Communication defects with astroglia contribute to early impairments in the motor cortex plasticity of SOD1G93A mice.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease, involving the selective degeneration of cortical upper synapses in the primary motor cortex (M1). Excitotoxicity in ALS occurs due to an imbalance between excitation and inhibition, closely linked to the loss/gain of astrocytic function. Using the ALS SOD1G93A mice, we investigated the astrocytic contribution for the electrophysiological alterations observed in the M1 of SOD1G93A mice, throughout disease progression. Results showed that astrocytes are involved in synaptic dysfunction observed in presymptomatic SOD1G93A mice, since astrocytic glutamate transport currents are diminished and pharmacological inhibition of astrocytes only impaired long-term potentiation and basal transmission in wild-type mice. Proteomic analysis revealed major differences in neuronal transmission, metabolism, and immune system in upper synapses, confirming early communication deficits between neurons and astroglia. These results provide valuable insights into the early impact of upper synapses in ALS and the lack of supportive functions of cortical astrocytes, highlighting the possibility of manipulating astrocytes to improve synaptic function.

Hyperbaric oxygen therapy as a complementary treatment in neuroblastoma - a narrative review.

Neuroblastoma is the most frequently diagnosed cancer during the first year of life. This neoplasm originates from neural crest cells derived from the sympathetic nervous system, adrenal medulla, or paraspinal ganglia. The clinical presentation can vary from an asymptomatic mass to symptoms resulting from local invasion and/or spread of distant disease spread. The natural history of neuroblastoma is highly variable, ranging from relatively indolent biological behavior to a high-risk clinical phenotype with a dismal prognosis. Age, stage, and biological features are important prognostic risk stratification and treatment assignment prognostic factors. The multimodal therapy approach includes myeloablative chemotherapy, radiotherapy, immunotherapy, and aggressive surgical resection. Hyperbaric oxygen therapy (HBOT) has been proposed as a complementary measure to overcome tumor hypoxia, which is considered one of the hallmarks of this cancer treatment resistance. This article aims to review the relevant literature on the neuroblastoma pathophysiology, clinical presentation, and different biological and genetic profiles, and to discuss its management, focusing on HBOT.

Comparison of Management and Outcomes in ERBB2-Low vs ERBB2-Zero Metastatic Breast Cancer in France.

Importance: ERBB2-low (ie, ERBB2 immunohistochemistry score of 1+ or 2+ in the absence of ERBB2 gene amplification) breast cancer (BC) is a new entity, with emerging dedicated treatments. Little is known about its prognosis and response to conventional therapy compared with ERBB2-zero breast tumors (ie, those with an immunohistochemistry score of 0). Objective: To compare the outcomes for patients with ERBB2-low metastatic BC (MBC) with those of patients with ERBB2-zero MBC. Design, Setting, and Participants: This cohort study was conducted from the Epidemiological Strategy and Medical Economics MBC platform and included patients with MBC treated between 2008 and 2016 in 18 French comprehensive cancer centers. The data analysis was conducted from July 16, 2020, to April 1, 2022. Main Outcomes and Measures: The main outcome was overall survival (OS), and the secondary outcome was progression-free survival under first-line treatments (PFS1). Results: The median (range) age was 60.0 (22.0-103.0) years. Among 15 054 patients with MBC, 4671 (31%) had ERBB2-low MBC and 10 383 (69%) had ERBB2-zero MBC. The proportion of ERBB2-low cancers was higher among patients with hormone receptor-positive MBC than those with hormone receptor-negative disease (4083 patients [33.0%] vs 588 patients [21.0%]). With a median follow-up of 49.5 months (95% CI, 48.6-50.4 months), the median OS of the ERBB2-low group was 38.0 months (95% CI, 36.4-40.5 months) compared with 33.9 months (95% CI, 32.9-34.9 months) for the ERBB2-zero group (P < .001). After adjustment for age, visceral metastases, number of metastatic sites, de novo disease, period of care, and hormone receptor status, patients with ERBB2-low MBC had slightly better OS compared with patients with ERBB2-zero MBC (adjusted hazard ratio, 0.95; 95% CI, 0.91-0.99; P = .02). In contrast, PFS1 did not differ by ERBB2 status (adjusted hazard ratio, 0.99; 95% CI, 0.95-1.02; P = .45). No significant differences in OS and PFS1 were observed in multivariate analyses by hormone receptor status and types of frontline treatment. Conclusions and Relevance: In this large cohort study, patients with ERBB2-low MBC had a slightly better OS than those with completely ERBB2-zero tumors, but identical PFS1, which could help guide treatment selection.

Monitoring and Managing Patients with Tuberous Sclerosis Complex: Current State of Knowledge.

Tuberous sclerosis complex (TSC) is a rare genetic disease of autosomal dominant transmission that, in most cases, results from the presence of pathogenic variants of the TSC1 or TSC2 genes, encoding hamartin and tuberin, respectively. It is a multisystemic disease, affecting most frequently the brain, skin, kidney, and heart. The wide variety of possible clinical manifestations, given this multisystem dimension, makes the follow-up of patients with TSC an exercise of multidisciplinarity. In fact, these patients may require the intervention of various medical specialties, which thus have to combine their efforts to practice a medicine that is truly holistic. The past few years have witnessed a dramatic leap not only in the diagnosis and management of TSC patients, with standard monitoring recommendations, but also in the therapeutic field, with the use of mTORC1 inhibitors. In this article, we review the clinical manifestations associated with TSC, as well as the treatment and follow-up strategies that should be implemented, from a multidisciplinary perspective.

Antioxidant and lipid supplementation improve the development of photoreceptor outer segments in pluripotent stem cell-derived retinal organoids.

The generation of retinal organoids from human pluripotent stem cells (hPSC) is now a well-established process that in part recapitulates retinal development. However, hPSC-derived photoreceptors that exhibit well-organized outer segment structures have yet to be observed. To facilitate improved inherited retinal disease modeling, we determined conditions that would support outer segment development in maturing hPSC-derived photoreceptors. We established that the use of antioxidants and BSA-bound fatty acids promotes the formation of membranous outer segment-like structures. Using new protocols for hPSC-derived retinal organoid culture, we demonstrated improved outer segment formation for both rod and cone photoreceptors, including organized stacked discs. Using these enhanced conditions to generate iPSC-derived retinal organoids from patients with X-linked retinitis pigmentosa, we established robust cellular phenotypes that could be ameliorated following adeno-associated viral vector-mediated gene augmentation. These findings should aid both disease modeling and the development of therapeutic approaches for the treatment of photoreceptor disorders.

Functional Recovery of a GCDH Variant Associated to Severe Deflavinylation-Molecular Insights into Potential Beneficial Effects of Riboflavin Supplementation in Glutaric Aciduria-Type I Patients.

Riboflavin is the biological precursor of two important flavin cofactors-flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN)-that are critical prosthetic groups in several redox enzymes. While dietary supplementation with riboflavin is a recognized support therapy in several inborn errors of metabolism, it has yet unproven benefits in several other pathologies affecting flavoproteins. This is the case for glutaric aciduria type I (GA-I), a rare neurometabolic disorder associated with mutations in the GCDH gene, which encodes for glutaryl-coenzyme A (CoA) dehydrogenase (GCDH). Although there are a few reported clinical cases that have responded to riboflavin intake, there is still not enough molecular evidence supporting therapeutic recommendation. Hence, it is necessary to elucidate the molecular basis in favor of riboflavin supplementation in GA-I patients. Here, using a combination of biochemical and biophysical methodologies, we investigate the clinical variant GCDH-p.Val400Met as a model for a phenotype associated with severe deflavinylation. Through a systematic analysis, we establish that recombinant human GCDH-p.Val400Met is expressed in a nonfunctional apo form, which is mainly monomeric rather than tetrameric. However, we show that exogenous FAD is a driver for structural reorganization of the mutant enzyme with concomitant functional recovery, improved thermolability, and resistance to trypsin digestion. Overall, these results establish proof of principle for the beneficial effects of riboflavin supplementation in GA-I patients.

Protocol for the Characterization of the Cytosine-Adenine-Guanine Tract and Flanking Polymorphisms in Machado-Joseph Disease: Impact on Diagnosis and Development of Gene-Based Therapies.

Polyglutamine spinocerebellar ataxias (SCAs) constitute a group of autosomal dominantly inherited neurodegenerative disorders with considerable phenotypic overlap. Definitive diagnoses rely on the detection of a mutation in each associated locus, comprising the abnormal expansion of the trinucleotide cytosine-adenine-guanine (CAG) in coding exons. Assessment of single nucleotide polymorphisms associated with the CAG expansion in the context of SCAs is also relevant for improving molecular diagnosis and for generating novel therapeutic strategies. The current study is focused on Machado-Joseph disease/SCA type 3, with the aim of developing a protocol for the accurate determination of the CAG length in exon 10 of the human ATXN3 gene and to characterize flanking polymorphisms. A single pair of primers was designed and validated, and two complementary PCR-based methods were established. In method I, PCR amplicons were cloned and sequenced, allowing the assessment of three single nucleotide polymorphisms in the vicinity of the CAG repeat (C987GG/G987GG, TAA1118/TAC1118, and C1178/A1178), which can constitute potential targets for personalized gene-based therapies. Method II combines PCR, capillary electrophoresis, and a size correction formula, enabling a time and cost-effective determination of the number of CAGs. The established protocol paves the way to overcome technical difficulties related to the molecular characterization of the CAG motif and intragenic polymorphisms in the context of Machado-Joseph disease/SCA type 3 and may prove useful when applied to other polyglutamine SCAs.

Antioxidant and Neuroprotective Potential of the Brown Seaweed Bifurcaria bifurcata in an in vitro Parkinson's Disease Model.

Bifurcaria bifurcata is a marine brown seaweed mainly found on the Atlantic coast. Herein, we report the antioxidant and neuroprotective activities of seven fractions (F1⁻F7) obtained by normal phase chromatography from the B. bifurcata dichloromethane extract, as well as of its two major isolated diterpenes. Total phenolic content of fractions was determined by the Folin⁻Ciocalteu method, while antioxidant activity was evaluated by the DPPH, ORAC, and FRAP assays. Neuroprotective effects were evaluated in a neurotoxic model induced by 6-hydroxydopamine (6-OHDA) in a human neuroblastoma cell line (SH-SY5Y), while the mechanisms associated to neuroprotection were investigated by the determination of mitochondrial membrane potential, H2O2 production, Caspase-3 activity, and by observation of DNA fragmentation. Fractions F4 and F5 exhibited the best neuroprotective and antioxidant activities, respectively. F4 fraction prevented changes in mitochondrial potential, and induced a reduction of H2O2 levels production and an increase in cell viability, suggesting that it may contain multi-target compounds acting on different pathways. Hence, this fraction was subjected to purification steps, affording the known diterpenes eleganolone and eleganonal. Both compounds exhibited antioxidant potential, being interesting candidates for further neuroprotective studies.

HPV16 induces a wasting syndrome in transgenic mice: Amelioration by dietary polyphenols via NF-κB inhibition.

Cancer patients often show a wasting syndrome for which there are little therapeutic options. Dietary polyphenols have been proposed for treating this syndrome, but their usefulness in cases associated with human papillomavirus (HPV)-induced cancers is unknown. We characterized HPV16-transgenic mice as a model of cancer cachexia and tested the efficacy of long-term oral supplementation with polyphenols curcumin and rutin. Both compounds were orally administered to six weeks-old HPV16-transgenic mice showing characteristic multi-step skin carcinogenesis, for 24weeks. Skin lesions and blood, liver and spleen inflammatory changes were characterized histologically and hematologically. Hepatic oxidative stress, skeletal muscle mass and the levels of muscle pro-inflammatory transcription factor NF-κB were also assessed. Skin carcinogenesis was associated with progressive, severe, systemic inflammation (leukocytosis, hepatitis, splenitis), significant mortality and cachexia. Curcumin and rutin totally suppressed mortality while reducing white blood cells and the incidence of splenitis and hepatitis. Rutin prevented muscle wasting more effectively than curcumin. Preservation of muscle mass and reduced hepatic inflammation were associated with down-regulation of the NF-κB canonical pathway and with reduced oxidative stress, respectively. These results point out HPV16-transgenic mice as a useful model for studying the wasting syndrome associated with HPV-induced cancers. Dietary NF-κB inhibitors may be useful resources for treating this syndrome.

Toxicidade de manipueira de mandioca (Manihot esculenta Crantz) e erva-de-rato (Palicourea marcgravii St. Hill) a adultos de Toxoptera citricida Kirkaldy (Homoptera: Aphididae) / Toxicity of cassava manipueira (Manihot esculenta Crantz) and erva-de-rato (Palicourea marcgravii St. Hill) to adults of Toxoptera citricida Kirkaldy (Homoptera: Aphididae)

A utilização de extratos de plantas pode ser uma alternativa para o controle de pragas. Dentre as plantas com atividade inseticida, destacam-se a erva-de-rato (Palicourea marcgravii) e o subproduto (manipueira) da produção de farinha de mandioca (Manihot esculenta), plantas comuns na região Amazônica. Esse trabalho teve, como principal objetivo, investigar o potencial inseticida da manipueira e do extrato de erva-de-rato sobre Toxoptera citricida (pulgão-preto do citros). Os extratos liofilizados de manipueira e de erva-de-rato foram pulverizados sobre plantas de citros contendo pulgões em cinco concentrações (10mg/ml, 20mg/ml, 30mg/ml, 40mg/ml e 50mg/ml). Todas as concentrações analisadas causaram mortalidade dos pulgões superior a 50 por cento, sendo que a maior concentração causou a mortalidade de todos os insetos. O potencial destes extratos demonstrado no experimento coloca os mesmos como uma alternativa ao uso de inseticidas sintéticos no controle do pulgão-preto dos citros.

The utilization of plant extracts might be an alternative for the control of crop pests. Between the plants with insecticide potential, stands-out: Erva-de-rato (Palicourea marcgravii) and the Cassava, a byproduct of the manipueira (Manihot esculenta),common plants in the amazon region. That work had as main objective , to investigate the insecticide potential of Manihot esculenta (manipueira of cassava) and Palicourea marcgravii (erva-de-rato) on Toxoptera citricida (brown citrus aphid), in experimental conditions. The freeze dryed Manipueira and and Erva-de-rato extracts, were sprayed on citrus plants infected by brown citros aphid. In laboratory, extracts of these two plants were obtained in five concentrations (10mg/ml, 20mg/ml, 30mg/ml, 40mg/ml and 50mg/ml). All the analyzed concentrations (10 to 50mg/ml) caused mortality on T. citricida of above 50 percent, and the higher concentration of 50mg/ml caused the mortality of all the insects (n = 100 percent) in application processes contact. The potential of these extracts, as demonstrated in the tests, confirms that they can be an insecticide alternative, for the control of the brown citrus aphid.