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Noribogaine (noribo) is the primary metabolite from ibogaine, an atypical psychedelic alkaloid isolated from the root bark of the African shrub Tabernanthe iboga . The main objective of this study was to test the hypothesis that molecular, electrophysiological, and behavioral responses of noribo are mediated by the 5-HT 2A receptor (5-HT 2A R) in mice. In that regard, we used male and female, 5-HT 2A R knockout (KO) and wild type (WT) mice injected with a single noribo dose (10 or 40 mg/kg; i.p.). After 30 min., locomotor activity was recorded followed by mRNA measurements by qPCR (immediate early genes; IEG, glutamate receptors, and 5-HT 2A R levels) and electrophysiology recordings of layer V pyramidal neurons from the medial prefrontal cortex. Noribo 40 decreased locomotion in male, but not female WT. Sex and genotype differences were observed for IEG and glutamate receptor expression. Expression of 5-HT 2A R mRNA increased in the mPFC of WT mice following Noribo 10 (males) or Noribo 40 (females). Patch-clamp recordings showed that Noribo 40 reduced the NMDA-mediated postsynaptic current density in mPFC pyramidal neurons only in male WT mice, but no effects were found for either KO males or females. Our results highlight that noribo produces sexually dimorphic effects while the genetic removal of 5HT 2A R blunted noribo-mediated responses to NMDA synaptic transmission.

Cerebellar atrophy (CA) is a frequent neuroimaging finding in paediatric neurology, usually associated with cerebellar ataxia. The list of genes involved in hereditary forms of CA is continuously growing and reveals its genetic complexity. We investigated ten cases with early-onset cerebellar involvement with and without ataxia by exome sequencing or by a targeted panel with 363 genes involved in ataxia or spastic paraplegia. Novel variants were investigated by in silico or experimental approaches. Seven probands carry causative variants in well-known genes associated with CA or cerebellar hypoplasia: SETX, CACNA1G, CACNA1A, CLN6 , CPLANE1 , and TBCD . The remaining three cases deserve special attention; they harbour variants in MAST1, PI4KA and CLK2 genes. MAST1 is responsible for an ultrarare condition characterised by global developmental delay and cognitive decline; our index case added ataxia to the list of concomitant associated symptoms. PIK4A is mainly related to hypomyelinating leukodystrophy; our proband presented with pure spastic paraplegia and normal intellectual capacity. Finally, in a patient who suffers from mild ataxia with oculomotor apraxia, the de novo novel CLK2 c.1120T>C variant was found. The protein expression of the mutated protein was reduced, which may indicate instability that would affect its kinase activity.

Neurodegeneration, characterized by the progressive deterioration of neurons and glial cells, is a feature of Alzheimer's disease (AD). The present study aims to demonstrate that the onset and early progression of neurodegenerative processes in transgenic mice models of AD can be delayed by a cocktail of neurotrophic factors and derived peptides named Nosustrophine, a nootropic supplement made by a peptide complex extracted from the young porcine brain, ensuring neuroprotection and improving neuro-functional recovery. Experimental 3xTg-APP/Bin1/COPS5 transgenic mice models of AD were treated with Nosustrophine at two different early ages, and their neuropathological hallmark and behavior response were analyzed. Results showed that Nosustrophine increased the activity of the immune system and reduced pathological changes in the hippocampus and cortex by halting the development of amyloid plaques, mainly seen in mice of 3-4 months of age, indicating that its effect is more preventive than therapeutic. Taken together, the results indicate the potent neuroprotective activity of Nosustrophine and its stimulating effects on neuronal plasticity. This study shows for the first time an effective therapy using nootropic supplements against degenerative diseases, although further investigation is needed to understand their molecular pathways.

Pharmacogenetics and DNA methylation influence therapeutic outcomes and provide insights into potential therapeutic targets for brain-related disorders. To understand the effect of genetic polymorphisms on drug response and disease risk, we analyzed the relationship between global DNA methylation, drug-metabolizing enzymes, transport genes, and pathogenic gene phenotypes in serum samples from two groups of patients: Group A, which showed increased 5-methylcytosine (5mC) levels during clinical follow-up, and Group B, which exhibited no discernible change in 5mC levels. We identified specific SNPs in several metabolizing genes, including CYP1A2 , CYP2C9 , CYP4F2 , GSTP1 , and NAT2 , that were associated with differential drug responses. Specific SNPs in CYP had a significant impact on enzyme activity, leading to changes in phenotypic distribution between the two patient groups. Group B, which contained a lower frequency of normal metabolizers and a higher frequency of ultra-rapid metabolizers compared to patients in Group A, did not show an improvement in 5mC levels during follow-up. Furthermore, there were significant differences in phenotype distribution between patient Groups A and B for several SNPs associated with transporter genes ( ABCB1 , ABCC2 , SLC2A9 , SLC39A8 , and SLCO1B1 ) and pathogenic genes ( APOE , NBEA , and PTGS2 ). These findings appear to suggest that the interplay between pharmacogenomics and DNA methylation has important implications for improving treatment outcomes in patients with brain-related disorders.

Dyslipidemia is a significant risk factor for cardiovascular disease and stroke. Our recent findings showed that RCI-1502, a bioproduct derived from the muscle of the European S. pilchardus, has lipid-lowering effects in the liver and heart in high-fat diet (HFD) fed mice. In the present follow-up study, we investigated the therapeutic potential of RCI-1502 on gene expression and DNA methylation in HFD-fed mice and in patients with dyslipidemia. Using LC-MS/MS, we identified 75 proteins in RCI-1502 that are primarily involved in binding and catalytic activity and which regulate pathways implicated in cardiovascular diseases. In HFD-fed mice, RCI-1502 treatment significantly reduced the expression of cardiovascular disease-related genes, including vascular cell adhesion molecule and angiotensin. RCI-1502 also decreased DNA methylation levels, which were elevated in HFD-fed mice, to levels similar to those in control animals. Furthermore, peripheral blood leukocyte DNA from dyslipidemic patients exhibited higher DNA methylation levels than healthy individuals, suggesting a potential association with cardiovascular risk. Serum analysis also revealed that RCI-1502 treatment regulated cholesterol and triglyceride levels in patients with dyslipidemia. Our findings appear to suggest that RCI-1502 is an epigenetic modulator for the treatment of cardiovascular diseases, specifically in individuals with dyslipidemia.

The presence of female athletes has only increased in recent years, as has the incidence of injuries in female sports activities. These injuries are conditioned by multiple factors, including hormonal agents. It is estimated that the menstrual cycle may be related to the predisposition to suffer an injury. However, a causal relationship has not yet been established. The aim of this study was to analyse the relationship between the menstrual cycle and injuries in female sports practice. A systematic search of the scientific literature available in PubMed, Medline, Scopus, Web of Science, and Sport Discus was carried out in January 2022. With 138 articles, only eight studies were found that met the selection criteria for this study. Peak estradiol is associated with increased laxity, strength, and poor use of neuromuscular control. Thus, the ovulatory phase is associated with an increased risk of injury. In conclusion, it seems that hormonal fluctuations throughout the menstrual cycle alter values such as laxity, strength, body temperature, and neuromuscular control, among others. This fact causes women to constantly adapt to hormonal variations, which exposes them to a higher risk of injury.

Neurodegenerative disorders (NDDs) are major health issues in Western countries. Despite significant efforts, no effective therapeutics for NDDs exist. Several drugs that target epigenetic mechanisms (epidrugs) have been recently developed for the treatment of NDDs, and several of these are currently being tested in clinical trials. Furthermore, various bioproducts have shown important biological effects for the potential prevention and treatment of these disorders. Here, we review the use of natural products as epidrugs to treat NDDs in order to explore the epigenetic effects and benefits of functional foods and natural bioproducts on neurodegeneration.

In this article, we identified a novel epileptogenic variant (G307R) of the gene SLC6A1 , which encodes the GABA transporter GAT-1. Our main goal was to investigate the pathogenic mechanisms of this variant, located near the neurotransmitter permeation pathway, and compare it with other variants located either in the permeation pathway or close to the lipid bilayer. The mutants G307R and A334P, close to the gates of the transporter, could be glycosylated with variable efficiency and reached the membrane, albeit inactive. Mutants located in the center of the permeation pathway (G297R) or close to the lipid bilayer (A128V, G550R) were retained in the endoplasmic reticulum. Applying an Elastic Network Model, to these and to other previously characterized variants, we found that G307R and A334P significantly perturb the structure and dynamics of the intracellular gate, which can explain their reduced activity, while for A228V and G362R, the reduced translocation to the membrane quantitatively accounts for the reduced activity. The addition of a chemical chaperone (4-phenylbutyric acid, PBA), which improves protein folding, increased the activity of GAT-1WT, as well as most of the assayed variants, including G307R, suggesting that PBA might also assist the conformational changes occurring during the alternative access transport cycle.

Information and Communication Technologies have led to a new way of life and, in particular, of socialization. The objective of this study is to analyse the image social media disseminate of news taken from digital newspapers, based on the opportunities and drawbacks attributed to smartphone use by teenagers. An essentially qualitative methodology was used, on a sample of 1704 news items published in digital newspapers. The results and conclusions show that smartphone use by teenagers improves development of their digital competence, presents new academic opportunities (through gamification or mobile learning) and provides them with digital tools for school and leisure. The widespread drawbacks reflect the effects of the device on the deterioration of health (dependence, stress, psychosocial problems) and emotions, thereby succinctly affecting academic performance. A noticeable increase of positive news about smartphones was published in the major newspapers in December, while that on its negative effects, in September.

Alzheimer's disease (AD), the most common cause of dementia, causes irreversible memory loss and cognitive deficits. Current AD drugs do not significantly improve cognitive function or cure the disease. Novel bioproducts are promising options for treating a variety of diseases, including neurodegenerative disorders. Targeting the epigenetic apparatus with bioactive compounds (epidrugs) may aid AD prevention treatment. The aims of this study were to determine the composition of a porcine brain-derived extract Nosustrophine, and whether treating young and older trigenic AD mice produced targeted epigenetic and neuroprotective effects against neurodegeneration. Nosustrophine regulated AD-related APOE and PSEN2 gene expression in young and older APP/BIN1/COPS5 mice, inflammation-related ( NOS3 and COX-2 ) gene expression in 3-4-month-old mice only, global (5mC)- and de novo DNA methylation ( DNMT3a ), HDAC3 expression and HDAC activity in 3-4-month-old mice; and SIRT1 expression and acetylated histone H3 protein levels in 8-9-month-old mice. Mass spectrometric analysis of Nosustrophine extracts revealed the presence of adenosylhomocysteinase, an enzyme implicated in DNA methylation, and nicotinamide phosphoribosyltransferase, which produces the NAD+ precursor, enhancing SIRT1 activity. Our findings show that Nosustrophine exerts substantial epigenetic effects against AD-related neurodegeneration and establishes Nosustrophine as a novel nutraceutical bioproduct with epigenetic properties (epinutraceutical) that may be therapeutically effective for prevention and early treatment for AD-related neurodegeneration.

Our clinical series comprises 124 patients with movement disorders (MDs) and/or ataxia with cerebellar atrophy (CA), many of them showing signs of neurodegeneration with brain iron accumulation (NBIA). Ten NBIA genes are accepted, although isolated cases compatible with abnormal brain iron deposits are known. The patients were evaluated using standardised clinical assessments of ataxia and MDs. First, NBIA genes were analysed by Sanger sequencing and 59 patients achieved a diagnosis, including the detection of the founder mutation PANK2 p.T528M in Romani people. Then, we used a custom panel MovDisord and/or exome sequencing; 29 cases were solved with a great genetic heterogeneity (34 different mutations in 23 genes). Three patients presented brain iron deposits with Fe-sensitive MRI sequences and mutations in FBXO7 , GLB1 , and KIF1A , suggesting an NBIA-like phenotype. Eleven patients showed very early-onset ataxia and CA with cortical hyperintensities caused by mutations in ITPR1 , KIF1A , SPTBN2 , PLA2G6 , PMPCA, and PRDX3 . The novel variants were investigated by structural modelling, luciferase analysis, transcript/minigenes studies, or immunofluorescence assays. Our findings expand the phenotypes and the genetics of MDs and ataxias with early-onset CA and cortical hyperintensities and highlight that the abnormal brain iron accumulation or early cerebellar gliosis may resembling an NBIA phenotype.

Alzheimer's Disease (AD) is a major health problem worldwide. The lack of efficacy of existing therapies for AD is because of diagnosis at late stages of the disease, limited knowledge of biomarkers, and molecular mechanisms of AD pathology, as well as conventional drugs that are focused on symptomatic rather than mechanistic features of the disease. The connection between epigenetics and AD, however, may be useful for the development of novel therapeutics or diagnostic biomarkers for AD. The aim of this study was to investigate a pathogenic role for epigenetics and other biomarkers in the male APP/BIN1/COPS5 triple-transgenic (3xTg) mouse model of AD. In the APP/BIN1/COPS5 3xTg-AD mouse hippocampus, sirtuin expression and activity decreased, HDAC3 expression and activity increased, PSEN1 mRNA levels were unchanged, PSEN2 and APOE expression was reduced, and levels of the pro-inflammatory marker IL-6 increased; levels of pro-inflammatory COX-2 and TNFα and apoptotic (NOS3) markers increased slightly, but these were non-significant. In fixed mouse-brain slices, immunoreactivity for CD11b and β-amyloid immunostaining increased. APP/BIN1/COPS5 3xTg-AD mice are a suitable model for evaluating epigenetic changes in AD, the discovery of new epigenetic-related biomarkers for AD diagnosis, and new epidrugs for the treatment of this neurodegenerative disease.

The first stage of the drug discovery process involves the identification of small compounds with biological activity. Iboga alkaloids are monoterpene indole alkaloids (MIAs) containing a fused isoquinuclidine-tetrahydroazepine ring. Both the natural products and the iboga-inspired synthetic analogs have shown a wide variety of biological activities. Herein, we describe the chemoenzymatic preparation of a small library of novel N -indolylethyl-substituted isoquinuclidines as iboga-inspired compounds, using toluene as a starting material and an imine Diels-Alder reaction as the key step in the synthesis. The new iboga series was investigated for its potential to promote the release of glial cell line-derived neurotrophic factor (GDNF) by C6 glioma cells, and to inhibit the growth of infective trypanosomes. GDNF is a neurotrophic factor widely recognized by its crucial role in development, survival, maintenance, and protection of dopaminergic neuronal circuitries affected in several neurological and psychiatric pathologies. Four compounds of the series showed promising activity as GDNF releasers, and a leading structure (compound 11 ) was identified for further studies. The same four compounds impaired the growth of bloodstream Trypanosoma brucei brucei (EC 50 1-8 μM) and two of them (compounds 6 and 14 ) showed a good selectivity index.

Background and objective : Prior studies have reported an activation of abdominal muscles during hypopressive exercises in women with pelvic floor disfunction. However, no previous research analyzed the effects of hypopressive exercise on abdominal muscles in healthy populations to understand the normal biomechanics of this area. The aim of this study was to examine the thickness of abdominal muscles at rest and during hypopressive exercise in supine and standing positions with ultrasound imaging in healthy adults. Methods : A cross-sectional study was carried out in 99 healthy university students. The thickness of the abdominal muscles at rest and during hypopressive exercise was assessed with ultrasound imaging in supine and standing positions. Results : During hypopressive exercise, there was a significant increase in the muscle thickness of transversus abdominis ( p < 0.001) and internal oblique ( p < 0.001) in supine and standing positions. External oblique only increased its thickness significantly in the standing position ( p < 0.001) and rectus abdominis did not change during the hypopressive exercise in any position ( p > 0.05). In conclusion, hypopressive exercises seem to increase the thickness of the deepest and most stabilized muscles such as transversus abdominis and internal oblique. Conclusions : These findings should be considered for future interventions with hypopressive exercises in healthy subjects.

This study analyzes the effects of hypopressive exercises on the abdominal thickness of healthy subjects and compares the performance between women and men. We conducted a transversal observational study in 98 subjects (63% women). The muscle thickness is analyzed in transversus abdominis, internal oblique, external oblique, and rectus abdominis with ultrasound imaging at rest and during the hypopressive exercise (HE) in supine and standing position. Comparisons between rest and hypopressive exercise are carried out in the two different positions and between women and men. In the supine position, there is a significant activation of the transversus abdominis and internal oblique during hypopressive exercise ( p < 0.001), and it is similar in both sexes, the external oblique is only activated significantly by men ( p < 0.001) and rectus abdominis had no significant activation ( p > 0.05). Our results show that standing transversus abdominis and external oblique significantly increased their thickness during HE with higher effects in men. Internal oblique also increased significantly, but with higher effects in women, and rectus abdominis had no significant increase. Men had similar effects to women during HE, with an activation of the deepest abdominal muscles. The unequal anatomy and the position could explain the different results obtained between the sexes.

Liver disease resulting from heart failure (HF) has generally been referred as "cardiac hepatopathy". One of its main forms is congestive hepatopathy (CH), which results from passive venous congestion in the setting of chronic right-sided HF. The current spectrum of CH differs from earlier reports with HF, due to ischemic cardiomyopathy and congenital heart disease having surpassed rheumatic valvular disease. The chronic passive congestion leads to sinusoidal hypertension, centrilobular fibrosis, and ultimately, cirrhosis ("cardiac cirrhosis") and hepatocellular carcinoma after several decades of ongoing injury. Contrary to primary liver diseases, in CH, inflammation seems to play no role in the progression of liver fibrosis, bridging fibrosis occurs between central veins to produce a "reversed lobulation" pattern and the performance of non-invasive diagnostic tests of liver fibrosis is poor. Although the clinical picture and prognosis is usually dominated by the underlying heart condition, the improved long-term survival of cardiac patients due to advances in medical and surgical treatments are responsible for the increased number of liver complications in this setting. Eventually, liver disease could become as clinically relevant as cardiac disease and further complicate its management.

DNA methylation is an epigenetic mechanism by which methyl groups are added to DNA, playing a crucial role in gene expression regulation. The aim of the present study is to compare methylation status of healthy subjects with that of patients with Alzheimer's, Parkinson's or Cerebrovascular diseases. We also analyze methylation status of a transgenic Alzheimer's disease mouse model (3xTg-AD). Our results show that both global methylation ( n = 141) and hydroxymethylation ( n = 131) levels are reduced in DNA samples from buffy coats of patients with neurodegenerative disorders and age-related cerebrovascular disease. The importance of methylation and hydroxymethylation reduction is stressed by the finding that DNMT3a mRNA levels are also downregulated in buffy coats of patients with Dementia ( n = 25). Global methylation is also reduced in brain, liver and serum samples of 3xTg-AD vs. wild type mice, such as DNMT3a mRNA levels that are also decreased in the brain of 3xTg-AD ( n = 10). These results suggest that the use of global methylation and hydroxymethylation levels, together with the study of DNMT3a expression, could be useful as a new diagnostic biomarker for these prevalent disorders.

Nematode parasites have a profound impact on humankind, infecting nearly one-quarter of the world's population, as well as livestock. There is a pressing need for discovering nematicides due to the spread of resistance to currently used drugs. The free-living nematode Caenorhabditis elegans is a formidable experimentally tractable model organism that offers key advantages in accelerating nematicide discovery. We report the screening of drug-like libraries using an overnight high-throughput C. elegans assay, based on an automated infrared motility reader. As a proof of concept, we screened the "Pathogen Box" library, and identical results to a previous screen using Haemonchus contortus were obtained. We then screened an in-house library containing a diversity of compound families. Most active compounds had a conjugation of an unsaturation with an electronegative atom (N, O, or S) and an aromatic ring. Importantly, we identified symmetric arylidene ketones and aryl hydrazine derivatives as novel nematicides. Furthermore, one of these compounds, (1E,2E)-1,2-bis(thiophen-3-ylmethylene)hydrazine, was active as a nematicide at 25 µm, but innocuous to the vertebrate model zebrafish at 50 µm. Our results identified novel nematicidal scaffolds and illustrate the value of C. elegans in accelerating nematicide discovery using a nonlabor-intensive automated assay that provides a simple overnight readout.