Structure-Dependent Effects of Phthalates on Intercellular and Intracellular Communication in Liver Oval Cells

Humans are exposed to phthalates released from plastics, cosmetics, or food on a daily basis. Phthalates have low acute liver toxicity, but their chronic exposures could induce molecular and cellular effects linked to adverse health outcomes, such as liver tumor promotion or chronic liver diseases. The alternation of gap junctional intercellular communication (GJIC) and MAPK-Erk1/2 pathways in liver progenitor or oval cells can disrupt liver tissue homeostatic mechanisms and affect the development and severity of these adverse outcomes. Our study with 20 different phthalates revealed their structurally dependent effects on liver GJIC and MAPK-Erk1/2 signaling in rat liver WB-F344 cell line with characteristics of liver oval cells. The phthalates with a medium-length side chain (3-6 C) were the most potent dysregulators of GJIC and activators of MAPK-Erk1/2. The effects occurred rapidly, suggesting the activation of non-genomic (non-transcriptional) mechanisms directly by the parental compounds. Short-chain phthalates (1-2 C) did not dysregulate GJIC even after longer exposures and did not activate MAPK-Erk1/2. Longer chain (>= 7 C) phthalates, such as DEHP or DINP, moderately activated MAPK-Erk1/2, but inhibited GJIC only after prolonged exposures (>12 h), suggesting that GJIC dysregulation occurs via genomic mechanisms, or (bio)transformation. Overall, medium-chain phthalates rapidly affected the key tissue homeostatic mechanisms in the liver oval cell population via non-genomic pathways, which might contribute to the development of chronic liver toxicity and diseases

Anionically-functionalized glycogen encapsulates melittin by multivalent interactions

We developed acid-functionalized glycogen conjugates as supramolecular carriers for efficient encapsulation and inhibition of a model cationic peptide melittin - the main component of honeybee venom. For this purpose, we synthesized and characterized a set of glycogens, functionalized to various degrees by several different acid groups. These conjugates encapsulate melittin up to a certain threshold amount, beyond which they precipitate. Computer simulations showed that sufficiently functionalized conjugates electrostatically attract melittin, resulting in its efficient encapsulation in a broad pH range around the physiological pH. Hemolytic assays confirmed in vitro that the effective inhibition of melittin’s hemolytic activity occurs for highly functionalized samples, whereas no inhibition is observed when using low-functionalized conjugates. It can be concluded that functional glycogens are promising carriers for cationic molecular cargos or antidotes against animal venoms under conditions, in which suitable properties such as biodegradability and biocompatibility are crucial