scholarly journals Biochemical and Histopathological Alterations in Different Tissues of Rats Due to Repeated Oral Dose Toxicity of Cymoxanil

Animals ◽  
2020 ◽  
Vol 10 (12) ◽  
pp. 2205
Author(s):  
Mohamed S. Ahmed ◽  
Ahmed H. Massoud ◽  
Aly S. Derbalah ◽  
Ashraf Al-Brakati ◽  
Mohsin A. Al-Abdawani ◽  
...  
Keyword(s):  
Toxicity Assessment ◽  
Significant Inhibition ◽  
High Dose ◽  
Rat Tissues ◽  
Biochemical Alterations ◽  
Histopathological Alterations ◽  
Piecemeal Necrosis ◽  
Oral Doses ◽  
Dose Dependent ◽  
Different Tissues

Evaluating potential adverse health impacts caused by pesticides is an important parameter in human toxicity. This study focuses on the importance of subchronic toxicity assessment of cymoxanil fungicide in rats with special reference to target biochemical enzymes and histopathological changes in different tissues. In this regard, a 21-day toxicity study with repeated cymoxanil oral doses was conducted. It has been shown that low doses (0.5 mg/kg) were less effective than medium (1 mg/kg) and high (2 mg/kg) doses. Moreover, high dose dose-treated rats showed piecemeal necrosis in the liver, interstitial nephritis and tubular degeneration in the kidneys, interstitial pneumonia and type II pneumocyte hyperplasia in the lungs, gliosis, spongiosis, and malacia in the brain, and testicular edema and degeneration in the testes. Cymoxanil significantly increased AST, ALT, and ALP in serum and liver, indicating tissue necrosis and possible leakage of these enzymes into the bloodstream. Creatinine levels increased, indicating renal damage. Similarly, significant inhibition was recorded in brain acetylcholinesterase, indicating that both synaptic transmission and nerve conduction were affected. Importantly, these histopathological and biochemical alterations were dose-dependent. Taken together, our study reported interesting biochemical and histopathological alterations in different rat tissues following repeated toxicity with oral doses of cymoxanil. Our study suggests future studies on different pesticides at different concentrations that would help urge governments to create more restrictive regulations concerning these compounds’ levels.

Metabolism is not a Major Contributor to the Toxicity of Piperaquine, a Major Partner Antimalarial in Artemisinin-Based Combination Therapy

2021 ◽  
Vol 22 ◽  
Author(s):  
Liyuan Zhang ◽  
Zhaohua Liu ◽  
Yunrui Zhang ◽  
Yuewu Xie ◽  
Jie Xing
Keyword(s):  
Histopathological Examination ◽  
High Dose ◽  
Mrna Levels ◽  
Apoptosis Pathway ◽  
Hepatocellular Damage ◽  
Serum Biochemical ◽  
Oral Doses ◽  
Dose Dependent ◽  
Cumulative Exposures

Background: Hepatocellular damage has been reported for the antimalarial piperaquine (PQ) in the clinic after cumulative doses. Objectives: The role of metabolism in PQ toxicity was evaluated, and the mechanism mediating PQ hepatotoxicity was investigated. Method: The toxicity of PQ and its major metabolite (PQ N-oxide; M1) in mice was evaluated in terms of serum biochemical parameters. The role of metabolism in PQ toxicity was investigated in mice pretreated with an inhibitor of CYP450 (ABT) and/or FMO enzyme (MMI). The dose-dependent pharmacokinetics of PQ and M1 were studied in mice. Histopathological examination was performed to reveal the mechanism mediating PQ hepatotoxicity. Results: Serum biochemical levels (ALT and BUN) increased significantly (P < 0.05) in mice after three-day oral doses of PQ (> 200 mg/kg/day), indicating hepatotoxicity and nephrotoxicity of PQ at a high dose. Weaker toxicity was observed for M1. Pretreatment with ABT and/or MMI did not increase PQ toxicity. PQ and M1 showed linear pharmacokinetics in mice after a single oral dose, and multiple oral doses led to their cumulative exposures. Histopathological examination showed that a high dose of PQ (> 200 mg/kg/day for three days) could induce hepatocyte apoptosis. The mRNA levels of targets in NF-κB and p53 pathways could be up-regulated by 2-30-fold in mice by PQ or M1. Conclusions: PQ metabolism led to detoxification of PQ, but there was a low possibility of altered toxicity induced by metabolism inhibition. The hepatotoxicity of PQ and its N-oxidation metabolite was partly mediated by NF-κB inflammatory pathway and p53 apoptosis pathway.

scholarly journals Evaluation of Antiepileptic Activity of Methanolic Leaves Extract of Tragia involucrata Linn. in Mice

2014 ◽  
Vol 17 ◽  
pp. 167-179 ◽  
Author(s):  
Ganapathi G. Varma ◽  
Benson K. Mathai ◽  
Kuntal Das ◽  
Girish Gowda ◽  
S. Rammohan ◽  
...  
Keyword(s):  
Lipid Peroxidation ◽  
Methanolic Extract ◽  
Significant Inhibition ◽  
High Dose ◽  
Maximal Electroshock ◽  
Antiepileptic Activity ◽  
Biochemical Estimation ◽  
Dose Dependent ◽  
The Brain

The present investigation was aimed to study an antiepileptic activity of methanolic extract of Tragia involucrata Linn in mice. In vivo screening models like maximal electroshock-induced convulsion (MES), pentylenetetrazole (PTZ) and picrotoxin (PTX) induced models are used to evaluate the antiepileptic effects of the extracts. The biochemical estimation was done by measuring the lipid peroxidation and reduced glutathione (GSH). In the MES induced convulsion, methanolic extract of Tragia involucrata (METI) at high dose (800 mg/kg body weight), showed high significant inhibition on tonic hind limb extension (THLE, 6.83 ±0.30***) and decrease in duration of stupor period (108.7 ±6.53***). In PTZ and PTX induced model METI (400 mg/kg and 800 mg/kg) showed significant delay on the onset of convulsions, decreased duration of convulsion and reduced mortality significantly. It also showed significant decrease in brain MDA level in lipid peroxidation profile, and increase in the brain glutathione levels in mice against PTZ induced convulsion. The results confirmed that Tragia involucrata Linn possesses dose dependent antiepileptic activity.

Melatonin actions in the heart; more than a hormone

2018 ◽  
Vol 1 (1) ◽  
pp. 21-26 ◽  
Author(s):  
Darío Acuña-Castroviejo ◽  
Maria T Noguiera-Navarro ◽  
Russel J Reiter ◽  
Germaine Escames
Keyword(s):  
Cell Membranes ◽  
Myocardial Cell ◽  
Rat Tissues ◽  
Dependent Manner ◽  
Broad Distribution ◽  
Multiple Organs ◽  
High Doses ◽  
Extrapineal Melatonin ◽  
Dose Dependent ◽  
Different Doses

Due to the broad distribution of extrapineal melatonin in multiple organs and tissues, we analyzed the presence and subcellular distribution of the indoleamine in the heart of rats. Groups of sham-operated and pinealectomized rats were sacrificed at different times along the day, and the melatonin content in myocardial cell membranes, cytosol, nuclei and mitochondria, were measured. Other groups of control animals were treated with different doses of melatonin to monitor its intracellular distribution. The results show that melatonin levels in the cell membrane, cytosol, nucleus, and mitochondria vary along the day, without showing a circadian rhythm. Pinealectomized animals trend to show higher values than sham-operated rats. Exogenous administration of melatonin yields its accumulation in a dose-dependent manner in all subcellular compartments analyzed, with maximal concentrations found in cell membranes at doses of 200 mg/kg bw melatonin. Interestingly, at dose of 40 mg/kg b.w, maximal concentration of melatonin was reached in the nucleus and mitochondrion. The results confirm previous data in other rat tissues including liver and brain, and support that melatonin is not uniformly distributed in the cell, whereas high doses of melatonin may be required for therapeutic purposes.

scholarly journals High-dose Glycerol Monolaurate Up-Regulated Beneficial Indigenous Microbiota without Inducing Metabolic Dysfunction and Systemic Inflammation: New Insights into Its Antimicrobial Potential

Nutrients ◽  
2019 ◽  
Vol 11 (9) ◽  
pp. 1981 ◽  
Author(s):  
Qiufen Mo ◽  
Aikun Fu ◽  
Lingli Deng ◽  
Minjie Zhao ◽  
Yang Li ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Systemic Inflammation ◽  
Body Weight Gain ◽  
High Dose ◽  
Dependent Manner ◽  
Glucose And Lipid Metabolism ◽  
Glycerol Monolaurate ◽  
Indigenous Microbiota ◽  
Anti Inflammatory ◽  
Dose Dependent

Glycerol monolaurate (GML) has potent antimicrobial and anti-inflammatory activities. The present study aimed to assess the dose-dependent antimicrobial-effects of GML on the gut microbiota, glucose and lipid metabolism and inflammatory response in C57BL/6 mice. Mice were fed on diets supplemented with GML at dose of 400, 800 and 1600 mg kg−1 for 4 months, respectively. Results showed that supplementation of GML, regardless of the dosages, induced modest body weight gain without affecting epididymal/brown fat pad, lipid profiles and glycemic markers. A high dose of GML (1600 mg kg−1) showed positive impacts on the anti-inflammatory TGF-β1 and IL-22. GML modulated the indigenous microbiota in a dose-dependent manner. It was found that 400 and 800 mg kg−1 GML improved the richness of Barnesiella, whereas a high dosage of GML (1600 mg kg−1) significantly increased the relative abundances of Clostridium XIVa, Oscillibacter and Parasutterella. The present work indicated that GML could upregulate the favorable microbial taxa without inducing systemic inflammation and dysfunction of glucose and lipid metabolism.

scholarly journals Dose-dependent response to infection with SARS-CoV-2 in the ferret model and evidence of protective immunity

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Kathryn A. Ryan ◽  
Kevin R. Bewley ◽  
Susan A. Fotheringham ◽  
Gillian S. Slack ◽  
Phillip Brown ◽  
...  
Keyword(s):  
Protective Immunity ◽  
Viral Rna ◽  
Dose Titration ◽  
High Dose ◽  
Lung Pathology ◽  
Upper Respiratory Tract ◽  
Virus Shedding ◽  
Upper Respiratory ◽  
Dose Dependent ◽  
Titration Study

AbstractThere is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5 × 106 pfu) and medium (5 × 104 pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5 × 102 pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5–15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease.

scholarly journals A rodent model of human dose-equivalent progestin-only implantable contraception

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Heather C. M. Allaway ◽  
Roger A. Pierson ◽  
Jesse Invik ◽  
Susan A. Bloomfield
Keyword(s):  
Repeated Measures ◽  
Ovarian Function ◽  
Virgin Female ◽  
Rodent Model ◽  
High Dose ◽  
Corpora Lutea ◽  
Average Dose ◽  
Estrus Cycle ◽  
Human Dose ◽  
Dose Dependent

Abstract Background Long-acting, reversible contraceptives (LARC; progestin only) are an increasingly common hormonal contraceptive choice in reproductive aged women looking to suppress ovarian function and menstrual cyclicity. The overall objective was to develop and validate a rodent model of implanted etonogestrel (ENG) LARC, at body size equivalent doses to the average dose received by women during each of the first 3 years of ENG subdermal rod LARC use. Methods Intact, virgin, female Sprague-Dawley rats (16-wk-old) were randomized to 1 of 4 groups (n = 8/group) of ENG LARC (high-0.30μg/d, medium-0.17μg/d, low-0.09μg/d, placebo-0.00μg/d) via a slow-release pellet implanted subcutaneously. Animals were monitored for 21 days before and 29 days following pellet implantation using vaginal smears, ultrasound biomicroscopy (UBM), saphenous blood draws, food consumption, and body weights. Data were analyzed by chi-square, non-parametric, univariate, and repeated measures 2-way ANOVA. Results Prior to pellet implantation there was no difference in time spent in estrus cycle phases among the treatment groups (p > 0.30). Following pellet implantation there was a dose-dependent impact on the time spent in diestrus and estrus (p < 0.05), with the high dose group spending more days in diestrus and fewer days in estrus. Prior to pellet insertion there was not an association between treatment group and estrus cycle classification (p = 0.57) but following pellet implantation there was a dose-dependent association with cycle classification (p < 0.02). Measurements from the UBM (ovarian volume, follicle count, corpora lutea count) indicate an alteration of ovarian function following pellet implantation. Conclusion Assessment of estrus cyclicity indicated a dose-response relationship in the shift to a larger number of acyclic rats and longer in duration spent in the diestrus phase. Therefore, each dose in this model mimics some of the changes observed in the ovaries of women using ENG LARC and provides an opportunity for investigating the impacts on non-reproductive tissues in the future.

scholarly journals Early and Late Cytologic Effects of Whole Body Irradiation on Human Marrow

Blood ◽  
1964 ◽  
Vol 23 (4) ◽  
pp. 471-487 ◽  
Author(s):  
T. M. FLIEDNER ◽  
GOULD A. ANDREWS ◽  
EUGENE P. CRONKITE ◽  
VICTOR P. BOND
Keyword(s):  
Dose Group ◽  
Animal Experiments ◽  
Giant Cells ◽  
Whole Body ◽  
High Dose ◽  
Multinucleated Cells ◽  
Exposed Individual ◽  
Interphase Cells ◽  
Cytologic Abnormalities ◽  
Dose Dependent

Abstract 1. Serial marrow studies were performed during the first few days in eight men accidentally exposed to a mixed neutron gamma irradiation. They showed the occurrence of a wave of cytologic abnormalities. These were identical with those seen in animal experiments 1-3 days after whole body irradiation. They were considered to be "mitotically connected" (M. C. Abn.) and included the occurrence of chromosomal bridges and chromosomal fragments in mitoses. In interphase cells, the main abnormalities were nuclear fragments ("karyomeres") in the cytoplasm of erythroblasts, myelocytic cells and lymphocytes; bi- and multinucleated cells; and giant cells. The peak of abnormalities in the erythropoietic forms was reachéd after 2 days; that in the myelopoietic cells 4 days after exposure. On the 4th day, there was a distinct dose-dependent difference in these abnormalities between the high dose group (236-365 rads) and the low dose group (22-68 rads). 2. Some cytologic abnormalities, as seen in increased regeneratory activity of the marrow, were found in marrow smears 3.5 years after the accident, although the peripheral blood counts and mitotic indices of the marrow were within normal range. Their significance is obscure. 3. A careful cytologic evaluation of serially aspirated marrow samples during the first hours and days after whole body exposure proves to be an additional important aid in the assessment of the exposed individual and may well prove to be useful in determining the degree of injury and thus the prognosis.

scholarly journals Effect of Synchronous Versus Sequential Regimens on the Pharmacokinetics and Biodistribution of Regorafenib with Irradiation

Pharmaceutics ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 386
Author(s):  
Tung-Hu Tsai ◽  
Yu-Jen Chen ◽  
Li-Ying Wang ◽  
Chen-Hsi Hsieh
Keyword(s):  
Stereotactic Body Radiation Therapy ◽  
In Vivo Studies ◽  
Control Group ◽  
High Dose ◽  
Dependent Manner ◽  
Hep G2 ◽  
Time Curve ◽  
Dose Dependent

This study was performed to evaluate the interaction between conventional or high-dose radiotherapy (RT) and the pharmacokinetics (PK) of regorafenib in concurrent or sequential regimens for the treatment of hepatocellular carcinoma. Concurrent and sequential in vitro and in vivo studies of irradiation and regorafenib were designed. The interactions of RT and regorafenib in vitro were examined in the human hepatoma Huh-7, HA22T and Hep G2 cell lines. The RT–PK phenomenon and biodistribution of regorafenib under RT were confirmed in a free-moving rat model. Regorafenib inhibited the viability of Huh-7 cells in a dose-dependent manner. Apoptosis in Huh-7 cells was enhanced by RT followed by regorafenib treatment. In the concurrent regimen, RT decreased the area under the concentration versus time curve (AUC)regorafenib by 74% (p = 0.001) in the RT2 Gy × 3 fraction (f’x) group and by 69% (p = 0.001) in the RT9 Gy × 3 f’x group. The AUCregorafenib was increased by 182.8% (p = 0.011) in the sequential RT2Gy × 1 f’x group and by 213.2% (p = 0.016) in the sequential RT9Gy × 1 f’x group. Both concurrent regimens, RT2Gy × 3 f’x and RT9Gy × 3 f’x, clearly decreased the biodistribution of regorafenib in the heart, liver, lung, spleen and kidneys, compared to the control (regorafenib × 3 d) group. The concurrent regimens, both RT2Gy × 3 f’x and RT9Gy × 3 f’x, significantly decreased the biodistribution of regorafenib, compared with the control group. The PK of regorafenib can be modulated both by off-target irradiation and stereotactic body radiation therapy (SBRT).

scholarly journals N-Acetyl Cysteine Overdose Inducing Hepatic Steatosis and Systemic Inflammation in Both Propacetamol-Induced Hepatotoxic and Normal Mice

Antioxidants ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 442
Author(s):  
Gunn-Guang Liou ◽  
Cheng-Chi Hsieh ◽  
Yi-Ju Lee ◽  
Pin-Hung Li ◽  
Ming-Shiun Tsai ◽  
...  
Keyword(s):  
Inbred Mouse ◽  
Serum Triglyceride ◽  
Mouse Strains ◽  
High Dose ◽  
Therapeutic Effects ◽  
Protein Nitration ◽  
Cholesterol Levels ◽  
Antioxidative Enzyme Activities ◽  
Acetyl Cysteine ◽  
Dose Dependent

Acetaminophen (APAP) overdose induces acute liver damage and even death. The standard therapeutic dose of N-acetyl cysteine (NAC) cannot be applied to every patient, especially those with high-dose APAP poisoning. There is insufficient evidence to prove that increasing NAC dose can treat patients who failed in standard treatment. This study explores the toxicity of NAC overdose in both APAP poisoning and normal mice. Two inbred mouse strains with different sensitivities to propacetamol-induced hepatotoxicity (PIH) were treated with different NAC doses. NAC therapy decreased PIH by reducing lipid oxidation, protein nitration and inflammation, and increasing glutathione (GSH) levels and antioxidative enzyme activities. However, the therapeutic effects of NAC on PIH were dose-dependent from 125 (N125) to 275 mg/kg (N275). Elevated doses of NAC (400 and 800 mg/kg, N400 and N800) caused additional deaths in both propacetamol-treated and normal mice. N800 treatments significantly decreased hepatic GSH levels and induced inflammatory cytokines and hepatic microvesicular steatosis in both propacetamol-treated and normal mice. Furthermore, both N275 and N400 treatments decreased serum triglyceride (TG) and induced hepatic TG, whereas N800 treatment significantly increased interleukin-6, hepatic TG, and total cholesterol levels. In conclusion, NAC overdose induces hepatic and systemic inflammations and interferes with fatty acid metabolism.

Prolactin stimulates food intake in a dose-dependent manner

1989 ◽  
Vol 256 (1) ◽  
pp. R276-R280 ◽  
Author(s):  
T. Gerardo-Gettens ◽  
B. J. Moore ◽  
J. S. Stern ◽  
B. A. Horwitz
Keyword(s):  
Food Intake ◽  
Female Rats ◽  
High Dose ◽  
Dependent Manner ◽  
Additional Control ◽  
The Mean ◽  
Ovine Prolactin ◽  
Dose Dependent ◽  
Medium Dose ◽  
Cumulative Food Intake

Lactation in the rat is marked by pronounced hyperphagia and suppression of brown fat (BAT) thermogenic capacity. We previously examined the possibility that elevated prolactin levels mediate these changes. The present study evaluated the effect of varying prolactin levels on food intake, BAT mitochondrial GDP binding, and carcass adiposity. Female rats were injected daily for 10 days with ovine prolactin at one of three doses: high = 3.0, medium = 1.0, or low = 0.3 micrograms/g body wt. Controls were injected with 0.9% NaCl. A group of uninjected rats served as an additional control. Cumulative food intake was significantly elevated in a dose-dependent manner in the prolactin-treated animals relative to the saline-injected and uninjected controls. Compared with the saline controls, the mean cumulative food intake was greatest at the high dose (20% increase), intermediate at the medium dose (17%), and smallest at the low dose (12%). Prolactin-treated rats gained significantly more weight during the experiment than did controls. Despite the hyperphagia in the prolactin-treated rats, no significant differences in BAT mitochondrial GDP binding were observed among the five groups. These data indicate that elevated prolactin levels stimulate food intake in a dose-dependent manner and that this hyperphagia is not accompanied by an increase in BAT mitochondrial GDP binding.

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