Biology subjects

Roselli, R.

Publications and source records attributed to Roselli, R..

3 recordsLinked to original sources

bioRxiv2024

A microbial derived bile acid acts as GPBAR1 agonist and RORγt inverse agonist and reverses inflammation in inflammatory bowel disease

The interplay between the dysbiotic microbiota and bile acids is a critical determinant for development of a dysregulated immune system in inflammatory bowel disease (IBD). Here we have investigated the fecal bile acid metabolome, gut microbiota composition, and immune responses in IBD patients and murine models of colitis and found that IBD associates with an elevated excretion of primary bile acids while secondary, allo- and oxo- bile acids were reduced in both human and mice models of IBD. These changes correlated with the disease severity, mucosal expression of pro-inflammatory cytokines and chemokines, and reduced inflow of anti-inflammatory macrophages and Treg in the gut. Analysis of bile acids metabolome in the feces allowed the identification of five bile acids: 3-oxo-DCA, 3-oxo-LCA, allo-LCA, iso-allo-LCA and 3-oxo-UDCA, whose excretion was selectively decreased in IBD patients and diseased mice. By transactivation assay and docking calculations all five bile acids were shown to act as GPBAR1 agonists and ROR{gamma}t inverse agonists, skewing Th17/Treg ratio and macrophage polarization toward an M2 phenotype. In a murine model of colitis, administration of 3-oxo-DCA suffices to reverse colitis development and intestinal dysbiosis in a GPBAR1-dependent manner. In vivo administration of 3-oxo-DCA to colitic mice also reserves disease severity and ROR{gamma}t activation induced by a ROR{gamma}t agonist and IL-23, a Th17 inducing cytokine. These results demonstrated intestinal excretion of 3-oxoDCA, a dual GPBAR1 agonist and ROR{gamma}t inverse agonist, is reduced in IBD and models of colitis and its restitution protects against colitis development, highlighting a potential role for this agent in IBD management.

immunology↗

bioRxiv2022

Next generation sequencing analysis of gastric cancer identifies the leukemia inhibitory factor receptor (LIFR) as a driving factor in gastric cancer progression and as a predictor of poor prognosis

Gastric cancer (GC) is the third cause of cancer-related-death worldwide. Nevertheless, because GC screening programs are not cost-effective, most patients receive diagnosis in the advanced stages, when surgical options are limited because the presence of diffuse disease. Peritoneal dissemination occurs in approximately one third of patients with GC and is a strong predictor of poor outcome. Despite the clinical relevance, biological and molecular mechanisms underlying the formation of peritoneal metastasis in GC remain poorly defined. To investigate this point, we conducted a high-throughput sequencing of transcriptome expression in paired samples of normal and neoplastic gastric mucosa in 31 GC patients with or without peritoneal carcinomatosis. The RNAseq analysis led to the discovery of a group of highly upregulated or downregulated genes that were differentially modulated in patients with peritoneal disease in comparison to GC patients without peritoneal involvement. Among these genes the leukemia inhibitory factor receptor (LIFR) and the one cut domain family member (ONECUT)2 were the only two genes that predicted survival at univariate statistical analysis. Because LIFR was the highest regulated gene we have further assessed whether this receptor plays a mechanistic role in GC dissemination. For this purpose, we have first assessed the expression of LIF, a member of IL-6 cytokine family, and LIFR in GC cell lines. Our results demonstrate that exposure of MKN45 cells to LIF, promoted a concentration-dependent proliferation and epithelial-mesenchymal transition (EMT) as shown by modulation of E-cadherin/vimentin gene expression along with JAK and STAT 3 phosphorylation and acquisition of a migratory phenotype. These features were reversed by in vitro treatment with a LIFR antagonist. Together, these data provide support to the notion that development of LIF/LIFR inhibitors might have a role in the treatment of GC.

cancer biology↗

bioRxiv2021

Discovery of a AhR flavonoid agonist that counter-regulates ACE2 expression in rodent models of inflammation and attenuates ACE2-SARS-CoV2 interaction in vitro

The severe acute respiratory syndrome (SARS)-CoV-2, a newly emerged coronavirus first identified in 2019, is the pathogenetic agent od Corona Virus Induced Disease (COVID)19. The virus enters the human cells after binding to the angiotensin converting enzyme (ACE) 2 receptor in target tissues. ACE2 expression is induced in response to inflammation. The colon expression of ACE2 is upregulated in patients with inflammatory bowel disease (IBD), highlighting a potential risk of intestinal inflammation in promoting viral entry in the human body. Because mechanisms that regulate ACE2 expression in the intestine are poorly understood and there is a need of anti-SARS-CoV2 therapies, we have settled to investigate whether natural flavonoids might regulate the expression of ACE2 in intestinal models of inflammation. The results of these studies demonstrated that pelargonidin, a natural flavonoid bind and activates the Aryl hydrocarbon Receptor (AhR) in vitro and reverses intestinal inflammation caused by chronic exposure to high fat diet or to the intestinal braking-barrier agent DSS in a AhR-dependent manner. In these two models, development of colon inflammation associated with upregulation of ACE2 mRNA expression. Colon levels of ACE2 mRNA were directly correlated with TNF mRNA levels. In contrast to ACE2 the angiotensin 1-7 receptor MAS was downregulated in the inflamed tissues. Molecular docking studies suggested that pelargonidin binds a fatty acid binding pocket on the receptor binding domain of SARS-CoV2 Spike protein. In vitro studies demonstrated that pelargonidin significantly reduces the binding of SARS-CoV2 Spike protein to ACE2 and reduces the SARS-CoV2 replication in a concentration-dependent manner. In summary, we have provided evidence that a natural flavonoid might hold potential in reducing intestinal inflammation and ACE2 induction in the inflamed colon in a AhR-dependent manner.

pharmacology and toxicology↗