Targeting glucosylceramide synthase induces antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cell models.

The EGFR tyrosine kinase inhibitor osimertinib has been approved for the first-line treatment of EGFR-mutated Non-Small Cell Lung Cancer (NSCLC) patients. Despite its efficacy, patients develop resistance. Mechanisms of resistance are heterogeneous and not fully understood, and their characterization is essential to find new strategies to overcome resistance. Ceramides are well-known regulators of apoptosis and are converted into glucosylceramides (GlcCer) by glucosylceramide synthase (GCS). A higher content of GlcCers was observed in lung pleural effusions from NSCLC patients and their role in osimertinib-resistance has not been documented. The aim of this study was to determine the therapeutic potential of inhibiting GCS in NSCLC EGFR-mutant models resistant to osimertinib in vitro and in vivo. Lipidomic analysis showed a significant increase in the intracellular levels of glycosylceramides, including GlcCers in osimertinib resistant clones compared to sensitive cells. In resistant cells, the GCS inhibitor PDMP caused cell cycle arrest, inhibition of 2D and 3D cell proliferation, colony formation and migration capability, and apoptosis induction. The intratumoral injection of PDMP completely suppressed the growth of OR xenograft models. This study demonstrated that dysregulation of ceramide metabolism is involved in osimertinib-resistance and targeting GCS may be a promising therapeutic strategy for patients progressed to osimertinib.

Social stress-induced depressive-like symptoms and changes in gut microbial and lipidomic profiles are prevented by pharmacological inhibition of FAAH activity in male rats.

Pharmacological inhibition of fatty acid amide hydrolase (FAAH) activity has antidepressant-like effects in preclinical models of stress. In this study, we investigated whether the antidepressant-like effects of FAAH inhibition are associated with corresponding changes in gut microbial and lipidomic profiles, which are emerging as critical components in the pathophysiology of depression. Adult male Wistar rats experienced five weeks of repeated social defeat or control procedure and were treated with the FAAH inhibitor URB694 (0.3 mg/kg/day, i.p.) or vehicle starting from the third week. Repeated social defeat induced the emergence of depressive-like behavioral (sucrose preference reduction and passive coping behaviors in the forced swim test) and neuroendocrine (increased corticosterone levels) changes, which were prevented by URB694 treatment. Repeated social defeat also provoked a significant variation in gut microbiota (changes in the relative abundance of 14 bacterial taxa) and lipidic (e.g., glycerophospholipids) composition. These stress-induced changes were prevented by URB694 treatment. These findings indicate that inhibition of FAAH activity with URB694 blocks the co-occurrence of depressive-like behavioral and neuroendocrine changes and alterations in gut microbial and lipid composition in rats exposed to repeated social defeat. In conclusion, these results suggest that the gut microbiota-lipid crosstalk may represent a novel biological target for FAAH inhibitors to enhance stress resilience.

The Integrated Probiotic Database: a genomic compendium of bifidobacterial health-promoting strains.

Background: The World Health Organization defines probiotics as "live microorganisms, which when administered in adequate amounts confer a health benefit on the host". In this framework, probiotic strains should be regarded as safe for human and animal consumption, i.e., they should possess the GRAS (generally recognized as safe) status, notified by the local authorities. Consistently, strains of selected Bifidobacterium species are extensively used as probiotic agents to prevent and ameliorate a broad spectrum of human and/or animal gastrointestinal disorders. Even though probiotic properties are often genus- or species-associated, strain-level differences in the genetic features conferring individual probiotic properties to commercialized bifidobacterial strains have not been investigated in detail. Methods: In this study, we built a genomic database named Integrated Probiotic DataBase (IPDB), whose first iteration consists of common bifidobacterial strains used in probiotic products for which public genome sequences were available, such as members of B. longum subsp. longum, B. longum subsp. infantis, B. bifidum, B. breve, and B. animalis subsp. lactis taxa. Furthermore, the IPDB was exploited to perform comparative genome analyses focused on genetic factors conferring structural, functional, and chemical features predicted to be involved in microbe-host and microbe-microbe interactions. Results and conclusion: Our analyses revealed strain-level genetic differences, underlining the importance of inspecting the strain-specific and outcome-specific efficacy of probiotics. In this context, IPDB represents a valuable resource for obtaining genetic information of well-established bifidobacterial probiotic strains.