rudyvdbrink/CitationDatabase huggingface dataset:
Intensity of acute aerobic exercise but not aerobic fitness impacts on corticospinal excitability.
Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme, 2019

Aerobic exercise (AE) modulates cortical excitability. It can alter both corticospinal excitability and intra-cortical networks, which has implications for its use as a tool to facilitate processes such as motor learning, where increased levels of excitability are conducive to the induction of neural plasticity. Little is known about how different intensities of AE modulate cortical excitability or how individual-level characteristics impact on it. Therefore, we investigated whether AE intensities, lower than those previously employed, would be effective in increasing cortical excitability. We also examined whether the aerobic fitness of individual participants was related to the magnitude of change in AE-induced cortical excitability. In both experiments we employed transcranial magnetic stimulation to probe corticospinal excitability before and after AE. We show that 20 min of continuous moderate- (40% and 50% of heart rate reserve, HRR), but not low- (30% HRR) intensity AE was effective at increasing corticospinal excitability. We also found that while we observed increased corticospinal excitability following 20 min of continuous moderate-intensity (50% HRR) AE, aerobic fitness was not related to the magnitude of change. Our results suggest that there is a lower bound intensity of AE that is effective at driving changes in cortical excitability, and that while individual-level characteristics are important predictors of response to AE, aerobic fitness is not. Overall these findings have implication for the way that AE is used to facilitate processes such as motor learning, where increased levels of cortical excitability and plasticity are favourable.
HOPX functions as a tumour suppressor in head and neck cancer.
Scientific reports, 2016

Head and neck squamous cell carcinoma (HNSCC) is generalized term that encompasses a diverse group of cancers that includes tumours of the oral cavity (OSCC), oropharynx (OPSCC) and nasopharynx (NPC). Genetic alterations that are common to all HNSCC types are likely to be important for squamous carcinogenesis. In this study, we have investigated the role of the homeodomain-only homeobox gene, HOPX, in the pathogenesis of HNSCC. We show that HOPX mRNA levels are reduced in OSCC and NPC cell lines and tissues and there is a general reduction of HOPX protein expression in these tumours and OPSCCs. HOPX promoter methylation was observed in a subset of HNSCCs and was associated with a worse overall survival in HPV negative tumours. RNAseq analysis of OSCC cells transfected with HOPX revealed a widespread deregulation of the transcription of genes related to epithelial homeostasis and ectopic over-expression of HOPX in OSCC and NPC cells inhibited cell proliferation, plating efficiency and migration, and enhanced sensitivity to UVA-induced apoptosis. Our results demonstrate that HOPX functions as a tumour suppressor in HNSCC and suggest a central role for HOPX in suppressing epithelial carcinogenesis.
Sex differences in the hypothalamic-pituitary-adrenal axis: An obstacle to antidepressant drug development?
British journal of pharmacology, 2019

Hypothalamic-pituitary-adrenal (HPA) axis dysfunction has long been implicated in the pathophysiology of depression, and HPA axis-based compounds have served as potential new therapeutic targets, but with no success. This review details sex differences from animal and human studies in the function of HPA axis elements (glucocorticoids, corticotropin releasing factor, and vasopressin) and related compounds tested as candidate antidepressants. We propose that sex differences contribute to the failure of novel HPA axis-based drugs in clinical trials. Compounds studied preclinically in males were tested in clinical trials that recruited more, if not exclusively, women, and did not control, but rather adjusted, for potential sex differences. Indeed, clinical trials of antidepressants are usually not stratified by sex or other important factors, although preclinical and epidemiological data support such stratification. In conclusion, we suggest that clinical testing of HPA axis-related compounds creates an opportunity for targeted, personalized antidepressant treatments based on sex. LINKED ARTICLES: This article is part of a themed section on The Importance of Sex Differences in Pharmacology Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.21/issuetoc.
Inflammation and reactive oxygen species in status epilepticus: Biomarkers and implications for therapy.
Epilepsy & behavior : E&B, 2019

Preclinical studies in immature and adult rodents and clinical observations show that neuroinflammation and oxidative stress are rapid onset phenomena occurring in the brain during status epilepticus and persisting thereafter. Notably, both neuroinflammation and oxidative stress contribute to the acute and long-term sequelae of status epilepticus thus representing potential druggable targets. Antiinflammatory drugs that interfere with the IL-1β pathway, such as anakinra, can control benzodiazepine-refractory status epilepticus in animals, and there is recent proof-of-concept evidence for therapeutic effects in children with Febrile infection related epilepsy syndrome (FIRES). Inhibitors of monoacylglycerol lipase and P2X7 receptor antagonists are also promising antiinflammatory drug candidates for rapidly aborting de novo status epilepticus and provide neuroprotection. Antiinflammatory and antioxidant drugs administered to rodents during status epilepticus and transiently thereafter, prevent long-term sequelae such as cognitive deficits and seizure progression in animals developing epilepsy. Some drugs are already in medical use and are well-tolerated, therefore, they may be considered for treating status epilepticus and its neurological consequences. Finally, markers of neuroinflammation and oxidative stress are measureable in peripheral blood and by neuroimaging, which offers an opportunity for developing prognostic and predictive mechanistic biomarkers in people exposed to status epilepticus. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures.
Distributions and relationships of chemically defined enteroendocrine cells in the rat gastric mucosa.
Cell and tissue research, 2019

This paper provides quantitative data on the distributions of enteroendocrine cells (EEC), defined by the hormones they contain, patterns of colocalisation between hormones and EEC relations to nerve fibres in the rat gastric mucosa. The rat stomach has three mucosal types: non-glandular stratified squamous epithelium of the fundus and esophageal groove, a region of oxyntic glands in the corpus, and pyloric glands of the antrum and pylorus. Ghrelin and histamine were both contained in closed cells, not contacting the lumen, and were most numerous in the corpus. Gastrin cells were confined to the antrum, and 5-hydroxytryptamine (5-HT) and somatostatin cells were more frequent in the antrum than the corpus. Most somatostatin cells had basal processes that in the antrum commonly contacted gastrin cells. Peptide YY (PYY) cells were rare and mainly in the antrum. The only numerous colocalisations were 5-HT and histamine, PYY and gastrin and gastrin and histamine in the antrum, but each of these populations was small. Peptide-containing nerve fibres were found in the mucosa. One of the most common types was vasoactive intestinal peptide (VIP) fibres. High-resolution analysis showed that ghrelin cells were closely and selectively approached by VIP fibres. In contrast, gastrin cells were not selectively innervated by VIP or CGRP fibres. The study indicates that there are distinct populations of gastric EEC and selective innervation of ghrelin cells. It also shows that, in contrast to EEC of the small intestine, the majority of EEC within the stomach contained only a single hormone.
Mitochondrial oxidative phosphorylation controls cancer cell's life and death decisions upon exposure to MAPK inhibitors.
Oncotarget, 2016

Although MAPK pathway inhibitors are becoming a promising anticancer strategy, they are insufficient to fully eliminate cancer cells and their long-term efficacy is strikingly limited in patients with BRAF-mutant melanomas. It is well established that BRAF inhibitors (BRAFi) hamper glucose uptake before the apparition of cell death. Here, we show that BRAFi induce an extensive restructuring of mitochondria including an increase in mitochondrial activity and biogenesis associated with mitochondrial network remodeling. Furthermore, we report a close interaction between ER and mitochondria in melanoma exposed to BRAFi. This physical connection facilitates mitochondrial Ca2+ uptake after its release from the ER. Interestingly, Mfn2 silencing disrupts the ER-mitochondria interface, intensifies ER stress and exacerbates ER stress-induced apoptosis in cells exposed to BRAFi in vitro and in vivo. This mitochondrial control of ER stress-mediated cell death is similar in both BRAF- and NRAS-mutant melanoma cells exposed to MEK inhibitors. This evidence reinforces the relevance in combining MAPK pathway inhibitors with mitochondriotropic drugs to improve targeted therapies.
Animal models in addiction research: A dimensional approach.
Neuroscience and biobehavioral reviews, 2019

Drug addiction affects approximately 10% of the population and these numbers are rising. Treatment and prevention of addiction are impeded by current diagnostic systems, such as DSM-5, which are based on outcomes rather than processes. Here, we review the importance of adopting a dimensional framework, specifically the Research Domain Criteria (RDoC), to identify protective and vulnerability mechanisms in addiction. We discuss how preclinical researchers should work within this framework to develop animal models based on domains of function. We highlight RDoC paradigms related to addiction and discuss how these can be used to investigate the biological underpinnings of an addiction cycle (i.e., binge/intoxication, negative affect, and craving). Using this information, we then outline the critical role of animal research in ongoing revisions to the RDoC matrix (specifically the functional significance of domains, constructs and subconstructs) and its contribution to the development and refinement of addiction theories. We conclude with an overview of the contribution that animal research has made to the development of pharmacological and behavioural treatments for addiction.
Patch clamp recordings from mouse retinal neurons in a dark-adapted slice preparation.
Journal of visualized experiments : JoVE, 2010

Our visual experience is initiated when the visual pigment in our retinal photoreceptors absorbs photons of light energy and initiates a cascade of intracellular events that lead to closure of cyclic-nucleotide-gated channels in the cell membrane. The resulting change in membrane potential leads in turn to reductions in the amount of neurotransmitter release from both rod and cone synaptic terminals. To measure how the light-evoked change in photoreceptor membrane potential leads to downstream activity in the retina, scientists have made electrophysiological recordings from retinal slice preparations for decades. In the past these slices have been cut manually with a razor blade on retinal tissue that is attached to filter paper; in recent years another method of slicing has been developed whereby retinal tissue is embedded in low gelling temperature agar and sliced in cool solution with a vibrating microtome. This preparation produces retinal slices with less surface damage and very robust light-evoked responses. Here we document how this procedure can be done under infrared light to avoid bleaching the visual pigment.
Activity-dependent gating of calcium spikes by A-type K+ channels controls climbing fiber signaling in Purkinje cell dendrites.
Neuron, 2014

In cerebellar Purkinje cell dendrites, heterosynaptic calcium signaling induced by the proximal climbing fiber (CF) input controls plasticity at distal parallel fiber (PF) synapses. The substrate and regulation of this long-range dendritic calcium signaling are poorly understood. Using high-speed calcium imaging, we examine the role of active dendritic conductances. Under basal conditions, CF stimulation evokes T-type calcium signaling displaying sharp proximodistal decrement. Combined mGluR1 receptor activation and depolarization, two activity-dependent signals, unlock P/Q calcium spikes initiation and propagation, mediating efficient CF signaling at distal sites. These spikes are initiated in proximal smooth dendrites, independently from somatic sodium action potentials, and evoke high-frequency bursts of all-or-none fast-rising calcium transients in PF spines. Gradual calcium spike burst unlocking arises from increasing inactivation of mGluR1-modulated low-threshold A-type potassium channels located in distal dendrites. Evidence for graded activity-dependent CF calcium signaling at PF synapses refines current views on cerebellar supervised learning rules.
A small-molecule enhancer of autophagy decreases levels of Abeta and APP-CTF via Atg5-dependent autophagy pathway.
FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2011

The hallmarks of Alzheimer's disease are the aggregates of amyloid-β (Αβ) peptide and tau protein. Autophagy is one major cellular pathway leading to the removal of aggregated proteins. We examined the possibility of inducing autophagy to reduce Aβ peptide and the amyloid precursor protein (APP)-derived fragment APP-CTF levels in cell lines and primary neuronal cultures. We found that induction of autophagy either by small-molecule enhancers of rapamycin (SMER)28, a small-molecule enhancer of autophagy, or following starvation greatly decreased the levels of Aβ peptide (apparent EC(50) of ∼10 μM) and APP-CTF (apparent EC(50) of ∼20 μM) in a γ-secretase-independent manner. Pharmacological inhibition of autophagy led to a significant accumulation of Aβ peptide and APP-CTF and diminished the effect of SMER28. Three essential components of the autophagic pathway, autophagy-related protein (Atg)5, Beclin1, and Ulk1, were shown to be involved in the degradation of Aβ and APP-CTF, and Atg5 was necessary for the effect of SMER28. In addition, the autophagic marker light chain 3-II cocompartmentalized with APP-CTF. These results support the involvement of autophagy in the clearance of Aβ and APP-CTF. We therefore propose that small molecule enhancers of autophagy, such as SMER28, may have therapeutic potential for the treatment of Alzheimer's disease and other proteinopathies.
The profile of behavioral and psychological symptoms in vascular cognitive impairment with and without dementia.
Annals of Indian Academy of Neurology, 2013

The objective of this study was to compare the occurrence and severity of behavioral and psychological symptoms of dementia (BPSD) between vascular dementia (VaD) and vascular cognitive impairment-no dementia (VCI-ND).
Attenuation of polyglutamine-induced toxicity by enhancement of mitochondrial OXPHOS in yeast and fly models of aging.
Microbial cell (Graz, Austria), 2016

Defects in mitochondrial biogenesis and function are common in many neurodegenerative disorders, including Huntington's disease (HD). We have previously shown that in yeast models of HD, enhancement of mitochondrial biogenesis through overexpression of Hap4, the catalytic subunit of the transcriptional complex that regulates mitochondrial gene expression, alleviates the growth arrest induced by expanded polyglutamine (polyQ) tract peptides in rapidly dividing cells. However, the mechanism through which
ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy.
Clinical cancer research : an official journal of the American Association for Cancer Research, 2014

Little is known about the optimal clinical use of ABT-888 (veliparib) for treatment of glioblastoma. ABT-888 is a PARP inhibitor undergoing extensive clinical evaluation in glioblastoma, because it may synergize with the standard-of-care temozolomide (TMZ). We have elucidated important factors controlling ABT-888 efficacy in glioblastoma.
Sex differences in the effects of prenatal bisphenol A exposure on autism-related genes and their relationships with the hippocampus functions.
Scientific reports, 2021

Our recent study has shown that prenatal exposure to bisphenol A (BPA) altered the expression of genes associated with autism spectrum disorder (ASD). In this study, we further investigated the effects of prenatal BPA exposure on ASD-related genes known to regulate neuronal viability, neuritogenesis, and learning/memory, and assessed these functions in the offspring of exposed pregnant rats. We found that prenatal BPA exposure increased neurite length, the number of primary neurites, and the number of neurite branches, but reduced the size of the hippocampal cell body in both sexes of the offspring. However, in utero exposure to BPA decreased the neuronal viability and the neuronal density in the hippocampus and impaired learning/memory only in the male offspring while the females were not affected. Interestingly, the expression of several ASD-related genes (e.g. Mief2, Eif3h, Cux1, and Atp8a1) in the hippocampus were dysregulated and showed a sex-specific correlation with neuronal viability, neuritogenesis, and/or learning/memory. The findings from this study suggest that prenatal BPA exposure disrupts ASD-related genes involved in neuronal viability, neuritogenesis, and learning/memory in a sex-dependent manner, and these genes may play an important role in the risk and the higher prevalence of ASD in males subjected to prenatal BPA exposure.
Short- and Long-Term Evaluation of Renal Function after Radical Cystectomy and Cutaneous Ureterostomy in High-Risk Patients.
Journal of clinical medicine, 2020

Deterioration of renal function has been reported after radical cystectomy (RC) with urinary diversion. We investigated renal function changes in elderly bladder cancer (BCa) patients who underwent RC with cutaneous ureterostomy (CU) urinary diversion. We performed a retrospective, observational study. BCa patients aged ≥75 with an American Society of Anesthesiologists (ASA) class greater than II were included. Glomerular filtration rate (GFR) was the main outcome measure. GFR values were recorded preoperatively, at discharge, at 6-month follow-up, and yearly up to 60 months. A total of 70 patients with a median age of 78.0 years were identified. Median preoperative GFR was 74.3 mL/min/1.73 m
A Pilot Study Investigating the Role of Gender in the Intergenerational Relationships between Gene Expression, Chronic Pain, and Adverse Childhood Experiences in a Clinical Sample of Youth with Chronic Pain.
Epigenomes, 2021

Chronic pain is a highly prevalent and costly issue that often emerges during childhood or adolescence and persists into adulthood. Adverse childhood experiences (ACEs) increase risk for several adverse health conditions, including chronic pain. Recent evidence suggests that parental trauma (ACEs, post-traumatic stress disorder (PTSD) symptoms) confers risk of poor health outcomes in their children. Intergenerational relationships between parental trauma and child chronic pain may be mediated by epigenetic mechanisms. A clinical sample of youth with chronic pain and their parents completed psychometrically sound questionnaires assessing ACEs, PTSD symptoms, and chronic pain, and provided a saliva sample. These were used to investigate the intergenerational relationships between four epigenetic biomarkers (COMT, DRD2, GR, and SERT), trauma, and chronic pain. The results indicated that the significant biomarkers were dependent upon the gender of the child, wherein parental ACEs significantly correlated with changes in DRD2 expression in female children and altered COMT expression in the parents of male children. Additionally, the nature of the ACE (maltreatment vs. household dysfunction) was associated with the specific epigenetic changes. There may be different pathways through which parental ACEs confer risk for poor outcomes for males and females, highlighting the importance of child gender in future investigations.
Transcranial direct current stimulation for refractory auditory hallucinations in schizophrenia.
The Journal of clinical psychiatry, 2013

Some patients with schizophrenia may suffer from continuous or severe auditory hallucinations that are refractory to antipsychotic drugs, including clozapine. Such patients may benefit from a short trial of once- to twice-daily transcranial direct current stimulation (tDCS) with the cathode placed over the left temporoparietal cortex and the anode over the left dorsolateral prefrontal cortex; negative, cognitive, and other symptoms, if present, may also improve. At present, the case for tDCS treatment of refractory auditory hallucinations rests on 1 well-conducted randomized, sham tDCS-controlled trial and several carefully documented and instructive case reports. Benefits with up to 3 years of maintenance tDCS have also been described. In patients with refractory auditory hallucinations, tDCS has been delivered at 1- to 3-mA current intensity during 20-30 minutes in once- to twice-daily sessions for up to 3 years with no apparent adverse effects. Transcranial direct current stimulation therefore appears to be a promising noninvasive brain stimulation technique for patients with antipsychotic-refractory auditory hallucinations.
Pluripotency regulators in human mesenchymal stem cells: expression of NANOG but not of OCT-4 and SOX-2.
Stem cells and development, 2011

Mesenchymal stem cells (MSCs) are adult multipotent cells able to differentiate toward mature mesodermal lineages. In spite of more than a decade of investigation, little is known about the molecular mechanisms regulating the undifferentiated state and the identity of distinct functional subpopulations in these cells. Transcription factors that regulate the maintenance of the pluripotent state in embryonic stem cells, including NANOG, SOX2, and OCT4, have been proposed to play a similar role also in adult stem cells, although with conflicting results. We performed a critical evaluation of expression of these 3 transcription factors and found that NANOG, but not OCT-4 and SOX-2, is expressed in cultured human adult MSCs. Actually, NANOG was not expressed in freshly isolated MSCs, but was detected only after in vitro culture. NANOG was detected only in proliferating cells, but not in MSCs induced to differentiate. The percentage of cells expressing NANOG was maintained throughout early passages of MSCs, but then started to decrease in late passages in MSCs from adipose tissue and heart but not from bone marrow. However, the number of NANOG-expressing cells did not associate with the proliferative and differentiative capabilities of MSC populations, neither its expression appeared to identify cells having stem or progenitor cell properties. Accordingly, we propose that activation of NANOG expression in MSCs is associated with, although cannot directly regulate, the transition from in vivo quiescence to adaptation to in vitro growth conditions.