Enhancing toxicity prediction for natural products in herbal medicine and dietary supplements: Integrating (Q)STR models and in vitro assays.

New approach methods (NAMs) are required to predict human toxicity effectively, particularly due to limitations in conducting in vivo studies. While NAMs have been established for various industries, such as cosmetics, pesticides, and drugs, their applications in natural products (NPs) are lacking. NPs' complexity (multiple ingredients and structural differences from synthetic compounds) complicates NAM development.

Single-cell RNA sequencing uncovers heterogenous immune cell responses upon exposure to food additive (E171) titanium dioxide.

The prospective use of food additive titanium dioxide (E171 TiO) in a variety of fields (food, pharmaceutics, and cosmetics) prompts proper cellular cytotoxicity and transcriptomic assessment. Interestingly, smaller-sized E171 TiO can translocate in bloodstream and induce a diverse immunological response by activating the immune system, which can be either pro-inflammatory or immune-suppressive. Nevertheless, their cellular or immunologic responses in a heterogeneous population of the immune system following exposure of food additive E171 TiO is yet to be elucidated.

Enhanced electrophysiological activity and neurotoxicity screening of environmental chemicals using 3D neurons from human neural precursor cells purified with PSA-NCAM.

The assessment of neurotoxicity for environmental chemicals is of utmost importance in ensuring public health and environmental safety. Multielectrode array (MEA) technology has emerged as a powerful tool for assessing disturbances in the electrophysiological activity. Although human embryonic stem cell (hESC)-derived neurons have been used in MEA for neurotoxicity screening, obtaining a substantial and sufficiently active population of neurons from hESCs remains challenging.

Safety assessment and gastrointestinal retention of orally administered cerium oxide nanoparticles in rats.

Cerium oxide nanoparticles (CeO NPs, NM-212) are well-known for their catalytic properties and antioxidant potential, and have many applications in various industries, drug delivery, and cosmetic formulations. CeO NPs exhibit strong antimicrobial activity and can be used to efficiently remove pathogens from different environments. However, knowledge of the toxicological evaluation of CeO NPs is too limited to support their safe use.

Hepa-ToxMOA: a pathway-screening method for evaluating cellular stress and hepatic metabolic-dependent toxicity of natural products.

In the field of drug discovery, natural products have emerged as therapeutic agents for diseases such as cancer. However, their potential toxicity poses significant obstacles in the developing effective drug candidates. To overcome this limitation, we propose a pathway-screening method based on imaging analysis to evaluate cellular stress caused by natural products.

Pathway-level multi-omics analysis of the molecular mechanisms underlying the toxicity of long-term tacrolimus exposure.

Tacrolimus (TAC)-based treatment is associated with nephrotoxicity and hepatotoxicity; however, the underlying molecular mechanisms responsible for this toxicity have not been fully explored. This study elucidated the molecular processes underlying the toxic effects of TAC using an integrative omics approach. Rats were sacrificed after 4 weeks of daily oral TAC administration at a dose of 5 mg/kg.

Integrated transcriptomic analysis of liver and kidney after 28 days of thioacetamide treatment in rats.

Unlabelled: Thioacetamide (TAA) was developed as a pesticide; however, it was soon found to cause hepatic and renal toxicity. To evaluate target organ interactions during hepatotoxicity, we compared gene expression profiles in the liver and kidney after TAA treatment. Sprague-Dawley rats were treated daily with oral TAA and then sacrificed, and their tissues were evaluated for acute toxicity (30 and 100 mg/kg bw/day), 7-day (15 and 50 mg/kg bw/day), and 4-week repeated-dose toxicity (10 and 30 mg/kg).

Systems-level multi-omics characterization provides novel molecular insights into indomethacin toxicity.

The mechanism of indomethacin toxicity at the systemic level is largely unknown. In this study, multi-specimen molecular characterization was conducted in rats treated with three doses of indomethacin (2.5, 5, and 10 mg/kg) for 1 week.

Diclofenac Disrupts the Circadian Clock and through Complex Cross-Talks Aggravates Immune-Mediated Liver Injury-A Repeated Dose Study in Minipigs for 28 Days.

Diclofenac effectively reduces pain and inflammation; however, its use is associated with hepato- and nephrotoxicity. To delineate mechanisms of injury, we investigated a clinically relevant (3 mg/kg) and high-dose (15 mg/kg) in minipigs for 4 weeks. Initially, serum biochemistries and blood-smears indicated an inflammatory response but returned to normal after 4 weeks of treatment.

ToxSTAR: drug-induced liver injury prediction tool for the web environment.

Summary: Drug-induced liver injury (DILI) is a challenging endpoint in predictive toxicology because of the complex reactive metabolites that cause liver damage and the wide range of mechanisms involved in the development of the disease. ToxSTAR provides structural similarity-based DILI analysis and in-house DILI prediction models that predict four DILI subtypes (cholestasis, cirrhosis, hepatitis and steatosis) based on drug and drug metabolite molecules.

Availability And Implementation: ToxSTAR is freely available at https://toxstar.

Bis-diamine administration during pregnancy induces developmental and reproductive toxicities in rats.

Background: Bis-diamine was developed as amebicidal and male contraceptive agents; however, it is also reported to induce characteristic congenital heart defects especially in the cardiac conotruncal area of rats. Because of its characteristic congenital heart defects, bis-diamine-induced animal models can be used for studying congenital heart defects. However, comprehensive toxicological information regarding bis-diamine-induced congenital heart defects in this animal model is not available.

Delineation of the molecular mechanisms underlying Colistin-mediated toxicity using metabolomic and transcriptomic analyses.

The mechanisms underlying colistin-induced toxicity are not fully understood. This study used untargeted metabolomics and transcriptomics to elucidate the molecular processes occurring in the liver and kidney of rats after treatment with colistin methanesulfonate (CMS). Rats were treated with 50 mg/kg CMS (high-dose), 25 mg/kg CMS (low-dose), or vehicle control, either as a single dose or once daily for 1 or 4 weeks.

Charge-Modulated Synthesis of Highly Stable Iron Oxide Nanoparticles for In Vitro and In Vivo Toxicity Evaluation.

The surface charge of iron oxide nanoparticles (IONPs) plays a critical role in the interactions between nanoparticles and biological components, which significantly affects their toxicity in vitro and in vivo. In this study, we synthesized three differently charged IONPs (negative, neutral, and positive) based on catechol-derived dopamine, polyethylene glycol, carboxylic acid, and amine groups, via reversible addition-fragmentation chain transfer-mediated polymerization (RAFT polymerization) and ligand exchange. The zeta potentials of the negative, neutral, and positive IONPs were -39, -0.

Development of a quantitative prediction algorithm for target organ-specific similarity of human pluripotent stem cell-derived organoids and cells.

Human pluripotent stem cell (hPSC)-derived organoids and cells have similar characteristics to human organs and tissues. Thus, in vitro human organoids and cells serve as a superior alternative to conventional cell lines and animal models in drug development and regenerative medicine. For a simple and reproducible analysis of the quality of organoids and cells to compensate for the shortcomings of existing experimental validation studies, a quantitative evaluation method should be developed.

Impedance Measurement System for Assessing the Barrier Integrity of Three-Dimensional Human Intestinal Organoids.

Human pluripotent stem cell (hPSC)-derived intestinal organoids (HIOs) hold unprecedented promise for basic biology and translational applications. However, developing a quantitative method to evaluate the epithelial cell membrane integrity of HIOs as an intestinal barrier model is a major challenge because of their complex three-dimensional (3D) structure. In this study, we developed an impedance system to measure the change in electrical resistance of 3D HIOs depending on the integrity of the intestinal epithelial cell membrane, which can reflect functionality and maturity.

TNFα enhances trovafloxacin-induced in vitro hepatotoxicity by inhibiting protective autophagy.

Trovafloxacin (TVX) is associated with idiosyncratic drug-induced liver injury (iDILI) and inflammation-mediated hepatotoxicity. However, the inflammatory stress-regulated mechanisms in iDILI remain unclear. Herein, we elucidated the novel role of tumor-necrosis factor alpha (TNFα), an inflammatory stress factor, in TVX-induced in vitro hepatotoxicity and synergistic toxicity.

Quantification of non-alcoholic fatty liver disease progression in 3D liver microtissues using impedance spectroscopy.

Non-alcoholic fatty liver disease (NAFLD) has become a global pandemic. However, a pharmacological cure has not been approved for NAFLD treatment. The greatest barriers to the development of new treatments are the ambiguous criteria among the NAFLD stages and the lack of quantitative methodologies for its disease assessment in a translatable preclinical model.

Toxicity of orally administered food-grade titanium dioxide nanoparticles.

This year, France banned the application of titanium dioxide nanoparticles as a food additive (hereafter, E171) based on the insufficient oral toxicity data. Here, we investigated the subchronic toxic responses of E171 (0, 10, 100, and 1,000 mg/kg) and tried to elucidate the possible toxic mechanism using AGS cells, a human stomach epithelial cell line. There were no dose-related changes in the Organisation for Economic Cooperation and Development test guideline-related endpoints.

An adverse outcome pathway for immune-mediated and allergic hepatitis: a case study with the NSAID diclofenac.

Many drugs have the potential to cause drug-induced liver injury (DILI); however, underlying mechanisms are diverse. The concept of adverse outcome pathways (AOPs) has become instrumental for risk assessment of drug class effects. We report AOPs specific for immune-mediated and drug hypersensitivity/allergic hepatitis by considering genomic, histo- and clinical pathology data of mice and dogs treated with diclofenac.

Amorphous silica nanoparticle-induced pulmonary inflammatory response depends on particle size and is sex-specific in rats.

Due to mass production and extensive use, the potential adverse health effects of amorphous silica nanoparticles (ASiNPs) have received a significant attention from the public and researchers. However, the relationship between physicochemical properties of ASiNPs and their health effects is still unclear. In this study, we manufactured two types of ASiNPs of different diameters (20 and 50 nm) and compared the toxic response induced in rats after intratracheal instillation (75, 150 or 300 μg/rat).

Cerium Aminoclay-A Potential Hybrid Biomaterial for Anticancer Therapy.

In this study, novel biomedical properties of Ce-aminoclay (CeAC) were investigated through in vitro and in vivo assays. CeAC (≥500 μg/mL) can selectively kill cancer cells (A549, Huh-1, AGS, C33A, HCT116, and MCF-7 cells) while leaving most normal cells unharmed (WI-38 and CCD-18Co cells). Notably, it displayed a high contrast of simultaneous imaging in HeLa cells by blue photoluminescence without any fluorescence dye.