[This corrects the article DOI: 10.3389/fphar.2022.1038730.].

Thyroid hormone (TH) signaling is involved in complex processes regulating development and energy balance, especially in organs with high-rate metabolism such as the retina. Despite evidence of TH involvement in regulation of retinal functions and disease susceptibility, a comprehensive analysis of the tissue distribution of the components of the retinal TH regulatory system is lacking. The aims of the present study were (i) to provide a detailed description of the retinal expression sites and localization patterns of deiodinases (DIO2 and DIO3), TH receptors (THRα and THRβ), and TH transporters (monocarboxylate transporter 8, MCT8, and organic anion-transporting polypeptide 1C1, OATP1C1); (ii) to recapitulate the retinal alterations following genetic deletions of specific TH regulatory elements in specific knockout (KO) mice. We first predicted the cell-specific expression of TH regulatory elements in mouse and human retina via bioinformatic analysis of single-cell RNAseq databases. The results were subsequently validated in mouse retinas with RNAscope and protein localization was assessed with immunofluorescence. Cone photoreceptor morphology and retinal layer thicknesses were evaluated in the retinas of KO mice. Dio2 mRNA was expressed by Müller glial cells and neuronal populations of the inner retina, while prominent DIO2 immunoreactivity was in cone photoreceptors, with an evident mismatch between mRNA and protein localization. DIO3 was expressed by virtually all neural cell populations of the retina. THRα and THRβ were predominantly localized to the inner and outer retina, respectively, with prominent expression of THRα in putative amacrine cells and ganglion cells, and of THRβ in cone photoreceptors. Both MCT8 and OATP1C1 were detected in the retinal pigment epithelium, in Müller glia, and in blood vessels. MCT8 was also expressed in some retinal ganglion cells. In KO mice, drastic alterations were observed in cone density and morphology and in retinal layer thickness following either Dio2 or Dio3 genetic deletion. In contrast, deletion of Thrs or TH transporters resulted in only minor changes, indicating potential compensatory mechanisms. The present mapping of the TH regulatory system in the mouse retina provides a framework for understanding molecular and cellular mechanisms regulating local TH availability and signaling in health and disease.

Introduction: Diabetic retinopathy (DR) is characterized by early retinal neurodegeneration accompanied by progressive alterations of the retinal microvasculature, both exacerbated by hyperglycemia-induced oxidative stress and inflammation. Mitochondrial dysfunction critically contributes to neuronal loss and vascular impairment. The 18 kDa Translocator Protein (TSPO) is a mitochondrial outer membrane protein whose expression is increased in activated retinal glial cells and represents a promising target to modulate neuroinflammation and oxidative stress. This study evaluates the therapeutic potential of the TSPO ligand PIGA-1138 in experimental models of DR. Methods: PIGA-1138 (3 µM in vitro; 10 mg/kg/day, i.p., in vivo) was evaluated in high glucose (HG)-exposed 661W retinal cells and in streptozotocin (STZ, 150 mg/kg)-induced diabetic C57BL/6J mice. Cell viability, mitochondrial function, oxidative stress, and Nrf2, HO-1, and SOD1 expression were assessed in vitro. Retinal function and morphology were evaluated in vivo by electroretinography (ERG), visual acuity testing, and optical coherence tomography (OCT) at 30 and 60 days after diabetes induction. Results: PIGA-1138 significantly improved cell viability, reducing apoptosis (TUNEL p ≤ 0.01), preserving mitochondrial membrane potential (MitoRed p ≤ 0.01), reducing oxidative damage, and enhancing Nrf2 nuclear translocation together with HO-1 (p ≤ 0.05) and SOD1 (p ≤ 0.01) expression in HG-treated retinal cells. In diabetic mice, treatment preserved ERG responses and limited retinal thinning at 60 days (p ≤ 0.01), while showing a trend toward preserving visual acuity. Conclusions: Targeting mitochondrial TSPO with PIGA-1138 attenuates key hallmarks of DR by mitigating oxidative stress, suppressing neuroinflammation, and preserving retinal structure and function. These findings support TSPO as a potential disease-modifying target for DR.

[This corrects the article DOI: 10.3389/fphar.2021.719951.].

Inflammatory Bowel Disease (IBD) is a chronic condition characterized by persistent mucosal inflammation driven by complex interactions among the gut microbiome, host immune genetics, and cellular metabolism. Emerging evidence highlights the central role of the Th17/Treg cell balance in maintaining intestinal immune tolerance, which is tightly regulated by microbe-derived metabolites and host metabolic pathways. In IBD, microbial dysbiosis and altered metabolite profiles disrupt this equilibrium, favoring pro-inflammatory responses. Moreover, genetic variants affecting immune regulation modulate individual susceptibility and disease course. Understanding how microbiome modulation, metabolic reprogramming, and genetic predisposition converge in IBD pathogenesis opens new avenues for precision medicine. This minireview discusses recent advances in this field, emphasizing novel microbiome-targeted strategies, metabolic interventions, and personalized immunomodulatory therapies aimed at restoring Th17/Treg homeostasis. Integrating microbiome, metabolome, and immunogenetic profiling may ultimately guide tailored treatments and improve long-term outcomes in IBD.

The journal retracts the article titled "Fatty acids dietary supplement exerts anti-inflammatory action and limits ganglion cell degeneration in the retina of the EAE mouse model of multiple sclerosis" [...].

The β-adrenoceptor (β-AR) system has been implicated in the pathological angiogenesis of the retina. Of the three β-ARs, the role of β3-AR remains to be elucidated. In a mouse model of oxygen-induced retinopathy (OIR), we investigated the role of β3-ARs using the 129S inbred mouse strain, which is highly responsive to hypoxia because of its marked imbalance between pro- and anti-angiogenic factors. We found that β3-AR activation with BRL37344 and CL316243, both potent, first-generation β3-AR agonists promotes the revascularization of the central retina in association with the restored astrocyte template. Recovered vascularization of the central retina prevents the onset of hypoxia thus impeding the activation of the pro-angiogenic pathway and inhibiting neovessel overgrowth in the mid periphery, blood-retinal barrier leakage and retinal dysfunction. Vessel rescue and recovered astrocyte density were found to be associated with protective effects against the OIR-related loss of retinal ganglion cells (RGCs) as also demonstrated by their recovered functional activity. RGC rescue occurs in connection with restored availability of neurotrophic factors that are otherwise impaired under hypoxia. Results from microdissected astrocytes were indicative of the possibility that astrocytes might contribute to retinal rescue. β3-AR has emerged as a potential intermediary in hypoxia-dependent neovascularization, thereby providing a rationale for exploring the causality between astrocyte recovery and retinal rescue with the aim of underlining the therapeutic potential of β3-AR agonists in proliferative retinopathies.

BACKGROUND/OBJECTIVES:Very long-chain acyl-CoA dehydrogenase deficiency (VLCADD) is an autosomal recessive disorder of mitochondrial fatty acid β-oxidation caused by pathogenic variants in ACADVL. The clinical spectrum is highly heterogeneous, ranging from lethal neonatal cardiomyopathy to late-onset myopathy. This study aims to characterize the rare c.215C>T (p.Ser72Phe) variant, identified in compound heterozygosity with the common pathogenic allele c.848T>C (p.Val283Ala) in a male neonate detected by newborn screening (NBS). METHODS:Genetic analysis was performed using Sanger sequencing on the proband and his family members. The pathogenicity of the p.Ser72Phe variant was evaluated through multiple bioinformatic predictors and interpreted according to ACMG/AMP guidelines. To understand the functional impact on the protein, structural modeling was conducted using FoldX 4.0 for energy calculations and UCSF ChimeraX for the visualization of conformational changes and cofactor-binding site perturbations in the VLCAD homodimer. RESULTS:At the end of the first postnatal week, liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis of dried blood spots of the proband revealed a markedly abnormal acylcarnitine profile, with C14:1 levels (1.837 μmol/L) approximately five times above the reference range. Clinical reports documented hypoketotic hypoglycemia, consistent with VLCADD. Segregation analysis demonstrated transmission of both variants within the family, with additional heterozygous and homozygous carriers identified. Bioinformatic predictions uniformly classified p.Ser72Phe as deleterious. This variant has an extremely low allele frequency and affects a highly conserved residue in the FAD-binding domain. Structural modeling with FoldX yielded a mean ΔΔG of +22.63 ± 5.48 kcal/mol, indicating a significant localized thermodynamic burden. Inspection of the mutant model in ChimeraX showed perturbation of the side-chain orientation and attenuation of the local hydrogen-bonding network at the FAD-binding site, together with increased steric packing around residue 72. Taken together, the clinical, genetic, and structural evidence support reclassification of p. Ser72Phe as likely pathogenic according to ACMG criteria, specifically applying the ClinGen ACADVL VCEP specifications. CONCLUSIONS:This study expands the ACADVL mutational spectrum and underscores the value of integrating sequencing, segregation, and structural bioinformatics in interpreting rare variants detected through NBS.

In the original publication [...].

The journal retracts the article titled, “A Dietary Combination of Forskolin with Homotaurine, Spearmint and B Vitamins Protects Injured Retinal Ganglion Cells in a Rodent Model of Hypertensive Glaucoma” [...]

[This corrects the article DOI: 10.3389/fbioe.2020.00144.].

PURPOSE. Alzheimer's disease (AD) induces changes in retinal structure/function, making the retina a suitable platform to study the molecular mechanisms of the disease. Dysregulation of some microRNAs (miRNAs) has also been found in AD pathogenesis. Here, we used the 5xFAD mouse to expand our knowledge on structural, functional, and molecular retinal alterations and to elucidate the retinal miRNA profile in this model of AD. METHODS. The 5xFAD mice at 3, 6, or 9 months of age, were used. Retinal function was evaluated with electroretinogram (ERG) and the Prusky water maze test. Retinal structure was investigated by optical coherence tomography. Molecular analyses included immunohistochemistry, Western blot, and ELISA. Retinal miRNAs were profiled and deregulated miRNAs were validated by qRT-PCR. RESULTS. Starting from 6 months, the 5xFAD mice showed altered ERG and visual acuity. The inner plexiform layer became thicker whereas the retinal ganglion cell (RGC) layer became thinner. In the RGC layer, the accumulation of amyloid beta was concomitant with RGC apoptosis, whereas tau protein phosphorylation was increased. Inflammatory processes were also activated and microgliosis became apparent. Five deregulated miRNAs were identified, four of which were validated. Two of these miRNAs were related to AD and involved in gene expression relevant to retinal function. CONCLUSIONS. The present findings confirm and expand our knowledge of the retinal disease in 5xFAD mice, and highlight that neuroinflammation, oxidative stress, and microgliosis participate in AD pathogenesis. The relationship between deregulated miRNAs and AD progression may open the field to miRNA-based strategies to slow down retinal dysfunction in AD.

Diabetic retinopathy (DR) is a leading cause of blindness characterized by early neurovascular damage driven by hyperglycemia-induced mechanisms, including inflammation. The system composed of the urokinase-type plasminogen activator (uPA) and its receptor (uPAR) has previously emerged as a potential regulator of the pro-inflammatory events in DR, possibly through the interaction of uPAR with its lateral partners, such as formyl peptide receptors (FPRs). This study explored whether the inhibition of uPAR/FPR1 crosstalk may reduce early neurovascular alterations in DR by targeting inflammation. To this aim, the new FPR1 antagonist N-19004 was tested in a rat model of streptozotocin-induced diabetes. N-19004 was administered subcutaneously for 7 days at 1 month from diabetes onset. Immunofluorescence, RT-qPCR, Western blot and Evans blue perfusion were performed to evaluate the effects of N-19004 on inflammation, reactive gliosis, blood-retinal barrier (BRB) integrity and apoptosis. In addition, electroretinogram (ERG) was used to assess N-19004 efficacy on retinal function. N-19004 inhibited the activation of inflammation-related transcription factors, including nuclear factor kappa-light-chain-enhancer of activated B cells and signal transducer and activator of transcription 3, leading to reduced interleukin-1β and tumor necrosis factor-α expression. The attenuation of inflammatory processes resulted in reduced glial activation, as indicated by lower glial fibrillary acidic protein expression and Müller cell gliosis. The anti-inflammatory activity of N-19004 was accompanied by decreased BRB breakdown, as demonstrated by N-19004-mediated reduction of vascular endothelial growth factor, increased levels of tight junction components and diminished vessel leakage. The amelioration of BRB integrity was associated with reduced activation of caspase 3 and partial preservation of scotopic ERG a- and b-wave amplitudes, thereby improving retinal viability and function in N-19004-treated STZ rats. These results support the possible involvement of uPAR/FPR1 interactions in the regulation of DR-related inflammation and suggest a novel therapeutic target for the management of the early phases of disease.

Background: Hereditary transthyretin amyloidosis (ATTRv) is a systemic disorder caused by homozygosity or compound heterozygosity for pathogenic mutations in the TTR gene, leading to destabilization of the transthyretin tetramer, misfolding of monomers, and subsequent amyloid fibril deposition. Among over 150 known TTR variants, p.Val142Ile is particularly associated with late-onset cardiac involvement and is the most prevalent amyloidogenic mutation in individuals of African and, to a lesser extent, European descent. This study reports the identification and familial segregation of the p.Val142Ile mutation in a large multigenerational family from Calabria (Southern Italy). Methods: Genomic DNA was extracted from peripheral blood, and Sanger sequencing of the TTR gene was performed in the proband and extended family. Results: The proband was a 75-year-old man with clinical features suggestive of cardiac amyloidosis. Genetic testing revealed homozygosity for the TTR p.Val142Ile variant. Family screening revealed multiple heterozygous carriers across three generations, most of whom were asymptomatic. Discussion: This is the first report of a native Calabrian family carrying this variant, previously unreported in this region, where p.Phe84Leu was considered the only endemic TTR mutation. Our findings expand the mutational landscape of ATTRv in Southern Italy and highlight the presence of p.Val142Ile in a previously unrecognized geographic area. These results reinforce the importance of including TTR sequencing in the work-up of unexplained cardiomyopathy, particularly in Southern Italy, where atypical variants may be emerging.

Glaucoma represents a social and economic burden due to both its increasing incidence and the lack of knowledge about its physiopathology and treatment strategies. The main factor hindering progress in glaucoma research is the disease’s heterogeneity, which depends on both genetic and environmental factors. This limitation directly affects glaucoma research, posing obstacles to the elucidation of risk factors, disease mechanisms, and treatment strategies. Therefore, the need emerges to integrate pre-clinical experimental observations from different experimental models to recapitulate different aspects of the disease and achieve a successful translation to clinics. Here, we reviewed the glaucoma models that are currently available for basic and translational research, with a specific focus on models based on rodents. Regarding genetic glaucoma models, we considered the main hallmarks and limitations of DBA/2J, glutamate/aspartate transporter/excitatory amino acid carrier 1, myocilin, connective tissue growth factor, optineurin, purinergic receptor 2Y, caveolin 1, and endothelin-1 mice. Regarding other glaucoma models, we considered rodent models based on intraocular pressure elevation via perturbation of aqueous humor dynamics or on direct degeneration of retinal ganglion cells via physical or chemical damage.

Aims/Purpose: To investigate if the retina might be considered a reliable tool to monitor Alzheimer's disease (AD) progression and a benchmark for testing novel gene therapy strategies.Methods: The morpho‐functional and molecular features of 5xFAD and wild‐type (WT) mice have been evaluated at different time points: 3, 6, and 9 months of age. To assess retinal function we used scotopic, photopic, and pattern electroretinogram. Retinal structure was evaluated through optical coherence tomography. Retinal sections were immunostained with rhodopsin, cone‐arrestin, and RNA binding protein mRNA processing factor in order to identify rods, cones, and retinal ganglion cells, respectively. Further retinal sections were immunostained with amyloid beta (Aβ) to visualize the presence of plaques. Western blot experiments were conducted to evaluate retinal levels of Aβ and Tau. Markers of neuroinflammation (NFκB and IL‐6) and oxidative stress (NRF2, HO‐1, and NQO1) were also assessed by Western blot. The retinal miRNome was analyzed to highlight the potentially dysregulated miRNAs between 5xFAD and WT.Results: We observed a progressive loss of visual function followed by retinal thinning starting at 6 months of age. Moreover, photoreceptor and ganglion cell degeneration were reported from 6 months of age. Concurrently, molecular analyses demonstrated retinal Aβ and phospho‐Tau accumulation, which correlated with the progressive increment in oxidative and inflammatory markers. The miRNome analyses revealed several dysregulated miRNAs at 6 months of age in 5xFAD mice, which return to control levels at 9 months of age.Conclusions: These data might pave the way for a possible novel gene therapy strategy based on reinstating miRNA homeostasis, to be preliminary tested in the easily accessible retina and then, if successful, in the brain.

PURPOSE. Retinitis pigmentosa (RP) is characterized by primary rod degeneration followed by secondary cone death. The urokinase-type plasminogen activator (uPA) and its cognate receptor (uPAR) have been recently suggested to regulate pro-inflammatory events in RP possibly through the interaction of uPAR with its lateral partners, including formyl peptide receptors (FPRs). This study explored whether the inhibition of the crosstalk between uPAR and FPR1 may counteract photoreceptor degeneration in the rd10 mouse model of RP. METHODS. The newly synthetized FPR1 antagonist N-19004 was subcutaneously administered to rd10 mice from post-natal day (PD) 10 to PD 30. The efficacy of N-19004 on retinal function and morphology was evaluated by electroretinogram (ERG) and optical coherence tomography (OCT), respectively. Immunofluorescence and Western blotting for key markers of photoreceptors, immune cells, gliosis, inflammation, oxidative stress, and downstream effectors of FPRs were also performed. RESULTS. N-19004 attenuated retinal dysfunction and mitigated both rod and cone degeneration. N-19004 administration also reduced activation of immune cells, gliosis, inflammation, oxidative stress, and apoptosis. The activation of Akt and ERK1/2 pathways was likely to be involved in the effects of N-19004. CONCLUSIONS. N-19004 increases photoreceptor resilience and preserves retinal function in rd10 mice. These effects are likely to be due to an N-19004-mediated reduction of neuroinflammation and oxidative stress, suggesting a novel therapeutic strategy for the treatment of RP.

In the original publication [...].

Background: The national guidelines, informed by evidence from the National Institutes of Health (NIH), define the cri-teria for genetic testing of BRCA1/2 and other genes associated with Hereditary Breast and Ovarian Cancer (HBOC) and Lynch Syndrome (LS). When a germline pathogenic variant (PV) is identified in an index case, clinical recommendations advise informing at-risk relatives about the availability of predictive genetic testing, as early identification of carriers allows for timely implementation of preventive measures. Methods:This retrospective observational study examined data collected between 2017 and 2024 at the Medical Genetics Unit of the “Renato Dulbecco” University Hospital in Catanzaro, Italy. The analysis focused on trends in the identification of individuals carrying PVs in cancer predisposition genes (CPGs) and the subsequent uptake of cascade genetic testing (CGT) among their family members. Results: Over the study period, from 116 probands were performed 257 CGTs on 251 relatives.A notable reduction of approximately ten years in median age was observed, 39% were found to carry familial mutation and were referred to personalized cancer prevention programs. Among these, 62% accessed Oncological Genetic Counselling (CGO) within one year of the proband’s diagnosis, suggesting effective communication and outreach. Conclusions: The findings highlight the critical role of effective CGO and intrafamilial communication in hereditary cancer prevention. The identification of PVs, followed by timely CGTs and implementation of preventive strategies, sig-nificantly contributes to early cancer risk management. Periodic monitoring of CGT uptake and outcome trends, as demonstrated in this study, is essential to refine and optimize genetic services and public health strategies.

Age-related macular degeneration (AMD) and diabetic retinopathy (DR) are leading causes of visual impairment in older people, with oxidative stress playing a central role in the development of these diseases. In this study, we showed that N-acetylcysteine ethyl ester (NACET) not only increases intracellular cysteine and glutathione levels, but also strongly stimulates the expression and activity of the transcription factor NRF2, a master regulator of oxidative stress response, in RPE cells. Using RNA interference, mass spectrometry and mutagenesis of the NRF2 regulator KEAP1, we identified direct cysteinylation of the sensor residues Cys226 and Cys613 on KEAP1 as the molecular mechanism underlying NRF2 activation after NACET treatment. Furthermore, we demonstrated that oral administration of NACET induces NRF2 activity in the retina in vivo, attenuates retinal aging hallmarks, and prevents diabetes-induced retinal neurodegeneration in mouse models. These results position NACET as a promising therapeutic candidate for age- and oxidative stress-related retinal diseases such as AMD and DR.