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Filippi L, Gulden S, Cammalleri M, Araimo G, Cavallaro G, Villamor E. Retinopathy of prematurity in the era of precision neonatology: from risk stratification to targeted therapies. World J Pediatr 2025:10.1007/s12519-025-00919-1. [PMID: 40380041 DOI: 10.1007/s12519-025-00919-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/19/2025]
Affiliation(s)
- Luca Filippi
- Department of Clinical and Experimental Medicine, Neonatology and Neonatal Intensive Care Unit, University of Pisa, Pisa, 56124, Italy
| | - Silvia Gulden
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, 20122, Italy
| | | | - Gabriella Araimo
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, 20122, Italy
| | - Giacomo Cavallaro
- Neonatal Intensive Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, 20122, Italy.
| | - Eduardo Villamor
- Division of Neonatology, MosaKids Children's Hospital, Maastricht University Medical Centre (MUMC+), Research Institute for Oncology and Reproduction (GROW), Maastricht University, P. Debyelaan 25, Maastricht, 6229HX, The Netherlands.
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Filippi L, Innocenti F, Pascarella F, Scaramuzzo RT, Morganti R, Bagnoli P, Cammalleri M, Dal Monte M, Calvani M, Pini A. β 3-Adrenoceptor Agonism to Mimic the Biological Effects of Intrauterine Hypoxia: Taking Great Strides Toward a Pharmacological Artificial Placenta. Med Res Rev 2025; 45:842-866. [PMID: 39604126 PMCID: PMC11976384 DOI: 10.1002/med.22092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2024] [Revised: 10/24/2024] [Accepted: 11/11/2024] [Indexed: 11/29/2024]
Abstract
At different stages of life, from embryonic to postnatal, varying oxygen concentrations modulate cellular gene expression by enhancing or repressing hypoxia-inducible transcription factors. During embryonic/fetal life, these genes encode proteins involved in adapting to a low-oxygen environment, including the induction of specific enzymes related to glycolytic metabolism, erythropoiesis, angiogenesis, and vasculogenesis. However, oxygen concentrations fluctuate during intrauterine life, enabling the induction of tissue-specific differentiation processes. Fetal well-being is thus closely linked to the physiological benefits of a dynamically hypoxic environment. Premature birth entails the precocious exposure of the immature fetus to a more oxygen-rich environment compared to the womb. As a result, preterm newborns face a condition of relative hyperoxia, which alters the postnatal development of organs and contributes to prematurity-related diseases. However, until recently, the molecular mechanism by which high oxygen tension alters normal fetal differentiation remained unclear. In this review, we discuss the research trajectory followed by our research group, which suggests that early exposure to a relatively hyperoxic environment may impair preterm neonates due to reduced expression of the β3-adrenoceptor. Additionally, we explore how these impairments could be prevented through the pharmacological stimulation of the remaining β3-adrenoceptors. Recent preclinical studies demonstrate that pharmacological stimulation of the β3-adrenoceptor can decouple exposure to hyperoxia from its harmful effects, offering a glimpse of the possibility to recreating the conditions typical of intrauterine life, even after premature birth.
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Affiliation(s)
- Luca Filippi
- Neonatology UnitAzienda Ospedaliero‐Universitaria PisanaPisaItaly
- Department of Clinical and Experimental MedicineUniversity of PisaPisaItaly
| | | | | | | | - Riccardo Morganti
- Section of StatisticsAzienda Ospedaliero‐Universitaria PisanaPisaItaly
| | - Paola Bagnoli
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
| | - Maurizio Cammalleri
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
| | - Massimo Dal Monte
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
| | - Maura Calvani
- Department of Pediatric Hematology‐OncologyMeyer Children's Hospital IRCCSFlorenceItaly
| | - Alessandro Pini
- Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
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Lucchesi M, Di Marsico L, Guidotti L, Lulli M, Filippi L, Marracci S, Dal Monte M. Hypoxia-Dependent Upregulation of VEGF Relies on β3-Adrenoceptor Signaling in Human Retinal Endothelial and Müller Cells. Int J Mol Sci 2025; 26:4043. [PMID: 40362282 PMCID: PMC12071845 DOI: 10.3390/ijms26094043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2025] [Revised: 04/23/2025] [Accepted: 04/23/2025] [Indexed: 05/15/2025] Open
Abstract
β-adrenoceptors (BARs) are involved in vascular endothelial growth factor (VEGF) production during retinal neovascularization. Here, using human retinal endothelial and Müller cells (hRECs and MIO-M1, respectively), we evaluated the effects exerted by hypoxia on BARs, hypoxia-inducible factor-1α subunit (HIF-1α) and VEGF, as well as the involvement of BAR3 and nitric oxide synthase (NOS) enzymes in hypoxia-induced VEGF production. We altered oxygen availability through a hypoxic incubator. BARs, HIF-1 α and VEGF levels were evaluated. Cells were treated with the BAR3 antagonist SR59230A, different NOS inhibitors or the NO donor SNAP. The influence of the BAR3/NOS axis on hypoxic VEGF production was assessed. Hypoxia upregulated BAR3, HIF-1α and VEGF in hRECs and MIO-M1 cells. SR59230A counteracted hypoxia-dependent VEGF increase in both cell lines, exerting no effect on HIF-1α upregulation. Treatments with NOS inhibitors prevented the hypoxia-dependent VEGF increase, while SNAP abrogated the effect of SR59230A in reducing hypoxia-induced VEGF upregulation. The present results corroborate the hypothesis that in the hypoxic retina, BAR3 influence on VEGF production is mediated by NO and suggest that, at least in endothelial and Müller cells, BAR3 activity is necessary to allow the HIF-1-mediated VEGF upregulation.
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Affiliation(s)
- Martina Lucchesi
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.L.); (L.D.M.); (L.G.); (S.M.)
| | - Lorenza Di Marsico
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.L.); (L.D.M.); (L.G.); (S.M.)
| | - Lorenzo Guidotti
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.L.); (L.D.M.); (L.G.); (S.M.)
| | - Matteo Lulli
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50121 Florence, Italy;
| | - Luca Filippi
- Department of Clinical and Experimental Medicine, Division of Neonatology and NICU, University of Pisa, 56126 Pisa, Italy;
| | - Silvia Marracci
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.L.); (L.D.M.); (L.G.); (S.M.)
| | - Massimo Dal Monte
- Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.L.); (L.D.M.); (L.G.); (S.M.)
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Hogan B, Mehta N, Caldwell AS, Marin AI, Gill ZS, Liske-Cervantes A, Mathias MT, Manoharan N, Palestine AG, Forest TEDC, Mandava N, Lynch AM, Patnaik JL. Risk of progression in intermediate age-related macular degeneration among patients using systemic beta-blockers. FRONTIERS IN OPHTHALMOLOGY 2025; 5:1535791. [PMID: 40297766 PMCID: PMC12034660 DOI: 10.3389/fopht.2025.1535791] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Accepted: 03/19/2025] [Indexed: 04/30/2025]
Abstract
Purpose This study aims to determine whether systemic beta-blocker use over time influences the progression from intermediate to advanced age-related macular degeneration (AMD). Methods This prospective cohort study utilized data from the University of Colorado Age-Related Macular Degeneration Registry at the UCHealth Sue Anschutz-Rodgers Eye Center. Patients with intermediate AMD (iAMD) enrolled between October 2014 and November 2021. At enrollment, patient demographics and medication history were recorded. Beta-blocker use was assessed at enrollment and at each follow-up visit. Participants were asked to return annually for imaging, and images were classified as either intermediate AMD or conversion to advanced non-neovascular (NNV) AMD or neovascular (NV) AMD by two vitreoretinal specialists using multimodal imaging. Time to conversion was analyzed using Kaplan-Meier curves for each advanced AMD phenotype and for overall conversion, stratified by beta-blocker status. Progression from intermediate to advanced AMD (NNV or NV) was determined using multimodal imaging, including optical coherence tomography, color fundus photography, and fundus autofluorescence of the posterior pole. Results A total of 292 patients were included in the study, with 22.6% using a systemic beta-blocker and 36.6% (n = 107) progressing from iAMD to advanced AMD in at least one eye. Patients on a beta-blocker at enrollment were more likely to convert to NV AMD (HR: 1.92 [95% CI: 1.04, 3.55], p-value = 0.036), but this association was no longer significant after adjusting for age and treated hypertension. No significant differences were observed in conversion to advanced NNV or any advanced AMD between groups (all p > 0.05). Conclusions In adjusted analyses, systemic beta-blocker use was not significantly associated with the risk of progression from iAMD to advanced NV or NNV AMD.
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Affiliation(s)
- Brady Hogan
- University of Colorado School of Medicine, Aurora, CO, United States
| | - Nihaal Mehta
- Department of Ophthalmology, University of Colorado School of Medicine, Anschutz
Medical Campus, Aurora, CO, United States
| | - Anne Strong Caldwell
- Department of Ophthalmology, University of Colorado School of Medicine, Anschutz
Medical Campus, Aurora, CO, United States
| | - A. Itzam Marin
- Department of Ophthalmology, University of Colorado School of Medicine, Anschutz
Medical Campus, Aurora, CO, United States
| | - Zafar S. Gill
- Department of Ophthalmology, University of Colorado School of Medicine, Anschutz
Medical Campus, Aurora, CO, United States
| | - Andres Liske-Cervantes
- Department of Ophthalmology, University of Colorado School of Medicine, Anschutz
Medical Campus, Aurora, CO, United States
| | - Marc T. Mathias
- Department of Ophthalmology, University of Colorado School of Medicine, Anschutz
Medical Campus, Aurora, CO, United States
| | - Niranjan Manoharan
- Department of Ophthalmology, University of Colorado School of Medicine, Anschutz
Medical Campus, Aurora, CO, United States
| | - Alan G. Palestine
- Department of Ophthalmology, University of Colorado School of Medicine, Anschutz
Medical Campus, Aurora, CO, United States
| | - Talisa E. de Carlo Forest
- Department of Ophthalmology, University of Colorado School of Medicine, Anschutz
Medical Campus, Aurora, CO, United States
| | - Naresh Mandava
- Department of Ophthalmology, University of Colorado School of Medicine, Anschutz
Medical Campus, Aurora, CO, United States
| | - Anne M. Lynch
- Department of Ophthalmology, University of Colorado School of Medicine, Anschutz
Medical Campus, Aurora, CO, United States
| | - Jennifer L. Patnaik
- Department of Ophthalmology, University of Colorado School of Medicine, Anschutz
Medical Campus, Aurora, CO, United States
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Dongdem JT, Etornam AE, Beletaa S, Alidu I, Kotey H, Wezena CA. The β 3-Adrenergic Receptor: Structure, Physiopathology of Disease, and Emerging Therapeutic Potential. Adv Pharmacol Pharm Sci 2024; 2024:2005589. [PMID: 39640497 PMCID: PMC11620816 DOI: 10.1155/2024/2005589] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2024] [Accepted: 10/24/2024] [Indexed: 12/07/2024] Open
Abstract
The discovery and characterization of the signal cascades of the β-adrenergic receptors have made it possible to effectively target the receptors for drug development. β-Adrenergic receptors are a class A rhodopsin type of G protein-coupled receptors (GPCRs) that are stimulated mainly by catecholamines and therefore mediate diverse effects of the parasympathetic nervous system in eliciting "fight or flight" type responses. They are detectable in several human tissues where they control a plethora of physiological processes and therefore contribute to the pathogenesis of several disease conditions. Given the relevance of the β-adrenergic receptor as a molecular target for many pathological conditions, this comprehensive review aims at providing an in-depth exploration of the recent advancements in β3-adrenergic receptor research. More importantly, we delve into the prospects of the β3-adrenergic receptor as a therapeutic target across a variety of clinical domains.
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Affiliation(s)
- Julius T. Dongdem
- Department of Chemical Pathology, School of Medicine, University for Development Studies, Tamale, Northern Region, Ghana
- Department of Biochemistry and Molecular Medicine, School of Medicine, University for Development Studies, Tamale, Northern Region, Ghana
| | - Axandrah E. Etornam
- Department of Biochemistry and Molecular Medicine, School of Medicine, University for Development Studies, Tamale, Northern Region, Ghana
| | - Solomon Beletaa
- Department of Biochemistry and Molecular Medicine, School of Medicine, University for Development Studies, Tamale, Northern Region, Ghana
| | - Issah Alidu
- Department of Biochemistry and Molecular Medicine, School of Medicine, University for Development Studies, Tamale, Northern Region, Ghana
| | - Hassan Kotey
- Department of Biochemistry and Molecular Medicine, School of Medicine, University for Development Studies, Tamale, Northern Region, Ghana
| | - Cletus A. Wezena
- Department of Microbiology, Faculty of Biosciences, University for Development Studies, Tamale, Northern Region, Ghana
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Maurya M, Liu CH, Bora K, Kushwah N, Pavlovich MC, Wang Z, Chen J. Animal Models of Retinopathy of Prematurity: Advances and Metabolic Regulators. Biomedicines 2024; 12:1937. [PMID: 39335451 PMCID: PMC11428941 DOI: 10.3390/biomedicines12091937] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2024] [Revised: 08/08/2024] [Accepted: 08/15/2024] [Indexed: 09/30/2024] Open
Abstract
Retinopathy of prematurity (ROP) is a primary cause of visual impairment and blindness in premature newborns, characterized by vascular abnormalities in the developing retina, with microvascular alteration, neovascularization, and in the most severe cases retinal detachment. To elucidate the pathophysiology and develop therapeutics for ROP, several pre-clinical experimental models of ROP were developed in different species. Among them, the oxygen-induced retinopathy (OIR) mouse model has gained the most popularity and critically contributed to our current understanding of pathological retinal angiogenesis and the discovery of potential anti-angiogenic therapies. A deeper comprehension of molecular regulators of OIR such as hypoxia-inducible growth factors including vascular endothelial growth factors as primary perpetrators and other new metabolic modulators such as lipids and amino acids influencing pathological retinal angiogenesis is also emerging, indicating possible targets for treatment strategies. This review delves into the historical progressions that gave rise to the modern OIR models with a focus on the mouse model. It also reviews the fundamental principles of OIR, recent advances in its automated assessment, and a selected summary of metabolic investigation enabled by OIR models including amino acid transport and metabolism.
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Affiliation(s)
| | | | | | | | | | | | - Jing Chen
- Department of Ophthalmology, Boston Children’s Hospital, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA
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Melecchi A, Canovai A, Amato R, Dal Monte M, Filippi L, Bagnoli P, Cammalleri M. Agonism of β3-Adrenoceptors Inhibits Pathological Retinal Angiogenesis in the Model of Oxygen-Induced Retinopathy. Invest Ophthalmol Vis Sci 2024; 65:34. [PMID: 39186263 PMCID: PMC11361380 DOI: 10.1167/iovs.65.10.34] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Accepted: 07/30/2024] [Indexed: 08/27/2024] Open
Abstract
Purpose In response to hypoxia, sympathetic fibers to the retina activate β-adrenoceptors (β-ARs) that play an important role in the regulation of vascular and neuronal functions. We investigated the role of β3-AR using the mouse model of oxygen-induced retinopathy (OIR). Methods Mouse pups were exposed to 75% oxygen at postnatal day 7 (PD7) followed by a return to room air at PD12. The β3-AR preferential agonist BRL37344 was subcutaneously administered once daily at different times after the return to room air. At PD17, the OIR mice underwent flash and pattern electroretinogram. After sacrifice, retinal wholemounts were used for vessel staining or immunohistochemistry for astrocytes, Müller cells, or retinal ganglion cells (RGCs). In retinal homogenates, the levels of markers associated with neovascularization (NV), the blood-retinal barrier (BRB), or astrocytes were determined by western blot, and quantitative reverse-transcription polymerase chain reaction was used to assess β3-AR messenger. Administration of the β3-AR antagonist SR59230A was performed to verify BRL37344 selectivity. Results β3-AR expression is upregulated in response to hypoxia, but its increase is prevented by BRL37344, which counteracts NV by inhibiting the pro-angiogenic pathway, activating the anti-angiogenic pathway, recovering BRB-associated markers, triggering nitric oxide production, and favoring revascularization of the central retina through recovered density of astrocytes that ultimately counteracts NV in the midperiphery. Vasculature rescue prevents dysfunctional retinal activity and counteracts OIR-associated retinal ganglion cell loss. Conclusions β3-AR has emerged as a crucial intermediary in hypoxia-dependent NV, suggesting a role of β3-AR agonists in the treatment of proliferative retinopathies.
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Affiliation(s)
| | | | - Rosario Amato
- Department of Biology, University of Pisa, Pisa, Italy
| | | | - Luca Filippi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Neonatology Unit, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy
| | - Paola Bagnoli
- Department of Biology, University of Pisa, Pisa, Italy
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Paradis H, Werdyani S, Zhai G, Gendron RL, Tabrizchi R, McGovern M, Jumper JM, Brinton D, Good WV. Genetic Variants of the Beta-Adrenergic Receptor Pathways as Both Risk and Protective Factors for Retinopathy of Prematurity. Am J Ophthalmol 2024; 263:179-187. [PMID: 38224928 DOI: 10.1016/j.ajo.2023.12.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 12/21/2023] [Accepted: 12/28/2023] [Indexed: 01/17/2024]
Abstract
PURPOSE There is strong evidence that genetic factors influence retinopathy of prematurity (ROP), a neovascular eye disease. It has been previously suggested that polymorphisms in the genes involved in β-adrenergic receptor (ADRβ) pathways could protect against ROP. Antagonists for the ADRβ are actively tested in clinical trials for ROP treatment, but not without controversy and safety concerns. This study was designed to assess whether genetic variations in components of the ADRβ signaling pathways associate with risk of developing ROP. DESIGN An observational case-control targeted genetic analysis. METHODS A study was carried out in premature participants with (n = 30) or without (n = 34) ROP and full-term controls (n = 20), who were divided into a discovery cohort and a validation cohort. ROP was defined using International Classification of Retinopathy of Prematurity criteria (ICROP). Targeted sequencing of 20 genes in the ADRβ pathways was performed in the discovery cohort. Polymerase chain reaction (PCR)/restriction enzyme analysis for some of the discovered ROP-associated variants was performed for validation of the results using the validation cohort. RESULTS The discovery cohort revealed 543 bi-allelic variants within 20 genes of the ADRβ pathways. Ten single-nucleotide variants (SNVs) in 5 genes including protein kinase A regulatory subunit 1α (PRKAR1A), rap guanine exchange factor 3 (RAPGEF3), adenylyl cyclase 4 (ADCY4), ADCY7, and ADCY9 were associated with ROP (P < .05). The most significant SNV was found in PRKAR1A (P = .001). Multiple variants located in the 3'-untranslated region (3'UTR) of RAPGEF3 were also associated with ROP (P < .05). PCR/restriction enzyme analysis of the 3'UTR of RAPGEF3 methodologically validated these findings. CONCLUSION SNVs in PRKAR1A may represent protective factors whereas SNVs in RAPGEF3 may represent risk factors for ROP. PRKAR1α has previously been implicated in retinal vascular development whereas the RAPGEF3 product has a role in the maintenance of vascular barrier function, 2 processes important in ROP. Multicenter validation of these newly discovered risk factors could lead to valuable tools for predicting and preventing the development of severe ROP.
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Affiliation(s)
- Hélène Paradis
- From the Division of BioMedical Sciences (H.P., S.W., G.Z., R.L.G., R.T.), Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Salem Werdyani
- From the Division of BioMedical Sciences (H.P., S.W., G.Z., R.L.G., R.T.), Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Guangju Zhai
- From the Division of BioMedical Sciences (H.P., S.W., G.Z., R.L.G., R.T.), Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Robert L Gendron
- From the Division of BioMedical Sciences (H.P., S.W., G.Z., R.L.G., R.T.), Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Reza Tabrizchi
- From the Division of BioMedical Sciences (H.P., S.W., G.Z., R.L.G., R.T.), Faculty of Medicine, Memorial University, St. John's, Newfoundland, Canada
| | - Margaret McGovern
- Smith Kettlewell Eye Research Institute (M.M., W.V.G.), San Francisco, California, USA
| | | | - Daniel Brinton
- East Bay Retina Consultants, Inc. (D.B.), Oakland, California, USA
| | - William V Good
- Smith Kettlewell Eye Research Institute (M.M., W.V.G.), San Francisco, California, USA.
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Scaramuzzo RT, Crucitta S, del Re M, Cammalleri M, Bagnoli P, Dal Monte M, Pini A, Filippi L. β3-adREnoceptor Analysis in CORD Blood of Neonates (β3 RECORD): Study Protocol of a Pilot Clinical Investigation. Life (Basel) 2024; 14:776. [PMID: 38929758 PMCID: PMC11204445 DOI: 10.3390/life14060776] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 06/12/2024] [Accepted: 06/14/2024] [Indexed: 06/28/2024] Open
Abstract
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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Affiliation(s)
| | - Stefania Crucitta
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (S.C.); (M.d.R.)
| | - Marzia del Re
- Clinical Pharmacology and Pharmacogenetics Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy; (S.C.); (M.d.R.)
| | - Maurizio Cammalleri
- Unit of General Physiology, Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.C.); (P.B.); (M.D.M.)
| | - Paola Bagnoli
- Unit of General Physiology, Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.C.); (P.B.); (M.D.M.)
| | - Massimo Dal Monte
- Unit of General Physiology, Department of Biology, University of Pisa, 56126 Pisa, Italy; (M.C.); (P.B.); (M.D.M.)
| | - Alessandro Pini
- Department of Experimental and Clinical Medicine, University of Florence, 50121 Florence, Italy;
| | - Luca Filippi
- Neonatology Unit, Azienda Ospedaliero Universitaria Pisana, 56126 Pisa, Italy
- Neonatology Unit, Department of Clinical and Experimental Medicine, University of Pisa, 56126 Pisa, Italy
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10
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Cammalleri M, Filippi L, Dal Monte M, Bagnoli P. A promising case of preclinical-clinical translation: β-adrenoceptor blockade from the oxygen-induced retinopathy model to retinopathy of prematurity. Front Physiol 2024; 15:1408605. [PMID: 38938747 PMCID: PMC11208707 DOI: 10.3389/fphys.2024.1408605] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/27/2024] [Indexed: 06/29/2024] Open
Abstract
Although compartmentalization of the eye seems to promote its experimental manipulation, drug penetration to its posterior part is severely limited by hard barriers thus hindering drug development for eye diseases. In particular, angiogenesis-related retinal diseases share common mechanisms and are responsible for the majority of cases of blindness. Their prevalence is globally increasing mostly because of the increased incidence of systemic pathologies in the adult. Despite the number of preclinical findings demonstrating the efficacy of novel treatments, therapy of retinal neovascular diseases still remains confined to intravitreal anti-vascular endothelial growth factor treatments with some extension to anti-inflammatory therapy. In the mare magnum of preclinical findings aimed to develop novel avenues for future therapies, most compounds, despite their efficacy in experimental models, do not seem to meet the criteria for their therapeutic application. In particular, the groove between preclinical findings and their clinical application increases instead of decreasing and the attempt to bridging the gap between them creates intense frustration and a sense of defeat. In this complex scenario, we will discuss here the role that overactivation of the sympathetic system plays in retinal vessel proliferation in response to hypoxia using the oxygen-induced retinopathy (OIR) model. The potential application of the beta-adrenoceptor (β-AR) blockade with propranolol to the treatment of retinopathy of prematurity will be also discussed in light of preclinical findings in the OIR model and clinical trials using propranolol in preterm infants either per os or as eye drops.
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Affiliation(s)
| | - Luca Filippi
- Neonatology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Paola Bagnoli
- Department of Biology, University of Pisa, Pisa, Italy
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Hellström A, Smith LEH, Hård AL. ROP: 80 Years after Its Detection - Where Do We Stand and How Long Will We Continue to Laser? Neonatology 2024; 121:608-615. [PMID: 38776885 PMCID: PMC11446300 DOI: 10.1159/000538907] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2024] [Accepted: 04/11/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND Retinopathy of prematurity (ROP), a potentially blinding disease, is increasing worldwide because of the increased survival of extremely preterm and preterm infants born where oxygen monitoring and ROP screening programs are insufficient. Repeated retinal examinations are stressful for infants, and laser photocoagulation treatment for sight-threatening ROP is destructive. The use of anti-VEGF agents instead of lasers is widespread but requires a long-term follow-up because of late recurrence of the disease. In addition, the optimal anti-VEGF agent dosage and long-term systemic effects require further study. SUMMARY Interventions preventing ROP would be far preferable, and systemic interventions might promote better development of the brain and other organs. Interventions such as improved oxygen control, provision of fresh maternal milk, supplementation with arachidonic acid and docosahexaenoic acid, and fetal hemoglobin preservation by reducing blood sample volumes may help prevent ROP and reduce the need for treatment. Free readily available online tools to predict severe ROP may reduce unnecessary eye examinations and select, for screening, those at a high risk of needing treatment. KEY MESSAGES Treatment warranting ROP is a sign of impaired neurovascular development in the central nervous system. Preventative measures to improve the outcomes are available. Screening can be refined using tools that can predict severe ROP. Laser treatment and anti-VEGF agents are valuable treatment modalities that may complement each other in recurrent ROP.
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Affiliation(s)
- Ann Hellström
- Department of Clinical Neuroscience, Institution of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Lois E H Smith
- The Department of Ophthalmology, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Anna-Lena Hård
- Department of Clinical Neuroscience, Institution of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden,
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12
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Shafique MA, Haseeb A, Uddin MMN, Asghar B, Chaudhry ER, Raqib MA, Ali SMS, Mustafa MS. Effectiveness of Propranolol in Preventing Severe Retinopathy of Prematurity: A Comprehensive Systematic Review and Meta-Analysis. Am J Ophthalmol 2024; 259:141-150. [PMID: 37979602 DOI: 10.1016/j.ajo.2023.11.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 10/02/2023] [Accepted: 11/11/2023] [Indexed: 11/20/2023]
Abstract
PURPOSE To learn more about the effectiveness of oral propranolol as a therapeutic alternative for preterm newborns with pre-existing retinopathy of prematurity (ROP) as well as an early prevention method for ROP, one of the most common but avoidable causes of juvenile blindness. STUDY DESIGN Meta-analysis of relevant literature. METHODS A total of 3464 papers were identified, with 2873 from PubMed, 39 from Scopus, 67 from Medline, and 16 from Embase. After screening, finally, a total of 8 studies were deemed suitable for review. Following the PRISMA guidelines, published literature was systematically assessed up to May 10, 2023. Trials and observational studies were included in which beta blockage was used to prevent severe ROP (defined as stage ≥3 or requiring treatment). A total of 3646 papers were identified, with 2873 from PubMed, 39 from Scopus, 67 from Medline, and 16 from Embase. After screening, a total of 8 studies were deemed suitable for review. RESULTS The use of propranolol is linked to a lower risk of disease development in ROP compared to other therapies or control groups, according to the overall risk ratio of 0.59 (95% CI = 0.42, 0.82; P = .002, I2 = 41%). Additionally, the overall risk ratio for plus disease is 0.42 (95% CI = 0.23, 0.78; P = .006, I2 = 0%), for laser photocoagulation is 0.48 (95% CI = 0.31, 0.74; P = .001; I2 = 2%), and for intravitreal injection of VEGF is 0.43 (95% CI = 0.24, 0.74; P = 0.003, I2 = 0%), suggesting that use of propranolol may reduce the likelihood of developing a disease such as plus disease, requiring laser photocoagulation or necessitating intravitreal injection of vascular endothelial growth factor for ROP, respectively. No statistically significant heterogeneity was found in this study (P > .10, I2 = 50%). It can be concluded from this that the results of the chosen studies were sufficiently comparable and consistent. CONCLUSION This study showed that oral propranolol given as a preventive treatment in premature newborns successfully prevented severe ROP. Propranolol dosage and timing must now be carefully considered in the context of the study population, as these factors may have a major impact on the observed outcomes and treatment success.
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Affiliation(s)
- Muhammad Ashir Shafique
- From the Jinnah Sindh Medical University (M.A.S., A.H., M.M.N.U., B.A., E.R.C., M.S.M.), Karachi, Sindh, Pakistan
| | - Abdul Haseeb
- From the Jinnah Sindh Medical University (M.A.S., A.H., M.M.N.U., B.A., E.R.C., M.S.M.), Karachi, Sindh, Pakistan
| | - Muhammad Musab Nafees Uddin
- From the Jinnah Sindh Medical University (M.A.S., A.H., M.M.N.U., B.A., E.R.C., M.S.M.), Karachi, Sindh, Pakistan
| | - Bushra Asghar
- From the Jinnah Sindh Medical University (M.A.S., A.H., M.M.N.U., B.A., E.R.C., M.S.M.), Karachi, Sindh, Pakistan
| | - Eymaan Riaz Chaudhry
- From the Jinnah Sindh Medical University (M.A.S., A.H., M.M.N.U., B.A., E.R.C., M.S.M.), Karachi, Sindh, Pakistan
| | - Moosa Abdur Raqib
- Liaquat College of Medicine & Dentistry (M.A.R.), Karachi, Sindh, Pakistan
| | | | - Muhammad Saqlain Mustafa
- From the Jinnah Sindh Medical University (M.A.S., A.H., M.M.N.U., B.A., E.R.C., M.S.M.), Karachi, Sindh, Pakistan.
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13
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Sadr A, Sargazi M, Banaie S, Asani M, Mehrad Majd H, Mohammadi SO, Maleki A. Topical Dorzolamide as Adjunctive Treatment With Intravitreal Bevacizumab in Bilateral Diabetic Macular Edema. Cureus 2024; 16:e54829. [PMID: 38529446 PMCID: PMC10961649 DOI: 10.7759/cureus.54829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/23/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND Intravitreal injection of anti-vascular endothelial growth factor (VEGF) agents is accepted as the gold standard treatment for center-involving diabetic macular edema (CI-DME). Adjunctive administration of topical dorzolamide may enhance the therapeutic effects of anti-VEGF agents. In this study, we compared the efficacy of topical dorzolamide plus intravitreal injection of bevacizumab (IVB) versus IVB alone in patients with bilateral DME. METHODS This prospective, randomized contralateral eye study was carried out in a tertiary referral ophthalmology center, Al-Zahra Eye Hospital, Zahedan, Iran, between April 2021 and April 2022. This study included 50 eyes of 25 patients with bilateral DME. All eyes received three consecutive monthly injections of IVB. For each patient, one eye was randomized to instill dorzolamide eye drops three times a day as an intervention, and the other received artificial tear drops as a placebo. Best-corrected visual acuity (BCVA), central macular thickness (CMT), and intraocular pressure (IOP) were evaluated before starting treatment and then monthly for the first three months. RESULTS Among 25 included patients, the average age was 56.64 ± 7.97 years, and 48% were female. BCVA did not improve significantly in any groups (P > 0.05). No significant difference was observed in terms of BCVA between the intervention and control groups (P > 0.05). The present study showed a decrease in CMT in both study groups (P < 0.05). At month 3, the decrease in mean CMT from baseline was significantly higher in eyes receiving topical dorzolamide compared to the control group (-88.92 ± 82.90 vs. -37.64 ± 86.16 µM, respectively; P = 0.037). IOP decreased significantly only in eyes receiving dorzolamide (P < 0.001). CONCLUSIONS The results of the present study indicate that adjunctive administration of topical dorzolamide has a beneficial effect on CMT reduction from baseline, but it did not have an additive effect on BCVA improvement compared to IVB monotherapy.
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Affiliation(s)
- Ata Sadr
- Ophthalmology, Zahedan University of Medical Sciences, Zahedan, IRN
| | - Meisam Sargazi
- Ophthalmology, Zahedan University of Medical Sciences, Zahedan, IRN
| | - Shahram Banaie
- Ophthalmology, Zahedan University of Medical Sciences, Zahedan, IRN
| | - Mahdi Asani
- Ophthalmology, Zahedan University of Medical Sciences, Zahedan, IRN
| | - Hassan Mehrad Majd
- Clinical Research Development Unit, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, IRN
| | - Seyed Omid Mohammadi
- Ophthalmology, Burnett School of Medicine, Texas Christian University, Fort Worth, USA
| | - Alireza Maleki
- Ophthalmology, Zahedan University of Medical Sciences, Zahedan, IRN
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14
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Pasha A, Tondo A, Favre C, Calvani M. Inside the Biology of the β3-Adrenoceptor. Biomolecules 2024; 14:159. [PMID: 38397396 PMCID: PMC10887351 DOI: 10.3390/biom14020159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/24/2024] [Accepted: 01/27/2024] [Indexed: 02/25/2024] Open
Abstract
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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Affiliation(s)
- Amada Pasha
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (A.P.); (A.T.); (C.F.)
- Department of Experimental and Clinical Biomedical Sciences, University of Florence, 50139 Florence, Italy
| | - Annalisa Tondo
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (A.P.); (A.T.); (C.F.)
| | - Claudio Favre
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (A.P.); (A.T.); (C.F.)
| | - Maura Calvani
- Department of Pediatric Hematology–Oncology, Meyer Children’s Hospital IRCCS, 50139 Florence, Italy; (A.P.); (A.T.); (C.F.)
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15
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Pascarella F, Scaramuzzo RT, Pini A, Cammalleri M, Bagnoli P, Ciantelli M, Filippi L. Propranolol: a new pharmacologic approach to counter retinopathy of prematurity progression. Front Pediatr 2024; 12:1322783. [PMID: 38292211 PMCID: PMC10824858 DOI: 10.3389/fped.2024.1322783] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2023] [Accepted: 01/04/2024] [Indexed: 02/01/2024] Open
Abstract
Despite the evident progress in neonatal medicine, retinopathy of prematurity (ROP) remains a serious threat to the vision of premature infants, due to a still partial understanding of the mechanisms underlying the development of this disease and the lack of drugs capable of arresting its progression. Although ROP is a multifactorial disease, retinal vascularization is strictly dependent on oxygen concentration. The exposition of the retina of a preterm newborn, still incompletely vascularized, to an atmosphere relatively hyperoxic, as the extrauterine environment, induces the downregulation of proangiogenic factors and therefore the interruption of vascularization (first ischemic phase of ROP). However, over the following weeks, the growing metabolic requirement of this ischemic retina produces a progressive hypoxia that specularly promotes the surge of proangiogenic factors, finally leading to proliferative retinopathy (second proliferative phase of ROP). The demonstration that the noradrenergic system is actively involved in the coupling between hypoxia and the induction of vasculogenesis paved the way for a pharmacologic intervention aimed at counteracting the interaction of noradrenaline with specific receptors and consequently the progression of ROP. A similar trend has been observed in infantile hemangiomas, the most common vascular lesion of childhood induced by pre-existing hypoxia, which shares similar characteristics with ROP. The fact that propranolol, an unselective antagonist of β1/2 adrenoceptors, counteracts the growth of infantile hemangiomas, suggested the idea of testing the efficacy of propranolol in infants with ROP. From preclinical studies, ongoing clinical trials demonstrated that topical administration of propranolol likely represents the optimal approach to reconcile its efficacy and maximum safety. Given the strict relationship between vessels and neurons, recovering retinal vascularization with propranolol may add further efficacy to prevent retinal dysfunction. In conclusion, the strategy of contrasting precociously the progression of the disease appears to be more advantageous than the current wait-and-see therapeutic approach, which instead is mainly focused on avoiding retinal detachment.
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Affiliation(s)
| | | | - Alessandro Pini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Maurizio Cammalleri
- Unit of General Physiology, Department of Biology, University of Pisa, Pisa, Italy
| | - Paola Bagnoli
- Unit of General Physiology, Department of Biology, University of Pisa, Pisa, Italy
| | | | - Luca Filippi
- Neonatology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
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16
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Ruan Y, Buonfiglio F, Gericke A. Adrenoceptors in the Eye - Physiological and Pathophysiological Relevance. Handb Exp Pharmacol 2024; 285:453-505. [PMID: 38082203 DOI: 10.1007/164_2023_702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/05/2024]
Abstract
The autonomic nervous system plays a crucial role in the innervation of the eye. Consequently, it comes as no surprise that catecholamines and their corresponding receptors have been extensively studied and characterized in numerous ocular structures, including the cornea, conjunctiva, lacrimal gland, trabecular meshwork, uvea, and retina. These investigations have unveiled substantial clinical implications, particularly in the context of treating glaucoma, a progressive neurodegenerative disorder responsible for irreversible vision loss on a global scale. The primary therapeutic approaches for glaucoma frequently involve the modulation of α1-, α2-, and β-adrenoceptors, making them pivotal targets. In this chapter, we offer a comprehensive overview of the expression, distribution, and functional roles of adrenoceptors within various components of the eye and its associated structures. Additionally, we delve into the pivotal role of adrenoceptors in the pathophysiology of glaucoma. Furthermore, we provide a concise historical perspective on adrenoceptor research, examine the distinct contributions of individual adrenoceptor subtypes to the treatment of various ocular conditions, and propose potential future avenues of exploration in this field.
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Affiliation(s)
- Yue Ruan
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Francesco Buonfiglio
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Adrian Gericke
- Department of Ophthalmology, University Medical Center, Johannes Gutenberg University Mainz, Mainz, Germany.
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17
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Silva Tavares Neto JED, Cyrino FVR, Lucena MM, Scott IU, Messias AMV, Jorge R. Intravitreal bevacizumab plus propranolol for neovascular age-related macular degeneration (the BEVALOL study): a phase I clinical trial. Int J Retina Vitreous 2023; 9:28. [PMID: 37055868 PMCID: PMC10099020 DOI: 10.1186/s40942-023-00460-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2023] [Accepted: 03/25/2023] [Indexed: 04/15/2023] Open
Abstract
BACKGROUND Given the persistently large public health impact of neovascular age-related macular degeneration (nARMD) despite many years of anti-VEGF therapy as the first-line treatment and the demonstrated ability of b-blockers to reduce neovascularization, a synergistic effect between an anti-VEGF agent and an intravitreal beta-blocker is important to investigate in the quest for therapeutic alternatives that maximize efficacy and/or reduce costs. The main purpose of this study is to investigate the safety of a 0.1 ml intravitreal injection of a combination of bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) to treat nARMD. METHODS Prospective phase I clinical trial that included patients with nARMD. Comprehensive ophthalmic evaluation was performed at baseline and included Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), biomicroscopy of the anterior and posterior segments, binocular indirect ophthalmoscopy, color fundus photography, spectral domain optical coherence tomography (OCT), OCT angiography (OCT-A), fluorescein angiography (Spectralis, Heidelberg), and full-field electroretinography (ERG). All eyes were treated with a 0.1 ml intravitreal injection of a combination of bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) within 1 week of baseline evaluation. The patients were reexamined at weeks 4, 8 and 12, and clinical evaluation and SD-OCT were performed at all follow-up visits. Additional injections of combination bevacizumab (1.25 mg/0.05 ml) and propranolol (50 g/0.05 ml) were administered at weeks 4 and 8. At the final study evaluation (week 12), color fundus photography, OCT-A, fluorescein angiography, and full-field ERG were repeated. RESULTS Eleven patients (11 eyes) completed all study visits of the 12 week study. Full field ERG b-waves did not show significant (p < 0.05) changes at week 12 compared to baseline. During the 12 week follow-up period, none of the study eyes developed intraocular inflammation, endophthalmitis or intraocular pressure elevation more than 4 mmHg over baseline. Mean ± SE BCVA (logMAR) was 0.79 ± 0.09 at baseline and was significantly (p < 0.05) improved to 0.61 ± 0.10 at week 4; 0.53 ± 0.10 at week 8; and 0.51 ± 0.09 at week 12. Mean ± SE central subfield thickness (CST) (μm) was 462 ± 45 at baseline and was significantly (p < 0.05) lower at 4, 8 and 12 weeks (385 ± 37; 356 ± 29 and 341 ± 24, respectively). CONCLUSIONS In this 12 week trial of a combination of intravitreal bevacizumab and propranolol for treatment of nARMD, no adverse events or signals of ocular toxicity were observed. Further studies using this combination therapy are warranted. Trial Registration Project registered in Plataforma Brasil with CAAE number 28108920.0.0000.5440 and approved in ethics committee of Clinics Hospital of Ribeirao Preto Medicine School of São Paulo University-Ribeirão Preto, São Paulo, Brazil (appreciation number 3.999.989 gave the approval).
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Affiliation(s)
- José Edísio da Silva Tavares Neto
- Department of Ophthalmology, Ribeirão Preto Medical School, University of São Paulo, 3900, Bandeirantes av., Ribeirão Preto, 14048-900, Brazil
| | - Francyne Veiga Reis Cyrino
- Department of Ophthalmology, Ribeirão Preto Medical School, University of São Paulo, 3900, Bandeirantes av., Ribeirão Preto, 14048-900, Brazil
| | - Moises Moura Lucena
- Department of Ophthalmology, Ribeirão Preto Medical School, University of São Paulo, 3900, Bandeirantes av., Ribeirão Preto, 14048-900, Brazil
| | - Ingrid U Scott
- Departments of Ophthalmology and Public Health Sciences, Penn State College of Medicine, Hershey, PA, USA
| | - André Márcio Vieira Messias
- Department of Ophthalmology, Ribeirão Preto Medical School, University of São Paulo, 3900, Bandeirantes av., Ribeirão Preto, 14048-900, Brazil
| | - Rodrigo Jorge
- Department of Ophthalmology, Ribeirão Preto Medical School, University of São Paulo, 3900, Bandeirantes av., Ribeirão Preto, 14048-900, Brazil.
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18
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Fevereiro-Martins M, Marques-Neves C, Guimarães H, Bicho M. Retinopathy of prematurity: A review of pathophysiology and signaling pathways. Surv Ophthalmol 2023; 68:175-210. [PMID: 36427559 DOI: 10.1016/j.survophthal.2022.11.007] [Citation(s) in RCA: 34] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 11/15/2022] [Accepted: 11/18/2022] [Indexed: 11/25/2022]
Abstract
Retinopathy of prematurity (ROP) is a vasoproliferative disorder of the retina and a leading cause of visual impairment and childhood blindness worldwide. The disease is characterized by an early stage of retinal microvascular degeneration, followed by neovascularization that can lead to subsequent retinal detachment and permanent visual loss. Several factors play a key role during the different pathological stages of the disease. Oxidative and nitrosative stress and inflammatory processes are important contributors to the early stage of ROP. Nitric oxide synthase and arginase play important roles in ischemia/reperfusion-induced neurovascular degeneration. Destructive neovascularization is driven by mediators of the hypoxia-inducible factor pathway, such as vascular endothelial growth factor and metabolic factors (succinate). The extracellular matrix is involved in hypoxia-induced retinal neovascularization. Vasorepulsive molecules (semaphorin 3A) intervene preventing the revascularization of the avascular zone. This review focuses on current concepts about signaling pathways and their mediators, involved in the pathogenesis of ROP, highlighting new potentially preventive and therapeutic modalities. A better understanding of the intricate molecular mechanisms underlying the pathogenesis of ROP should allow the development of more effective and targeted therapeutic agents to reduce aberrant vasoproliferation and facilitate physiological retinal vascular development.
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Affiliation(s)
- Mariza Fevereiro-Martins
- Laboratório de Genética and Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Investigação Científica Bento da Rocha Cabral, Lisboa, Portugal; Departamento de Oftalmologia, Hospital Cuf Descobertas, Lisboa, Portugal.
| | - Carlos Marques-Neves
- Centro de Estudos das Ci.¼ncias da Visão, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal; Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Lisboa, Portugal.
| | - Hercília Guimarães
- Departamento de Ginecologia-Obstetrícia e Pediatria, Faculdade de Medicina, Universidade do Porto, Porto, Portugal.
| | - Manuel Bicho
- Laboratório de Genética and Grupo Ecogenética e Saúde Humana, Instituto de Saúde Ambiental, Faculdade de Medicina, Universidade de Lisboa, Portugal; Instituto de Investigação Científica Bento da Rocha Cabral, Lisboa, Portugal.
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19
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Dong Q, Qi B, Zhang B, Zhuang X, Chen S, Zhou Q, Zhang BN, Li S. Overactivation of Norepinephrine-β2-Adrenergic Receptor Axis Promotes Corneal Neovascularization. Invest Ophthalmol Vis Sci 2023; 64:20. [PMID: 36897151 PMCID: PMC10010442 DOI: 10.1167/iovs.64.3.20] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/11/2023] Open
Abstract
Purpose To investigate the role of the sympathetic nervous system in corneal neovascularization (CNV) and to identify the downstream pathway involved in this regulation. Methods Three types of CNV models were constructed with C57BL/6J mice, including the alkali burn model, suture model, and basic fibroblast growth factor (bFGF) corneal micropocket model. Subconjunctival injection of the sympathetic neurotransmitter norepinephrine (NE) was administered in these three models. Control mice received injections of water of the same volume. The corneal CNV was detected using slit-lamp microscopy and immunostaining with CD31, and the results were quantified by ImageJ. The expression of β2-adrenergic receptor (β2-AR) was stained with mouse corneas and human umbilical vein endothelial cells (HUVECs). Furthermore, the anti-CNV effects of β2-AR antagonist ICI-118,551 (ICI) were examined with HUVEC tube formation assay and with a bFGF micropocket model. Additionally, partial β2-AR knockdown mice (Adrb2+/-) were used to establish the bFGF micropocket model, and the corneal CNV size was quantified based on the slit-lamp images and vessel staining. Results Sympathetic nerves invaded the cornea in the suture CNV model. The NE receptor β2-AR was highly expressed in corneal epithelium and blood vessels. The addition of NE significantly promoted corneal angiogenesis, whereas ICI effectively inhibited CNV invasion and HUVEC tube formation. Adrb2 knockdown significantly reduced the cornea area occupied by CNV. Conclusions Our study found that sympathetic nerves grow into the cornea in conjunction with newly formed vessels. The addition of the sympathetic neurotransmitter NE and activation of its downstream receptor β2-AR promoted CNV. Targeting β2-AR could potentially be used as an anti-CNV strategy.
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Affiliation(s)
- Qiaoqiao Dong
- Eye Institute of Shandong First Medical University, Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan, China.,School of Ophthalmology, Shandong First Medical University, Qingdao, China.,Aier Eye Hospital of Wuhan University (Wuhan Aier Eye Hospital), Wuhan, China
| | - Benxiang Qi
- School of Ophthalmology, Shandong First Medical University, Qingdao, China.,Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.,State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao, China
| | - Bin Zhang
- School of Ophthalmology, Shandong First Medical University, Qingdao, China.,Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.,State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao, China
| | - Xiaoyun Zhuang
- Eye Institute of Shandong First Medical University, Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan, China.,School of Ophthalmology, Shandong First Medical University, Qingdao, China.,Department of Ophthalmology, School of Clinical Medicine, Weifang Medical University, Weifang, China
| | - Shijiu Chen
- Eye Institute of Shandong First Medical University, Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan, China.,School of Ophthalmology, Shandong First Medical University, Qingdao, China.,Department of Medicine, Qingdao University, Qingdao, China
| | - Qingjun Zhou
- School of Ophthalmology, Shandong First Medical University, Qingdao, China.,Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.,State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao, China
| | - Bi Ning Zhang
- School of Ophthalmology, Shandong First Medical University, Qingdao, China.,Eye Institute of Shandong First Medical University, Qingdao Eye Hospital of Shandong First Medical University, Qingdao, China.,State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao, China
| | - Suxia Li
- Eye Institute of Shandong First Medical University, Eye Hospital of Shandong First Medical University (Shandong Eye Hospital), Jinan, China.,School of Ophthalmology, Shandong First Medical University, Qingdao, China.,State Key Laboratory Cultivation Base, Shandong Provincial Key Laboratory of Ophthalmology, Qingdao, China
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β-Adrenoreceptors as Therapeutic Targets for Ocular Tumors and Other Eye Diseases-Historical Aspects and Nowadays Understanding. Int J Mol Sci 2023; 24:ijms24054698. [PMID: 36902129 PMCID: PMC10003534 DOI: 10.3390/ijms24054698] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 02/21/2023] [Accepted: 02/24/2023] [Indexed: 03/05/2023] Open
Abstract
β-adrenoreceptors (ARs) are members of the superfamily of G-protein-coupled receptors (GPCRs), and are activated by catecholamines, such as epinephrine and norepinephrine. Three subtypes of β-ARs (β1, β2, and β3) have been identified with different distributions among ocular tissues. Importantly, β-ARs are an established target in the treatment of glaucoma. Moreover, β-adrenergic signaling has been associated with the development and progression of various tumor types. Hence, β-ARs are a potential therapeutic target for ocular neoplasms, such as ocular hemangioma and uveal melanoma. This review aims to discuss the expression and function of individual β-AR subtypes in ocular structures, as well as their role in the treatment of ocular diseases, including ocular tumors.
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Cammalleri M, Amato R, Dal Monte M, Filippi L, Bagnoli P. The β3 adrenoceptor in proliferative retinopathies: "Cinderella" steps out of its family shadow. Pharmacol Res 2023; 190:106713. [PMID: 36863427 DOI: 10.1016/j.phrs.2023.106713] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/14/2023] [Accepted: 02/27/2023] [Indexed: 03/04/2023]
Abstract
In the retina, hypoxic condition leads to overgrowing leaky vessels resulting in altered metabolic supply that may cause impaired visual function. Hypoxia-inducible factor-1 (HIF-1) is a central regulator of the retinal response to hypoxia by activating the transcription of numerous target genes, including vascular endothelium growth factor, which acts as a major player in retinal angiogenesis. In the present review, oxygen urge by the retina and its oxygen sensing systems including HIF-1 are discussed in respect to the role of the beta-adrenergic receptors (β-ARs) and their pharmacologic manipulation in the vascular response to hypoxia. In the β-AR family, β1- and β2-AR have long been attracting attention because their pharmacology is intensely used for human health, while β3-AR, the third and last cloned receptor is no longer increasingly emerging as an attractive target for drug discovery. Here, β3-AR, a main character in several organs including the heart, the adipose tissue and the urinary bladder, but so far a supporting actor in the retina, has been thoroughly examined in respect to its function in retinal response to hypoxia. In particular, its oxygen dependence has been taken as a key indicator of β3-AR involvement in HIF-1-mediated responses to oxygen. Hence, the possibility of β3-AR transcription by HIF-1 has been discussed from early circumstantial evidence to the recent demonstration that β3-AR acts as a novel HIF-1 target gene by playing like a putative intermediary between oxygen levels and retinal vessel proliferation. Thus, targeting β3-AR may implement the therapeutic armamentarium against neovascular pathologies of the eye.
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Affiliation(s)
| | - Rosario Amato
- Department of Biology, University of Pisa, Pisa, Italy
| | | | - Luca Filippi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Paola Bagnoli
- Department of Biology, University of Pisa, Pisa, Italy.
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Luo Y, Liu J, Feng W, Lin D, Song G, Chen M, Zheng H. Use of β‑blockers and risk of age‑related macular degeneration among hypertensive patients: An insight from The National Health and Nutrition Examination Survey. MEDICINE INTERNATIONAL 2023; 3:10. [PMID: 36793623 PMCID: PMC9922801 DOI: 10.3892/mi.2023.70] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 10/12/2022] [Accepted: 01/26/2023] [Indexed: 01/31/2023]
Abstract
Although age-related macular degeneration (AMD) is the leading cause of legal blindness, the treatment methods for AMD are limited. The aim of the present study was to examine the association between oral β-blockers (BBs) and the risk of developing AMD among hypertensive patients. For this purpose, a total of 3,311 hypertensive patients from the National Health and Nutrition Examination Survey were included in the study. The use of BBs and treatment duration data were collected using a self-reported questionnaire. AMD was diagnosed by gradable retinal images. Multivariate-adjusted survey-weighted univariate logistic regression was used to confirm the association between the use of BBs and the risk of developing AMD. The results revealed that the use of BBs exerted a beneficial effect (odds ratio (OR), 0.34; 95% confidence interval (95% CI, 0.13-0.92; P=0.04) in late-stage AMD in the multivariate adjusted model. When the BBs were classified into non-selective BBs and selective BBs, the protective effect in late-stage AMD was still observed in the non-selective BBs (OR, 0.20; 95% CI, 0.07-0.61; P<0.001). After accounting for treatment duration, long-term treatment with BBs (>6 years) was also found to reduce the risk of late-stage AMD (OR, 0.13; 95% CI, 0.03-0.63; P=0.01). In late-stage AMD, the long-term use of BBs was beneficial for geographic atrophy (OR, 0.07; 95% CI, 0.02-0.28; P<0.001). On the whole, the present study demonstrates that the use of non-selective BBs exerted a beneficial effect against the risk of late-stage AMD among hypertensive patients. Long-term treatment with BBs was also associated with lower risk of developing AMD. These findings may provide novel strategies for the management and treatment of AMD.
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Affiliation(s)
- Yili Luo
- Department of Ophthalmology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Jianpeng Liu
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Wangqiang Feng
- Department of Ophthalmology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Da Lin
- Department of Ophthalmology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Guangwei Song
- Department of Ophthalmology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Mengji Chen
- Department of Ophthalmology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
| | - Haihua Zheng
- Department of Ophthalmology, The Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325027, P.R. China
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Liu JL, Zheng YH, Chen LJ, Zhang KK, Li JH, Yang JZ, Li XW, Zhao D, Xie XL, Wang Q. mRNA microarray analysis for the identification of potential biomarkers for vital reaction in burned skin: a preliminary pilot study. Forensic Sci Med Pathol 2022; 18:319-328. [PMID: 35543929 DOI: 10.1007/s12024-022-00474-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/13/2022] [Indexed: 12/14/2022]
Abstract
The identification of ante- and post-mortem burns is challenging in forensic pathology. In this study, microarray analysis was used to detect the mRNA expression profiles in the skin of an experimental burn mouse model; the results were validated using RT-qPCR. Differentially expressed mRNAs (DE-mRNAs) were assessed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Our results revealed that mRNA expression of 501 genes was significantly different, of which 273 were upregulated and 228 were downregulated in ante-mortem burned mice skin. The expression levels of eight random mRNAs were consistent when measured using the microarray assay-based method and RT-qPCR. Genes from different functional categories and signalling pathways were enriched, including interleukin-20 binding, type IV hypersensitivity, negative regulation of acute inflammatory response, sensory organ development, endocytosis, neuroactive ligand-receptor interaction, and Jak-STAT signalling pathway. Only five of the eight mRNAs exhibited consistent changes in expression between burned skin samples of mice and human autopsy specimens. Our findings showed that DE-mRNAs revealed using microarray are potential biomarkers of ante-mortem burns. However, DE-mRNAs identified from experimental animal models cannot be directly extended to autopsy specimens without careful validation.
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Affiliation(s)
- Jia-Li Liu
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1023, South Shatai Road, Guangzhou, 510515, China
| | - Ye-Hua Zheng
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1023, South Shatai Road, Guangzhou, 510515, China
| | - Li-Jian Chen
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1023, South Shatai Road, Guangzhou, 510515, China
| | - Kai-Kai Zhang
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1023, South Shatai Road, Guangzhou, 510515, China
| | - Jia-Hao Li
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1023, South Shatai Road, Guangzhou, 510515, China
| | - Jian-Zheng Yang
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1023, South Shatai Road, Guangzhou, 510515, China
| | - Xiu-Wen Li
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1023, South Shatai Road, Guangzhou, 510515, China
| | - Dong Zhao
- Key Laboratory of Evidence Science (China University of Political Science and Law), Ministry of Education, Beijing, 100088, China
| | - Xiao-Li Xie
- Department of Toxicology, School of Public Health, Southern Medical University, (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, Guangzhou, 510515, China.
| | - Qi Wang
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1023, South Shatai Road, Guangzhou, 510515, China.
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Su S, Zou P, Yang G, Wang Y, Liu L, Liu Y, Zhang J, Ding Y. Propranolol ameliorates retinopathy of prematurity in mice by downregulating HIF-1α via the PI3K/Akt/ERK pathway. Pediatr Res 2022; 93:1250-1257. [PMID: 35986147 DOI: 10.1038/s41390-022-02211-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Revised: 06/13/2022] [Accepted: 06/28/2022] [Indexed: 11/09/2022]
Abstract
BACKGROUND Retinopathy of prematurity (ROP) is the leading cause of blindness in infants, and elevation of HIF-1α through the PI3K/Akt and ERK pathways is implicated in ROP pathogenesis. The mechanism of action of propranolol in ROP remains controversial. We investigated the effect of propranolol on ROP and explored its potential mechanisms of action in an oxygen-induced retinopathy (OIR) mouse model. METHODS OIR mice were first treated with propranolol intraperitoneally, and the retina integrity was measured by FITC-dextran and hematoxylin-eosin staining. The expression of HIF-1α, VEGF, and key signaling pathway proteins was determined using real-time PCR and western blotting. RESULTS FITC-dextran staining showed that propranolol treatment reduced damage to retinal morphology in OIR mice. Mice treated with propranolol showed a reduced number of nuclei of vascular endothelial cells penetrating the inner limiting membrane of the retina, confirming the therapeutic effect of propranolol on ROP. Further analysis showed that HIF-1α and PI3K/Akt/ERK pathway protein levels were significantly elevated in OIR mice. In contrast, propranolol treatment downregulated the expression of these proteins, indicating that the PI3K/Akt/ERK/HIF-1α axis is associated with propranolol-induced ROP alleviation. CONCLUSIONS Propranolol has a therapeutic function against ROP, likely through the downregulation of HIF-1α via the PI3K/Akt/ERK pathway. IMPACT Propranolol can reduce the formation of abnormal retinal neovascularization in oxygen-induced retinopathy (OIR) models, and reduce leaking, tortuous, and abnormally expanding retinal blood vessels. Propranolol possibly improves OIR by inhibiting the activated ERK and HIF-1α pathways. Furthermore, propranolol may downregulate HIF-1α via the PI3K/Akt/ERK pathway to ameliorate retinopathy of prematurity. This study elucidated that the therapeutic effect of propranolol in OIR mice does not involve the VEGFR-2 pathway.
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Affiliation(s)
- Shaomin Su
- Department of Neonatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China.,Department of Neonatology, Shenzhen Children's Hospital, Shenzhen, China
| | - Peicen Zou
- Department of Neonatology, Capital Institute of Pediatrics, Beijing, China
| | - Guangran Yang
- Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing, China
| | - Yajuan Wang
- Department of Neonatology, Children's Hospital, Capital Institute of Pediatrics, Beijing, China.
| | - Lei Liu
- Department of Neonatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Ying Liu
- Department of Neonatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Jinjing Zhang
- Department of Neonatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
| | - Yijun Ding
- Department of Neonatology, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, China
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Propranolol: A “Pick and Roll” Team Player in Benign Tumors and Cancer Therapies. J Clin Med 2022; 11:jcm11154539. [PMID: 35956154 PMCID: PMC9369479 DOI: 10.3390/jcm11154539] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2022] [Revised: 07/28/2022] [Accepted: 08/02/2022] [Indexed: 12/10/2022] Open
Abstract
Research on cancer therapies focuses on processes such as angiogenesis, cell signaling, stemness, metastasis, and drug resistance and inflammation, all of which are influenced by the cellular and molecular microenvironment of the tumor. Different strategies, such as antibodies, small chemicals, hormones, cytokines, and, recently, gene editing techniques, have been tested to reduce the malignancy and generate a harmful microenvironment for the tumor. Few therapeutic agents have shown benefits when administered alone, but a few more have demonstrated clear improvement when administered in combination with other therapeutic molecules. In 2008 (and for the first time in the clinic), the therapeutic benefits of the β-adrenergic receptor antagonist, propranolol, were described in benign tumors, such as infantile hemangioma. Propranolol, initially prescribed for high blood pressure, irregular heart rate, essential tremor, and anxiety, has shown, in the last decade, increasing evidence of its antitumoral properties in more than a dozen different types of cancer. Moreover, the use of propranolol in combination therapies with other drugs has shown synergistic antitumor effects. This review highlights the clinical trials in which propranolol is taking part as adjuvant therapy at single administration or in combinatorial human trials, arising as a good pick and roll partner in anticancer strategies.
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Lucchesi M, Marracci S, Amato R, Filippi L, Cammalleri M, Dal Monte M. Neurosensory Alterations in Retinopathy of Prematurity: A Window to Neurological Impairments Associated to Preterm Birth. Biomedicines 2022; 10:biomedicines10071603. [PMID: 35884908 PMCID: PMC9313429 DOI: 10.3390/biomedicines10071603] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Revised: 06/21/2022] [Accepted: 07/04/2022] [Indexed: 11/16/2022] Open
Abstract
Retinopathy of prematurity (ROP) is one of the main blinding diseases affecting preterm newborns and is classically considered a vascular disorder. The premature exposure to the extrauterine environment, which is hyperoxic in respect to the intrauterine environment, triggers a cascade of events leading to retinal ischemia which, in turn, makes the retina hypoxic thus setting off angiogenic processes. However, many children with a history of ROP show persistent vision impairment, and there is evidence of an association between ROP and neurosensory disabilities. This is not surprising given the strict relationship between neuronal function and an adequate blood supply. In the present work, we revised literature data evidencing to what extent ROP can be considered a neurodegenerative disease, also taking advantage from data obtained in preclinical models of ROP. The involvement of different retinal cell populations in triggering the neuronal damage in ROP was described along with the neurological outcomes associated to ROP. The situation of ROP in Italy was assessed as well.
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Affiliation(s)
- Martina Lucchesi
- Department of Biology, University of Pisa, 56127 Pisa, Italy; (M.L.); (S.M.); (R.A.); (M.C.)
| | - Silvia Marracci
- Department of Biology, University of Pisa, 56127 Pisa, Italy; (M.L.); (S.M.); (R.A.); (M.C.)
| | - Rosario Amato
- Department of Biology, University of Pisa, 56127 Pisa, Italy; (M.L.); (S.M.); (R.A.); (M.C.)
| | - Luca Filippi
- Department of Clinical and Experimental Medicine, Division of Neonatology and NICU, University of Pisa, 56126 Pisa, Italy;
| | - Maurizio Cammalleri
- Department of Biology, University of Pisa, 56127 Pisa, Italy; (M.L.); (S.M.); (R.A.); (M.C.)
| | - Massimo Dal Monte
- Department of Biology, University of Pisa, 56127 Pisa, Italy; (M.L.); (S.M.); (R.A.); (M.C.)
- Correspondence: ; Tel.: +39-050-2211426
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27
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Dysregulated genomic and coding-transcriptomic factors in retinopathy of prematurity. GENE REPORTS 2022. [DOI: 10.1016/j.genrep.2022.101558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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HIF-1-Dependent Induction of β3 Adrenoceptor: Evidence from the Mouse Retina. Cells 2022; 11:cells11081271. [PMID: 35455951 PMCID: PMC9029465 DOI: 10.3390/cells11081271] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2022] [Revised: 04/06/2022] [Accepted: 04/07/2022] [Indexed: 02/01/2023] Open
Abstract
A major player in the homeostatic response to hypoxia is the hypoxia-inducible factor (HIF)-1 that transactivates a number of genes involved in neovessel proliferation in response to low oxygen tension. In the retina, hypoxia overstimulates β-adrenoceptors (β-ARs) which play a key role in the formation of pathogenic blood vessels. Among β-ARs, β3-AR expression is increased in proliferating vessels in concomitance with increased levels of HIF-1α and vascular endothelial growth factor (VEGF). Whether, similarly to VEGF, hypoxia-induced β3-AR upregulation is driven by HIF-1 is still unknown. We used the mouse model of oxygen-induced retinopathy (OIR), an acknowledged model of retinal angiogenesis, to verify the hypothesis of β3-AR transcriptional regulation by HIF-1. Investigation of β3-AR regulation over OIR progression revealed that the expression profile of β3-AR depends on oxygen tension, similar to VEGF. The additional evidence that HIF-1α stabilization decouples β3-AR expression from oxygen levels further indicates that HIF-1 regulates the expression of the β3-AR gene in the retina. Bioinformatics predicted the presence of six HIF-1 binding sites (HBS #1-6) upstream and inside the mouse β3-AR gene. Among these, HBS #1 has been identified as the most suitable HBS for HIF-1 binding. Chromatin immunoprecipitation-qPCR demonstrated an effective binding of HIF-1 to HBS #1 indicating the existence of a physical interaction between HIF-1 and the β3-AR gene. The additional finding that β3-AR gene expression is concomitantly activated indicates the possibility that HIF-1 transactivates the β3-AR gene. Our results are indicative of β3-AR involvement in HIF-1-mediated response to hypoxia.
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Filippi L, Cammalleri M, Amato R, Ciantelli M, Pini A, Bagnoli P, Dal Monte M. Decoupling Oxygen Tension From Retinal Vascularization as a New Perspective for Management of Retinopathy of Prematurity. New Opportunities From β-adrenoceptors. Front Pharmacol 2022; 13:835771. [PMID: 35126166 PMCID: PMC8814365 DOI: 10.3389/fphar.2022.835771] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Accepted: 01/05/2022] [Indexed: 12/20/2022] Open
Abstract
Retinopathy of prematurity (ROP) is an evolutive and potentially blinding eye disease that affects preterm newborns. Unfortunately, until now no conservative therapy of active ROP with proven efficacy is available. Although ROP is a multifactorial disease, premature exposition to oxygen concentrations higher than those intrauterine, represents the initial pathogenetic trigger. The increase of oxygenation in a retina still incompletely vascularized promotes the downregulation of proangiogenic factors and finally the interruption of vascularization (ischemic phase). However, the increasing metabolic requirement of the ischemic retina induces, over the following weeks, a progressive hypoxia that specularly increases the levels of proangiogenic factors finally leading to proliferative retinopathy (proliferative phase). Considering non-modifiable the coupling between oxygen levels and vascularization, so far, neonatologists and ophthalmologists have "played defense", meticulously searching the minimum necessary concentration of oxygen for individual newborns, refining their diagnostic ability, adopting a careful monitoring policy, ready to decisively intervene only in a very advanced stage of disease progression. However, recent advances have demonstrated the possibility to pharmacologically modulate the relationship between oxygen and vascularization, opening thus the perspective for new therapeutic or preventive opportunities. The perspective of a shift from a defensive towards an attack strategy is now at hand.
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Affiliation(s)
- Luca Filippi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | | | - Rosario Amato
- Department of Biology, University of Pisa, Pisa, Italy
| | | | - Alessandro Pini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Paola Bagnoli
- Department of Biology, University of Pisa, Pisa, Italy
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Infantile hemangiomas β 3-adrenoceptor overexpression is associated with nonresponse to propranolol. Pediatr Res 2022; 91:163-170. [PMID: 33654276 DOI: 10.1038/s41390-021-01385-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 12/15/2020] [Accepted: 01/07/2021] [Indexed: 12/27/2022]
Abstract
BACKGROUND Propranolol (antagonist of β1-/β2-AR but minimally active against β3-AR) is currently the first-line treatment for infantile hemangiomas (IH). Its efficacy is attributed to the blockade of β2-AR. However, its success rate is ~60%. Considering the growing interest in the angiogenic role of β3-ARs, we evaluated a possible relationship between β3-AR expression and response to propranolol. METHODS Fifteen samples of surgical biopsies were collected from patients with IH. Three were taken precociously from infants and then successfully treated with propranolol (responder group). Twelve were taken later, from residual lesions noncompletely responsive to propranolol (nonresponder group). A morphometrical analysis of the percentage of β1-, β2-, and β3-ARs positively stained area was compared between the two groups. RESULTS While no difference was found in both β1- and β2-AR expression level, a statistically significant increase of β3-AR positively stained area was observed in the nonresponder group. CONCLUSIONS Although the number of biopsies is insufficient to draw definitive conclusions, and the different β-AR pattern may be theoretically explained by the different timing of samplings, this study suggests a possible correlation between β3-AR expression and the reduced responsiveness to propranolol treatment. This study could pave the way for new therapeutic perspectives to manage IH. IMPACT Propranolol (unselective antagonist of β1 and β2-ARs) is currently the first-line treatment for IHs, with a success rate of ~60%. Its effectiveness has been attributed to its ability to block β2-ARs. However, β3-ARs (on which propranolol is minimally active) were significantly more expressed in hemangioma biopsies taken from patients nonresponsive to propranolol. This study suggests a possible role of β3-ARs in hemangioma pathogenesis and a possible new therapeutic target.
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Abstract
Retinopathy of prematurity (ROP) is an alteration in the development of the immature retina vascularization that frequently occurs in premature infants and is one of the leading causes of childhood blindness worldwide. In threshold stage retinopathy, laser photocoagulation is the standard treatment, particularly in those located in zone II. However, this therapy destroys parts of the retina and can lead to significant eye complications later in life. For this reason, in the last few years, antivascular endothelial growth factor agents are being used as monotherapy or as coadjuvant with laser, especially in retinopathy located in zone I. More recently, the administration of oral propranolol has been used as prevention and/or treatment of prethreshold retinopathy with encouraging results. This review provides an overview of the current evidence on newer treatment strategies for ROP. KEY POINTS: · Laser is the standard treatment in threshold retinopathy of prematurity (ROP).. · Prethreshold stages of the ROP have no treatment.. · Propranolol may prevent the progression of ROP..
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Affiliation(s)
- Aldo Bancalari
- Department of Pediatrics, Faculty of Medicine, University of Concepcion, Concepcion, Chile
| | - Ricardo Schade
- Ophthalmology Service, Guillermo Grant Benavente Hospital, Concepcion, Chile
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Filippi L, Pini A, Cammalleri M, Bagnoli P, Dal Monte M. β3-Adrenoceptor, a novel player in the round-trip from neonatal diseases to cancer: Suggestive clues from embryo. Med Res Rev 2021; 42:1179-1201. [PMID: 34967048 PMCID: PMC9303287 DOI: 10.1002/med.21874] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 09/29/2021] [Accepted: 12/15/2021] [Indexed: 01/19/2023]
Abstract
The role of the β-adrenoceptors (β-ARs) in hypoxia-driven diseases has gained visibility after the demonstration that propranolol promotes the regression of infantile hemangiomas and ameliorates the signs of retinopathy of prematurity (ROP). Besides the role of β2-ARs, preclinical studies in ROP have also revealed that β3-ARs are upregulated by hypoxia and that they are possibly involved in retinal angiogenesis. In a sort of figurative round trip, peculiarities typical of ROP, where hypoxia drives retinal neovascularization, have been then translated to cancer, a disease equally characterized by hypoxia-driven angiogenesis. In this step, investigating the role of β3-ARs has taken advantage of the assumption that cancer growth uses a set of strategies in common with embryo development. The possibility that hypoxic induction of β3-ARs may represent one of the mechanisms through which primarily embryo (and then cancer, as an astute imitator) adapts to grow in an otherwise hostile environment, has grown evidence. In both cancer and embryo, β3-ARs exert similar functions by exploiting a metabolic shift known as the Warburg effect, by acquiring resistance against xenobiotics, and by inducing a local immune tolerance. An additional potential role of β3-AR as a marker of stemness has been suggested by the finding that its antagonism induces cancer cell differentiation evoking that β3-ARs may help cancer to grow in a nonhospital environment, a strategy also exploited by embryos. From cancer, the round trip goes back to neonatal diseases for which new possible interpretative keys and potential pharmacological perspectives have been suggested.
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Affiliation(s)
- Luca Filippi
- Department of Clinical and Experimental Medicine, Neonatology and Neonatal Intensive Care UnitUniversity of PisaPisaItaly
| | - Alessandro Pini
- Department of Experimental and Clinical MedicineUniversity of FlorenceFlorenceItaly
| | - Maurizio Cammalleri
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
| | - Paola Bagnoli
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
| | - Massimo Dal Monte
- Department of Biology, Unit of General PhysiologyUniversity of PisaPisaItaly
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Giurdanella G, Longo A, Distefano A, Olivieri M, Cristaldi M, Cosentino A, Agafonova A, Caporarello N, Lupo G, Anfuso CD. The Anti-Inflammatory Effect of the β1-Adrenergic Receptor Antagonist Metoprolol on High Glucose Treated Human Microvascular Retinal Endothelial Cells. Cells 2021; 11:cells11010051. [PMID: 35011613 PMCID: PMC8750370 DOI: 10.3390/cells11010051] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2021] [Revised: 12/16/2021] [Accepted: 12/21/2021] [Indexed: 12/11/2022] Open
Abstract
Hyperglycemia-induced impairment of the blood-retinal barrier represents the main pathological event in diabetic retinopathy that is elicited by a reduced cellular response to an accumulation of reactive oxygen species (ROS) and increased inflammation. The purpose of the study was to evaluate whether the selective β1-adrenoreceptor (β1-AR) antagonist metoprolol could modulate the inflammatory response to hyperglycemic conditions. For this purpose, human retinal endothelial cells (HREC) were treated with normal (5 mM) or high glucose (25 mM, HG) in the presence of metoprolol (10 μM), epinephrine (1 μM), or both compounds. Metoprolol prevented both the HG-induced reduction of cell viability (MTT assays) and the modulation of the angiogenic potential of HREC (tube formation assays) reducing the TNF-α, IL-1β, and VEGF mRNA levels (qRT-PCR). Moreover, metoprolol prevented the increase in phospho-ERK1/2, phospho-cPLA2, COX2, and protein levels (Western blot) as well as counteracting the translocation of ERK1/2 and cPLA2 (high-content screening). Metoprolol reduced ROS accumulation in HG-stimulated HREC by activating the anti-oxidative cellular response mediated by the Keap1/Nrf2/HO-1 pathway. In conclusion, metoprolol exerted a dual effect on HG-stimulated HREC, decreasing the activation of the pro-inflammatory ERK1/2/cPLA2/COX2 axis, and counteracting ROS accumulation by activating the Keap1/Nrf2/HO-1 pathway.
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Affiliation(s)
- Giovanni Giurdanella
- Biochemistry Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (G.G.); (A.L.); (A.D.); (A.C.); (A.A.); (C.D.A.)
| | - Anna Longo
- Biochemistry Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (G.G.); (A.L.); (A.D.); (A.C.); (A.A.); (C.D.A.)
| | - Alfio Distefano
- Biochemistry Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (G.G.); (A.L.); (A.D.); (A.C.); (A.A.); (C.D.A.)
| | - Melania Olivieri
- U.O. Clinical Pathology, Department of Hematology, AUSL Romagna, 47522 Cesena, Italy;
| | | | - Alessia Cosentino
- Biochemistry Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (G.G.); (A.L.); (A.D.); (A.C.); (A.A.); (C.D.A.)
| | - Aleksandra Agafonova
- Biochemistry Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (G.G.); (A.L.); (A.D.); (A.C.); (A.A.); (C.D.A.)
| | - Nunzia Caporarello
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN 55905, USA;
| | - Gabriella Lupo
- Biochemistry Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (G.G.); (A.L.); (A.D.); (A.C.); (A.A.); (C.D.A.)
- Correspondence:
| | - Carmelina Daniela Anfuso
- Biochemistry Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, 95123 Catania, Italy; (G.G.); (A.L.); (A.D.); (A.C.); (A.A.); (C.D.A.)
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Hassanpour K, Nourinia R, Gerami E, Mahmoudi G, Esfandiari H. Ocular Manifestations of the Sturge-Weber Syndrome. J Ophthalmic Vis Res 2021; 16:415-431. [PMID: 34394871 PMCID: PMC8358762 DOI: 10.18502/jovr.v16i3.9438] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 04/08/2021] [Indexed: 11/24/2022] Open
Abstract
Sturge-Weber syndrome (SWS) or encephalotrigeminal angiomatosis is a non-inherited congenital disorder characterized by neurologic, skin, and ocular abnormalities. A somatic activating mutation (R183Q) in the GNAQ gene during early embryogenesis has been recently recognized as the etiology of vascular abnormalities in SWS. Approximately, half of the patients with SWS manifest ocular involvement including glaucoma as the most common ocular abnormality followed by choroidal hemangioma (CH). The underlying pathophysiology of glaucoma in SWS has not been completely understood yet. Early onset glaucoma comprising 60% of SWS glaucoma have lower success rates after medical and surgical treatments compared with primary congenital glaucoma. Primary angle surgery is associated with modest success in the early onset SWS glaucoma while the success rate significantly decreases in late onset glaucoma. Filtration surgery is associated with a higher risk of intraoperative and postoperative choroidal effusion and suprachoroidal hemorrhage. CH is reported in 40-50% of SWS patients. The goal of treatment in patients with CH is to induce involution of the hemangioma, with reduction of subretinal and intraretinal fluid and minimal damage to the neurosensory retina. The decision for treating diffuse CHs highly depends on the patient's visual acuity, the need for glaucoma surgery, the presence of subretinal fluid (SRF), its chronicity, and the potential for visual recovery.
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Affiliation(s)
- Kiana Hassanpour
- Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran.,Department of Ophthalmology, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ramin Nourinia
- Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ebrahim Gerami
- Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ghavam Mahmoudi
- Ophthalmic Research Center, Research Institute for Ophthalmology and Vision Science, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamed Esfandiari
- Department of Ophthalmology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
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Hatefi A, Zare Shahneh A, Ansari Pirsaraie Z, Alizadeh AM, Atashnak MP, Masoudi R, Pio F. The stimulation and inhibition of beta-2 adrenergic receptor on the inflammatory responses of ovary and immune system in the aged laying hens. BMC Vet Res 2021; 17:195. [PMID: 34022889 PMCID: PMC8140518 DOI: 10.1186/s12917-021-02892-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 04/28/2021] [Indexed: 12/26/2022] Open
Abstract
Background Ovarian chronic inflammation has been known to incidence in the laying hen mainly via increasing laying frequency and microbial infection, especially during late stage of production period. This study was aimed to evaluate beta-2 adrenergic agonist (Beta-2 Adrenergic Agonist, BAA) Salmeterol and beta blocker (Beta Blocker, BB) Propranolol on the gene expression of the ovarian pro- and anti-inflammatory mediators, inflammatory responses of immune system, ovarian functions and, hormones in the laying hens on the late stage of production period. Forty-eight White Leghorn hens aged 92 weeks were used for 4 weeks to be supplemented by Salmeterol and Propranolol. Ovulation rate and follicular growth were determined based on laying frequency and ovarian visual evaluation, respectively; the mRNA expressions of follicular beta-2 adrenergic receptor (Beta-2 Adrenergic Receptor, β2ADR), cyclooxygenases (Cyclooxygenases, COX) 1 and 2, and cytokines were measured by real-time PCR. The plasma concentration of ovarian hormones, cellular, and humoral immune responses were measured via ELISA, heterophil to lymphocyte ratio (Heterophil to Lymphocyte ratio, H:L), and sheep red blood cell (Sheep Red Blood Cell, SRBC) test, respectively. Results As compared to control, both of BAA Salmeterol and BB Propranolol resulted in a significant decrease in the mRNA expression of β2ADR, cyclooxygenases, and pro- and anti-inflammatory cytokines (P < 0.01). A significant elevation was observed in the ovulation rate (P < 0.05), plasma estradiol content on both treated groups (P < 0.05), and the content of progesterone and was just significantly (P < 0.05) increased in Salmeterol group. H:L was reduced in BAA group (P < 0.05), and immunoglobulin (Ig) M was elevated in both treated hens, when compared to control. The results indicated that Salmeterol significantly increases body weight (P < 0.05). Conclusion The stimulation and inhibition of beta-2 adrenergic signaling could reduce ovarian inflammatory condition in addition to enhancing laying efficiency in the aged laying hens.
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Affiliation(s)
- Ali Hatefi
- Department of Animal Science, University of Tehran, Karaj, Iran.
| | | | | | | | - Mohammad Pouya Atashnak
- Molecular Biology and Biochemistry Department, Simon Fraser University, Burnaby, British Columbia, Canada
| | - Reza Masoudi
- Animal Science Research Institute of Iran (ASRI), Agricultural Research Education and Extension Organization (AREEO), Karaj, Iran
| | - Frederic Pio
- Molecular Biology and Biochemistry Department, Simon Fraser University, Burnaby, British Columbia, Canada
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Obeid A, Hsu J, Ehmann D, Gao X, Sridhar J, Chiang A, Park CH, Ho AC. TOPICAL DORZOLAMIDE-TIMOLOL WITH INTRAVITREOUS ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR FOR RETINAL VEIN OCCLUSION: A PILOT STUDY. Retin Cases Brief Rep 2021; 15:120-126. [PMID: 29864044 DOI: 10.1097/icb.0000000000000752] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
PURPOSE To evaluate topical dorzolamide hydrochloride-timolol maleate as an adjunct therapy to intravitreous anti-vascular endothelial growth factor injections in eyes with retinal vein occlusion resistant to treatment. METHODS Retinal vein occlusion patients with a history of persistent macular edema, despite fixed-interval intravitreous anti-vascular endothelial growth factor injections, were enrolled between April 4, 2016, and June 4, 2017. On enrollment, patients were instructed to administer one drop of topical dorzolamide-timolol twice daily for the duration of the study. They were maintained on the same anti-vascular endothelial growth factor drug and same interval between injections as preenrollment for the subsequent two visits. Primary outcome measures were change in central foveal thickness, central subfield thickness, and thickest macular cut at the final study visit. RESULTS Eight patients (8 eyes) were eligible for enrollment and completed the study. There was a significant decrease in central foveal thickness (P = 0.02), central subfield thickness (P = 0.03), and thickest macular cut (P = 0.01) between the enrollment visit and the final visit. There was a decrease in mean (±SD) logarithm of the minimal angle of resolution from 0.52 (±0.35) (20/66, Snellen equivalent) at the enrollment visit to 0.41 (±0.35) (20/51, Snellen equivalent) at the final visit (P = 0.08). CONCLUSION Topical dorzolamide-timolol may have a beneficial anatomical and functional effect in eyes with macular edema secondary to retinal vein occlusion resistant to treatment.
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Affiliation(s)
- Anthony Obeid
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - Jason Hsu
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - David Ehmann
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - Xinxiao Gao
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
- Beijing Anzhen Hospital, Capital Medical University, Beijing, China ; and
| | - Jayanth Sridhar
- Bascom Palmer Eye Institute, University of Miami School of Medicine, Miami, Florida
| | - Allen Chiang
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - Carl H Park
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - Allen C Ho
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
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Qadri A, Cai CL, Deslouches K, Siddiqui F, Aranda JV, Beharry KD. Ocular Versus Oral Propranolol for Prevention and/or Treatment of Oxygen-Induced Retinopathy in a Rat Model. J Ocul Pharmacol Ther 2021; 37:112-130. [PMID: 33535016 DOI: 10.1089/jop.2020.0092] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023] Open
Abstract
Purpose: Propranolol, a nonselective B1/B2 adrenoceptor antagonist, promotes the regression of infantile hemangiomas likely through suppression of vascular endothelial growth factor (VEGF), which prompted its use for the prevention of retinopathy of prematurity. We tested the hypothesis that topical ocular propranolol is safe and effective for reducing the severity of oxygen-induced retinopathy (OIR) in the neonatal rat intermittent hypoxia (IH) model. Methods: At birth (P0), rat pups were randomly assigned to room air or neonatal intermittent hypoxia (IH) consisting of 50% O2 with brief episodes of hypoxia (12% O2) from P0 to P14, during which they received a single daily dose of oral propranolol (1 mg/kg/day in 50 μL in sterile normal saline) or topical ocular propranolol (0.2% in 10 μL in normal saline) from P5 to P14. Placebo-controlled littermates received 50 μL oral or 10 μL topical ocular sterile normal saline. Retinal vascular and astrocyte integrity; retinal histopathology and morphometry; and angiogenesis biomarkers were determined. Results: Topical ocular propranolol improved retinal vascular damage and preserved the astrocytic template, but did not completely prevent OIR. The beneficial effects of propranolol were associated with reduced ocular VEGF and increased endogenous soluble inhibitor, sVEGFR-1, when administered topically. Conclusions: Propranolol failed to completely prevent severe OIR, however, it prevented astrocyte degeneration resulting from neonatal IH-induced damage. We conclude that the mechanisms of propranolol's beneficial effects in neonatal IH may involve in part, astrocyte preservation.
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Affiliation(s)
- Areej Qadri
- Division of Neonatal/Perinatal Medicine, Department of Pediatrics, State University of New York, Brooklyn, New York, USA
| | - Charles L Cai
- Division of Neonatal/Perinatal Medicine, Department of Pediatrics, State University of New York, Brooklyn, New York, USA
| | - Karen Deslouches
- Division of Neonatal/Perinatal Medicine, Department of Pediatrics, State University of New York, Brooklyn, New York, USA
| | - Faisal Siddiqui
- Division of Neonatal/Perinatal Medicine, Department of Pediatrics, State University of New York, Brooklyn, New York, USA
| | - Jacob V Aranda
- Division of Neonatal/Perinatal Medicine, Department of Pediatrics, State University of New York, Brooklyn, New York, USA.,Department of Ophthalmology, Downstate Medical Center, State University of New York, Brooklyn, New York, USA.,State University of New York Eye Institute, New York, New York, USA
| | - Kay D Beharry
- Division of Neonatal/Perinatal Medicine, Department of Pediatrics, State University of New York, Brooklyn, New York, USA.,Department of Ophthalmology, Downstate Medical Center, State University of New York, Brooklyn, New York, USA.,State University of New York Eye Institute, New York, New York, USA
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Arima M, Fujii Y, Sonoda KH. Translational Research in Retinopathy of Prematurity: From Bedside to Bench and Back Again. J Clin Med 2021; 10:331. [PMID: 33477419 PMCID: PMC7830975 DOI: 10.3390/jcm10020331] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 01/09/2021] [Accepted: 01/15/2021] [Indexed: 12/11/2022] Open
Abstract
Retinopathy of prematurity (ROP), a vascular proliferative disease affecting preterm infants, is a leading cause of childhood blindness. Various studies have investigated the pathogenesis of ROP. Clinical experience indicates that oxygen levels are strongly correlated with ROP development, which led to the development of oxygen-induced retinopathy (OIR) as an animal model of ROP. OIR has been used extensively to investigate the molecular mechanisms underlying ROP and to evaluate the efficacy of new drug candidates. Large clinical trials have demonstrated the efficacy of anti-vascular endothelial growth factor (VEGF) agents to treat ROP, and anti-VEGF therapy is presently becoming the first-line treatment worldwide. Anti-VEGF therapy has advantages over conventional treatments, including being minimally invasive with a low risk of refractive error. However, long-term safety concerns and the risk of late recurrence limit this treatment. There is an unmet medical need for novel ROP therapies, which need to be addressed by safe and minimally invasive therapies. The recent progress in biotechnology has contributed greatly to translational research. In this review, we outline how basic ROP research has evolved with clinical experience and the subsequent emergence of new drugs. We discuss previous and ongoing trials and present the candidate molecules expected to become novel targets.
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Affiliation(s)
- Mitsuru Arima
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan; (Y.F.); (K.-H.S.)
- Center for Clinical and Translational Research, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka 8128582, Japan
| | - Yuya Fujii
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan; (Y.F.); (K.-H.S.)
| | - Koh-Hei Sonoda
- Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan; (Y.F.); (K.-H.S.)
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Hsu J, Patel SN, Wolfe JD, Shah CP, Chen E, Jenkins TL, Wibbelsman TD, Obeid A, Mikhail M, Garg SJ, Ho AC, Chiang A, Spirn MJ, Vander JF. Effect of Adjuvant Topical Dorzolamide-Timolol vs Placebo in Neovascular Age-Related Macular Degeneration: A Randomized Clinical Trial. JAMA Ophthalmol 2021; 138:560-567. [PMID: 32239190 DOI: 10.1001/jamaophthalmol.2020.0724] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Importance Some eyes with neovascular age-related macular degeneration (AMD) have persistent exudation despite frequent intravitreal anti-vascular endothelial growth factor (VEGF) injections. Adjuvant therapies that further reduce edema may improve vision outcomes. Objective To compare the short-term effect of topical dorzolamide-timolol vs placebo in eyes with neovascular AMD that have persistent exudation following intravitreal anti-VEGF injections. Design, Setting, and Participants Randomized placebo-controlled clinical trial with enrollment from March 1, 2017, through October 30, 2018. Multicenter trial at 4 clinical sites in the United States. Sixty-three patients with neovascular AMD who had persistent exudation despite intravitreal anti-VEGF injections at 4-week, 5-week, or 6-week intervals. Interventions Patients were randomized to use dorzolamide-timolol or artificial tears for the study duration. They continued to receive the same anti-VEGF drug at the same interval as the 2 visits before enrollment for 3 additional study visits. Main Outcomes and Measures The primary outcome measure was change in mean central subfield thickness on optical coherence tomography from baseline to visit 3 (approximately 3 months). Secondary measures included change in mean maximum subretinal fluid height, mean maximum pigment epithelial detachment height, and mean visual acuity (VA). Results This trial included 52 patients. All 27 patients (100%) assigned to dorzolamide-timolol and 23 of 25 (92%) assigned to placebo were analyzed for the primary outcome. Mean (SD) age was 78.4 (7) years, and 34 of 50 patients (68%) were women. Mean (SD) injections were 20.5 (14) (range, 4-58) before enrollment. Mean (SD) baseline logMAR VA was 0.361 (0.26) (approximate Snellen equivalent, 20/50). Comparing the dorzolamide-timolol with placebo group from baseline to visit 3, mean (SD) change in central subfield thickness (primary outcome) was -36.6 (54) μm vs 1.7 (52.3) μm (difference, 30.8; 95% CI, 0.3-61.3; P = .04); secondary outcomes: maximum PED height was -39.1 (65) μm vs 1.1 (16) μm (difference, 39.6; 95% CI, 9.6-69.6; P = .01) and change in VA from baseline to visit 3 was -2.3 (5) vs 0.3 (1) letters (difference, 2.6 letters; 95% CI, -1.9 to 7.1 letters; P = .78). Conclusions and Relevance These findings suggest use of dorzolamide-timolol in patients with neovascular AMD with persistent exudation resulted in anatomic but not visual acuity improvements compared with placebo at approximately 3 months. Additional clinical trials with longer follow-up and larger sample sizes presumably would be needed to determine the role, if any, of dorzolamide-timolol in neovascular AMD. Trial Registration ClinicalTrials.gov Identifier: NCT03034772.
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Affiliation(s)
- Jason Hsu
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - Samir N Patel
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - Jeremy D Wolfe
- Associated Retinal Consultants, William Beaumont Hospital, Royal Oak, Michigan
| | - Chirag P Shah
- Ophthalmic Consultants of Boston, Boston, Massachusetts
| | - Eric Chen
- Retina Consultants of Houston, Houston, Texas
| | - Thomas L Jenkins
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - Turner D Wibbelsman
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - Anthony Obeid
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - Mikel Mikhail
- Associated Retinal Consultants, William Beaumont Hospital, Royal Oak, Michigan
| | - Sunir J Garg
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - Allen C Ho
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - Allen Chiang
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - Marc J Spirn
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
| | - James F Vander
- The Retina Service of Wills Eye Hospital, Mid Atlantic Retina, Philadelphia, Pennsylvania
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Kong HB, Zheng GY, He BM, Zhang Y, Zhou Q. Clinical Efficacy and Safety of Propranolol in the Prevention and Treatment of Retinopathy of Prematurity: A Meta-Analysis of Randomized Controlled Trials. Front Pediatr 2021; 9:631673. [PMID: 33643978 PMCID: PMC7902715 DOI: 10.3389/fped.2021.631673] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Accepted: 01/04/2021] [Indexed: 12/22/2022] Open
Abstract
Objective: To perform a meta-analysis of randomized controlled trials verifying clinical efficacy and safety of propranolol in pre-term newborns with retinopathy of prematurity (ROP). Methods: We searched the literature databases (Pubmed, Embase, The Cochrane Library, Web of Science, CNKI, WanFang, VIP, CBM) for publications before August 10, 2020, and the World Health Organization's International Clinical Trials Registry and ClinicalTrials.gov for ongoing trials. Randomized controlled trials (RCTs) of propranolol for the prevention or treatment of ROP were included. The quality of the included studies was primarily assessed by the RCT tool of the Cochrane Collaboration. The included studies were quantified using a meta-analysis of relative risk (RR) estimated with a random effect model. Results: Our original search identified 171 articles, and five studies met our criteria. A meta-analysis was performed that showed that infants orally treated with propranolol had a decreased risk of disease progression: stage progression had an RR = 0.65 [95% confidence interval (CI), 0.47-0.88]), plus disease had an RR = 0.43 [95% CI, 0.22-0.82]. The demands for additional treatments had similar protective results: laser photocoagulations had an RR = 0.55 [95% CI, 0.35-0.86]), and intravitreal injection of anti-vascular endothelial growth factor had an RR = 0.45 [95% CI, 0.22-0.90]). The oral administration of propranolol was associated with an increased risk of adverse events (RR = 2.01 [95% CI, 1.02-3.97]). High-risk adverse events included bradycardia, hypotension, not gaining enough weight, bronchospasm, hypoglycemia, apnea, and increasing ventilator need. Subgroup analysis of ROP phases and stages found that the risk in stage 2 ROP of the second phase and the individual risk factors (stage progression, RR = 0.42 [95% CI, 0.27-0.65]; plus disease, RR = 0.40 [95% CI, 0.17-0.93]; laser photocoagulation, RR = 0.31 [95% CI, 0.14-0.68]) have statistically significant differences compared with other phases and stages. Conclusions: Pre-term newborns with ROP, especially in stage 2 ROP of the second phase, who were orally given propranolol have a reduced risk of disease progression and demand for additional treatments, but the safety needs more attention.
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Affiliation(s)
- Haibo B Kong
- Department of Pediatrics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Guoyuan Y Zheng
- Department of Neuroelectrophysiology, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Baomei M He
- Department of Pediatrics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Ying Zhang
- Department of Pediatrics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
| | - Qin Zhou
- Department of Pediatrics, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China
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The Role of Adrenoceptors in the Retina. Cells 2020; 9:cells9122594. [PMID: 33287335 PMCID: PMC7761662 DOI: 10.3390/cells9122594] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Revised: 11/29/2020] [Accepted: 12/01/2020] [Indexed: 01/16/2023] Open
Abstract
The retina is a part of the central nervous system, a thin multilayer with neuronal lamination, responsible for detecting, preprocessing, and sending visual information to the brain. Many retinal diseases are characterized by hemodynamic perturbations and neurodegeneration leading to vision loss and reduced quality of life. Since catecholamines and respective bindings sites have been characterized in the retina, we systematically reviewed the literature with regard to retinal expression, distribution and function of alpha1 (α1)-, alpha2 (α2)-, and beta (β)-adrenoceptors (ARs). Moreover, we discuss the role of the individual adrenoceptors as targets for the treatment of retinal diseases.
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Filippi L, Dal Monte M. A safety review of drugs used for the treatment of retinopathy of prematurity. Expert Opin Drug Saf 2020; 19:1409-1418. [PMID: 32954858 DOI: 10.1080/14740338.2020.1826927] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
INTRODUCTION Retinopathy of Prematurity (ROP) is a sight-threatening disease representing one of the main disabling diseases affecting premature newborns. Presently, ROP is treated by surgical interventions and drug therapies are limited to the off-label use of a little amount of molecules approved for other pathologies. AREAS COVERED Many drugs that may potentially be used in treating ROP are recently proposed, in many cases after the demonstration of their effectiveness in preclinical studies. In this review, the authors discuss safety and effectiveness of the main proposed approaches in the pharmacologic treatment of the disease, including approaches based on oxygen therapy and nutritional interventions. EXPERT OPINION Surgical approaches to ROP are not without side effects. However, most of the proposed pharmacologic interventions can also raise specific concerns. In particular, these approaches follow a curative paradigm and are proposed in patients once the disease has progressed, with an effectiveness that is often smaller than expected. A goal in the treatment of ROP would be moving the paradigm toward a preventive approach that could be potentially effective in treating extremely low birth weight preterm infants before ROP becomes manifest.
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Affiliation(s)
- Luca Filippi
- Neonatal Intensive Care Unit, Medical Surgical Fetal-Neonatal Department, "A. Meyer" University Children's Hospital , Florence, Italy
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Novel Insights into Beta 2 Adrenergic Receptor Function in the rd10 Model of Retinitis Pigmentosa. Cells 2020; 9:cells9092060. [PMID: 32917020 PMCID: PMC7563182 DOI: 10.3390/cells9092060] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2020] [Revised: 08/31/2020] [Accepted: 09/08/2020] [Indexed: 12/18/2022] Open
Abstract
Background: In retinitis pigmentosa (RP), inherited rod death is followed by cone loss and blindness. Why cones die is still a matter of consideration. Here, we investigate the pathogenic role of the sympathetic transmission in the rd10 mouse model of RP. Methods: Retinal levels of beta adrenergic receptor (BAR) 2 and norepinephrine (NE) were measured. After administration of the BAR1/2 blocker propranolol or the hypoxia-inducible factor (HIF)-1 activator dimethyloxalylglycine (DMOG), retinal levels of HIF-1α, BAR2 or proteins involved in BAR2 desensitization were also measured. In DMOG treated mice, expression and localization of BAR2, inflammatory markers and cone arrestin were determined. Finally, rd10 mice were subjected to electroretinogram (ERG) analysis to assess rod and cone function. Results: In the rd10 retina, BAR2 overexpression and NE accumulation were found, with BAR2 immunoreactivity localized to Müller cells. BAR2 overexpression was likely due to desensitization defects. Upregulated levels of BAR2 were drastically reduced by propranolol that also restored desensitization defects. Due to the low level of HIF-1 consequent to the hyperoxic environment in the rd10 retina, we hypothesized a link between HIF-1 and BAR2. HIF-1α stabilization with DMOG resulted in i. increased HIF-1α accumulation, ii. decreased BAR2 levels, iii. restored desensitization processes, iv. reduced expression of inflammatory markers and v. increased cone survival without improved retinal function. Conclusions: Our results support a pathogenic role of the sympathetic system in RP that might help to understand why rd10 mice show a positive response to BAR blockers.
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Calvani M, Dabraio A, Subbiani A, Buonvicino D, De Gregorio V, Ciullini Mannurita S, Pini A, Nardini P, Favre C, Filippi L. β3-Adrenoceptors as Putative Regulator of Immune Tolerance in Cancer and Pregnancy. Front Immunol 2020; 11:2098. [PMID: 32983164 PMCID: PMC7492666 DOI: 10.3389/fimmu.2020.02098] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2020] [Accepted: 08/03/2020] [Indexed: 12/14/2022] Open
Abstract
Understanding the mechanisms of immune tolerance is currently one of the most important challenges of scientific research. Pregnancy affects the immune system balance, leading the host to tolerate embryo alloantigens. Previous reports demonstrated that β-adrenergic receptor (β-AR) signaling promotes immune tolerance by modulation of NK and Treg, mainly through the activation of β2-ARs, but recently we have demonstrated that also β3-ARs induce an immune-tolerant phenotype in mice bearing melanoma. In this report, we demonstrate that β3-ARs support host immune tolerance in the maternal microenvironment by modulating the same immune cells populations as recently demonstrated in cancer. Considering that β3-ARs are modulated by oxygen levels, we hypothesize that hypoxia, through the upregulation of β3-AR, promotes the biological shift toward a tolerant immunophenotype and that this is the same trick that embryo and cancer use to create an aura of immune-tolerance in a competent immune environment. This study confirms the analogies between fetal development and tumor progression and suggests that the expression of β3-ARs represents one of the strategies to induce fetal and tumor immune tolerance.
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Affiliation(s)
- Maura Calvani
- Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy
| | - Annalisa Dabraio
- Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.,Department of Health Sciences, University of Florence, Florence, Italy
| | - Angela Subbiani
- Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.,Department of Health Sciences, University of Florence, Florence, Italy
| | | | - Veronica De Gregorio
- Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy.,Department of Health Sciences, University of Florence, Florence, Italy
| | - Sara Ciullini Mannurita
- Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy
| | - Alessandro Pini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Patrizia Nardini
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | - Claudio Favre
- Department of Paediatric Haematology-Oncology, A. Meyer University Children's Hospital, Florence, Italy
| | - Luca Filippi
- Neonatal Intensive Care Unit, Medical Surgical Feto-Neonatal Department, A. Meyer University Children's Hospital, Florence, Italy
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Navarro-Partida J, Altamirano-Vallejo JC, Lopez-Naranjo EJ, Gonzalez-De la Rosa A, Manzano-Ramírez A, Apatiga-Castro LM, Armendáriz-Borunda J, Santos A. Topical Triamcinolone Acetonide-Loaded Liposomes as Primary Therapy for Macular Edema Secondary to Branch Retinal Vein Occlusion: A Pilot Study. J Ocul Pharmacol Ther 2020; 36:393-403. [PMID: 32564664 DOI: 10.1089/jop.2019.0143] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023] Open
Abstract
Purpose: To explore safety and therapeutic efficacy of a topical ophthalmic triamcinolone acetonide-loaded liposome formulation (TA-LF) as primary therapy in patients with macular edema (ME) secondary to branch retinal vein occlusion (BRVO). Methods: Twelve eyes of 12 patients with ME secondary to BRVO were exposed to a topical instillation of 1 drop of TA-LF (TA 0.2%) 6 times a day for 12 weeks to evaluate safety and efficacy. Best corrected visual acuity (BCVA) intraocular pressure (IOP), slit lamp examination, and central foveal thickness (CFT) were analyzed at every visit. In addition, the morphology of TA-LF was analyzed using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Results: Patients presented a significant improvement of BCVA and CFT without significant IOP modification (P = 0.94). Treated eyes showed BCVA improvement from 40 ± 12.05 to 64.83 ± 15.97 letters and CFT reduction from 682.91 ± 278.60 to 271.58 ± 57.66 μm after 12 weeks of TA-LF therapy (P < 0.001). No adverse events, including IOP rising, were registered. SEM analysis of liposomal formulations showed that liposome (LP) size depends on its concentration. As the concentration of TA increased, the average size of LPs and the number of larger particles increased as well. TEM study displayed that LP formulation efficiently solubilizes TA crystals in nanoparticles and encapsulates them. Conclusion: LPs can function as nanocarriers of TA and they could be used as topical ophthalmic primary therapy instead of intravitreal drugs in patients with ME secondary to BRVO.
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Affiliation(s)
- Jose Navarro-Partida
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Campus Guadalajara, Zapopan, Mexico.,Centro de Retina Medica y Quirúrgica, S.C., Centro Medico Puerta de Hierro, Zapopan, Mexico
| | - Juan Carlos Altamirano-Vallejo
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Campus Guadalajara, Zapopan, Mexico.,Centro de Retina Medica y Quirúrgica, S.C., Centro Medico Puerta de Hierro, Zapopan, Mexico
| | | | - Alejandro Gonzalez-De la Rosa
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Campus Guadalajara, Zapopan, Mexico.,Centro de Retina Medica y Quirúrgica, S.C., Centro Medico Puerta de Hierro, Zapopan, Mexico
| | | | - Luis Miguel Apatiga-Castro
- Universidad Nacional Autonoma de Mexico (UNAM), Centro de Física Aplicada y Tecnología Avanzada, Querétaro, Mexico
| | - Juan Armendáriz-Borunda
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Campus Guadalajara, Zapopan, Mexico.,Instituto de Biología Molecular y Terapia Génica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Mexico
| | - Arturo Santos
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Campus Guadalajara, Zapopan, Mexico.,Centro de Retina Medica y Quirúrgica, S.C., Centro Medico Puerta de Hierro, Zapopan, Mexico
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Filippi L, Bruno G, Domazetovic V, Favre C, Calvani M. Current Therapies and New Targets to Fight Melanoma: A Promising Role for the β3-Adrenoreceptor. Cancers (Basel) 2020; 12:cancers12061415. [PMID: 32486190 PMCID: PMC7352170 DOI: 10.3390/cancers12061415] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/15/2020] [Accepted: 05/25/2020] [Indexed: 02/07/2023] Open
Abstract
Melanoma is one of the most aggressive types of cancer and the most deadly skin cancer. According to World Health Organization, about 132,000 melanoma skin cancers occur globally each year. Thanks to the efficacy of new therapies, life expectation has been improved over the last years. However, some malignant melanomas still remain unresponsive to these therapies. The β-adrenergic system, among its many physiological roles, has been recognized as the main mediator of stress-related tumorigenic events. In particular, catecholamine activation of β-adrenergic receptors (β-ARs) affects several processes that sustain cancer progression. Among the β-AR subtypes, the β3-AR is emerging as an important regulator of tumorigenesis. In this review, we summarize data of different experimental studies focused on β3-AR involvement in tumor development in various types of cancer and, particularly, in melanoma. Taken together, the preclinical evidences reported in this review demonstrate the crucial role of β3-AR in regulating the complex signaling network driving melanoma progression. Therefore, a need exists to further disseminate this new concept and to investigate more deeply the role of β3-AR as a possible therapeutic target for counteracting melanoma progression at clinical level.
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Affiliation(s)
- Luca Filippi
- Neonatal Intensive Care Unit, Medical Surgical Feto-Neonatal Department, A. Meyer University Children’s Hospital, 50139 Florence, Italy
- Correspondence: (L.F.); (G.B.)
| | - Gennaro Bruno
- Department of Health Science, University of Florence, 50139 Florence, Italy;
- Department of Paediatric Haematology-Oncology, A. Meyer University Children’s Hospital, 50139 Florence, Italy; (C.F.); (M.C.)
- Correspondence: (L.F.); (G.B.)
| | - Vladana Domazetovic
- Department of Health Science, University of Florence, 50139 Florence, Italy;
- Department of Paediatric Haematology-Oncology, A. Meyer University Children’s Hospital, 50139 Florence, Italy; (C.F.); (M.C.)
| | - Claudio Favre
- Department of Paediatric Haematology-Oncology, A. Meyer University Children’s Hospital, 50139 Florence, Italy; (C.F.); (M.C.)
| | - Maura Calvani
- Department of Paediatric Haematology-Oncology, A. Meyer University Children’s Hospital, 50139 Florence, Italy; (C.F.); (M.C.)
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Carroll L, Owen LA. Current evidence and outcomes for retinopathy of prematurity prevention: insight into novel maternal and placental contributions. EXPLORATION OF MEDICINE 2020; 1:4-26. [PMID: 32342063 PMCID: PMC7185238 DOI: 10.37349/emed.2020.00002] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 11/27/2019] [Indexed: 12/11/2022] Open
Abstract
Retinopathy of prematurity (ROP) is a blinding morbidity of preterm infants, which represents a significant clinical problem, accounting for up to 40% of all childhood blindness. ROP displays a range of severity, though even mild disease may result in life-long visual impairment. This is complicated by the fact that our current treatments have significant ocular and potentially systemic effects. Therefore, disease prevention is desperately needed to mitigate the life-long deleterious effects of ROP for preterm infants. Although ROP demonstrates a delayed onset of retinal disease following preterm birth, representing a potential window for prevention, we have been unable to sufficiently alter the natural disease course and meaningfully prevent ROP. Prevention therapeutics requires knowledge of early ROP molecular changes and risk, occurring prior to clinical retinal disease. While we still have an incomplete understanding of these disease mechanisms, emerging data integrating contributions of maternal/placental pathobiology with ROP are poised to inform novel approaches to prevention. Herein, we review the molecular basis for current prevention strategies and the clinical outcomes of these interventions. We also discuss how insights into early ROP pathophysiology may be gained by a better understanding of maternal and placental factors playing a role in preterm birth.
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Affiliation(s)
- Lara Carroll
- Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, UT 4132, USA
| | - Leah A. Owen
- Department of Ophthalmology and Visual Sciences, University of Utah, Salt Lake City, UT 4132, USA
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Dal Monte M, Evans BA, Arioglu-Inan E, Michel MC. Upregulation of β 3-adrenoceptors-a general marker of and protective mechanism against hypoxia? Naunyn Schmiedebergs Arch Pharmacol 2019; 393:141-146. [PMID: 31853614 DOI: 10.1007/s00210-019-01780-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Accepted: 11/22/2019] [Indexed: 12/17/2022]
Abstract
β3-Adrenoceptors exhibit a restricted expression pattern, particularly in humans. However, they have been found to be upregulated in various cancers and under several conditions associated with hypoperfusion such as congestive heart failure and diabetes for instance in the heart and other tissues. These conditions are frequently associated with hypoxia. Furthermore, direct induction of hypoxia has consistently been reported to cause upregulation of β3-adrenoceptors across various tissues of multiple species including humans, rats, dogs, and fish. While a canonical hypoxia-response element in the promoter of the human β3-adrenoceptor gene may play a role in this, no such sequence was found in rodent homologs. Moreover, not all upregulation of β3-adrenoceptor protein is accompanied by increased expression of corresponding mRNA, indicating that the upregulation may involve factors other than transcriptional changes. We propose that upregulation of β3-adrenoceptors at the mRNA and/or protein level is a general marker of hypoxic conditions. Moreover, it may be an additional pathway whereby cells and tissues adapt to reduced oxygen levels.
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Affiliation(s)
| | - Bronwyn A Evans
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia
| | - Ebru Arioglu-Inan
- Department. of Pharmacology, Faculty of Pharmacy, Ankara University, Ankara, Turkey
| | - Martin C Michel
- Department. of Pharmacology, Johannes Gutenberg University, Mainz, Germany.
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Spotlight on ROS and β3-Adrenoreceptors Fighting in Cancer Cells. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:6346529. [PMID: 31934266 PMCID: PMC6942895 DOI: 10.1155/2019/6346529] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 11/26/2019] [Indexed: 02/07/2023]
Abstract
The role of ROS and RNS is a long-standing debate in cancer. Increasing the concentration of ROS reaching the toxic threshold can be an effective strategy for the reduction of tumor cell viability. On the other hand, cancer cells, by maintaining intracellular ROS concentration at an intermediate level called “mild oxidative stress,” promote the activation of signaling that favors tumor progression by increasing cell viability and dangerous tumor phenotype. Many chemotherapeutic treatments induce cell death by rising intracellular ROS concentration. The persistent drug stimulation leads tumor cells to simulate a process called hormesis by which cancer cells exhibit a biphasic response to exposure to drugs used. After a first strong response to a low dose of chemotherapeutic agent, cancer cells start to decrease the response even if high doses of drugs were used. In this framework, β3-adrenoreceptors (β3-ARs) fit with an emerging antioxidant role in cancer. β3-ARs are involved in tumor proliferation, angiogenesis, metastasis, and immune tolerance. Its inhibition, by the selective β3-ARs antagonist (SR59230A), leads cancer cells to increase ROS concentration thus inducing cell death and to decrease NO levels thus inhibiting angiogenesis. In this review, we report an overview on reactive oxygen biology in cancer cells focusing on β3-ARs as new players in the antioxidant pathway.
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Oral propranolol in prevention of severe retinopathy of prematurity: a systematic review and meta-analysis. J Perinatol 2019; 39:1584-1594. [PMID: 31570797 DOI: 10.1038/s41372-019-0503-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Revised: 07/10/2019] [Accepted: 07/31/2019] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To systematically assess the efficacy of oral beta blockage treatment in primary (before established) and secondary (in threshold stages) prevention of severe retinopathy of prematurity (ROP) in premature infants born ≤32 weeks gestational age. STUDY DESIGN Following the PRISMA guidelines, published literature was systematically assessed up to April 27, 2018. Trials and observational studies, in which beta blockage was used to prevent severe ROP (defined as stage ≥3, or requiring treatment) were included. Meta-analyses including random effects models were conducted to determine the overall effect of oral beta blockage on prevention of ROP. RESULTS Six studies (five clinical trials and one observational study) including 461 infants met inclusion criteria using propranolol. The pooled relative risk (RR) of severe ROP in the primary and secondary prophylaxis groups were 0.65 (95% CI 0.43-0.98, NNT = 7) and 0.48 (95% CI 0.35-0.65, NNT = 6) in RCTs, respectively. The RR of severe ROP in one observational study was 0.21 (95% CI 0.08-0.55) with a NNT of 3. There were low heterogeneity and publication bias. Side effects occurred in 8.4% of participants on propranolol. CONCLUSIONS Systematic assessment of studies showed that prophylactic oral propranolol appeared to be effective in preventing severe ROP in premature infants ≤32 weeks gestational age. Additional well powered, multinational, randomized control trials reporting on long-term outcomes are needed.
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