Biology subjects

Bellini, R.

Publications and source records attributed to Bellini, R..

7 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↗

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↗

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↗

bioRxiv2021

Aedes albopictus bionomics in Procida Island, a promising Mediterranean site for the assessment of innovative and community-based integrated pest management methods.

The colonization of Mediterranean Europe and of other temperate regions by Aedes albopictus created in the last decades an unprecedented nuisance problem in highly infested areas, as well as a new public health threat due to the species competence to transmit exotic arboviruses, such as dengue, chikungunya and zika. The Sterile Insect Technique (SIT) and the Incompatible Insect Technique (IIT) are insecticide-free mosquito-control methods relying on mass release of irradiated/manipulated males which are believed to have a potential in complementing existing and only partially effective control tools. Testing and implementing these approaches are challenging and selection of study sites is an instrumental and crucial step. We carried out a 4-year study in Procida Island (Gulf of Naples, Italy) in strict collaboration with local administrators and citizens to estimate: i) the temporal dynamics, spatial distribution, and population size of Ae. albopictus; and ii) the dispersal and survival of irradiated males. Overall, results provide insights on the bionomics of the mosquito in Southern Europe and draw attention to Procida Island as an ideal site to test innovative control programs against Ae. albopictus which may be used in other Mediterranean and temperate areas."

ecology↗

bioRxiv2020

Field competitiveness of Aedes albopictus irradiated males in pilot Sterile Insect Technique trials in Northern Italy

Vector-borne diseases account for 17% of infectious diseases, leading to more than one million deaths each year. Mosquitoes are responsible for 90% of the casualties and alternative control methods to insecticides are urgently needed, especially against Aedes vectors. Aedes albopictus is a particularly important species, causing major public health problems because it is a vector of several arboviruses and has a strong invasive behaviour. Various genetic control methods have been proposed to be integrated into the management strategies of Aedes species, among which the sterile insect technique (SIT), which proved efficient against various insect pests and vectors. However, the ability of released irradiated sterile male mosquitoes to compete with their wild counterparts and induce sterility in wild females, which is critical to the success of this strategy, remained poorly defined. Here, we assessed the field competitiveness of Ae. albopictus irradiated male using data from six release trials implemented in Northern Italy for three years. Sterile males were capable of inducing a good level of sterility in the wild female population, however with high variability in time and space. The field competitiveness of the released males was strongly negatively correlated with the ratio of sterile to wild males. This should be taken into consideration when designing future programmes to suppress field populations of Aedes mosquitoes.

ecology↗

bioRxiv2020

A litmus test for harmonized mosquito monitoring across Europe and Africa

The accelerating rate of outbreaks from mosquito borne diseases are urging the development of updated and effective tools for the surveillance of insect populations and their larval habitats. Harmonized field protocols help to build a comprehensive picture on species-specific vector ecology and generate important knowledge for implementing coordinated mosquito surveillance programs at regional scales and across continents. In this study, we test the efficiency and potential barriers of available harmonized protocols from earlier EU project VectorNet. As a kind of litmus test for such protocols, we specifically aim to capture the ecoregional variation of breeding site characteristics and population density of five mosquito vectors in Europe and Africa. As expected, the five species considered show different aquatic habitat preferences. Culex pipiens, Aedes albopictus in Europe and Ae. aegypti in Africa select breeding habitats within specific volume classes, while Anopheles gambiae and An. coluzzii may select breeding habitats based on seasonal availability. Population densities in aquatic habitats greatly varied across species and countries, but larval production sites of Ae. albopictus generate populations with higher ratio of pupae compared to the other species. This result underlines the fundamental ecological difference between the selected vector species disregarding of the ecoregion. Mean water temperatures had limited variation across species and higher among countries. Understanding the ecology of native and non-native mosquito vectors is key in evaluating transmission risks for diseases such as West Nile, chikungunya and dengue fevers, zika and malaria. The available harmonized field protocols are a valuable tool for achieving homogeneous mosquito surveillance in Europe and Africa.

ecology↗