Metabolic, Organoleptic and Transcriptomic Impact of Saccharomyces cerevisiae Genes Involved in the Biosynthesis of Linear and Substituted Esters.

Esters constitute a broad family of volatile compounds impacting the organoleptic properties of many beverages, including wine and beer. They can be classified according to their chemical structure. Higher alcohol acetates differ from fatty acid ethyl esters, whereas a third group, substituted ethyl esters, contributes to the fruitiness of red wines. Derived from yeast metabolism, the biosynthesis of higher alcohol acetates and fatty acid ethyl esters has been widely investigated at the enzymatic and genetic levels. As previously reported, two pairs of esterases, respectively encoded by the paralogue genes ATF1 and ATF2, and EEB1 and EHT1, are mostly involved in the biosynthesis of higher alcohol acetates and fatty acid ethyl esters. These esterases have a moderate effect on the biosynthesis of substituted ethyl esters, which depend on mono-acyl lipases encoded by MGL2 and YJU3. The functional characterization of such genes helps to improve our understanding of substituted ester metabolism in the context of wine alcohol fermentation. In order to evaluate the overall sensorial impact of esters, we attempted to produce young red wines without esters by generating a multiple esterase-free strain (Δatf1, Δatf2, Δeeb1, and Δeht1). Surprisingly, it was not possible to obtain the deletion of MGL2 in the Δatf1/Δatf2/Δeeb1/Δeht1 background, highlighting unsuspected genetic incompatibilities between ATF1 and MGL2. A preliminary RNA-seq analysis depicted the overall effect of the Δatf1/Δatf2/Δeeb1/Δeht1 genotype that triggers the expression shift of 1124 genes involved in nitrogen and lipid metabolism, but also chromatin organization and histone acetylation. These findings reveal unsuspected regulatory roles of ester metabolism in genome expression for the first time.

New Paradigms of Old Psychedelics in Schizophrenia.

Psychedelics such as lysergic acid diethylamide (LSD), psilocybin (magic mushrooms), and mescaline exhibit intense effects on the human brain and behaviour. In recent years, there has been a surge in studies investigating these drugs because clinical studies have shown that these once banned drugs are well tolerated and efficacious in medically supervised low doses called microdosing. Psychedelics have demonstrated efficacy in treating neuropsychiatric maladies such as difficult to treat anxiety, depression, mood disorders, obsessive compulsive disorders, suicidal ideation, posttraumatic stress disorder, and also in treating substance use disorders. The primary mode of action of psychedelics is activation of serotonin 5-HT2A receptors affecting cognition and brain connectivity through the modulation of several downstream signalling pathways via complex molecular mechanisms. Some atypical antipsychotic drugs (APDs) primarily exhibit pharmacological actions through 5-HT2A receptors, which are also the target of psychedelic drugs. Psychedelic drugs including the newer second generation along with the glutamatergic APDs are thought to mediate pharmacological actions through a common pathway, i.e., a complex serotonin-glutamate receptor interaction in cortical neurons of pyramidal origin. Furthermore, psychedelic drugs have been reported to act via a complex interplay between 5HT2A, mGlu2/3, and NMDA receptors to mediate neurobehavioral and pharmacological actions. Findings from recent studies have suggested that serotoninergic and glutamatergic neurotransmissions are very closely connected in producing pharmacological responses to psychedelics and antipsychotic medication. Emerging hypotheses suggest that psychedelics work through brain resetting mechanisms. Hence, there is a need to dig deeply into psychedelic neurobiology to uncover how psychedelics could best be used as scientific tools to benefit psychiatric disorders including schizophrenia.

A holistic QBD approach to design galactose conjugated PLGA polymer and nanoparticles to catch macrophages during intestinal inflammation.

Recruited macrophages in inflammation attract various ligand-receptor drug delivery approaches. Galactose bound nanocarriers are promising to catch macrophages because of surface-expressed macrophage galactose type-lectin-C (MGL-2) receptor. The present study reported fabrication of galactose conjugated PLGA (GAL-PLGA) polymer and nanoparticles under quality by design (QBD) approach to investigate macrophages targeting potential at inflamed intestine. GAL-PLGA nanoparticles were fabricated through O/W emulsion-evaporation method under QBD approach and Box-Behnken design. Obtained GAL-PLGA nanoparticles have optimum particle size (~118 nm), drug entrapment (87%) and zeta potential (-9.5). TGA, XPRD and FTIR confirmed stability and negate drug-polymer interactions. Further, nanoparticles have considerable hemocompatibility, biocompatibility and cellular uptake; macrophage uptake was inhibited by D-galactose confirming involvement of MGL-2. Moreover, drug retention studies in the DSS-colitis model provide background for potential of nanoparticles to target and reside inflamed intestine. It is concluded that GAL-PLGA nanoparticles are suitable platform to target macrophages at the inflamed intestine through oral route.

Impaired macrophage autophagy increases the immune response in obese mice by promoting proinflammatory macrophage polarization.

Recent evidence that excessive lipid accumulation can decrease cellular levels of autophagy and that autophagy regulates immune responsiveness suggested that impaired macrophage autophagy may promote the increased innate immune activation that underlies obesity. Primary bone marrow-derived macrophages (BMDM) and peritoneal macrophages from high-fat diet (HFD)-fed mice had decreased levels of autophagic flux indicating a generalized impairment of macrophage autophagy in obese mice. To assess the effects of decreased macrophage autophagy on inflammation, mice with a Lyz2-Cre-mediated knockout of Atg5 in macrophages were fed a HFD and treated with low-dose lipopolysaccharide (LPS). Knockout mice developed systemic and hepatic inflammation with HFD feeding and LPS. This effect was liver specific as knockout mice did not have increased adipose tissue inflammation. The mechanism by which the loss of autophagy promoted inflammation was through the regulation of macrophage polarization. BMDM and Kupffer cells from knockout mice exhibited abnormalities in polarization with both increased proinflammatory M1 and decreased anti-inflammatory M2 polarization as determined by measures of genes and proteins. The heightened hepatic inflammatory response in HFD-fed, LPS-treated knockout mice led to liver injury without affecting steatosis. These findings demonstrate that autophagy has a critical regulatory function in macrophage polarization that downregulates inflammation. Defects in macrophage autophagy may underlie inflammatory disease states such as the decrease in macrophage autophagy with obesity that leads to hepatic inflammation and the progression to liver injury.