Toxicogenomic Analysis of Cardiotoxicity in Rats

2008 ◽  
Vol 1 ◽  
pp. GEI.S851 ◽  
Author(s):  
Brad Hirakawa ◽  
Bart A. Jessen ◽  
Oscar Illanes ◽  
Ann de Peyster ◽  
Thomas McDermott ◽  
...  
Keyword(s):  
Gene Expression ◽  
Carbon Tetrachloride ◽  
Rapid Assessment ◽  
Negative Control ◽  
Histopathological Analysis ◽  
Sprague Dawley ◽  
Post Dose ◽  
Sprague Dawley Rats ◽  
Control Compound

Evidence of cardiotoxicity in the preclinical testing of drugs will often lead to compound attrition. The standard method for identifying cardiotoxic compounds involves histopathological analysis of tissue sections, a resource intensive process. In an effort to reduce attrition and capture safety endpoints early within the drug discovery paradigm, a more rapid assessment of target organ effects is desired. Here we describe the results of a preliminary study in which a group of common genes were affected by in vivo exposure to compounds known to cause dose-dependant cardiotoxicity. Adult male Sprague-Dawley rats were treated intraperitoneally with a single dose of digoxin (20 mg/kg), doxorubicin (30 mg/kg), isoproterenol (70 mg/kg), lipopolysaccharide (10 mg/kg) or carbon tetrachloride (800 mg/kg) and euthanized either 6 or 24 hours post-dose. Digoxin, doxorubicin, isoproterenol, and lipopolysaccharide were chosen for this study based on their diverse mechanisms of cardiotoxicity. Carbon tetrachloride, a known liver toxicant, was chosen as a non-cardiotoxic negative control. Genes commonly affected by all four cardiotoxic compounds were grouped together as a list of potential biomarkers. Gene expression changes were subsequently quantified using quantitative PCR. These genes were compared to those affected by novel experimental compounds previously shown to cause cardiotoxicity in rats. These compounds also affected over half of the genes on the biomarker list, whereas the non-cardiotoxic control compound did not affect any genes on the biomarkers list. These data indicate that measuring changes in gene expression could aid in the prioritization of compounds before they are tested in more resource intensive studies.

scholarly journals Regulation of mdrlb gene expression in Fischer, Wistar and Sprague-Dawley rats in vivo and in vitro

1996 ◽  
Vol 17 (3) ◽  
pp. 451-457 ◽  
Author(s):  
Barbara A. Hill ◽  
Paul C. Brown ◽  
Karl-Heinz Preisegger ◽  
Jeffrey A. Silverman
Keyword(s):  
Gene Expression ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

scholarly journals Freeze Dried extracts of Bidens biternata (Lour.) Merr. And Sheriff. show significant Antidiarrheal activity in ‐vivo Models of Diarrhea

2016 ◽  
Author(s):  
Dennis Gacigi Kinuthia ◽  
Anne W. Muriithi ◽  
Peter Waweru Mwangi
Keyword(s):  
Normal Saline ◽  
Castor Oil ◽  
Contractile Activity ◽  
Positive Control ◽  
Negative Control ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Freeze Dried ◽  
Adrenergic Blocker

ABSTRACTEthnopharmacological relevance of the studyDiarrhea remains one of the main killers of children aged below five years. Traditional antidiarrheal remedies form a potentially viable source of novel low cost efficacious antidiarrheal remedies in low resource settings. There is therefore a pressing to scientifically evaluate these remedies.Aim of the studyThis study aimed to investigate the in vivo and in vitro antidiarrheal activity of Bidens biternata a herb species used in traditional Ayurvedic medicine in the management of diarrhea.Materials and MethodsIn the castor oil test twenty (20) adult Sprague-Dawley rats were randomized to the negative control (normal saline), positive control (5 mg/kg loperamide), (200 mg/kg Bidens biternata extract) and (400 mg/kg Bidens biternata extract) groups (n=5 in each group). Castor oil (4 ml/kg) was then administered to the animals one hour after administration of the respective treatments after which the total mass of fecal output excreted after four (4) hours was determined.In the charcoal meal test fifteen (15) Sprague Dawley rats were randomized to the negative control (normal saline 5 ml/kg orally), the positive control (atropine sulphate 0.1 mg/kg i.p) and test (400 mg/kg Bidens biternata extract) groups (n=5). Charcoal meal was then administered via oral gavage to each rat thirty (30) minutes after the administration of the various treatments. The distance covered by the charcoal meal from the pylorus was then determined after sacrifice of the animals.In the enteropooling test twenty (20) Sprague-Dawley rats were randomized to the negative control (5% v/v ethanol in normal saline), positive control (5 mg/kg loperamide) and test (400 mg/kg Bidens biternata extract) groups and prostaglandin E2 (PGE2) (100μg/kg) administered immediately after the treatments. The animals were then sacrificed half an hour later and the volume of the small intestine contents determined. The effects of different concentrations of Bidens biternata extract (0.5. 1.0, 2.0, 3.0 and 5.0 mg/ml) on jejunal contraction were investigated and a dose-response curve constructed using the experimental data after which The ED50 dose determined. The effect of tamsulosin (α1 adrenergic blocker), yohimbine (α2 adrenergic blocker), propranolol (β adrenergic blocker) and naloxone (μ opioid blocker) on the contractile activity of the extract were also investigated.The experimental data were expressed as mean ± standard error of mean (SEM) and then analyzed using one way ANOVA followed by Tukey’s post hoc test in cases of significance (set at p<0.05).ResultsThe freeze dried extracts of Bidens biternata had significant antidiarrhealeffects in the castor oil induced diarrhea model (p=0.0075) with maximal activity being observed at the 400mg/kg dosage level (1.66± 0.81g vs. 4.54 ± 0.51 g negative control, p=0.01). Bidens biternata extract had significant effects on intestinal motility in the charcoal meal test compared to the control group (43.61 ± 4.42% vs. 60.54 ± 3.33%: p= 0.02). Bidens biternata extract had a significant effect on PGE2 induced enteropooling (3.06 ± 0.07 ml vs. 4.74 ± 0.10 ml; p<0.001).The freeze dried extracts of Bidens biternata had a significant negative effect on the contractility of the isolated rabbit jejunum (p<0.001). The effects of the extract were significantly attenuated by tamsulosin (53.94 ± 4.20% vs. 80.57 ± 4.09%; p=0.0067) and naloxone (53.94 ± 4.20% vs. 73.89 ± 7.26 %; p=0.0358). Yohimbine (p=0.4598) and propranolol (p=0.5966) however did not have any significant effect on the contractile activity of the extract.ConclusionsThe freeze dried extract of Bidens biternata possess significant antidiarrhealactivity in both in vitro and in vivo models which appears to be mediated by modulating both the intestinal motility as well as the secretory activity. The results of this study also validate its traditional use as an antidiarrheal remedy.

scholarly journals Hyperlipidemia Preventing Activities of Standardized Ethanolic Extract of Red Spinach (Amaranthus tricolor L.): An In Vivo Study in Male Sprague-Dawley Rats

2018 ◽  
pp. 102-108
Author(s):  
Dimas Adhi Pradana ◽  
Lalily Apriani ◽  
Sitarina Widyarini
Keyword(s):  
Triglyceride Level ◽  
Ethanolic Extract ◽  
Positive Control ◽  
Negative Control ◽  
Control Treatment ◽  
Sprague Dawley ◽  
Amaranthus Tricolor ◽  
Lipid Metabolism Disorders ◽  
Sprague Dawley Rats

Lipid metabolism disorders can lead to hyperlipidemia that triggers atherosclerosis. This study aimed to identify the potential of standardized ethanolic extract of red spinach (Amaranthus tricolor L.) to prevent hyperlipidemia by referring to the reduction of triglyceride level and total cholesterols in male Sprague-Dawley rats. A total of 30 experimental animals was put into 6 groups, including normal, positive control (0.9 mg/kgBW of simvastatin), negative control, treatment I (200 mg/kgBW of extract), treatment II (400 mg/kgBW of extract), and treatment III (800 mg/kgBW of extract). Preventive therapy and positive control were administered from day 1 to day 67. Hyperlipidemia was induced by feeding pure lard and duck yolk to the rats twice daily from day 8 to day 67. Determination of triglyceride level and total cholesterols was conducted on day 0 and day 67. The findings revealed that the treatment groups with ethanolic extract of red spinach at doses of 200 mg/kgBW, 400 mg/kgBW, and 800 mg/kgBW had statistically significant differences (p

Acute hypoxia upregulates NOS gene expression in rats

1997 ◽  
Vol 273 (3) ◽  
pp. R905-R910 ◽  
Author(s):  
B. Gess ◽  
K. Schricker ◽  
M. Pfeifer ◽  
A. Kurtz
Keyword(s):  
Gene Expression ◽  
Carbon Monoxide ◽  
Acute Hypoxia ◽  
Mrna Levels ◽  
General Effect ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Flow Through ◽  
Ribonuclease Protection

This study aimed to investigate the influence of acute tissue hypoxygenation on the expression of NO synthase (NOS) genes in vivo. To this end, male Sprague-Dawley rats were exposed either to 9% oxygen or to 0.1% carbon monoxide for 6 h, and mRNA levels of NOS-I, -II, and -III in kidneys, livers, lungs, and left and right heart ventricles were assayed by ribonuclease protection. For comparison, mRNA levels of erythropoietin were also measured in these tissues. NOS-III mRNA was highly abundant in all organs investigated. NOS-II mRNA was detected in lungs and hearts but not in kidneys and livers. NOS-I mRNA was found in kidneys, lungs, and hearts but not in livers. NOS-III mRNA levels were upregulated by hypoxia in all tissues examined, with the least effect (1.2-fold) in the left ventricle and the greatest effect (2.6-fold) in the lung. NOS-II mRNA was substantially downregulated in the ventricles by both treatments but not changed in the lung. NOS-I mRNA was upregulated by carbon monoxide in kidneys and lungs and by 9% oxygen in the lung. These findings suggest that NOS-III and possibly also NOS-I gene expression behave like oxygen-regulated genes, whereas the general effect of tissue hypoxygenation on NOS-II gene expression is less clear. Because NOS-III is primarily expressed in endothelial cells, a general upregulation of NOS in these cells may be of relevance for the regulation and maintenance of blood flow through hypoxic tissues.

Local mechanisms for acupoint sensitization in gall bladder meridian of foot shaoyang-a gene chip study

2019 ◽  
Vol 44 (2) ◽  
pp. 77-87
Author(s):  
Koichi Ishida ◽  
Liyue Qin ◽  
Ting Wang ◽  
Ying Lei ◽  
Weiwei Hu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Gall Bladder ◽  
Interleukin 1 ◽  
Gene Chip ◽  
Molecular Evidence ◽  
Sprague Dawley ◽  
Sprague Dawley Rats ◽  
Bladder Meridian ◽  
Integrin Linked Kinase ◽  
Necrosis Factor

Acupuncture manipulations are clinically important to traditional Chinese medicine, yet the biological mechanisms have not been fully understood. This study aimed to investigate continuous stimulation-induced gene expression changes at stimulated and non-stimulated adjacent acupoints in the same meridian. Catgut embedding into acupoint (CEP) was conducted at acupoint Yanglingquan (gall bladder meridian of foot-shaoyang 34, GB34) of Sprague Dawley rats once or continuously for eight weeks, and gene expression changes at GB34 were assessed by gene chip array analysis 72 h after the last CEP treatment. A total of 688 genes exhibited opposite changes in expression between the two treatments, and 1,336 genes were regulated only by the eight-week CEP treatment. Ingenuity Pathway Analysis revealed that among these differentially regulated genes by one-time and eight-week CEP treatment, insulin-like growth factor-1 pathway and integrin-linked kinase pathway, and Wnt/~ catenin signaling pathway match the observed gene changes to predicted up/down regulation patterns. Upstream analysis further predicted six molecules, namely, tumor necrosis factor, interleukin 1~, interleukin la, kallikrein-related peptidase 5, protein kinase Ca, and catenin ~1. On the other hand, continuous eight-week CEP stimulation at acupoint Xuanzhong (GB39) caused similar changes in the expression of 32 genes at acupoints GB34 and Fengshi (GB31) on the same meridian. Taken together, our results provide the first molecular evidence for the local acupoints' mechanisms for acupoint sensitization theory, and implicate the existence of signaling pathways, either direct or indirect, between acupoints within the meridian GB.

Toxicokinetic and Genotoxicity Study of NNK in Male Sprague-Dawley Rats Following Nose-Only Inhalation Exposure, Intraperitoneal Injection, and Oral Gavage

2021 ◽  
Author(s):  
Shu-Chieh Hu ◽  
Matthew S Bryant ◽  
Estatira Sepehr ◽  
Hyun-Ki Kang ◽  
Raul Trbojevich ◽  
...  
Keyword(s):  
Human Lung ◽  
Inhalation Exposure ◽  
Systemic Exposure ◽  
Sprague Dawley ◽  
Oral Gavage ◽  
Sd Rats ◽  
New Information ◽  
Sprague Dawley Rats ◽  
Tissue Specimens

Abstract The tobacco-specific nitrosamine NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone] is found in tobacco products and tobacco smoke. NNK is a potent genotoxin and human lung carcinogen; however, there are limited inhalation data for the toxicokinetics (TK) and genotoxicity of NNK in vivo. In the present study, a single dose of 5x10−5, 5x10−3, 0.1, or 50 mg/kg body weight (BW) of NNK, 75% propylene glycol (vehicle control), or air (sham control) was administered to male Sprague-Dawley (SD) rats (9-10 weeks age) via nose-only inhalation (INH) exposure for 1 hour. For comparison, the same doses of NNK were administered to male SD rats via intraperitoneal (IP) injection and oral gavage (PO). Plasma, urine, and tissue specimens were collected at designated timepoints and analyzed for levels of NNK and its major metabolite 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and tissue levels of DNA adduct O6-methylguanine by LC/MS/MS. TK data analysis was performed using a non-linear regression program. For the genotoxicity subgroup, tissues were collected at 3 hours post-dosing for comet assay analysis. Overall, the TK data indicated that NNK was rapidly absorbed and metabolized extensively to NNAL after NNK administration via the three routes. The IP route had the greatest systemic exposure to NNK. NNK metabolism to NNAL appeared to be more efficient via INH than IP or PO. NNK induced significant increases in DNA damage in multiple tissues via the three routes. The results of this study provide new information and understanding of the toxicokinetics and genotoxicity of NNK.

scholarly journals Preclinical Characterization of the Distribution, Catabolism, and Elimination of a Polatuzumab Vedotin-Piiq (POLIVY®) Antibody–Drug Conjugate in Sprague Dawley Rats

2021 ◽  
Vol 10 (6) ◽  
pp. 1323
Author(s):  
Victor Yip ◽  
M. Violet Lee ◽  
Ola M. Saad ◽  
Shuguang Ma ◽  
S. Cyrus Khojasteh ◽  
...  
Keyword(s):  
B Cell Lymphoma ◽  
The United States ◽  
Clinical Development ◽  
Sprague Dawley ◽  
Antibody Drug Conjugate ◽  
Post Dose ◽  
Drug Conjugate ◽  
Sprague Dawley Rats ◽  
A Minor ◽  
Antibody Drug

Polatuzumab vedotin (or POLIVY®), an antibody–drug conjugate (ADC) composed of a polatuzumab monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a cleavable dipeptide linker, has been approved by the United States Food and Drug Administration (FDA) for the treatment of diffuse large B-cell lymphoma (DLBCL). To support the clinical development of polatuzumab vedotin, we characterized the distribution, catabolism/metabolism, and elimination properties of polatuzumab vedotin and its unconjugated MMAE payload in Sprague Dawley rats. Several radiolabeled probes were developed to track the fate of different components of the ADC, with 125I and 111In used to label the antibody component and 3H to label the MMAE payload of the ADC. Following a single intravenous administration of the radiolabeled probes into normal or bile-duct cannulated rats, blood, various tissues, and excreta samples were collected over 7–14 days post-dose and analyzed for radioactivity and to characterize the metabolites/catabolites. The plasma radioactivity of polatuzumab vedotin showed a biphasic elimination profile similar to that of unconjugated polatuzumab but different from unconjugated radiolabeled MMAE, which had a fast clearance. The vast majority of the radiolabeled MMAE in plasma remained associated with antibodies, with a minor fraction as free MMAE and MMAE-containing catabolites. Similar to unconjugated mAb, polatuzumab vedotin showed a nonspecific distribution to multiple highly perfused organs, including the lungs, heart, liver, spleen, and kidneys, where the ADC underwent catabolism to release MMAE and other MMAE-containing catabolites. Both polatuzumab vedotin and unconjugated MMAE were mainly eliminated through the biliary fecal route (>90%) and a small fraction (<10%) was eliminated through renal excretion in the form of catabolites/metabolites, among which, MMAE was identified as the major species, along with several other minor species. These studies provided significant insight into ADC’s absorption, distribution, metabolism, and elimination (ADME) properties, which supports the clinical development of POLIVY.

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