Effect of a neural relay on liver regeneration in mice: activation of serotonin release from the gastrointestinal tract.
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ABSTRACT:
SUBMITTER: Inoue R
PROVIDER: S-EPMC5832978 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PURPOSE OF REVIEW:To assess the role of serotonin and its control in the manifestations and treatment of lower functional gastrointestinal disorders. RECENT FINDINGS:Recent literature has explored several novel concepts in the association of serotonin and symptoms, alterations in tissue levels of serotonin and its reuptake protein, aspects of the genetic determinants of serotonergic function (particularly 5-HTTLPR) and its relationship to gastrointestinal motor and sensory functions, and novel serotonergic agents used in therapy of lower functional gastrointestinal disorders. The most consistent findings are the increase in plasma 5-hydroxytryptamine (5-HT) in diarrheal diseases and reduction in constipation. The serotonin transporter in platelets has an impact on the circulating level of 5-HT. Meta-analysis shows that 5-HTTLPR genotype is not significantly associated with irritable bowel syndrome in Whites or Asians. New 5-HT3 antagonists and 5-HT4 agonists are efficacious and promise to provide relief for patients if they can pass regulatory hurdles. SUMMARY:Although the most relevant implication for clinical practice remains the evidence that serotonergic agents are efficacious in the treatment of chronic constipation, chronic diarrhea and irritable bowel syndrome, the role of genetic control of 5-HT and its receptors is the subject of ongoing research, and is likely to enhance understanding of the mechanisms and treatment of these diseases.
| S-EPMC2694720 | biostudies-literature
Project description:Serotonin (5-hydroxytryptamine; 5-HT) is abundantly present throughout the gastrointestinal tract and stored mostly in enterochromaffin (EC) cells, which are located on the mucosal surface. 5-HT released from EC cells stimulate both intrinsic and extrinsic nerves, which results in various physiological and pathophysiological responses, such as gastrointestinal contractions. EC cells are believed to have the ability to respond to the chemical composition of the luminal contents of the gut; however, the underlying molecular and cellular mechanisms have not been identified. Here, we demonstrate that the transient receptor potential (TRP) cation channel TRPA1, which is activated by pungent compounds or cold temperature, is highly expressed in EC cells. We also found that TRPA1 agonists, including allyl isothiocyanate and cinnamaldehyde, stimulate EC cell functions, such as increasing intracellular Ca(2+) levels and 5-HT release, by using highly concentrated EC cell fractions and a model of EC cell function, the RIN14B cell line. Furthermore, we showed that allyl isothiocyanate promotes the contraction of isolated guinea pig ileum via the 5-HT(3) receptor. Taken together, our results indicate that TRPA1 acts as a sensor molecule for EC cells and may regulate gastrointestinal function.
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Project description:mice gastrointestinal tract microbiota metagenome Raw sequence reads
| PRJNA660631 | ENA
Project description:To determine the role of gastrointestinal carriage in Klebsiella pneumoniae liver abscess, we studied 43 patients. Bacterial isolates from liver and fecal samples from 10 patients with this condition and 7 healthy carriers showed identical serotypes and genotypes with the same virulence. This finding indicated that gastrointestinal carriage is a predisposing factor for liver abscess.
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Project description:Stem cell therapies seem to be an appropriate tool for the treatment of a variety of diseases, especially when a substantial cell loss leads to a severe clinical impact. This is the case in most neuronal cell losses. Unfortunately, adequate neural stem cell sources are hard to find and current alternatives, such as induced programmed stem cells, still have incalculable risks. Evidence of neurogenesis in the adult human enteric nervous system brought up a new perspective. In humans the appendix harbors enteric neuronal tissue and is an ideal location where the presence of neural stem cells is combined with a minimal invasive accessibility. In this study appendices from adults and children were investigated concerning their neural stem cell potential. From each appendix tissue samples were collected, and processed for immunohistochemistry or enteric neural progenitor cell generation. Free-floating enteric neurospheres (EnNS's) could be generated after 6 days in vitro. EnNS's were either used for transplantation into rat brain slices or differentiation experiments. Both transplanted spheres and control cultures developed an intricate network with glia, neurons and interconnecting fibers, as seen in primary enteric cultures before. Neuronal, glial and neural stem cell markers could be identified both in vitro and in vivo by immunostaining. The study underlines the potential of the enteric nervous system as an autologous neural stem cell source. Using the appendix as a potential target opens up a new perspective that might lead to a relatively unproblematic harvest of neural stem cells.
| S-EPMC3762931 | biostudies-literature
Project description:The myelin-derived neurite growth inhibitor Nogo has been proposed to play a major role in blocking axon regeneration in the CNS after injuries. However, past studies have produced mixed results regarding the regenerative phenotype of various Nogo-deficient mouse lines after experimental spinal cord injury. Two lines did not display enhanced corticospinal tract (CST) regeneration, and one displayed modest regeneration. A fourth line, a Nogo-A,B gene-trap mutant, was instead reported to exhibit extensive CST regeneration, but the results were later found to be inadvertently confounded with an axon labeling artifact. Of the four Nogo mutant lines studied so far, three continue to express some isoform(s) of Nogo, leaving open the question whether any remaining Nogo protein contributes to the modest regenerative phenotype reported in some. The remaining Nogo mutant line studied was confounded by the unexplained rescue of embryonic lethality associated with this mutation. To gain a better understanding of the contribution of Nogo as an inhibitor of regeneration of CNS axons, and particularly CST axons, we reanalyzed the Nogo-A,B gene-trap mutant line and analyzed a novel, fully viable Nogo deletion mutant line that is null for all known isoforms of Nogo. Our analyses failed to reveal any enhanced CST regeneration after experimental spinal cord injury in either line. These results indicate that Nogo alone does not account for lack of CST regeneration and have implications for current therapeutic development for spinal cord injury in humans by targeting Nogo.
| S-EPMC2747754 | biostudies-literature
Project description:This study investigated the role of N6-methyladenosine RNA methylation in liver regeneration following partial hepatectomy in mice. We created a liver-specific knockout mouse model by the deletion of Mettl3, a key component of the N6-methyladenosine methyltransferase complex, using the albumin-Cre system. Mettl3 liver-specific knockout mice and their wild-type littermates were subjected to 2/3 partial hepatectomy. Transcriptomic changes in liver tissue at 48 h after partial hepatectomy were detected by RNA-seq. Immunohistochemistry and immunofluorescence were used to determine protein expression levels of Ki67, hepatocyte nuclear factor 4 alpha, and cytokeratin 19. Terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling was also performed. Liver weight/body weight ratios after partial hepatectomy were significantly lower in Mettl3 liver-specific knockout mice than in wild-type mice at 48 h after 2/3 partial hepatectomy (3.1% ± 0.11% vs. 2.7% ± 0.03%). Compared with wild-type littermates, Mettl3 liver-specific knockout mice showed reduced bromodeoxyuridine staining and reduced Ki-67 expression at 48 h after 2/3 partial hepatectomy. RNA-seq analysis showed that Mettl3 liver-specific knockout delayed the cell cycle progression in murine liver by downregulating the expression levels of genes encoding cyclins D1, A2, B1, and B2. Loss of Mettl3-mediated N6-methyladenosine function led to attenuated liver regeneration by altering the mRNA decay of suppressor of cytokine signaling 6, thereby inhibiting the phosphorylation of signal transducer and activator of transcription 3 during early liver regeneration. These results demonstrated the importance of N6-methyladenosine mRNA modification in liver regeneration and suggest that Mettl3 targeting might facilitate liver regeneration.
| S-EPMC9243324 | biostudies-literature
Project description:Hepatocyte nuclear factor 4 alpha (HNF4α) is critical for hepatic differentiation. Recent studies have highlighted its role in inhibition of hepatocyte proliferation and tumor suppression. However, the role of HNF4α in liver regeneration (LR) is not known. We hypothesized that hepatocytes modulate HNF4α activity when navigating between differentiated and proliferative states during LR. Western blotting analysis revealed a rapid decline in nuclear and cytoplasmic HNF4α protein levels, accompanied with decreased target gene expression, within 1 hour after two-thirds partial hepatectomy (post-PH) in C57BL/6J mice. HNF4α protein expression did not recover to pre-PH levels until day 3. Hepatocyte-specific deletion of HNF4α (HNF4α-KO [knockout]) in mice resulted in 100% mortality post-PH, despite increased proliferative marker expression throughout regeneration. Sustained loss of HNF4α target gene expression throughout regeneration indicated that HNF4α-KO mice were unable to compensate for loss of HNF4α transcriptional activity. Deletion of HNF4α resulted in sustained proliferation accompanied by c-Myc and cyclin D1 overexpression and a complete deficiency of hepatocyte function after PH. Interestingly, overexpression of degradation-resistant HNF4α in hepatocytes delayed, but did not prevent, initiation of regeneration after PH. Finally, adeno-associated virus serotype 8 (AAV8)-mediated reexpression of HNF4α in hepatocytes of HNF4α-KO mice post-PH restored HNF4α protein levels, induced target gene expression, and improved survival of HNF4α-KO mice post-PH. Conclusion: In conclusion, these data indicate that HNF4α reexpression following initial decrease is critical for hepatocytes to exit from cell cycle and resume function during the termination phase of LR. These results indicate the role of HNF4α in LR and have implications for therapy of liver failure.
| S-EPMC6551324 | biostudies-literature
Project description:BackgroundImmune cell activation and perpetuation of inflammation have been attributed to the neurotransmitter serotonin (5-hydroxytryptamine; 5-HT). Our hypothesis was that the 5-HT system plays a role in GI health and immunity in post-weaning piglets. A disruption of the 5-HT system post-weaning with transcriptional upregulation of 5-HT receptors may be linked to increased cytokine mRNA abundance and immune system activation.MethodsThe objective of this exploratory study was to assess the relationship between 5-HT receptor expression and immune system biomarkers in piglets at 1 (n = 9) and 15 (n = 10) days post-weaning. The mRNA transcript abundance of three 5-HT receptors (5-HTR3, 5-HTR4, and 5-HTR7) measured in jejunum and colon tissues were used to determine the relationship with the immune system and jejunal morphometry at 2 timepoints post-weaning using correlations, mixed models, and multivariate analysis techniques.ResultsOverall, 5-HT receptor mRNA expression decreased from day 1 to day 15 post-weaning. Time × tissue interactions showed the lowest 5-HTR3 expression in the colon and lower 5-HTR7 expression in the jejunum at 15 days post-weaning. 5-HTR3 and 5-HTR4 expression were negatively associated with pro-inflammatory (IFN-ɣ) and anti-inflammatory (IL-10 and IL-12β) cytokines in jejunum, and with TNF-α in the colon at 1-day post-weaning. At 15 days post-weaning, 5-HTR3 in the colon was negatively associated with pro-inflammatory (IL-1α, IL-1β, TNF-α, IL-8, and IFN-ɣ) and anti-inflammatory (IL-10 and IL-12β) cytokines. Furthermore, 5-HTR7 expressed a predominantly pro-inflammatory profile (IFN-α, IL-1α, IL-1β, IL-8, TNF-α and IL-12α) in the jejunum at the same timepoint, whereas colonic 5-HTR7 expression was negatively correlated with IL-1α, IL-1β, IL-10 and TGF-β. Lastly, positive correlations were found for increased expression of 5-HTR4 receptor with villus height, 5-HTR7 receptor expression and crypt depth, and increased expression of 5-HTR3 and 5-HTR4 receptor with villus height to crypt depth ratio at 1-day post-weaning.ConclusionsThe 5-HT receptor mRNA abundance was associated with the immune system and intestinal morphometry in piglets. The 5-HT receptors were highly expressed at weaning in both jejunum and colon tissues relative to 15 days post-weaning. Although a clear relationship between immune system and 5-HTR expression is observed, particularly at day 15, a cause-consequence cannot be proven with current data. Further research is warranted to elucidate the effects of 5-HT on gastrointestinal inflammation during the weaning process in piglets, which could be the basis for new interventions to ease weaning stress.
| S-EPMC8796611 | biostudies-literature
Project description:Acetaminophen (APAP) overdose is a major cause of acute liver failure. Peripheral 5-hydroxytryptamine (serotonin, 5-HT) is a cytoprotective neurotransmitter which is also involved in the hepatic physiological and pathological process. This study seeks to investigate the mechanisms involved in APAP-induced hepatotoxicity, as well as the role of 5-HT in the liver's response to APAP toxicity. We induced APAP hepatotoxicity in mice either sufficient of serotonin (wild-type mice and TPH1-/- plus 5- Hydroxytryptophan (5-HTP)) or lacking peripheral serotonin (Tph1-/- and wild-type mice plus p-chlorophenylalanine (PCPA)). Mice with sufficient 5-HT exposed to acetaminophen have a significantly lower mortality rate and a better outcome compared with mice deficient of 5-HT. This difference is at least partially attributable to a decreased level of inflammation, oxidative stress and endoplasmic reticulum (ER) stress, Glutathione (GSH) depletion, peroxynitrite formation, hepatocyte apoptosis, elevated hepatocyte proliferation, activation of 5-HT2B receptor, less activated c-Jun NH₂-terminal kinase (JNK) and hypoxia-inducible factor (HIF)-1α in the mice sufficient of 5-HT versus mice deficient of 5-HT. We thus propose a physiological function of serotonin that serotonin could ameliorate APAP-induced liver injury mainly through inhibiting hepatocyte apoptosis ER stress and promoting liver regeneration.
| S-EPMC4309973 | biostudies-literature