scholarly journals Novel understanding on genetic mechanisms of enteric neuropathies leading to severe gut dysmotility

2021 ◽  
Vol 65 (s1) ◽  
Author(s):  
Francesca Bianco ◽  
Giulia Lattanzio ◽  
Luca Lorenzini ◽  
Chiara Diquigiovanni ◽  
Maurizio Mazzoni ◽  
...  
Keyword(s):  
Nervous System ◽  
Molecular Mechanisms ◽  
Fine Tuning ◽  
Enteric Neurons ◽  
Variable Degree ◽  
Intestinal Epithelial ◽  
Bioactive Substances ◽  
Smooth Musculature ◽  
Genetic Mechanisms ◽  
Intestinal Pseudo Obstruction

The enteric nervous system (ENS) is the third division of the autonomic autonomic nervous system and the largest collection of neurons outside the central nervous system (CNS). The ENS has been referred to as “the brain in the gut” or “the second brain of the human body” because of its highly integrated neural circuits controlling a vast repertoire of gut functions, including absorption/secretion, splanchnic blood vessels, some immunological aspects, intestinal epithelial barrier, and gastrointestinal (GI) motility. The latter function is the result of the ENS fine-tuning over smooth musculature, along with the contribution of other key cells, such as enteric glia (astrocyte like cells supporting and contributing to neuronal activity), interstitial cells of Cajal (the pacemaker cells of the GI tract involved in neuromuscular transmission), and enteroendocrine cells (releasing bioactive substances, which affect gut physiology). Any noxa insult perturbing the ENS complexity may determine a neuropathy with variable degree of neuro-muscular dysfunction. In this review, we aim to cover the most recent update on genetic mechanisms leading to enteric neuropathies ranging from Hirschsprung’s disease (characterized by lack of any enteric neurons in the gut wall) up to more generalized form of dysmotility such as chronic intestinal pseudo-obstruction (CIPO) with a significant reduction of enteric neurons. In this line, we will discuss the role of the RAD21 mutation, which we have demonstrated in a family whose affected members exhibited severe gut dysmotility. Other genes contributing to gut motility abnormalities will also be presented. In conclusion, the knowledge on the molecular mechanisms involved in enteric neuropathy may unveil strategies to better manage patients with neurogenic gut dysmotility and pave the way to targeted therapies.

scholarly journals G protein-coupled receptor trafficking and signaling: new insights into the enteric nervous system

2019 ◽  
Vol 316 (4) ◽  
pp. G446-G452 ◽  
Author(s):  
Simona E. Carbone ◽  
Nicholas A. Veldhuis ◽  
Arisbel B. Gondin ◽  
Daniel P. Poole
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Intestinal Inflammation ◽  
Receptor Expression ◽  
Enteric Neurons ◽  
Future Research ◽  
Detailed Knowledge ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are essential for the neurogenic control of gastrointestinal (GI) function and are important and emerging therapeutic targets in the gut. Detailed knowledge of both the distribution and functional expression of GPCRs in the enteric nervous system (ENS) is critical toward advancing our understanding of how these receptors contribute to GI function during physiological and pathophysiological states. Equally important, but less well defined, is the complex relationship between receptor expression, ligand binding, signaling, and trafficking within enteric neurons. Neuronal GPCRs are internalized following exposure to agonists and under pathological conditions, such as intestinal inflammation. However, the relationship between the intracellular distribution of GPCRs and their signaling outputs in this setting remains a “black box”. This review will briefly summarize current knowledge of agonist-evoked GPCR trafficking and location-specific signaling in the ENS and identifies key areas where future research could be focused. Greater understanding of the cellular and molecular mechanisms involved in regulating GPCR signaling in the ENS will provide new insights into GI function and may open novel avenues for therapeutic targeting of GPCRs for the treatment of digestive disorders.

scholarly journals Role of corticosterone in the murine enteric nervous system during fasting

2014 ◽  
Vol 307 (9) ◽  
pp. G905-G913 ◽  
Author(s):  
Katrien Lowette ◽  
Jan Tack ◽  
Pieter Vanden Berghe
Keyword(s):  
Nervous System ◽  
Mrna Expression ◽  
Myenteric Plexus ◽  
Cannabinoid Receptor ◽  
Fine Tuning ◽  
Enteric Neurons ◽  
Neuronal Markers ◽  
Electrical Pulses

Food intake depends on a tightly controlled interplay of appetite hormones and the enteric (ENS) and central nervous system. Corticosterone (CORT) levels, which are mainly studied with regard to stress, are also increased during fasting. However, the role of CORT in the ENS remains elusive. Therefore, we investigated whether CORT modulates activity of enteric neurons and whether its intracellular regulator, 11β-hydroxysteroid dehydrogenase (HSD) type 1, is present in the myenteric plexus, using immunohistochemistry and RT-qPCR. Effects of CORT on neuronal activity and expression of neuronal markers in the myenteric plexus were assessed via Ca2+ imaging and RT-qPCR, respectively, whereas modulations in mixing behavior were measured by video imaging. 11β-HSD-1 was present in enteric neurons along the gastrointestinal tract, and its expression increased after fasting (control: 0.58 ± 0.09 vs. fasted: 1.5 ± 0.23; P < 0.05). CORT incubation significantly reduced neuronal Ca2+ transients in tissues stimulated by electrical pulses (control: 1.31 ± 0.01 vs. CORT: 1.27 ± 0.01, P < 0.01) and in cultured neurons (control: 1.85 ± 0.03 vs. CORT: 1.76 ± 0.03, P < 0.05). CORT decreased small intestinal mixing ( P < 0.05). Incubation of muscle myenteric plexus preparations with CORT induced an increase in cannabinoid receptor 1 (CB1, P < 0.05) and synaptobrevin ( P < 0.05) but not in 11β-HSD-1 mRNA expression. In addition, fasting induced significant elevations in synaptobrevin ( P < 0.05) and CB1 ( P < 0.01) mRNA expression. In conclusion, we suggest CORT to be a downstream factor in a feeding state-related pathway that modulates important proteins in the fine tuning of enteric neurotransmission and gastrointestinal motility.

scholarly journals Hyperglycaemia-Induced Downregulation in Expression of nNOS Intramural Neurons of the Small Intestine in the Pig

2019 ◽  
Vol 20 (7) ◽  
pp. 1681 ◽  
Author(s):  
Michał Bulc ◽  
Katarzyna Palus ◽  
Michał Dąbrowski ◽  
Jarosław Całka
Keyword(s):  
Nitric Oxide ◽  
Nervous System ◽  
Small Intestine ◽  
Enteric Nervous System ◽  
Molecular Mechanisms ◽  
Muscle Relaxation ◽  
Biologically Active ◽  
Enteric Neurons ◽  
Smooth Muscle Relaxation ◽  
Gi Tract

Diabetic autonomic peripheral neuropathy (PN) involves a broad spectrum of organs. One of them is the gastrointestinal (GI) tract. The molecular mechanisms underlying the pathogenesis of digestive complications are not yet fully understood. Digestion is controlled by the central nervous system (CNS) and the enteric nervous system (ENS) within the wall of the GI tract. Enteric neurons exert regulatory effects due to the many biologically active substances secreted and released by enteric nervous system (ENS) structures. These include nitric oxide (NO), produced by the neural nitric oxide synthase enzyme (nNOS). It is a very important inhibitory factor, necessary for smooth muscle relaxation. Moreover, it was noted that nitrergic innervation can undergo adaptive changes during pathological processes. Additionally, nitrergic neurons function may be regulated through the synthesis of other active neuropeptides. Therefore, in the present study, using the immunofluorescence technique, we first examined the influence of hyperglycemia on the NOS- containing neurons in the porcine small intestine and secondly the co-localization of nNOS with vasoactive intestinal polypeptide (VIP), galanin (GAL) and substance P (SP) in all plexuses studied. Following chronic hyperglycaemia, we observed a reduction in the number of the NOS-positive neurons in all intestinal segments studied, as well as an increased in investigated substances in nNOS positive neurons. This observation confirmed that diabetic hyperglycaemia can cause changes in the neurochemical characteristics of enteric neurons, which can lead to numerous disturbances in gastrointestinal tract functions. Moreover, can be the basis of an elaboration of these peptides analogues utilized as therapeutic agents in the treatment of GI complications.

scholarly journals The enteric nervous system of the human and mouse colon at a single-cell resolution

2019 ◽  
Author(s):  
Eugene Drokhlyansky ◽  
Christopher S. Smillie ◽  
Nicholas Van Wittenberghe ◽  
Maria Ericsson ◽  
Gabriel K. Griffin ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Single Cell ◽  
Molecular Mechanisms ◽  
Current Model ◽  
Human Colon ◽  
Enteric Neurons ◽  
Stem Cell Maintenance ◽  
Reference Map ◽  
Human And Mouse

AbstractAs the largest branch of the autonomic nervous system, the enteric nervous system (ENS) controls the entire gastrointestinal tract, but remains incompletely characterized. Here, we develop RAISIN RNA-seq, which enables the capture of intact single nuclei along with ribosome-bound mRNA, and use it to profile the adult mouse and human colon to generate a reference map of the ENS at a single-cell resolution. This map reveals an extraordinary diversity of neuron subsets across intestinal locations, ages, and circadian phases, with conserved transcriptional programs that are shared between human and mouse. These data suggest possible revisions to the current model of peristalsis and molecular mechanisms that may allow enteric neurons to orchestrate tissue homeostasis, including immune regulation and stem cell maintenance. Human enteric neurons specifically express risk genes for neuropathic, inflammatory, and extra-intestinal diseases with concomitant gut dysmotility. Our study therefore provides a roadmap to understanding the ENS in health and disease.

scholarly journals NEUROIMMUNOENDOCRINE REGULATION OF THE SKIN FUNCTIONING

2019 ◽  
Vol 21 (5) ◽  
pp. 807-820
Author(s):  
O. A. Bashkina ◽  
M. A. Samotrueva ◽  
A. K. Azhikova ◽  
L. R. Paknnova
Keyword(s):  
Nervous System ◽  
Molecular Mechanisms ◽  
Parasympathetic Nervous System ◽  
Skin Diseases ◽  
Healing Process ◽  
Skin Inflammation ◽  
Skin Wound ◽  
Social Consequences ◽  
Immune Functions ◽  
Bioactive Substances

The review deals with modern ideas of neuroimmunoendocrine regulation of physiological and pathophysiological processes in skin. The present data are provided which indicate to composite mechanisms of intercellular interactions in complex regulating systems (nervous, immune, endocrine) acting at the level of skin in normal conditions, as well during the posttraumatic period. We describe different modes for participation of endocrine and nervous systems in immunologically induced skin inflammation. The data are provided confirming localization of adrenergic receptors on membranes of immunocompetent cells and leukocytes, on regulatory effects of hypothalamus upon immune functions, about multidirectional actions upon inflammation of sympathetic and parasympathetic nervous system etc.There are sufficient data on promotion of pathophysiological changes and reconstitution processes in the skin due to effects of local immune cells and bioactive substances expressed by them. The course of skin wound regeneration depend on the type of damage, degree and a phase of healing process. Posttraumatic reparative potential of skin is often limited by the infectious processes initiated by local microflora, products of cell disintegration and necrotic tissues. The cause-effect relationship is proven by arising inflammation which is implemented by inclusion of immune protection responses. The increased necrotic area and suppuration of the wound occurs die to inhibition of system of the phagocytizing macrophages. However, activation of this system brings about formation of the connective tissue capsule around the inflammation focus within early terms.We also discuss the issues of reparative skin regeneration which of great medico-social value, in connection with considerable prevalence of traumatic events and their social consequences, followed by expressed cosmetic defects. Evolving neurocognitive problems lead to decreased quality of the patient’s life, development of social disadaptation and further deprivation. The role of nervous system and psychological frustration in genesis of skin manifestations requires future development of the modern scientific direction, i.e., psychodermatology.Understanding of molecular mechanisms regulating the neuroimmunocutaneous interactions offers new prospectives in treatment of some skin diseases, as well as activation of the damaged skin recovery. According to the data presented in the review article, one may conclude on relevance of further studies on reparative potential of skin under interactions of homeostatic regulatory systems.

scholarly journals SARS-CoV-2 and the Nervous System: From Clinical Features to Molecular Mechanisms

2020 ◽  
Vol 21 (15) ◽  
pp. 5475 ◽  
Author(s):  
Manuela Pennisi ◽  
Giuseppe Lanza ◽  
Luca Falzone ◽  
Francesco Fisicaro ◽  
Raffaele Ferri ◽  
...  
Keyword(s):  
Nervous System ◽  
Molecular Mechanisms ◽  
Neuronal Damage ◽  
Neurological Complications ◽  
Neurological Manifestations ◽  
Wide Range ◽  
Inflammatory State ◽  
Acute Polyneuropathy ◽  
The Central Nervous System ◽  
The Impact

Increasing evidence suggests that Severe Acute Respiratory Syndrome-coronavirus-2 (SARS-CoV-2) can also invade the central nervous system (CNS). However, findings available on its neurological manifestations and their pathogenic mechanisms have not yet been systematically addressed. A literature search on neurological complications reported in patients with COVID-19 until June 2020 produced a total of 23 studies. Overall, these papers report that patients may exhibit a wide range of neurological manifestations, including encephalopathy, encephalitis, seizures, cerebrovascular events, acute polyneuropathy, headache, hypogeusia, and hyposmia, as well as some non-specific symptoms. Whether these features can be an indirect and unspecific consequence of the pulmonary disease or a generalized inflammatory state on the CNS remains to be determined; also, they may rather reflect direct SARS-CoV-2-related neuronal damage. Hematogenous versus transsynaptic propagation, the role of the angiotensin II converting enzyme receptor-2, the spread across the blood-brain barrier, the impact of the hyperimmune response (the so-called “cytokine storm”), and the possibility of virus persistence within some CNS resident cells are still debated. The different levels and severity of neurotropism and neurovirulence in patients with COVID-19 might be explained by a combination of viral and host factors and by their interaction.

scholarly journals Immune Actions on the Peripheral Nervous System in Pain

2021 ◽  
Vol 22 (3) ◽  
pp. 1448
Author(s):  
Jessica Aijia Liu ◽  
Jing Yu ◽  
Chi Wai Cheung
Keyword(s):  
Chronic Pain ◽  
Nervous System ◽  
Peripheral Nervous System ◽  
Immune Cells ◽  
Molecular Mechanisms ◽  
Process Integration ◽  
Current Knowledge ◽  
Therapeutic Strategies ◽  
Lipid Mediators ◽  
Cellular Changes

Pain can be induced by tissue injuries, diseases and infections. The interactions between the peripheral nervous system (PNS) and immune system are primary actions in pain sensitizations. In response to stimuli, nociceptors release various mediators from their terminals that potently activate and recruit immune cells, whereas infiltrated immune cells further promote sensitization of nociceptors and the transition from acute to chronic pain by producing cytokines, chemokines, lipid mediators and growth factors. Immune cells not only play roles in pain production but also contribute to PNS repair and pain resolution by secreting anti-inflammatory or analgesic effectors. Here, we discuss the distinct roles of four major types of immune cells (monocyte/macrophage, neutrophil, mast cell, and T cell) acting on the PNS during pain process. Integration of this current knowledge will enhance our understanding of cellular changes and molecular mechanisms underlying pain pathogenies, providing insights for developing new therapeutic strategies.

scholarly journals Deficiency of Lipin2 Results in Enhanced NF-κB Signaling and Osteoclast Formation in RAW-D Murine Macrophages

2021 ◽  
Vol 22 (6) ◽  
pp. 2893
Author(s):  
Asami Watahiki ◽  
Seira Hoshikawa ◽  
Mitsuki Chiba ◽  
Hiroshi Egusa ◽  
Satoshi Fukumoto ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Osteoclast Formation ◽  
Fine Tuning ◽  
Nuclear Accumulation ◽  
Innate Immune Responses ◽  
Osteoclastic Resorption ◽  
Bone Disorder ◽  
Proinflammatory Responses ◽  
Potential Therapeutic Intervention

Lipin2 is a phosphatidate phosphatase that plays critical roles in fat homeostasis. Alterations in Lpin2, which encodes lipin2, cause the autoinflammatory bone disorder Majeed syndrome. Lipin2 limits lipopolysaccharide (LPS)-induced inflammatory responses in macrophages. However, little is known about the precise molecular mechanisms underlying its anti-inflammatory function. In this study, we attempted to elucidate the molecular link between the loss of lipin2 function and autoinflammatory bone disorder. Using a Lpin2 knockout murine macrophage cell line, we showed that lipin2 deficiency enhances innate immune responses to LPS stimulation through excessive activation of the NF-κB signaling pathway, partly because of TAK1 signaling upregulation. Lipin2 depletion also enhanced RANKL-mediated osteoclastogenesis and osteoclastic resorption activity accompanied by NFATc1 dephosphorylation and increased nuclear accumulation. These results suggest that lipin2 suppresses the development of autoinflammatory bone disorder by fine-tuning proinflammatory responses and osteoclastogenesis in macrophages. Therefore, this study provides insights into the molecular pathogenesis of monogenic autoinflammatory bone disorders and presents a potential therapeutic intervention.

scholarly journals Comparative Transcriptome Analysis Reveals Genetic Mechanisms of Sugarcane Aphid Resistance in Grain Sorghum

2021 ◽  
Vol 22 (13) ◽  
pp. 7129
Author(s):  
Desalegn D. Serba ◽  
Xiaoxi Meng ◽  
James Schnable ◽  
Elfadil Bashir ◽  
J. P. Michaud ◽  
...  
Keyword(s):  
Differential Expression ◽  
Molecular Mechanisms ◽  
Grain Sorghum ◽  
Lipid Binding ◽  
Multiple Time ◽  
Melanaphis Sacchari ◽  
Resistant Genotype ◽  
Sugarcane Aphid ◽  
Genetic Mechanisms ◽  
Moderately Resistant

The sugarcane aphid, Melanaphis sacchari (Zehntner) (Hemiptera: Aphididae) (SCA), has become a major pest of grain sorghum since its appearance in the USA. Several grain sorghum parental lines are moderately resistant to the SCA. However, the molecular and genetic mechanisms underlying this resistance are poorly understood, which has constrained breeding for improved resistance. RNA-Seq was used to conduct transcriptomics analysis on a moderately resistant genotype (TAM428) and a susceptible genotype (Tx2737) to elucidate the molecular mechanisms underlying resistance. Differential expression analysis revealed differences in transcriptomic profile between the two genotypes at multiple time points after infestation by SCA. Six gene clusters had differential expression during SCA infestation. Gene ontology enrichment and cluster analysis of genes differentially expressed after SCA infestation revealed consistent upregulation of genes controlling protein and lipid binding, cellular catabolic processes, transcription initiation, and autophagy in the resistant genotype. Genes regulating responses to external stimuli and stress, cell communication, and transferase activities, were all upregulated in later stages of infestation. On the other hand, expression of genes controlling cell cycle and nuclear division were reduced after SCA infestation in the resistant genotype. These results indicate that different classes of genes, including stress response genes and transcription factors, are responsible for countering the physiological effects of SCA infestation in resistant sorghum plants.

scholarly journals Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior

2021 ◽  
Author(s):  
Young-Min Han ◽  
Min Sun Kim ◽  
Juyeong Jo ◽  
Daiha Shin ◽  
Seung-Hae Kwon ◽  
...  
Keyword(s):  
Inhibitory Action ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Middle Phase ◽  
Temporal Shift

AbstractThe fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

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