Diabetic retinopathy (DR) is one of the most prevalent secondary complications associated with diabetes. Specifically, Type 1 Diabetes Mellitus (T1D) has an immune component that may determine the evolution of DR by compromising the immune response of the retina, which is mediated by microglia. In the early stages of DR, the permeabilization of the blood–retinal barrier allows immune cells from the peripheral system to interact with the retinal immune system. The use of new bioactive molecules, such as 3-(2,4-dihydroxyphenyl)phthalide (M9), with powerful anti-inflammatory activity, might represent an advance in the treatment of diseases like DR by targeting the immune systems responsible for its onset and progression. Our research aimed to investigate the molecular mechanisms involved in the interaction of specific cells of the innate immune system during the progression of DR and the reduction in inflammatory processes contributing to the pathology. In vitro studies were conducted exposing Bv.2 microglial and Raw264.7 macrophage cells to proinflammatory stimuli for 24 h, in the presence or absence of M9. Ex vivo and in vivo approaches were performed in BB rats, an animal model for T1D. Retinal explants from BB rats were cultured with M9. Retinas from BB rats treated for 15 days with M9 via intraperitoneal injection were analyzed to determine survival, cellular signaling, and inflammatory markers using qPCR, Western blot, or immunofluorescence approaches. Retinal structure images were acquired via Spectral-Domain–Optical Coherence Tomography (SD-OCT). Our results show that the treatment with M9 significantly reduces inflammatory processes in in vitro, ex vivo, and in vivo models of DR. M9 works by inhibiting the proinflammatory responses during DR progression mainly affecting immune cell responses. It also induces an anti-inflammatory response, primarily mediated by microglial cells, leading to the synthesis of Arginase-1 and Hemeoxygenase-1(HO-1). Ultimately, in vivo administration of M9 preserves the retinal integrity from the degeneration associated with DR progression. Our findings demonstrate a specific interaction between both retinal and systemic immune cells in the progression of DR, with a differential response to treatment, mainly driven by microglia in the anti-inflammatory action. In vivo treatment with M9 induces a switch in immune cell phenotypes and functions that contributes to delaying the DR progression, positioning microglial cells as a new and specific therapeutic target in DR.

Background/Objectives: Diabetic retinopathy is an ocular disease caused by changes in the expression of inflammatory mediators and increased oxidative stress in the retina and is the leading cause of vision loss in diabetic patients. Currently, there is no treatment capable of reversing retinal damage, which represents a significant burden on the quality of life of patients. (1R)-1-Dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin stands outs as a prototype of the sp²-iminoglycolipids family for its beneficial neuroprotective effect against this chronic eye disease. Critical issues related to the low solubility and bioavailability of this glycolipid in biological settings are overcome by its encapsulation in a Zeolitic-Imidazolate Framework (ZIF) structure, resulting in homogeneous and biocompatible GlycoZIF nanoparticles. Cell studies show an enhanced cellular uptake compared with the free glycolipid, and importantly, its bioactivity is preserved once released inside cells. Methods: Extensive in vitro and ex vivo assays with diabetic retinopathy models unveil the mechanistic pathways of the designed GlycoZIF. Results: A reduction in proinflammatory mediators, increased heme oxygenase-1 level, inhibition of NLRP3 inflammasome, and reduced reactive gliosis is shown. Conclusions: These findings demonstrate for the first time the potential of Glyco-modified ZIFs for the treatment of diabetes-related ocular problems by controlling the immune-mediated inflammatory response.

Background/Objectives: Inflammation is a critical contributor to the development of diabetic retinopathy (DR). In the early stages of DR, the compromised permeability of the blood–retina barrier facilitates the infiltration of macrophages and the activation of microglia. These specific retinal immune cells can adopt morphologies M1 or M2, linked to pro- or anti-inflammatory responses, respectively. This dual response represents a new therapeutic target against DR progression. This study aimed to investigate the modulation of the response M1/M2 and the molecular mechanism of two algal diterpenoids, rugukadiol A (RK) and ruguloptone A (RL), in the early inflammatory events associated with DR. Methods: LPS-stimulated microglial (Bv.2) and macrophage (RAW264.7) cells and an ex vivo physiological model of DR were used to analyze the effects of RK and RL on M1 and M2 inflammatory markers. Results: Compounds RK and RL, besides decreasing the expression of the M1 pro-inflammatory factors iNOS, Il6 mRNA, and NLRP3 in LPS-stimulated Bv.2 cells, caused enhancements in Arg-1 mRNA and Il10 mRNA expression consistent with the induction of an M2 anti-inflammatory response. RK promoted p38α-MAPK phosphorylation, suggesting a non-classical activation of p38α related to the induction of anti-inflammatory responses. Consistently, treatment of retinal explants of BB rats in the early stages of DR with RL decreased M1 pro-inflammatory mediators and induced M2 anti-inflammatory markers, with a reduction in gliosis and a phenotype switch from activated to resting microglia. Conclusions: This study provides the first evidence of algal diterpenoids attenuating pro-inflammatory mediators and promoting the resolution of inflammation in a diabetic retinopathy context, thus opening the way to further explore this class of marine natural products and analogs for early DR management.

Huntington’s disease (HD) is a devastating disorder caused by aberrant expansion of CAG repeats in the HTT gene. Striatal dysfunction has been widely studied in HD mouse models. However, cumulative evidence indicates that the retina can also be functionally altered with consequences for visual function and circadian rhythms. The retina is the most exposed part of the central nervous system that can be used for monitoring the health status of patients using noninvasive techniques. To establish the retina as an appropriate tissue for HD studies, we linked the retinal alterations with those in the inner brain. We confirmed the malfunction of the R6/1 retinas, which underwent a rearrangement of their transcriptome as extensive as in the striatum, indicating a profound retinal affectation in HD. Tissue-enriched genes were downregulated in both areas, but a neuroinflammation signature was specifically induced in the R6/1 retina due to glial activation that was reminiscent of the situation in HD patient’s brains. These phenomena were confirmed in the zQ175 strain, and were accompanied by a differential impairment of the autophagy system between both tissues. Overall, these results demonstrated the suitability of the mouse retina as a research model for HD.

(1R)-1-Dodecylsulfonyl-5N,6O-oxomethylidenenojirimycin is considered a prominent representative member of the sp2-iminoglycolipid (sp2-IGL) family. Numerous structure-activity relationship studies performed over the years have provided valuable information that allow the validation of the hydrophobic tail of twelve carbon atoms connected to the sulfonyl group as responsible for the immunomodulatory potential. Additionally, recent studies underpin the relevant role played by the glycone space in combination with the validated aglycone fragment to enhance the pharmacological benefits as anti-inflammatory, antiproliferative and leishmanicidal agents. Specifically, replacement of the hydroxyl group placed at C2 of the bicyclic piperidine carbamate scaffold 5N,6O-oxomethylidenenojirimycin by fluorine or hydrogen atoms, as well as the installation of monocyclic aromatic hydrocarbons at O3 position, have considerably improved the therapeutic utility of these glycolipid mimetics as multi-target agents. Building on these findings, novel structural modifications based on nitrogen-functionalities at C2 (azido, amino, acetamido and acetylhydrazino) have been implemented in this work. Biological information collected from in vitro models reveal that the epimeric compounds 8 and 14, which feature the azido group, are the most potent antiproliferative sp2-IGLs in the series. These data are consistent with the remarkable leishmanicidal potential against two species of protozoan parasites of the genus Leishmania (Leishmaniadonovani and Leishmaniamajor). Likewise, research conducted with the 2-azido-2-deoxy derivative 8 in in vitro (retinal immune cells) and ex vivo (retinal explants) diabetic retinopathy-related inflammatory models, confirm its anti-inflammatory potential by downregulating key pro-inflammatory cytokines, activating the heme oxygenase-1 and reducing reactive gliosis.