scholarly journals Paracrine modulation of cholangiocyte serotonin synthesis orchestrates biliary remodeling in adults

2011 ◽  
Vol 300 (2) ◽  
pp. G303-G315 ◽  
Author(s):  
Alessia Omenetti ◽  
Liu Yang ◽  
Raul R. Gainetdinov ◽  
Cynthia D. Guy ◽  
Steve S. Choi ◽  
...  
Keyword(s):  
Serotonin Receptor ◽  
Tryptophan Hydroxylase ◽  
De Novo ◽  
Biliary Tree ◽  
Hepatocyte Proliferation ◽  
Passive Release ◽  
Duct Ligation ◽  
Culture Models ◽  
Serotonin Receptor Agonists ◽  
Serotonin Biosynthesis

Paracrine signaling between cholangiocytes and stromal cells regulates biliary remodeling. Cholangiocytes have neuroepithelial characteristics and serotonin receptor agonists inhibit their growth, but whether they are capable of serotonin biosynthesis is unknown. We hypothesized that cholangiocytes synthesize serotonin and that cross talk between liver myofibroblasts (MF) and cholangiocytes regulates this process to influence biliary remodeling. Transwell cultures of cholangiocytes ± MF, and tryptophan hydroxylase-2 knockin (TPH2KI) mice with an inactivating mutation of the neuronal tryptophan hydroxylase (TPH) isoform, TPH2, were evaluated. Results in the cell culture models confirm that cholangiocytes have serotonin receptors and demonstrate for the first time that these cells express TPH2 and produce serotonin, which autoinhibits their growth but stimulates MF production of TGF-β1. Increased TGF-β1, in turn, counteracts autocrine inhibition of cholangiocyte growth by repressing cholangiocyte TPH2 expression. Studies of TPH2KI mice confirm that TPH2-mediated production of serotonin plays an important role in remodeling damaged bile ducts because mice with decreased TPH2 function have reduced biliary serotonin levels and exhibit excessive cholangiocyte proliferation, accumulation of aberrant ductules and liver progenitors, and increased liver fibrosis after bile duct ligation. This new evidence that cholangiocytes express the so-called neuronal isoform of TPH, synthesize serotonin de novo, and deploy serotonin as an autocrine/paracrine signal to regulate regeneration of the biliary tree complements earlier work that revealed that passive release of serotonin from platelets stimulates hepatocyte proliferation. Given the prevalent use of serotonin-modulating drugs, these findings have potentially important implications for recovery from various types of liver damage.

scholarly journals 5HT1A Serotonin Receptor Agonists Inhibit Plasmodium falciparum by Blocking a Membrane Channel

2003 ◽  
Vol 47 (12) ◽  
pp. 3806-3809 ◽  
Author(s):  
Christopher P. Locher ◽  
Peter C. Ruben ◽  
Jiri Gut ◽  
Philip J. Rosenthal
Keyword(s):  
Serotonin Receptor ◽  
Surface Membrane ◽  
Resistant Isolate ◽  
Neurological Involvement ◽  
Membrane Channel ◽  
Transport Pathway ◽  
Human Lung Fibroblast ◽  
Receptor Agonists ◽  
Serotonin Receptor Agonists

ABSTRACT Toidentify new leads for the treatment of Plasmodium falciparum malaria, we screened a panel of serotonin (5-hydroxytryptamine [5HT]) receptor agonists and antagonists and determined their effects on parasite growth. The 5HT1A receptor agonists 8-hydroxy-N-(di-n-propyl)-aminotetralin (8-OH-DPAT), 2,5-dimethoxy-4-iodoamphetamine, and 2,5-dimethoxy-4-bromophenylethylamine inhibited the growth of P. falciparum in vitro (50% inhibitory concentrations, 0.4, 0.7, and 1.5 μM, respectively). In further characterizing the antiparasitic effects of 8-OH-DPAT, we found that this serotonin receptor agonist did not affect the growth of Leishmania infantum, Trypanosoma cruzi, Trypanosoma brucei brucei, or Trichostrongylus colubriformis in vitro and did not demonstrate cytotoxicity against the human lung fibroblast cell line MRC-5. 8-OH-DPAT had similar levels of growth inhibition against several different P. falciparum isolates having distinct chemotherapeutic resistance phenotypes, and its antimalarial effect was additive when it was used in combination with chloroquine against a chloroquine-resistant isolate. In a patch clamp assay, 8-OH-DPAT blocked a P. falciparum surface membrane channel, suggesting that serotonin receptor agonists are a novel class of antimalarials that target a nutrient transport pathway. Since there may be neurological involvement with the use of 8-OH-DPAT and other serotonin receptor agonists in the treatment of falciparum malaria, new lead compounds derived from 8-OH-DPAT will need to be modified to prevent potential neurological side effects. Nevertheless, these results suggest that 8-OH-DPAT is a new lead compound with which to derive novel antimalarial agents and is a useful tool with which to characterize P. falciparum membrane channels.

Oral Serotonin Receptor Agonists

2005 ◽  
Vol 23 (3) ◽  
pp. 259-274 ◽  
Author(s):  
Jennifer H Lofland ◽  
David B Nash
Keyword(s):  
Serotonin Receptor ◽  
Receptor Agonists ◽  
Serotonin Receptor Agonists

scholarly journals The Lack of Nrf2 Causes Hepatocyte Dedifferentiation and Reduced Albumin Production in an Experimental Extrahepatic Cholestasis Model

2021 ◽  
Author(s):  
Guo-Ying Wang ◽  
Veronica Garcia ◽  
Joonyong Lee ◽  
Jennifer Yanum ◽  
Huaizhou Jiang ◽  
...  
Keyword(s):  
Epithelial Differentiation ◽  
Hepatocyte Proliferation ◽  
Sham Operation ◽  
Wild Type ◽  
Ductular Reaction ◽  
Extrahepatic Cholestasis ◽  
Liver Size ◽  
Duct Ligation ◽  
Albumin Production ◽  
In The Wild

AbstractThe transcription factor Nrf2 modulates the initiation and progression of a number of diseases including liver disorders. The aim of this study was to evaluate whether Nrf2 mediates hepatic adaptive responses to cholestasis. Wild-type and Nrf2-null mice were subjected to bile duct ligation (BDL) or a sham operation. Various assessments were performed at different days after surgery. Significant genotype-dependent changes in liver size, biliary ductular reaction, hepatocyte proliferation, and fibrotic response were not observed. However, as cholestasis progressed to Day 15 post-BDL, hepatocytes in the wild-type mice exhibited a tendency to dedifferentiate, indicated by the very weak expression of hepatic progenitor markers: CD133 and fibroblast growth factor-inducible 14 (Fn14). During the same period, Nrf2 deficiency augmented this tendency, manifested by higher CD133 expression, earlier, stronger, and continuous induction of Fn14 expression, and markedly reduced albumin production. Remarkably, as cholestasis advanced to the late stage (40 days after BDL), hepatocytes in the wild-type mice exhibited a Fn14+ phenotype and strikingly upregulated the expression of deleted in malignant brain tumor 1 (DMBT1), a protein essential for epithelial differentiation during development. In contrast, at this stage, hepatocytes in the Nrf2-null mice entirely inhibited the upregulation of DMBT1 expression, displayed a strong CD133+/Fn14+ phenotype indicative of severe dedifferentiation, and persistently reduced albumin production. Collectively, our studies revealed that Nrf2 maintains hepatocytes in the differentiated state potentially via the increased activity of the Nrf2/DMBT1 pathway during cholestasis. These findings enable us to gain novel insight into how hepatocytes respond to cholestasis.New and NoteworthyWe found that, when hepatocytes are exposed to cholestasis, they exhibit a tendency of dedifferentiation. In this case, Nrf2 is highly activated to markedly up-regulate the expression of epithelial differentiation gene DMBT1, which potentially prevent hepatocytes from dedifferentiation. Our findings revealed a plastic property of hepatocytes in response to cholestasis and demonstrated a novel Nrf2/DMBT1 pathway likely controlling this property of hepatocytes.

scholarly journals ePrescribing: Reducing Costs through In-Class Therapeutic Interchange

2016 ◽  
Vol 07 (04) ◽  
pp. 1168-1181 ◽  
Author(s):  
Shane Stenner ◽  
Rohini Chakravarthy ◽  
Kevin Johnson ◽  
William Miller ◽  
Julie Olson ◽  
...  
Keyword(s):  
Health Plan ◽  
Proton Pump ◽  
Serotonin Receptor ◽  
Cost Savings ◽  
Employee Health ◽  
Prescription Data ◽  
Therapeutic Interchange ◽  
Reducing Costs ◽  
Serotonin Receptor Agonists ◽  
Outpatient Prescriptions

SummaryIntroduction Spending on pharmaceuticals in the US reached $373.9 billion in 2014. Therapeutic interchange offers potential medication cost savings by replacing a prescribed drug for an equally efficacious therapeutic alternative.Methods Hard-stop therapeutic interchange recommendation alerts were developed for four medication classes (HMG-CoA reductase inhibitors, serotonin receptor agonists, intranasal steroid sprays, and proton-pump inhibitors) in an electronic prescription-writing tool for outpatient prescriptions. Using prescription data from January 2012 to June 2015, the Compliance Ratio (CR) was calculated by dividing the number of prescriptions with recommended therapeutic interchange medications by the number of prescriptions with non-recommended medications to measure effectiveness. To explore potential cost savings, prescription data and medication costs were analyzed for the 45,000 Vanderbilt Employee Health Plan members.Results for all medication classes, significant improvements were demonstrated – the CR improved (proton-pump inhibitors 2.8 to 5.32, nasal steroids 2.44 to 8.16, statins 2.06 to 5.51, and serotonin receptor agonists 0.8 to 1.52). Quarterly savings through the four therapeutic interchange interventions combined exceeded $200,000 with an estimated annual savings for the health plan of $800,000, or more than $17 per member.Conclusion A therapeutic interchange clinical decision support tool at the point of prescribing resulted in increased compliance with recommendations for outpatient prescriptions while producing substantial cost savings to the Vanderbilt Employee Health Plan – $17.77 per member per year.Therapeutic interchange rules require rational targeting, appropriate governance, and vigilant content updates.Citation: Stenner SP, Chakravarthy R, Johnson KB, Miller WL, Olson J, Wickizer M, Johnson NN, Ohmer R, Uskavitch DR, Bernard GR, Neal EB, Lehmann CU. eprescribing: reducing costs through in-class therapeutic interchange.

scholarly journals Transcriptional activation by growth hormone of HNF-6-regulated hepatic genes, a potential mechanism for improved liver repair during biliary injury in mice

2008 ◽  
Vol 295 (2) ◽  
pp. G357-G366 ◽  
Author(s):  
Minhua Wang ◽  
Michael Chen ◽  
Guoqiang Zheng ◽  
Barney Dillard ◽  
Mike Tallarico ◽  
...  
Keyword(s):  
Growth Hormone ◽  
Transcriptional Activation ◽  
Target Genes ◽  
Recombinant Adenovirus ◽  
Hepatic Function ◽  
Hepatocyte Proliferation ◽  
Expression Vectors ◽  
Sham Operation ◽  
Duct Ligation ◽  
Liver Repair

Growth hormone (GH) function is mediated through multiple endocrine pathways. In the liver, GH also transcriptionally activates hepatocyte nuclear factor-6 (HNF-6; OC-1), a liver-enriched transcription factor that regulates the expression of genes essential to hepatic function. We hypothesize that GH modulates hepatic function in the normal and injured liver through HNF-6 and HNF-6 target genes. CD1 mice received PBS or GH for the 1-, 7-, and 28-day course of Sham operation or bile duct ligation (BDL). Proliferation-, metabolic-, and profibrotic-specific hepatic functions were assessed with a focus on candidate HNF-6 transcriptional target genes. Confirmation of HNF-6 regulation was done by analysis of target gene expression in liver infected with recombinant adenovirus AdHNF-6 expression vectors. GH administration upregulated HNF-6 expression throughout the course of liver injury. This was associated with increased expression of HNF-6 proliferative target genes cyclin D1 and metabolic gene Cyp7A1 and downregulation of profibrogenic TGFb2R. Hepatic function improved such as enhanced hepatocyte proliferation, higher cholesterol clearance throughout the course of injury, and attenuated fibrogenic response at day 28 of BDL. GH treatment also transcriptionally increased albumin expression in an HNF-6-independent manner. This was associated with enhanced serum albumin levels. In conclusion, the GH/HNF-6 axis is a potential in vivo mechanism underlying GH diverse function in the liver to modulate the liver repair response to BDL.

scholarly journals Effects of 5-HT1A serotonin receptor agonists on parkinsonism

1999 ◽  
Vol 79 ◽  
pp. 43
Author(s):  
Masahiro Nomoto ◽  
Takao Shimizu ◽  
Shunsuke Tsujimura ◽  
Takeo Fukuda
Keyword(s):  
Serotonin Receptor ◽  
Receptor Agonists ◽  
Serotonin Receptor Agonists

scholarly journals α-Synuclein conformational strains spread, seed and target neuronal cells differentially after injection into the olfactory bulb

2019 ◽  
Vol 7 (1) ◽  
Author(s):  
Nolwen L. Rey ◽  
Luc Bousset ◽  
Sonia George ◽  
Zachary Madaj ◽  
Lindsay Meyerdirk ◽  
...  
Keyword(s):  
Olfactory Bulb ◽  
De Novo ◽  
Structural Features ◽  
Alpha Synuclein ◽  
Ample Evidence ◽  
Neuronal Connections ◽  
Wild Type Female ◽  
Culture Models ◽  
The Brain

AbstractAlpha-synuclein inclusions, the hallmarks of synucleinopathies, are suggested to spread along neuronal connections in a stereotypical pattern in the brains of patients. Ample evidence now supports that pathological forms of alpha-synuclein propagate in cell culture models and in vivo in a prion-like manner. However, it is still not known why the same pathological protein targets different cell populations, propagates with different kinetics and leads to a variety of diseases (synucleinopathies) with distinct clinical features. The aggregation of the protein alpha-synuclein yields different conformational polymorphs called strains. These strains exhibit distinct biochemical, physical and structural features they are able to imprint to newly recruited alpha-synuclein. This had led to the view that the clinical heterogeneity observed in synucleinopathies might be due to distinct pathological alpha-synuclein strains.To investigate the pathological effects of alpha-synuclein strains in vivo, we injected five different pure strains we generated de novo (fibrils, ribbons, fibrils-65, fibrils-91, fibrils-110) into the olfactory bulb of wild-type female mice. We demonstrate that they seed and propagate pathology throughout the olfactory network within the brain to different extents. We show strain-dependent inclusions formation in neurites or cell bodies. We detect thioflavin S-positive inclusions indicating the presence of mature amyloid aggregates.In conclusion, alpha-synuclein strains seed the aggregation of their cellular counterparts to different extents and spread differentially within the central nervous system yielding distinct propagation patterns. We provide here the proof-of-concept that the conformation adopted by alpha-synuclein assemblies determines their ability to amplify and propagate in the brain in vivo. Our observations support the view that alpha-synuclein polymorphs may underlie different propagation patterns within human brains.

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