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Age-related macular degeneration (AMD) leads to gradual central vision loss and is the third leading cause of irreversible blindness worldwide. The underlying mechanisms for this progressive neurodegenerative disease remain unclear and there is currently no preventive treatment for dry AMD. Sodium iodate (NaIO3) has been reported to induce AMD-like retinal pathology in mice. We established a mouse model for AMD to evaluate the effects of quercetin on NaIO3-induced retinal apoptosis, and to investigate the pertinent underlying mechanisms. Our in vitro results indicated that quercetin protected human retinal pigment epithelium (ARPE-19) cells from NaIO3-induced apoptosis by inhibiting reactive oxygen species production and loss of mitochondrial membrane potential as detected by Annexin V-FITC/PI flow cytometry. We also evaluated the relative expression of proteins in the apoptosis pathway. Quercetin downregulated the protein expressions of Bax, cleaved caspase-3, and cleaved PARP and upregulated the expression of Bcl-2 through reduced PI3K and pAKT expressions. Furthermore, our in vivo results indicated that quercetin improved retinal deformation and increased the thickness of both the outer nuclear layer and inner nuclear layer, whereas the expression of caspase-3 was inhibited. Taken together, these results demonstrate that quercetin could protect retinal pigment epithelium and the retina from NaIO3-induced cell apoptosis via reactive oxygen species-mediated mitochondrial dysfunction, involving the PI3K/AKT signaling pathway. This suggests that quercetin has the potential to prevent and delay AMD and other retinal diseases involving NaIO3-mediated apoptosis.

The management of vision-threatening retinal diseases remains challenging due to the lack of an effective drug delivery system. Encapsulated cell therapy (ECT) offers a promising approach for the continuous delivery of therapeutic agents without the need for immunosuppressants. In this context, an injectable and terminable collagen–alginate composite (CAC) ECT gel, designed with a Tet-on pro-caspase-8 system, was developed as a safe intraocular drug delivery platform for the sustained release of glial-cell-line-derived neurotrophic factor (GDNF) to treat retinal degenerative diseases. This study examined the potential clinical application of the CAC ECT gel, focusing on its safety, performance, and termination through doxycycline (Dox) administration in the eyes of healthy New Zealand White rabbits, as well as its therapeutic efficacy in rabbits with sodium-iodate (SI)-induced retinal degeneration. The findings indicated that the CAC ECT gel can be safely implanted without harming the retina or lens, displaying resistance to degradation, facilitating cell attachment, and secreting bioactive GDNF. Furthermore, the GDNF levels could be modulated by the number of implants. Moreover, Dox administration was effective in terminating gel function without causing retinal damage. Notably, rabbits with retinal degeneration treated with the gels exhibited significant functional recovery in both a-wave and b-wave amplitudes and showed remarkable efficacy in reducing photoreceptor apoptosis. Given its biocompatibility, mechanical stability, controlled drug release, terminability, and therapeutic effectiveness, our CAC ECT gel presents a promising therapeutic strategy for various retinal diseases in a clinical setting, eliminating the need for immunosuppressants.

Age-related macular degeneration (AMD), one of the leading causes of blindness worldwide, causes personal suffering and high socioeconomic costs. While there has been progress in the treatments for the neovascular form of AMD, no therapy is yet available for the more common dry form, also known as geographic atrophy. We analysed the retinal tissue in a mouse model of retinal degeneration caused by sodium iodate (NaIO3)-induced retinal pigment epithelium (RPE) atrophy to understand the underlying pathology. RNA sequencing (RNA-seq), qRT-PCR, Western blot, immunohistochemistry of the retinas and multiplex ELISA of the mouse serum were applied to find the pathways involved in the degeneration. NaIO3 caused patchy RPE loss and thinning of the photoreceptor layer. This was accompanied by the increased retinal expression of complement components c1s, c3, c4, cfb and cfh. C1s, C3, CFH and CFB were complement proteins, with enhanced deposition at day 3. C4 was upregulated in retinal degeneration at day 10. Consistently, the transcript levels of proinflammatory ccl-2, -3, -5, il-1β, il-33 and tgf-β were increased in the retinas of NaIO3 mice, but vegf-a mRNA was reduced. Macrophages, microglia and gliotic Müller cells could be a cellular source for local retinal inflammatory changes in the NaIO3 retina. Systemic complement and cytokines/chemokines remained unaltered in this model of NaIO3-dependent retinal degeneration. In conclusion, systemically administered NaIO3 promotes degenerative and inflammatory processes in the retina, which can mimic the hallmarks of geographic atrophy.

Field data from an iodine-rich, coastal environment point to the molecular steps involved in the formation of new aerosol particles from iodine vapours over coastal regions. Aerosol particle formation in coastal regions Sulfuric acid and organic vapours are thought to be involved in the formation of new aerosol particles in the atmosphere over continental regions, whereas iodine oxide vapours have been implicated in particle formation in coastal regions. But direct molecular-level observations of nucleation under atmospheric field conditions are lacking. Mikko Sipilä et al . report field data from Mace Head, Ireland, and supporting data from northern Greenland and Queen Maud Land, Antarctica, that allow for the identification of the molecular steps involved in new particle formation from iodine vapours in an iodine-rich, coastal atmospheric environment. Initial particle formation occurs primarily by uptake and sequential addition of iodic acid, followed by restructuring of molecules in clusters and subsequent evaporation of water. Homogeneous nucleation and subsequent cluster growth leads to the formation of new aerosol particles in the atmosphere 1 . The nucleation of sulfuric acid and organic vapours is thought to be responsible for the formation of new particles over continents 1 , 2 , whereas iodine oxide vapours have been implicated in particle formation over coastal regions 3 , 4 , 5 , 6 , 7 . The molecular clustering pathways that are involved in atmospheric particle formation have been elucidated in controlled laboratory studies of chemically simple systems 2 , 8 , 9 , 10 , but direct molecular-level observations of nucleation in atmospheric field conditions that involve sulfuric acid, organic or iodine oxide vapours have yet to be reported 11 . Here we present field data from Mace Head, Ireland, and supporting data from northern Greenland and Queen Maud Land, Antarctica, that enable us to identify the molecular steps involved in new particle formation in an iodine-rich, coastal atmospheric environment. We find that the formation and initial growth process is almost exclusively driven by iodine oxoacids and iodine oxide vapours, with average oxygen-to-iodine ratios of 2.4 found in the clusters. On the basis of this high ratio, together with the high concentrations of iodic acid (HIO 3 ) observed, we suggest that cluster formation primarily proceeds by sequential addition of HIO 3 , followed by intracluster restructuring to I 2 O 5 and recycling of water either in the atmosphere or on dehydration. Our study provides ambient atmospheric molecular-level observations of nucleation, supporting the previously suggested role of iodine-containing species in the formation of new aerosol particles 3 , 4 , 5 , 6 , 7 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , and identifies the key nucleating compound.

The Notch and transforming growth factor-β (TGFβ) signaling pathways are two intracellular mechanisms that control fibrosis in general but whether they play a major role in retinal fibrosis is less clear. Here we study how these two signaling pathways regulate Müller cell-dominated retinal fibrosis and . Human MIO-M1 Müller cells were treated with Notch ligands and TGFβ1, either alone or in combination. Western blots were performed to study changes in γ-secretase proteases, Notch downstream effectors, endogenous TGFβ1, phosphorylated Smad3 (p-Smad3) and extracellular matrix (ECM) proteins. We also studied the effects of RO4929097, a selective γ-secretase inhibitor, on expression of ECM proteins after ligand stimulation. Müller cell viability was studied by AlamarBlue and cytotoxicity by lactate cytotoxicity assays. Finally, we studied changes in Notch and TGFβ signaling and tested the effect of intravitreal injections of the Notch pathway inhibitor RO4929097 on retinal fibrosis resulted from Sodium iodate (NaIO )-induced retinal injury in mice. We also studied the safety of intravitreal injections of RO4929097 in normal mice. Treatment of Müller cells with Notch ligands upregulated γ-secretase proteases and Notch downstream effectors, with increased expression of endogenous TGFβ1, TGFβ receptors and p-Smad3. TGFβ1 upregulated the expression of proteins associated with both signaling pathways in a similar manner. Notch ligands and TGFβ1 had additive effects on overexpression of ECM proteins in Müller cells which were inhibited by RO4929097. Notch and TGFβ ligands stimulated Müller cell proliferation which was inhibited by RO4929097 without damaging the cells. NaIO -induced retinal injury activated both Notch and TGFβ signaling pathways . Intravitreal injection of RO4929097 prevented Müller cell gliosis and inhibited overexpression of ECM proteins in this murine model. We found no safety concerns for up to 17 days after an intravitreal injection of RO4929097. Inhibiting Notch signaling might be an effective way to prevent retinal fibrosis. This study is of clinical significance in developing a treatment for preventing fibrosis in proliferative vitreoretinopathy, proliferative diabetic retinopathy and wet age-related macular degeneration.

Aim Iodine (I) deficiency is distinct from other micronutrient deficiencies in human populations in having a high endemic prevalence both in well-developed and in developing countries. The very low concentration of iodine in agricultural soils and cereal-based foods is widely believed to be the main reason of iodine deficiency in humans, especially in developing countries. In the present study, the possibility of using iodine containing fertilizers for agronomic biofortification of cereal grains with iodine was studied. The aim was to establish the best application method (to the soil or as foliar spray), the best form of iodine (potassium iodate or potassium iodide) and the optimal dose of iodine. Additionally, experiments were conducted to study transport of iodine in plants and localization of iodine within the grains. Materials and methods Experiments were conducted both under greenhouse conditions and in the field on wheat ( Triticum aestivum ) grown in Turkey and Pakistan, on rice ( Oryza sativa ) grown in Brazil, Thailand and Turkey and on maize ( Zea mays ) grown in Turkey. The iodine concentration in the grain, localization of iodine in different grain fractions of wheat (i.e., endosperm, bran and embryo) and iodine concentration of both brown rice and polished rice was analyzed. In short-term experiments, the translocation of iodine from older into younger leaves was also studied. Inductively coupled plasma mass spectrometry (ICP-MS) was used for analysis of iodine in plant and soil samples. Results In greenhouse experiments on wheat, soil-applied potassium iodide (KI) and potassium iodate (KIO 3 ) at increasing rates (i.e., 0, 0.1, 0.25, 1, 2.5, 5, 10 and 20 mg I kg −1 soil) both iodine forms substantially increased iodine concentration in the shoot, with the highest shoot iodine resulting from the KI treatments. However, these soil treatments did not affect iodine concentrations in the wheat grain, with the exception of the highest iodine rates (i. e., 10 and 20 mg I kg −1 soil) which also depressed the grain yield. In contrast to the soil applications, foliar spray of KI and KIO 3 at increasing rates during heading and early milk stages did enhance grain iodine concentrations up to 5- to 10-fold without affecting grain yield. Including KNO 3 or a surfactant to the iodine containing foliar spray further increased the grain iodine concentration. In a short-term experiment using young wheat plants, it was found that iodine is translocated from older into younger leaves after immersion of the older leaves in solutions containing KI or KIO 3 . Adding KNO 3 or a surfactant in the immersion solution also promoted leaf absorption and translocation of iodine into younger leaves. Field experiments conducted in different countries confirmed that foliar application with increasing rates of iodine significantly increased grain iodine concentrations in wheat, brown rice and maize. This increase was also found in the iodine concentration of the endosperm part of wheat grains and in polished rice. Conclusions The results of the present study clearly show that foliar application of iodine containing fertilizers is highly effective in increasing grain iodine concentrations in wheat, rice and maize. Presented results suggest that iodine is translocated from shoot to grain by transport in the phloem. Spraying KIO 3 up to the rate of 0.05% w / v is suggested as the optimal form and rate to be used in agronomic biofortification with iodine. The substantial increase in grain iodine concentrations could contribute to the prevention of iodine deficiency in human populations with low dietary iodine intake. The reasons behind the higher effectiveness of foliar-applications compared to the soil applications of iodine fertilizers in improving grain iodine concentration are discussed.

Iodine is a reactive trace element in atmospheric chemistry that destroys ozone and nucleates particles. Iodine emissions have tripled since 1950 and are projected to keep increasing with rising O3 surface concentrations. Although iodic acid (HIO3) is widespread and forms particles more efficiently than sulfuric acid, its gas-phase formation mechanism remains unresolved. Here, in CLOUD atmospheric simulation chamber experiments that generate iodine radicals at atmospherically relevant rates, we show that iodooxy hypoiodite, IOIO, is efficiently converted into HIO3 via reactions (R1) IOIO + O3 → IOIO4 and (R2) IOIO4 + H2O → HIO3 + HOI + (1)O2. The laboratory-derived reaction rate coefficients are corroborated by theory and shown to explain field observations of daytime HIO3 in the remote lower free troposphere. The mechanism provides a missing link between iodine sources and particle formation. Because particulate iodate is readily reduced, recycling iodine back into the gas phase, our results suggest a catalytic role of iodine in aerosol formation.Iodic acid (HIO3) forms aerosols very efficiently, but its gas-phase formation mechanism is not well understood. Atmospheric simulation chamber experiments, quantum chemical calculations and kinetic modelling have now revealed that HIO3 forms as an early iodine oxidation product from hypoiodite. The mechanism explains field measurements and suggests a catalytic role for iodine in particle formation.

Adsorption–desorption of iodine in two forms, viz., iodide (I−) and iodate (IO 3 − ), in three types of soil were investigated. The soils were: red soil developed on Quaternary red earths (REQ)— clayey, kaolintic thermic plinthite Aquult, Inceptisol soil (IS) and alluvial soil (AS)—Fluvio-marine yellow loamy soil. The isothermal curves of iodine adsorption on soils were described by Langmuir and Freundlich equation, and the maximum adsorption values (y m) were obtained from the simple Langmuir model. As compared with the iodide, the iodate was adsorbed in higher amounts by the soils tested. Among three soils, the REQ soil adsorbed more iodine (I− and IO 3 − ) than the IS and AS. The distribution coefficient (K d) of iodine in the soils decreased exponentially with increasing iodine loading concentration. Desorption of iodine in soil was increased correspondingly with increasing adsorption values. The REQ soil had a greater affinity for iodine than the IS and AS at the same iodine loadings. In the pot experiment cultivated with pakchoi (Brassica chinensis L.) and added with two exogenous iodine sources, the iodide form was quickly taken up by pakchoi and caused more toxicity to the vegetable. The rate of iodine loss from soil was higher for iodide form as compared with the iodate. The iodine bioavailability was the highest but the persistence was the weakest in AS among the three soils tested, and the REQ soil showed just the opposite trend to that of the AS soil. This study is of theoretical importance to understand the relationship between iodine adsorption–desorption characteristics and their bioavailability in different soils and it also has practical implications for seeking effective alternatives of iodine biofortification to prevent iodine deficiency disorders.

Background Age-related macular degeneration (AMD) is the leading cause of blindness in elderly people in the developed world, and the number of people affected is expected to almost double by 2040. The retina presents one of the highest metabolic demands in our bodies that is partially or fully fulfilled by mitochondria in the neuroretina and retinal pigment epithelium (RPE), respectively. Together with its post-mitotic status and constant photooxidative damage from incoming light, the retina requires a tightly-regulated housekeeping system that involves autophagy. The natural polyphenol Urolithin A (UA) has shown neuroprotective benefits in several models of aging and age-associated disorders, mostly attributed to its ability to induce mitophagy and mitochondrial biogenesis. Sodium iodate (SI) administration recapitulates the late stages of AMD, including geographic atrophy and photoreceptor cell death. Methods A combination of in vitro, ex vivo and in vivo models were used to test the neuroprotective potential of UA in the SI model. Functional assays (OCT, ERGs), cellular analysis (flow cytometry, qPCR) and fine confocal microscopy (immunohistochemistry, tandem selective autophagy reporters) helped address this question. Results UA alleviated neurodegeneration and preserved visual function in SI-treated mice. Simultaneously, we observed severe proteostasis defects upon SI damage induction, including autophagosome accumulation, that were resolved in animals that received UA. Treatment with UA restored autophagic flux and triggered PINK1/Parkin-dependent mitophagy, as previously reported in the literature. Autophagy blockage caused by SI was caused by severe lysosomal membrane permeabilization. While UA did not induce lysosomal biogenesis, it did restore upcycling of permeabilized lysosomes through lysophagy. Knockdown of the lysophagy adaptor SQSTM1/p62 abrogated viability rescue by UA in SI-treated cells, exacerbated lysosomal defects and inhibited lysophagy. Conclusions Collectively, these data highlight a novel putative application of UA in the treatment of AMD whereby it bypasses lysosomal defects by promoting p62-dependent lysophagy to sustain proteostasis. Graphical Abstract

Age-related macular degeneration (AMD) is a global health challenge. AMD causes visual impairment and blindness, particularly in older individuals. This multifaceted disease progresses through various stages, from asymptomatic dry to advanced wet AMD, driven by various factors including inflammation and oxidative stress. Current treatments are effective mainly for wet AMD; the therapeutic options for dry AMD are limited. Photobiomodulation (PBM) using low-energy light in the red-to-near-infrared range is a promising treatment for retinal diseases. This study investigated the effects of multi-wavelength PBM (680, 780, and 830 nm) on sodium iodate-induced oxidatively damaged retinal tissue. In an in vivo rat model of AMD induced by sodium iodate, multi-wavelength PBM effectively protected the retinal layers, reduced retinal apoptosis, and prevented rod bipolar cell depletion. Furthermore, PBM inhibited photoreceptor degeneration and reduced retinal pigment epithelium toxicity. These results suggest that multi-wavelength PBM may be a useful therapeutic strategy for AMD, mitigating oxidative stress, preserving retinal integrity, and preventing apoptosis.