scholarly journals Why Is Zeaxanthin the Most Concentrated Xanthophyll in the Central Fovea?

Nutrients ◽  
2020 ◽  
Vol 12 (5) ◽  
pp. 1333
Author(s):  
Justyna Widomska ◽  
John Paul SanGiovanni ◽  
Witold K. Subczynski
Keyword(s):  
Cell Function ◽  
Fold Increase ◽  
Redox Balance ◽  
Biochemical Properties ◽  
Age Related Macular Degeneration ◽  
Molar Ratio ◽  
Retinal Eccentricity ◽  
Age Related ◽  
High Concentrations ◽  
Central Fovea

Diet-based xanthophylls (zeaxanthin and lutein) are conditionally essential polar carotenoids preferentially accreted in high concentrations (1 mM) to the central retina, where they have the capacity to impart unique physiologically significant biophysical biochemical properties implicated in cell function, rescue, and survival. Macular xanthophylls interact with membrane-bound proteins and lipids to absorb/attenuate light energy, modulate oxidative stress and redox balance, and influence signal transduction cascades implicated in the pathophysiology of age-related macular degeneration. There is exclusive transport, sequestration, and appreciable bioamplification of macular xanthophylls from the circulating carotenoid pool to the retina and within the retina to regions required for high-resolution sensory processing. The distribution of diet-based macular xanthophylls and the lutein metabolite meso-zeaxanthin varies considerably by retinal eccentricity. Zeaxanthin concentrations are 2.5-fold higher than lutein in the cone-dense central fovea. This is an ~20-fold increase in the molar ratio relative to eccentric retinal regions with biochemically detectable macular xanthophylls. In this review, we discuss how the differences in the specific properties of lutein and zeaxanthin could help explain the preferential accumulation of zeaxanthin in the most vulnerable region of the macula.

scholarly journals Systemic exposure following intravitreal administration of therapeutic agents: an integrated pharmacokinetic approach. 2. THR-687

2021 ◽  
Author(s):  
Marc Vanhove ◽  
Jean-Marc Wagner ◽  
Bernard Noppen ◽  
Bart Jonckx ◽  
Elke Vermassen ◽  
...  
Keyword(s):  
General Circulation ◽  
Pharmacokinetic Model ◽  
Systemic Exposure ◽  
Age Related Macular Degeneration ◽  
Whole Body ◽  
Pharmacological Agents ◽  
Age Related ◽  
Pharmacokinetic Properties ◽  
High Concentrations ◽  
Systemic Compartment

AbstractIntravitreal (IVT) injection remains the preferred administration route of pharmacological agents intended for the treatment of back of the eye diseases such as diabetic macular edema (DME) and neovascular age-related macular degeneration (nvAMD). The procedure enables drugs to be delivered locally at high concentrations whilst limiting whole body exposure and associated risk of systemic adverse events. Nevertheless, intravitreally-delivered drugs do enter the general circulation and achieving an accurate understanding of systemic exposure is pivotal for the evaluation and development of drugs administered in the eye. We report here the full pharmacokinetic properties of THR-687, a pan RGD integrin antagonist currently in clinical development for the treatment of DME, in both rabbit and minipig. Pharmacokinetic characterization included description of vitreal elimination, of systemic pharmacokinetics, and of systemic exposure following IVT administration. For the latter, we present a novel pharmacokinetic model that assumes clear partition between the vitreous humor compartment itself where the drug is administered and the central systemic compartment. We also propose an analytical solution to the system of differential equations that represent the pharmacokinetic model, thereby allowing data analysis with standard nonlinear regression analysis. The model accurately describes circulating levels of THR-687 following IVT administration in relevant animal models, and we suggest that this approach is relevant to a range of drugs and analysis of subsequent systemic exposure.

scholarly journals Development of an ultra-sensitive human IL-33 biomarker assay for age-related macular degeneration and asthma drug development

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Elaine Mai ◽  
Joyce Chan ◽  
Levina Goon ◽  
Braeden K. Ego ◽  
Jack Bevers ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Inflammatory Diseases ◽  
Interleukin 1 ◽  
Age Related Macular Degeneration ◽  
Reduced Form ◽  
Enzyme Linked Immunosorbent Assay ◽  
Interleukin 33 ◽  
Age Related ◽  
Significant Difference ◽  
High Concentrations

Abstract Background Over the past decade, human Interleukin 33 (hIL-33) has emerged as a key contributor to the pathogenesis of numerous inflammatory diseases. Despite the existence of several commercial hIL-33 assays spanning multiple platform technologies, their ability to provide accurate hIL-33 concentration measurements and to differentiate between active (reduced) and inactive (oxidized) hIL-33 in various matrices remains uncertain. This is especially true for lower sample volumes, matrices with low hIL-33 concentrations, and matrices with elevated levels of soluble Interleukin 1 Receptor-Like 1 (sST2), an inactive form of ST2 that competes with membrane bound ST2 for hIL-33 binding. Results We tested the performance of several commercially available hIL-33 detection assays in various human matrices and found that most of these assays lacked the sensitivity to accurately detect reduced hIL-33 at biologically relevant levels (sub-to-low pg/mL), especially in the presence of human sST2 (hsST2), and/or lacked sufficient target specificity. To address this, we developed and validated a sensitive and specific enzyme-linked immunosorbent assay (ELISA) capable of detecting reduced and total hIL-33 levels even in the presence of high concentrations of sST2. By incorporating the immuno-polymerase chain reaction (iPCR) platform, we further increased the sensitivity of this assay for the reduced form of hIL-33 by ~ 52-fold. Using this hIL-33 iPCR assay, we detected hIL-33 in postmortem human vitreous humor (VH) samples from donors with age-related macular degeneration (AMD) and found significantly increased hIL-33 levels when compared to control individuals. No statistically significant difference was observed in aqueous humor (AH) from AMD donors nor in plasma and nasosorption fluid (NF) from asthma patients compared to control individuals. Conclusions Unlike existing commercial hIL-33 assays, our hIL-33 bioassays are highly sensitive and specific and can accurately quantify hIL-33 in various human clinical matrices, including those with high levels of hsST2. Our results provide a proof of concept of the utility of these assays in clinical trials targeting the hIL-33/hST2 pathway.

TIMP3 mutation in Sorsby's fundus dystrophy: molecular insights

2005 ◽  
Vol 7 (24) ◽  
pp. 1-15 ◽  
Author(s):  
Zheng Li ◽  
Michael P. Clarke ◽  
Michael D. Barker ◽  
Norman McKie
Keyword(s):  
Peripheral Vision ◽  
Genetic Model ◽  
Single Gene ◽  
The Elderly ◽  
Developed Countries ◽  
Biochemical Properties ◽  
Age Related Macular Degeneration ◽  
Autosomal Dominant Disorder ◽  
Age Related ◽  
Sorsby's Fundus Dystrophy

Sorsby's fundus dystrophy (SFD) is a rare autosomal dominant disorder that results in degeneration of the macular region of the retina, with onset usually in the fourth to fifth decade of life. It leads to the rapid loss of central vision, often followed by further loss of peripheral vision. SFD shares several pathological features commonly found in the ‘wet’ or exudative form of age-related macular degeneration (AMD), the most common cause of blindness in the elderly in developed countries. These phenotypic similarities have led to SFD being proposed as an acceptable genetic model for AMD. Whereas AMD appears to have a complex aetiology, with both genetic and environmental factors playing a role, SFD has been shown to be a single-gene disorder, linked to mutations in exon 5 of the tissue inhibitor of metalloproteinases 3 (TIMP3) gene on chromosome 22q12-q13. This review confines itself to a discussion of the known biochemical properties of the wild-type and SFD TIMP3 proteins and attempts to relate these to the pathology encountered in SFD patients. We also discuss briefly how, despite the lack of inherited mutations in the structural gene, the TIMP3 protein might play a role in the onset and progression of AMD.

scholarly journals Oxidative stress-mediated TXNIP loss causes RPE dysfunction

2019 ◽  
Vol 51 (10) ◽  
pp. 1-13 ◽  
Author(s):  
Min Ji Cho ◽  
Sung-Jin Yoon ◽  
Wooil Kim ◽  
Jongjin Park ◽  
Jangwook Lee ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Function ◽  
Pigment Epithelium ◽  
Retinal Pigment ◽  
Common Factor ◽  
Age Related Macular Degeneration ◽  
Autophagic Flux ◽  
Blood Retinal Barrier ◽  
Rpe Cells ◽  
Age Related

Abstract The disruption of the retinal pigment epithelium (RPE), for example, through oxidative damage, is a common factor underlying age-related macular degeneration (AMD). Aberrant autophagy also contributes to AMD pathology, as autophagy maintains RPE homeostasis to ensure blood–retinal barrier (BRB) integrity and protect photoreceptors. Thioredoxin-interacting protein (TXNIP) promotes cellular oxidative stress by inhibiting thioredoxin reducing capacity and is in turn inversely regulated by reactive oxygen species levels; however, its role in oxidative stress-induced RPE cell dysfunction and the mechanistic link between TXNIP and autophagy are largely unknown. Here, we observed that TXNIP expression was rapidly downregulated in RPE cells under oxidative stress and that RPE cell proliferation was decreased. TXNIP knockdown demonstrated that the suppression of proliferation resulted from TXNIP depletion-induced autophagic flux, causing increased p53 activation via nuclear localization, which in turn enhanced AMPK phosphorylation and activation. Moreover, TXNIP downregulation further negatively impacted BRB integrity by disrupting RPE cell tight junctions and enhancing cell motility by phosphorylating, and thereby activating, Src kinase. Finally, we also revealed that TXNIP knockdown upregulated HIF-1α, leading to the enhanced secretion of VEGF from RPE cells and the stimulation of angiogenesis in cocultured human retinal microvascular endothelial cells. This suggests that the exposure of RPE cells to sustained oxidative stress may promote choroidal neovascularization, another AMD pathology. Together, these findings reveal three distinct mechanisms by which TXNIP downregulation disrupts RPE cell function and thereby exacerbates AMD pathogenesis. Accordingly, reinforcing or restoring BRB integrity by targeting TXNIP may serve as an effective therapeutic strategy for preventing or attenuating photoreceptor damage in AMD.

Multimodal Physiological Medicine and Macular Degeneration

2010 ◽  
Vol 04 (01) ◽  
pp. 101
Author(s):  
George W Rozakis ◽  
Sergey A Dzugan ◽  
◽  
Keyword(s):  
Stem Cell ◽  
Macular Degeneration ◽  
Retinal Pigment Epithelial ◽  
Cell Function ◽  
Retinal Pigment Epithelial Cell ◽  
Retinal Pigment ◽  
Age Related Macular Degeneration ◽  
Pigment Epithelial ◽  
Age Related ◽  
Steroidal Hormones

Multimodal physiological medicine is the art of restoring physiology to youthful levels for the purpose of preventing and treating age-related diseases. Age-related macular degeneration (AMD) is presented as a disease that is caused by multiple errors of physiology including deficiencies of the steroidal hormones dehydroepiandrosterone (DHEA), pregnenolone, oestriol, oestradiol, oestrone, testosterone and progesterone as well as deficiencies in melatonin, zinc and other nutrients. It is proposed that multiple steroidal deficiency results in a compensatory attempt to synthesise hormones from cholesterol in the macula and that this conversion is dysfunctional in AMD, resulting in cholesterol-laden drusen. Furthermore, it is suggested that physiological errors indirectly lead to retinal pigment epithelial cell failure due to a decline in stem cell function. It is suggested that macular degeneration can be safely and more efficaciously treated with combinations of hormones, nutrients and vitamins and that such treatment strikes at the underlying cause(s) of the disease and may reduce associated cardiovascular risk.

scholarly journals Statistical optimization of culture medium composition for enhanced zeaxanthin production by Cyanophycean microalgae Trichodesmium thiebautii (NIOT 152)

2020 ◽  
Vol 13 (41) ◽  
pp. 4307-4318
Author(s):  
Priyanka Srinivasan ◽  
Keyword(s):  
Response Surface Methodology ◽  
Response Surface ◽  
Sea Water ◽  
Fold Increase ◽  
Medium Composition ◽  
Statistical Optimization ◽  
Age Related Macular Degeneration ◽  
Medium Components ◽  
Age Related ◽  
Trichodesmium Thiebautii

Background/Objectives: Zeaxanthin is a xanthophyll carotenoid revered for its role in the prevention of age related macular degeneration. The study evaluated the zeaxanthin accumulation of the marine Cyanophycean alga Trichodesmium thiebautii (NIOT 152). A sequential statistical technique was applied to optimize the Artificial Sea Water nutrient medium (ASN-III) components for enhancing the zeaxanthin accumulation in T. thiebautii. Methods: A two-level statistical approach involving Plackett-Burman (PB) design to screen the most important nutrients influencing the zeaxanthin accumulation followed by Response surface methodology (RSM) was employed. The results of PB design revealed sodium nitrate, disodium EDTA, magnesium sulphate and sodium carbonate as the crucial medium components for increasing zeaxanthin accumulation. Further, RSM was employed to study the interaction between these factors and identified an optimum concentration of the ingredients for higher zeaxanthin production. Findings: The optimized medium components resulted in 2.33 fold increase in zeaxanthin accumulation (4.3 ± 1.29 mg L-1) as compared to ASN III medium (1.84 ± 0.12 mg L-1). Novelty: There are only few studies on laboratory cultured Trichodesmium and only very few reports are available regarding pigment production from Trichodesmium sp. The present study successfully demonstrated the statistical optimization of ASN III medium to improve zeaxanthin accumulation by Trichodesmium thiebautii. Keywords: ASN III medium; zeaxanthin; Trichodesmium thiebautii; Plackett-Burman; response surface methodology REFERENCE

Consecutive case series of 244 age-related macular degeneration patients undergoing implantation with an extended macular vision IOL

2017 ◽  
Vol 28 (2) ◽  
pp. 198-203 ◽  
Author(s):  
Muhammad A. Qureshi ◽  
Scott J. Robbie ◽  
Fritz H. Hengerer ◽  
Gerd U. Auffarth ◽  
Ina Conrad-Hengerer ◽  
...  
Keyword(s):  
Visual Acuity ◽  
Macular Degeneration ◽  
Perioperative Complications ◽  
Case Series ◽  
Age Related Macular Degeneration ◽  
Retinal Eccentricity ◽  
Consecutive Case ◽  
Refractive Outcomes ◽  
Age Related ◽  
Corrected Distance Visual Acuity

Purpose: To determine safety and visual outcomes in eyes with age-related macular degeneration (AMD) implanted with a novel intraocular lens (IOL) that delivers an optimized retinal image to all macular areas within 10 degrees of retinal eccentricity. Methods: This was a consecutive case series of 244 eyes with dry/stable wet AMD and logMAR visual acuity ≥0.3 implanted with iolAMD Eyemax monoTM (London Eye Hospital Pharma), a single-piece, injectable, hydrophobic acrylic IOL sited in the capsular bag. Primary outcome was safety. Secondary outcomes were changes in corrected distance visual acuity (CDVA) and corrected near visual acuity (CNVA) (logMAR). Results: Mean age at surgery was 80 years. Mean duration of follow-up was 3 months (range 1-16 months). No eyes had worsening of CDVA. Frequency of perioperative complications was equivalent to standard IOL implantation. Postoperative refractive outcomes were within ±1 D of the target refraction in 88% of cases. Mean preoperative CDVA improved from 1.06 to 0.71 postoperatively (mean of differences -0.35; 95% confidence interval [CI] -0.3886 to -0.3223; p<0.0001), equating to an approximate Early Treatment Diabetic Retinopathy Study gain of 18 letters. Mean preoperative CNVA (N-point; logMAR conversion) improved from 1.36 to 0.88 postoperatively (mean of differences -0.48; 95% CI -0.53 to -0.44; p<0.0001). Conclusions: This novel IOL appears safe in the short to medium term. Improvements in postoperative CDVA and CNVA exceed those observed with standard implants.

Studies of a benzoporphyrin derivative with Pluronics

2002 ◽  
Vol 80 (10) ◽  
pp. 1321-1326 ◽  
Author(s):  
N Hioka ◽  
R K Chowdhary ◽  
N Chansarkar ◽  
D Delmarre ◽  
E Sternberg ◽  
...  
Keyword(s):  
Ethylene Oxide ◽  
Self Assembly ◽  
Kinetic Studies ◽  
Age Related Macular Degeneration ◽  
Molar Ratio ◽  
Ionic Surfactant ◽  
Age Related ◽  
Triblock Polymer ◽  
Poly Ethylene Oxide ◽  
Poly Ethylene

The synthetic route for the benzoporphyrin derivatives produces two regioisomers in equimolar quantities (ring A and B isomers). A derivative of the A-ring product, BPD-MA (benzoporphyrin-derivative monoacid ring A, verteporfin), has recently been approved in North America and Europe for the treatment of age-related macular degeneration. The B-ring isomers, contrary to the A-ring isomers, exhibit high aggregation in many formulations, which results in inadequate drug delivery for clinical uses. To avoid aggregation, a non-ionic surfactant polymer such as a Pluronic — poly(ethylene oxide)-poly(propylene oxide)-poly(ethylene oxide) — may be used as a formulation excipient. The triblock polymer investigated here is designated P123 (or poloxamer 403). When used to formulate a monoacid benzoporphyrin B-ring derivative (2), a critical micelle concentration of P123 in water occurred at approximately 0.015 to 0.03%. The apparent pKa of compound 2 was dependent on its concentration in P123, and decreased as the molar ratio (P123:2) increased. High concentrations of P123 and neutral pH were found to be the best conditions to maintain the drug in its monomeric form. Kinetic studies suggest that the aggregate of 2 contains several molecules, and is formed by a catalyzed self-assembly process. Samples with 1 mg mL–1 of drug, at pH = 7.4, and 4.8% of Pluronic showed satisfactory capacity to load and keep monomers stable. This formulation has potential PDT applications.Key words: Pluronic, poloxamers, block copolymers, photosensitizing drug, photodynamic therapy (PDT), formulation, micelles.

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