Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease or Charcot disease, is a fatal neurodegenerative disease that affects motor neurons (MNs) and leads to death within 2–5 years ...of diagnosis, without any effective therapy available. Although the pathological mechanisms leading to ALS are still unknown, a wealth of evidence indicates that an excessive reactive oxygen species (ROS) production associated with an inefficient antioxidant defense represents an important pathological feature in ALS. Substantial evidence indicates that oxidative stress (OS) is implicated in the loss of MNs and in mitochondrial dysfunction, contributing decisively to neurodegeneration in ALS. Although the modulation of OS represents a promising approach to protect MNs from degeneration, the fact that several antioxidants with beneficial effects in animal models failed to show any therapeutic benefit in patients raises several questions that should be analyzed. Using specific queries for literature search on PubMed, we review here the role of OS-related mechanisms in ALS, including the involvement of altered mitochondrial function with repercussions in neurodegeneration. We also describe antioxidant compounds that have been mostly tested in preclinical and clinical trials of ALS, also describing their respective mechanisms of action. While the description of OS mechanism in the different mutations identified in ALS has as principal objective to clarify the contribution of OS in ALS, the description of positive and negative outcomes for each antioxidant is aimed at paving the way for novel opportunities for intervention. In conclusion, although antioxidant strategies represent a very promising approach to slow the progression of the disease, it is of utmost need to invest on the characterization of OS profiles representative of each subtype of patient, in order to develop personalized therapies, allowing to understand the characteristics of antioxidants that have beneficial effects on different subtypes of patients.
Neurodevelopment in Infants Exposed to Zika Virus In Utero Lopes Moreira, M. Elisabeth; Nielsen-Saines, Karin; Brasil, Patricia ...
New England journal of medicine/The New England journal of medicine,
12/2018, Volume:
379, Issue:
24
Journal Article
Peer reviewed
Open access
Exposure to Zika virus in utero has been associated with neurodevelopmental abnormalities. In this letter, the results of long-term follow-up of Brazilian children exposed to ZIKV in utero are ...reported.
Effective data management is crucial for scientific integrity and reproducibility, a cornerstone of scientific progress. Well-organized and well-documented data enable validation and building on ...results. Data management encompasses activities including organization, documentation, storage, sharing, and preservation. Robust data management establishes credibility, fostering trust within the scientific community and benefiting researchers' careers. In experimental biomedicine, comprehensive data management is vital due to the typically intricate protocols, extensive metadata, and large datasets. Low-throughput experiments, in particular, require careful management to address variations and errors in protocols and raw data quality. Transparent and accountable research practices rely on accurate documentation of procedures, data collection, and analysis methods. Proper data management ensures long-term preservation and accessibility of valuable datasets. Well-managed data can be revisited, contributing to cumulative knowledge and potential new discoveries. Publicly funded research has an added responsibility for transparency, resource allocation, and avoiding redundancy. Meeting funding agency expectations increasingly requires rigorous methodologies, adherence to standards, comprehensive documentation, and widespread sharing of data, code, and other auxiliary resources. This review provides critical insights into raw and processed data, metadata, high-throughput versus low-throughput datasets, a common language for documentation, experimental and reporting guidelines, efficient data management systems, sharing practices, and relevant repositories. We systematically present available resources and optimal practices for wide use by experimental biomedical researchers.
Surgical risk stratification is crucial for enhancing perioperative assistance and allocating resources efficiently. However, existing models may not capture the complexity of surgical care in ...Brazil. Using data from various healthcare settings nationwide, we developed a new risk model for 30-day in-hospital mortality (the Ex-Care BR model).
A retrospective cohort study was conducted in 10 hospitals from different geographic regions in Brazil. Data were analysed using multilevel logistic regression models. Model performance was assessed using the area under the receiver operating characteristic curve (AUROC), Brier score, and calibration plots. Derivation and validation cohorts were randomly assigned.
A total of 107,372 patients were included, and 30-day in-hospital mortality was 2.1% (n=2261). The final risk model comprised four predictors related to the patient and surgery (age, ASA physical status classification, surgical urgency, and surgical size), and the random effect related to hospitals. The model showed excellent discrimination (AUROC=0.93, 95% confidence interval CI, 0.93–0.94), calibration, and overall performance (Brier score=0.017) in the derivation cohort (n=75,094). Similar results were observed in the validation cohort (n=32,278) (AUROC=0.93, 95% CI, 0.92–0.93).
The Ex-Care BR is the first model to consider regional and organisational peculiarities of the Brazilian surgical scene, in addition to patient and surgical factors. It is particularly useful for identifying high-risk surgical patients in situations demanding efficient allocation of limited resources. However, a thorough exploration of mortality variations among hospitals is essential for a comprehensive understanding of risk.
NCT05796024.
Doxorubicin (DOX) is a widely used anticancer drug that could be even more effective if its clinical dosage was not limited because of delayed cardiotoxicity. Beating stem cell-derived cardiomyocytes ...are a preferred in vitro model to further uncover the mechanisms of DOX-induced cardiotoxicity. Our objective was to use cultured induced-pluripotent stem cell(iPSC)-derived mouse cardiomyocytes (Cor.At) to investigate the effects of DOX on cell and mitochondrial metabolism, as well as on stress responses.
Non-proliferating and beating Cor.At cells were treated with 0.5 or 1 μM DOX for 24 h, and morphological, functional and biochemical changes associated with mitochondrial bioenergetics, DNA-damage response and apoptosis were measured. Both DOX concentrations decreased ATP levels and SOD2 protein levels and induced p53-dependent caspase activation. However, differential effects were observed for the two DOX concentrations. The highest concentration induced a high degree of apoptosis, with increased nuclear apoptotic morphology, PARP-1 cleavage and decrease of some OXPHOS protein subunits. At the lowest concentration, DOX increased the expression of p53 target transcripts associated with mitochondria-dependent apoptosis and decreased transcripts related with DNA-damage response and glycolysis. Interestingly, cells treated with 0.5 μM DOX presented an increase in PDK4 transcript levels, accompanied by an increase in phospho-PDH and decreased PDH activity. This was accompanied by an apparent decrease in basal and maximal oxygen consumption rates (OCR) and in basal extracellular acidification rate (ECAR). Cells pre-treated with the PDK inhibitor dichloroacetate (DCA), with the aim of restoring PDH activity, partially recovered OCR and ECAR.
The results suggest that the higher DOX concentration mainly induces p53-dependent apoptosis, whereas for the lower DOX concentration the cardiotoxic effects involve bioenergetic failure, unveiling PDH as a possible therapeutic target to decrease DOX cardiotoxicity.
•DOX induced dose-dependent morphological and functional changes.•DOX induced p53-related caspase activation and decreased SOD2 content.•DOX affected p53 target transcripts associated with apoptosis and DNA-damage.•DOX induced PDK4 transcription and PDH inactivation resulting in bioenergetic failure.•Bioenergetic dysfunction was ameliorated by pre-treatment with DCA.
Parkinson's Disease (PD) is characterized by dopaminergic neurodegeneration in the substantia nigra. The exact mechanism by which dopaminergic neurodegeneration occurs is still unknown; however, ...mitochondrial dysfunction has long been implicated in PD pathogenesis. To investigate the sub-cellular events that lead to disease progression and to develop personalized interventions, non-neuronal cells which are collected in a minimally invasive manner can be key to test interventions aimed at improving mitochondrial function. We used human skin fibroblasts from sporadic PD (sPD) patients as a cell proxy to detect metabolic and mitochondrial alterations which would also exist in a non-neuronal cell type. In this model, we used a glucose-free/galactose- glutamine- and pyruvate-containing cell culture medium, which forces cells to be more dependent on oxidative phosphorylation (OXPHOS) for energy production, in order to reveal hidden metabolic and mitochondrial alterations present in fibroblasts from sPD patients.
We demonstrated that fibroblasts from sPD patients show hyperpolarized and elongated mitochondrial networks and higher mitochondrial ROS concentration, as well as decreased ATP levels and glycolysis-related ECAR. Our results also showed that abnormalities of fibroblasts from sPD patients became more evident when stimulating OXPHOS. Under these culture conditions, fibroblasts from sPD cells presented decreased basal respiration, ATP-linked OCR and maximal respiration, and increased mitochondria-targeting phosphorylation of DRP1 when compared to control cells.
Our work validates the relevance of using fibroblasts from sPD patients to study cellular and molecular changes that are characteristic of dopaminergic neurodegeneration of PD, and shows that forcing mitochondrial OXPHOS uncovers metabolic defects that were otherwise hidden.
•Fibroblasts from sporadic Parkinson's disease (PD) patients were used as a cell proxy to detect metabolic and mitochondrial alterations.•Fibroblasts from sporadic PD patients showed hyperpolarized and elongated mitochondrial network.•Fibroblasts from sporadic PD patients have more mitochondrial ROS, as well as decreased ATP levels.•Forcing mitochondrial OXPHOS uncovers metabolic defects that were otherwise not obvious in high-glucose culture media.
This study evaluated the biocompatibility of a new silicone-based sealer (GuttaFlow Bioseal) in rat subcutaneous tissue and compared the results with those for GuttaFlow2 and AH Plus. Each of 16 ...Wistar rats received four subcutaneous tissue implants, namely, GuttaFlow Bioseal, GuttaFlow2, AH Plus, and one empty polyethylene tube. Eight rats were euthanized at day 8 and the remaining eight at day 30. Histological sections were stained with haematoxylin and eosin and analysed with a light microscope. Scores were established for inflammatory reaction, macrophage infiltrate, thickness of the fibrous capsule, and vascular changes. Differences between groups were assessed by using the Friedman test with Bonferroni correction. Histological analysis showed that GuttaFlow Bioseal had the lowest inflammatory reaction of all tested sealers at day 8. At day 30, the silicone-based sealers had similar inflammation profiles, but inflammation scores were nonsignificantly higher for AH Plus than for the negative control. The inflammatory reaction decreased from day 8 to day 30 in all sealers. GuttaFlow Bioseal had the most macrophage infiltrate. Under the present experimental conditions, GuttaFlow Bioseal induced limited inflammatory reactions at days 8 and 30, and initial inflammatory reactions to GuttaFlow2 and AH Plus subsided within 30 days. All tested sealers exhibited satisfactory biocompatibility at day 30 after subcutaneous implantation.
Background
Amyotrophic lateral sclerosis (ALS) is a fatal and rapidly progressing neurodegenerative disease that affects motor neurons. This disease is associated with oxidative stress especially in ...mutant superoxide dismutase 1 (mutSOD1) patients. However, less is known for the most prevalent sporadic ALS form, due to a lack of disease models. Here, we studied oxidative stress profiles in lymphoblasts from ALS patients with mutSOD1 or unknown (undSOD1) mutations.
Methods
mutSOD1 and undSOD1 lymphoblasts, as well as sex/age‐matched controls (3/group) were obtained from Coriell and divided into 46 years‐old‐men (C1), 46 years‐old‐women (C2) or 26/27 years‐old‐men (C3) cohorts. Growth curves were performed, and several parameters associated with redox homeostasis were evaluated, including SOD activity and expression, general oxidative stress levels, lipid peroxidation, response to oxidative stimulus, glutathione redox cycle, catalase expression, and activity, and Nrf2 transcripts. Pooled (all cohorts) and paired (intra‐cohort) statistical analyses were performed, followed by clustering and principal component analyses (PCA).
Results
Although a high heterogeneity among lymphoblast redox profiles was found between cohorts, clustering analysis based on 7 parameters with high chi‐square ranking (total SOD activity, oxidative stress levels, catalase transcripts, SOD1 protein levels, metabolic response to mM concentrations of tert‐butyl hydroperoxide, glutathione reductase activity, and Nrf2 transcript levels) provided a perfect cluster segregation between samples from healthy controls and ALS (undSOD1 and mutSOD1), also visualized in the PCA.
Conclusions
Our results show distinct redox signatures in lymphoblasts from mutSOD1, undSOD1 and healthy controls that can be used as therapeutic targets for ALS drug development.
With the increase in life expectancy and consequent aging of the world's population, the prevalence of many neurodegenerative diseases is increasing, without concomitant improvement in diagnostics ...and therapeutics. These diseases share neuropathological hallmarks, including mitochondrial dysfunction. In fact, as mitochondrial alterations appear prior to neuronal cell death at an early phase of a disease's onset, the study and modulation of mitochondrial alterations have emerged as promising strategies to predict and prevent neurotoxicity and neuronal cell death before the onset of cell viability alterations. In this work, differentiated SH-SY5Y cells were treated with the mitochondrial-targeted neurotoxicants 6-hydroxydopamine and rotenone. These compounds were used at different concentrations and for different time points to understand the similarities and differences in their mechanisms of action. To accomplish this, data on mitochondrial parameters were acquired and analyzed using unsupervised (hierarchical clustering) and supervised (decision tree) machine learning methods. Both biochemical and computational analyses resulted in an evident distinction between the neurotoxic effects of 6-hydroxydopamine and rotenone, specifically for the highest concentrations of both compounds.
The NRF2–KEAP1 system is a fundamental component of the cellular response that controls a great variety of transcriptional targets that are mainly involved in the regulation of redox homeostasis and ...multiple cytoprotective mechanisms that confer adaptation to the stress conditions. The pleiotropic response orchestrated by NRF2 is particularly relevant in the context of oncogenic activation, wherein this transcription factor acts as a key driver of tumor progression and cancer cells’ resistance to treatment. For this reason, NRF2 has emerged as a promising therapeutic target in cancer cells, stimulating extensive research aimed at the identification of natural, as well as chemical, NRF2 inhibitors. Excitingly, the influence of NRF2 on cancer cells’ biology extends far beyond its mere antioxidant function and rather encompasses a functional crosstalk with the mitochondrial network that can influence crucial aspects of mitochondrial homeostasis, including biogenesis, oxidative phosphorylation, metabolic reprogramming, and mitophagy. In the present review, we summarize the current knowledge of the reciprocal interrelation between NRF2 and mitochondria, with a focus on malignant tumors and cancer stem cells.
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