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Gardenia, as a medicinal and edible herb, has the pharmacological activity of protecting the liver and cholagogue, but the hepatotoxicity induced by the chemical component genipin (GP) limits its application. The aim of this study was to evaluate the acute and subacute hepatotoxicity of genipin in normal mice and mice with α-naphthalene isothiocyanate (ANIT)-induced liver injury. The results of the acute study showed that the LD50 of genipin was 510 mg/kg. Genipin exhibited hepatotoxicity in normal and jaundiced mice at doses of 125 mg/kg, 250 mg/kg, and 500 mg/kg, which increased with dose. In a 28-day subacute study, the 50 mg/kg and 100 mg/kg dose groups showed some pharmacodynamic effects at 7 days but exhibited hepatotoxicity that increased with time and improved after drug withdrawal. In addition, based on proteomics, the mechanism of liver injury induced by genipin may be related to the disruption of the UDP-glucuronosyltransferase system and cytochrome P450 enzyme activity. In conclusion, this study showed that genipin hepatotoxicity was time- and dose dependent, but it is worth mentioning that hepatotoxicity was reversible. It is hoped that this study will provide a scientific basis for circumventing the adverse effects of genipin.

Coptosapelta flavescens Korth. is one of the medicinal plants used as a traditional medicine in Vietnam for a long time. However, few documents proved its safety for a long time. Therefore, the study aimed to determine the toxicity effects of the aqueous extract of C. flavescens by determining its effects after subchronic oral administration in Swiss albino mice. The toxicity of C. flavescens extract was tested at doses of 400 and 1200 mg/kg, respectively, over 30 and 60 days on an in vivo model. Animal weight, behavior, and condition changes were monitored throughout the process. At the end of the observation periods, hematological indices and histopathological features of the animal specimens were analyzed. The administration of C. flavescens extract at doses of 400 and 1200 mg/kg caused a weight difference in male mice after 30 days and in both sexes after 60 days of administration compared to the control group. There were no significant changes in hematological parameters and biochemical indexes of the liver and kidney compared with the control group. The histological structure of the liver showed changes when treated with C. flavescens at both doses after 60 days, whereas the histological structure of the kidneys exhibited differences only at the dose of 400 mg/kg. Overall, the findings of this study indicate that Coptosapelta flavescens Korth. is unlikely to have subacute and subchronic oral toxicity. However, there are some minor effects on the liver and kidneys.

Background and aim: Garlic essential oil (GEO) isolated from Garlic (Allium sativum L.) exerts biological activities in disease prevention, particularly in metabolic and liver diseases, and is used for a dietary therapy for centuries. However, due to the side effects associated with the excessive consumption of GEO, there is a need to evaluate the safety of the GEO. Experimental procedure: Ames test using five Salmonella typhimurium strains (TA98, TA100, TA102, TA1535, and TA1537) and Chinese hamster ovary (CHO–K1) cells with or without metabolic activation (S9 system), and mammalian erythrocyte micronucleus test were used to assess the genotoxicity and clastogenic effects of GEO. A repeated dose of GEO (15, 25, and 50 mg/kg body weight, p.o.) were administrated to ICR mice for 28 days to ascertain the subacute toxicity of GEO. Results and conclusions: The results of the Ames test with or without S9 system indicated that GEO did not induce mutagenicity nor have clastogenic effects in CHO–K1 cells with or without S9 activation. Furthermore, GEO did not affect the ratio of immature to total erythrocytes or the number of micronuclei in immature erythrocytes of ICR mice after 24 and 48 h. In a 28-day oral toxicity assessment, GEO (15, 25, and 50 mg/kg body weight, p.o.)-fed ICR mice exhibited normal behaviors, mortality, body weight, daily intake, hematology, clinical biochemistry, and organ weight. GEO shows no genotoxicity, and the no-observed-adverse-effect level (NOAEL) for GEO is considered to be greater than 50 mg/kg bw/day orally for 28 days in mice.

Ferula communis L. is thought to possess a wide range of therapeutic qualities. This plant's safety is critical regarding its potential uses as a medicine. Using the techniques outlined in the OECD recommendations, the present study aimed to assess the acute and subacute toxicity profiles of Ferula communis aqueous extract (FC-Ext) in mice. In the acute study, the FC-Ext was administered to adult male and female Swiss albino mice through oral and intraperitoneal routes at doses of 0–4 g/kg. The general behavioral effects, mortality rates, and latency of mortality were evaluated for a period of 14 days. For the sub-acute dose study, the FC-Ext was administered orally to adult mice at doses of 125, 250, and 500 mg/kg on a daily basis for 28 days. Body weight and selected biochemical and hematological parameters were measured, and histological examinations of the liver, kidney, and spleen were conducted to assess any signs of organ damage at the end of the treatment period. The results of the acute toxicity study demonstrated that the LD50 values for the oral and intraperitoneal administration of FC-Ext were 3.6 g/kg and 2.3 g/kg, respectively. In the subacute toxicity study of FC-Ext, no significant changes in body weight were observed. However, a substantial increase in the weights of the liver, kidney, and spleen was observed in male mice. The administration of FC-Ext to mice at doses higher than 250 mg/kg resulted in a decrease in white blood cells and platelets in both sexes and a reduction in red blood cells and mean corpuscular hemoglobin concentration in males and hemoglobin in females. No changes in biochemical parameters were observed. Microscopic examination of vital organs such as the liver, kidney, and spleen revealed no significant injuries. Based on the current results, the aqueous extract of Ferula communis has low toxicity. These findings provide important information about the toxicity profile of the traditional medicine plant Ferula communis.

Premna integrifolia L. (Lamiaceae) is widely used in herbal formulation “Dashmoolarishta” which is useful in postnatal care. Ethyl acetate extract obtained from the leaves was evaluated for phenolic content and its antioxidant activity. Acute and subacute toxicity of the extract was studied in mice of both sexes to get an idea about LD50 value and assessed its safety profile before its application as a protective agent against different toxicities induced by xenobiotics. Phenol enriched extract (phenol content is 63.10 ± 1.26 mg/g of gallic acid equivalent and flavonoid content 75.33 ± 0.23 mg/g of rutin equivalent) showed good antioxidant activity. In acute toxicity studies it was observed that single different doses (300−5000 mg/kg b.wt.) of extract did not show any mortality of mice. Thus the LD50 of the extract was determined, and it was higher than 5000 mg/kg. There was no major change in behavioral and general appearance of mice. External morphology of liver, kidneys, lungs, spleen and heart did not show any effect of treatment. In subacute toxicity no statistically significant change in body weight, relative organ weight, food intake and water uptake, hematological, biochemical parameters were reported after comparison with control. Extract did not show significant effect in the level of antioxidant enzymes in the liver of mice of treated groups. No histopathological changes were observed in liver and kidney tissues. Thus, extract did not show any sign of toxic effects, when administered orally to male and female mice at dose level up to 1000 mg/kg. So, it can be utilized as protective agent against toxicity produced by different xenobiotics.

Dacryodes edulis (G. Don) H.J. Lam) is the most popular species under the genus Dacryodes. It is well known for its nutritional and ethno-medicinal uses in South-eastern and South-western Nigeria. This study was aimed to evaluate the toxicity of the aqueous-methanol fraction of crude methanol extract of Dacryodes edulis leaves (AMDE). The test rats were randomized to groups of single oral treatment of AMDE (10−5000 mg/kgbw) for the acute toxicity study. They were monitored for obvious signs of behavioural change and mortality. For the subacute toxicity study, the rats were randomized to three daily treatment groups (of 200, 400 and 600 mg/kgbw of AMDE) for 28 days. The fourth group (control) received 2.5 %v/v DMSO. At the end of the experiment, blood samples were collected for hematology and clinical chemistry evaluation. The histopathology of the livers and kidneys were assessed using the excised organs. The cytotoxicity and genotoxicity of AMDE were also evaluated using Allium cepa model. The result showed that acute administration of AMDE, up to a dose of 5000 mg/kgbw did not result in mortality of the test rats. The observed median lethal dose (LD50) was greater than 5000 mg/kgbw. The subacute oral administration of AMDE for 28 days showed no significant (p > 0.05) effect on liver function, kidney function indices, organ - body weight ratio, but significantly (p

Objective: The present study aimed to investigate the acute and subacute toxicity profile of fucoidan obtained from Sargassum wightii Greville, a brown marine algae in order to assess its safety. Methods: Fucoidan was isolated from Sargassum wightii Greviile and subjected to FTIR analysis to confirm the functional groups. In acute toxicity study, a single dose of fucoidan (2000 mg/kg) was orally administered to three female rats as per OECD guideline 423. OECD guidelines 407 was adopted for subacute toxicity study. Fucoidan was orally administered to male and female rats at doses of 100, 200 and 400 mg/kg. Hematological, biochemical and histopathological analyses were carried out. Results: FTIR analysis confirmed the presence of major functional groups. The animals did not show any remarkable toxic signs or mortality in acute toxicity study at single oral administration of fucoidan at the dose of 2000 mg/kg bodyweight. In subacute toxicity, no statistically significant difference in body weight, relative weight of vital organs, food and water intake compared to the control group was observed. Serum glucose and cholesterol showed a statistically significant reduction at all the doses when compared to normal control and the reduction was in a dose dependent manner. There were no other changes observed in biochemical or haematological parameters. Histopathological analysis showed no significant toxic signs at organ levels in treated groups when compared to normal control. Conclusions: Based on the results obtained from acute and subacute toxicity study, fucoidan is considered to be safe in the models tested, which encourages its long term administration for medicinal uses. This study supports the application of fucoidan as a traditional medicine.

Anacardic acid extracted from cashew nut shells of Anacardium occidentale L has demonstrated important biological activities, such as antibacterial activity against the cariogenic specie Streptococcus mutans. Zein nanoparticles containing anacardic acid (9.375 μg/mL) were evaluated in terms of toxicity and genotoxicity in vivo. The subacute toxicity assay was used to evaluate the cumulative effects of the oral administration of nanoencapsulated anacardic acid at 2.25 and 112.5 μg/kg for 7 days in mice, simulating a mouth rinse short-term clinical course treatment. Blank zein nanoparticles and saline solution 0.9 % were used as negative controls. Peripheral blood samples were collected to evaluate the genotoxicity in polychromatic erythrocytes using the micronucleus test. The animals were anesthetized, euthanized and the target organs collected, weighed and submitted to histopathological analysis. Liver, kidney and spleen relative weights did not change. Nevertheless, stomach, lung and heart increased the relative weights in the group receiving the highest dose, in which occasional histopathological findings were also identified. Both doses maintained the micronucleus frequency within the normal range and the animals treated with the highest dose presented a discrete weight lost, which could explain the organs’ relative weight reductions. Blank and anacardic acid loaded zein nanoparticles were nontoxic when administered repeatedly for 7 days, as no relevant histopathological changes neither genotoxicity were observed. These preparations demonstrated limited toxicity under the conditions used in this study and could become an antibacterial alternative for preventing/treating oral infections in short-term treatments.

Oxidative stress status, as a disruption of redox homeostasis, in the blood sera of Wistar rats caused by repeated application of selected acetylcholinesterase reactivators - asoxime, obidoxime, K027, K048, K074, and K075 were evaluated. Throughout this study, each oxime in a dose of 0.1 of LD 50 /kg im was given 2x/week for 4 weeks. Then, seven days after the last oximes' application, markers of lipid peroxidation (malondialdehyde, MDA), and protein oxidation (advanced oxidation protein products, AOPP), as well as the activity of antioxidant enzymes (catalase, CAT, superoxide dismutase, SOD, reduced glutathione, GSH, and oxidized glutathione, GSSG), were determined. Oxidative stress parameters, MDA and AOPP were significantly highest in the K048-, K074- and K075-treated groups (p < 0.001). The activity of CAT was significantly elevated in the obidoxime-treated group (p < 0.05), while treatment with K027, K048, and K074 induced high elevation in SOD levels (p < 0.01, p < 0.001). Interestingly, the activity of GSH in each oxime-treated group was significantly elevated. Unlike, treatment with obidoxime caused elevation in GSSG levels (p < 0.01). As a continuation of our previously published data, these results assure that applied oximes following subacute treatment ameliorated the oxidative status and further adverse systemic toxic effects in rats., Competing Interests: Declaration of competing interest The authors declare that they have no known competing for financial interests or personal relationships that could have appeared to influence the work reported in this paper. None., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Vitex doniana Sweet fruit, an under-utilised crop specie of Ghana, has not been validated for its ethnomedical use in managing inflammatory conditions. Therefore, the study sought to investigate its anti-inflammatory and antioxidant activities as well as isolate and quantify one of its active constituents. Materials and methods: In-vivo anti-inflammatory activity of the methanol fruit extract was evaluated using the carrageenan-induced oedema model in chicks. The in-vitro antioxidant property was also investigated using the 2, 2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The acute and subacute toxicity studies of the fruit extract were evaluated in rodent models. Results: No signs of autonomic and central nervous system stimulation/depression were recorded. The LD50 by oral route, was estimated to be beyond 3000 mg/kg. Subacute studies revealed an increase in red blood cell and lymphocyte counts. Liver enzymes, serum proteins and bilirubin levels did not significantly increase. The crude extracts at doses of 10, 30 and 100 mg/kg inhibited paw oedema considerably. The ethyl acetate fraction showed the highest antioxidant activity (IC50 = 99.35 ± 0.77 μg/mL). Oleanolic acid, isolated from the ethyl acetate extract, showed significant anti-inflammatory and antioxidant activities. A sensitive high-performance liquid chromatography method for the detection and estimation of oleanolic acid, as a biomarker compound for V. doniana fruit, was developed and validated for quality assurance purposes. Conclusion: The extract of V. doniana fruits possesses considerable anti-inflammatory and antioxidant properties and was non-toxic under laboratory conditions.

Maduramicin, an extensively used anticoccidial drug, has been introduced into environment due to poorly absorbed in the intestine of broiler chicken. To understand the potential ecological toxicity of maduramicin on aquatic organisms, acute and subacute toxicity, hemolymph biochemistry, histopathology and the expressions of drug metabolism and stress response genes of crayfish (Procambius clarkii) were investigated in this study. For the first time, the 96 h median lethal concentration (LC50) of maduramicin on crayfish was 67.03 mgL−1 with a 95% confidence interval (54.06–81.32 mgL−1). Then, the crayfish were exposed to 0.7 mgL−1 (1/100 LC50), 3.5 mgL−1 (1/20 LC50) and 7.0 mgL−1 (1/10 LC50) maduramicin for 28 days. Maduramicin significantly altered biochemical parameters including AST, ALT, CK, LDH and ALP of hemolymph in crayfish at several time points. The activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) of crayfish gills, hepatopancreas and abdominal muscle were significantly decreased or elevated by different concentrations of maduramicin treatment at varying time points. Furthermore, histopathological damage of crayfish gills, hepatopancreas and abdominal muscle were observed in a concentration-dependent manner. The expressions of metabolic and stress response genes (CYP450, GST, COX1, COX2, HSP70 and MT) in hepatopancreas of crayfish were significantly up-regulated by maduramicin (7.0 mgL−1) treatment for 8 h to 7 d, and returned to normal levels after the removal of maduramicin for 3–7 days. In conclusion, our findings demonstrated that environmental exposure of maduramicin threaten to the health of crayfish living in the areas nearby livestock farms or pharmaceutical factory. Crayfish exhibited resistance to the stress of maduramicin via activating drug metabolite and detoxification pathways.

Oxidative stress status and morphological injuries in the brain of Wistar rats induced by repeated application of selected acetylcholinesterase reactivators - asoxime, obidoxime, K027, K048, K074, and K075 were evaluated. Each oxime in a dose of 0.1 of LD 50 /kg im was given 2x/week for 4 weeks. Markers of lipid peroxidation (malondialdehyde, MDA), and protein oxidation (advanced oxidation protein products, AOPP), as well as the activity of antioxidant enzymes (catalase, CAT, superoxide dismutase, SOD, glutathione reductase, GR, and glutathione peroxidase, GPx), were estimated in the brain tissue homogenates on day 35 of the study. Brain alterations were carefully quantified by semiquantitative grading scales - brain damage score (BDS). Oxidative stress parameters, MDA and AOPP were significantly highest in the asoxime-, obidoxime- and K075-treated groups (p < 0.001). The activity of SOD and CAT was significantly elevated in the obidoxime-, K048-, and K075-treated groups (p < 0.001). Besides, GR was markedly decreased in the obidoxime- and K074-treated groups (p < 0.01), while treatment with K048, K074 and K075 induced extremely high elevation in GPx levels (p < 0.001). In the same groups of rats, brain alterations associated with polymorphonuclear cell infiltrate were significantly more severe than those observed in animals receiving only asoxime or K027 (p < 0.001). The presented results confirmed that treatment with different oximes significantly improved the oxidative status and attenuated signs of inflammation in rats' brains. Presented results, together with our previously published data can help to predict likely adverse systemic toxic effects, and target organ systems, which are crucial for establishing risk categories, as well as in dose selection of K-oximes as drug candidates., Competing Interests: Declaration of competing interest The authors declare that they have no known competing for financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Meloxicam, a non-steroidal anti-inflammatory drug (NSAID) for the treatment of osteoarthritis. Despite being more effective against pain mediated by inflammation, it is associated with gastrointestinal, cardiovascular, and renal toxicity. In the current study, acute single-dose (2000 mg/kg) and subacute (500, 1000, and 2000 mg kg -1 for 28 days) dermal toxicity analyses of meloxicam emulgel were conducted in Wistar rats. Various biochemical, hematological, histopathological and immunohistochemical parameters were evaluated. The dermal LD 50 (lethal dose) of meloxicam emulgel was found to be > 2000 mg/kg. No significant adverse effects of meloxicam emulgel following topical administration in subacute toxicity studies were noticed. IL-1β was not expressed post treatment with meloxicam emulgel. IL-1β is an influential pro-inflammatory cytokine that is decisive for host-defence consequence to injury and infection. Therefore, using data gleaned from the extant study, topical administration of meloxicam emulgel may be regarded as safe as the "no observed adverse effect level" (NOAEL) was >2000 mg/kg in experimental animals., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Objective: Metabonomics was used to analyze and explore the biomarkers and possible mechanisms of liver and kidney subacute toxicity induced by garidi-5 in rats., Methods: Taking garidi-5 as the target drug and SD rats as the research objects, each administration group except the normal group was intragastric administration of the corresponding drug solution for 28 d. The serum, liver and kidney samples of rats were detected by metabolomics and characterized by principal component analysis (PCA) and partial least squares discriminant analysis (PLS-DA) to identify the sensitive markers and metabolic pathways of liver and kidney subacute toxicity., Results: Metabolomics analysis showed that compared with the normal group (Z), the 52, 64 and 54 different metabolites were identified in the serum, liver and kidney samples of garidi-5 high dose group (GG), which were mainly enriched in ABC transporters, arginine and proline metabolism, nicotinate and nicotinamide metabolism, central carbon metabolism in cancer pathways., Conclusion: The preliminarily suggested that garidi-5 can damage the liver and kidney by affecting the ABC transporters, arginine and proline metabolism, nicotinate and nicotinamide metabolism pathways, etc. Trimethylamine N -oxide, l -pyroglutamic acid, glycine-betaine, xanthine, glutathione, l -leucine, cytidine, l -arginine, spermidine, urea, 5-aminovaleric acid, creatine, l -glutamic acid, 1-methylnicotinamide and S -adenosyl- l -methionine can be used as potential biomarkers of liver and kidney toxicity sensitivity., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Tianjin Press of Chinese Herbal Medicines. Published by ELSEVIER B.V.)

Piper amalago L. (Piperaceae) is traditionally used due to its anti-inflammatory, analgesic, diuretic, and antiparasitic properties. However, few studies have focused on its adverse effects, compromising its safe use. This study evaluated the toxicological safety of ethanolic extract from Piper amalago leaves (EEPA), through subacute toxicity and genotoxicity assays in rodents. In subacute toxicity, 100, 200 or 300 mg/kg of EEPA were tested in female Wistar rats, by gavage, for 28 days. For genotoxicity test, female Swiss mice were orally treated with 17.5, 175 or 1750 mg/kg of EEPA and the comet, micronucleus, and splenic phagocytic assays were evaluated. In subacute toxicity, the extract induced an increase in the food and water intakes, as well as in the liver absolute weight, and in the heart and kidney relative weights. EEPA also provoked alterations in histopathological analysis of liver and in hemato-biochemical parameters, evidenced by a decrease in hematocrit levels and albumin levels, and an increase in the number of platelets and in alkaline phosphatase and cholesterol levels. However, EEPA did not presented genotoxic nor mutagenic properties. EEPA showed hemato-biochemical toxicity profile in rats and should be used with caution, especially when for prolonged period., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Artemisinin-hydroxychloroquine sulfate tablets (AH) are considered a relatively inexpensive and novel combination therapy for treating all forms of malaria, especially aminoquinoline drugs-resistant strains of P.falciparum. We aim to carry out acute and subacute oral toxicity studies in rats to acquire preclinical data on the safety of AH. Acute toxicity was evaluated in Sprague-Dawley (SD) rats at a single dose of 1980, 2970, 4450, 6670, and 10000 mg/kg. A 14-days subacute toxicity was assessed in SD rats at doses of 0, 146, 219, 328, and 429 mg/kg. The median lethal dose (LD 50 ) of acute oral administration of AH in rats is found to be 3119 mg/kg, and toxic symptoms include decreased spontaneous activity, dyspnea, bristling, soft feces, spasticity, and convulsion. Repeated doses of AH have toxic effects on the nervous system, skin, blood system, liver, kidney, and spleen in rats. The main toxic reactions include epilation, emaciation, mental irritability, decreased body weight gain and food consumption, changes in the hematological and biochemical parameters, especially pathological lesions in the liver, kidney, and spleen. The no-observed-adverse-effect level (NOAEL) and lowest-observed-adverse-effect level (LOAEL) of AH are considered to be 219 mg/kg and 328 mg/kg, respectively., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The biological safety of mesoporous silica nanoparticles (MSNs) has gradually attracted attention. However, few studies of their toxicity to the intestine and mechanism are available. In this study, their primary structures were characterized, and their subacute toxicity to mice was investigated. After 2 weeks of intragastric administration of MSNs, they significantly enhanced serum ALP, ALT, AST and TNF-α levels and caused infiltration of inflammatory cells in the spleen and intestines. MSNs induced intestinal oxidative stress and colonic epithelial cell apoptosis in mice. Intestinal epithelial cells exhibited mitochondrial ridge rupture and membrane potential decrease after MSN treatment. Additionally, MSNs increased ROS and NLRP3 levels and inhibited expression of the autophagy proteins LC3-II and Beclin1. MSNs significantly changed the intestinal flora diversity in mice, especially for harmful bacteria, leading to intestinal microecology imbalance. Meanwhile, MSNs influenced the expression of metabolites, which were involved in a range of metabolic pathways, including pyrimidine metabolism, central carbon metabolism in cancer, protein digestion and absorption, mineral absorption, ABC transport and purine metabolism. These results indicated that the subacute toxicity of mesoporous silicon was mainly caused by intestinal damage. Thus, our research provides additional evidence about the safe dosage of MSNs in the clinical and food industries., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Maduramicin, an extensively used anticoccidial drug, has been introduced into environment due to poorly absorbed in the intestine of broiler chicken. To understand the potential ecological toxicity of maduramicin on aquatic organisms, acute and subacute toxicity, hemolymph biochemistry, histopathology and the expressions of drug metabolism and stress response genes of crayfish (Procambius clarkii) were investigated in this study. For the first time, the 96 h median lethal concentration (LC 50 ) of maduramicin on crayfish was 67.03 mgL -1 with a 95% confidence interval (54.06-81.32 mgL -1 ). Then, the crayfish were exposed to 0.7 mgL -1 (1/100 LC 50 ), 3.5 mgL -1 (1/20 LC 50 ) and 7.0 mgL -1 (1/10 LC 50 ) maduramicin for 28 days. Maduramicin significantly altered biochemical parameters including AST, ALT, CK, LDH and ALP of hemolymph in crayfish at several time points. The activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) of crayfish gills, hepatopancreas and abdominal muscle were significantly decreased or elevated by different concentrations of maduramicin treatment at varying time points. Furthermore, histopathological damage of crayfish gills, hepatopancreas and abdominal muscle were observed in a concentration-dependent manner. The expressions of metabolic and stress response genes (CYP450, GST, COX1, COX2, HSP70 and MT) in hepatopancreas of crayfish were significantly up-regulated by maduramicin (7.0 mgL -1 ) treatment for 8 h to 7 d, and returned to normal levels after the removal of maduramicin for 3-7 days. In conclusion, our findings demonstrated that environmental exposure of maduramicin threaten to the health of crayfish living in the areas nearby livestock farms or pharmaceutical factory. Crayfish exhibited resistance to the stress of maduramicin via activating drug metabolite and detoxification pathways., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Water extract of Gastrodia elata Blume (WGE) has great potential as an anti-depressant and could be developed as a functional food. This study aims to assess the safety of WGE using in vitro and in vivo genotoxicity assays and a 28-day oral toxicity study. Results from a bacterial reverse mutation assay (Ames test) using five Salmonella typhimurium strains (TA98, TA100, TA102, TA1535, and TA1537) with or without metabolic activation (S9 system) showed that WGE did not induce mutagenicity. Nor did it induce clastogenic effects in Chinese hamster ovary (CHO-K1) cells with or without S9 activation. Moreover, WGE did not affect the proportion of immature to total erythrocytes or the number of micronuclei in immature erythrocytes of ICR mice. Finally, a dose-dependent 28-day repeated dose toxicity assessment of WGE (2040, 4080, and 8065 mg/kg body weight, p.o.) in mice revealed no adverse effects on behavior, mortality, body weight, haematology, clinical biochemistry, or organ weight. No toxicopathologic lesions were detected following administration of high-dose WGE compared to controls. In conclusion, WGE has no significant mutagenic or toxic properties, and the no-observed-adverse-effect level (NOAEL) of WGE can be defined as at least 8065 mg/kg/day orally for 28 days for male and female mice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Ailanthone (AIL) has many biological activities including antimalarial, antiviral and anticancer. Our previous study also found that AIL targets p23 against castration-resistant prostate cancer. In this report, the preclinical safety of AIL was evaluated by acute toxicity, subacute toxicity and toxicokinetics in mice. In the acute toxicity study, the LD 50 of AIL was 27.3 mg/kg, and severe pathological damages were mainly found in the liver and gastrointestinal tract. In the subacute toxicity study, mice were orally administered at doses of 2.5, 5 and 10 mg/kg for 28 days. The results showed the body weight of male mice in the 10 mg/kg dose group decreased, but that of female mice increased. Biochemical and histopathological analysis showed that AIL could cause steatohepatitis, splenomegaly, gastrointestinal mucosal damage and reproductive system abnormalities. In addition, AIL presented the reversible hematotoxicity. To determine the relationship between AIL toxicity and dose/exposure in vivo, toxicokinetics of AIL were carried out after a single oral dose of 15 mg/kg. The stomach was identified as the main target organ, followed by the intestine and kidney. On the basis of this study, the dose of 2.5 mg/kg had no adverse effect on mice. To sum up, this study is the first time to evaluate the systemic toxicity of AIL, which is useful for the further development of AIL., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Midkine antisense oligonucleotide (MK-ASODN) nanoliposomes have previously been shown to have inhibitory activity against hepatocellular carcinoma growth. Herein we report the 4-week sub-chronic toxicity of MK-ASODN nanoliposomes in SD rats. The adverse effects included loss of body weight gain and food consumption, peri-rhinal bleeding, piloerection, peri-anal filth, and kidney, liver, spleen, thymus, lung, and injection site lesions at high doses. Macroscopic changes were observed in the kidneys of the high-dose group, accompanied by a variation in urine protein and white blood cells, blood urea nitrogen, and serum creatinine. The increased spleen and liver coefficient, and the variation in circulating white blood cells, lymphocytes, and eosinophils in the high-dose group demonstrated that inflammation was caused by MK-ASODN nanoliposomes and was consistent with the macroscopic changes in the spleen and liver. The main necropsy findings of the animals that died were macroscopic changes in the lung. No severe toxic effects or mortalities occurred in the low- and medium-dose groups. However, a No Adverse Effect Level (NOAEL) was not identified since there were changes in organs deemed to be adverse at all dose levels. Thus, the maximum tolerated dose of MK-ASODN nanoliposomes for rats was considered to be 6 mg/kg/day., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Oryeong-san is a traditional herbal formula that is used for the treatment of common genitourinary diseases in Korea and other Asian countries. However, little is known about its safety and influence on drug metabolism. In the present study, we investigated the subacute toxicity of an Oryeong-san water extract (OSWE) in rats and its effects on activities of drug-metabolizing enzymes. Subacute toxicity was modeled in animals exposed to treatment with the extract at multiple doses. Rats were given OSWE by oral gavage at 0, 1000, 2000 and 5000 mg/kg/day for 4 weeks. We checked general observations and investigated any changes of body/organ weight, food consumption, hematology, serum biochemistry, and urinalysis in vivo; and the activities of human microsomal cytochrome P450s (CYP450s) and UDP-glucuronosyltransferase (UGT) isozymes in vitro. We found that OSWE caused no significant toxicological changes at the doses tested. Therefore, the no observed adverse effect level of OSWE was more than 5000 mg/kg/day for male and female rats. OSWE inhibited the activities of CYP2C19 (IC 50 : 737.69 μg/mL) and CYP2E1 (IC 50 : 177.77 μg/mL). These results indicate that OSWE may be safe with no drug-related toxicity for up to 4 weeks and provide useful information concerning its potential to interact with conventional drugs or other herbal medicines., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Ambinine, the major alkaloid of the tuber of Corydalis ambigua var. amurensis, has protective effects on H 9 C 2 myocardial cells. In the present paper, we observed that ambinine demonstrates activities of both anticoagulation and thrombolysis in vitro by significantly degrading the blood clot and delaying the plasma recalcification time (PRT) in a dose-dependent manner (0.5-2 mg/mL). We further studied its safety profile of acute and subacute toxicity by repeated-dose intravenous injection. The median lethal dosage (LD 50 ) of mice given by oral and intravenous administration of ambinine were approximate 800, 41.60 mg/kg, respectively. The acute toxicity research results suggested that compared with an intravenous administration, the oral route is safer to administer ambinine as the promising lead compound for thrombosis. In subacute toxicity research, when mice were given ambinine at doses of 1.40 and 2.10 mg/kg for 7 days by injection, significant alteration of the relative kidney weight, the relative liver weight and serum biochemistry parameters and marked histopathological changes of them were found., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Mulberry (Morus alba L.) leaves are of broad popular use for food or remedy purposes due to their bioactive properties, especially antidiabetic activity and antioxidative activity. The present study aimed to assess the toxicological profile of mulberry leaf extract (MLE), through acute, subacute toxicity and genotoxicity tests. Male and female rats received by gavage 15.0 g/kg bw of MLE in the acute toxicity test, and 0, 1.88, 3.75 and 7.50 g/kg bw/d of MLE for subacute toxicity test. In the acute toxicity study, no mortality or behavioral changes were observed, indicating the LD 50 is higher than 15.0 g/kg bw. In the subacute toxicity test, no significant changes were observed in hematological, biochemical or histopathological parameters in the animals exposed. The no-observed-adverse-effect level in the subacute toxicity study was considered to be 7.50 g/kg bw/d, the highest dose tested. In the genotoxicity study, MLE showed no mutagenic activity in the Ames assay and no evidence of potential to induce chromosome aberrations or sperm abnormalities in mice exposed to 10 g/kg bw. Collectively, aqueous extract of mulberry leaves could be considered safe, and the results support the application of MLE as novel food ingredient or product., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Auraptene (AUR) is a natural, bioactive, monoterpene coumarin ether. It has anti-inflammatory, anti-carcinogenic, anti-bacterial, neuroprotective, and hepatoprotective properties. The aim of the present study was to assess the acute and subacute toxicity of oral administration of AUR in rats by evaluating clinical signs, haematology, biochemical factors, pathological changes and immune-toxicity. Acute administration of AUR in doses of 125, 250, 500, 1000 and 2000 mg/kg body weight had no mortality or clinical signs in a period of two days. To evaluate subacute toxicity, AUR was administrated for 28 days by oral gavage in doses of 125 and 250 mg/kg. There were significant differences in the haematological and biochemical data of the treated and untreated groups. However, almost all haematological differences were within normal reference ranges. Subacute administration of AUR showed no toxic histopathological effects on organ tissue. Evaluation of immune-toxicity also revealed no significant differences between treatment and untreated groups., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Clinopodium chinense (Benth.) O. Ktze (Labiatae), known as 'Duanxueliu' in the Chinese Pharmacopoeia, has been widely used as a traditional Chinese medicine for the treatment of hemorrhagic disease. Total flavonoids from Clinopodium chinense (Benth.) O. Ktze (TFCC), the most active ingredient, possess a variety of properties, such as antioxygenation. Until now, evidence-based toxicity data on TFCC has been limited. This study evaluated the acute (in mice and rat) and the 28-day repeated-dose (in rat) toxicity study of TFCC, respectively. In acute study, oral administration of TFCC to rats and mice did not induce toxicity or mortality up to the maximum doses of 4000 and 5000 mg/kg, respectively. In subacute toxicity study, we administered TFCC at daily doses of 70, 210, and 630 mg/kg for 4 consecutive weeks to rats via gavage. We observed no changes in food consumption, water intake, body weight, chemistry and hematological parameters, organ weight, gross pathology or histopathology. No animals from any group died. These findings indicate that TFCC is relatively nontoxic, and provide practical guidance for selecting a safe dose for further investigation of TFCC in animal studies or clinical trials., (Copyright © 2017. Published by Elsevier Inc.)

KR33493, a newly developed FAS-associated factor 1 (FAF1) inhibitor for Parkinson's disease, is being evaluated in a Phase I clinical trial. In the present study, the subchronic toxicity of KR33493 in Sprague-Dawley (SD) rats and beagle dogs was investigated at various oral doses for 28 and 14 days, respectively. During the study, food consumption, body weights, organ weights, gross findings, and mortality were examined; and ophthalmoscopy, electrocardiography, hematology, serum biochemistry, urinalysis, histopathology, and toxicokinetics were performed. In rats, weight gain decreased in both sexes at 500 mg/kg/day, with no significant differences. In dogs, some significant differences compared with the control were found during the trial; however, at the end of recovery periods, these were no longer observed and there was no dose correlation. Some histopathological findings were observed, but these were considered as incidental changes. Since no other significant changes were observed, doses above 500 and 1000 mg/kg KR33493 in rat and dogs, respectively, caused no observed adverse effects. Therefore, based on these results, the Phase 1 clinical trial for KR33493 was approved by the Korean Food & Drug Administration., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Nε-(carboxymethyl)lysine (CML) as a novel potential noxious compound in various food products has aroused extensive concern in recent years. This study aimed to investigate the oral acute and subacute toxicity of CML in mice as per OECD 420 and 407 guidelines. Acute administration of 2000 and 5000 mg/kg CML did not induce any mortality within 14 days, nevertheless some toxicological symptoms and histopathological changes were observed. The estimated LD50 of CML was >5000 mg/kg. In subacute toxicity test, CML was dosed at 200, 500 and 1000 mg/kg in both genders for 28 days. The body weights reduced which was accompanied with the decrease of food consumptions. Hematology parameters viz. RBC, HGB and MCH showed minor alteration but these were still within normal range. Biochemical analysis of hepatic and renal function markers showed significant elevating in AST, ALT, Cr and BUN etc. Histopathological alterations were observed in lung, liver, kidney and spleen. Subacute toxicity of CML involved oxidative stress caused by reducing antioxidant enzyme (SOD and GSH-Px) activities, and significantly increasing lipid peroxide (MDA) level. In conclusion, CML was unlikely to present an acute hazard, but repeated administration could produce deleterious effects on mice especially inducing liver and kidney damage through oxidative stress., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Moniliformin is a Fusarium mycotoxin mainly produced by several species infecting grains in different climatic conditions. According to our previous studies, it is acutely toxic to rats, with an LD50 cut-off value of 25mg/kg b.w. To further assess the possible health risks of low dose exposure to moniliformin, a subacute oral toxicity study was conducted in Sprague-Dawley rats, adapting OECD guideline 407. Five dose groups and two satellite groups, each consisting of five male rats, were daily exposed to moniliformin by gavage. Two rats in the highest dose group, showed decreased activity followed by acute heart failure and death. The rats of the lower doses (<9mg/kg b.w.) showed no signs of toxicity. The daily intake of moniliformin strongly reduced the phagocytic activity of neutrophils in all dose groups. The decrease continued in the satellite group during the follow-up period, indicating a severe impact on the immune system and a LOAEL value of 3mg/kg b.w. for moniliformin. Moniliformin was rapidly excreted into urine, ranging between 20.2 and 31.5% daily and showed no signs of accumulation. The concentration of moniliformin in faeces was less than 2%, which suggests efficient absorption from the gastrointestinal tract., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Erycibe is a relatively small genus in the family Convolvulaceae with over 10 identified species. Some Erycibe plant species are purportedly toxic at high doses. However, few toxicology studies have been conducted on those species. In this study, the toxicity of 40% ethanolic extracts of Erycibeobtusifolia, Erycibeschmidtii, and Erycibeellipptimba was evaluated. E. ellipptimba has been reported to be more toxic due to containing larger amounts of Baogongteng C, an alkaloid with known toxicity. Thus, E. ellipptimba was chosen for further toxicology study here. An HPLC-MS method was developed to identify the main components and determine the percentages of Baogongteng C in total alkaloid of E. ellipptimba (EWA). The toxicity of total alkaloid and Baogongteng C was evaluated and compared. The results indicated that Baogongteng A and Baogongteng C are the major toxic chemical compounds of the Erycibe species tested. The results also suggest EWA is cholinergic. Finally, in a subacute toxicity study of EWA, alterations observed with high dosage suggest that the liver and kidney could be the target organs of toxicity., (Copyright © 2014 Elsevier Inc. All rights reserved.)