scholarly journals MicroRNA-223 restricts liver fibrosis by inhibiting the TAZ-IHH-GLI2 and PDGF signaling pathways via the crosstalk of multiple liver cell types

2021 ◽  
Vol 17 (4) ◽  
pp. 1153-1167
Author(s):  
Xiaolin Wang ◽  
Wonhyo Seo ◽  
Seol Hee Park ◽  
Yaojie Fu ◽  
Seonghwan Hwang ◽  
...  
Keyword(s):  
Liver Fibrosis ◽  
Signaling Pathways ◽  
Liver Cell ◽  
Cell Types ◽  
Pdgf Signaling

scholarly journals Cell Signals Influencing Hepatic Fibrosis

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Min Cong ◽  
Keiko Iwaisako ◽  
Chunyan Jiang ◽  
Tatiana Kisseleva
Keyword(s):  
Liver Fibrosis ◽  
Signaling Pathways ◽  
Hepatic Fibrosis ◽  
Intracellular Signaling ◽  
Therapeutic Targets ◽  
Cell Types ◽  
Cell Type ◽  
Chronic Injury ◽  
Intracellular Signaling Pathways ◽  
Molecular Pathophysiology

Liver fibrosis is the result of the entire organism responding to a chronic injury. Every cell type in the liver contributes to the fibrosis. This paper first discusses key intracellular signaling pathways that are induced during liver fibrosis. The paper then examines the effects of these signaling pathways on the major cell types in the liver. This will provide insights into the molecular pathophysiology of liver fibrosis and should identify therapeutic targets.

Endocannabinoids and Liver Disease. II. Endocannabinoids in the pathogenesis and treatment of liver fibrosis

2008 ◽  
Vol 294 (2) ◽  
pp. G357-G362 ◽  
Author(s):  
Sören V. Siegmund ◽  
Robert F. Schwabe
Keyword(s):  
Liver Fibrosis ◽  
Signaling Pathways ◽  
Hepatic Cirrhosis ◽  
Endocannabinoid System ◽  
Cell Types ◽  
Chronic Injury ◽  
High Incidence ◽  
Complex Signaling ◽  
Injured Liver

Hepatic fibrosis is the response of the liver to chronic injury and is associated with portal hypertension, progression to hepatic cirrhosis, liver failure, and high incidence of hepatocellular carcinoma. On a molecular level, a large number of signaling pathways have been shown to contribute to the activation of fibrogenic cell types and the subsequent accumulation of extracellular matrix in the liver. Recent evidence suggests that the endocannabinoid system is an important part of this complex signaling network. In the injured liver, the endocannabinoid system is upregulated both at the level of endocannabinoids and at the endocannabinoid receptors CB1 and CB2. The hepatic endocannabinoid system mediates both pro- and antifibrogenic effects by activating distinct signaling pathways that differentially affect proliferation and death of fibrogenic cell types. Here we will summarize current findings on the role of the hepatic endocannabinoid system in liver fibrosis and discuss emerging options for its therapeutic exploitation.

scholarly journals Tim-3 enhances FcεRI-proximal signaling to modulate mast cell activation

2015 ◽  
Vol 212 (13) ◽  
pp. 2289-2304 ◽  
Author(s):  
Binh L. Phong ◽  
Lyndsay Avery ◽  
Tina L. Sumpter ◽  
Jacob V. Gorman ◽  
Simon C. Watkins ◽  
...  
Keyword(s):  
T Cells ◽  
Mast Cell ◽  
Signaling Pathways ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Cell Types ◽  
Mast Cell Activation ◽  
Positive Role ◽  
Ample Evidence

T cell (or transmembrane) immunoglobulin and mucin domain protein 3 (Tim-3) has attracted significant attention as a novel immune checkpoint receptor (ICR) on chronically stimulated, often dysfunctional, T cells. Antibodies to Tim-3 can enhance antiviral and antitumor immune responses. Tim-3 is also constitutively expressed by mast cells, NK cells and specific subsets of macrophages and dendritic cells. There is ample evidence for a positive role for Tim-3 in these latter cell types, which is at odds with the model of Tim-3 as an inhibitory molecule on T cells. At this point, little is known about the molecular mechanisms by which Tim-3 regulates the function of T cells or other cell types. We have focused on defining the effects of Tim-3 ligation on mast cell activation, as these cells constitutively express Tim-3 and are activated through an ITAM-containing receptor for IgE (FcεRI), using signaling pathways analogous to those in T cells. Using a variety of gain- and loss-of-function approaches, we find that Tim-3 acts at a receptor-proximal point to enhance Lyn kinase-dependent signaling pathways that modulate both immediate-phase degranulation and late-phase cytokine production downstream of FcεRI ligation.

MO262THE SINGLE-CELL TRANSCRIPTOMICS OF HUMAN IGA NEPHROPATHY

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Yong Zhong ◽  
Xiangcheng Xiao
Keyword(s):  
Gene Expression ◽  
Single Cell ◽  
Signaling Pathways ◽  
Iga Nephropathy ◽  
Molecular Mechanisms ◽  
Mesangial Cells ◽  
Therapeutic Targets ◽  
Cell Types ◽  
Receptor Crosstalk ◽  
Overt Proteinuria

Abstract Background and Aims The exact molecular mechanisms underlying IgA nephropathy (IgAN) remains incompletely defined. Therefore, it is necessary to further elucidate the mechanism of IgA nephropathy and find novel therapeutic targets. Method Single-cell RNA sequencing (scRNA-seq) was applied to kidney biopsies from 4 IgAN and 1 control subjects to define the transcriptomic landscape at the single-cell resolution. Unsupervised clustering analysis of kidney specimens was used to identify distinct cell clusters. Differentially expressed genes and potential signaling pathways involved in IgAN were also identified. Results Our analysis identified 14 cell subsets in kidney biopsies from IgAN patients, and analyzed changing gene expression in distinct renal cell types. We found increased mesangial expression of several novel genes including MALAT1, GADD45B, SOX4 and EDIL3, which were related to proliferation and matrix accumulation and have not been reported in IgAN previously. The overexpressed genes in tubule cells of IgAN were mainly enriched in inflammatory pathways including TNF signaling, IL-17 signaling and NOD-like receptor signaling. Moreover, the receptor-ligand crosstalk analysis revealed potential interactions between mesangial cells and other cells in IgAN. Specifically, IgAN with overt proteinuria displayed elevated genes participating in several signaling pathways which may be involved in pathogenesis of progression of IgAN. Conclusion The comprehensive analysis of kidney biopsy specimen demonstrated different gene expression profile, potential pathologic ligand-receptor crosstalk, signaling pathways in human IgAN. These results offer new insight into pathogenesis and identify new therapeutic targets for patients with IgA nephropathy.

scholarly journals Cell Surface Expression of Endosomal Toll-Like Receptors—A Necessity or a Superfluous Duplication?

2021 ◽  
Vol 11 ◽  
Author(s):  
Matylda Barbara Mielcarska ◽  
Magdalena Bossowska-Nowicka ◽  
Felix Ngosa Toka
Keyword(s):  
Immune Response ◽  
Cell Membrane ◽  
Cell Surface ◽  
Signaling Pathways ◽  
Distinct Group ◽  
Cell Types ◽  
Cysteine Proteases ◽  
Cell Surface Expression ◽  
Critical Event ◽  
Toll Like Receptors

Timely and precise delivery of the endosomal Toll-like receptors (TLRs) to the ligand recognition site is a critical event in mounting an effective antimicrobial immune response, however, the same TLRs should maintain the delicate balance of avoiding recognition of self-nucleic acids. Such sensing is widely known to start from endosomal compartments, but recently enough evidence has accumulated supporting the idea that TLR-mediated signaling pathways originating in the cell membrane may be engaged in various cells due to differential expression and distribution of the endosomal TLRs. Therefore, the presence of endosomal TLRs on the cell surface could benefit the host responses in certain cell types and/or organs. Although not fully understood why, TLR3, TLR7, and TLR9 may occur both in the cell membrane and intracellularly, and it seems that activation of the immune response can be initiated concurrently from these two sites in the cell. Furthermore, various forms of endosomal TLRs may be transported to the cell membrane, indicating that this may be a normal process orchestrated by cysteine proteases—cathepsins. Among the endosomal TLRs, TLR3 belongs to the evolutionary distinct group and engages a different protein adapter in the signaling cascade. The differently glycosylated forms of TLR3 are transported by UNC93B1 to the cell membrane, unlike TLR7, TLR8, and TLR9. The aim of this review is to reconcile various views on the cell surface positioning of endosomal TLRs and add perspective to the implication of such receptor localization on their function, with special attention to TLR3. Cell membrane-localized TLR3, TLR7, and TLR9 may contribute to endosomal TLR-mediated inflammatory signaling pathways. Dissecting this signaling axis may serve to better understand mechanisms influencing endosomal TLR-mediated inflammation, thus determine whether it is a necessity for immune response or simply a circumstantial superfluous duplication, with other consequences on immune response.

scholarly journals Hepatoprotective and Antifibrotic Effects of Indonesian Propolis

2019 ◽  
Vol 51 (3) ◽  
pp. 134-140
Author(s):  
Diding Heri Prasetyo ◽  
Sarsono Sarsono ◽  
Ida Nurwati ◽  
Prihandjojo Andri Putranto ◽  
Martini Martini ◽  
...  
Keyword(s):  
Liver Cirrhosis ◽  
Liver Fibrosis ◽  
Liver Damage ◽  
Liver Cell ◽  
Hepatic Cirrhosis ◽  
Cell Damage ◽  
Liver Cells ◽  
Control Group ◽  
Mice Model ◽  
Liver Cell Damage

Liver cirrhosis is the irreversible stage in liver damage process which occurs after liver fibrosis due to necro-inflammatory activities and liver fibrosis. Therefore, inhibition of liver inflammation and fibrosis is very important to prevent liver cirrhosis. This study aimed to analyze the effect of ethanol extract of propolis (EEP) from mount Lawu, Indonesia to prevent liver damage and fibrosis progression in mice with hepatic cirrhosis. This study was performed during the period of June 2018 to May 2019 on a sample of 32 male Balb/C mice divided into control group (P1), induction of carbon tetrachloride (CCl4 ) group (P2), induction of 50 mg/BW CCl4 + EEP group (P3), and (induction of 100 mg/KgBW CCl4 + EEP (P4) with each group consisted of eight mice. The CCl4 in olive oil was administered intraperitoneally three times a week for six weeks. Mean differences between group was determined using ANOVA test with a significance level of 0.05. The induction of CCl4 increased liver cell damage and serum alanin aminotransferase (ALT) level. However, the addition of EEP significantly (p<0.001) reduced liver cell damage as seen in P3 (54.38±4.17 per 100 liver cells) and P4 (37.13±4.36 per 100 liver cells) groups and serum alanin aminotransferase (ALT) as seen in P3 (291.19±113.92 U/L) and P4 (229.38±73.45 U/L) groups. The APRI scores were also reduced after EEP as seen in P3 (0.738±0.292) and P4 (0.513±0.253) groups. Thus, EEP isolates from Gunung Lawu can reduce liver cell damage and fibrosis in mice model of hepatic cirrhosis.

Comparative analysis of expression profiles of chemokines, chemokine receptors, and components of signaling pathways mediated by chemokines in eight cell types during rat liver regeneration

Genome ◽  
2010 ◽  
Vol 53 (8) ◽  
pp. 608-618 ◽  
Author(s):  
Xiaoguang Chen ◽  
Cunshuan Xu ◽  
Fuchun Zhang ◽  
Ji Ma
Keyword(s):  
Liver Regeneration ◽  
Signaling Pathways ◽  
Expression Profiles ◽  
Gradient Centrifugation ◽  
Cell Types ◽  
Cellular Level ◽  
Pcr Analysis ◽  
Immunomagnetic Bead ◽  
Percoll Density Gradient Centrifugation ◽  
Chemokine Signaling

It has been documented that chemokines can positively regulate liver regeneration at the tissue level after partial hepatectomy. However, the precise mechanism of the effects of chemokines on regeneration at the cellular level remains poorly defined. In this study, 8 cell types from rat regenerating liver at 8 recovery time points after 2/3 hepatectomy were isolated and purified using Percoll density gradient centrifugation and immunomagnetic bead methods. The expression profiles of each cell type were monitored using a microarray. RT-PCR analysis was performed to validate the reliability of the microarray results. The results showed that, on the whole, the expression profiles of chemokine and receptor genes varied among different cell types; most genes involved in chemokine signaling pathways showed an increase in expression across the 8 liver cell types during liver regeneration. The implication of these genes in regeneration was analyzed by bioinformatics and systems biology methods. According to the microarray results and gene synergy, activation of chemokine signaling pathways at 24 h in biliary epithelial cells and at 2–12 h in dendritic cells may be triggered by CCL2–CCR2 and CCL7–CCR3, respectively; activation of Plc/Pkc and Pi3k/Akt pathways at 2–12 h in sinusoidal endothelial cells might be caused by CCL7–CCR1; and activation of the Src/Ptk, Src/Vav, and Plc/Pkc pathways at the priming stage may be related to the inductive effect of CCL7. These data suggest the potential relevance of the pro-inflammatory chemokines for liver regeneration at the cellular level.

Differential activation of focal adhesion kinase, Rho and Rac by the ninth and tenth FIII domains of fibronectin

1999 ◽  
Vol 112 (17) ◽  
pp. 2937-2946
Author(s):  
N.A. Hotchin ◽  
A.G. Kidd ◽  
H. Altroff ◽  
H.J. Mardon
Keyword(s):  
Growth Factor ◽  
Focal Adhesion Kinase ◽  
Signaling Pathways ◽  
Focal Adhesion ◽  
Cell Attachment ◽  
Cell Types ◽  
Integrin Receptors ◽  
3T3 Cells ◽  
Swiss 3T3 ◽  
Kinase Phosphorylation

Fibronectins are widely expressed extracellular matrix ligands that are essential for many biological processes. Fibronectin-induced signaling pathways are elicited in diverse cell types when specific integrin receptors bind to the ninth and tenth FIII domains, FIII9-10. Integrin-mediated signal transduction involves activation of signaling pathways of the growth factor-dependent Ras-related small GTP-binding proteins Rho and Rac, and phosphorylation of focal adhesion kinase. We have dissected the requirement of FIII9 and FIII10 for Rho and Rac activity and phosphorylation of focal adhesion kinase in BHK fibroblasts and Swiss 3T3 cells. We demonstrate that FIII10 supports cell attachment but does not induce phosphorylation of focal adhesion kinase. In Swiss 3T3 cells, growth factor-independent phosphorylation of focal adhesion kinase and downstream adhesion events are dependent upon the presence of FIII9 in the intact FIII9-10 pair, whereas FIII10-mediated focal adhesion kinase phosphorylation requires a synergistic signal from growth factors. Furthermore, FIII10 is able to elicit cellular responses mediated by Rho, but not Rac, whereas FIII9-10 can elicit both Rho- and Rac-mediated responses. We propose that activation of specific integrin subunits by the FIII10 and FIII9-10 ligands elicits distinct signaling events. This may represent a general molecular mechanism for activation of receptor-specific signaling pathways by a multi-domain ligand.

scholarly journals The Endothelium as a Driver of Liver Fibrosis and Regeneration

Cells ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 929 ◽  
Author(s):  
Erica Lafoz ◽  
Maria Ruart ◽  
Aina Anton ◽  
Anna Oncins ◽  
Virginia Hernández-Gea
Keyword(s):  
Endothelial Cells ◽  
Liver Fibrosis ◽  
Liver Injury ◽  
Stellate Cell ◽  
Public Health Problem ◽  
Cell Types ◽  
Regenerative Process ◽  
Research Field ◽  
Major Public Health Problem ◽  
Liver Sinusoidal Endothelial Cells

Liver fibrosis is a common feature of sustained liver injury and represents a major public health problem worldwide. Fibrosis is an active research field and discoveries in the last years have contributed to the development of new antifibrotic drugs, although none of them have been approved yet. Liver sinusoidal endothelial cells (LSEC) are highly specialized endothelial cells localized at the interface between the blood and other liver cell types. They lack a basement membrane and display open channels (fenestrae), making them exceptionally permeable. LSEC are the first cells affected by any kind of liver injury orchestrating the liver response to damage. LSEC govern the regenerative process initiation, but aberrant LSEC activation in chronic liver injury induces fibrosis. LSEC are also main players in fibrosis resolution. They maintain liver homeostasis and keep hepatic stellate cell and Kupffer cell quiescence. After sustained hepatic injury, they lose their phenotype and protective properties, promoting angiogenesis and vasoconstriction and contributing to inflammation and fibrosis. Therefore, improving LSEC phenotype is a promising strategy to prevent liver injury progression and complications. This review focuses on changes occurring in LSEC after liver injury and their consequences on fibrosis progression, liver regeneration, and resolution. Finally, a synopsis of the available strategies for LSEC-specific targeting is provided.

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