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Scientific Reports Jan 2022Scoparone (6,7-dimethoxycoumarin) is a simple coumarin from botanical drugs of Artemisia species used in Traditional Chinese Medicine and Génépi liquor. However, its...
Scoparone (6,7-dimethoxycoumarin) is a simple coumarin from botanical drugs of Artemisia species used in Traditional Chinese Medicine and Génépi liquor. However, its bioavailability to the brain and potential central effects remain unexplored. We profiled the neuropharmacological effects of scoparone upon acute and subchronic intraperitoneal administration (2.5-25 mg/kg) in Swiss mice and determined its brain concentrations and its effects on the endocannabinoid system (ECS) and related lipids using LC-ESI-MS/MS. Scoparone showed no effect in the forced swimming test (FST) but, administered acutely, led to a bell-shaped anxiogenic-like behavior in the elevated plus-maze test and bell-shaped procognitive effects in the passive avoidance test when given subchronically and acutely. Scoparone rapidly but moderately accumulated in the brain (Cmax < 15 min) with an apparent first-order elimination (95% eliminated at 1 h). Acute scoparone administration (5 mg/kg) significantly increased brain arachidonic acid, prostaglandins, and N-acylethanolamines (NAEs) in the FST. Conversely, subchronic scoparone treatment (2.5 mg/kg) decreased NAEs and increased 2-arachidonoylglycerol. Scoparone differentially impacted ECS lipid remodeling in the brain independent of serine hydrolase modulation. Overall, the unexpectedly potent central effects of scoparone observed in mice could have toxicopharmacological implications for humans.
Topics: Animals; Arachidonic Acid; Arachidonic Acids; Avoidance Learning; Behavior, Animal; Biological Availability; Brain; Cognition; Coumarins; Endocannabinoids; Ethanolamines; Glycerides; Infusions, Parenteral; Lipid Metabolism; Male; Maze Learning; Mice; Prostaglandins
PubMed: 35039558
DOI: 10.1038/s41598-021-04741-3 -
Particle and Fibre Toxicology Nov 2023Nanoplastics (NPs) could be released into environment through the degradation of plastic products, and their content in the air cannot be ignored. To date, no studies...
BACKGROUND
Nanoplastics (NPs) could be released into environment through the degradation of plastic products, and their content in the air cannot be ignored. To date, no studies have focused on the cardiac injury effects and underlying mechanisms induced by respiratory exposure to NPs.
RESULTS
Here, we systematically investigated the cardiotoxicity of 40 nm polystyrene nanoplastics (PS-NPs) in mice exposed via inhalation. Four exposure concentrations (0 µg/day, 16 µg/day, 40 µg/day and 100 µg/day) and three exposure durations (1 week, 4 weeks, 12 weeks) were set for more comprehensive information and RNA-seq was performed to reveal the potential mechanisms of cardiotoxicity after acute, subacute and subchronic exposure. PS-NPs induced cardiac injury in a dose-dependent and time-dependent manner. Acute, subacute and subchronic exposure increased the levels of injury biomarkers and inflammation and disturbed the equilibrium between oxidase and antioxidase activity. Subacute and subchronic exposure dampened the cardiac systolic function and contributed to structural and ultrastructural damage in heart. Mechanistically, violent inflammatory and immune responses were evoked after acute exposure. Moreover, disturbed energy metabolism, especially the TCA cycle, in the myocardium caused by mitochondria damage may be the latent mechanism of PS-NPs-induced cardiac injury after subacute and subchronic exposure.
CONCLUSION
The present study evaluated the cardiotoxicity induced by respiratory exposure to PS-NPs from multiple dimensions, including the accumulation of PS-NPs, cardiac functional assessment, histology observation, biomarkers detection and transcriptomic study. PS-NPs resulted in cardiac injury structurally and functionally in a dose-dependent and time-dependent manner, and mitochondria damage of myocardium induced by PS-NPs may be the potential mechanism for its cardiotoxicity.
Topics: Animals; Mice; Cardiotoxicity; Polystyrenes; Microplastics; Myocardium; Biomarkers; Nanoparticles
PubMed: 38031128
DOI: 10.1186/s12989-023-00557-3 -
Food and Chemical Toxicology : An... Mar 2022The organosulfur compounds (OSC) extracted from Allium spp. exhibit antibacterial, antifungal, and antioxidant properties. The agri-food industry is taking advantage of...
The organosulfur compounds (OSC) extracted from Allium spp. exhibit antibacterial, antifungal, and antioxidant properties. The agri-food industry is taking advantage of these properties by using them as natural feed and food additives. In the present work, an acute and a subchronic 90-days toxicity studies have been conducted for the first time to assess the safety of the OSC propyl-propane-thiosulfinate (PTS). Both studies were carried out following the Organization for Economic Co-operation and Development test guidelines (425 and 408, respectively). The acute study provided a maximum tolerated dose (MTD) of 175 mg/kg and the subchronic study established the Non Observed Adverse Effect Level (NOAEL) ≥ 55 mg/kg body weight (b.w.)/day in both sexes. In addition, the subchronic study performed on rats exposed to 14, 28 and 55 mg/kg b.w./day PTS, revealed no changes in any of the hematological parameters measured as well as no differences in body weight and water/food consumption. However, biochemical parameters were altered in some groups, although they were not biologically significant (Ca in female rats, and the thyroids hormones T3 and T4 in rat males). Furthermore, the histopathological assessment evidenced no abnormality on the gastrointestinal, respiratory, lymphoid, urinary, circulatory, nervous, musculoskeletal, and reproductive systems.
Topics: Allium; Animals; Dose-Response Relationship, Drug; Female; Lethal Dose 50; Male; Plant Extracts; Rats; Thiosulfonic Acids; Toxicity Tests
PubMed: 35077829
DOI: 10.1016/j.fct.2022.112827 -
Food and Chemical Toxicology : An... Jun 2023Use of cannabidiol (CBD) in humans has increased considerably in recent years. While currently available studies suggest that CBD is relatively safe for human...
Use of cannabidiol (CBD) in humans has increased considerably in recent years. While currently available studies suggest that CBD is relatively safe for human consumption, data from publicly available studies on CBD conducted according to modern testing guidelines are lacking. In the current study, the potential for toxicity following repeated oral exposure to hemp-derived CBD isolate was evaluated in male and female Sprague Dawley rats. No adverse treatment-related effects were observed following administration of CBD via oral gavage for 14 and 90 days at concentrations up to 150 and 140 mg/kg-bw/d, respectively. Microscopic liver and adrenal gland changes observed in the 90-day study were determined to be resolved after a 28-day recovery period. CBD was well tolerated at these dose levels, and the results of this study are comparable to findings reported in unpublished studies conducted with other CBD isolates. The current studies were conducted as part of a broader research program to examine the safety of CBD.
Topics: Rats; Animals; Male; Humans; Female; Cannabidiol; Rats, Sprague-Dawley; Cannabis; Administration, Oral
PubMed: 37105391
DOI: 10.1016/j.fct.2023.113778 -
Biological & Pharmaceutical Bulletin Feb 2021Subtilisin NAT, a Bacillus subtilisin, is widely applied as a functional food and considered to be one of the most exploitable potential oral thrombolytic agents....
Subtilisin NAT, a Bacillus subtilisin, is widely applied as a functional food and considered to be one of the most exploitable potential oral thrombolytic agents. Subtilisin QK, another Bacillus subtilisin, is a serine protease fermented by Bacillus subtilis 02 and has a better thrombolytic effect. Therefore, subtilisin QK is typically used for evaluating the safety of Bacillus subtilisins. Here, we conduct several good laboratory practice (GLP)-compliant studies in non-rodent animal, i.e., in Beagle dogs, including acute toxicity, subchronic toxicity, and safety pharmacology studies. No adverse effects were evident in the acute and 28-d subchronic toxicity studies at doses up to 40000 FU/kg and 16000 FU/kg/d, respectively. In evaluating the pharmacological safety of up to 2000FU/kg subtilisin QK, we found no significant differences between the electrocardiograms, blood pressures, and respiration of beagle dogs. These findings suggest the safety of Bacillus subtilisin, providing reliable pharmacological and toxicological data for its development and popularization as a functional food and drug.
Topics: Animals; Dogs; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Fibrinolytic Agents; Male; Subtilisins; Toxicity Tests, Acute; Toxicity Tests, Subchronic
PubMed: 33281147
DOI: 10.1248/bpb.b20-00659 -
BMC Pharmacology & Toxicology Jun 2021Subtilisin QK is a serine protease in the subtilisin family, and is fermented by Bacillus subtilis QK02. The fibrinolytic activity of subtilisin QK was measured by...
BACKGROUND
Subtilisin QK is a serine protease in the subtilisin family, and is fermented by Bacillus subtilis QK02. The fibrinolytic activity of subtilisin QK was measured by detecting low molecular weight degradation products using a spectrophotometric method developed by Japan Bio Science Laboratory Co., Ltd. Subtilisin QK powder can maintain its fibrinolytic activity for more than 24 months when it is stored at room temperature and protected from light. Our previous results showed that subtlisin QK directly degraded cross-linked fibrins in the fibrin plate assay and effectively inhibited thrombosis in the mouse thrombus model. The aim of this study was to determine the acute toxicity, potential subchronic toxicity, and safety pharmacology of subtilisin QK in Sprague-Dawley (SD) rats.
METHODS
In the acute toxicity study, a single oral dose of 100,000 FU/kg was administered to 10 female and 10 male SD rats. In the 28-day subchronic toxicity, 60 female and 60 male SD rats were randomly assigned to four experimental groups (daily oral dose of 0, 2500, 7500 and 25,000 FU/kg). In the safety pharmacology study, 20 female and 20 male SD rats were randomly assigned to four experimental groups (single oral dose of 0, 500, 1500 and 5000 FU/kg).
RESULTS
No death occurred and no adverse effects were observed in the acute toxicity study at a dose of 100,000 FU/kg. In the 28-day subchronic toxicity study, several hematological and blood biochemical parameters showed increases or decreases; however, due to the lack of a dose-response relationship, these differences were considered unrelated to treatment. In the safety pharmacology study, no adverse effects were observed on the central nervous of SD rats post-administration up to a dose of 5000 FU/kg subtilisin QK.
CONCLUSION
The results showed that oral consumption of subtilisin QK is of low toxicological concern. No adverse effects were observed at doses of 2500, 7500, and 25,000 FU/kg in the 28-day subchronic toxicity, and the no-observed-adverse-effect level (NOAEL) of subtilisin QK was 25,000 FU/kg.
Topics: Administration, Oral; Animals; Female; Fibrinolytic Agents; Male; Rats, Sprague-Dawley; Subtilisins; Toxicity Tests, Acute; Toxicity Tests, Subchronic; Rats
PubMed: 34172094
DOI: 10.1186/s40360-021-00506-w -
Evidence-based Complementary and... 2021, a traditional plant on Ulleung Island in the Republic of Korea, has been recognized for its multiple medicinal properties. However, potential toxicity and safety...
, a traditional plant on Ulleung Island in the Republic of Korea, has been recognized for its multiple medicinal properties. However, potential toxicity and safety analyses of have not been previously investigated. Therefore, this study aimed to evaluate the safety profile of ethanolic extract of leaves and stems (EAG) in terms of genotoxicity and subchronic oral animal toxicity under OECD guidelines and GLP conditions. Toxicological assessments were performed at doses of 1,250, 2,500, and 5,000 mg/kg/day in a 13-week oral repeated-dose toxicity study of EAG in male and female SD rats. In addition, an Ames test, an mammalian chromosomal aberration test, and a micronucleus test were performed. No toxicological changes in clinical signs, body weights, water and food consumption, urinalysis, hematology, clinical biochemistry, gross findings, and histopathological examinations were observed in subchronic oral animal toxicity. In addition, EAG gave negative results when evaluated using and genotoxicity tests. In conclusion, the no-observed-adverse-effect level (NOAEL) of EAG was considered to be 5,000 mg/kg/day, and no target organs were identified in both sexes of rats. EAG was also classified as nonmutagenic and nonclastogenic in genotoxicity testing. Collectively, these results show a lack of general toxicity and genotoxicity for EAG that supports clinical work for development as a herbal medicine.
PubMed: 35003288
DOI: 10.1155/2021/1018101 -
Toxicology Research Dec 2022Filamentous fungus biomass is a protein-rich food, which can serve as an alternative to animal, plant, and legume protein sources. is a filamentous fungus that...
Filamentous fungus biomass is a protein-rich food, which can serve as an alternative to animal, plant, and legume protein sources. is a filamentous fungus that typically grows in tropical and sub-tropical regions. Traditionally, has served as a model eukaryotic organism due to its ease of growth and propagation and suitability for genetic manipulation. However, filamentous fungi, such as , have also been consumed or used to produce fermented foods for centuries and have been developed into protein-rich biomass ingredients to be used in conventional foods and meat substitutes. A panel of toxicological tests including genotoxic, acute, and subchronic studies were conducted on dried biomass to support its safe use in food. The dried biomass was found to be not genotoxic in a bacterial reverse mutation (Ames) assay, an in vitro chromosomal aberration test, and an in vivo micronucleus test. In the acute and subchronic toxicity studies, rats were orally gavaged with biomass at concentrations of 0, 1,000, 2,500, and 5,000 mg/kg body weight/day for 14 and 90 days, respectively. At the conclusion of the studies, there were no test article-related toxicity results observed in clinical observations, body weight, food consumption, ophthalmology, hematology, clinical chemistry, coagulation, thyroid hormone, urinalysis, and macroscopic and microscopic findings. The no-observed-adverse-effect level for the dried biomass ingredient was determined to be 5,000 mg/kg body weight/day, the highest dose tested.
PubMed: 36569482
DOI: 10.1093/toxres/tfac069 -
Toxicology Research Mar 2021Pomegranate ( L.) is a fruit used extensively in traditional medicine by ancient and modern cultures. Different parts of the tree and fruit, such as leaf, peel,...
Pomegranate ( L.) is a fruit used extensively in traditional medicine by ancient and modern cultures. Different parts of the tree and fruit, such as leaf, peel, pericarp, aril, seed, and juice contain considerable amounts of phenolic compounds with high antioxidant activities. To improve its storability, pomegranate juice was microencapsulated by spray drying. The present study evaluated microencapsulated pomegranate juice (MPJ) for toxic effects in Wistar rats and CD-1 mice to determine if MPJ can be considered safe for human consumption and used as a nutraceutical. No deaths or deleterious effects occurred when high doses of 5000 mg/kg were orally administered in rats for 14 days, indicating an absence of subacute toxicity. Similarly, 3000 mg/kg MPJ administered to CD-1 mice for 90 days did not show subchronic toxicity. In fact, MPJ resulted in lowered weight gain in both rats and mice. Cytotoxic and microbiological analyses of MPJ were also performed. MPJ did not cause any cytotoxicity in epithelial cell culture as tested using the Alamar blue assay. Additionally, histopathological analysis of kidney and liver corroborated the absence of toxicity in CD-1 mice. The microbial load of the MPJ was low, and no pathogenic bacteria were present. In conclusion, the results reported here show that high doses of MPJ are apparently innocuous in rats and mice for the 14 and 90 days investigated, respectively. Although preliminary, our results suggest that MPJ may be safe to ingest and may even have beneficial effects in reducing weight gain.
PubMed: 33884181
DOI: 10.1093/toxres/tfab013 -
Toxicology Reports 2021A novel 6-phytase (Phytase TSP, trade name OptiPhos® PLUS) with improved thermostability has been developed for use in animal feed. The safety of the new phytase was...
A novel 6-phytase (Phytase TSP, trade name OptiPhos® PLUS) with improved thermostability has been developed for use in animal feed. The safety of the new phytase was evaluated by testing for genotoxicity and subchronic toxicity. In and genotoxicity assays Phytase TSP concentrate was not mutagenic and did not induce biologically or statistically significant increases in the frequency of micronucleated polychromatic erythrocytes. In a subchronic toxicity study, male and female rats administered 100, 500 or 1000 mg/kg body weight/day of Phytase TSP concentrate oral gavage for 90 days had no mortalities, and no treatment-related effects on body weight, food consumption, clinical observations or ophthalmology. Furthermore, there were no changes in haematology, clinical chemistry, urinalysis, gross pathology, organ weights or histopathology that could be attributed to the test article. Several endpoints exhibited statistically significant effects, but none was dose-related or considered to be of toxicological relevance. Based on these results, Phytase TSP concentrate (OptiPhos® PLUS) was not genotoxic and the No Observed Adverse Effect Level (NOAEL) for male and female rats was 1000 mg/kg body weight/day.
PubMed: 33437655
DOI: 10.1016/j.toxrep.2020.12.015