Review Open Access
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 14, 2020; 26(10): 1005-1019
Published online Mar 14, 2020. doi: 10.3748/wjg.v26.i10.1005
Role of spleen tyrosine kinase in liver diseases
Dhadhang Wahyu Kurniawan, Gert Storm, Jai Prakash, Ruchi Bansal
Dhadhang Wahyu Kurniawan, Gert Storm, Jai Prakash, Ruchi Bansal, Department of Biomaterials Science and Technology, Faculty of Science and Technology, Technical Medical Centre, University of Twente, Enschede 7500, the Netherlands
Dhadhang Wahyu Kurniawan, Department of Pharmacy, Universitas Jenderal Soedirman, Purwokerto 53132, Indonesia
Gert Storm, Department of Pharmaceutics, University of Utrecht, Utrecht 3454, the Netherlands
Ruchi Bansal, Department of Pharmacokinetics, Toxicology and Targeting, Groningen Research Institute of Pharmacy, University of Groningen, Enschede 7500, the Netherlands
ORCID number: Dhadhang Wahyu Kurniawan (0000-0003-4843-3756); Gert Storm (0000-0003-4296-2761); Jai Prakash (0000-0003-1050-650X); Ruchi Bansal (0000-0003-2470-5876).
Author contributions: Kurniawan DW drafted and wrote the review; Bansal R critically reviewed and revised the review; Storm G and Prakash J read the review and provided their feedback; All the authors have read the review, contributed in language editing, and approved the final version.
Supported by the Endowment Fund for the Education Republic of Indonesia (Lembaga Pengelola Dana Pendidikan/LPDP RI), No. 44/LPDP/2015.
Conflict-of-interest statement: Authors declare no conflict of interests for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Ruchi Bansal, PhD, Assistant Professor, Department of Biomaterials Science and Technology, Technical Medical Centre, Faculty of Science and Technology, Zuidhorst 245, University of Twente, Enschede 7500, the Netherlands. r.bansal@utwente.nl
Received: November 29, 2019
Peer-review started: November 29, 2019
First decision: January 7, 2020
Revised: January 14, 2020
Accepted: February 28, 2020
Article in press: February 28, 2020
Published online: March 14, 2020

Abstract

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase expressed in most hematopoietic cells and non-hematopoietic cells and play a crucial role in both immune and non-immune biological responses. SYK mediate diverse cellular responses via an immune-receptor tyrosine-based activation motifs (ITAMs)-dependent signalling pathways, ITAMs-independent and ITAMs-semi-dependent signalling pathways. In liver, SYK expression has been observed in parenchymal (hepatocytes) and non-parenchymal cells (hepatic stellate cells and Kupffer cells), and found to be positively correlated with the disease severity. The implication of SYK pathway has been reported in different liver diseases including liver fibrosis, viral hepatitis, alcoholic liver disease, non-alcoholic steatohepatitis and hepatocellular carcinoma. Antagonism of SYK pathway using kinase inhibitors have shown to attenuate the progression of liver diseases thereby suggesting SYK as a highly promising therapeutic target. This review summarizes the current understanding of SYK and its therapeutic implication in liver diseases.

Key Words: Spleen tyrosine kinase, Liver diseases, Inflammation, Targeted therapeutics, Spleen tyrosine kinase inhibitors

Core tip: Spleen tyrosine kinase has reported to be positively correlated with disease severity and has shown to play a crucial role in the pathogenesis of liver diseases. Therefore, specific targeting of spleen tyrosine kinase pathway using kinase inhibitors is a highly promising therapeutic approach for the treatment of liver diseases.



INTRODUCTION

Spleen tyrosine kinase (SYK) is a cytoplasmic non-receptor protein tyrosine kinase (PTK) that consists of two SYK homology 2 domains (SH2) and a C-terminal tyrosine kinase domain. These domains are interconnected by two linker regions: Interdomain A between the two SH2 domains and Interdomain B between the C-terminal SH2 domain and the kinase domain (Figure 1). SYK is a member of the Zeta-chain-associated protein kinase 70/SYK family of the PTKs, with the estimated molecular weight of 70 kDa[1,2]. SYK is highly expressed in hematopoietic cells including mast cells, neutrophils, macrophages, platelets, B cells and immature T cells, and is important in signal transduction in these cells[2,3]. In Immune cells, SYK mainly functions via interaction of its tandem SH2 domains with immunoreceptor tyrosine-based activation motifs (ITAMs). In mast cells, SYK mediates downstream signaling via high-affinity IgE receptors, FcεRI and in neutrophils, macrophages, monocytes and platelets downstream signalling is mediated via Igγ receptors, FcγR[4-6]. SYK plays a key role in signaling downstream of the B and T cell receptors, hence also exhibit an important role in early lymphocyte development[4,7-10]. Upon activation, SYK modulates downstream signaling events that drive inflammatory pathways of both the innate and adaptive immune systems[11]. Besides ITAM-dependent signalling pathway, SYK also mediates ITAM-independent signaling via integrins and C-type lectins. For instance, SYK induces β2 integrin-mediated respiratory burst, spreading, and site-directed migration of neutrophils towards inflammatory lesions[12].

Figure 1
Figure 1 Structure of spleen tyrosine kinase. Spleen tyrosine kinase contains tandem pair of spleen tyrosine kinase homology 2 which connected by interdomain A and separated by interdomain B from the catalytic (kinase) domain. SYK: Spleen tyrosine kinase; SH2: Spleen tyrosine kinase homology 2; ITAM: Immune-receptor tyrosine-based activation motifs.

The multifactorial role of SYK in the immune system has attracted attention in the past years. SYK is recognized as a potential target for the treatment of inflammatory diseases such as rheumatoid arthritis, asthma, allergic rhinitis, renal disorders, liver fibrosis and autoimmune diseases[3,7,13-23]. In particular, the prevention of activation of cells via immune complexes or antigen-triggered Fc receptor signaling and prevention of B cell receptor-mediated events are believed to have increasing therapeutic potential of SYK[24,25].

Besides hematopoietic cells, SYK has also been shown to be expressed in non-hematopoietic cells including fibroblasts, epithelial cells, hepatocytes, neuronal cells, and vascular endothelial cells[7,26]. Here, SYK has shown to be involved in signalling events leading to activation of mitogen activated protein kinase (MAPK) by G-protein-coupled receptors in hepatocytes[26,27]. Besides being implicated in hepatocytes, SYK is also expressed in hepatic macrophages, hepatic stellate cells (HSCs) and hepatic sinusoidal endothelial cells in liver[28]. However, studies investigating SYK signalling pathway in liver diseases are still limited. This review highlights and discusses the opportunities and challenges of SYK as a potential target for the treatment of liver diseases.

SPLEEN TYROSINE KINASE SIGNALLING MECHANISMS

Immunoreceptor signalling through SYK requires the SYK kinase activity as well as both SH2 domains[29]. The SYK kinase domain remain inactive during resting state but can be activated by interaction of both SH2 domains to dual phosphorylated ITAMs[30]. Phosphorylation of tyrosine residues within the linker regions (interdomain A or B) also results in kinase activation even in the absence of phosphorylated ITAM binding[29,30]. Binding of the SH2 domains of SYK to phosphorylated ITAMs is a critical step in SYK activation and downstream signalling[31]. SYK itself can catalyse the autophosphorylation of its linker tyrosine’s, leading to sustained SYK activation after a transient ITAM phosphorylation. In addition, SYK itself can phosphorylate ITAMs, suggesting the existence of a positive-feedback loop during initial ITAM-mediated SYK activation[32]. Tsang et al[33] showed that SYK can be fully triggered by phosphorylation or binding of its SH2 domains to the dual-phosphorylated immune-receptor tyrosine based activity motif (ppITAM) (Figure 2)[33,34]. Recently, Slomiany and Slomiany demonstrated lipopolysaccharides (LPS)-induced SYK activation and phosphorylation on serine residues mediated by protein kinase Cδ that is required for its recruitment to the membrane-anchored TLR4, followed by subsequent SYK activation through tyrosine phosphorylation. Hence, the intermediate phase of protein kinase Cδ-mediated SYK phosphorylation on serine residues affects the inflammatory response[35]. The activated SYK binds to a number of downstream signalling effectors and amplifies the inflammatory signal propagation by affecting transcription factors activation and their assembly to transcriptional complexes involved in expression of the proinflammatory genes[36].

Figure 2
Figure 2 Basis of spleen tyrosine kinase activation. In the resting state, spleen tyrosine kinase is auto-inhibited, because of the binding of interdomain A and interdomain B to the kinase domain. This auto-inhibited conformation can be activated by binding of the two spleen tyrosine kinase homology 2 domains to dually phosphorylated immune-receptor tyrosine-based activation motifs or by phosphorylation of linker tyrosine’s in interdomain A or B. SH2: Spleen tyrosine kinase homology 2; ITAM: Immune-receptor tyrosine-based activation motifs.
SPLEEN TYROSINE KINASE IN LIVER FIBROSIS

Liver fibrosis, triggered by hepatitis B/C viral infection (viral hepatitis), alcohol abuse (alcoholic liver disease) or non-alcoholic steatohepatitis (NASH) etc., is characterized by an excessive deposition of extracellular matrix (ECM) proteins[37], leading to tissue scarring that further progresses to end-stage liver cirrhosis and hepatocellular carcinoma[38].

Liver fibrosis poses a major health problem accounting for more than 1 million people deaths per year worldwide[39]. Moreover, there is no therapeutic treatment available to date[40]. The central player that produces ECM resulting in liver fibrosis is HSCs[41]. HSCs are normally localized in the peri-sinusoidal area, termed as space of Disse, as quiescent cells in a healthy liver and functions as retinoid storage cells[42]. Owing to hepatic injury, quiescent HSCs phenotypically transdifferentiate into activated, contractile, highly proliferative and ECM-producing myofibroblasts[43].

SYK has been documented to play a critical role in the activation of HSCs and its upregulation is evidenced in hepatic fibrosis/cirrhosis in hepatitis B and C patients, alcoholic hepatitis as well as in NASH patients[28,44]. Upregulated SYK further aggravate fibrosis by augmenting trans-communication between hepatocytes and HSCs[28]. Blockage of SYK pathway using SYK inhibitors abrogated HSCs activation, thereby ameliorated liver fibrosis and hepatocellular carcinoma (HCC) development in vivo in animal models[28]. SYK has also shown to mediate its function via expression of transcription factors associated with HSCs activation (cAMP response element-binding protein, CBP; myeloblastosis proto-oncogene, MYB and myelocytomatosis proto-oncogene, MYC) and proliferation (MYC and cyclin D1, CCND1)[28]. Furthermore, two isoforms of SYK i.e., the full-length SYK (L) and an alternatively spliced SYK (S) have been suggested whereby SYK (L) but not SYK (S) found to play a major role in liver fibrosis while SYK (S) has been associated with increased tumorigenicity, HCC invasiveness and metastases[28].

Interestingly, the crosstalk between SYK and Wnt (portamanteau of int and wg, wingless-related integration site) signalling pathways also mediates activation of HSCs and accumulation of immune cells at the site of fibrosis[28]. Wnt signalling has been shown to be upregulated in activated HSCs and blockade of canonical Wnt pathway by adenoviral mediated transduction of Wnt antagonist (Dickkopf-1) or via selective inhibitors reinstates quiescent phase of HSCs in cultured cells[45,46]. In-depth investigation at a genetic level revealed overexpression of certain transcriptional factors (MYB, CBP and MYC) which plays a vital role in the activation of HSCs[47,48]. Notably, both the canonical Wnt pathway and SYK has shown to regulate the expression of MYC and CBP[23,49] highlighting SYK-Wnt crosstalk during liver fibrogenesis. SYK has also shown to promote expression of several other target genes including Wnt in activated macrophages in a similar manner as in HSCs and this potential crosstalk between SYK and other signalling pathways warrants further investigation. Dissection of the trans-communication between signalling pathways is of great importance in order to highlight prominent therapeutic targets to hinder liver inflammation and fibrogenesis. SYK is the major signalling pathway and is also shown to be expressed in recruited macrophages, besides HSCs, in the hepatic fibrosis[20,28]. Selective blocking of SYK or its deletion in macrophages has been correlated with the diminished activation of macrophages, which is indicated by a reduction in the expression of Fc gamma receptors, monocyte chemoattractant protein 1 (MCP-1), tumour necrosis factor α (TNF-α) and interleukin 6 (IL-6)[5]. In summary, activation of HSCs under the influence of SYK signalling leads to the secretion of soluble factors in the form of cytokines and chemokines. These factors not only facilitate the recruitment of macrophages (and other immune cells) but also arbitrates their activation to further worsen the site of fibrosis.

SPLEEN TYROSINE KINASE IN VIRAL HEPATITIS

In the recent study, SYK expression was found to be highly induced in the liver tissues of HBV- and HCV-infected patients. Furthermore, markedly increased expression of SYK was observed in HCV-infected hepatocytes which in turn promoted reciprocal higher SYK expression in HSCs thereby inducing HSCs activation and disease development[28,50]. Furthermore, the preliminary study analysing gene expression profiles in Egyptian HCC patients associated with HCV, showed that SYK is one of the most up-regulated gene out of 180 genes that were up-regulated[51].

HCV is also associated with B lymphocyte proliferative disorders, as evidenced by the binding of HCV to B-cell surface receptor CD81[52]. CD81 (cluster of differentiation 81, also known as TAPA1), is identified as a target of an antibody that controlled B-cell proliferation. Engagement of CD81 with HCV[53,54], leads to ezrin and radixin phosphorylation through SYK activation[55,56]. Ezrin and radixin are members of the ERM (ezrin, radixin, moesin) family of actin-binding proteins[56]. Hence, ezrin-moesin-radixin proteins and SYK are important therapeutic host targets for the development of HCV treatment[57].

SYK is also an important regulator and therapeutic target against HCV infection in hepatocytes[55]. SYK expression has been observed near the plasma membrane of hepatocytes in HCV-infected patients[57,58]. HCV non-structural protein 5A has been shown to physically and directly interact with SYK hence promoting the malignant transformation of HCV-infected hepatocytes[58]. These studies suggests that the strategies blocking SYK activation before HCV-CD81 interaction, and/or modulating HCV post-entry and trafficking within target cells involving SYK, F-actin, stable microtubules and EMR proteins provide novel opportunities for the development of anti-HCV therapies[55].

SPLEEN TYROSINE KINASE IN ALCOHOLIC LIVER DISEASE

The pathogenesis of alcoholic liver disease (ALD) is multifactorial involving many complex processes including ethanol-mediated liver injury, inflammation in response to the injury, and intestinal permeability and microbiome changes[59-61] as depicted in Figure 3. Alcohol and its metabolites generate reactive oxygen species (ROS) and induce hepatocyte injury through mitochondrial damage and endoplasmic reticulum (ER) stress[62-64]. Damaged hepatocytes release pro-inflammatory cytokines and chemokines resulting in the recruitment and activation of immune cells. Central cell types involved in ALD progression are macrophages that have an important role in inducing liver inflammation[65] by stimulating infiltration of immune cells (including monocytes) and activation of Kupffer cells (KCs, resident hepatic macrophages)[59]. The early communication of hepatocyte damage is mediated by KCs through damage-associated molecular patterns (DAMPs) released by dying hepatocytes or pathogen-associated molecular patterns (DAMPs) including lipopolysaccharides (LPS) via pattern recognition receptors (PRRs) such as Toll-like receptors (TLRs), and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signalling and inflammasome activation etc. In ALD, resident and recruited macrophages in the liver are activated by TLR4 (Toll-like receptor 4) signalling pathway regulated by bacterial endotoxin (LPS) that is elevated in the portal and systemic circulation due to increased intestinal permeability after excessive alcohol intake[66,67]. However, there are also other mechanisms that regulate macrophage activation, such as hepatocyte injury and lipid accumulation, histone acetylation in ethanol-exposed macrophages and complement system[68]. SYK also plays an important role in TLR4 signalling, and SYK phosphorylation in neutrophils and monocytes has been correlated with pro-inflammatory cytokine secretion including TNF-α and MCP-1[69]. Interestingly, SYK phosphorylation has also been shown to be regulated by LPS/TLR adaptor molecules MyD88/IRAKM (IL-1R-associated kinase M)/mincle axis linking LPS-induced hepatocyte cell death with inflammation during ALD disease pathogenesis. Zhou et al[70] has shown that damaged hepatocytes releases endogenous mincle ligand spliceosome-associated protein 130 as a danger signal that together with LPS synergistically drives liver inflammation including inflammasome activation during ALD[70].

Figure 3
Figure 3 Role of spleen tyrosine kinase in alcoholic liver disease and non-alcoholic steatohepatitis pathogenesis. Excessive alcohol consumption and Increased fat accumulation due to an increased fat biogenesis and reduced metabolism, causes hepatocellular injury that generates reactive oxygen species, release of pro-inflammatory cytokines and chemokines leading to activation of resident macrophages (Kupffer cells), and recruitment of circulating immune cells including neutrophils and monocytes. Overconsumption of alcohol also trigger the production of lipopolysaccharides due to increased intestinal permeability. Increased levels of pathogen-associated molecular patterns (Lipopolysaccharides) and damage-associated molecular patterns (released from dying hepatocytes) that in turn interacts with toll-like receptors e.g., toll-like receptor 4 resulting in the activation of spleen tyrosine kinase signaling pathway, NF-κB signaling pathway, and inflammasome activation. These processes develop into liver inflammation and fibrosis via increased infiltration and activation of immune cells and hepatic stellate cells, respectively. SYK: Spleen tyrosine kinase; LPS: Lipopolysaccharides; PAMPs: Pathogen-associated molecular patterns; DAMPs: Damage-associated molecular patterns; TLRs: Toll-like receptors; HSCs: Hepatic stellate cells; ROS: Reactive oxygen species.

Several studies have documented the increased SYK expression and phosphorylation in the livers of alcoholic hepatitis (AH) patients[44]. Interestingly, increased SYK phosphorylation was observed in ballooned hepatocytes with Mallory-Denk Bodies, co-localized with ubiquitinated proteins in the cytoplasm suggesting the critical role of SYK in hepatocytes during ER stress[71,72]. SYK regulates hepatic cell death via TRAF family member associated NF-Ƙβ activator (TANK)-binding kinase 1/interferon (IFN) regulatory factor 3 (TBK1/IRF3) signaling[20]. SYK has also been reported to play an important role in lipid accumulation, and treatment with SYK inhibitor prevented progressive steatosis by suppressing lipid biogenesis and increasing lipid metabolism in both in vitro cell culture and in vivo in ALD mouse models exhibiting moderate ASH and chronic alcohol drinking[20]. SYKY525/526 phosphorylation indicates SYK activation and is a prerequisite for its downstream modulatory function[73]. In addition, total SYK and activated pSYKY525/526 expression was found to be significantly increased in the circulating blood monocytes, and PBMCs in AH/cirrhosis patients[20]. Since SYK is closely involved in the pathogenesis of ALD, SYK inhibition could prevent and/or attenuate alcohol-induced liver inflammation, cell death, steatosis and subsequently fibrosis in various phases of ALD[20,73].

SPLEEN TYROSINE KINASE IN NON-ALCOHOLIC STEATOHEPATITIS

NASH is characterized by increasing accumulation of so-called toxic lipids in hepatocytes, that can develop into cirrhosis and primary liver cancer[74]. NASH is the more severe and clinically significant form of NAFLD (non-alcoholic fatty liver disease)[75], characterized by hepatic cell injury, steatosis together with inflammation, resulting into fibrosis signified by deposition of extracellular matrix mainly composed of collagen/fibrin fibrils[76]. The progression of NASH is associated with a progressive build-up of danger signals particularly PRRs including TLRs, and nucleotide oligomerization domain-like receptors (NLRs)[77] that engage multiple receptors during immune response[78].

As also mentioned earlier, the interaction of LPS with TLR4 plays a major role in linking innate immunity with inflammatory response and the activation of KCs[77,79,80]. Activated KCs produce inflammatory cytokines and chemokines such as IL-1β, IL-6, iNOS, FcγR1, and CCL2 that contribute to the recruitment of circulating monocytes and macrophages into the inflammed liver during NASH development mostly similar to ASH[81]. Activated KCs also secrete TNF superfamily ligands such as TNF-α and TNF-related apoptosis-inducing ligand, inducing apoptosis of adjacent hepatocytes and inflammation, and is crucial for triggering NASH development[81-83] as shown in Figure 3.

Activated KCs instigates TLR4 and recruit an activated SYK, which is also expressed in HSCs, hepatocytes, and cholangiocytes[77,84-86]. SYK plays a role in IL1-induced chemokine release via association with TRAF-6 (TNF receptor activating factor 6), which is a shared molecule in multiple signalling pathways and is recruited through interactions of adaptor MyD88 and IRAK-1 (IL1 receptor-associated kinase 1) with TLR4[87-89]. Likewise, TLR4 transduces signals via the B-cell receptor (BCR) leading to activation of SYK, which is important for B-cell survival, proliferation[90], and BCR-mediated immune response[5]. Lipid peroxidation products, derived from phospholipid oxidation are one of the sources of neo-antigens that are able to promote an adaptive immune response in NASH[91]. The involvement of T and B cells in the progression of NASH automatically implicate role of SYK in this process.

Recently, we have shown the positive correlation of SYK expression with the increasing NAS score (NAFLD activity score) in livers from NASH patients as compared to normal livers[44]. As aforementioned, the role of SYK in NASH is not only via PRR pathways, but also through NLR pathways. The role of several NLRs have been crucial in the formation of inflammasomes and the nomenclature of inflammasomes is hence based on the NLR[92]. SYK is required for NLRP3 (NLR protein 3) inflammasome activation[93], that forms an IL-1β-processing inflammasome complex. Inflammasome activation has been shown to be associated with the late stages of NASH, and not in early steatosis in mice[94]. Inflammasome activation can be induced by free fatty acids and these free fatty acids can also induce apoptosis and the release of danger signals in hepatocytes[94,95]. Consequently, pharmacological inhibition of NLRP3 inflammasome in vivo has been demonstrated to reduce liver inflammation, hepatocyte injury, and liver fibrosis in NASH[44,96].

SPLEEN TYROSINE KINASE IN HEPATOCELLULAR CARCINOMA

Hepatocyte apoptosis and compensatory proliferation are the key drivers for HCC development, and SYK has been suggested to play a key role in HCC progression. In HCC, intestinal microbiota and TLR4 link inflammation and carcinogenesis in the chronically injured liver, and SYK regulate this link mediated via LPS-TLR4 interaction[97]. The intimate correlation between SYK methylation and loss-of-expression, together with the role of SYK methylation in gene silencing, indicates that epigenetic inactivation of SYK contributes to the progression of HCC[98] signifying SYK methylation and loss of SYK expression as predictors of poor overall survival in patients with HCC. Furthermore, methylation of SYK promoter was found to be inversely regulated in HCC cells. Restoring SYK expression in SYK-silenced HCC cell lines decreased hepatocellular growth, cell migration and invasion but increased cell adhesion[99,100].

On the other hand, checkpoint kinase 1 (CHK1) was found to be overexpressed and correlated with poor survival of HCC patients. CHK1 phosphorylate tumor suppressor SYK isoform, SYK (L) at Ser295 and induce its proteasomal degradation. However, non-phosphorylated mutant form of SYK (L) has been shown to suppress proliferation, colony formation, migration and tumor growth in HCC lines. Therefore, a strong inverse correlation between the expression levels of CHK1 and SYK (L) was observed in patients with HCC[101]. Interestingly, Hong et al[102] showed that another SYK isoform, SYK (S) promotes tumour growth, downregulates apoptosis, enhances metastasis and counteracts the opposing effects of SYK (L). These studies suggest that SYK (L) downregulation or SYK (S) upregulation are the strong predictors of poor clinical outcome in patients with HCC.

SMALL MOLECULES SPLEEN TYROSINE KINASE INHIBITORS

Over the past decade, SYK signalling pathway has been recognized as a promising target for the therapeutic intervention in different diseases including autoimmune and inflammatory disorders, fibrotic diseases and tumour. However, specificity and selectivity remain the major concern for the development of drugs targeting ubiquitously expressed kinases. Hence, debate about the specificity of SYK inhibitors has been a major point of discussion and has still not reached an appropriate conclusion since the first SYK inhibitors entered into medicinal chemistry optimization[25,103,104]. Over the past few years, several SYK inhibitors have been designed while many are still in development, and the molecular structures of some of these SYK inhibitors are depicted in Figure 4. Several SYK inhibitors are been evaluated in preclinical and clinical studies in different diseases[103,105], as highlighted in Table 1[106-127].

Table 1 Summary of pre-clinical and clinical studies using spleen tyrosine kinase inhibitors.
CompoundMedical conditionDescription/effectRef.
Fostamatinib (R788)Ulcerative colitisSuppression of TNFα, T cells and neutrophils[106]
Rheumatoid arthritisReduced inflammation and tissue damage, suppressed clinical arthritis, pannus formation and synovitis[107,108]
Chronic lymphocytic leukemia and Non-Hodgkin lymphomaDisruption of BCR signaling inhibiting the proliferation and survival of malignant B cells[109,110]
Ischemia-reperfusion induced intestinal and lung damageImpaired release of pro-inflammatory and coagulation mediators, reduced neutrophils, macrophages and platelet accumulations[111]
GlomerulonephritisReduced proteinuria, glomerular macrophage and CD8 cells, MCP-1 and IL-1β, and renal injury[112]
Entospletinib (GS-9973)Chronic lymphocytic leukemiaDecreased inflammation and disruption of chemokine/cytokine circuits (BCR signaling)[113-115]
Diffuse large B-cell lymphomaDisruption of BCR signaling inhibiting the proliferation and survival of malignant B cells[116]
Cherubisme (craniofacial disorder)Ameliorates inflammation and bone destruction in the mouse model of cherubism[117]
Cerdulatinib (PRT062070)Diffuse large B-cell lymphomaDisruption of BCR signalling inhibiting the proliferation and survival of malignant B cells[118,119]
TAK-659Epstein-Barr virus-associated lymphomaInhibited tumour development and metastases[120]
Chronic lymphocytic leukemiaDecreased tumour survival, myeloid cell proliferation and metastasis[121]
R406 (tamatinib)Immunocomplexes mediated inflammationInhibits several critical modes of the inflammatory cascade[122]
Human plateletsInhibition of activation of CLEC-2 (C-type lectin 2, platelet receptor), and platelet activation[123]
Chronic lymphocytic leukemiaInhibition of constitutive and BCR-induced SYK activation, abrogation of CLL cell survival, migration, and paracrine signalling[124]
LeukemiaReduced tyrosine phosphorylation and c-Myc expression, blockade of tumorigenic cells proliferation transformed by oncogenes[125]
Megakaryocytic leukemiaInduced apoptosis, reduced cell proliferation and blockade of STAT5 signalling[126]
GlomerulonephritisDownregulated MCP-1 production from mesangial cells and macrophages[112]
PiceatannolOral squamous cell carcinomaInhibited tumour cell proliferation, induced of apoptosis, attenuated VEGF and MMP9 expression, and decreased metastases[127]
Figure 4
Figure 4 Molecular structure of several spleen tyrosine kinase inhibitors. R406, GS-9973, PRT062070, and Piceatannol have been studied in liver diseases, while R788 and TAK-659 are being investigated in other diseases.

Some of the above mentioned SYK inhibitors have been explored in liver diseases and are presented in Table 2. R406 has been shown to reduce SYK expression and phosphorylation in macrophages, and other hepatic cells and has been shown to ameliorate non-alcoholic and alcoholic steatohepatitis by inhibiting steatosis, inflammation and fibrosis suggesting multi-faceted effects of this highly selective SYK inhibitor[20,44]. GS-9973 is a new emerging, selective and potent inhibitor of SYK that was evaluated in activated HSCs and showed anti-fibrotic effects in rodent liver fibrosis models[28]. Very recently, two new inhibitors PRT062607 and Piceatannol have been investigated in myeloid cells to reveal their protective effect against liver fibrosis and hepatocarcinogenesis in vivo. Both inhibitors selectively blocked SYK phosphorylation, significantly reduced the infiltration of inflammatory cells and HSCs trans-differentiation, and inhibited malignant transformation in fibrotic livers[128].

Table 2 Spleen tyrosine kinase inhibitors implicated in liver diseases.
InhibitorMechanism of actionTherapeutic effectRef.
R406Blocking of Fc receptor signalling pathway, NF-κB signalling pathway and inflammasome activationReduced SYK expression and phosphorylation resulting in attenuated liver steatosis, inflammation and fibrosis in ASH and NASH murine models[20,44]
GS-9973Decreased expression of HSCs activation (CBP, MYB, MYC) and HSCs proliferation factors (MYC and CCND1)Inhibition of HSCs proliferation and HSC activation resulting in amelioration of fibrosis and hepatocarcinogenesis[28]
PRT062607 and piceatannolIncreased intra-tumoral p16, p53 and decreased expression of Bcl-xL and SMAD4. Decreased expression of genes regulating angiogenesis, apoptosis, cell cycle regulation and cellular senescence. Down-regulation of mTOR, IL-8 signalling and oxidative phosphorylationReduced HSCs differentiation and infiltration of inflammatory cells including T cells, B cells and myeloid cells, reduced oncogenic progression. Marked attenuation of toxin-induced liver fibrosis, associated hepatocellular injury, intra-hepatic inflammation and hepatocarcinogenesis[128]

Despite the encouraging results with SYK inhibitors, some issues remain unresolved e.g., their long-term safety has not yet been demonstrated. Moreover, due to the ubiquitous expression of SYK in different cells, concerns have been raised about the possibility of side-effects owing to the overall inhibition of the multiple cellular functions[2,127]. A major challenge therefore is how to inhibit pathological processes without disrupting physiological cell functions[129]. Nanotechnology is an interesting and promising alternative to improve the efficacy and therapeutic effect of the SYK inhibitor. Using polymeric poly lactic-co-glycolic acid (PLGA) nanoparticles, we have demonstrated improved therapeutic effectivity of R406 in MCD-diet induced NASH[44]. In this study, we have shown that R406, when encapsulated in PLGA polymeric nanoparticles, reduced expression of total SYK and activation of pSYK in macrophages in vitro, and attenuated steatosis, inflammation and fibrosis in vivo in MCD-diet induced NASH mouse model[44].

CONCLUSION

In this review, we have highlighted the implication of SYK signalling pathways in different diseases, more importantly in liver diseases. SYK plays a multifaceted role in liver diseases such as liver fibrosis, alcoholic liver disease, non-alcoholic steatohepatitis, viral hepatitis, and hepatocellular carcinoma. Furthermore, several SYK-related mechanisms have been understood in the past decade which led to the development of numerous small-molecule inhibitors that have been and are currently evaluated in vitro, in vivo in different animal models and in clinical trials in patients for different indications. These inhibitors have shown highly potent effects in the tested models and therefore is a promising therapeutic target that should be explored further in pre-clinical and clinical studies. To improve the therapeutic efficacy and clinical use of SYK inhibitors with improved safety profile and reduce the side effects, nanotechnology approaches, such as polymeric nanoparticles, liposomal-mediated delivery, or micelles, and finally organ (tumour)-targeted drug delivery could be explored.

Footnotes

Manuscript source: Invited manuscript

Specialty type: Gastroenterology and hepatology

Country of origin: Netherlands

Peer-review report classification

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Grade C (Good): C

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Corresponding Author's Membership in Professional Societies: Netherlands Society of Gastroenterology; American Association for the Study of Liver Diseases; European Association for the Study of Liver.

P-Reviewer: El-Razek AA, Slomiany BL S-Editor: Zhang L L-Editor: A E-Editor: Zhang YL

References
1.  Lowell CA. Src-family and Syk kinases in activating and inhibitory pathways in innate immune cells: signaling cross talk. Cold Spring Harb Perspect Biol. 2011;3.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 131]  [Cited by in F6Publishing: 141]  [Article Influence: 11.9]  [Reference Citation Analysis (0)]
2.  Riccaboni M, Bianchi I, Petrillo P. Spleen tyrosine kinases: biology, therapeutic targets and drugs. Drug Discov Today. 2010;15:517-530.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 74]  [Cited by in F6Publishing: 68]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
3.  Pamuk ON, Tsokos GC. Spleen tyrosine kinase inhibition in the treatment of autoimmune, allergic and autoinflammatory diseases. Arthritis Res Ther. 2010;12:222.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 48]  [Cited by in F6Publishing: 42]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
4.  Mócsai A, Ruland J, Tybulewicz VL. The SYK tyrosine kinase: a crucial player in diverse biological functions. Nat Rev Immunol. 2010;10:387-402.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 742]  [Cited by in F6Publishing: 704]  [Article Influence: 61.8]  [Reference Citation Analysis (0)]
5.  Schweighoffer E, Nys J, Vanes L, Smithers N, Tybulewicz VLJ. TLR4 signals in B lymphocytes are transduced via the B cell antigen receptor and SYK. J Exp Med. 2017;214:1269-1280.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 47]  [Cited by in F6Publishing: 42]  [Article Influence: 9.4]  [Reference Citation Analysis (0)]
6.  Turner M, Schweighoffer E, Colucci F, Di Santo JP, Tybulewicz VL. Tyrosine kinase SYK: essential functions for immunoreceptor signalling. Immunol Today. 2000;21:148-154.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 288]  [Cited by in F6Publishing: 95]  [Article Influence: 13.1]  [Reference Citation Analysis (0)]
7.  Bradshaw JM. The Src, Syk, and Tec family kinases: distinct types of molecular switches. Cell Signal. 2010;22:1175-1184.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 151]  [Cited by in F6Publishing: 139]  [Article Influence: 12.6]  [Reference Citation Analysis (0)]
8.  Cornall RJ, Cheng AM, Pawson T, Goodnow CC. Role of Syk in B-cell development and antigen-receptor signaling. Proc Natl Acad Sci USA. 2000;97:1713-1718.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 80]  [Cited by in F6Publishing: 74]  [Article Influence: 3.6]  [Reference Citation Analysis (0)]
9.  Keller B, Stumpf I, Strohmeier V, Usadel S, Verhoeyen E, Eibel H, Warnatz K. High SYK Expression Drives Constitutive Activation of CD21low B Cells. J Immunol. 2017;198:4285-4292.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 18]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
10.  Burton AR, Pallett LJ, McCoy LE, Suveizdyte K, Amin OE, Swadling L, Alberts E, Davidson BR, Kennedy PT, Gill US, Mauri C, Blair PA, Pelletier N, Maini MK. Circulating and intrahepatic antiviral B cells are defective in hepatitis B. J Clin Invest. 2018;128:4588-4603.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 103]  [Cited by in F6Publishing: 62]  [Article Influence: 25.8]  [Reference Citation Analysis (0)]
11.  Frommhold D, Mannigel I, Schymeinsky J, Mocsai A, Poeschl J, Walzog B, Sperandio M. Spleen tyrosine kinase Syk is critical for sustained leukocyte adhesion during inflammation in vivo. BMC Immunol. 2007;8:31.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 44]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
12.  Mócsai A, Zhou M, Meng F, Tybulewicz VL, Lowell CA. Syk is required for integrin signaling in neutrophils. Immunity. 2002;16:547-558.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 307]  [Cited by in F6Publishing: 163]  [Article Influence: 15.4]  [Reference Citation Analysis (0)]
13.  Pamuk ON, Lapchak PH, Rani P, Pine P, Dalle Lucca JJ, Tsokos GC. Spleen tyrosine kinase inhibition prevents tissue damage after ischemia-reperfusion. Am J Physiol Gastrointest Liver Physiol. 2010;299:G391-G399.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 33]  [Article Influence: 2.8]  [Reference Citation Analysis (0)]
14.  Geahlen RL. Getting Syk: spleen tyrosine kinase as a therapeutic target. Trends Pharmacol Sci. 2014;35:414-422.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 135]  [Cited by in F6Publishing: 126]  [Article Influence: 16.9]  [Reference Citation Analysis (0)]
15.  McAdoo SP, Reynolds J, Bhangal G, Smith J, McDaid JP, Tanna A, Jackson WD, Masuda ES, Cook HT, Pusey CD, Tam FW. Spleen tyrosine kinase inhibition attenuates autoantibody production and reverses experimental autoimmune GN. J Am Soc Nephrol. 2014;25:2291-2302.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 20]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
16.  Patterson H, Nibbs R, McInnes I, Siebert S. Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases. Clin Exp Immunol. 2014;176:1-10.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 123]  [Cited by in F6Publishing: 113]  [Article Influence: 15.4]  [Reference Citation Analysis (0)]
17.  Kaur M, Singh M, Silakari O. Inhibitors of switch kinase 'spleen tyrosine kinase' in inflammation and immune-mediated disorders: a review. Eur J Med Chem. 2013;67:434-446.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 37]  [Cited by in F6Publishing: 34]  [Article Influence: 4.1]  [Reference Citation Analysis (0)]
18.  Ma TK, McAdoo SP, Tam FW. Spleen Tyrosine Kinase: A Crucial Player and Potential Therapeutic Target in Renal Disease. Nephron. 2016;133:261-269.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 15]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
19.  Chen KH, Hsu HH, Yang HY, Tian YC, Ko YC, Yang CW, Hung CC. Inhibition of spleen tyrosine kinase (syk) suppresses renal fibrosis through anti-inflammatory effects and down regulation of the MAPK-p38 pathway. Int J Biochem Cell Biol. 2016;74:135-144.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 11]  [Cited by in F6Publishing: 12]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
20.  Bukong TN, Iracheta-Vellve A, Saha B, Ambade A, Satishchandran A, Gyongyosi B, Lowe P, Catalano D, Kodys K, Szabo G. Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease. Hepatology. 2016;64:1057-1071.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 33]  [Cited by in F6Publishing: 27]  [Article Influence: 5.5]  [Reference Citation Analysis (0)]
21.  McAdoo S, Tam FWK. Role of the Spleen Tyrosine Kinase Pathway in Driving Inflammation in IgA Nephropathy. Semin Nephrol. 2018;38:496-503.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 8]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
22.  Sanderson MP, Lau CW, Schnapp A, Chow CW. Syk: a novel target for treatment of inflammation in lung disease. Inflamm Allergy Drug Targets. 2009;8:87-95.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Coffey G, DeGuzman F, Inagaki M, Pak Y, Delaney SM, Ives D, Betz A, Jia ZJ, Pandey A, Baker D, Hollenbach SJ, Phillips DR, Sinha U. Specific inhibition of spleen tyrosine kinase suppresses leukocyte immune function and inflammation in animal models of rheumatoid arthritis. J Pharmacol Exp Ther. 2012;340:350-359.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 82]  [Cited by in F6Publishing: 75]  [Article Influence: 7.5]  [Reference Citation Analysis (0)]
24.  Koyama Y, Brenner DA. Liver inflammation and fibrosis. J Clin Invest. 2017;127:55-64.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 379]  [Cited by in F6Publishing: 221]  [Article Influence: 75.8]  [Reference Citation Analysis (0)]
25.  Singh R, Masuda ES, Payan DG. Discovery and development of spleen tyrosine kinase (SYK) inhibitors. J Med Chem. 2012;55:3614-3643.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 53]  [Article Influence: 5.6]  [Reference Citation Analysis (0)]
26.  Yanagi S, Inatome R, Takano T, Yamamura H. Syk expression and novel function in a wide variety of tissues. Biochem Biophys Res Commun. 2001;288:495-498.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 110]  [Cited by in F6Publishing: 105]  [Article Influence: 5.2]  [Reference Citation Analysis (0)]
27.  Tsuchida S, Yanagi S, Inatome R, Ding J, Hermann P, Tsujimura T, Matsui N, Yamamura H. Purification of a 72-kDa protein-tyrosine kinase from rat liver and its identification as Syk: involvement of Syk in signaling events of hepatocytes. J Biochem. 2000;127:321-327.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 34]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
28.  Qu C, Zheng D, Li S, Liu Y, Lidofsky A, Holmes JA, Chen J, He L, Wei L, Liao Y, Yuan H, Jin Q, Lin Z, Hu Q, Jiang Y, Tu M, Chen X, Li W, Lin W, Fuchs BC, Chung RT, Hong J. Tyrosine kinase SYK is a potential therapeutic target for liver fibrosis. Hepatology. 2018;68:1125-1139.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 36]  [Article Influence: 10.8]  [Reference Citation Analysis (0)]
29.  Keshvara LM, Isaacson C, Harrison ML, Geahlen RL. Syk activation and dissociation from the B-cell antigen receptor is mediated by phosphorylation of tyrosine 130. J Biol Chem. 1997;272:10377-10381.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 62]  [Cited by in F6Publishing: 58]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
30.  Zhang Y, Oh H, Burton RA, Burgner JW, Geahlen RL, Post CB. Tyr130 phosphorylation triggers Syk release from antigen receptor by long-distance conformational uncoupling. Proc Natl Acad Sci USA. 2008;105:11760-11765.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 36]  [Article Influence: 3.1]  [Reference Citation Analysis (0)]
31.  Grucza RA, Fütterer K, Chan AC, Waksman G. Thermodynamic study of the binding of the tandem-SH2 domain of the Syk kinase to a dually phosphorylated ITAM peptide: evidence for two conformers. Biochemistry. 1999;38:5024-5033.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 44]  [Cited by in F6Publishing: 43]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
32.  Rolli V, Gallwitz M, Wossning T, Flemming A, Schamel WW, Zürn C, Reth M. Amplification of B cell antigen receptor signaling by a Syk/ITAM positive feedback loop. Mol Cell. 2002;10:1057-1069.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 218]  [Cited by in F6Publishing: 95]  [Article Influence: 11.5]  [Reference Citation Analysis (0)]
33.  Tsang E, Giannetti AM, Shaw D, Dinh M, Tse JK, Gandhi S, Ho H, Wang S, Papp E, Bradshaw JM. Molecular mechanism of the Syk activation switch. J Biol Chem. 2008;283:32650-32659.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 89]  [Cited by in F6Publishing: 56]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
34.  Kulathu Y, Hobeika E, Turchinovich G, Reth M. The kinase Syk as an adaptor controlling sustained calcium signalling and B-cell development. EMBO J. 2008;27:1333-1344.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 62]  [Article Influence: 4.5]  [Reference Citation Analysis (0)]
35.  Slomiany BL, Slomiany A. Helicobacter pylori LPS-induced gastric mucosal spleen tyrosine kinase (Syk) recruitment to TLR4 and activation occurs with the involvement of protein kinase Cδ. Inflammopharmacology. 2018;26:805-815.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 6]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
36.  Slomiany BL, Slomiany A. Syk: a new target for attenuation of Helicobacter pylori-induced gastric mucosal inflammatory responses. Inflammopharmacology. 2019;27:203-211.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3]  [Cited by in F6Publishing: 4]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
37.  Bataller R, Brenner DA. Liver fibrosis. J Clin Invest. 2005;115:209-218.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 3033]  [Cited by in F6Publishing: 1550]  [Article Influence: 178.4]  [Reference Citation Analysis (0)]
38.  Parola M, Pinzani M. Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. Mol Aspects Med. 2019;65:37-55.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 121]  [Cited by in F6Publishing: 127]  [Article Influence: 30.3]  [Reference Citation Analysis (0)]
39.  Asrani SK, Devarbhavi H, Eaton J, Kamath PS. Burden of liver diseases in the world. J Hepatol. 2019;70:151-171.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 615]  [Cited by in F6Publishing: 559]  [Article Influence: 153.8]  [Reference Citation Analysis (0)]
40.  Schuppan D, Ashfaq-Khan M, Yang AT, Kim YO. Liver fibrosis: Direct antifibrotic agents and targeted therapies. Matrix Biol. 2018;68-69:435-451.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 144]  [Cited by in F6Publishing: 140]  [Article Influence: 36.0]  [Reference Citation Analysis (0)]
41.  Gieseck RL, Wilson MS, Wynn TA. Type 2 immunity in tissue repair and fibrosis. Nat Rev Immunol. 2018;18:62-76.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 305]  [Cited by in F6Publishing: 295]  [Article Influence: 61.0]  [Reference Citation Analysis (0)]
42.  Tsuchida T, Friedman SL. Mechanisms of hepatic stellate cell activation. Nat Rev Gastroenterol Hepatol. 2017;14:397-411.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 770]  [Cited by in F6Publishing: 749]  [Article Influence: 154.0]  [Reference Citation Analysis (0)]
43.  Nishikawa K, Osawa Y, Kimura K. Wnt/β-Catenin Signaling as a Potential Target for the Treatment of Liver Cirrhosis Using Antifibrotic Drugs. Int J Mol Sci. 2018;19.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 35]  [Cited by in F6Publishing: 32]  [Article Influence: 8.8]  [Reference Citation Analysis (0)]
44.  Kurniawan DW, Jajoriya AK, Dhawan G, Mishra D, Argemi J, Bataller R, Storm G, Mishra DP, Prakash J, Bansal R. Therapeutic inhibition of spleen tyrosine kinase in inflammatory macrophages using PLGA nanoparticles for the treatment of non-alcoholic steatohepatitis. J Control Release. 2018;288:227-238.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 16]  [Cited by in F6Publishing: 19]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
45.  Cheng JH, She H, Han YP, Wang J, Xiong S, Asahina K, Tsukamoto H. Wnt antagonism inhibits hepatic stellate cell activation and liver fibrosis. Am J Physiol Gastrointest Liver Physiol. 2008;294:G39-G49.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 181]  [Cited by in F6Publishing: 182]  [Article Influence: 12.1]  [Reference Citation Analysis (0)]
46.  Akcora BÖ, Storm G, Bansal R. Inhibition of canonical WNT signaling pathway by β-catenin/CBP inhibitor ICG-001 ameliorates liver fibrosis in vivo through suppression of stromal CXCL12. Biochim Biophys Acta Mol Basis Dis. 2018;1864:804-818.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 31]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
47.  Wang X, Tang X, Gong X, Albanis E, Friedman SL, Mao Z. Regulation of hepatic stellate cell activation and growth by transcription factor myocyte enhancer factor 2. Gastroenterology. 2004;127:1174-1188.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 43]  [Cited by in F6Publishing: 44]  [Article Influence: 2.4]  [Reference Citation Analysis (0)]
48.  Mann J, Mann DA. Transcriptional regulation of hepatic stellate cells. Adv Drug Deliv Rev. 2009;61:497-512.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 85]  [Cited by in F6Publishing: 84]  [Article Influence: 6.5]  [Reference Citation Analysis (0)]
49.  Tokunaga Y, Osawa Y, Ohtsuki T, Hayashi Y, Yamaji K, Yamane D, Hara M, Munekata K, Tsukiyama-Kohara K, Hishima T, Kojima S, Kimura K, Kohara M. Selective inhibitor of Wnt/β-catenin/CBP signaling ameliorates hepatitis C virus-induced liver fibrosis in mouse model. Sci Rep. 2017;7:325.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 31]  [Cited by in F6Publishing: 30]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
50.  Aouar B, Kovarova D, Letard S, Font-Haro A, Florentin J, Weber J, Durantel D, Chaperot L, Plumas J, Trejbalova K, Hejnar J, Nunès JA, Olive D, Dubreuil P, Hirsch I, Stranska R. Dual Role of the Tyrosine Kinase Syk in Regulation of Toll-Like Receptor Signaling in Plasmacytoid Dendritic Cells. PLoS One. 2016;11:e0156063.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 25]  [Article Influence: 3.8]  [Reference Citation Analysis (0)]
51.  Zekri AR, Hafez MM, Bahnassy AA, Hassan ZK, Mansour T, Kamal MM, Khaled HM. Genetic profile of Egyptian hepatocellular-carcinoma associated with hepatitis C virus Genotype 4 by 15 K cDNA microarray: preliminary study. BMC Res Notes. 2008;1:106.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 19]  [Article Influence: 1.6]  [Reference Citation Analysis (0)]
52.  Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, Weiner AJ, Houghton M, Rosa D, Grandi G, Abrignani S. Binding of hepatitis C virus to CD81. Science. 1998;282:938-941.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1501]  [Cited by in F6Publishing: 1407]  [Article Influence: 62.5]  [Reference Citation Analysis (0)]
53.  Brazzoli M, Bianchi A, Filippini S, Weiner A, Zhu Q, Pizza M, Crotta S. CD81 is a central regulator of cellular events required for hepatitis C virus infection of human hepatocytes. J Virol. 2008;82:8316-8329.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 138]  [Cited by in F6Publishing: 88]  [Article Influence: 9.9]  [Reference Citation Analysis (0)]
54.  Zhang J, Randall G, Higginbottom A, Monk P, Rice CM, McKeating JA. CD81 is required for hepatitis C virus glycoprotein-mediated viral infection. J Virol. 2004;78:1448-1455.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 265]  [Cited by in F6Publishing: 156]  [Article Influence: 14.7]  [Reference Citation Analysis (0)]
55.  Bukong TN, Kodys K, Szabo G. Human ezrin-moesin-radixin proteins modulate hepatitis C virus infection. Hepatology. 2013;58:1569-1579.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 20]  [Cited by in F6Publishing: 19]  [Article Influence: 2.2]  [Reference Citation Analysis (0)]
56.  Coffey GP, Rajapaksa R, Liu R, Sharpe O, Kuo CC, Krauss SW, Sagi Y, Davis RE, Staudt LM, Sharman JP, Robinson WH, Levy S. Engagement of CD81 induces ezrin tyrosine phosphorylation and its cellular redistribution with filamentous actin. J Cell Sci. 2009;122:3137-3144.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 40]  [Article Influence: 3.2]  [Reference Citation Analysis (0)]
57.  Bukong TN, Kodys K, Szabo G. A Novel Human Radixin Peptide Inhibits Hepatitis C Virus Infection at the Level of Cell Entry. Int J Pept Res Ther. 2014;20:269-276.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 4]  [Cited by in F6Publishing: 3]  [Article Influence: 0.5]  [Reference Citation Analysis (0)]
58.  Inubushi S, Nagano-Fujii M, Kitayama K, Tanaka M, An C, Yokozaki H, Yamamura H, Nuriya H, Kohara M, Sada K, Hotta H. Hepatitis C virus NS5A protein interacts with and negatively regulates the non-receptor protein tyrosine kinase Syk. J Gen Virol. 2008;89:1231-1242.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 19]  [Cited by in F6Publishing: 21]  [Article Influence: 1.4]  [Reference Citation Analysis (0)]
59.  Dunn W, Shah VH. Pathogenesis of Alcoholic Liver Disease. Clin Liver Dis. 2016;20:445-456.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 59]  [Cited by in F6Publishing: 58]  [Article Influence: 9.8]  [Reference Citation Analysis (0)]
60.  Gao B, Bataller R. Alcoholic liver disease: pathogenesis and new therapeutic targets. Gastroenterology. 2011;141:1572-1585.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 1046]  [Cited by in F6Publishing: 1007]  [Article Influence: 95.1]  [Reference Citation Analysis (0)]
61.  Szabo G, Mandrekar P. A recent perspective on alcohol, immunity, and host defense. Alcohol Clin Exp Res. 2009;33:220-232.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 247]  [Cited by in F6Publishing: 232]  [Article Influence: 17.6]  [Reference Citation Analysis (0)]
62.  Stickel F, Datz C, Hampe J, Bataller R. Pathophysiology and Management of Alcoholic Liver Disease: Update 2016. Gut Liver. 2017;11:173-188.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 90]  [Cited by in F6Publishing: 68]  [Article Influence: 18.0]  [Reference Citation Analysis (0)]
63.  Petrasek J, Iracheta-Vellve A, Csak T, Satishchandran A, Kodys K, Kurt-Jones EA, Fitzgerald KA, Szabo G. STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proc Natl Acad Sci USA. 2013;110:16544-16549.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 190]  [Cited by in F6Publishing: 177]  [Article Influence: 21.1]  [Reference Citation Analysis (0)]
64.  Lieber CS. Alcoholic fatty liver: its pathogenesis and mechanism of progression to inflammation and fibrosis. Alcohol. 2004;34:9-19.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 419]  [Cited by in F6Publishing: 381]  [Article Influence: 23.3]  [Reference Citation Analysis (0)]
65.  Guo J, Friedman SL. Toll-like receptor 4 signaling in liver injury and hepatic fibrogenesis. Fibrogenesis Tissue Repair. 2010;3:21.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 172]  [Cited by in F6Publishing: 164]  [Article Influence: 14.3]  [Reference Citation Analysis (0)]
66.  Szabo G. Gut-liver axis in alcoholic liver disease. Gastroenterology. 2015;148:30-36.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 314]  [Cited by in F6Publishing: 303]  [Article Influence: 39.3]  [Reference Citation Analysis (0)]
67.  Roh YS, Seki E. Toll-like receptors in alcoholic liver disease, non-alcoholic steatohepatitis and carcinogenesis. J Gastroenterol Hepatol. 2013;28 Suppl 1:38-42.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 147]  [Cited by in F6Publishing: 150]  [Article Influence: 18.4]  [Reference Citation Analysis (0)]
68.  Petrasek J, Mandrekar P, Szabo G. Toll-like receptors in the pathogenesis of alcoholic liver disease. Gastroenterol Res Pract. 2010;2010.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 57]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
69.  Miller YI, Choi SH, Wiesner P, Bae YS. The SYK side of TLR4: signalling mechanisms in response to LPS and minimally oxidized LDL. Br J Pharmacol. 2012;167:990-999.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 85]  [Cited by in F6Publishing: 82]  [Article Influence: 9.4]  [Reference Citation Analysis (0)]
70.  Zhou H, Yu M, Zhao J, Martin BN, Roychowdhury S, McMullen MR, Wang E, Fox PL, Yamasaki S, Nagy LE, Li X. IRAKM-Mincle axis links cell death to inflammation: Pathophysiological implications for chronic alcoholic liver disease. Hepatology. 2016;64:1978-1993.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 42]  [Cited by in F6Publishing: 37]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
71.  Afifiyan N, Tillman B, French BA, Masouminia M, Samadzadeh S, French SW. Over expression of proteins that alter the intracellular signaling pathways in the cytoplasm of the liver cells forming Mallory-Denk bodies. Exp Mol Pathol. 2017;102:106-114.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 10]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
72.  Afifiyan N, Tillman B, French BA, Sweeny O, Masouminia M, Samadzadeh S, French SW. The role of Tec kinase signaling pathways in the development of Mallory Denk Bodies in balloon cells in alcoholic hepatitis. Exp Mol Pathol. 2017;103:191-199.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 9]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]
73.  Bukong TN, Iracheta-Vellve A, Gyongyosi B, Ambade A, Catalano D, Kodys K, Szabo G. Therapeutic Benefits of Spleen Tyrosine Kinase Inhibitor Administration on Binge Drinking-Induced Alcoholic Liver Injury, Steatosis, and Inflammation in Mice. Alcohol Clin Exp Res. 2016;40:1524-1530.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 17]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
74.  Machado MV, Diehl AM. Pathogenesis of Nonalcoholic Steatohepatitis. Gastroenterology. 2016;150:1769-1777.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 169]  [Cited by in F6Publishing: 156]  [Article Influence: 28.2]  [Reference Citation Analysis (0)]
75.  Dowman JK, Tomlinson JW, Newsome PN. Pathogenesis of non-alcoholic fatty liver disease. QJM. 2010;103:71-83.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 392]  [Cited by in F6Publishing: 366]  [Article Influence: 30.2]  [Reference Citation Analysis (0)]
76.  Fang YL, Chen H, Wang CL, Liang L. Pathogenesis of non-alcoholic fatty liver disease in children and adolescence: From "two hit theory" to "multiple hit model". World J Gastroenterol. 2018;24:2974-2983.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in CrossRef: 89]  [Cited by in F6Publishing: 73]  [Article Influence: 22.3]  [Reference Citation Analysis (1)]
77.  Bieghs V, Trautwein C. Innate immune signaling and gut-liver interactions in non-alcoholic fatty liver disease. Hepatobiliary Surg Nutr. 2014;3:377-385.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 22]  [Reference Citation Analysis (0)]
78.  Ganz M, Bukong TN, Csak T, Saha B, Park JK, Ambade A, Kodys K, Szabo G. Progression of non-alcoholic steatosis to steatohepatitis and fibrosis parallels cumulative accumulation of danger signals that promote inflammation and liver tumors in a high fat-cholesterol-sugar diet model in mice. J Transl Med. 2015;13:193.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 72]  [Cited by in F6Publishing: 66]  [Article Influence: 10.3]  [Reference Citation Analysis (0)]
79.  Kiziltas S. Toll-like receptors in pathophysiology of liver diseases. World J Hepatol. 2016;8:1354-1369.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 50]  [Article Influence: 9.5]  [Reference Citation Analysis (1)]
80.  Nath B, Levin I, Csak T, Petrasek J, Mueller C, Kodys K, Catalano D, Mandrekar P, Szabo G. Hepatocyte-specific hypoxia-inducible factor-1α is a determinant of lipid accumulation and liver injury in alcohol-induced steatosis in mice. Hepatology. 2011;53:1526-1537.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 133]  [Cited by in F6Publishing: 127]  [Article Influence: 12.1]  [Reference Citation Analysis (0)]
81.  Alisi A, Carpino G, Oliveira FL, Panera N, Nobili V, Gaudio E. The Role of Tissue Macrophage-Mediated Inflammation on NAFLD Pathogenesis and Its Clinical Implications. Mediators Inflamm. 2017;2017:8162421.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 72]  [Cited by in F6Publishing: 68]  [Article Influence: 14.4]  [Reference Citation Analysis (0)]
82.  Day CP. From fat to inflammation. Gastroenterology. 2006;130:207-210.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 269]  [Cited by in F6Publishing: 268]  [Article Influence: 16.8]  [Reference Citation Analysis (0)]
83.  Carpino G, Nobili V, Renzi A, De Stefanis C, Stronati L, Franchitto A, Alisi A, Onori P, De Vito R, Alpini G, Gaudio E. Macrophage Activation in Pediatric Nonalcoholic Fatty Liver Disease (NAFLD) Correlates with Hepatic Progenitor Cell Response via Wnt3a Pathway. PLoS One. 2016;11:e0157246.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 35]  [Article Influence: 6.3]  [Reference Citation Analysis (0)]
84.  Caligiuri A, Gentilini A, Marra F. Molecular Pathogenesis of NASH. Int J Mol Sci. 2016;17.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 79]  [Cited by in F6Publishing: 71]  [Article Influence: 13.2]  [Reference Citation Analysis (0)]
85.  Yu J, Marsh S, Hu J, Feng W, Wu C. The Pathogenesis of Nonalcoholic Fatty Liver Disease: Interplay between Diet, Gut Microbiota, and Genetic Background. Gastroenterol Res Pract. 2016;2016:2862173.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 65]  [Article Influence: 9.5]  [Reference Citation Analysis (0)]
86.  Mao Y, Yu F, Wang J, Guo C, Fan X. Autophagy: a new target for nonalcoholic fatty liver disease therapy. Hepat Med. 2016;8:27-37.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 28]  [Article Influence: 10.0]  [Reference Citation Analysis (0)]
87.  Chattopadhyay S, Sen GC. Tyrosine phosphorylation in Toll-like receptor signaling. Cytokine Growth Factor Rev. 2014;25:533-541.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 54]  [Article Influence: 7.0]  [Reference Citation Analysis (0)]
88.  Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48:322-335.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 488]  [Cited by in F6Publishing: 464]  [Article Influence: 34.9]  [Reference Citation Analysis (0)]
89.  Chaudhary A, Fresquez TM, Naranjo MJ. Tyrosine kinase Syk associates with toll-like receptor 4 and regulates signaling in human monocytic cells. Immunol Cell Biol. 2007;85:249-256.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 60]  [Cited by in F6Publishing: 61]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
90.  Flynn R, Allen JL, Luznik L, MacDonald KP, Paz K, Alexander KA, Vulic A, Du J, Panoskaltsis-Mortari A, Taylor PA, Poe JC, Serody JS, Murphy WJ, Hill GR, Maillard I, Koreth J, Cutler CS, Soiffer RJ, Antin JH, Ritz J, Chao NJ, Clynes RA, Sarantopoulos S, Blazar BR. Targeting Syk-activated B cells in murine and human chronic graft-versus-host disease. Blood. 2015;125:4085-4094.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 71]  [Cited by in F6Publishing: 66]  [Article Influence: 10.1]  [Reference Citation Analysis (0)]
91.  Magee N, Zou A, Zhang Y. Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells. Biomed Res Int. 2016;2016:5170402.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 54]  [Cited by in F6Publishing: 57]  [Article Influence: 9.0]  [Reference Citation Analysis (0)]
92.  Szabo G, Csak T. Inflammasomes in liver diseases. J Hepatol. 2012;57:642-654.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 288]  [Cited by in F6Publishing: 282]  [Article Influence: 28.8]  [Reference Citation Analysis (0)]
93.  Malik AF, Hoque R, Ouyang X, Ghani A, Hong E, Khan K, Moore LB, Ng G, Munro F, Flavell RA, Shi Y, Kyriakides TR, Mehal WZ. Inflammasome components Asc and caspase-1 mediate biomaterial-induced inflammation and foreign body response. Proc Natl Acad Sci USA. 2011;108:20095-20100.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 68]  [Cited by in F6Publishing: 61]  [Article Influence: 6.2]  [Reference Citation Analysis (0)]
94.  Csak T, Ganz M, Pespisa J, Kodys K, Dolganiuc A, Szabo G. Fatty acid and endotoxin activate inflammasomes in mouse hepatocytes that release danger signals to stimulate immune cells. Hepatology. 2011;54:133-144.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 408]  [Cited by in F6Publishing: 393]  [Article Influence: 37.1]  [Reference Citation Analysis (0)]
95.  Mehal WZ. The inflammasome in liver injury and non-alcoholic fatty liver disease. Dig Dis. 2014;32:507-515.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 41]  [Cited by in F6Publishing: 42]  [Article Influence: 5.1]  [Reference Citation Analysis (0)]
96.  Mridha AR, Wree A, Robertson AAB, Yeh MM, Johnson CD, Van Rooyen DM, Haczeyni F, Teoh NC, Savard C, Ioannou GN, Masters SL, Schroder K, Cooper MA, Feldstein AE, Farrell GC. NLRP3 inflammasome blockade reduces liver inflammation and fibrosis in experimental NASH in mice. J Hepatol. 2017;66:1037-1046.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 321]  [Cited by in F6Publishing: 331]  [Article Influence: 64.2]  [Reference Citation Analysis (0)]
97.  Song IJ, Yang YM, Inokuchi-Shimizu S, Roh YS, Yang L, Seki E. The contribution of toll-like receptor signaling to the development of liver fibrosis and cancer in hepatocyte-specific TAK1-deleted mice. Int J Cancer. 2018;142:81-91.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 22]  [Cited by in F6Publishing: 20]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
98.  Yuan Y, Wang J, Li J, Wang L, Li M, Yang Z, Zhang C, Dai JL. Frequent epigenetic inactivation of spleen tyrosine kinase gene in human hepatocellular carcinoma. Clin Cancer Res. 2006;12:6687-6695.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 53]  [Cited by in F6Publishing: 35]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
99.  Shin SH, Lee KH, Kim BH, Lee S, Lee HS, Jang JJ, Kang GH. Downregulation of spleen tyrosine kinase in hepatocellular carcinoma by promoter CpG island hypermethylation and its potential role in carcinogenesis. Lab Invest. 2014;94:1396-1405.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 5]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
100.  Carone C, Olivani A, Dalla Valle R, Manuguerra R, Silini EM, Trenti T, Missale G, Cariani E. Immune Gene Expression Profile in Hepatocellular Carcinoma and Surrounding Tissue Predicts Time to Tumor Recurrence. Liver Cancer. 2018;7:277-294.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 10]  [Cited by in F6Publishing: 16]  [Article Influence: 2.5]  [Reference Citation Analysis (0)]
101.  Hong J, Hu K, Yuan Y, Sang Y, Bu Q, Chen G, Yang L, Li B, Huang P, Chen D, Liang Y, Zhang R, Pan J, Zeng YX, Kang T. CHK1 targets spleen tyrosine kinase (L) for proteolysis in hepatocellular carcinoma. J Clin Invest. 2012;122:2165-2175.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 55]  [Article Influence: 6.7]  [Reference Citation Analysis (0)]
102.  Hong J, Yuan YF, Wang JP, Liao Y, Zou RH, Zhu CL, Li BK, Liang Y, Huang PZ, Wang ZW, Lin WY, Zeng YX, Dai JL, Chung RT. Expression of variant isoforms of the tyrosine kinase SYK determines the prognosis of hepatocellular carcinoma. Cancer Res. 2014;74:1845-56.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 14]  [Article Influence: 3.4]  [Reference Citation Analysis (0)]
103.  Liu D, Mamorska-Dyga A. Syk inhibitors in clinical development for hematological malignancies. J Hematol Oncol. 2017;10:145.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 67]  [Cited by in F6Publishing: 63]  [Article Influence: 13.4]  [Reference Citation Analysis (0)]
104.  Thoma G, Veenstra S, Strang R, Blanz J, Vangrevelinghe E, Berghausen J, Lee CC, Zerwes HG. Orally bioavailable Syk inhibitors with activity in a rat PK/PD model. Bioorg Med Chem Lett. 2015;25:4642-4647.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 2]  [Cited by in F6Publishing: 2]  [Article Influence: 0.3]  [Reference Citation Analysis (0)]
105.  Lucas MC, Bhagirath N, Chiao E, Goldstein DM, Hermann JC, Hsu PY, Kirchner S, Kennedy-Smith JJ, Kuglstatter A, Lukacs C, Menke J, Niu L, Padilla F, Peng Y, Polonchuk L, Railkar A, Slade M, Soth M, Xu D, Yadava P, Yee C, Zhou M, Liao C. Using ovality to predict nonmutagenic, orally efficacious pyridazine amides as cell specific spleen tyrosine kinase inhibitors. J Med Chem. 2014;57:2683-2691.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 15]  [Cited by in F6Publishing: 13]  [Article Influence: 1.9]  [Reference Citation Analysis (0)]
106.  Can G, Ayvaz S, Can H, Demirtas S, Aksit H, Yilmaz B, Korkmaz U, Kurt M, Karaca T. The Syk Inhibitor Fostamatinib Decreases the Severity of Colonic Mucosal Damage in a Rodent Model of Colitis. J Crohns Colitis. 2015;9:907-917.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 9]  [Article Influence: 1.1]  [Reference Citation Analysis (0)]
107.  Weinblatt ME, Genovese MC, Ho M, Hollis S, Rosiak-Jedrychowicz K, Kavanaugh A, Millson DS, Leon G, Wang M, van der Heijde D. Effects of fostamatinib, an oral spleen tyrosine kinase inhibitor, in rheumatoid arthritis patients with an inadequate response to methotrexate: results from a phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Arthritis Rheumatol. 2014;66:3255-3264.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in F6Publishing: 1]  [Reference Citation Analysis (0)]
108.  Gomez-Puerta JA, Mócsai A. Tyrosine kinase inhibitors for the treatment of rheumatoid arthritis. Curr Top Med Chem. 2013;13:760-773.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 23]  [Cited by in F6Publishing: 22]  [Article Influence: 2.9]  [Reference Citation Analysis (0)]
109.  Suljagic M, Longo PG, Bennardo S, Perlas E, Leone G, Laurenti L, Efremov DG. The Syk inhibitor fostamatinib disodium (R788) inhibits tumor growth in the Eμ- TCL1 transgenic mouse model of CLL by blocking antigen-dependent B-cell receptor signaling. Blood. 2010;116:4894-4905.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 91]  [Cited by in F6Publishing: 97]  [Article Influence: 7.6]  [Reference Citation Analysis (0)]
110.  Friedberg JW, Sharman J, Sweetenham J, Johnston PB, Vose JM, Lacasce A, Schaefer-Cutillo J, De Vos S, Sinha R, Leonard JP, Cripe LD, Gregory SA, Sterba MP, Lowe AM, Levy R, Shipp MA. Inhibition of Syk with fostamatinib disodium has significant clinical activity in non-Hodgkin lymphoma and chronic lymphocytic leukemia. Blood. 2010;115:2578-2585.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 552]  [Cited by in F6Publishing: 521]  [Article Influence: 42.5]  [Reference Citation Analysis (0)]
111.  Lapchak PH, Kannan L, Rani P, Pamuk ON, Ioannou A, Dalle Lucca JJ, Pine P, Tsokos GC. Inhibition of Syk activity by R788 in platelets prevents remote lung tissue damage after mesenteric ischemia-reperfusion injury. Am J Physiol Gastrointest Liver Physiol. 2012;302:G1416-G1422.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 8]  [Article Influence: 0.8]  [Reference Citation Analysis (0)]
112.  Smith J, McDaid JP, Bhangal G, Chawanasuntorapoj R, Masuda ES, Cook HT, Pusey CD, Tam FW. A spleen tyrosine kinase inhibitor reduces the severity of established glomerulonephritis. J Am Soc Nephrol. 2010;21:231-236.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 57]  [Cited by in F6Publishing: 27]  [Article Influence: 4.4]  [Reference Citation Analysis (0)]
113.  Burke RT, Meadows S, Loriaux MM, Currie KS, Mitchell SA, Maciejewski P, Clarke AS, Dipaolo JA, Druker BJ, Lannutti BJ, Spurgeon SE. A potential therapeutic strategy for chronic lymphocytic leukemia by combining Idelalisib and GS-9973, a novel spleen tyrosine kinase (Syk) inhibitor. Oncotarget. 2014;5:908-915.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 45]  [Cited by in F6Publishing: 43]  [Article Influence: 6.4]  [Reference Citation Analysis (0)]
114.  Sharman J, Hawkins M, Kolibaba K, Boxer M, Klein L, Wu M, Hu J, Abella S, Yasenchak C. An open-label phase 2 trial of entospletinib (GS-9973), a selective spleen tyrosine kinase inhibitor, in chronic lymphocytic leukemia. Blood. 2015;125:2336-2343.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 113]  [Cited by in F6Publishing: 116]  [Article Influence: 16.1]  [Reference Citation Analysis (0)]
115.  Sharman J, Di Paolo J. Targeting B-cell receptor signaling kinases in chronic lymphocytic leukemia: the promise of entospletinib. Ther Adv Hematol. 2016;7:157-170.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 18]  [Cited by in F6Publishing: 18]  [Article Influence: 3.0]  [Reference Citation Analysis (0)]
116.  Burke JM, Shustov A, Essell J, Patel-Donnelly D, Yang J, Chen R, Ye W, Shi W, Assouline S, Sharman J. An Open-label, Phase II Trial of Entospletinib (GS-9973), a Selective Spleen Tyrosine Kinase Inhibitor, in Diffuse Large B-cell Lymphoma. Clin Lymphoma Myeloma Leuk. 2018;18:e327-e331.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 17]  [Cited by in F6Publishing: 13]  [Article Influence: 4.3]  [Reference Citation Analysis (0)]
117.  Yoshimoto T, Hayashi T, Kondo T, Kittaka M, Reichenberger EJ, Ueki Y. Second-Generation SYK Inhibitor Entospletinib Ameliorates Fully Established Inflammation and Bone Destruction in the Cherubism Mouse Model. J Bone Miner Res. 2018;33:1513-1519.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 9]  [Cited by in F6Publishing: 6]  [Article Influence: 2.3]  [Reference Citation Analysis (0)]
118.  Coffey G, Betz A, DeGuzman F, Pak Y, Inagaki M, Baker DC, Hollenbach SJ, Pandey A, Sinha U. The novel kinase inhibitor PRT062070 (Cerdulatinib) demonstrates efficacy in models of autoimmunity and B-cell cancer. J Pharmacol Exp Ther. 2014;351:538-548.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 38]  [Cited by in F6Publishing: 35]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
119.  Ma J, Xing W, Coffey G, Dresser K, Lu K, Guo A, Raca G, Pandey A, Conley P, Yu H, Wang YL. Cerdulatinib, a novel dual SYK/JAK kinase inhibitor, has broad anti-tumor activity in both ABC and GCB types of diffuse large B cell lymphoma. Oncotarget. 2015;6:43881-43896.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 30]  [Cited by in F6Publishing: 27]  [Article Influence: 5.0]  [Reference Citation Analysis (0)]
120.  Cen O, Kannan K, Huck Sappal J, Yu J, Zhang M, Arikan M, Ucur A, Ustek D, Cen Y, Gordon L, Longnecker R. Spleen Tyrosine Kinase Inhibitor TAK-659 Prevents Splenomegaly and Tumor Development in a Murine Model of Epstein-Barr Virus-Associated Lymphoma. mSphere. 2018;3.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 6]  [Cited by in F6Publishing: 4]  [Article Influence: 1.5]  [Reference Citation Analysis (0)]
121.  Purroy N, Carabia J, Abrisqueta P, Egia L, Aguiló M, Carpio C, Palacio C, Crespo M, Bosch F. Inhibition of BCR signaling using the Syk inhibitor TAK-659 prevents stroma-mediated signaling in chronic lymphocytic leukemia cells. Oncotarget. 2017;8:742-756.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 13]  [Cited by in F6Publishing: 11]  [Article Influence: 3.3]  [Reference Citation Analysis (0)]
122.  Braselmann S, Taylor V, Zhao H, Wang S, Sylvain C, Baluom M, Qu K, Herlaar E, Lau A, Young C, Wong BR, Lovell S, Sun T, Park G, Argade A, Jurcevic S, Pine P, Singh R, Grossbard EB, Payan DG, Masuda ES. R406, an orally available spleen tyrosine kinase inhibitor blocks fc receptor signaling and reduces immune complex-mediated inflammation. J Pharmacol Exp Ther. 2006;319:998-1008.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 342]  [Cited by in F6Publishing: 332]  [Article Influence: 21.4]  [Reference Citation Analysis (0)]
123.  Spalton JC, Mori J, Pollitt AY, Hughes CE, Eble JA, Watson SP. The novel Syk inhibitor R406 reveals mechanistic differences in the initiation of GPVI and CLEC-2 signaling in platelets. J Thromb Haemost. 2009;7:1192-1199.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 63]  [Cited by in F6Publishing: 58]  [Article Influence: 4.8]  [Reference Citation Analysis (0)]
124.  Quiroga MP, Balakrishnan K, Kurtova AV, Sivina M, Keating MJ, Wierda WG, Gandhi V, Burger JA. B-cell antigen receptor signaling enhances chronic lymphocytic leukemia cell migration and survival: specific targeting with a novel spleen tyrosine kinase inhibitor, R406. Blood. 2009;114:1029-1037.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 173]  [Cited by in F6Publishing: 169]  [Article Influence: 13.3]  [Reference Citation Analysis (0)]
125.  Wossning T, Herzog S, Köhler F, Meixlsperger S, Kulathu Y, Mittler G, Abe A, Fuchs U, Borkhardt A, Jumaa H. Deregulated Syk inhibits differentiation and induces growth factor-independent proliferation of pre-B cells. J Exp Med. 2006;203:2829-2840.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 56]  [Cited by in F6Publishing: 54]  [Article Influence: 3.5]  [Reference Citation Analysis (0)]
126.  Sprissler C, Belenki D, Maurer H, Aumann K, Pfeifer D, Klein C, Müller TA, Kissel S, Hülsdünker J, Alexandrovski J, Brummer T, Jumaa H, Duyster J, Dierks C. Depletion of STAT5 blocks TEL-SYK-induced APMF-type leukemia with myelofibrosis and myelodysplasia in mice. Blood Cancer J. 2014;4:e240.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 9]  [Article Influence: 1.0]  [Reference Citation Analysis (0)]
127.  Baluom M, Grossbard EB, Mant T, Lau DT. Pharmacokinetics of fostamatinib, a spleen tyrosine kinase (SYK) inhibitor, in healthy human subjects following single and multiple oral dosing in three phase I studies. Br J Clin Pharmacol. 2013;76:78-88.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 32]  [Cited by in F6Publishing: 30]  [Article Influence: 4.0]  [Reference Citation Analysis (0)]
128.  Torres-Hernandez A, Wang W, Nikiforov Y, Tejada K, Torres L, Kalabin A, Wu Y, Haq MIU, Khan MY, Zhao Z, Su W, Camargo J, Hundeyin M, Diskin B, Adam S, Rossi JAK, Kurz E, Aykut B, Shadaloey SAA, Leinwand J, Miller G. Targeting SYK signaling in myeloid cells protects against liver fibrosis and hepatocarcinogenesis. Oncogene. 2019;38:4512-4526.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 8]  [Cited by in F6Publishing: 10]  [Article Influence: 2.7]  [Reference Citation Analysis (0)]
129.  Kyttaris VC, Tsokos GC. Syk kinase as a treatment target for therapy in autoimmune diseases. Clin Immunol. 2007;124:235-237.  [PubMed]  [DOI]  [Cited in This Article: ]  [Cited by in Crossref: 27]  [Cited by in F6Publishing: 29]  [Article Influence: 1.8]  [Reference Citation Analysis (0)]