Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation.

Metazoans viability depends on their ability to regulate metabolic processes and also to respond to harmful challenges by mounting anti-stress responses; these adaptations were fundamental forces during evolution. Central to anti-stress responses are a number of short-lived transcription factors that by functioning as stress sensors mobilize genomic responses aiming to eliminate stressors. We show here that increased expression of nuclear factor erythroid 2-related factor (Nrf2) in Drosophila activated cytoprotective modules and enhanced stress tolerance. However, while mild Nrf2 activation extended lifespan, high Nrf2 expression levels resulted in developmental lethality or, after inducible activation in adult flies, in altered mitochondrial bioenergetics, the appearance of Diabetes Type 1 hallmarks and aging acceleration. Genetic or dietary suppression of Insulin/IGF-like signaling (IIS) titrated Nrf2 activity to lower levels, largely normalized metabolic pathways signaling, and extended flies' lifespan. Thus, prolonged stress signaling by otherwise cytoprotective short-lived stress sensors perturbs IIS resulting in re-allocation of resources from growth and longevity to somatic preservation and stress tolerance. These findings provide a reasonable explanation of why most (if not all) cytoprotective stress sensors are short-lived proteins, and it also explains the build-in negative feedback loops (shown here for Nrf2); the low basal levels of these proteins, and why their suppressors were favored by evolution

Φωτοθρόμβωση φυσιολογικών αγγείων του αμφιβληστροειδή και χοριοειδή κουνελιών με τη χρήση diode laser και Φθαλοκυανίνης

Ιn the current work the effectiveness of phthalocyanine and a diode laser in photothrombosis of normal retinal and choroidal vessels was evaluated. Big retinal vessels of temporal myelin wing were irradiated using a 670 nm diode laser at 2mW, after the injection of chloroaluminum sulfonated phthalocyanine (5mg/kg) in thirty albino rabbits. Animals were followed up to a maximum of 12 months using fundus photography, fluoroangiography, and histology. Photothrombosis of the irradiated retinal vessels and of underlying choroidal vessels resulted in all treated eyes after 13 to 17.5 min of irradiation. The retinal vessels were patent again by the 7th day after the procedure. Choroidal vessels remained closed during the whole follow-up period. Light and electron microscopy demonstrated occupation of irradiated choroidal and retinal vessels by plateletthrombi. Damage of endothelial cell structure of these vessels could be seen. Outer retinal and RPE damage localized at irradiation area was observed. The combination of phthalocyanine with a low power diode laser is a simple and effective way for the induction of photodynamic thrombosis in fundus vessels.Στη μελέτη αυτή ελέγχθηκε η αποτελεσματικότης της φθαλοκυανίνης σε συνδιασμό με ένα διοδικό laser για τη δημιουργία φωτοθρόμβωσης φυσιολογικών αγγείων του αμφιβληστροειδή και χοριοειδή. Τα μεγάλα κροταφικά αμφιβληστροειδικά αγγεία τριάντα λευκών κουνελιών ακτινοβολήθηκαν με ένα διοδικό laser (670nm) 2mW μετά την έγχυση της τετρασουλφονιωμένης χλωροαργιλικής φθαλοκυανίνης (5mg/kg). Τα ζώα παρακολουθήθηκαν μέχρι 12 μήνες με φλουραγγειογραφία και φωτογραφία βυθού καθώς και με ιστολογική μελέτη. Φωτοθρόμβωση τόσο των ακτινοβολημένων επιφανειακών αμφιβληστροειδικών όσο και των υποκείμενων χοριοειδικών αγγείων επετεύχθη σε όλα τα ζώα μετά από 13 έως 17,5 λεπτά ακτινοβολίας. Τα αμφιβληστροειδικά αγγεία ήταν πάλι βατά μετά από 7 ημέρες από την ακτινοβολία. Στα χοριοειδικά αγγεία δεν αποκαταστάθηκε η αιματική ροή καθ'όλο το διάστημα της παρακολούθησης. Η φωτονική και ηλεκτρονική μικροσκοπία έδειξε κατάληψη των ακτινοβολημένων αμφιβληστροειδικών και χοριοειδικών αγγείων από θρόμβο αιμοπεταλίων, καθώς και καταστροφή των ενδοθηλιακών τους κυττάρων. Η βλάβη η οποία παρατηρήθηκε στις εξωτερικές στιβάδες του αμφιβληστροειδή και στο μελάγχρουν επιθήλιο εντοπίζεται στην ακτινοβολημένη περιοχή. Ο συνδιασμός της φθαλοκυανίνης με ένα χαμηλής ισχύος διοδικού laser είναι απλός και αποτελεσματικός τρόπος για την πρόκληση φωτοθρόμβωσης φυσιολογικών αγγείων του βυθού

Treatment of atopic eyelid disease using topical tacrolimus following corticosteroid discontinuation in a patient with open-angle glaucoma.

To report a case of atopic eyelid disease treatment using topical tacrolimus in a patient with open-angle glaucoma following corticosteroid discontinuation. Interventional case report. A 59-year-old white man with a history of treated open-angle glaucoma (latanoprost 0.005%) was referred to our department for atopic eyelid disease. The patient had received previous treatment with topical corticosteroid ointments (hydrocortisone acetate 1%/dexamethasone 0.1% ointments) that, even though they were effective in controlling atopic eyelid disease, were complicated by markedly elevated intraocular pressure (IOP) (steroid responder). Topical steroids were discontinued while other treatment modalities (such as eyelid hygiene, artificial tears, topical antihistamine drugs, topical mast cell stabilizers, or topical/oral antibiotics) were proven ineffective. Topical tacrolimus 0.03% ointment (Protopic; Fujisawa, Dublin, Ireland) was applied to the eyelid skin twice daily. An improvement of eyelid inflammation was observed while eczematous skin lesions and erosions were resolved within 15 days. After 6 months of continued topical tacrolimus treatment, there was no evidence of atopic dermatitis recurrence. During this period IOP remained controlled without any evidence of deregulation. Treatment of atopic eyelid disease with topical tacrolimus, following corticosteroid discontinuation in a steroid responder patient with open-angle glaucoma, seems to be an effective alternative treatment to corticosteroids without the risk of IOP increase

Immunogenicity of SARS-CoV-2 BNT162b2 Vaccine in People with Diabetes: A Prospective Observational Study

The mRNA-based BNT162b2 vaccine has demonstrated high efficacy against severe SARS-CoV-2. However, data regarding immune response in people with diabetes mellitus (DM) after vaccination with the BNT162b2 vaccine are limited. In this prospective observational study, we examined humoral immune response in participants with and without DM after vaccination with the BNT162b2 mRNA vaccine. A total of 174 participants (58 with and 116 without diabetes, matched for age) were included. Antibodies were measured 21 days after the first dose, 7–15 days after the second dose, and 70–75 days after the second and before the third dose of the vaccine. Antibodies were measured by an anti-SARS-CoV-2 receptor-binding domain IgG (Abs-RBD-IgG) assay by a chemiluminescent microparticle immune assay; values > 50 AU/mL are considered protective from severe disease. Almost 17% of participants with DM did not develop adequate humoral immune response to the BNT162b2 mRNA vaccine after the first dose; however, it was high and similar after the second dose in both participants with and without DM and remained so almost 2 months after the second dose of the vaccine. Geometric mean values of Abs-RBD-IgG were not significantly different between participants with and without DM during the study. At least two doses of the BNT162b2 vaccine are necessary to ensure adequate and sustainable immune response in people with DM. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Hyperactivation of Nrf2 increases stress tolerance at the cost of aging acceleration due to metabolic deregulation

Metazoans viability depends on their ability to regulate metabolic processes and also to respond to harmful challenges by mounting anti-stress responses; these adaptations were fundamental forces during evolution. Central to anti-stress responses are a number of short-lived transcription factors that by functioning as stress sensors mobilize genomic responses aiming to eliminate stressors. We show here that increased expression of nuclear factor erythroid 2-related factor (Nrf2) in Drosophila activated cytoprotective modules and enhanced stress tolerance. However, while mild Nrf2 activation extended lifespan, high Nrf2 expression levels resulted in developmental lethality or, after inducible activation in adult flies, in altered mitochondrial bioenergetics, the appearance of Diabetes Type 1 hallmarks and aging acceleration. Genetic or dietary suppression of Insulin/IGF-like signaling (IIS) titrated Nrf2 activity to lower levels, largely normalized metabolic pathways signaling, and extended flies’ lifespan. Thus, prolonged stress signaling by otherwise cytoprotective short-lived stress sensors perturbs IIS resulting in re-allocation of resources from growth and longevity to somatic preservation and stress tolerance. These findings provide a reasonable explanation of why most (if not all) cytoprotective stress sensors are short-lived proteins, and it also explains the build-in negative feedback loops (shown here for Nrf2); the low basal levels of these proteins, and why their suppressors were favored by evolution. © 2018 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd