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Graphical abstract, Highlights • GLP-compliant 90-day study on β-ionone epoxide following OECD guideline. • β-Ionone epoxide produces no adverse effects at doses up to 80 mg/kg bw/day in rats. • β-Ionone epoxide had no effect on reproductive functionality parameters., In a 90-day GLP-compliant study groups of Sprague-Dawley rats (10/sex/group) were fed diets containing β-ionone epoxide, a fragrance material and a flavoring substance, at dietary concentrations providing target intakes of 0, 20, 40 and 80 mg/kg bw/day. There were no deaths and no adverse changes in clinical observations, ophthalmological examinations, body weight, body weight gain, food consumption, food efficiency; hematology, serum chemistry, urinalysis parameters; or in macroscopic findings attributable to β-ionone epoxide administration. Increased absolute and relative liver weights in high dose females without correlating hepatic histopathological findings were considered non-adverse. Cortical vacuolation of adrenal zona fasciculata was observed in high-dose males but was considered non-adverse due to the nondegenerative nature of this alteration. β-Ionone epoxide did not influence estrus cyclicity in females and did not affect sperm morphology or epididymal sperm count, homogenization-resistant spermatid count and motility measurements in male rats. The no-observed-adverse-effect level (NOAEL) for administration of β-ionone epoxide in the diet was determined to be the highest dose tested of 80 mg/kg bw/day.

Highlights • Four-week repeated-dose toxicity of intramuscular DSS was studied in minipigs. • DSS administration at ≥10 mg/kg/day causes toxicity and injection-site reaction. • The NOAEL of DSS after 4-week administration was 2 mg/kg/day in minipigs., Diclofenac sodium salt (DSS) is a widely used nonsteroidal anti-inflammatory drug. The present study was performed under good laboratory practice (GLP) regulations to investigate the toxicity of DSS after 4 weeks of repeated intramuscular administration at doses of 0, 2, 10, or 20 mg/kg/day in 32 minipigs and to evaluate the DSS effect following a 2-week recovery period. Dose-related clinical signs and alterations of hematological or clinical chemistry parameters, organ weight, and macroscopic as well as histopathological findings in hepatic, renal, gastrointestinal, skin and injection sites were observed in both sexes’ animals of the 10 or 20 mg/kg/day group. With the exception of the skin-related findings, most symptoms showed a tendency to resolve after the 2-week recovery period. The systemic exposure (AUClast) of DSS in plasma showed similar pattern to the increase rate of the dose and similar values between males and females except for the female 20 mg/kg dose group (56 %) on Day1. The systemic exposure showed a decreasing trend in the 10 or 20 mg/kg group after 4-week of repeated administration compared to Day1. The no-observed-adverse-effect level of DSS in this study was considered to be 2 mg/kg/day in both male and female minipigs.

Highlights • Rats fed a 4 % fibrillated cellulose diet for 90-days showed no systemic toxicity. • The no-observed-adverse-effect level (NOAEL) is greater than 2194.2 mg/kg/day (male) and 2666.6 mg/kg/day (female). • Fibrillated cellulose raises no concerns as a food ingredient at this concentration., Novel forms of fibrillated cellulose offer improved attributes for use in foods. Conventional cellulose and many of its derivatives are already widely used as food additives and are authorized as safe for use in foods in many countries. However, novel forms have not yet been thoroughly investigated using standardized testing methods. This study assesses the 90-day dietary toxicity of fibrillated cellulose, as compared to a conventional cellulose, Solka Floc. Sprague Dawley rats were fed 2 %, 3 %, or 4 % fibrillated cellulose for 90 consecutive days, and parallel Solka Floc groups were used as controls. Survival, clinical observations, body weight, food consumption, ophthalmologic evaluations, hematology, serum chemistry, urinalysis, post-mortem anatomic pathology, and histopathology were monitored and performed. No adverse observations were noted in relation to the administration of fibrillated cellulose. Under the conditions of this study and based on the toxicological endpoints evaluated, the no-observed-adverse-effect level (NOAEL) for fibrillated cellulose was 2194.2 mg/kg/day (males) and 2666.6 mg/kg/day (females), corresponding to the highest dose tested (4 %) for male and female Sprague Dawley rats. These results demonstrate that fibrillated cellulose behaves similarly to conventional cellulose and raises no safety concerns when used as a food ingredient at these concentrations.

Bisphenol A and its derivatives are recognized as endocrine disruptors based on their complex effects on estrogen receptor (ER) signaling. While the effects of bisphenol derivatives on ERα have been thoroughly evaluated, how these chemicals affect ERβ signaling is less well understood. Herein, we sought to identify novel ERβ ligands using a radioligand competitive binding assay to screen a chemical library of bisphenol derivatives. Many of the compounds identified showed intriguing dual activities as both ERα agonists and ERβ antagonists. Docking simulations of these compounds and ERβ suggested that they bound not only to the canonical binding site of ERβ but also to the coactivator binding site located on the surface of the receptor, suggesting that they act as coactivator-binding inhibitors (CBIs). Receptor-ligand binding experiments using WT and mutated ERβ support the presence of a second ligand-interaction position at the coactivator-binding site in ERβ, and direct binding experiments of ERβ and a coactivator peptide confirmed that these compounds act as CBIs. Our study is the first to propose that bisphenol derivatives act as CBIs, presenting critical insight for the future development of ER signaling-based drugs and their potential to function as endocrine disruptors.

Graphical abstract, On March 11, 2020, the World Health Organization (WHO) declared the severe acute respiratory syndrome caused by coronavirus 2 (SARS-CoV-2) a global pandemic. As of July 2020, SARS-CoV-2 has infected more than 14 million people and provoked more than 590,000 deaths, worldwide. From the beginning, a variety of pharmacological treatments has been empirically used to cope with the life-threatening complications associated with Corona Virus Disease 2019 (COVID-19). Thus far, only a couple of them and not consistently across reports have been shown to further decrease mortality, respect to what can be achieved with supportive care. In most cases, and due to the urgency imposed by the number and severity of the patients’ clinical conditions, the choice of treatment has been limited to repurposed drugs, approved for other indications, or investigational agents used for other viral infections often rendered available on a compassionate-use basis. The rationale for drug selection was mainly, though not exclusively, based either i) on the activity against other coronaviruses or RNA viruses in order to potentially hamper viral entry and replication in the epithelial cells of the airways, and/or ii) on the ability to modulate the excessive inflammatory reaction deriving from dysregulated host immune responses against the SARS-CoV-2. In several months, an exceptionally large number of clinical trials have been designed to evaluate the safety and efficacy of anti-COVID-19 therapies in different clinical settings (treatment or pre- and post-exposure prophylaxis) and levels of disease severity, but only few of them have been completed so far. This review focuses on the molecular mechanisms of action that have provided the scientific rationale for the empirical use and evaluation in clinical trials of structurally different and often functionally unrelated drugs during the SARS-CoV-2 pandemic.