International Journal of Toxicology最新文献

ZYGK1 is a novel small molecule glucokinase (GK) activator. The purpose of this study was to assess the repeated dose toxicity of ZYGK1 in male and female Wistar rats and its effect on pregnancy and embryo-fetal development in pregnant female Wistar rats. ZYGK1 was administered by oral gavage to rats at 15, 30, 60, and 120 mg/kg, once a day, for 28 consecutive days. For studying the effect on pregnancy and embryo-fetal development, ZYGK1 was administered by oral gavage at 60 and 120 mg/kg from gestation day (GD) 6 to 15, to presumed pregnant female Wistar rats. Hypoglycemia was observed at all doses of ZYGK1 in male and female rats in the general toxicity study, but no toxic effects were observed, except partially reversible axonal degeneration in peripheral nerves. ZYGK1 treatment in pregnant female rats caused hypoglycemia and decreased the fetal body weight. Treatment from GD 6 to 15 caused no significant fetal abnormalities, except incidental fetal skeleton anomalies. Thus, ZYGK1 may lead to maternal hypoglycemia, but no significant developmental toxicity was observed.

Compiling evidence strongly suggests the involvement of environmental toxicants, including heavy metals (aluminum, arsenic, lead, copper, cadmium, mercury, and manganese), pesticides, and solvents, as the prime culprits of neurodegenerative disorders, including Alzheimer's disease and Parkinson's disease. The pathogenesis of environmental toxicant-induced neurodegenerative disease remains elusive. Studies carried out in the last decade suggest that dysfunctional mitochondria are increasingly recognized as a key factor in the progression of neurodegenerative diseases. Mitochondria, the essential organelles that regulate cellular energy production, are particularly vital in neurons, which have high energy demands and depend on proper mitochondrial function for survival. Environmental toxicants have been shown to impair mitochondrial membranes, disrupt the electron transport chain, increase oxidative stress, and damage mitochondrial DNA, leading to progressive neurodegeneration, with mitochondrial fragmentation and oxidative stress that worsens neurodegeneration. There are currently no disease-modifying treatments available for most neurodegenerative disorders, largely due to the lack of suitable molecular targets. Targeting mitochondria presents a rational strategy for neuroprotective therapy, with the potential to slow or halt disease progression. In view of this, this review highlights the central role of mitochondria in environmental toxicant-induced neurodegeneration, emphasizing how environmental exposures drive mitochondrial dysfunction and accelerate disease progression. Understanding these mechanisms is crucial for identifying environmental risk factors and developing targeted interventions. This will provide a foundation for future research targeting mitochondria and developing suitable therapeutic interventions for neurodegenerative diseases.

Polyethylene glycols (PEGs) are amphiphilic polymers that are used extensively in consumer products and PEGylated biotherapeutics. Although PEGs are considered biologically inert with a low toxicity, anti-PEG antibodies have been detected in patients receiving treatment with PEGylated biotherapeutics as well as in healthy individuals. Despite continual exposure in daily life, the prevalence of PEGs within the general population remains unclear. This study aimed to evaluate a healthy population for the presence of PEGs. A validated enzyme-linked immunosorbent assay (ELISA) platform was used to analyze 200 plasma samples from healthy adults for the presence of PEGs. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was also used to analyze the samples for the presence of four PEG analytes: PEG3350; PEG4000; PEG10000; and PEG2ru20K COOH, a 20 kDa PEG used to modify therapeutic proteins. The detection limit for PEG3350 calculated by extrapolation with linear regression was assumed to be 3.60 ng/mL. PEG levels above the lower limit of quantification (LLOQ) (21.6 ng/mL) were detected in 41 plasma samples, range 22.1-43.9 ng/mL, using the ELISA platform. None of the samples were found to contain detectable levels of PEG4000, PEG10000, or PEG2ru20K COOH. Following extrapolation, PEG3350 levels above the LLOQ (3.60 ng/mL) were detected in 154 plasma samples, range 3.69-46.0 ng/mL. Using an ELISA platform and HPLC-MS/MS analysis, PEGs were detected in the plasma of 77.4% of healthy adults. The findings are suggestive that expanding worldwide exposure to PEGs may have resulted in a much higher incidence of detectable plasma burdens of PEG than was previously realized.

Platelet hyperactivation represents a significant risk factor for atherosclerotic cardiovascular diseases. This study investigated the expression and functional roles of integrin αvβ3 and (Multimerin 1) MMRN1 in platelets from atherosclerotic conditions and evaluated the therapeutic potential of integrin αvβ3 antagonism in atherosclerotic progression. We examined the expression patterns of αvβ3 and MMRN1 in platelets from healthy controls, patients with coronary heart disease (CHD), and patients with acute myocardial infarction (AMI) using qRT-PCR and ELISA techniques. The correlation between αvβ3 and MMRN1 expression levels with platelet counts and aggregation was analyzed. Additionally, we established a mouse model of atherosclerosis to investigate the effects of an αvβ3 antagonist (SB273005) and MMRN1 knockdown on platelet activation and atherosclerosis progression. Our findings revealed positive correlations between MMRN1 and αvβ3 expression levels with both platelet counts and aggregation. Notably, elevated platelet counts and aggregation observed in CHD and AMI patient samples were effectively reduced by the αvβ3 antagonist treatment. Furthermore, both αvβ3 antagonist treatment and MMRN1 knockdown significantly ameliorated disease severity in the mouse atherosclerosis model. These results demonstrate that upregulation of αvβ3 integrin and MMRN1 contributes to platelet hyperactivation in atherosclerotic vascular diseases, and targeting the αvβ3/MMRN1 axis may serve as a promising intervention strategy for the clinical management of atherosclerotic vascular diseases.

Technological advances and the desire to reduce dependence on animal models have brought human-relevant models to the forefront of drug development. This paradigm shift is leveraging the advances in in vitro systems and new approach methodologies (NAMs), which was the focus of a workshop convened by the Health and Environmental Sciences Institute (HESI) in May 2024. Highlights included discussions on predicting cardiac failure modes and the utility of human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), microfluidic systems like BioFlux™, and engineered heart tissues in enhancing early-stage drug safety assessments. Regulatory perspectives underscored the challenges and potential for integrating NAMs into submissions, advocating for standardized reporting and validation protocols. Case studies where NAMs offered superior predictivity compared to traditional methods are emerging and offer insights into a roadmap forward. However, there remains a need for collaboration among academia, industry, and regulatory bodies to ensure robust validation and adoption. These efforts aim to refine cardiovascular drug discovery, reduce attrition rates, and accelerate the transition toward more ethical and efficient preclinical testing paradigms.

HFO-1234ze(E) is being developed as a next-generation propellant (excipient), with near zero global warming potential, for use in pressurized metered dose inhalers. In accordance with regulatory guidance, an assessment of the carcinogenic potential of HFO-1234ze(E) was required to gain regulatory approval as a new excipient. HFO-1234ze(E) was therefore evaluated in two-year carcinogenicity studies in mice and rats by the inhalation route of administration. Study assessments included in-life observations, organ weights, histopathology, and hematology. Group mean (sex combined) inhaled doses were 2132, 6218, and 21,193 mg/kg/day in mice and 379, 120,8 and 3918 mg/kg/day in rats; in both studies, control animals were exposed to air alone under the same conditions as HFO-1234ze(E)-exposed animals. HFO-1234ze(E) was well tolerated at all doses. There were no HFO-1234ze(E)-related in-life effects and no neoplastic or non-neoplastic findings or effects on hematology in either study. In summary, HFO-1234ze(E) was not carcinogenic in mice or rats. These data support the use of HFO-1234ze(E) as a medical propellant.

Byakangelicol, a furanocoumarin derived from Angelica dahurica, possesses anti-inflammatory and antitumor activities. Since cytochrome P450 2A6 (CYP2A6) is the major enzyme responsible for coumarin metabolism, it is important to evaluate the effect of byakangelicol on CYP enzyme activity. The purpose was to explore the effects of byakangelicol on CYPs and to provide a reference for its drug development and clinical application. The present study investigated the impact of byakangelicol on CYPs in human liver microsomes (HLMs). Byakangelicol demonstrated the capacity to suppress the activities of CYP1A2, 2A6, and 3A4 in HLMs, with IC₅₀ values of 19.42, 10.11, and 12.80 μM, respectively. Byakangelicol exhibited competitive inhibition of CYP1A2 and 2A6 with K_i values of 9.86 μM and 5.23 μM, whereas the inhibitory effect on CYP3A4 was noncompetitive with a K_i value of 6.55 μM. In addition, the inhibitory effect of byakangelicol on CYP3A4 was found to be time-dependent (K_inact = 0.041 min^-1 and K_I = 6.67 μM). This study revealed the inhibitory properties of byakangelicol on CYP1A2, 2A6, and 3A4 activity in HLMs. It suggests the potential for drug-drug interactions when byakangelicol is co-administered with drugs metabolized by these CYPs. These findings offer a foundation for investigating the interaction of byakangelicol with other drugs, which may assist in clinical prescription and drug development.

Sukré™, a highly purified l-arabinose produced from hydrolyzed acacia, has potential uses as a natural sweetener. To evaluate the safety of l-arabinose, a battery of GLP-compliant in vitro and in vivo studies were conducted with Sukré™ (Compound Solutions, Inc, USA). No mortality, morbidity, or adverse effects were observed in a 28-day subchronic toxicity study conducted in rats administered doses up to 7200 mg/kg bw/day Sukré™ by gavage. Thus, the 28-day oral subchronic NOAEL for Sukré™ in male and female Wistar rats was 7200 mg/kg bw/day, the highest dose tested. Furthermore, results of in vitro studies (a bacterial reverse mutation assay, a mammalian chromosomal aberration study, and a mammalian micronucleus study) demonstrate that Sukré™ was non-mutagenic and non-clastogenic. Collectively, these observations indicate that oral consumption of Sukré™ is not of toxicological concern and provide supportive evidence for the safe oral consumption of Sukré™ as an ingredient in foods.

The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed the safety of five Equisetum arvense-derived ingredients as used in cosmetic products; all of these ingredients are reported to function as skin-conditioning agents in cosmetics. Industry should use current good manufacturing practices to minimize impurities that could be present in these botanical ingredients. The Panel reviewed data relevant to the safety of these ingredients in cosmetic formulations, and concluded that the five Equisetum arvense-derived ingredients are safe in cosmetics in the present practices of use and concentration described in this safety assessment.

This is a safety assessment of Cholesterol as used in cosmetics. This ingredient is reported to function primarily as an emulsifier. The Expert Panel for Cosmetic Ingredient Safety (Panel) reviewed relevant animal and human data related to this ingredient. The Panel concluded that Cholesterol is safe as a cosmetic ingredient in the practices of use and concentrations as described in the safety assessment.