Dataset Information

?2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin.

ABSTRACT: The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While ?1- and ?-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about ?2-AR-mediated effects and their expression pattern during liver fibrosis and cirrhosis. We explored the expression of ?2-AR in two models of experimental liver fibrosis. We further evaluated the capacity of the ?2-AR blocker mesedin to deactivate hepatic stellate cells (HSCs) and to increase the permeability of human liver sinusoidal endothelial cells (hLSECs). The mRNA of ?2a-, ?2b-, and ?2c-AR subtypes was uniformly upregulated in carbon tetrachloride-treated mice vs the controls, while in bile duct-ligated mice, only ?2b-AR increased in response to liver injury. In murine HSCs, mesedin led to a decrease in ?-smooth muscle actin, transforming growth factor-? and ?2a-AR expression, which was indicated by RT-qPCR, immunocytochemistry, and Western blot analyses. In a hLSEC line, an increased expression of endothelial nitric oxide synthase was detected along with downregulated transforming growth factor-?. In conclusion, we suggest that the ?2-AR blockade alleviates the activation of HSCs and may increase the permeability of liver sinusoids during liver injury.

SUBMITTER: Schwinghammer UA

PROVIDER: S-EPMC7072854 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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α2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin.

Schwinghammer Ute A UA Melkonyan Magda M MM Hunanyan Lilit L Tremmel Roman R Weiskirchen Ralf R Borkham-Kamphorst Erawan E Schaeffeler Elke E Seferyan Torgom T Mikulits Wolfgang W Yenkoyan Konstantin K Schwab Matthias M Danielyan Lusine L

Cells 20200218 2

The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While α1- and β-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about α2-AR-mediated effects and their expression pattern during liver fibrosis and cirrhosis. We explored the expression of α2-AR in two models of experimental liver fibrosis. We further evaluated the capacity of the α2-AR blocker mesedin to deactivate hepatic stellate ...[more]

PMID: 32085378

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Project description:Background:Moringa peregrina (M. peregrina) is an edible, drought-resistant tree that is native to semi-arid countries. It is used as a painkiller in folk medicine. Aims:To study the antinociceptive effects of the leaf extract of M. peregrina in mice. Study Design:Animal experimentation. Methods:We employed thermal (hot plate and tail-immersion tests) and chemical (writhing and formalin tests) pain models in male BALB/c mice (eight animals per group) to investigate the mechanisms involved in the antinociceptive actions of M. peregrina. Additionally, we identified the chemical constituents present in the extract of M. peregrina by using liquid chromatography-mass spectrometry analysis, and predicted the possible active constituents that interact with the receptor based on molecular docking simulations. Results:In the writhing test, 200 mg/kg of M. peregrina extract restricted abdominal cramps by up to 55.97% (p<0.001). Further, it reduced the time of paw-licking in the early and late phases of formalin test by up to 56.8% and 65.5%, respectively, as compared to the percentage inhibitions of 50.5% and 48.4% produced by 30 mg/kg diclofenac sodium in the early and late phases, respectively (p<0.05). This effect was abrogated by yohimbine (1 mg/kg, intraperitoneally), but not by methysergide (5 mg/kg, intraperitoneally), in the late phase only, which indicates that the action of M. peregrina in formalin test is not mediated by 5-HT2 serotonin receptors, but rather via α2-adrenergic receptors. In the hot plate test, but not on tail-immersion test, the high dose (400 mg/kg) of the extract increased the latency time after 30 minutes of its administration. Yohimbine antagonized the action of M. peregrina in the hot plate test. Based on LC-MS analysis, the major constituents found in M. peregrina methanolic extract were chrysoeriol 7-O-diglucoside, lupeol acetate, quercetin, and rutin. Depending on the molecular docking results, the activity of M. peregrina extract could be due to the binding of chrysoeriol 7-O-diglucoside, quercetin, and rutin to the α2-adrenergic receptor. Conclusion:Interaction with the α2-adrenergic receptor serves as a possible mechanism of the M. peregrina analgesic effect.

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Project description:BackgroundThe use of umbilical cord mesenchymal stem cells (UC-MSCs) is a burgeoning method for the treatment of liver cirrhosis. However, the secretory phenotype and regulatory ability of UC-MSCs are easily affected by their microenvironment. Ensuring a specific microenvironment to enhance the UC-MSCs phenotype is a potential strategy for improving their therapeutic efficacy. The aim of this study was to explore therapeutic UC-MSCs phenotypes for improving liver fibrosis.MethodsRNA-sequencing was used to analyze the response pattern of UC-MSCs after exposure to the serum of cirrhotic patients with HBV. Using immunohistochemistry, quantitative polymerase chain reaction, and immunofluorescence techniques, we evaluated the therapeutic effect of UC-MSCs pretreated with interferon alpha 2 (IFN-α2) (pre-MSCs) in an animal model of cirrhosis. Immunoblotting, ELISA, and other techniques were used to analyze the signaling pathways underlying the IFN-induced changes in UC-MSCs.ResultsUC-MSCs exposed to the serum of patients with hepatitis B-induced cirrhosis showed an enhanced response to type I IFN. The activated type I IFN signal induced the highest secretion of colony-stimulating factor 3 (CSF-3), interleukin (IL)-8, and chemokine (C-C motif) ligand 20 (CCL20) by the UC-MSCs. Pre-MSCs showed a higher therapeutic efficacy than untreated UC-MSCs in an animal model of liver fibrosis. Immunohistochemical analysis revealed that pre-MSCs could recruit neutrophils resulting in an increase in the secretion of matrix metalloprotease 8 that alleviated fibrosis. When neutrophils in animals were depleted, the therapeutic effect of pre-MSCs on fibrosis was inhibited. IFN-α2 altered the secretory phenotype of UC-MSCs by activating phosphorylated signal transducer and activator of transcription 1 and 2 (p-STAT1 and p-STAT2).ConclusionsPre-MSCs exhibited enhanced secretion of CSF-3, IL-8, and CCL20 and recruited neutrophils to alleviate fibrosis. This new strategy can improve cell therapy for liver cirrhosis.

Dataset Information

?2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin.

Publications

α2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin.

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