RESUMO
This article presents a groundbreaking perspective on carotenoids, focusing on their innovative applications and transformative potential in human health and medicine. Research jointly delves deeper into the bioactivity and bioavailability of carotenoids, revealing therapeutic uses and technological advances that have the potential to revolutionize medical treatments. We explore pioneering therapeutic applications in which carotenoids are used to treat chronic diseases such as cancer, cardiovascular disease, and age-related macular degeneration, offering novel protective mechanisms and innovative therapeutic benefits. Our study also shows cutting-edge technological innovations in carotenoid extraction and bioavailability, including the development of supramolecular carriers and advanced nanotechnology, which dramatically improve the absorption and efficacy of these compounds. These technological advances not only ensure consistent quality but also tailor carotenoid therapies to each patient's health needs, paving the way for personalized medicine. By integrating the latest scientific discoveries and innovative techniques, this research provides a prospective perspective on the clinical applications of carotenoids, establishing a new benchmark for future studies in this field. Our findings underscore the importance of optimizing carotenoid extraction, administration, bioactivity, and bioavailability methods to develop more effective, targeted, and personalized treatments, thus offering visionary insight into their potential in modern medical practices.
Assuntos
Disponibilidade Biológica , Carotenoides , Carotenoides/química , Carotenoides/farmacocinética , Humanos , Doenças Cardiovasculares/tratamento farmacológico , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Animais , Degeneração Macular/tratamento farmacológico , Degeneração Macular/metabolismoRESUMO
Non-exudative age-related macular degeneration (NE-AMD) is the leading blindness cause in the elderly. Clinical and experimental evidence supports that early alterations in macular retinal pigment epithelium (RPE) mitochondria play a key role in NE-AMD-induced damage. Mitochondrial dynamics (biogenesis, fusion, fission, and mitophagy), which is under the central control of AMP-activated kinase (AMPK), in turn, determines mitochondrial quality. We have developed a NE-AMD model in C57BL/6J mice induced by unilateral superior cervical ganglionectomy (SCGx), which progressively reproduces the disease hallmarks circumscribed to the temporal region of the RPE/outer retina that exhibits several characteristics of the human macula. In this work we have studied RPE mitochondrial structure, dynamics, function, and AMPK role on these parameters' regulation at the nasal and temporal RPE from control eyes and at an early stage of experimental NE-AMD (i.e., 4 weeks post-SCGx). Although RPE mitochondrial mass was preserved, their function, which was higher at the temporal than at the nasal RPE in control eyes, was significantly decreased at 4 weeks post-SCGx at the same region. Mitochondria were bigger, more elongated, and with denser cristae at the temporal RPE from control eyes. Exclusively at the temporal RPE, SCGx severely affected mitochondrial morphology and dynamics, together with the levels of phosphorylated AMPK (p-AMPK). AMPK activation with metformin restored RPE p-AMPK levels, and mitochondrial dynamics, structure, and function at 4 weeks post-SCGx, as well as visual function and RPE/outer retina structure at 10 weeks post-SCGx. These results demonstrate a key role of the temporal RPE mitochondrial homeostasis as an early target for NE-AMD-induced damage, and that pharmacological AMPK activation could preserve mitochondrial morphology, dynamics, and function, and, consequently, avoid the functional and structural damage induced by NE-AMD.
Assuntos
Proteínas Quinases Ativadas por AMP , Modelos Animais de Doenças , Degeneração Macular , Camundongos Endogâmicos C57BL , Mitocôndrias , Dinâmica Mitocondrial , Epitélio Pigmentado da Retina , Animais , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Camundongos , Degeneração Macular/patologia , Degeneração Macular/metabolismo , Epitélio Pigmentado da Retina/metabolismo , Epitélio Pigmentado da Retina/patologia , Proteínas Quinases Ativadas por AMP/metabolismo , Humanos , Metformina/farmacologiaRESUMO
Purpose: The carotenoids lutein (L), zeaxanthin (Z), and meso-zeaxanthin deposit at the macula as macular pigment (MP) and provide visual benefits and protection against macular diseases. The present study investigated MP, its nutritional and environmental determinants, and its constituent carotenoids in serum from a Mexican sample, in healthy participants and with metabolic diseases. Additionally, we compared these variables with an Irish sample. Methods: MP was measured in 215 subjects from a rural community in Mexico with dual-wavelength autofluorescence imaging reported as MP optical volume (MPOV). Dietary intake and serum concentrations of L and Z were evaluated. Results: The mean MPOV was 8429 (95% confidence interval, 8060-8797); range. 1171-15,976. The mean L and Z serum concentrations were 0.25 ± 0.15 µmol/L and 0.09 ± 0.04 µmol/L, respectively. The MPOV was positively correlated with L and Z serum concentrations (r = 0.347; P < 0.001 and r = 0.311; P < 0.001, respectively), but not with L + Z dietary estimates. Subjects with daily sunlight exposure of more than 50% were found to have significantly higher MPOV than those with less than 50% (P = 0.005). MPOV and serum concentrations of L and Z were significantly higher in the Mexican sample compared with the Irish sample, but this difference was not reflected in dietary analysis. Conclusions: These new data from a Mexican sample provide evidence of the multifactorial interactions and environmental determinants of MP such as sunlight exposure and dietary patterns. These findings will be essential for future studies in Mexico for eye health, visual function, and ocular pathology.
Assuntos
Carotenoides/metabolismo , Exposição Ambiental , Degeneração Macular/epidemiologia , Pigmento Macular/metabolismo , População Rural , Visão Ocular , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Suplementos Nutricionais , Humanos , Degeneração Macular/diagnóstico , Degeneração Macular/etiologia , Degeneração Macular/metabolismo , México , Pessoa de Meia-Idade , Adulto JovemRESUMO
The prevalence of age-related macular degeneration (AMD) has increased in the last years. Although anti-VEGF agents have improved the prognosis of exudative AMD, dry AMD has still devastating effects on elderly people vision. Oxidative stress and inflammation are mechanisms involved in AMD pathogenesis and its progression. Molecular pathways involving epidermal growth factor receptor (EGFR), bone morphogenetic protein (BMP4) and the nuclear erythroid related factor 2 (Nrf2) are behind oxidative stress in AMD due to their participation in antioxidant cellular pathways. As a consequence of the disbalance produced in the antioxidant mechanisms, there is an activation of innate and adaptative immune response with cell recruitment, changes in complement factors expression, and modification of cellular milieu. Different therapies are being studied to treat dry AMD based on the possible effects on antioxidant molecular pathways or their action on the immune response. There is a wide range of treatments presented in this review, from natural antioxidant compounds to cell and gene therapy, based on their mechanisms. Finally, we hypothesize that alpha-1-antitrypsin (AAT), an anti-inflammatory and immunomodulatory molecule that can also modulate antioxidant cellular defenses, could be a good candidate for testing in AMD. This article is part of the special ssue on 'The Quest for Disease-Modifying Therapies for Neurodegenerative Disorders'.
Assuntos
Degeneração Macular/fisiopatologia , Degeneração Macular/terapia , Estresse Oxidativo , Envelhecimento , Animais , Antioxidantes , Humanos , Degeneração Macular/imunologia , Degeneração Macular/metabolismoRESUMO
ABSTRACT Age-related macular degeneration is the most important cause of irreversible vision loss in the elderly and has been considered a severe public health problem. Current treatments have only been successful in delaying the loss of central vision. Due to increased life expectancy, governments and researchers have been challenged to seek more efficient and successful treatments for age-related macular degeneration. Considering its relevance for public health and the need of further research, this article aims to address age-related macular degeneration objectively, tackling on the current knowledge about its pathophysiology, potential molecular biomarkers, main prevention procedures and treatments, as well as introducing possible molecules that may be a therapeutic target in this disease.
RESUMO Degeneração macular relacionada à idade é a causa mais importante de perda irreversível da visão em idosos, e é considerada um sério problema de saúde pública. Os tratamentos atuais são bem-sucedidos apenas ao postergar a perda da visão central. Devido à maior expectativa de vida, os governos e pesquisadores têm dificuldade de encontrar tratamentos mais eficientes e exitosos para degeneração macular relacionada à idade. Considerando sua relevância para saúde pública e a necessidade de mais pesquisas, este artigo procura abordar a degeneração macular relacionada à idade de forma objetiva, abordando os conhecimentos atuais sobre sua fisiopatologia, potenciais biomarcadores moleculares, principais procedimentos de prevenção e tratamentos, e apresentar possíveis moléculas que podem ser alvo terapêutico nessa doença.
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Humanos , Degeneração Macular/fisiopatologia , Degeneração Macular/metabolismo , Degeneração Macular/prevenção & controle , Degeneração Macular/terapia , Biomarcadores/metabolismoRESUMO
Non-exudative age-related macular degeneration (NE-AMD) represents the leading cause of blindness in the elderly. The macular retinal pigment epithelium (RPE) lies in a high oxidative environment because its high metabolic demand, mitochondria concentration, reactive oxygen species levels, and macular blood flow. It has been suggested that oxidative stress-induced damage to the RPE plays a key role in NE-AMD pathogenesis. The fact that the disease limits to the macular region raises the question as to why this area is particularly susceptible. We have developed a NE-AMD model induced by superior cervical ganglionectomy (SCGx) in C57BL/6J mice, which reproduces the disease hallmarks exclusively circumscribed to the temporal region of the RPE/outer retina. The aim of this work was analyzing RPE regional differences that could explain AMD localized susceptibility. Lower melanin content, thicker basal infoldings, higher mitochondrial mass, and higher levels of antioxidant enzymes, were found in the temporal RPE compared with the nasal region. Moreover, SCGx induced a decrease in the antioxidant system, and in mitochondria mass, as well as an increase in mitochondria superoxide, lipid peroxidation products, nuclear Nrf2 and heme oxygenase-1 levels, and in the occurrence of damaged mitochondria exclusively at the temporal RPE. These findings suggest that despite the well-known differences between the human and mouse retina, it might not be NE-AMD pathophysiology which conditions the localization of the disease, but the macular RPE histologic and metabolic specific attributes that make it more susceptible to choroid alterations leading initially to a localized RPE dysfunction/damage, and secondarily to macular degeneration.
Assuntos
Degeneração Macular/fisiopatologia , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Epitélio Pigmentado da Retina/fisiopatologia , Animais , Modelos Animais de Doenças , Ganglionectomia/métodos , Expressão Gênica , Heme Oxigenase-1/genética , Heme Oxigenase-1/metabolismo , Humanos , Peroxidação de Lipídeos , Degeneração Macular/etiologia , Degeneração Macular/genética , Degeneração Macular/metabolismo , Masculino , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/patologia , Fator 2 Relacionado a NF-E2/genética , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo , Epitélio Pigmentado da Retina/inervação , Epitélio Pigmentado da Retina/metabolismo , Gânglio Cervical Superior/lesões , Gânglio Cervical Superior/cirurgia , Fatores de TempoRESUMO
Age-related macular disease (AMD) and diabetic retinopathy (DR) are prevalent diseases. Vascular endothelial growth factor (VEGF) related retinal neovascularization is a common feature in both. Consequently, both pathologies are treated with anti-VEGF therapy. We have previously reported a lower incidence of AMD in patients with DR compared to controls. The present study hypothesizes that DR in stages in which the concentration of intravitreal VEGF is increased, might have a protective role for both the onset and development of AMD.
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Neovascularização de Coroide , Retinopatia Diabética/metabolismo , Degeneração Macular/metabolismo , Oxigênio/metabolismo , Neovascularização Retiniana , Fator A de Crescimento do Endotélio Vascular/metabolismo , Idoso , Inibidores da Angiogênese/uso terapêutico , Retinopatia Diabética/complicações , Humanos , Degeneração Macular/complicações , Pessoa de Meia-Idade , Modelos Teóricos , Neovascularização Patológica , Epitélio Pigmentado da Retina/metabolismo , Degeneração Macular Exsudativa/complicações , Degeneração Macular Exsudativa/metabolismoRESUMO
Purpose: The mutation R345W in EFEMP1 (fibulin-3) causes macular degeneration. This study sought to determine whether proteoglycan content and diffusion across Bruch's membrane are altered in Efemp1ki/ki mice carrying this mutation or in Efemp1-/- mice. Methods: Proteoglycans in mouse Bruch's membranes were stained with Cupromeronic Blue (CB). Heparan sulfated proteoglycan (HSPG) and chondroitin/dermatan sulfate proteoglycan (C/DSPG) distributions were visualized following treatments with chondroitinase ABC (C-ABC) or nitrous acid. Total sulfated glycosaminoglycans (sGAGs) in Bruch's membrane/choroid (BrM/Ch) were measured with dimethylmethylene blue (DMMB). Matrix metalloprotease (MMP)-2, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-3 were examined by immunofluorescence and quantified using Image J. Molecules with different Stokes radius (Rs) were allowed simultaneously to diffuse through mouse BrM/Ch mounted in a modified Ussing chamber. Samples were quantified using gel exclusion chromatography. Results: HSPGs and C/DSPGs were markedly increased in Efemp1ki/ki Bruch's membrane, and MMP-2 and MMP-9 were decreased, but TIMP-3 was increased. Diffusion across Efemp1ki/ki Bruch's membrane was impaired. In contrast, the proteoglycan amount in Efemp1-/- Bruch's membrane was not significantly different, but the size of proteoglycans was much larger. MMP-2, MMP-3, and TIMP-3 levels were similar to that of Efemp1+/+ mice, but they were localized diffusely in retinal pigment epithelium (RPE) cells instead of Bruch's membrane. Diffusion across Efemp1-/- Bruch's membrane was enhanced. Conclusions: Mutant fibulin-3 causes proteoglycan accumulation, reduction of MMP-2 and MMP-9, but increase of TIMP-3, and impairs diffusion across Bruch's membrane. Fibulin-3 ablation results in altered sizes of proteoglycans, altered distributions of MMP-2, MMP-9, and TIMP-3, and enhances diffusion across Bruch's membrane.
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Lâmina Basilar da Corioide/metabolismo , DNA/genética , Proteínas da Matriz Extracelular/genética , Degeneração Macular/genética , Mutação , Proteoglicanas/metabolismo , Envelhecimento/genética , Animais , Lâmina Basilar da Corioide/patologia , Análise Mutacional de DNA , Modelos Animais de Doenças , Proteínas da Matriz Extracelular/metabolismo , Degeneração Macular/diagnóstico , Degeneração Macular/metabolismo , Camundongos , Camundongos MutantesRESUMO
PURPOSE: Retinal photocoagulation and nondamaging laser therapy are used for treatment of macular disorders, without understanding of the response mechanism and with no rationale for dosimetry. To establish a proper titration algorithm, we measured the range of tissue response and damage threshold. We then evaluated safety and efficacy of nondamaging retinal therapy (NRT) based on this algorithm for chronic central serous chorioretinopathy (CSCR) and macular telangiectasia (MacTel). METHODS: Retinal response to laser treatment below damage threshold was assessed in pigmented rabbits by expression of the heat shock protein HSP70 and glial fibrillary acidic protein (GFAP). Energy was adjusted relative to visible titration using the Endpoint Management (EpM) algorithm. In clinical studies, 21 eyes with CSCR and 10 eyes with MacTel were treated at 30% EpM energy with high spot density (0.25-diameter spacing). Visual acuity, retinal and choroidal thickness, and subretinal fluid were monitored for 1 year. RESULTS: At 25% EpM energy and higher, HSP70 was expressed acutely in RPE, and GFAP upregulation in Müller cells was observed at 1 month. Damage appeared starting at 40% setting. Subretinal fluid resolved completely in 81% and partially in 19% of the CSCR patients, and visual acuity improved by 12 ± 3 letters. Lacunae in the majority of MacTel patients decreased while preserving the retinal thickness, and vision improved by 10 letters. CONCLUSIONS: Heat shock protein expression in response to hyperthermia helps define the therapeutic window for NRT. Lack of tissue damage enables high-density treatment to boost clinical efficacy, therapy in the fovea, and retreatments to manage chronic diseases.
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Terapia a Laser/métodos , Macula Lutea/cirurgia , Degeneração Macular/cirurgia , Acuidade Visual , Animais , Modelos Animais de Doenças , Análise de Elementos Finitos , Angiofluoresceinografia , Seguimentos , Fundo de Olho , Proteínas de Choque Térmico HSP72/biossíntese , Humanos , Imuno-Histoquímica , Macula Lutea/metabolismo , Macula Lutea/patologia , Degeneração Macular/diagnóstico , Degeneração Macular/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Coelhos , Fatores de Tempo , Tomografia de Coerência Óptica , Resultado do TratamentoRESUMO
Oxidative stress has a critical role in the pathogenesis of Age-related Macular Degeneration (AMD), a multifactorial disease that includes age, gene variants of complement regulatory proteins and smoking as the main risk factors. Stress-induced premature cellular senescence (SIPS) is postulated to contribute to this condition. In this study, we hypothesized that oxidative damage, promoted by endogenous or exogenous sources, could elicit a senescence response in RPE cells, which would in turn dysregulate the expression of major players in AMD pathogenic mechanisms. We showed that exposure of a human RPE cell line (ARPE-19) to a cigarette smoke concentrate (CSC), not only enhanced Reactive Oxygen Species (ROS) levels, but also induced 8-Hydroxydeoxyguanosine-immunoreactive (8-OHdG) DNA lesions and phosphorylated-Histone 2AX-immunoreactive (p-H2AX) nuclear foci. CSC-nuclear damage was followed by premature senescence as shown by positive senescence associated-ß-galactosidase (SA-ß-Gal) staining, and p16(INK4a) and p21(Waf-Cip1) protein upregulation. N-acetylcysteine (NAC) treatment, a ROS scavenger, decreased senescence markers, thus supporting the role of oxidative damage in CSC-induced senescence activation. ARPE-19 senescent cultures were also established by exposure to hydrogen peroxide (H2O2), which is an endogenous stress source produced in the retina under photo-oxidation conditions. Senescent cells upregulated the proinflammatory cytokines IL-6 and IL-8, the main markers of the senescence-associated secretory phenotype (SASP). Most important, we show for the first time that senescent ARPE-19 cells upregulated vascular endothelial growth factor (VEGF) and simultaneously downregulated complement factor H (CFH) expression. Since both phenomena are involved in AMD pathogenesis, our results support the hypothesis that SIPS could be a principal player in the induction and progression of AMD. Moreover, they would also explain the striking association of this disease with cigarette smoking.