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Alcohol (Fayetteville, N.Y.) May 2017Epigenetic mechanisms are important for facilitating gene-environment interactions in many disease etiologies, including Fetal Alcohol Spectrum Disorders (FASD).... (Review)
Review
Epigenetic mechanisms are important for facilitating gene-environment interactions in many disease etiologies, including Fetal Alcohol Spectrum Disorders (FASD). Extensive research into the role of DNA methylation and miRNAs in animal models has illuminated the complex role of these mechanisms in FASD. In contrast, histone modifications have not been as well researched, due in part to being less stable than DNA methylation and less well-characterized in disease. It is now apparent that even changes in transient marks can have profound effects if they alter developmental trajectories. In addition, many histone methylations are now known to be relatively stable and can propagate themselves. As technologies and knowledge have advanced, a small group has investigated the role of histone modifications in FASD. Here, we synthesize the data on the effects of prenatal alcohol exposure (PAE) on histone modifications. Several key points are evident. AS with most alcohol-induced outcomes, timing and dosage differences yield variable effects. Nevertheless, these studies consistently find enrichment of H3K9ac, H3K27me2,3, and H3K9me2, and increased expression of histone acetyltransferases and methyltransferases. The consistency of these alterations may implicate them as key mechanisms underlying FASD. Histone modification changes do not often correlate with gene expression changes, though some important examples exist. Encouragingly, attempts to reproduce specific histone modification changes are very often successful. We comment on possible directions for future studies, focusing on further exploration of current trends, expansion of time-point and dosage regimes, and evaluation of biomarker potential.
Topics: Acetylation; Alcohol Drinking; Animals; Brain; Chromatin Assembly and Disassembly; DNA Methylation; Disease Models, Animal; Epigenesis, Genetic; Female; Fetal Alcohol Spectrum Disorders; Gestational Age; Histocompatibility Antigens; Histone Acetyltransferases; Histone-Lysine N-Methyltransferase; Histones; Humans; Maternal Exposure; Methylation; Pregnancy; Prenatal Exposure Delayed Effects; Protein Processing, Post-Translational
PubMed: 28431792
DOI: 10.1016/j.alcohol.2017.01.005 -
Molecular Genetics and Metabolism Jun 2023Lacking direct neuropathological data, neuroimaging exploration has become the most powerful tool to give insight into pathophysiological alterations of early-treated... (Review)
Review
Lacking direct neuropathological data, neuroimaging exploration has become the most powerful tool to give insight into pathophysiological alterations of early-treated PKU (ETPKU) patients. We conducted a systematic review of neuroimaging studies in ETPKU patients to explore 1) the occurrence of consistent neuroimaging alterations; 2) the relationship between them and neurological and cognitive disorders; 3) the contribution of neuroimaging in the insight of neuropathological background of ETPKU subjects; 4) whether brain neuroimaging may provide additional information in the monitoring of the disease course. Thirty-eight studies met the inclusion criteria for the full-text review, including morphological T1/T2 sequences, diffusion brain imaging (DWI/DTI) studies, brain MRI volumetric, functional neuroimaging studies, neurotransmission and brain energetic imaging studies. Non-progressive brain white matter changes were the most frequent and precocious alterations. As confirmed in hundreds of young adults with ETPKU, they affect over 90% of ETPKU patients. Consistent correlations are emerging between microstructural alteration (as detected by DWI/DTI) and metabolic control, which have also been confirmed in a few interventional trials. Volumetric studies detected later and less consistent cortical and subcortical grey matter alterations, which seem to be influenced by the patient's age and metabolic control. The few functional neuroimaging studies so far showed preliminary but interesting data about cortical activation patterns, skill performance, and brain connectivity. Further research is mandatory in these more complex areas. Recurrent methodological limitations include restricted sample sizes concerning the clinical variability of the disease, large age-range, variable measures of metabolic control, and prevalence of cross-sectional rather than longitudinal interventional studies.
Topics: Young Adult; Humans; Cross-Sectional Studies; Phenylketonurias; Brain; Neuroimaging; White Matter
PubMed: 37149991
DOI: 10.1016/j.ymgme.2023.107588 -
The Mental Health Clinician Nov 2016Schizophrenia is a severe disorder affecting approximately 1% of the population. Historically, alterations of dopaminergic function were considered the primary cause of...
Schizophrenia is a severe disorder affecting approximately 1% of the population. Historically, alterations of dopaminergic function were considered the primary cause of schizophrenia. However, for many patients, drugs that alter dopaminergic function do not consistently lead to resolution of the symptoms of schizophrenia. Thus, there is an increased interest in pathophysiologic processes that result in altered neurodevelopment and plasticity associated with schizophrenia. Brain-derived neurotrophic factor (BDNF) is a neurotrophin involved in neurogenesis, synaptic plasticity, cognition, and neurotransmission. Genetic polymorphism, expression, and function of BDNF have been implicated in psychiatric diseases, including schizophrenia. This review discusses BDNF, its role in neurologic processes, and the evidence implicating BDNF in schizophrenia.
PubMed: 29955483
DOI: 10.9740/mhc.2016.11.285 -
Current Pharmaceutical Design 2016Molecular pathogenesis of hepatocellular carcinoma is complex and implies a multistep process involving different genetic and epigenetic alterations, as well as altered... (Review)
Review
BACKGROUND
Molecular pathogenesis of hepatocellular carcinoma is complex and implies a multistep process involving different genetic and epigenetic alterations, as well as altered molecular pathways. Among these features, oxidative stress and mitochondria dysfunction represent an important trigger to hepatocarcinogenesis regardless of underlying liver disease etiology. An important part of the actual cancer research is focused on the molecular mechanisms and the signaling pathways involved in the process of so called "mitochondrial malignancy".
METHOD
Aim of this review is to summarize the main molecular mechanisms and the pathological consequences of oxidative stress and mitochondrial dysfunction in liver cancer. Furthermore, an up-to-date insight in therapeutic implications of the aforementioned processes is consistently developed. A literature search was conducted using PubMed until October 2015, based on English language journals.
RESULTS
Mitochondrial dysfunction may dramatically alter cell growth and proliferation by means of several "retrograde" mitochondria-nucleus signaling pathways, all of which have been shown to play a significant role in hepatocarcinogenesis. Nuclear oncogenes and tumor suppressors alike regulate mitochondrial turnover and function in a thick cross-talk whose role is fundamental in human oncology.
CONCLUSION
The current knowledge on the role of mitochondrial signaling and oxidative stress in hepatocarcinogenesis seems to support the use of antioxidant agents in hepatocarcinoma patients, for instance in the adjuvant setting after radical treatments where their favorable cost-effective and safety profile may enable long-terms therapies aimed at preventing tumor recurrence. Data from randomized-controlled trials are warranted in order to confirm these promising results.
Topics: Animals; Antineoplastic Agents; Antioxidants; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Mitochondria; Oxidative Stress; Signal Transduction
PubMed: 26861645
DOI: 10.2174/1381612822666160209153624 -
Ecology and Evolution Dec 2021Trait and functional trait approaches have revolutionized ecology improving our understanding of community assembly, species coexistence, and biodiversity loss. Focusing... (Review)
Review
Trait and functional trait approaches have revolutionized ecology improving our understanding of community assembly, species coexistence, and biodiversity loss. Focusing on traits promotes comparability across spatial and organizational scales, but terms must be used consistently. While several papers have offered definitions, it remains unclear how ecologists operationalize "trait" and "functional trait" terms. Here, we evaluate how researchers and the published literatures use these terms and explore differences among subdisciplines and study systems (taxa and biome). By conducting both a survey and a literature review, we test the hypothesis that ecologists' working definition of "trait" is adapted or altered when confronting the realities of collecting, analyzing and presenting data. From 486 survey responses and 712 reviewed papers, we identified inconsistencies in the understanding and use of terminology among researchers, but also limited inclusion of definitions within the published literature. Discrepancies were not explained by subdiscipline, system of study, or respondent characteristics, suggesting there could be an inconsistent understanding even among those working in related topics. Consistencies among survey responses included the use of morphological, phonological, and physiological traits. Previous studies have called for unification of terminology; yet, our study shows that proposed definitions are not consistently used or accepted. Sources of disagreement include trait heritability, defining and interpreting function, and dealing with organisms in which individuals are not clearly recognizable. We discuss and offer guidelines for overcoming these disagreements. The diversity of life on Earth means traits can represent different features that can be measured and reported in different ways, and thus, narrow definitions that work for one system will fail in others. We recommend ecologists embrace the breadth of biodiversity using a simplified definition of "trait" more consistent with its common use. Trait-based approaches will be most powerful if we accept that traits are at least as diverse as trait ecologists.
PubMed: 34938447
DOI: 10.1002/ece3.8321 -
Exploration of Targeted Anti-tumor... 2021To investigate alterations in transcription of genes, encoding Ca toolkit proteins, in oesophageal adenocarcinoma (OAC) and to assess associations between gene...
AIM
To investigate alterations in transcription of genes, encoding Ca toolkit proteins, in oesophageal adenocarcinoma (OAC) and to assess associations between gene expression, tumor grade, nodal-metastatic stage, and patient survival.
METHODS
The expression of 275 transcripts, encoding components of the Ca toolkit, was analyzed in two OAC datasets: the Cancer Genome Atlas [via the University of Alabama Cancer (UALCAN) portal] and the oesophageal-cancer, clinical, and molecular stratification [Oesophageal Cancer Clinical and Molecular Stratification (OCCAMS)] dataset. Effects of differential expression of these genes on patient survival were determined using Kaplan-Meier log-rank tests. OAC grade- and metastatic-stage status was investigated for a subset of genes. Adjustment for the multiplicity of testing was made throughout.
RESULTS
Of the 275 Ca-toolkit genes analyzed, 75 displayed consistent changes in expression between OAC and normal tissue in both datasets. The channel-encoding genes, -methyl--aspartate receptor 2D (), transient receptor potential (TRP) ion channel classical or canonical 4 (), and TRP ion channel melastatin 2 () demonstrated the greatest increase in expression in OAC in both datasets. Nine genes were consistently upregulated in both datasets and were also associated with improved survival outcomes. The 6 top-ranking genes for the weighted significance of altered expression and survival outcomes were selected for further analysis: voltage-gated Ca channel subunit α 1D (), voltage-gated Ca channel auxiliary subunit α2 δ4 (), junctophilin 1 (), acid-sensing ion channel 4 (), , and secretory pathway Ca ATPase 2 (). , , and were also upregulated in advanced OAC tumor grades and nodal-metastatic stages in both datasets.
CONCLUSIONS
This study has unveiled alterations of the Ca toolkit in OAC, compared to normal tissue. Such Ca signalling findings are consistent with those from studies on other cancers. Genes that were consistently upregulated in both datasets might represent useful markers for patient diagnosis. Genes that were consistently upregulated, and which were associated with improved survival, might be useful markers for patient outcome. These survival-associated genes may also represent targets for the development of novel chemotherapeutic agents.
PubMed: 36046118
DOI: 10.37349/etat.2021.00063 -
International Journal of Molecular... Jul 2022DNA double-strand breaks (DSBs), classified as the most harmful type of DNA damage based on the complexity of repair, lead to apoptosis or tumorigenesis. In aging, DNA... (Review)
Review
DNA double-strand breaks (DSBs), classified as the most harmful type of DNA damage based on the complexity of repair, lead to apoptosis or tumorigenesis. In aging, DNA damage increases and DNA repair decreases. This is exacerbated in disease, as post-mortem tissue from patients diagnosed with mild cognitive impairment (MCI) or Alzheimer's disease (AD) show increased DSBs. A novel role for DSBs in immediate early gene (IEG) expression, learning, and memory has been suggested. Inducing neuronal activity leads to increases in DSBs and upregulation of IEGs, while increasing DSBs and inhibiting DSB repair impairs long-term memory and alters IEG expression. Consistent with this pattern, mice carrying dominant AD mutations have increased baseline DSBs, and impaired DSB repair is observed. These data suggest an adaptive role for DSBs in the central nervous system and dysregulation of DSBs and/or repair might drive age-related cognitive decline (ACD), MCI, and AD. In this review, we discuss the adaptive role of DSBs in hippocampus-dependent learning, memory, and IEG expression. We summarize IEGs, the history of DSBs, and DSBs in synaptic plasticity, aging, and AD. DSBs likely have adaptive functions in the brain, and even subtle alterations in their formation and repair could alter IEGs, learning, and memory.
Topics: Alzheimer Disease; Animals; DNA; DNA Breaks, Double-Stranded; DNA Repair; Hippocampus; Mice; Neurons
PubMed: 35955487
DOI: 10.3390/ijms23158352 -
The Science of the Total Environment Feb 2023Anthropogenic stressors on the environment are increasing at unprecedented rates and include urbanization, nutrient pollution, water management, altered land use and...
Anthropogenic stressors on the environment are increasing at unprecedented rates and include urbanization, nutrient pollution, water management, altered land use and climate change. Their effects on disease vectors are poorly understood. A series of full factorial experiments investigated how key human induced abiotic pressures, and interactions between these, affect population parameters of the cosmopolitan disease vector, Culex pipiens s.l. Selected pressures include eutrophication, salinity, mean temperature, and temperature fluctuation. Data were collected for each individual pressure and for potential interactions between eutrophication, salinization and temperature. All experiments assessed survival, time to pupation, time to emergence, sex-ratio and ovipositioning behavior. The results show that stressors affect vector survival, may speed up development and alter female to male ratio, although large differences between stressors exist to quite different extents. While positive effects of increasing levels of eutrophication on survival were consistent, negative effects of salinity on survival were only apparent at higher temperatures, thus indicating a strong interaction effect between salinization and temperature. Temperature had no independent effect on larval survival. Overall, increasing eutrophication and temperatures, and the fluctuations thereof, lowered development rate, time to pupation and time to emergence while increasing levels of salinity increased development time. Higher levels of eutrophication positively impacted egg-laying behavior; the reverse was found for salinity while no effects of temperature on egg-laying behavior were observed. Results suggest large and positive impacts of anthropogenically induced habitat alterations on mosquito population dynamics. Many of these effects are exacerbated by increasing temperatures and fluctuations therein. In a world where eutrophication and salinization are increasingly abundant, mosquitoes are likely important benefactors. Ultimately, this study illustrates the importance of including multiple and combined stressors in predictive models as well as in prevention and mitigation strategies, particularly because they resonate with possible, but yet underdeveloped action plans.
Topics: Animals; Male; Female; Humans; Culicidae; Mosquito Vectors; Culex; Eutrophication; Larva; Temperature
PubMed: 36302419
DOI: 10.1016/j.scitotenv.2022.159716 -
Biological Psychiatry Sep 2015For over a century, clinicians have consistently described the paradoxical co-existence in posttraumatic stress disorder (PTSD) of sensory intrusive hypermnesia and... (Review)
Review
For over a century, clinicians have consistently described the paradoxical co-existence in posttraumatic stress disorder (PTSD) of sensory intrusive hypermnesia and declarative amnesia for the same traumatic event. Although this amnesia is considered as a critical etiological factor of the development and/or persistence of PTSD, most current animal models in basic neuroscience have focused exclusively on the hypermnesia, i.e., the persistence of a strong fear memory, neglecting the qualitative alteration of fear memory. The latest is characterized by an underrepresentation of the trauma in the context-based declarative memory system in favor of its overrepresentation in a cue-based sensory/emotional memory system. Combining psychological and neurobiological data as well as theoretical hypotheses, this review supports the idea that contextual amnesia is at the core of PTSD and its persistence and that altered hippocampal-amygdalar interaction may contribute to such pathologic memory. In a first attempt to unveil the neurobiological alterations underlying PTSD-related hypermnesia/amnesia, we describe a recent animal model mimicking in mice some critical aspects of such abnormal fear memory. Finally, this line of argument emphasizes the pressing need for a systematic comparison between normal/adaptive versus abnormal/maladaptive fear memory to identify biomarkers of PTSD while distinguishing them from general stress-related, potentially adaptive, neurobiological alterations.
Topics: Animals; Disease Models, Animal; Fear; Humans; Memory Disorders; Mice; Stress Disorders, Post-Traumatic
PubMed: 26238378
DOI: 10.1016/j.biopsych.2015.06.017 -
Biophysical Reviews Aug 2023Diabetes mellitus (DM) leads to medical complications, the epidemiologically most important of which is diabetic peripheral neuropathy (DPN). Electrophysiology is a... (Review)
Review
Diabetes mellitus (DM) leads to medical complications, the epidemiologically most important of which is diabetic peripheral neuropathy (DPN). Electrophysiology is a major component of neural functioning and several studies have been undertaken to elucidate the neural electrophysiological alterations caused by DM and their mechanisms of action. Due to the importance of electrophysiology for neuronal function, the review of the studies dealing predominantly with electrophysiological parameters and mechanisms in the neuronal somata of peripheral neural ganglia of diabetic animals during the last 45 years is here undertaken. These studies, using predominantly techniques of electrophysiology, most frequently patch clamp for voltage clamp studies of transmembrane currents through ionic channels, have investigated the experimental DPN. They also have demonstrated that various cellular and molecular mechanisms of action of diabetic physiopathology at the level of biophysical electrical parameters are affected in DPN. Thus, they have demonstrated that several passive and active transmembrane voltage parameters, related to neuronal excitability and neuronal functions, are altered in diabetes. The majority of the studies agreed that DM produces depolarization of the resting membrane potential; alters excitability, increasing and decreasing it in dorsal root ganglia (DRG) and in nodose ganglion, respectively. They have tried to relate these changes to sensorial alterations of DPN. Concerning ionic currents, predominantly studied in DRG, the most frequent finding was increases in Na, Ca, and TRPV1 cation current, and decreases in K current. This review concluded that additional studies are needed before an understanding of the hierarchized, time-dependent, and integrated picture of the contribution of neural electrophysiological alterations to the DPN could be reached. DM-induced electrophysiological neuronal alterations that so far have been demonstrated, most of them likely important, are either consistent with the DPN symptomatology or suggest important directions for improvement of the elucidation of DPN physiopathology, which the continuation seems to us very relevant.
PubMed: 37681090
DOI: 10.1007/s12551-023-01094-1