Biology subjects

Catalanotti, B.

Publications and source records attributed to Catalanotti, B..

5 recordsLinked to original sources

bioRxiv2026

From Structure to Dynamics: Activation Mechanism of the G Protein-Coupled Bile Acid Receptor 1-Gs Complex

The G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5) is a key mediator of bile acid signaling, exerting its physiological effects through coupling with the stimulatory G protein (Gs). This interaction is essential for stabilizing the receptors active conformation and triggering downstream signaling. Among endogenous ligands, lithocholic acid (LCA) is the most potent natural agonist. However, the dynamic features underlying its binding and activation mechanisms remain poorly defined. In this study, we investigated the molecular basis of the interaction between LCA and GPBAR1, as well as the functional consequences of this interaction on receptor activation by integrating homology modelling, molecular docking, and molecular dynamics (MD) simulations. Our calculations reveal that LCA binding stabilizes the active state of GPBAR1, biasing the conformational ensemble of TM5 and TM6, as well as the main microswitches. These ligand-induced rearrangements enhance the coupling interface with the 5 helix of Gs and facilitate allosteric communication between the orthosteric and intracellular sites. Overall, our findings provide dynamic insight into how LCA modulates GPBAR1 activation and G protein engagement, highlighting its role as a molecular effector in bile acid signaling, and furnishing molecular detail relevant to ongoing efforts in GPBAR1-targeted compound development.

bioinformatics↗

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↗

bioRxiv2023

Bile Acids Serve As Endogenous Antagonists Of The Leukemia Inhibitory Factor (LIF) Receptor in Oncogenesis

The leukemia inhibitory factor (LIF) is member of IL-6 family of cytokines involved immune regulation, morphogenesis and oncogenesis. In cancer tissues, LIF binds a heterodimeric receptor (LIFR), formed by a LIFR{beta} subunit and glycoprotein(gp)130, promoting epithelial mesenchymal transition and cell growth. Bile acids are cholesterol metabolites generated at the interface of host metabolism and the intestinal microbiota. Here we demonstrated that bile acids serve as endogenous antagonist to LIFR in oncogenesis. The tissue characterization of bile acids content in non-cancer and cancer biopsy pairs from gastric adenocarcinomas (GC) demonstrated that bile acids accumulate within cancer tissues, with glyco-deoxycholic acid (GDCA) functioning as negative regulator of LIFR expression. In patient-derived organoids (hPDOs) from GC patients, GDCA reverses LIF-induced stemness and proliferation. In summary, we have identified the secondary bile acids as the first endogenous antagonist to LIFR supporting a development of bile acid-based therapies in LIF-mediated oncogenesis.

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↗

bioRxiv2020

Hijacking SARS-Cov-2/ACE2 receptor interaction by natural and semi-synthetic steroidal agents acting on functional pockets on receptor binding region

The coronavirus disease 2019 (COVID-19) is a respiratory tract infection caused by the severe acute respiratory syndrome coronavirus (SARS)-CoV-2. In the light of the urgent need to identify novel approaches to be used in the emergency phase, a largely explored strategy has been the repurpose of clinically available drugs as new antivirals, by targeting different viral proteins. In this paper, we describe a drug repurposing strategy based on a virtual screening of druggable pockets located in the central β-sheet core of the SARS-CoV-2 Spike protein RBD supported by in vitro tests identifying several steroidal derivatives as SARS-CoV-2 entry inhibitors. Our results demonstrate that several potential binding sites exist in the SARS CoV-2 S protein, and that the occupancy of these pockets reduces the ability of the S protein RBD to bind to the ACE2 consensus in vitro. In particular, natural occurring and clinically available steroids as glycyrrhetinic and oleanolic acids, as well as the bile acids derivatives glyco-UDCA and obeticholic acid have been shown to be effective in preventing virus entry in the case of low viral load. All together, these results might help to define novel approaches to reduce the viral load by using SARS-CoV-2 entry inhibitors.Competing Interest StatementThis paper was supported by a research grant by BAR Pharmaceuticals S.r.L. to the Department of Pharmacy of the University of Napoli Federico II and to the Department of Surgical and Biomedical Sciences, University of Perugia. The authors declare the following competing financial interest(s): S.F., A.Z. and B.C. have filed an Italian patent application no.102020000011092 in the name of BAR Pharmaceuticals S.r.L. on the compounds described in this paper. View Full Text

pharmacology and toxicology↗