Ebselen and Diphenyl Diselenide Inhibit SARS-CoV-2 Replication at Non-Toxic Concentrations to Human Cell Lines.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was the causative agent of the COVID-19 pandemic, a global public health problem. Despite the numerous studies for drug repurposing, there are only two FDA-approved antiviral agents (Remdesivir and Nirmatrelvir) for non-hospitalized patients with mild-to-moderate COVID-19 symptoms. Consequently, it is pivotal to search for new molecules with anti-SARS-CoV-2 activity and to study their effects in the human immune system.

Increased plasma level of terminal complement complex in AMD patients: potential functional consequences for RPE cells.

Purpose: Polymorphisms in complement genes are risk-associated for age-related macular degeneration (AMD). Functional analysis revealed a common deficiency to control the alternative complement pathway by risk-associated gene polymorphisms. Thus, we investigated the levels of terminal complement complex (TCC) in the plasma of wet AMD patients with defined genotypes and the impact of the complement activation of their plasma on second-messenger signaling, gene expression, and cytokine/chemokine secretion in retinal pigment epithelium (RPE) cells.

[Ocular side effects of modern oncological therapy : Immunological checkpoint and MEK/BRAF signal transduction inhibitors].

In recent years, checkpoint inhibitors have revolutionized the treatment of previously untreatable malignant tumors, significantly improving the life expectancy as well as quality of life in many cases. Checkpoint inhibitors comprise a group of drugs with different mechanisms of action. These include immunological checkpoint inhibitors (iCPI) and intracellular signal transduction inhibitors; however, both substance classes can cause inflammatory or toxic ocular side effects.

Pathogenesis of Bacterial Uveitis.

Purpose: To describe the pathogenesis and the general immune mechanisms of the most frequent causes of bacterial uveitis.

Methodology: Narrative review.

Results: Both extra- and intracellular bacteria can induce uveitis, whereas intracellular bacteria are generally transported into the inner eye via cells of the innate immune system, mainly macrophages.

Kaempferol counteracts toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in D. melanogaster: An implication of its mitoprotective activity.

The current study aimed to investigate whether kaempferol (KMP), the major bioactive component of green leafy vegetables, could counteract the toxicity elicited by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in Drosophila melanogaster or not. First, we performed a dose-response curve, where adult wild-type flies were fed on diet-containing different concentrations of KMP throughout their lifespan. Afterward, flies were fed on a diet containing MPTP (500 μM) and KMP (20 and 40 μM) for 7 days.

Antigenic mimicry - The key to autoimmunity in immune privileged organs.

The eye and the brain are the best investigated immune privileged sites for T cell mediated autoimmune diseases, with several experimental animal models in multiple species like experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune uveitis (EAU). It was difficult to explain autoimmunity to antigens which are sequestered behind blood-organ barriers since those barriers can only be passed by already activated lymphocytes. Antigen-specific lymphocytes must therefore be activated outside of the immune privileged target organs by crossreactivity of immune receptors to similar antigens, designated as "antigenic mimicry".

A new small molecule DHODH-inhibitor [KIO-100 (PP-001)] targeting activated T cells for intraocular treatment of uveitis - A phase I clinical trial.

Unlabelled: Uveitis is a T cell-mediated, intraocular inflammatory disease and one of the main causes of blindness in industrialized countries. There is a high unmet need for new immunomodulatory, steroid-sparing therapies, since only ciclosporin A and a single TNF-α-blocker are approved for non-infectious uveitis. A new small molecule inhibitor of dihydroorotate dehydrogenase (DHODH), an enzyme pivotal for synthesis of pyrimidines, has a high potency for suppressing T and B cells and has already proven highly effective for treating uveitis in experimental rat models.

FoxP3 expression by retinal pigment epithelial cells: transcription factor with potential relevance for the pathology of age-related macular degeneration.

Background: Forkhead-Box-Protein P3 (FoxP3) is a transcription factor and marker of regulatory T cells, converting naive T cells into Tregs that can downregulate the effector function of other T cells. We previously detected the expression of FoxP3 in retinal pigment epithelial (RPE) cells, forming the outer blood-retina barrier of the immune privileged eye.

Methods: We investigated the expression, subcellular localization, and phosphorylation of FoxP3 in RPE cells in vivo and in vitro after treatment with various stressors including age, retinal laser burn, autoimmune inflammation, exposure to cigarette smoke, in addition of IL-1β and mechanical cell monolayer destruction.

Immunogenicity of Novel AAV Capsids for Retinal Gene Therapy.

Objectives: AAV vectors are widely used in gene therapy, but the prevalence of neutralizing antibodies raised against AAV serotypes in the course of a natural infection, as well as innate and adaptive immune responses induced upon vector administration, is still considered an important limitation. In ocular gene therapy, vectors applied subretinally bear the risk of retinal detachment or vascular leakage. Therefore, new AAV vectors that are suitable for intravitreal administration for photoreceptor transduction were developed.

Short exposure to ethyl and methylmercury prompts similar toxic responses in Drosophila melanogaster.

Methylmercury (MeHg) and ethylmercury (EtHg) are important mercury organic forms in terms of human poisoning. Since the comparative effects of compounds are mainly in vitro, this study was designed to investigate the toxicities induced by MeHg and EtHg in an in vivo study using adult Drosophila melanogaster (D. melanogaster).

Uveitis in Tumor Patients Treated with Immunological Checkpoint- and Signal Transduction Pathway-Inhibitors.

Purpose: New tumor therapies like immune checkpoint inhibitors and small molecule inhibitors of MEK and BRAF have increased the patient's survival rate but can be burdened with severe side-effects including uveitis. Here, we show the spectrum, treatment, and outcome of uveitis types induced by tumor treatment.

Methods: In this retrospective study, we have included 54 patients from different centers who were developing uveitis under tumor therapy.

Posterior subcapsular cataracts are a late effect after acute exposure to 0.5 Gy ionizing radiation in mice.

Purpose: The long-term effect of low and moderate doses of ionizing radiation on the lens is still a matter of debate and needs to be evaluated in more detail.

Material And Methods: We conducted a detailed histological analysis of eyes from B6C3F1 mice cohorts after acute gamma irradiation (Co source; 0.063 Gy/min) at young adult age of 10 weeks with doses of 0.

Molecular Mimicry and Uveitis.

Molecular or antigenic mimicry is a term for the similarity of different antigens, which can be confused by the immune system. Antigen recognition by antibodies and T cell receptors is specific, but not restricted to a single antigen. Both types of receptors specifically recognize antigens and are expressed with a very high but still restricted variability compared to the number of different antigens they potentially could bind.

Is glaucoma an autoimmune disease?

There is increasing evidence from animal and human studies that glaucoma is an autoimmune disease. Evidence for this hypothesis includes the fact that antibodies as well as T-cell responses to heat-shock proteins (HSPs) are detectable in some patients with glaucoma and in an animal model of the disease. As in the human disease, experimental animal models of glaucoma have been found to demonstrate neurodegenerative changes in the optic nerve associated with immunoglobulin and T-cell infiltration.

Chronic heat treatment positively impacts metabolic profile of ovariectomized rats: association with heat shock response pathways.

Low estrogen levels may predispose women to increased bodyweight and dyslipidemia. Previous studies from our laboratory suggest an involvement of depressed heat shock response (HSR) in this scenario because estrogen potently stimulates HSR. As heat treatment induces the expression of the anti-inflammatory heat shock proteins of the 70-kDa family (HSP70) and its accompanying HSR, we aimed to investigate whether chronic heat treatment promotes beneficial effects on biometric, lipid profile, oxidative stress, and HSR in ovariectomized rats.

Methyl and Ethylmercury elicit oxidative stress and unbalance the antioxidant system in Saccharomyces cerevisiae.

Methylmercury (MeHg) and Ethylmercury (EtHg) are toxic to the central nervous system. Human exposure to MeHg and EtHg results mainly from the consumption of contaminated fish and thimerosal-containing vaccines, respectively. The mechanisms underlying the toxicity of MeHg and EtHg are still elusive.

Resolution of uveitis.

Autoimmune uveitis is a sight-threatening, rare disease, potentially leading to blindness. Uveitis is a synonym for intraocular inflammation, presenting as various clinical phenotypes with different underlying immune responses in patients, whereas different animal models usually represent one certain clinical and immunological type of uveitis due to genetic uniformity and the method of disease induction. T cells recognizing intraocular antigens initiate the disease, recruiting inflammatory cells (granulocytes, monocytes/macrophages) to the eyes, which cause the damage of the tissue.

Effects of High-Fat Diet on eHSP72 and Extra-to-Intracellular HSP70 Levels in Mice Submitted to Exercise under Exposure to Fine Particulate Matter.

Obesity, air pollution, and exercise induce alterations in the heat shock response (HSR), in both intracellular 70 kDa heat shock proteins (iHSP70) and the plasmatic extracellular form (eHSP72). Extra-to-intracellular HSP70 ratio (H-index = eHSP70/iHSP70 ratio) represents a candidate biomarker of subclinical health status. This study investigated the effects of moderate- and high-intensity exercise in the HSR and oxidative stress parameters, in obese mice exposed to fine particulate matter (PM).

Are rats more human than mice?

In contrast to rats, mouse models are nowadays generally used for the investigation of immune responses and immune-mediated diseases, there are many different strains and mouse-specific tools available, and it is easy to generate transgenic and constitutive or inducible knockout mice for any gene. Many immune markers and mechanisms have been detected in mice and have been introduced as gold standard in immunology, however, some turned out to be not unconditionally transferable to the human immune system. Rats have been used more frequently in former days but are mostly outstripped by mice due to the fact that fewer strains are available, they need more space than mice, are more expensive to maintain and breed, and it is extremely difficult to generate transgenic or ko-rats.

The immunopathogenesis of chronic and relapsing autoimmune uveitis - Lessons from experimental rat models.

Autoimmune diseases usually follow a relapsing-remitting or a chronic progressive course. To understand the underlying immunopathogenesis we investigated experimental Lewis rat models displaying both disease types, which were only dependent on the autoantigen peptide used for immunization. Retinal S-Antigen-peptide PDSAg induces chronic, monophasic disease, whilst interphotoreceptor retinoid-binding protein (IRBP)-peptide R14 causes a spontaneously relapsing-remitting course.

Intraocular DHODH-inhibitor PP-001 suppresses relapsing experimental uveitis and cytokine production of human lymphocytes, but not of RPE cells.

Background: Uveitis is a potentially blinding inflammatory disease of the inner eye with a high unmet need for new therapeutic interventions. Here, we wanted to investigate the suppressive effect of the intraocular application of the small molecule dihydroorotate dehydrogenase (DHODH)-inhibitor PP-001 on experimental relapsing rat uveitis and furthermore determine its effect on proliferation and cytokine secretion of human peripheral blood lymphocytes (PBL) and human retinal pigment epithelial (RPE) cells in vitro.

Methods: Spontaneously relapsing uveitis was induced in rats by immunization with interphotoreceptor retinoid-binding protein (IRBP) peptide R14.

Anaphylatoxins Activate Ca, Akt/PI3-Kinase, and FOXO1/FoxP3 in the Retinal Pigment Epithelium.

Purpose: The retinal pigment epithelium (RPE) is a main target for complement activation in age-related macular degeneration (AMD). The anaphylatoxins C3a and C5a have been thought to mostly play a role as chemoattractants for macrophages and immune cells; here, we explore whether they trigger RPE alterations. Specifically, we investigated the RPE as a potential immunoregulatory gate, allowing for active changes in the RPE microenvironment in response to complement.

The Role of IFN-alpha in Experimental and Clinical Uveitis.

Purpose: IFN-α is the only treatment capable of inducing long-term remission in some patients with ocular Behçet's disease. In this review, we focus on immune mechanisms of IFN-α in animal models and patients and compare the outcome of different clinical studies.

Methods: Review of literature using PubMed and Google and original data from rat models with monophasic/chronic or relapsing experimental autoimmune uveitis treated with IFN-α.