The mechanistic functional landscape of retinitis pigmentosa: a machine learning-driven approach to therapeutic target discovery.

Background: Retinitis pigmentosa is the prevailing genetic cause of blindness in developed nations with no effective treatments. In the pursuit of unraveling the intricate dynamics underlying this complex disease, mechanistic models emerge as a tool of proven efficiency rooted in systems biology, to elucidate the interplay between RP genes and their mechanisms. The integration of mechanistic models and drug-target interactions under the umbrella of machine learning methodologies provides a multifaceted approach that can boost the discovery of novel therapeutic targets, facilitating further drug repurposing in RP.

An SPM-Enriched Marine Oil Supplement Shifted Microglia Polarization toward M2, Ameliorating Retinal Degeneration in Mice.

Retinitis pigmentosa (RP) is the most common inherited retinal dystrophy causing progressive vision loss. It is accompanied by chronic and sustained inflammation, including M1 microglia activation. This study evaluated the effect of an essential fatty acid (EFA) supplement containing specialized pro-resolving mediators (SPMs), on retinal degeneration and microglia activation in mice, a model of RP, as well as on LPS-stimulated BV2 cells.

Do Intestinal Unicellular Parasites Have a Role in the Inflammatory and Redox Status among the Severely Obese?

The diagnosis of obesity comprises subjects with totally different phenotypes and metabolic profiles. Systemic inflammation and oxidative stress derived from the white adipose tissue are suggested as the link between this disease and the development of insulin resistance and metabolic comorbidities. The presence of unicellular eukaryotic parasites colonizing the human gut ecosystem is a common circumstance, and yet their influence on the inflammatory and redox status of the obese host has not been assessed.

NUTRARET: Effect of 2-Year Nutraceutical Supplementation on Redox Status and Visual Function of Patients With Retinitis Pigmentosa: A Randomized, Double-Blind, Placebo-Controlled Trial.

Oxidative stress plays a major role in the pathogenesis of retinitis pigmentosa (RP). The main goal of this study was to evaluate the effect of 2-year nutritional intervention with antioxidant nutraceuticals on the visual function of RP patients. Secondly, we assessed how nutritional intervention affected ocular and systemic redox status.

Nutraceutical Supplementation Ameliorates Visual Function, Retinal Degeneration, and Redox Status in rd10 Mice.

Background: Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive degeneration of photoreceptor cells. Ocular redox status is altered in RP suggesting oxidative stress could contribute to their progression. In this study, we investigated the effect of a mixture of nutraceuticals with antioxidant properties (NUT) on retinal degeneration in rd10 mice, a model of RP.

Retinal Inflammation, Cell Death and Inherited Retinal Dystrophies.

Inherited retinal dystrophies (IRDs) are a group of retinal disorders that cause progressive and severe loss of vision because of retinal cell death, mainly photoreceptor cells. IRDs include retinitis pigmentosa (RP), the most common IRD. IRDs present a genetic and clinical heterogeneity that makes it difficult to achieve proper treatment.

Redox Status, Dose and Antioxidant Intake in Healthcare Workers Occupationally Exposed to Ionizing Radiation.

The purpose of this study was to evaluate the relationship between blood redox status, dose and antioxidant dietary intake of different hospital staff groups exposed to low doses of ionizing radiation (LDIR) (Interventional Radiology and Cardiology, Radiation Oncology, and Nuclear Medicine) and non-exposed. Personal dose equivalent (from last year and cumulative), plasma antioxidant markers (total antioxidant capacity, extracellular superoxide dismutase activity, and glutathione/oxidized glutathione ratio), oxidative stress markers (nitrites and nitrates, and lipid peroxidation) and dietary intake (antioxidant capacity using ORAC values) were collected and analyzed from 28 non-exposed healthcare workers and 42 healthcare workers exposed to LDIR. Hospital staff exposed to LDIR presented a redox imbalance in blood that seems to correlate with dose.

Intravitreal administration of adalimumab delays retinal degeneration in rd10 mice.

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by the progressive and irreversible loss of vision. We previously found that intraperitoneal administration of Adalimumab, a monoclonal anti-TNFα antibody, slowed down retinal degeneration in the murine model of RP, the rd10 mice. The aims of this study were to improve its neuroprotective effect and to deepen understanding of the molecular mechanisms involved in this effect.

Oxidative Stress, a Crossroad Between Rare Diseases and Neurodegeneration.

Oxidative stress is an imbalance between production and accumulation of oxygen reactive species and/or reactive nitrogen species in cells and tissues, and the capacity of detoxifying these products, using enzymatic and non-enzymatic components, such as glutathione. Oxidative stress plays roles in several pathological processes in the nervous system, such as neurotoxicity, neuroinflammation, ischemic stroke, and neurodegeneration. The concepts of oxidative stress and rare diseases were formulated in the eighties, and since then, the link between them has not stopped growing.

HIF-1α stabilization reduces retinal degeneration in a mouse model of retinitis pigmentosa.

Retinitis pigmentosa (RP) is a group of inherited retinal dystrophies characterized by progressive and irreversible loss of vision due to rod and cone degeneration. Evidence suggests that an inappropriate oxygen level could contribute to its pathogenesis. Rod cell death could increase oxygen concentration, reduce hypoxia-inducible factor 1 (HIF-1α) and contribute to cone cell death.

cGMP-Phosphodiesterase Inhibition Prevents Hypoxia-Induced Cell Death Activation in Porcine Retinal Explants.

Retinal hypoxia and oxidative stress are involved in several retinal degenerations including diabetic retinopathy, glaucoma, central retinal artery occlusion, or retinopathy of prematurity. The second messenger cyclic guanosine monophosphate (cGMP) has been reported to be protective for neuronal cells under several pathological conditions including ischemia/hypoxia. The purpose of this study was to evaluate whether the accumulation of cGMP through the pharmacological inhibition of phosphodiesterase (PDE) with Zaprinast prevented retinal degeneration induced by mild hypoxia in cultures of porcine retina.

Adalimumab Reduces Photoreceptor Cell Death in A Mouse Model of Retinal Degeneration.

Growing evidence suggests that inflammation is involved in the progression of retinitis pigmentosa (RP) both in patients and in animal models. The aim of this study was to investigate the effect of Adalimumab, a monoclonal anti-TNFα antibody, on retinal degeneration in a murine model of human autosomal recessive RP, the rd10 mice at postnatal day (P) 18. In our housing conditions, rd10 retinas were seriously damaged at P18.

Targeted next generation sequencing for molecular diagnosis of Usher syndrome.

Background: Usher syndrome is an autosomal recessive disease that associates sensorineural hearing loss, retinitis pigmentosa and, in some cases, vestibular dysfunction. It is clinically and genetically heterogeneous. To date, 10 genes have been associated with the disease, making its molecular diagnosis based on Sanger sequencing, expensive and time-consuming.

Infliximab reduces Zaprinast-induced retinal degeneration in cultures of porcine retina.

Background: cGMP-degrading phosphodiesterase 6 (PDE6) mutations cause around 4 to 5% of retinitis pigmentosa (RP), a rare form of retinal dystrophy. Growing evidence suggests that inflammation is involved in the progression of RP. The aims of this study were to corroborate the presence of high TNFα concentration in the eyes of RP patients and to evaluate whether the blockade of TNFα with Infliximab, a monoclonal anti-TNFα antibody, prevented retinal degeneration induced by PDE6 inhibition in cultures of porcine retina.

Altered antioxidant-oxidant status in the aqueous humor and peripheral blood of patients with retinitis pigmentosa.

Retinitis Pigmentosa is a common form of hereditary retinal degeneration constituting the largest Mendelian genetic cause of blindness in the developed world. It has been widely suggested that oxidative stress possibly contributes to its pathogenesis. We measured the levels of total antioxidant capacity, free nitrotyrosine, thiobarbituric acid reactive substances (TBARS) formation, extracellular superoxide dismutase (SOD3) activity, protein, metabolites of the nitric oxide/cyclic GMP pathway, heme oxygenase-I and inducible nitric oxide synthase expression in aqueous humor or/and peripheral blood from fifty-six patients with retinitis pigmentosa and sixty subjects without systemic or ocular oxidative stress-related disease.

Cerebral oedema is not responsible for motor or cognitive deficits in rats with hepatic encephalopathy.

Background & Aims: Low-grade cytotoxic oedema is considered a main contributor to the neurological (motor and cognitive) alterations in patients with hepatic encephalopathy (HE). This assumption is mainly based on studies with cultured astrocytes treated with very large ammonia concentrations or with animal models of acute liver failure with strong HE. However, the possible contribution of cerebral oedema (vasogenic or cytotoxic) to cognitive or motor alterations in chronic mild HE has not been demonstrated.

Phosphodiesterase inhibition induces retinal degeneration, oxidative stress and inflammation in cone-enriched cultures of porcine retina.

Inherited retinal degenerations affecting both rod and cone photoreceptors constitute one of the causes of incurable blindness in the developed world. Cyclic guanosine monophosphate (cGMP) is crucial in the phototransduction and, mutations in genes related to its metabolism are responsible for different retinal dystrophies. cGMP-degrading phosphodiesterase 6 (PDE6) mutations cause around 4-5% of the retinitis pigmentosa, a rare form of retinal degeneration.

Study of USH1 splicing variants through minigenes and transcript analysis from nasal epithelial cells.

Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by congenital profound deafness, vestibular areflexia and prepubertal retinitis pigmentosa. The first purpose of this study was to determine the pathologic nature of eighteen USH1 putative splicing variants found in our series and their effect in the splicing process by minigene assays. These variants were selected according to bioinformatic analysis.

Two novel disease-causing mutations in the CLRN1 gene in patients with Usher syndrome type 3.

Purpose: To identify the genetic defect in Spanish families with Usher syndrome (USH) and probable involvement of the CLRN1 gene.

Methods: DNA samples of the affected members of our cohort of USH families were tested using an USH genotyping array, and/or genotyped with polymorphic markers specific for the USH3A locus. Based on these previous analyses and clinical findings, CLRN1 was directly sequenced in 17 patients susceptible to carrying mutations in this gene.

Mutational screening of the USH2A gene in Spanish USH patients reveals 23 novel pathogenic mutations.

Background: Usher Syndrome type II (USH2) is an autosomal recessive disorder, characterized by moderate to severe hearing impairment and retinitis pigmentosa (RP). Among the three genes implicated, mutations in the USH2A gene account for 74-90% of the USH2 cases.

Methods: To identify the genetic cause of the disease and determine the frequency of USH2A mutations in a cohort of 88 unrelated USH Spanish patients, we carried out a mutation screening of the 72 coding exons of this gene by direct sequencing.

p38 MAP kinase is a therapeutic target for hepatic encephalopathy in rats with portacaval shunts.

Objective: Inflammation plays a role in neurological alterations in patients with hepatic encephalopathy (HE). Animal models of HE show neuroinflammation. Treatment with ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), reduces neuroinflammation and restores cognitive and motor function in rats with HE due to portacaval shunts (PCS).

Novel mutations in the USH1C gene in Usher syndrome patients.

Purpose: Usher syndrome type I (USH1) is an autosomal recessive disorder characterized by severe-profound sensorineural hearing loss, retinitis pigmentosa, and vestibular areflexia. To date, five USH1 genes have been identified. One of these genes is Usher syndrome 1C (USH1C), which encodes a protein, harmonin, containing PDZ domains.

Brain region-selective mechanisms contribute to the progression of cerebral alterations in acute liver failure in rats.

Background & Aims: Patients with acute liver failure (ALF) often die of intracranial pressure (IP) and cerebral herniation. Main contributors to increased IP are ammonia, glutamine, edema, and blood flow. The sequence of events and underlying mechanisms, as well as the temporal pattern, regional distribution, and contribution of each parameter to the progression of neurologic deterioration and IP, are unclear.

Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy.

Background & Aims: Hyperammonemia and inflammation cooperate to induce neurological alterations in hepatic encephalopathy. Recent studies in animal models suggest that chronic hyperammonemia and neuroinflammation impair learning ability by the same mechanism. Chronic hyperammonemia might induce inflammatory factors in the brain that impair cognitive function.

Cyclic GMP pathways in hepatic encephalopathy. Neurological and therapeutic implications.

Cyclic GMP (cGMP) modulates important cerebral processes including some forms of learning and memory. cGMP pathways are strongly altered in hyperammonemia and hepatic encephalopathy (HE). Patients with liver cirrhosis show reduced intracellular cGMP in lymphocytes, increased cGMP in plasma and increased activation of soluble guanylate cyclase by nitric oxide (NO) in lymphocytes, which correlates with minimal HE assessed by psychometric tests.