kidney weight/body weight (KW/BW) ratio along with plasma renin content and renal tissue biomarkers i.e., thiobarbituric acid reactive substance (TBAR) and reduced glutathione (GSH) levels were estimated.. The administration of rutin significantly (P<0.05) attenuated the 2K1C of left kidney induced elevated systolic and diastolic pressure in a dose dependent manner. In addition, it also reduces the ratio of KW/BW along with a decrease in plasma renin content, tissue TBARS and increase the GSH levels. There were no significant changes observed in heart rate. Similar results were observed in aliskiren treated group.. The anti-hypertensive effect of rutin may be a useful herbal medicine for the management of hypertension due to its potential free radical scavenging, inhibition of lipid peroxidation and plasma renin inhibitory action.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Dose-Response Relationship, Drug; Fumarates; Glutathione; Heart Rate; Hypertension, Renovascular; Male; Organ Size; Rats; Rats, Sprague-Dawley; Renin; Rutin; Thiobarbituric Acid Reactive Substances

Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, is involved in hypertension. We tested whether aliskiren treatment in early postnatal life can reduce ADMA and regulate the renin-angiotensin system to prevent hypertension in rat offspring exposed to maternal caloric restriction (CR).. Four groups of 12-week-old male offspring were sacrificed: control, CR, CR+aliskiren, and CR+losartan group. The CR group included offspring from 50% food-restricted maternal rats. The CR+aliskiren and CR+losartan groups were produced by treating CR offspring with oral aliskiren 10 mg/kg/day or losartan 20 mg/kg/day between 2-4 weeks of age, respectively.. Blood pressure increased in CR rats, which was prevented by aliskiren or losartan. CR increased plasma ADMA levels, which aliskiren prevented. Renal renin and prorenin receptor (PRR) expression increased in CR rats treated with aliskiren, whereas both were reduced by losartan. Both aliskiren and losartan decreased renal mRNA expression of angiotensinogen, angiotensin II type 2 receptor, and Mas in CR rats. However, aliskiren increased angiotensin II type 2 receptor and Mas protein levels in CR kidneys.. Early aliskiren therapy prevents CR-induced hypertension via ADMA reduction, decreases angiotensinogen expression, and increases renal angiotensin II type 2 receptor and Mas protein.

Topics: Amides; Angiotensin-Converting Enzyme 2; Animals; Animals, Newborn; Arginine; Blood Pressure; Blotting, Western; Body Weight; Caloric Restriction; Female; Fumarates; Gene Expression Regulation; Histone Deacetylases; Hypertension; Losartan; Male; Peptidyl-Dipeptidase A; Rats, Sprague-Dawley

Angiotensin-converting enzyme inhibitors and angiotensin AT1 receptor blockers reduce myocardial ischemia-reperfusion injury via bradykinin B2 receptor- and angiotensin AT2 receptor-mediated mechanisms. The renin inhibitor aliskiren increases cardiac tissue kallikrein and bradykinin levels. In the present study, we investigated the effect of aliskiren on myocardial ischemia-reperfusion injury and the roles of B2 and AT2 receptors in this effect. Female Sprague-Dawley rats were treated with aliskiren (10 mg/kg per day) and valsartan (30 mg/kg per day), alone or in combination, together with the B2 receptor antagonist icatibant (0.5 mg/kg per day) or the AT2 receptor antagonist PD123319 (30 mg/kg per day), for 4 weeks before myocardial ischemia-reperfusion injury. Aliskiren increased cardiac bradykinin levels and attenuated valsartan-induced increases in plasma angiotensin II levels. In vehicle-treated rats, myocardial infarct size (% area at risk, mean±SEM, n=7-13) was 43±3%. This was reduced to a similar extent by aliskiren, valsartan, and their combination to 24±3%, 25±3%, and 22±2%, respectively. Icatibant reversed the cardioprotective effects of aliskiren and the combination of aliskiren plus valsartan, but not valsartan alone, indicating that valsartan-induced cardioprotection was not mediated by the B2 receptor. PD123319 reversed the cardioprotective effects of aliskiren, valsartan, and the combination of aliskiren plus valsartan. Aliskiren protects the heart from myocardial ischemia-reperfusion injury via a B2 receptor- and AT2 receptor-mediated mechanism, whereas cardioprotection by valsartan is mediated via the AT2 receptor. In addition, aliskiren attenuates valsartan-induced increases in angiotensin II levels, thus preventing AT2 receptor-mediated cardioprotection by valsartan.

Topics: Amides; Angiotensin II Type 2 Receptor Blockers; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Bradykinin; Bradykinin B2 Receptor Antagonists; Cardiotonic Agents; Drug Therapy, Combination; Female; Fumarates; Imidazoles; Models, Animal; Myocardial Infarction; Myocardial Reperfusion Injury; Pyridines; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 2; Receptor, Bradykinin B2; Tetrazoles; Valine; Valsartan

Aliskiren is the first orally bioavailable direct renin inhibitor approved for the treatment of hypertension in adults. Juvenile toxicity studies in rats were initiated to support treatment in the pediatric population.. In Study 1, aliskiren oral administration was initiated on postpartum day (PPD) 14, after nephrogenesis was completed, and continued through PPD 70 at doses of 0, 30, 100, and 300 mg/kg/day. In-life, clinical pathology, anatomic pathology, developmental, behavioral, reproductive, and toxicokinetics evaluations were performed. In Study 2, oral administration was initiated on PPD 8, before completion of nephrogenesis, and continued through PPD 35/36. In-life, clinical pathology, anatomic pathology, developmental, and toxicokinetics evaluations were performed.. With dosing initiated on PPD 8, mortality at 100 and 300 mg/kg/day and slightly increased kidney weight at 100 mg/kg/day occurred. Decreased absolute lymphocyte count at 300 mg/kg/day at the end of dosing occurred with dosing initiated on PPD 14. There were clinical signs and transient effects on body weight gains in both studies. There were no changes in other parameters. Systemic exposure was much higher on PPD 8 and 14 compared with adult rats on PPD 64.. All effects produced by aliskiren, including kidney effects, were reversible. Increased exposure in very young animals is considered to be the result of immature drug transporter systems.

Topics: Administration, Oral; Amides; Animals; Antihypertensive Agents; Behavior, Animal; Body Weight; Dose-Response Relationship, Drug; Female; Fumarates; Hypertension; Kidney; Lymphocyte Count; Male; Maternal Exposure; Postpartum Period; Rats; Rats, Sprague-Dawley; Reproduction; Toxicity Tests; Toxicokinetics

In the present study, we investigated the ameliorative potential of aliskiren in dextran sulfate sodium (DSS) induced colitis in mice. Aliskiren (3 and 10mg/kg, i.p.) was administered for 10 days from the day of DSS administration. The severity of colitis in mice was assessed using body weight loss, colon and spleen weight, hematological parameters, food intake, stool consistency, rectal bleeding and colon shortening. Colonic malondialdehyde (MDA), myeloperoxidase (MPO) and renin mRNA levels were also estimated. Furthermore, TNF-α and IL-6 in plasma and colon were analyzed. The results showed that aliskiren (10mg/kg, i.p.) significantly improved the severity of colitis by, decrease in weight loss, improvement in food intake and stool consistency, decrease in rectal bleeding, decrease in relative colon and spleen weight and improvement in colonic shortening. Aliskiren (10mg/kg, i.p.) improved blood hemoglobin, red blood cells (RBC) and hematocrit. Colonic malondialdehyde (MDA), MPO and histolopathological score were significantly diminished by aliskiren (10mg/kg, i.p.). Furthermore, aliskiren (10mg/kg, i.p.) significantly diminished the elevated levels of TNF-α, IL-6 and renin mRNA in inflammed colon. These results indicate involvement of renin in colitis and inhibition of renin by aliskiren ameliorates colitis.

Topics: Amides; Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Colitis; Colon; Cytokines; Dextran Sulfate; Eating; Erythrocytes; Female; Fumarates; Gene Expression Regulation; Hematocrit; Hemoglobins; Malondialdehyde; Mice; Organ Size; Peroxidase; Renin; RNA, Messenger; Spleen

Aliskiren, a direct renin inhibitor (DRI), has therapeutic effects in patients with hypertension and associated complications, but its potential mechanism in diabetic nephropathy is lacking. The effects of aliskiren in Streptozotocin (STZ)-induced renal complication in diabetic rats were investigated. Aliskiren treatment for eight weeks at the dose of 10 mg/kg/day, via osmotic mini-pump, induced improvement in blood glucose levels, systolic blood pressure (BP) and serum creatinine. Improvement of insulin resistance by aliskiren was confirmed by increased glucose translocation in liver and muscle and hence insulin levels. The treated group also showed improvement in glomerulosclerosis and tubulointerstitial injury. Aliskiren treatment also improved albumin levels in plasma, suppressed profibrotic and proinflammatory cytokine synthesis viz TNF-α and TGF-β and angiogenesis by a decrease in VEGF. In addition, the level of total proteins and GFR via cystatin c and beta-2microglobulin along with adiponectin and erythropoietin were also improved. These results suggest that the beneficial organ protective effect of aliskiren is mediated by improvement in insulin resistance as well as a direct anti-fibrotic effect in the target organ in STZ-induced diabetic rats with a slight effect on blood pressure. Aliskiren may be a useful therapeutic agent in the treatment of type 2 diabetes and diabetic nephropathy.

Topics: Amides; Animals; Biomarkers; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Nephropathies; DNA Fragmentation; Extracellular Matrix; Fumarates; Glomerular Filtration Rate; Glucose Transporter Type 2; Glucose Transporter Type 4; Hemodynamics; Humans; Inflammation; Insulin; Insulin Resistance; Liver; Mice; Muscles; Rats; Rats, Wistar; ROC Curve

Doxorubicin (DXR) is one of the most effective and widely used anthracycline antibiotics. However, its clinical application is hampered by toxic effects in many organs. Nephrotoxicity is one of the major side effects of anthracycline antibiotics. This study was designed to investigate the possible protective effects of aliskiren (a direct renin inhibitor) in DXR-induced nephrotoxicity in rats.. Wistar albino rats were intraperitoneally (ip) injected with DXR and renin activity, albumin, total protein, urea, creatinine levels in plasma and ultrastructural changes in podocytes were assessed.. Rats subjected to DXR administration had significant (p<0.01) increases in systolic blood pressure, plasma renin activity, plasma concentration of urea, creatinine and tissue malondialdehyde and significant (p<0.01) reductions in plasma concentrations of albumin, total protein and antioxidant defense (reduced glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT)) in renal tissues. Furthermore, DXR-induced nephrotoxicity has also been characterized by broadening of podocyte foot processes, enlargement of glomerular basement membrane width and reduction in slit pore diameter. The above effects of DXR were significantly (p<0.01) prevented by aliskiren treatment.. These findings revealed that the blockade of renin activity by aliskiren is a promising approach in the treatment of DXR-induced nephrotoxicity.

Topics: Amides; Animals; Antioxidants; Benzimidazoles; Benzoates; Blood Pressure; Body Weight; Creatinine; Doxorubicin; Fumarates; Kidney Diseases; Lipid Peroxidation; Organ Size; Oxidative Stress; Podocytes; Rats; Rats, Wistar; Renin; Serum Albumin; Systole; Telmisartan; Urea

We have demonstrated previously that overactivity of the renin-angiotensin system (RAS) is associated with whole body and skeletal muscle insulin resistance in obese Zucker (fa/fa) rats. Moreover, this obesity-associated insulin resistance is reduced by treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor (type 1) blockers. However, it is currently unknown whether specific inhibition of renin itself, the rate-limiting step in RAS functionality, improves insulin action in obesity-associated insulin resistance. Therefore, the present study assessed the effect of chronic, selective renin inhibition using aliskiren on glucose tolerance, whole body insulin sensitivity, and insulin action on the glucose transport system in skeletal muscle of obese Zucker rats. Obese Zucker rats were treated for 21 days with either vehicle or aliskiren (50 mg/kg body wt ip). Renin inhibition was associated with a significant lowering (10%, P < 0.05) of resting systolic blood pressure and induced reductions in fasting plasma glucose (11%) and free fatty acids (46%) and homeostatic model assessment for insulin resistance (13%). Glucose tolerance (glucose area under the curve) and whole body insulin sensitivity (inverse of the glucose-insulin index) during an oral glucose tolerance test were improved by 15% and 16%, respectively, following chronic renin inhibition. Moreover, insulin-stimulated glucose transport activity in isolated soleus muscle of renin inhibitor-treated animals was increased by 36% and was associated with a 2.2-fold greater Akt Ser(473) phosphorylation. These data provide evidence that chronic selective inhibition of renin activity leads to improvements in glucose tolerance and whole body insulin sensitivity in the insulin-resistant obese Zucker rat. Importantly, chronic renin inhibition is associated with upregulation of insulin action on skeletal muscle glucose transport, and it may involve improved Akt signaling. These data support the strategy of targeting the RAS to improve both blood pressure regulation and insulin action in conditions of insulin resistance.

Topics: Amides; Animals; Biological Transport; Blood Pressure; Body Weight; Disease Models, Animal; Fatty Acids, Nonesterified; Female; Fumarates; Glucose; Insulin; Insulin Resistance; Muscle, Skeletal; Obesity; Phosphorylation; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; Renin; Signal Transduction

Topics: Amides; Animals; Bile Ducts; Blood Pressure; Body Weight; Fumarates; Hemodynamics; Hypertension, Portal; Ligation; Liver Cirrhosis, Experimental; Male; Nitric Oxide Synthase Type III; Rats; Rats, Sprague-Dawley; Renin-Angiotensin System

Aliskiren is a direct renin inhibitor (DRI) and provides an organ-protective effect in human and animal experiments. However, there is no current evidence of the effect of DRI on insulin resistance and metabolic abnormalities in type 2 diabetic animals. Methods. We investigated the effects and molecular mechanism of aliskiren in db/db mice and cultured mesangial cells (MCs).. Aliskiren treatment for 3 months at a dose of 25 mg/kg/day via an osmotic mini-pump did not induce significant changes in blood glucose levels, systolic blood pressure, serum creatinine and electrolyte levels. However, aliskiren treatment improved insulin resistance confirmed by insulin tolerance test and various biomarkers including homeostasis model assessment index levels and lipid abnormalities. The treated group also exhibited significant improvement in cardiac functional and morphological abnormalities including left ventricular hypertrophy, and induced phenotypic changes in adipose tissue. Aliskiren treatment also markedly decreased urinary albumin excretion, glomerulosclerosis and suppressed profibrotic and proinflammatory cytokine synthesis and improved renal lipid metabolism. In cultured MCs, high glucose stimulation increased MC renin concentration. Furthermore, renin treatment directly up-regulates synthesis of proinflammatory and profibrotic cytokines, which were abolished by prior treatment with aliskiren and angiotensin receptor (AT1) antagonist. These results suggest that the beneficial effect of aliskiren is mediated by an angiotensin-dependent mechanism.. Together, these results imply that aliskiren provides an organ-protective effect through improvement in insulin resistance and lipid abnormality, as well as direct anti-fibrotic effect in target organ in db/db mice. Aliskiren may be a useful new therapeutic agent in the treatment of type 2 diabetes mellitus and diabetic nephropathy.

Topics: Amides; Animals; Biomarkers, Tumor; Blood Glucose; Blood Pressure; Blotting, Western; Body Weight; Cells, Cultured; Diabetes Complications; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Fumarates; Gene Expression Profiling; Humans; Immunoenzyme Techniques; Insulin; Insulin Resistance; Male; Mesangial Cells; Mice; Mice, Mutant Strains; Oligonucleotide Array Sequence Analysis; Renin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been demonstrated to have the adverse effects on human health. In this study, we applied a metabolomic approach in conjunction with unsupervised and supervised machine learning methods to investigate the toxic effects of TCDD. By using liquid chromatography/quadrupole time-of-flight mass spectrometry, non-targeted metabolomic analysis revealed the metabolic signatures of the toxicity in aryl hydrocarbon receptor (AhR)-high affinity C57BL/6J (C6) mice as well as low affinity strain-DBA/2J (D2) mice. Lysophospholipids and long chain fatty acids were strikingly elevated in the C6 mice exposed to TCDD in both liver and skeletal muscle tissues. Meanwhile, the level of palmitoylcarnitine, which is one of the important indicators in fatty acid β-oxidation, increased significantly. Moreover, several nucleosides and amino acids decreased markedly. On the other hand, much less differentiating metabolites were highlighted in another strain-D2 mouse model. Taking liver and skeletal muscle tissues together, the levels of inosine, valine and glutamine decreased significantly. One lysophospholipid and two fatty acids were found to be enhanced. The principal components analysis and support vector machine clustering results also exhibited discriminations in the liver and skeletal muscle tissues of the mice. The obtained results indicated that TCDD could disrupt several metabolic pathways, including fatty acid biosynthesis and amino acid metabolism in both C6 and D2 mice. The increased rate of fatty acid beta-oxidation, however, was only observed in the liver and skeletal muscle tissues of C6 mice. The perturbation of the tricarboxylic acid (TCA) cycle was testified in two strains but the change was much slighter in D2 mice. It was of particular interest to note that the succinate level was enhanced in the liver tissues of both strains, and particularly, the change was up to 11.49-fold in the liver of C6 mice treated with TCDD. Collectively, the discrimination of D2 mice was not as distinct as that of C6 mice when exposed to the same dosage. Furthermore, D2 was confirmed to be less-sensitive rather than resistant to a high dose of TCDD.

Topics: Animals; Artificial Intelligence; Body Weight; Citric Acid; Environmental Pollutants; Fumarates; Humans; Liver; Malates; Male; Metabolome; Mice; Mice, Inbred C57BL; Mice, Inbred DBA; Multivariate Analysis; Muscle, Skeletal; Phenotype; Polychlorinated Dibenzodioxins; Principal Component Analysis; Succinic Acid

1. Aliskiren is a renin inhibitor with an IC(50) of 0.6 nmol/L for human renin, 4.5 nmol/L for mouse renin and 80 nmol/L for rat renin. 2. In the present study, we compared the effects of aliskiren (10 mg/kg per day), the angiotensin-converting enzyme inhibitor perindopril (0.2 mg/kg per day) and their combination on angiotensin and bradykinin peptides in female heterozygous (mRen-2)27 rats, transgenic for the mouse renin gene. 3. All three treatments produced similar reductions in systolic blood pressure, heart weight and plasma aldosterone levels and reduced angiotensin II levels in lung, but only perindopril and the combination reduced angiotensin II levels in kidney of (mRen-2)27 rats. In contrast, aliskiren and the combination, but not perindopril alone, increased cardiac bradykinin levels. Aliskiren increased immunostaining for tissue kallikrein in the heart and reduced cardiac fibrosis. 4. We investigated the mechanism underlying the increase in bradykinin levels following aliskiren treatment in Sprague-Dawley rats, in which aliskiren has a lower potency for renin inhibition. Aliskiren (10 mg/kg per day) reduced renal angiotensin levels within 24 h, but treatment for > 24 h was required to increase cardiac bradykinin levels. Moreover, 3 mg/kg per day aliskiren increased cardiac bradykinin levels, but did not reduce renal angiotensin levels. Aliskiren did not potentiate the hypotensive effects of bradykinin; however, it increased tissue kallikrein, but not plasma kallikrein, mRNA levels in the heart. 5. These data demonstrate that the aliskiren-induced increase in cardiac bradykinin levels is independent of renin inhibition and changes in bradykinin metabolism, but is associated with increased tissue kallikrein gene expression.

Topics: Aldosterone; Amides; Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Body Weight; Bradykinin; Female; Fumarates; Heart; Kallikreins; Kidney; Lung; Mice; Myocytes, Cardiac; Perindopril; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Tissue Kallikreins

The effect of renin inhibition on type 2 diabetes is still unclear. The present study was undertaken to examine the efficacy of aliskiren, a direct renin inhibitor, on cardiovascular injuries, glucose intolerance and pancreatic injury in a mouse model of type 2 diabetes.. Groups of db/db mice, with obesity and type 2 diabetes, were treated with aliskiren (3, 6, 12 and 25 mg kg(-1) day(-1)) or hydralazine (80 mg kg(-1) day(-1)) for 6 weeks, and the protective effects were extensively compared among groups.. All sub-pressor and hypotensive doses of aliskiren significantly attenuated cardiac fibrosis, macrophage infiltration and coronary remodelling, and improved vascular endothelial function in db/db mice. These protective effects of aliskiren were attributed to the attenuation of cardiac p22(phox)-related NADPH oxidase-induced superoxide and the restoration of vascular endothelial nitric oxide synthase (eNOS) production. Aliskiren at the highest dose (25 mg kg(-1) day(-1)), but not at lower doses, partially reduced glucose intolerance in db/db mice. Furthermore, the highest dose of aliskiren significantly attenuated the decreases in pancreatic islet insulin content and beta cell mass, and prevented pancreatic islet fibrosis in db/db mice, being associated with the reduction of 8-hydroxy-2'-deoxyguanosine-positive cells and Nox2 (also known as Cybb) expression in pancreatic islets by aliskiren.. Our work provides the first evidence that direct renin inhibition with aliskiren protects against cardiovascular complications and pancreatic injury, through the attenuation of oxidative stress. Thus, we propose that aliskiren may be a promising therapeutic agent for type 2 diabetes.

Topics: Amides; Animals; Antihypertensive Agents; Blood Pressure; Body Weight; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Fumarates; Glucose Intolerance; Hydralazine; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Obesity; Organ Size; Pancreas; Renin

The objective of this study was to evaluate effects of fumarate on ruminal ammonia accumulation and fiber digestion in vitro and on feed intake and nutrient utilization in dairy does. Batch cultures of mixed rumen microorganisms were used to study effects of different concentrations of fumarate on fermentation with various N sources (ammonia as ammonium bicarbonate, casein amino acids, casein peptides, gelatin peptides) and feeds (bermudagrass hay, mixed diet of 60% bermudagrass hay plus 40% concentrate) for 6 and 24h, respectively. Substrates were grouped into pairs for separate incubations. Monosodium fumarate was added to incubation tubes to achieve final concentrations of 0, 5, and 10mM fumarate. More ammonia accumulated at the end of incubation with added ammonium bicarbonate. Ammonia concentration was higher for peptide compared with amino acid incubation, and for casein peptide compared with gelatin peptide. Addition of fumarate linearly decreased ammonia for all N sources and for feed substrates. For all substrate types, fumarate treatment increased acetate, propionate, and total volatile fatty acids (VFA), decreased acetate to propionate ratio, and tended to reduce branched-chain VFA. Digestion of feed neutral detergent fiber (NDF) by rumen microorganisms was improved by fumarate along with elevated endoglucanase and xylanase activities. In an animal metabolism experiment, 8 dairy does (4 per treatment) were used in a completely randomized design for 21 d. Does were fed a hay plus concentrate diet without (control) or with fumarate (6 g/head per day) supplementation to determine feed intake, whole-tract nutrient digestibility, and N utilization. Fumarate treatment did not affect weight change or feed intake but increased whole-tract digestion of gross energy, crude protein, and cellulose. Digested N was increased by fumarate supplementation; however, N retention was unaffected. Plasma glucose concentration was elevated with fumarate but urea N concentration remained unchanged. Fumarate addition had significant effects on rumen microbial fermentation by decreasing ammonia and branched-chain VFA, and by increasing acetate and propionate, and NDF digestion. These effects were reflected in the improvement in whole-tract gross energy, crude protein, and cellulose digestion and elevated plasma glucose concentration when dairy does were supplemented with fumarate.

Topics: Ammonia; Animal Nutritional Physiological Phenomena; Animals; Bacteria; Blood Glucose; Blood Urea Nitrogen; Body Weight; Dairying; Diet; Dietary Fiber; Dietary Supplements; Digestion; Eating; Female; Fermentation; Fumarates; Goats; Random Allocation; Rumen

Gender and body weight influence the pharmacokinetics and pharmacodynamics of many drugs. This pooled analysis of 17 clinical studies evaluated the effect of gender, body mass index (BMI), body weight, and lean body weight (LBW) on the pharmacokinetics of the direct renin inhibitor aliskiren in healthy volunteers (n = 392). A separate pooled analysis of 5 clinical studies in patients with hypertension (n = 2327) assessed the influence of gender and BMI on the effects of aliskiren on plasma renin activity and blood pressure. Area under the aliskiren plasma concentration-time curve (AUC(τ)) was 22% lower and the peak aliskiren plasma concentration (C(max)) was 24% lower in men than women (P < .05). BMI was not significantly correlated with AUC(τ) (r = 0.005; P = .917); AUC(τ) was negatively correlated with body weight (r = -0.235; P < .0001) and LBW (r = -0.295; P < .0001). Results were similar for C(max). Adjusting individual aliskiren AUC(τ) and C(max) values for overall mean body weight or LBW abolished gender differences. Based on r(2) values, LBW variation accounted for 8.9% of aliskiren AUC(τ) variation. In patients with hypertension, gender and BMI did not significantly influence the effects of aliskiren on plasma renin activity or blood pressure. It was concluded that lower systemic exposure to aliskiren in men versus women relates to differences in body weight; neither gender nor body weight has clinically relevant effects on the pharmacokinetics or pharmacodynamics of aliskiren.

Topics: Adult; Amides; Antihypertensive Agents; Blood Pressure; Body Composition; Body Mass Index; Body Weight; Clinical Trials as Topic; Female; Fumarates; Humans; Hypertension; Male; Renin; Sex Characteristics

Supplementation of some organic acids to a P-deficient diet has been shown to improve phytate P utilization. Two experiments were conducted from 0 to 16 d in battery brooders to determine the effect of various organic acids supplementation on phytate P utilization. In both experiments, birds were fed P-deficient corn and soybean meal-based diets. In experiment 1, citric acid, malic acid, fumaric acid, and EDTA were supplemented. Experiment 2 had a 2 x 2 factorial design with 2 sources of Met, 2-hydroxy-4-(methylthio) butanoic acid (HMB) and dl-Met, with or without 500 U/kg of phytase. In experiment 1, the addition of citric, malic, and fumaric acids increased percentage of bone ash, but only the effect of citric acid was significant. The addition of citric and malic acids also significantly increased the retention of P and phytate P (P<0.05). In experiment 2, the addition of phytase to the diet significantly increased 16-d BW gain, feed intake, percentage of bone ash, milligrams of bone ash, phytate P disappearance, and decreased the incidence of P-deficiency rickets. Methionine source did not affect 16-d BW gain, feed intake, feed efficiency, milligrams of bone ash, or P rickets incidence. However, the birds fed HMB had a higher percentage of bone ash and phytate P disappearance compared with the groups fed dl-Met only when phytase was added to the diets. The additions of citric acid and HMB improved phytate P utilization. However, the reason why some organic acids are effective whereas others are not is not apparent.

Topics: 6-Phytase; Animal Nutritional Physiological Phenomena; Animals; Body Weight; Carboxylic Acids; Chelating Agents; Chickens; Citric Acid; Edetic Acid; Female; Fumarates; Malates; Male; Minerals; Phosphorus; Phytic Acid; Poultry Diseases; Random Allocation; Rickets

Blockade of the renin-angiotensin system (RAS) with either ACE inhibitors or angiotensin receptor blocker is a key therapeutic strategy in slowing progression of diabetic nephropathy. Interruption of the RAS may also be achieved by blocking the activity of renin, the rate-limiting step in angiotensin II biosynthesis. However, it is not known whether drugs in this class also reduce the structural and functional manifestations of diabetic nephropathy.. Using diabetic transgenic (mRen-2)27 rats, a rodent model of advanced diabetic nephropathy, we compared the efficacy of the renin inhibitor, aliskiren (10 mg kg(-1) day(-1) by osmotic mini-pump), with the ACE inhibitor, perindopril (0.2 mg kg(-1) day(-1) in drinking water), over a 16 week period.. Both perindopril and aliskiren reduced blood pressure, albuminuria and structural injury in experimental diabetic nephropathy, although not to the same extent. Aliskiren, at the dose used, did not reduce systemic blood pressure as much as perindopril, but both compounds were equally effective in reducing albuminuria and glomerulosclerosis in diabetic animals. The magnitude of interstitial fibrosis was attenuated to a greater degree by aliskiren than by perindopril.. These findings suggest that therapies aimed at different targets within the RAS may not have identical effects in attenuating structural injury in experimental diabetic nephropathy.

Topics: Aldosterone; Amides; Animals; Body Weight; Diabetes Mellitus, Experimental; Diabetic Nephropathies; Female; Fumarates; Kidney; Organ Size; Rats; Rats, Inbred Strains; Renin

Two studies were conducted to examine the effects of dietary inclusion of fumaric acid on performance and carcass composition of broiler chickens. Fumaric acid was added to nutritionally complete diets at levels of 0, .125, .25, and .5% and fed from 1 to 49 days under simulated commercial conditions. In one trial, samples of birds were processed to determine dressing percentage and abdominal fat content. In the first trial (mixed sex broilers), the addition of .125% fumaric acid significantly (P less than .05) improved 49-day body weight of females and average weight gain of both sexes with no effect on feed utilization. Feed consumption was significantly increased when diets contained .125 or .50% fumaric acid. In the second trial (male broilers), 49-day body weight was significantly (P less than .05) improved by the addition of .125 and .25% fumaric acid. There were no significant differences in feed consumption; feed utilization was improved by the addition of all levels of fumaric acid. Dietary fumaric acid had no adverse effects on dressing percentage, abdominal fat content, or mortality rate.

Topics: Animals; Body Weight; Chickens; Eating; Female; Fumarates; Male; Random Allocation; Sex Characteristics; Weight Gain

The effect of dietary citric acid (CA) and fumaric acid (FA) on pig weight gain (ADG) and gain/feed (G/F) was studied in two trials using 192 crossbred, 4-wk-old weaning pigs. Three dietary levels (0, 1.5 or 3.0%) of either FA (Trial 1) or CA (Trial 2) with or without an antibiotic supplement (110 mg chlortetracycline, 110 mg sulfamethazine and 55 mg penicillin/kg diet) formed six treatment combinations in each trial. These six diets were fed to two replicate pens of eight pigs each for a 4-wk period. In Trial 1, ADG was improved (P less than .01) during wk 1, and G/F was improved during wk 1 (P less than .01) as well as during wk 1 to 2 (P less than .05) for pigs consuming FA-supplemented diets. In Trial 2, CA had no beneficial influence on ADG during the 4-wk trial. However, feed intake during wk 1 was depressed (P less than .05) by adding CA, as was G/F during wk 1 to 2 (P less than .05). Based on these results, FA was selected to be used in a nutrient balance study. Twelve 4-wk-old weanling pigs were fed one of three diets: control (C), C + 1.5% FA, or C + antibiotic supplement (A). Diet digestible energy (DE), ME and N-corrected ME (MEN) were not different among treatments. Nitrogen balance, percentage N retained and apparent N digestibility were not affected by dietary treatment. Calcium balance and percentage of Ca retained were unaffected by diet.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animal Feed; Animals; Anti-Bacterial Agents; Body Weight; Citrates; Citric Acid; Fumarates; Swine

Two feeding trials were carried out to determine the potential use of fumaric acid and calcium formate in diets for broiler chickens. In the first study using male broiler chicks fed to 21 days of age, fumaric acid was added at 0, .5, 1.0 and 1.5% and calcium formate was added at 0, .72, 1.48, 2.20, and 2.89%. All combinations of fumaric acid and calcium formate were evaluated in a 4 x 5 factorial arrangement of treatments. Addition of .5 or 1.0% fumaric acid significantly (P less than .05) improved body weights of broilers but did not influence feed utilization. Addition of calcium formate at levels greater than .72% significantly reduced both body weight and feed utilization. There was no significant interaction between levels of fumaric acid and calcium formate. In a second trial, male and female broiler chicks were grown to 49 days of age using diets containing 0, .5, 1.0, and 1.5% calcium formate. Addition of .5 or 1.0% calcium formate had no significant effect on weight gains or feed utilization. Addition of 1.5% calcium formate significantly reduced body weights of both males and females at 21 and 42 days. At 49 days of age, body weights of males fed 1.5% calcium formate did not differ from those of males fed the control diet, but were significantly less than those of males fed diets with .5 or 1.0% calcium formate. Female body weights at 49 days of age were significantly depressed by addition of 1.5% calcium formate.

Topics: Animals; Body Weight; Chickens; Diet; Formates; Fumarates; Male

Six experiments involving 706 newly weaned 28- to 32-d-old pigs were conducted to evaluate the efficacy of copper (Cu) sulfate (to provide 250 mg/kg Cu), antibiotic-sulfa combinations [chlortetracycline, 110 mg/kg + penicillin, 55 mg/kg + sulfamethazine, 110 mg/kg; i.e., Aureo-Sulfa-Penicillin (ASP) or tylosin, 110 mg/kg + sulfamethazine, 110 mg/kg; i.e., Tylosin-Sulfa (TS)] and anhydrous citric or fumaric acid (.75 to 1.5% of the diet). The basal experimental diet was a 19% crude protein (CP)-fortified corn-soybean meal diet (1.08% lysine) containing 7% dried whey and 3% fish meal. Marked and consistent gain and gain/feed responses occurred from the Cu supplement, particularly during the first week postweaning. The antibiotic-sulfa combinations were less efficacious than Cu during the 1-wk postweaning stress period. During either the 1- or 3-wk growth periods, ASP and TS showed additivity with Cu in promoting rate and efficiency of weight gain. Liver Cu was increased by Cu addition to the diet, but neither ASP nor TS affected Cu deposition in the liver. In a factorial experiment involving 17% (1.01% lysine) or 20% CP (1.23% lysine) corn-soybean meal diets containing either no dried whey or an addition of 25% whey, Cu supplementation elicited marked improvements in rate and efficiency of weight gain, particularly in diets without added whey. Likewise, whey addition improved pig performance, especially when added to the diets containing no supplemental Cu.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Anti-Bacterial Agents; Body Weight; Citrates; Citric Acid; Copper; Copper Sulfate; Drug Combinations; Food Additives; Fumarates; Liver; Sulfonamides; Swine

Four growth experiments were conducted to assess the effects of organic acid supplementation on performance of starter and finisher pigs. Three 4-wk starter experiments utilized 392 pigs fed simple corn-soybean meal diets. A fourth experiment employed 135 finisher pigs in a 6-wk study. Each of the starter experiments was initiated immediately after weaning; piglets were 30 +/- 3 d of age. In Exp. 1, weanling pigs fed a 19% crude protein, simple corn-soybean meal diet were compared with pigs fed similar diets supplemented with 2% propionic, fumaric, or citric acid. Addition of each acid improved (P less than .07) efficiency of gain, while propionate depressed (P less than .05) feed intake. Additions of 1, 2, 3 or 4% fumarate were made in Exp. 2, resulting in linear daily gain and feed efficiency improvements (P less than .05). In Exp. 3, a possible protein-sparing effect of fumaric acid was investigated. Increasing protein levels from 16 to 20% improved daily gain (P less than .01) and feed efficiency (P less than .0001); fumarate supplementation (2%) increased (P less than .01) gain:feed. However, there was no protein X fumaric acid interaction. In Exp. 4, no treatment effects were noted with performance of finisher pigs fed a 14% crude protein, corn-soybean meal diet was compared with that of pigs fed similar diets supplemented with 1.5 or 3% fumaric acid.

Topics: Animals; Body Weight; Citrates; Citric Acid; Dietary Proteins; Energy Metabolism; Female; Food, Fortified; Fumarates; Glycine max; Hydrogen-Ion Concentration; Male; Propionates; Swine; Zea mays

Topics: Animals; Body Composition; Body Weight; Diet; Dose-Response Relationship, Drug; Female; Fumarates; Growth; Rats; Rats, Inbred Strains

Topics: Animals; Body Weight; Female; Food Additives; Fumarates; Minerals; Rats; Rats, Inbred Strains; Trace Elements

Topics: Administration, Oral; Amines; Animals; Appetite Depressants; Body Weight; Dietary Fats; Female; Fumarates; Heart; Hypertension, Pulmonary; Organ Size; Oxazoles; Pulmonary Circulation; Rats

Topics: Administration, Oral; Amines; Animals; Appetite Depressants; Blood Pressure; Body Weight; Depression, Chemical; Epinephrine; Female; Fumarates; Heart Rate; Injections, Intraperitoneal; Lung; Male; Norepinephrine; Organ Size; Oxazoles; Pulmonary Artery; Pulmonary Circulation; Rats; Stimulation, Chemical; Time Factors; Vascular Resistance

Topics: Acetylcholinesterase; Adenosine Triphosphatases; Animals; Body Weight; Brain; Brain Stem; Cerebellum; Diencephalon; Fumarates; Hydro-Lyases; Mitochondria; Nutrition Disorders; Organ Size; Rats; Telencephalon

Topics: Adrenal Glands; Animals; Body Weight; Brain; Cycloheptanes; Digestive System; Fatty Liver; Fumarates; Genitalia; Heart; Kidney; Kidney Tubules; Lung; Lymph Nodes; Parasympatholytics; Propylamines; Rats; Spleen

Topics: Adrenal Glands; Adrenalectomy; Alcohol Oxidoreductases; Animals; Body Weight; Diet; Dietary Carbohydrates; Fructose; Fumarates; Glucose; Glucose-6-Phosphatase; Glutaminase; Glycerolphosphate Dehydrogenase; Hydro-Lyases; Hypophysectomy; Isomerases; L-Lactate Dehydrogenase; L-Serine Dehydratase; Liver; Liver Glycogen; Lyases; Malate Dehydrogenase; Male; Nucleoside Diphosphate Sugars; Organ Size; Oxidoreductases; Pentosephosphates; Pituitary Gland; Proteins; Rats; Transferases; Uracil Nucleotides