β3 Adrenoceptor Agonism Prevents Hyperoxia-Induced Colonic Alterations

Filippi, Luca; Nardini, Patrizia; Zizi, Virginia; Molino, Marta; Fazi, Camilla; Calvani, Maura; Carrozzo, Francesco; Cavallaro, Giacomo; Giuseppetti, Giorgia; Calosi, Laura; Crociani, Olivia; Pini, Alessandro

doi:10.3390/biom13121755

Cited by 3 publications

(2 citation statements)

References 50 publications

(79 reference statements)

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“…Early human placental tissue matured under a hypoxic environment necessary to induce specific placental metabolic activities [153]. The premature contact of immature organs with oxygenated ambientes, which have a moderate hyperoxic environment compared to physiologic intra-uterine hypoxia, could control their growing process by reducing β3-AR expression and impairing its role in organ maturation [154].…”

Section: β3-ar In the Myometrium And Pregnancymentioning

confidence: 99%

Inside the Biology of the β3-Adrenoceptor

Pasha,

Tondo,

Favre

et al. 2024

Biomolecules

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Since the first discovery in 1989, the β3-adrenoceptor (β3-AR) has gained great attention because it showed the ability to regulate many physiologic and metabolic activities, such as thermogenesis and lipolysis in brown and white adipose tissue, respectively (BAT, WAT), negative inotropic effects in cardiomyocytes, and relaxation of the blood vessels and the urinary bladder. The β3-AR has been suggested as a potential target for cancer treatment, both in adult and pediatric tumors, since under hypoxia its upregulation in the tumor microenvironment (TME) regulates stromal cell differentiation, tumor growth and metastases, signifying that its agonism/antagonism could be useful for clinical benefits. Promising results in cancer research have proposed the β3-AR being targeted for the treatment of many conditions, with some drugs, at present, undergoing phase II and III clinical trials. In this review, we report the scientific journey followed by the research from the β3-Ars’ discovery, with focus on the β3-Ars’ role in cancer initiation and progression that elects it an intriguing target for novel antineoplastic approaches. The overview highlights the great potential of the β3-AR, both in physiologic and pathologic conditions, with the intention to display the possible benefits of β3-AR modulation in cancer reality.

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Section: β3-ar In the Myometrium And Pregnancymentioning

confidence: 99%

Inside the Biology of the β3-Adrenoceptor

Pasha,

Tondo,

Favre

et al. 2024

Biomolecules

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“…In this study, we report how exposure to high concentrations of oxygen induces severe anatomical damage to the colon and a significant reduction in the number of colonic cells expressing β3-AR. Interestingly, the administration of a β3-AR agonist significantly prevented colonic length reduction, restored the production of mucins, and, surprisingly, reduced the alteration of the colonic myenteric plexus [ 60 ], suggesting that β3-AR agonism may represent a future therapeutic option for disorders induced by hyperoxia-impaired development, typical of prematurity disorders.…”

Section: Introductionmentioning

confidence: 99%

β3-adREnoceptor Analysis in CORD Blood of Neonates (β3 RECORD): Study Protocol of a Pilot Clinical Investigation

Scaramuzzo,

Crucitta,

del Re

et al. 2024

Life

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Background and Objective: The embryo and the fetus develop in a physiologically hypoxic environment, where vascularization is sustained by HIF-1, VEGF, and the β-adrenergic system. In animals, β3-adrenoceptors (β3-ARs), up-regulated by hypoxia, favor global fetal wellness to such an extent that most diseases related to prematurity are hypothesized to be induced or aggravated by a precocious β3-AR down-regulation, due to premature exposure to a relatively hyperoxic environment. In animals, β3-AR pharmacological agonism is currently investigated as a possible new therapeutic opportunity to counteract oxygen-induced damages. Our goal is to translate the knowledge acquired in animals to humans. Recently, we have demonstrated that fetuses become progressively more hypoxemic from mid-gestation to near-term, but starting from the 33rd–34th week, oxygenation progressively increases until birth. The present paper aims to describe a clinical research protocol, evaluating whether the expression level of HIF-1, β3-ARs, and VEGF is modulated by oxygen during intrauterine and postnatal life, in a similar way to animals. Materials and Methods: In a prospective, non-profit, single-center observational study we will enroll 100 preterm (group A) and 100 full-term newborns (group B). We will collect cord blood samples (T0) and measure the RNA expression level of HIF-1, β3-ARs, and VEGF by digital PCR. In preterms, we will also measure gene expression at 48–72h (T1), 14 days (T2), and 30 days (T3) of life and at 40 ± 3 weeks of post-menstrual age (T4), regardless of the day of life. We will compare group A (T0) vs. group B (T0) and identify any correlations between the values obtained from serial samples in group A and the clinical data of the patients. Our protocol has been approved by the Pediatric Ethical Committee for Clinical Research of the Tuscany region (number 291/2022). Expected Results: The observation that in infants, the HIF-1/β3-ARs/VEGF axis shows similar modulation to that of animals could suggest that β3-ARs also promote fetal well-being in humans.

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Protective Effects of Beta-3 Adrenoceptor Agonism on Mucosal Integrity in Hyperoxia-Induced Ileal Alterations

Nardini,

Zizi,

Molino

et al. 2024

Antioxidants

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Organogenesis occurs in the uterus under low oxygen levels (4%). Preterm birth exposes immature newborns to a hyperoxic environment, which can induce a massive production of reactive oxygen species and potentially affect organ development, leading to diseases such as necrotizing enterocolitis. The β3-adrenoreceptor (β3-AR) has an oxygen-dependent regulatory mechanism, and its activation exerts an antioxidant effect. To test the hypothesis that β3-AR could protect postnatal ileal development from the negative impact of high oxygen levels, Sprague–Dawley rat pups were raised under normoxia (21%) or hyperoxia (85%) for the first 2 weeks after birth and treated or not with BRL37344, a selective β3-AR agonist, at 1, 3, or 6 mg/kg. Hyperoxia alters ileal mucosal morphology, leading to increased cell lipid oxidation byproducts, reduced presence of β3-AR-positive resident cells, decreased junctional protein expression, disrupted brush border, mucin over-production, and impaired vascularization. Treatment with 3 mg/kg of BRL37344 prevented these alterations, although not completely, while the lower 1 mg/kg dose was ineffective, and the higher 6 mg/kg dose was toxic. Our findings indicate the potential of β3-AR agonism as a new therapeutic approach to counteract the hyperoxia-induced ileal alterations and, more generally, the disorders of prematurity related to supra-physiologic oxygen exposure.

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β3 Adrenoceptor Agonism Prevents Hyperoxia-Induced Colonic Alterations

Cited by 3 publications

References 50 publications

Inside the Biology of the β3-Adrenoceptor

Inside the Biology of the β3-Adrenoceptor

β3-adREnoceptor Analysis in CORD Blood of Neonates (β3 RECORD): Study Protocol of a Pilot Clinical Investigation

Protective Effects of Beta-3 Adrenoceptor Agonism on Mucosal Integrity in Hyperoxia-Induced Ileal Alterations

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