Enterochromaffin cells were the first endocrine cells of the gastrointestinal tract to be chemically distinguished, almost 150 years ago. It is now known that the chromaffin reaction of these cells ...was due to their content of the reactive aromatic amine, 5‐hydroxytryptamine (5‐HT, also known as serotonin). They have commonly been thought to be a special class of gut endocrine cells (enteroendocrine cells) that are distinct from the enteroendocrine cells that contain peptide hormones. The study by Martin et al. in the current issue of this journal reveals that the patterns of expression of nutrient receptors and transporters differ considerably between chromaffin cells of the mouse duodenum and colon. However, even within regions, chromaffin cells differ; in the duodenum there are chromaffin cells that contain both secretin and 5‐HT, cholecystokinin and 5‐HT, and all three of secretin, cholecystokinin, and 5‐HT. Moreover, the ratios of these different cell types differ substantially between species. And, in terms of function, 5‐HT has many roles, including in appetite, motility, fluid secretion, release of digestive enzymes and bone metabolism. The paper thus emphasizes the need to define the many different classes of enterochromaffin cells and relate this to their roles.
Enterochromaffin cells have commonly been thought to be a special class of gut endocrine cells that are distinct from the enteroendocrine cells that contain peptide hormones. This review indicates that they overlap with peptide hormone‐containing cells and exhibit considerable heterogeneity.
The brain-gut-microbiome axis (BGMA) is a pivotal contributor to human health. A large body of research, especially from animal models, has revealed bidirectional, causal relationships between the ...BGMA and sex. In particular, sex steroids appear to be affected by the BGMA, to influence the BGMA, and to moderate environmental effects on the BGMA. However, animal research on the relationship between sex and the BGMA has not translated well to human models. We contend that this is due in part to an oversimplified approach to sex: although BGMA researchers have traditionally approached sex as a unidimensional, dichotomous variable, it is in fact multidimensional and is comprised of both multi-categorical and continuous dimensions. We also contend that research on the BGMA in humans should approach gender as a variable that is distinct from sex and that gender may influence the BGMA through pathways that are independent from the effects of sex alone. Research practices that consider the complexity and distinctiveness of sex and gender in relation to the human BGMA will not only yield improved understanding of this consequential system, but will also enhance the development of treatments for adverse health outcomes with BGMA-related etiologies. We conclude with recommendations for the implementation of such practices.
Mental health problems are often assumed to have their roots in early-life experiences. However, memories acquired in infancy are rapidly forgotten in nearly all species (including humans). As yet, a ...testable mechanism on how early-life experiences have a lasting impact on mental health is lacking. In these experiments, we tested the idea that infant adversity leads to an early transition into adult-like fear retention, allowing infant memories to have a longer-lasting influence. Rats were exposed to maternal separation (3 h per day) across postnatal days (P) 2-14, or their mother was given corticosterone in her drinking water across the same period. Infant rats were then trained to fear a conditioned stimulus (CS) paired with an aversive unconditioned stimulus (US) on P17. Retention of the fear association was then tested 1-55 days later. When tested one day after the CS-US association was formed, both standard-reared (SR) and maternally-separated (MS) rats exhibited strong memory. However, when tested 10 days later, SR rats exhibited robust forgetting, whereas MS rats exhibited near-perfect retention. These effects were mimicked by exposing the mother to the stress hormone corticosterone in the drinking water. Finally, fear associations in P17 MS rats were retained for up to 30 days. Our findings point to differences in retention of fear as one factor that might underlie the propensity of stress-exposed individuals to exhibit early anxiety symptoms and suggest that manipulations of the corticosterone system may hold the key to ameliorating some of the effects of early stress on persistent retention of fear.
To determine if there are in vivo differences in γ-aminobutyric acid (GABA) in the motor cortex and subcortical white matter of patients with amyotrophic lateral sclerosis (ALS) compared with healthy ...controls using proton magnetic resonance spectroscopy (1H-MRS).
In this cross-sectional study, 10 patients with ALS and 9 age- and sex-matched healthy controls (HCs) underwent 3T edited 1H-MRS to quantify GABA centered on the motor cortex and the subcortical white matter.
Compared with healthy controls, patients with ALS had significantly lower levels of GABA in the left motor cortex (1.42 ± 0.27 arbitrary institutional units vs. 1.70 ± 0.24 arbitrary institutional units, p = 0.038). There was no significant difference in GABA levels between groups in the subcortical white matter (p > 0.05).
Decreased levels of GABA are present in the motor cortex of patients with ALS compared to HCs. Findings are consistent with prior reports of alterations in GABA receptors in the motor cortex as well as increased cortical excitability in the context of ALS. Larger, longitudinal studies are needed to confirm these findings and to further our understanding of the role of GABA in the pathogenesis of ALS.
Painful diabetic neuropathy Peltier, Amanda; Goutman, Stephen A; Callaghan, Brian C
BMJ (Online),
05/2014, Letnik:
348, Številka:
may06 1
Journal Article
Recenzirano
Diabetes is a worldwide epidemic, and associated neuropathy is its most costly and disabling complication. Given the rising prevalence of painful diabetic neuropathy, it is increasingly important ...that we understand the best ways to diagnose and treat this condition. Diagnostic tests in this field are evolving rapidly. These include the use of skin biopsies to measure small unmyelinated fibers, as well as even newer techniques that can measure both small unmyelinated fibers and large myelinated fibers in the same biopsy. The main treatments for painful diabetic neuropathy remain management of the underlying diabetes and drugs for the relief of pain. However, emerging evidence points to major differences between type 1 and type 2 diabetes, including the ability of glycemic control to prevent neuropathy. Enhanced glucose control is much more effective at preventing neuropathy in patients with type 1 diabetes than in those with type 2 disease. This dichotomy emphasizes the need to study the pathophysiologic differences between the two types of diabetes, because different treatments may be needed for each condition. The impact of the metabolic syndrome on neuropathy in patients with type 2 diabetes may account for the difference between the two types of diabetes and requires further study. Finally, neuropathic pain is under-recognized and undertreated despite an ever evolving list of effective drugs. Evidence exists to support several drugs, but the optimal sequence and combination of these drugs are still to be determined.
Recently, scientific interest in the brain-gut axis has grown dramatically, particularly with respect to the link between gastrointestinal and psychiatric dysfunction. However, the role of gut ...function in early emotional dysregulation is yet to be examined, despite the prevalence and treatment resistance of early-onset psychiatric disorders. The present studies utilized a developmental rodent model of early-life stress (ELS) to explore this gap. Rats were exposed to maternal separation (MS) on postnatal days 2-14. Throughout MS, dams received either vehicle or a probiotic formulation (previously shown to reduce gastrointestinal dysfunction) in their drinking water. Replicating past research, untreated MS infants exhibited an adult-like profile of long-lasting fear memories and fear relapse following extinction. In contrast, probiotic-exposed MS infants exhibited age-appropriate infantile amnesia and resistance to relapse. These effects were not mediated by changes in pups' or dams' anxiety at the time of training, nor by maternal responsiveness. Overall, probiotics acted as an effective and non-invasive treatment to restore normal developmental trajectories of emotion-related behaviors in infant rats exposed to ELS. These results provide promising initial evidence for this novel approach to reduce the risk of mental health problems in vulnerable individuals. Future studies are needed to test this treatment in humans exposed to ELS and to elucidate mechanisms for the observed behavioral changes.
Recent studies suggest that the accumulation of atypical, 1-deoxysphingolipids that lack the C1 hydroxyl group may be associated with diabetic neuropathy (DN). We hypothesized that specific plasma ...1-deoxysphingolipids associate with DN severity, and that alterations in plasma serine and alanine associate with 1-deoxysphingolipid elevation in patients with type 2 diabetes (T2D). We examined individual 1-deoxysphingolipid species using LC/MS/MS in plasma samples from 75 individuals including lean controls (LC, n = 19), those with obesity (n = 19), obesity with T2D without DN (ob/T2D, n = 18), and obesity with T2D with DN (Ob/T2D/DN, n = 19). We observed a step wise increase in 1-deoxydihydroceramides across these four groups (spearman correlation coefficient r = 0.41, p = 0.0002). Mean total concentrations of 1-deoxydihydroceramides, and most individual 1-deoxydihydroceramide species, were higher in ob/T2D/DN versus LC group (8.939 vs. 5.195 pmol/100 μL for total 1-deoxydihydroceramides p = 0.005). No significant differences in 1-deoxydihydroceramides were observed between the ob/T2D and ob/T2D/DN groups. l-alanine was higher and l-serine lower in ob/T2D/DN versus LC groups (326.2 vs. 248.0 μM, p = 0.0086 and 70.2 vs. 89.8 μM, p = 0.0110), consistent with a potential contribution of these changes to the observed 1-deoxysphingolipids profiles. 1-deoxydihydroceramides correlated inversely with leg intraepidermal nerve fiber density (CC -0.40, p = 0.003). These findings indicate that 1-deoxydihydroceramides may be important biomarkers and/or mediators of DN.
•Plasma deoxydihydroceramides correlate with diabetic neuropathy severity.•Advanced mass spectrometry methods reveal elevated deoxydihydroceramides in diabetes.•Low plasma serine associated with elevations in deoxydihydroceramides in diabetes.
While epigenetic mechanisms such as DNA methylation and histone modification are known to be important for gene suppression, relatively little is still understood about the interplay between these ...systems. The UHRF1 protein can interact with both DNA methylation and repressive chromatin marks, but its primary function in humans has been unclear. To determine what that was, we first established stable UHRF1 knockdowns (KD) in normal, immortalized human fibroblasts using targeting shRNA, since CRISPR knockouts (KO) were lethal. Although these showed a loss of DNA methylation across the whole genome, transcriptional changes were dominated by the activation of genes involved in innate immune signalling, consistent with the presence of viral RNA from retrotransposable elements (REs). We confirmed using mechanistic approaches that 1) REs were demethylated and transcriptionally activated; 2) this was accompanied by activation of interferons and interferon-stimulated genes and 3) the pathway was conserved across other adult cell types. Restoring UHRF1 in either transient or stable KD systems could abrogate RE reactivation and the interferon response. Notably, UHRF1 itself could also re-impose RE suppression independent of DNA methylation, but not if the protein contained point mutations affecting histone 3 with trimethylated lysine 9 (H3K9me3) binding. Our results therefore show for the first time that UHRF1 can act as a key regulator of retrotransposon silencing independent of DNA methylation.
The adverse effects of early‐life stress are pervasive, with well‐established mental and physical health consequences for exposed individuals. The impact of early adverse experiences is also highly ...persistent, with documented increases in risk for mental illness across the life span that are accompanied by stable alterations in neural function and hormonal responses to stress. Here, we review some of these ‘stress phenotypes’, with a focus on intermediary factors that may signal risk for long‐term mental health outcomes, such as altered development of the fear regulation system. Intriguingly, recent research suggests that such stress phenotypes may persist even beyond the life span of the individuals, with consequences for their offspring and grand‐offspring. Phenotypic characteristics may be transmitted to future generations via either the matriline or the patriline, a phenomenon that has been demonstrated in both human and animal studies. In this review, we highlight behavioral and epigenetic factors that may contribute to this multigenerational transmission and discuss the potential of various treatment approaches that may halt the cycle of stress phenotypes.
Various animal and human models have been used to study the transmission of stressed phenotypes across generations.
Functional variomics provides the foundation for personalized medicine by linking genetic variation to disease expression, outcome and treatment, yet its utility is dependent on appropriate assays to ...evaluate mutation impact on protein function. To fully assess the effects of 106 missense and nonsense variants of PTEN associated with autism spectrum disorder, somatic cancer and PTEN hamartoma syndrome (PHTS), we take a deep phenotypic profiling approach using 18 assays in 5 model systems spanning diverse cellular environments ranging from molecular function to neuronal morphogenesis and behavior. Variants inducing instability occur across the protein, resulting in partial-to-complete loss-of-function (LoF), which is well correlated across models. However, assays are selectively sensitive to variants located in substrate binding and catalytic domains, which exhibit complete LoF or dominant negativity independent of effects on stability. Our results indicate that full characterization of variant impact requires assays sensitive to instability and a range of protein functions.
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