Application of a skin and liver Chip2 microphysiological model to investigate the route-dependent toxicokinetics and toxicodynamics of consumer-relevant doses of genistein.

The HUMMIC skin-liver Chip2 microphysiological system using EpiDerm™ and HepaRG and stellate liver spheroids was used to evaluate the route-specific metabolism and toxicodynamic effects of genistein. Human-relevant exposure levels were compared: 60 nM representing the plasma concentration expected after topical application of a cosmetic product and 1 μM representing measured plasma concentrations after ingesting soya products. Genistein was applied as single and repeated topical and/or systemic doses.

Suitability of different reconstructed human skin models in the skin and liver Chip2 microphysiological model to investigate the kinetics and first-pass skin metabolism of the hair dye, 4-amino-2-hydroxytoluene.

The HUMIMIC skin-liver Chip2 microphysiological systems model using the epidermal model, EpiDerm™, was reported previously to mimic application route-dependent metabolism of the hair dye, 4-amino-2-hydroxytoluene (AHT). Therefore, we evaluated the use of alternative skin models-SkinEthic™, EpiDermFT™ and PhenionFT™-for the same purpose. In static incubations, AHT permeation was similar using SkinEthic™ and EpiDerm™ models.

Development of a microphysiological skin-liver-thyroid Chip3 model and its application to evaluate the effects on thyroid hormones of topically applied cosmetic ingredients under consumer-relevant conditions.

All cosmetic ingredients registered in Europe must be evaluated for their safety using non-animal methods. Microphysiological systems (MPS) offer a more complex higher tier model to evaluate chemicals. Having established a skin and liver HUMIMIC Chip2 model demonstrating how dosing scenarios impact the kinetics of chemicals, we investigated whether thyroid follicles could be incorporated to evaluate the potential of topically applied chemicals to cause endocrine disruption.

Biophysical and pharmacokinetic characterization of a small-molecule inhibitor of RUNX1/ETO tetramerization with anti-leukemic effects.

Acute myeloid leukemia (AML) is a malignant disease of immature myeloid cells and the most prevalent acute leukemia among adults. The oncogenic homo-tetrameric fusion protein RUNX1/ETO results from the chromosomal translocation t(8;21) and is found in AML patients. The nervy homology region 2 (NHR2) domain of ETO mediates tetramerization; this oligomerization is essential for oncogenic activity.

Use of in vitro metabolism and biokinetics assays to refine predicted in vivo and in vitro internal exposure to the cosmetic ingredient, phenoxyethanol, for use in risk assessment.

A novel approach was developed to help characterize the biokinetics of the cosmetic ingredient, phenoxyethanol, to help assess the safety of the parent and its major stable metabolite. In the first step of this non-animal tiered approach, primary human hepatocytes were used to confirm or refute in silico predicted metabolites, and elucidate the intrinsic clearance of phenoxyethanol. A key result was the identification of the major metabolite, phenoxyacetic acid (PAA), the exposure to which in the kidney was subsequently predicted to far exceed that of phenoxyethanol in blood or other tissues.

Demonstration of the first-pass metabolism in the skin of the hair dye, 4-amino-2-hydroxytoluene, using the Chip2 skin-liver microphysiological model.

We used TissUse's HUMIMIC Chip2 microfluidic model, incorporating reconstructed skin models and liver spheroids, to investigate the impact of consumer-relevant application scenarios on the metabolic fate of the hair dye, 4-amino-2-hydroxytoluene (AHT). After a single topical or systemic application of AHT to Chip2 models, medium was analysed for parent and metabolites over 5 days. The metabolic profile of a high dose (resulting in a circuit concentration of 100 μM based on 100% bioavailability) of AHT was the same after systemic and topical application to 96-well EpiDerm™ models.

Characterization of application scenario-dependent pharmacokinetics and pharmacodynamic properties of permethrin and hyperforin in a dynamic skin and liver multi-organ-chip model.

Microphysiological systems (MPS) aim to mimic the dynamic microenvironment and the interaction between tissues. While MPS exist for investigating pharmaceuticals, the applicability of MPS for cosmetics ingredients is yet to be evaluated. The HUMIMIC Chip2 ("Chip2″), is the first multi-organ chip technology to incorporate skin models, allowing for the topical route to be tested.

Pharmacological properties of TRPM3 isoforms are determined by the length of the pore loop.

Background And Purpose: Transient receptor potential melastatin 3 (TRPM3) is a non-selective cation channel that plays a pivotal role in the peripheral nervous system as a transducer of painful heat signals. Alternative splicing gives rise to several TRPM3 variants. The functional consequences of these splice isoforms are poorly understood.

Ca-dependent regulation and binding of calmodulin to multiple sites of Transient Receptor Potential Melastatin 3 (TRPM3) ion channels.

TRPM3 proteins assemble to Ca-permeable cation channels in the plasma membrane, which act as nociceptors of noxious heat and mediators of insulin and cytokine release. Here we show that TRPM3 channel activity is strongly dependent on intracellular Ca. Conceivably, this effect is attributed to the Ca binding protein calmodulin, which binds to TRPM3 in a Ca-dependent manner.