Summary
Background
Serotonin (5‐hydroxytryptamine, 5‐HT) is an important mediator of every major gut‐related function. Recent investigations also suggest that 5‐HT can influence the development and ...severity of inflammation within the gut, particularly in the setting of inflammatory bowel disease (IBD).
Aim
To review the roles that the intestinal serotonin signalling system plays in gut function, with a specific focus on IBD.
Methods
We reviewed manuscripts from 1952 to 2017 that investigated and discussed roles for 5‐HT signalling in gastrointestinal function and IBD, as well as the influence of inflammation on 5‐HT signalling elements within the gut.
Results
Inflammation appears to affect every major element of intestinal 5‐HT signalling, including 5‐HT synthesis, release, receptor expression and reuptake capacity. Importantly, many studies (most utilising animal models) also demonstrate that modulation of selective serotonergic receptors (via agonism of 5‐HT4R and antagonism of 5‐HT3R) or 5‐HT signal termination (via serotonin reuptake inhibitors) can alter the likelihood and severity of intestinal inflammation and/or its complicating symptoms. However, there are few human studies that have studied these relationships in a targeted manner.
Conclusions
Insights discussed in this review have strong potential to lead to new diagnostic and therapeutic tools to improve the management of IBD and other related disorders. Specifically, strategies that focus on modifying the activity of selective serotonin receptors and reuptake transporters in the gut could be effective for controlling disease activity and/or its associated symptoms. Further studies in humans are required, however, to more completely understand the pathophysiological mechanisms underlying the roles of 5‐HT in this setting.
Quantitative RT-PCR: Pitfalls and Potential Freeman, Willard M; Walker, Stephen J; Vrana, Kent E
BioTechniques,
1999-January-01, 1999, 1999-Jan, 1999-01-00, 19990101, Letnik:
26, Številka:
1
Journal Article
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Reverse transcription PCR (RT-PCR) represents a sensitive and powerful tool for analyzing RNA. While it has tremendous potential for quantitative applications, a comprehensive knowledge of its ...technical aspects is required. Successful quantitative RT-PCR involves correction for experimental variations in individual RT and PCR efficiencies. This review addresses the mathematics of RT-PCR, choice of RNA standards (internal vs. external) and quantification strategies (competitive, noncompetitive and kinetic real-time amplification). Finally, the discussion turns to practical considerations in experimental design. It is hoped that this review will be appropriate for those undertaking these experiments for the first time or wishing to improve (or validate) a technique in what is frequently a confusing and contradictory field.
DNA hybridization arrays also known as macroarrays, microarrays and/or highdensity oligonucleotide arrays (Gene Chips™) bring gene expression analysis to a genomic scale by permitting investigators ...to simultaneously examine changes in the expression of literally thousands of genes. For hybridization arrays, the general approach is to immobilize gene-specific sequences (probes) on a solid state matrix (nylon membranes, glass microscope slides, silicon/ceramic chips). These sequences are then queried with labeled copies of nucleic acids from biological samples (targets). The underlying theory is that the greater the expression of a gene, the greater the amount of labeled target, and hence, the greater output signal. In spite of the simplicity of the experimental design, there are at least four different platforms and several different approaches to processing and labeling the biological samples. Moreover, investigators must also determine whether they will utilize commercially available arrays or generate their own. This review will cover the status of the hybridization array field with an eye toward underlying principles and available technologies. Future developments and technological trends will also be evaluated.
Abstract Compulsive drug abuse has been conceptualized as a behavioral state where behavioral stimuli override normal decision making. Clinical studies of methamphetamine users have detailed decision ...making changes and imaging studies have found altered metabolism and activation in the parietal cortex. To examine the molecular effects of amphetamine (AMPH) on the parietal cortex, gene expression responses to amphetamine challenge (7.5 mg/kg) were examined in the parietal cortex of rats pretreated for nine days with either saline, non-neurotoxic amphetamine, or neurotoxic AMPH dosing regimens. The neurotoxic AMPH exposure three doses of 7.5 mg/kg/day AMPH (6 h between doses), for nine days produced histological signs of neurotoxicity in the parietal cortex while a non-neurotoxic dosing regimen (2.0 mg/kg/day×3) did not. Neurotoxic AMPH pretreatment resulted in significantly diminished AMPH challenge-induced mRNA increases of activity-regulated cytoskeletal protein (ARC), nerve growth-factor inducible protein A (NGFI-A), and nerve growth-factor inducible protein B (NGFI-B) in the parietal cortex while neither saline pretreatment nor non-neurotoxic AMPH pretreatment did. This effect was specific to these genes as tissue plasminogen activator (t-PA), neuropeptide Y (NPY) and c-jun expression in response to AMPH challenge was unaltered or enhanced by amphetamine pretreatments. In the striatum, there were no differences between saline, neurotoxic AMPH, and non-neurotoxic AMPH pretreatments on ARC, NGFI-A or NGFI-B expression elicited by the AMPH challenge. These data indicate that the responsiveness of synaptic plasticity-related genes is sensitive to disruption specifically in the parietal cortex by threshold neurotoxic AMPH exposures.
Information about the nature of manganese (Mn)-binding ligands in plasma and serum, and its transport mechanism across the blood-brain barrier (BBB) is sparse. Most studies to date have focused on ...distribution, excretion, and accumulation of intravenous and intraperitoneal solutions of soluble divalent salts of Mn. Mn is transported in the blood primarily in the divalent oxidation state (Mn2+) and crosses the BBB via specific carriers at a rate far slower than in other tissues. Mn transport across the BBB occurs both in the 2+ and 3+ oxidation state. Within the CNS, Mn accumulates primarily within astrocytes, presumably because the astrocyte-specific enzyme, glutamine synthetase (GS), represents an important regulatory target of Mn. Compared to Mn2+, Mn3+ has a slower elimination rate and therefore, may have a greater tendency to accumulate in tissues. Furthermore, in view of the dependence of Mn accumulation within the CNS on iron (Fe) homeostasis, the oxidation state of Mn may represent a key determinant in the differential distribution, accumulation and secretion profiles of Mn, a fact that has received little attention in experimental biology toxicology. Accordingly, the distribution and membrane transport of Mn emphasizes the importance of: 1) the oxidation state of Mn, as it governs the affinity of Mn to endogenous ligands, and 2) the reaction of Mn3+ with transferrin, the plasma iron-carrying protein. This review will focus on transport kinetics of Mn across the BBB (both in the 2+ and 3+ oxidation state), the putative role of transferrin in the transport of Mn across the BBB, the transport of Mn by astrocytes, as well as the physiological significance of Mn to the function GS.
Like many elements, fluorine (which generally occurs in nature as fluoride) is beneficial to human health in trace amounts, but can be toxic in excess. The links between low intakes of fluoride and ...dental protection are well known; however, fluoride is a powerful calcium-seeking element and can interfere with the calcified structure of bones and teeth in the human body at higher concentrations causing dental or skeletal fluorosis. One of the main exposure routes is via drinking water and the World Health Organisation currently sets water quality guidelines for the element. In Central Europe, groundwater resources that exceed the guideline value of 1.5 mg l-¹ are widespread and effects on health of high fluoride in water have been reported. The aim of the current project was to develop a geographic information system (GIS) to aid the identification of areas where high-fluoride waters and fluorosis may be a problem; hence, where water treatment technologies should be targeted. The development of the GIS was based upon the collation and digitisation of existing information relevant to fluoride risk in Ukraine, Moldova, Hungary and Slovakia assembled for the first time in a readily accessible form. In addition, geochemistry and health studies to examine in more detail the relationships between high-fluoride drinking waters and health effects in the population were carried out in Moldova and Ukraine demonstrating dental fluorosis prevalence rates of 60-90% in adolescents consuming water containing 2-7 mg l-¹ fluoride.
Tyrosine hydroxylase catalyzes the rate-limiting step in the biosynthesis of the catecholamines dopamine, norepinephrine, and epinephrine. Therefore, the regulation of tyrosine hydroxylase enzyme ...number and intrinsic enzyme activity represents the central means for controlling the synthesis of these important biogenic amines. An intricate scheme has evolved whereby tyrosine hydroxylase activity is modulated by nearly every documented form of regulation. Beginning with the genomic DNA, evidence exists for the transcriptional regulation of tyrosine hydroxylase mRNA levels, alternative RNA processing, and the regulation of RNA stability. There is also experimental support for the role of both translational control and enzyme stability in establishing steady-state levels of active tyrosine hydroxylase protein. Finally, mechanisms have been proposed for feedback inhibition of the enzyme by catecholamine products, allosteric modulation of enzyme activity, and phosphorylation-dependent activation of the enzyme by various different kinase systems. Given the growing literature suggesting that different tissues regulate tyrosine hydroxylase mRNA levels and activity in different ways, regulatory mechanisms provide not only redundancy but also diversity in the control of catecholamine biosynthesis.
Cytotoxic and genotoxic potential of dopamine Stokes, Alan H.; Hastings, Teresa G.; Vrana, Kent E.
Journal of neuroscience research,
03/1999, Letnik:
55, Številka:
6
Journal Article
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