Synthesis, evaluation and mechanistic insights of novel IMPDH inhibitors targeting ESKAPEE bacteria.

Antimicrobial resistance poses a significant threat to global health, necessitating the development of novel therapeutic agents with unique mechanisms of action. Inosine 5'-monophosphate dehydrogenase (IMPDH), an essential enzyme in guanine nucleotide biosynthesis, is a promising target for the discovery of new antimicrobial agents. High-throughput screening studies have previously identified several urea-based leads as potential inhibitors, although many of these are characterised by reduced chemical stability.

SDHi fungicides: An example of mitotoxic pesticides targeting the succinate dehydrogenase complex.

Succinate dehydrogenase inhibitors (SDHi) are fungicides used to control the proliferation of pathogenic fungi in crops. Their mode of action is based on blocking the activity of succinate dehydrogenase (SDH), a universal enzyme expressed by all species harboring mitochondria. The SDH is involved in two interconnected metabolic processes for energy production: the transfer of electrons in the mitochondrial respiratory chain and the oxidation of succinate to fumarate in the Krebs cycle.

Mitochondrial Dysfunction as a Hallmark of Environmental Injury.

Environmental factors including diet, sedentary lifestyle and exposure to pollutants largely influence human health throughout life. Cellular and molecular events triggered by an exposure to environmental pollutants are extremely variable and depend on the age, the chronicity and the doses of exposure. Only a fraction of all relevant mechanisms involved in the onset and progression of pathologies in response to toxicants has probably been identified.

MEHP/ethanol co-exposure favors the death of steatotic hepatocytes, possibly through CYP4A and ADH involvement.

Liver steatosis has been associated with various etiological factors (obesity, alcohol, environmental contaminants). How those factors work together to induce steatosis progression is still scarcely evaluated. Here, we tested whether phthalates could potentiate death of steatotic hepatocytes when combined with ethanol.

Mechanisms involved in the death of steatotic WIF-B9 hepatocytes co-exposed to benzo[a]pyrene and ethanol: a possible key role for xenobiotic metabolism and nitric oxide.

We previously demonstrated that co-exposing pre-steatotic hepatocytes to benzo[a]pyrene (B[a]P), a carcinogenic environmental pollutant, and ethanol, favored cell death. Here, the intracellular mechanisms underlying this toxicity were studied. Steatotic WIF-B9 hepatocytes, obtained by a 48h-supplementation with fatty acids, were then exposed to B[a]P/ethanol (10 nM/5 mM, respectively) for 5 days.

Possible Involvement of Mitochondrial Dysfunction and Oxidative Stress in a Cellular Model of NAFLD Progression Induced by Benzo[a]pyrene/Ethanol CoExposure.

Exposure to xenobiotics could favor the transition of nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis in obese patients. Recently, we showed in different models of NAFL that benzo[a]pyrene (B[a]P) and ethanol coexposure induced a steatohepatitis-like state. One model was HepaRG cells incubated with stearate and oleate for 2 weeks.

Membrane Remodeling as a Key Player of the Hepatotoxicity Induced by Co-Exposure to Benzo[a]pyrene and Ethanol of Obese Zebrafish Larvae.

The rise in prevalence of non-alcoholic fatty liver disease (NAFLD) constitutes an important public health concern worldwide. Including obesity, numerous risk factors of NAFLD such as benzo[a]pyrene (B[a]P) and ethanol have been identified as modifying the physicochemical properties of the plasma membrane in vitro thus causing membrane remodeling-changes in membrane fluidity and lipid-raft characteristics. In this study, the possible involvement of membrane remodeling in the in vivo progression of steatosis to a steatohepatitis-like state upon co-exposure to B[a]P and ethanol was tested in obese zebrafish larvae.

Co-exposure to benzo[a]pyrene and ethanol induces a pathological progression of liver steatosis in vitro and in vivo.

Hepatic steatosis (i.e. lipid accumulation) and steatohepatitis have been related to diverse etiologic factors, including alcohol, obesity, environmental pollutants.

Zebrafish larva as a reliable model for in vivo assessment of membrane remodeling involvement in the hepatotoxicity of chemical agents.

The easy-to-use in vivo model, zebrafish larva, is being increasingly used to screen chemical-induced hepatotoxicity, with a good predictivity for various mechanisms of liver injury. However, nothing is known about its applicability in exploring the mechanism called membrane remodeling, depicted as changes in membrane fluidity or lipid raft properties. The aim of this study was, therefore, to substantiate the zebrafish larva as a suitable in vivo model in this context.