Search

Oncotherapy can shape intestinal microbiota, which, in turn, may influence therapy effectiveness. Furthermore, microbiome signatures during treatments can be leveraged for the development of personalised therapeutic protocols in cancer treatment based on the identification of microbiota profiles as prognostic tools. Here, for the first time, the trajectory of gut and salivary microbiota in a patient treated with Larotrectinib, a targeted therapy approved for diagnosed glioblastoma multiforme neurotrophic tyrosine receptor kinase (NTRK) gene fusion-positive, has been accurately investigated. We based our analyses on histological diagnosis, genomic and epigenomic profiling of tumour DNA, and faecal and salivary full-length 16S rRNA gene sequencing. The study clearly evidenced a remodelling of the bacterial communities following 1 month of the NTRK-inhibitor treatment, at both gut and oral levels. We reported a boosting of specific bacteria also described in response to other chemotherapeutic approaches, such as Enterococcus faecium , E. hirae , Akkermansia muciniphila , Barnesiella intestinihominis , and Bacteroides fragilis. Moreover, several bacterial species were similarly modulated upon Larotrectinib in faecal and saliva samples. Our results suggest a parallel dynamism of microbiota profiles in both body matrices possibly useful to identify microbial biomarkers as contributors to precision medicine in cancer therapies. [ABSTRACT FROM AUTHOR]

The Aryl hydrocarbon receptor (AHR) is a cytosolic receptor and ligand-activated transcription factor widely expressed across various cell types in the body. Its signaling is vital for host responses at barrier sites, regulating epithelial renewal, barrier integrity, and the activities of several types of immune cells. This makes AHR essential for various cellular responses during aging, especially those governing inflammation and immunity. In this review, we provided an overview of the mechanisms by which the AHR mediates inflammatory response at gut and brain level through signals from intestinal microbes. The age-related reduction of gut microbiota functions is perceived as a trigger of aberrant immune responses linking gut and brain inflammation to neurodegeneration. Thus, we explored gut microbiome impact on the nature and availability of AHR ligands and outcomes for several signaling pathways involved in neurodegenerative diseases and age-associated decline of brain functions, with an insight on Parkinson's and Alzheimer's diseases, the most common neurodegenerative diseases in the elderly. Specifically, we focused on microbial tryptophan catabolism responsible for the production of several AHR ligands. Perspectives for the development of microbiota-based interventions targeting AHR activity are presented for a healthy aging. [ABSTRACT FROM AUTHOR]

Gut dysbiosis has been involved in the pathogenesis and progression of Parkinson's disease (PD), but the mechanisms through which gut microbiota (GM) exerts its influences deserve further study. Recently, we proposed a two-hit mouse model of PD in which ceftriaxone (CFX)-induced dysbiosis amplifies the neurodegenerative phenotype generated by striatal 6-hydroxydopamine (6-OHDA) injection in mice. Low GM diversity and the depletion of key gut colonizers and butyrate producers were the main signatures of GM alteration in this model. Here, we used the phylogenetic investigation of communities by reconstruction of unobserved states (PICRUSt2) to unravel candidate pathways of cell-to-cell communication associated with dual-hit mice and potentially involved in PD progression. We focused our analysis on short-chain fatty acids (SCFAs) metabolism and quorum sensing (QS) signaling. Based on linear discriminant analysis, combined with the effect size results, we found increased functions linked to pyruvate utilization and a depletion of acetate and butyrate production in 6-OHDA+CFX mice. The specific arrangement of QS signaling as a possible result of the disrupted GM structure was also observed. With this exploratory study, we suggested a scenario in which SCFAs metabolism and QS signaling might represent the effectors of gut dysbiosis potentially involved in the designation of the functional outcomes that contribute to the exacerbation of the neurodegenerative phenotype in the dual-hit animal model of PD. [ABSTRACT FROM AUTHOR]

Plant natural products offer promise in combating multi-drug resistance by acting as antibacterial agents through various mechanisms. A metabolomic-guided phytochemical investigation, based on a LC-HRMS/MS and Molecular Networking combined approach, was carried out on an extract of M. alba L. (mulberry) twigs, a common of byproduct of mulberry utilization. Molecular Networking uncovered different clusters of prenylated polyphenols, glycosylated phenolic compounds, and Diels-Alder dimers, steering the phytochemical profiling of this extract. This led to the swift annotation and subsequent isolation of 17 secondary metabolites including stilbenoids, flavonoids, and flavanones. Isolated metabolites were tested for their antimicrobial activity against Staphylococcus species. The most active compound resulted to be kuwanon C, exhibiting a MIC value of 8 μg/mL against the methicillin resistant S. aureus (MRSA) strain and a biofilm producer strain of S. epidermidis. We also observed an interaction between 4 μg/mL of kuwanon C in combination with low oxacillin dosage against the MRSA. Thanks to the high chemical structure similarity of isolated metabolites, structure-activity relationships of these versatile scaffolds have been postulated. [Display omitted] [ABSTRACT FROM AUTHOR]

The [1,2,3]-triazolo [1,5-a] quinoxalin-4(5 H )-one scaffold and its analogues triazole-fused heterocyclic compounds are relevant structural templates in both natural and synthetic biologically active compounds. However, their medicinal chemistry applications are often limited due to the lack of synthetic protocols combining straightforward generation of the central core while also allowing extensive decoration activity for drug discovery purposes. Herein, we report a "refreshed" synthesis of the [1,2,3]-triazolo [1,5- a ]quinoxalin-4(5 H )-one core, encompassing the use of eco-compatible catalysts and reaction conditions. We have also performed a sustainable and extensive derivatization campaign at both the endocyclic amide nitrogen and the ester functionality, comprehensively exploring the reaction scope and overcoming some of the previously reported difficulties in introducing functional groups on this structural template. Finally, we unveiled a preliminary biological investigation for the newly generated chemical entities. Our assessment of the compounds on different bacterial species (two S. aureus strains, three P. aeruginosa strains, K. pneumonia ), and two fungal C. albicans strains, as well as the evaluation of their activity on S. epidermidis biofilm formation, foster further optimization for the retrieved hit compounds 9 , 14 , and 20 ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Pelliccia, Alfano, Gomes Da Assunção, Turco, Lembo, Summa, Buommino and Brindisi.)