Revistas
Revista:
BIOMEDICINES
ISSN 2227-9059
Vol. 10
N° 4
Año 2022
Págs.746
It is without doubt that the gene therapy field is currently in the spotlight for the development of new therapeutics targeting unmet medical needs. Thus, considering the gene therapy scenario, neurological diseases in general and neurodegenerative disorders in particular are emerging as the most appealing choices for new therapeutic arrivals intended to slow down, stop, or even revert the natural progressive course that characterizes most of these devastating neurodegenerative processes. Since an extensive coverage of all available literature is not feasible in practical terms, here emphasis was made in providing some advice to beginners in the field with a narrow focus on elucidating the best delivery route available for fulfilling any given AAV-based therapeutic approach. Furthermore, it is worth nothing that the number of ongoing clinical trials is increasing at a breathtaking speed. Accordingly, a landscape view of preclinical and clinical initiatives is also provided here in an attempt to best illustrate what is ongoing in this quickly expanding field.
Revista:
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
ISSN 1422-0067
Vol. 22
N° 12
Año 2021
Págs.6389
It is without any doubt that precision medicine therapeutic strategies targeting neurodegenerative disorders are currently witnessing the spectacular rise of newly designed approaches based on the use of viral vectors as Trojan horses for the controlled release of a given genetic payload. Among the different types of viral vectors, adeno-associated viruses (AAVs) rank as the ones most commonly used for the purposes of either disease modeling or for therapeutic strategies. Here, we reviewed the current literature dealing with the use of AAVs within the field of Parkinson's disease with the aim to provide neuroscientists with the advice and background required when facing a choice on which AAV might be best suited for addressing a given experimental challenge. Accordingly, here we will be summarizing some insights on different AAV serotypes, and which would be the most appropriate AAV delivery route. Next, the use of AAVs for modeling synucleinopathies is highlighted, providing potential readers with a landscape view of ongoing pre-clinical and clinical initiatives pushing forward AAV-based therapeutic approaches for Parkinson's disease and related synucleinopathies.
Revista:
ANTIOXIDANTS
ISSN 2076-3921
Vol. 10
N° 8
Año 2021
Págs.1311
Blood-Brain barrier (BBB) disruption is a hallmark of central nervous system (CNS) dysfunction, and oxidative stress is one of the molecular mechanisms that may underlie this process. NADPH oxidases (NOX) are involved in oxidative stress-mediated vascular dysfunction and participate in the pathophysiology of its target organs. The NADPH oxidase 5 (NOX5) isoform is absent in rodents, and although little is known about the role it may play in disrupting the BBB, it has recently been implicated in experimental stroke. Our aim was to investigate the role of NADPH oxidase 5 (NOX5) in promoting vascular alterations and to identify its impact on the cognitive status of aged mice. No differences were detected in the arterial blood pressure or body weight between knock-in mice expressing endothelial NOX5 and the control mice. The Morris water maze test showed memory impairments in the aged knock-in mice expressing NOX5 compared with their control littermates. For assessing the BBB integrity, we studied the protein expression of two tight junction (TJ) proteins: Zonula occludens-1 (ZO-1) and occludin. Compared to the control animals, Aged NOX5 mice exhibited reduced levels of both proteins, demonstrating an alteration of the BBB integrity. Our data indicate that vascular NOX5 may favor behavioral changes with aging through oxidative stress-mediated BBB breakdown.
Revista:
ANTIOXIDANTS
ISSN 2076-3921
Vol. 10
N° 2
Año 2021
Págs.194
Oxidative stress constitutes a key molecular mechanism in the development of cardiovascular diseases. A potential relationship between reactive oxygen species (ROS) driven by the NADPH oxidase family (NOX) and the unfolded protein response (UPR) has been postulated. Nevertheless, there is a lack of information about the crosstalk between NOX5 homologue and the UPR in a cardiovascular context. The main aim was to analyze NOX5-mediated ROS effects in the UPR and its importance in cardiovascular diseases. To this effect, we used an adenoviral NOX5-beta overexpression model in human aortic endothelial cells (HAEC) and a conditional endothelial NOX5 knock-in mouse. Using expression arrays, we investigated NOX5-induced genomic changes in HAEC. Compared with the control HAEC, 298 genes were differentially expressed. Gene ontology analysis revealed the activation of numerous cellular routes, the most relevant being the UPR pathway. Using real-time PCR and Western Blot experiments, we confirmed that NOX5 overexpression induced changes in the expression of the UPR components, which were associated with increased apoptosis. Moreover, in endothelial-specific NOX5 knock-in mice, we found changes in the expression of the UPR components genes. In these mice, myocardial infarction was performed by permanent coronary artery ligation; however, NOX5 expression was not associated with differences in the UPR components mRNA levels. In these animals, we found significant associations between the U
Revista:
INTERNATIONAL JOURNAL OF BIOCHEMISTRY AND CELL BIOLOGY
ISSN 1357-2725
Vol. 128
Año 2020
Págs.105851
Oxidative stress is one of the main mechanisms involved in the pathophysiology of vascular diseases. Among others, oxidative stress promotes endothelial dysfunction, and accelerated ageing and remodelling of vasculature. Lately, NADPH oxidases have been demonstrated to be involved in cardiovascular diseases. NADPH oxidase 5 has emerged as a new player in oxidative stress-mediated endothelial alterations, involved in the pathophysiology of hypertension, diabetes, atherosclerosis, myocardial infarction and stroke. This oxidase seems to mediate its detrimental effects by promoting inflammation. NADPH oxidase 5 has been studied in a lesser extent compared with the other members of the NADPH oxidase family due to its loss in the rodent genome, the main experimental research model. In addition, its potential as a therapeutic target remains unexplored given the lack of specific inhibitors. In this review the latest findings on NADPH oxidase 5 regulation, implications in vascular pathophysiology and therapeutic approaches will be updated.Oxidative stress is one of the main mechanisms involved in the pathophysiology of vascular diseases. Among others, oxidative stress promotes endothelial dysfunction, and accelerated ageing and remodelling of vasculature. Lately, NADPH oxidases have been demonstrated to be involved in cardiovascular diseases. NADPH oxidase 5 has emerged as a new player in oxidative stress-mediated endothelial alterations, involved in the pathophysiology of hypertension, diabetes, atherosclerosis, myocardial infarction and stroke. This oxidase seems to mediate its detrimental effects by promoting inflammation. NADPH oxidase 5 has been studied in a lesser extent compared with the other members of the NADPH oxidase family due to its loss in the rodent genome, the main experimental research model. In addition, its potential as a therapeutic target remains unexplored given the lack of specific inhibitors. In this review the latest findings on NADPH oxidase 5 regulation, implications in vascular pathophysiology and therapeutic approaches will be updated.
Revista:
CELLS
ISSN 2073-4409
Vol. 9
N° 3
Año 2020
Págs.637
Oxidative stress is a main molecular mechanism that underlies cardiovascular diseases. A close relationship between reactive oxygen species (ROS) derived from NADPH oxidase (NOX) activity and the prostaglandin (PG) biosynthesis pathway has been described. However, little information is available about the interaction between NOX5 homolog-derived ROS and the PG pathway in the cardiovascular context. Our main goal was to characterize NOX5-derived ROS effects in PG homeostasis and their potential relevance in cardiovascular pathologies. For that purpose, two experimental systems were employed: an adenoviral NOX5-beta overexpression model in immortalized human aortic endothelial cells (TeloHAEC) and a chronic infarction in vivo model developed from a conditional endothelial NOX5 knock-in mouse. NOX5 increased cyclooxygenase-2 isoform (COX-2) expression and prostaglandin E-2 (PGE(2)) production through nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) in TeloHAEC. Protein kinase C (PKC) activation and intracellular calcium level (Ca++) mobilization increased ROS production and NOX5 overexpression, which promoted a COX-2/PGE(2) response in vitro. In the chronic infarction model, mice encoding endothelial NOX5 enhanced the cardiac mRNA expression of COX-2 and PGES, suggesting a COX-2/PGE(2) response to NOX5 presence in an ischemic situation. Our data support that NOX5-derived ROS may modulate the COX-2/PGE(2) axis in endothelial cells, which might play a relevant role in the pathophysiology of heart infarction.
Revista:
FREE RADICAL BIOLOGY AND MEDICINE
ISSN 0891-5849
Vol. 139
N° S1
Año 2019
Págs.S17 - S17
Revista:
FREE RADICAL BIOLOGY AND MEDICINE
ISSN 0891-5849
Vol. 120
N° Supl. 1
Año 2018
Págs.S101 - S101
Revista:
NATURE MEDICINE
ISSN 1078-8956
Vol. 24
N° 12
Año 2018
Págs.1899 - 1909
Acute intermittent porphyria (AIP) results from haploinsufficiency of porphobilinogen deaminase (PBGD), the third enzyme in the heme biosynthesis pathway. Patients with AIP have neurovisceral attacks associated with increased hepatic heme demand. Phenobarbital-challenged mice with AIP recapitulate the biochemical and clinical characteristics of patients with AIP, including hepatic overproduction of the potentially neurotoxic porphyrin precursors. Here we show that intravenous administration of human PBGD (hPBGD) mRNA (encoded by the gene HMBS) encapsulated in lipid nanoparticles induces dose-dependent protein expression in mouse hepatocytes, rapidly normalizing urine porphyrin precursor excretion in ongoing attacks. Furthermore, hPBGD mRNA protected against mitochondrial dysfunction, hypertension, pain and motor impairment. Repeat dosing in AIP mice showed sustained efficacy and therapeutic improvement without evidence of hepatotoxicity. Finally, multiple administrations to nonhuman primates confirmed safety and translatability. These data provide proof-of-concept for systemic hPBGD mRNA as a potential therapy for AIP.
Revista:
FREE RADICAL RESEARCH
ISSN 1071-5762
Vol. 51
N° 4
Año 2017
Págs.389 - 396
Vascular calcification is a common feature in atherosclerosis and associates with cardiovascular events. Oxidative stress may be involved in the pathogenesis of vascular calcification. Previous studies have shown that the phagocytic NADPH oxidase is associated with atherosclerosis. The objective of the present study was to investigate the association between phagocytic NADPH oxidase-mediated superoxide production and coronary artery calcium (CAC). NADPH oxidase-mediated superoxide production was determined by chemiluminescence and CAC by computed tomography in 159 asymptomatic men free of overt clinical atherosclerosis. Multivariate linear regression analyses were used to assess the relationship between CAC and NADPH oxidase-mediated superoxide production. Compared with individuals in the lowest score of CAC (= 0 Agatston units), those in the upper score (> 400 Agatston units) showed higher superoxide production (p < 0.05). In correlation analysis, superoxide production positively (p < 0.01) correlated with CAC, which in multivariate analysis remained significant after adjusting for age, HDL-cholesterol, triglycerides, body mass index, smoking, arterial hypertension and diabetes mellitus. In conclusion, in a population of men without clinically overt atherosclerotic disease, increased NADPH oxidase-mediated superoxide production associated with enhanced CAC. Albeit descriptive, these findings suggest a potential involvement of phagocytic NADPH oxidase-mediated oxidative stress in CAC.
Capítulos de libros
Libro:
Telomeres, diet and human disease: advances and therapeutic opportunities
Lugar de Edición: Boca Ratón (Florida)
Editorial: CRC Press Taylor and Francis Group
Año 2018
Págs.39 - 54
Libro:
Obesity: oxidative stress and dietary antioxidants
Lugar de Edición: Londres
Editorial: Academic Press
Año 2018
Págs.93 - 110
Oxidative stress, a pathological situation created by an imbalance between reactive oxygen species production and antioxidant capacity, is a critical mechanism that underlies the pathophysiology of cardiovascular diseases and is involved in obesity, metabolic syndrome, and diabetes. The nicotinamide adenine dinucleotide phosphate (NADPH) oxidase enzyme family is the main source of reactive oxygen species and its expression and activity is enhanced and plays a critical role in the onset and/or development of cardiovascular diseases. The phagocytic NADPH oxidase, a member of the NADPH oxidase family present in lymphocytes, monocytes, and neutrophils, has been implicated in the pathophysiology of these vascular and metabolic disorders, by promoting detrimental prooxidant processes that could increase the morbidity and mortality in these diseases. A present challenge consists of the development of novel NADPH oxidase-selective drugs that could prevent and/or treat cardiovascular and metabolic diseases.