Background/Objectives: The microphthalmia-associated transcription factor (Mitf) has been found to play an important role in eye development, structure, and function. The Mitf gene is responsible for controlling cellular processes in a range of cell types, contributing to multiple eye development processes. In this review, we survey what is now known about the impact of Mitf on eye structure and function in retinal disorders. Several mutations in the human and mouse Mitf gene are now known, and the effects of these on eye phenotype are addressed. We discuss the importance of Mitf in regulating ion transport across the retinal pigment epithelium (RPE) and the vasculature of the eye. Methods: The literature was searched using the PubMed, Scopus, and Google Scholar databases. Fundus and Optical Coherence Tomography (OCT) images from mice were obtained with a Micron IV rodent imaging system. Results: Defects in neural-crest-derived melanocytes resulting from any Mitf mutations lead to hypopigmentation in the eye, coat, and inner functioning of the animals. While many Mitf mutations target RPE cells in the eye, fewer impact osteoclasts at the same time. Some of the mutations in mice lead to microphthalmia, and ultimately vision loss, while other mice show a normal eye size; however, the latter, in some cases, show hypopigmentation in the fundus and the choroid is depigmented and thickened, and in rare cases Mitf mutations lead to progressive retinal degeneration. Conclusions: The Mitf gene has an impact on the structure and function of the retina and its vasculature, the RPE, and the choroid in the adult eye.

The metabolic syndrome (MetS) is a complex disease of metabolic abnormalities, including obesity, insulin resistance, hypertension and dyslipidaemia, and it is associated with an increased risk of cardiovascular disease (CVD). Diabetic retinopathy (DR) is the leading cause of vision loss among working-aged adults around the world and is the most frequent complication in type 2 diabetic (T2D) patients. The gut microbiota are a complex ecosystem made up of more than 100 trillion of microbial cells and their composition and diversity have been identified as potential risk factors for the development of several metabolic disorders, including MetS, T2D, DR and CVD. Biomarkers are used to monitor or analyse biological processes, therapeutic responses, as well as for the early detection of pathogenic disorders. Here, we discuss molecular mechanisms underlying MetS, the effects of biological sex in MetS-related DR and gut microbiota, as well as the latest advances in biomarker research in the field. We conclude that sex may play an important role in gut microbiota influencing MetS-related DR.

Mutations in the mouse microphthalmia-associated transcription factor (Mitf) gene affect retinal pigment epithelium (RPE) differentiation and development and can lead to hypopigmentation, microphthalmia, deafness, and blindness. For instance, an association has been established between loss-of-function mutations in the mouse Mitf gene and a variety of human retinal diseases, including Waardenburg type 2 and Tietz syndromes. Although there is evidence showing that mice with the homozygous Mitf^mi mutation manifest microphthalmia and osteopetrosis, there are limited or no data on the effects of the heterozygous condition in the eye. Mitf mice can therefore be regarded as an important model system for the study of human disease. Thus, we characterized Mitf^mi/+ mice at 1, 3, 12, and 18 months old in comparison with age-matched wild-type mice. The light- and dark-adapted electroretinogram (ERG) recordings showed progressive cone-rod dystrophy in Mitf^mi/+ mice. The RPE response was reduced in the mutant in all age groups studied. Progressive loss of pigmentation was found in Mitf^mi/+ mice. Histological retinal sections revealed evidence of retinal degeneration in Mitf^mi/+ mice at older ages. For the first time, we report a mouse model of progressive cone-rod dystrophy and RPE dysfunction with a mutation in the Mitf gene.

Purpose: Mice carrying pathogenic variants in the microphthalmia transcription factor (Mitf) gene show structural and functional changes in the retina and retinal pigment epithelium. The purpose of this study was to assess the vascular changes in Mitf mice carrying pathogenic variants by determining their retinal vessel diameter.Methods: Mice examined in this study were: B6‐Mitf^mi‐vga9/+ (n = 6), B6‐Mitf^{mi‐enu22(398)} /Mitf^{mi‐enu22(398)} (n = 6) and C57BL/6J wild type mice (n = 6), all 3 months old. Fundus images were taken with a Micron IV camera after intraperitoneal injection of fluorescein salt. Images were adjusted to enhance contrast and a custom written MATLAB program used to extract the mean vascular diameter at a pre‐defined distance from the optic disc. The number of vessels, mean diameter and mean total diameter were examined.Results: The mean diameter of retinal veins in Mitf^{mi‐enu22(398)}/Mitf^{mi‐enu22(398)} mice was 18.8% larger than in wild type (p = 0.026). No differences in the mean diameter of the retinal arteries were found between the genotypes. Mitf^{mi‐enu22(398)}/Mitf^{mi‐enu22(398)} mice have 17.2% more retinal arteries (p = 0.026), and 15.6% more retinal veins (p = 0.041) than wild type. A 24.8% increase was observed in the mean combined arterial diameter in mice with the Mitf^{mi‐enu22(398)/}Mitf^{mi‐enu22(398)} compared to wild type mice (p = 0.024). A 38.6% increase was found in the mean combined venular diameter in mice with the Mitf^{mi‐enu22(398)}/Mitf^{mi‐enu22(398)} pathogenic variation as compared to wild type (p = 0.004). The mean combined retinal venular diameter in the Mitf^mi‐vga9/+ mice was 17.8% larger than in wild type (p = 0.03).Conclusion: An increase in vascularization of the retina in Mitf^{mi‐enu22(398)} /Mitf^{mi‐enu22(398)} mice was found, indicating an increased demand for blood flow to the retina.

We report the regioselective chemical derivatization of (R)-2-((4-aminophenethyl)amino)-1-phenylethan-1-ol, the primary metabolite of the β₃-Adrenergic Receptor (β₃-AR) agonist mirabegron, with prototypical Carbonic Anhydrase Inhibitors (CAIs) to afford the carbamates 10-14 and the ureido derivatives 15-18. Such compounds were endowed in vitro with distinct inhibition profiles for the human (h) Carbonic Anhydrases (CAs) and showed preferential agonisms for the β₃-AR subtype. Among them, 14 induced remarkable intraocular pressure (IOP) lowering in an in vivo transient model of ocular hypertension, with the maximal effect at 120 min post-administration at 1% w/v concentration. Furthermore, the high stability of the compounds in rabbit plasma and their ability to induce full vasodilation in isolated porcine retinal arteries suggested that the observed in vivo effects likely result from a combination of conventional aqueous humor reduction and modulation of ocular vascular tone, both of which are mediated by CAs and β-ARs. The pronounced melanosomal accumulation of representative compounds 14 and 16 highlights their potential as ideal candidates for evaluating pharmacokinetic profiles in ophthalmic applications. The results of this study provide strong evidence for the biomedical repurposing of a neglected metabolite through a novel class of dual-targeting ligands, also offering a promising strategy to help counteract the ongoing decline in drug discovery.

It has been demonstrated previously that a variety of carbonic anhydrase inhibitors (CAIs) can induce vasodilation in pre-contracted retinal arteriolar segments although with different efficacy and potency. Since the CAIs tested so far are able to permeate cell membranes and inhibit both intracellular and extracellular isoforms of the enzyme, it is not clear whether extra- or intracellular isoforms or mechanisms are mediating their vasodilatory effects. By means of small wire myography, we have tested the effects of four new CAIs on wall tension in pre-contracted retinal arteriolar segments that demonstrably do not enter cell membranes but have high affinity to both cytosolic and membrane-bound isoforms of CA. At concentrations between 10⁻⁶ M to 10⁻³ M, none of the four membrane impermeant CAIs had any significant effect on arteriolar wall tension, while the membrane permeant CAI benzolamide (10⁻³ M) fully dilated all arteriolar segments tested. This suggests that CAI act as vasodilators through cellular mechanisms located in the cytoplasm of vascular cells.