Zhankuic acid A as a novel JAK2 inhibitor for the treatment of concanavalin A-induced hepatitis

Chen, Yu Fon; Wang, Sheng-Hung; Chang, Shang‐Jen; Shiau, Ai‐Li; Her, Lu Shiun; Shieh, Gia Shing; Chen, Chin Fu; Chang, Chao Ching; Su, Yu; Wu, Chao; Wu, Tian Shung

doi:10.1016/j.bcp.2014.06.026

Cited by 9 publications

(8 citation statements)

References 52 publications

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“…Zhankuic acid A (ZAA), a major pharmacologically active compound in fruiting bodies of Taiwanofungus camphoratus , acts as a JAK2 inhibitor that inhibits downstream signaling mediated by STATs and IRFs. Anti-inflammatory and hepatoprotective functions of ZAA have been evaluated in mice with acute hepatitis, leaving ZAA as a potential therapeutic agent for the treatment of inflammatory diseases (201). Thymoquinone (TQ) is a compound derived from black cumin, which indirectly inhibits IRF3 by affecting NF-κB and Activator protein 1 (AP1).…”

Section: Current Irf Inhibitory Strategiesmentioning

confidence: 99%

Direct Inhibition of IRF-Dependent Transcriptional Regulatory Mechanisms Associated With Disease

et al. 2019

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Interferon regulatory factors (IRFs) are a family of homologous proteins that regulate the transcription of interferons (IFNs) and IFN-induced gene expression. As such they are important modulating proteins in the Toll-like receptor (TLR) and IFN signaling pathways, which are vital elements of the innate immune system. IRFs have a multi-domain structure, with the N-terminal part acting as a DNA binding domain (DBD) that recognizes a DNA-binding motif similar to the IFN-stimulated response element (ISRE). The C-terminal part contains the IRF-association domain (IAD), with which they can self-associate, bind to IRF family members or interact with other transcription factors. This complex formation is crucial for DNA binding and the commencing of target-gene expression. IRFs bind DNA and exert their activating potential as homo or heterodimers with other IRFs. Moreover, they can form complexes (e.g., with Signal transducers and activators of transcription, STATs) and collaborate with other co-acting transcription factors such as Nuclear factor-κB (NF-κB) and PU.1. In time, more of these IRF co-activating mechanisms have been discovered, which may play a key role in the pathogenesis of many diseases, such as acute and chronic inflammation, autoimmune diseases, and cancer. Detailed knowledge of IRFs structure and activating mechanisms predisposes IRFs as potential targets for inhibition in therapeutic strategies connected to numerous immune system-originated diseases. Until now only indirect IRF modulation has been studied in terms of antiviral response regulation and cancer treatment, using mainly antisense oligonucleotides and siRNA knockdown strategies. However, none of these approaches so far entered clinical trials. Moreover, no direct IRF-inhibitory strategies have been reported. In this review, we summarize current knowledge of the different IRF-mediated transcriptional regulatory mechanisms and how they reflect the diverse functions of IRFs in homeostasis and in TLR and IFN signaling. Moreover, we present IRFs as promising inhibitory targets and propose a novel direct IRF-modulating strategy employing a pipeline approach that combines comparative in silico docking to the IRF-DBD with in vitro validation of IRF inhibition. We hypothesize that our methodology will enable the efficient identification of IRF-specific and pan-IRF inhibitors that can be used for the treatment of IRF-dependent disorders and malignancies.

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Section: Current Irf Inhibitory Strategiesmentioning

confidence: 99%

Direct Inhibition of IRF-Dependent Transcriptional Regulatory Mechanisms Associated With Disease

et al. 2019

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“…During investigations of AIH, concanavalin A (Con A)-induced hepatitis, a well-established mouse model of immune-mediated liver injury, has been recognized as the best experimental model for AIH research (5)(6)(7). In addition, previous studies suggest that pro-inflammatory cytokines and T lymphocytes are important in the pathogenesis of AIH (6,8). Furthermore, a single intravenous (i.v.)…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, a single intravenous (i.v.) injection of Con A has been demonstrated to induce fulminant, T cell-dependent hepatitis and major inflammatory cytokine production, including tumor necrosis factor (TNF)-α, interferon (IFN)-γ and interleukin (IL)-6 (8). Overexpression of pro-inflammatory cytokines is associated with recruitment and activation of immune cell infiltration, which results in aberrant expression of inflammatory genes, ultimately resulting in hepatitis or other diseases (such as lung injury, lung cancer, gastritis and neurogenic inflammation) (9).…”

Section: Introductionmentioning

confidence: 99%

Protectin D1 reduces concanavalin A-induced liver injury by inhibiting NF-κB-mediated CX3CL1/CX3CR1 axis and NLR family, pyrin domain containing 3 inflammasome activation

Ren

Meng

Yan

et al. 2016

Molecular Medicine Reports

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Protectin D1 (PD1) is a bioactive product generated from docosahexaenoic acid, which may exert anti-inflammatory effects in various inflammatory diseases. However, the underlying molecular mechanism of its anti‑inflammatory activity on concanavalin A (Con A)-induced hepatitis remains unknown. The aim of the present study was to investigate the protective effects of PD1 against Con A‑induced liver injury and the underlying mechanisms via intravenous injection of PD1 prior to Con A administration. C57BL/6 mice were randomly divided into four experimental groups as follows: Control group, Con A group (30 mg/kg), 20 µg/kg PD1 + Con A (30 mg/kg) group and 10 µg/kg PD1 + Con A (30 mg/kg) group. PD1 pretreatment was demonstrated to significantly inhibit elevated plasma aminotransferase levels, high mobility group box 1 and liver necrosis, which were observed in Con A‑induced hepatitis. Furthermore, compared with the Con A group, PD1 pretreatment prevented the production of pro‑inflammatory cytokines, including tumor necrosis factor‑α, interferon‑γ and interleukin‑2, ‑1β and ‑6. In addition, pretreatment with PD1 markedly downregulated cluster of differentiation (CD)4+, CD8+ and natural killer T (NKT) cell infiltration in the liver. PD1 pretreatment was observed to suppress the messenger RNA and protein expression levels of NLR family, pyrin domain containing 3 and Toll‑like receptor (TLR) 4 in liver tissue samples. Further data indicated that PD1 pretreatment inhibited the activation of the nuclear factor κ‑light‑chain‑enhancer of activated B cells (NF‑κB) signaling pathway and chemokine (C‑X3‑C motif) ligand 1 (CX3CL1)/chemokine (C-X3-C motif) receptor 1 (CX3CR1) axis by preventing phosphorylation of nuclear factor of κ light polypeptide gene enhancer in B-cells inhibitor, α and NF‑κB in Con A‑induced liver injury. Therefore, these results suggest that PD1 administration protects mice against Con A‑induced liver injury via inhibition of various inflammatory cytokines and, in part, by suppressing CD4+, CD8+ and NKT cell infiltration in the liver and the NF‑κB‑activated CX3CL1/CX3CR1 signaling pathway. The beneficial effect of PD1 may be associated with the inhibition of TLR4 expression and the downregulation of NF‑κB activation. In conclusion, PD1 appears to be a potential natural bioproduct, and provide a promising strategy, for the prevention of hepatic injury in patients with chronic or acute liver disease.

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“…In HCC cells, activation/phosphorylation of STAT3 at tyrosine 705 residue is majorly mediated by JAK family kinases, especially JAK2 (Fang et al, 2017). Compounds identified from AC have been reported to inhibit the phosphorylation of JAK2 and STAT3 in cancer cells (Yeh et al, 2013; Chen et al, 2014). Reduction of p-STAT3 (Tyr705) can probably be attributed to the suppression of JAK2 activation.…”

Section: Discussionmentioning

confidence: 99%

“…Crude extracts or constituents of AC have been reported to have anti-liver cancer properties (Hsu et al, 2005; Hsieh et al, 2011; Lai et al, 2016). Several signaling pathways, such as the PI3K/AKT, AMPK/mTOR and JAK2/STAT3 pathways, are shown to be involved in these effects (Chiang et al, 2010; Chen et al, 2014, 2015). Because the tree species in the wild is becoming endangered, mass production of AC in nature is difficult.…”

Section: Introductionmentioning

confidence: 99%

Antrodia camphorata Mycelia Exert Anti-liver Cancer Effects and Inhibit STAT3 Signaling in vitro and in vivo

Zhu

et al. 2018

Front. Pharmacol.

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Hepatocellular carcinoma (HCC), the major form of primary liver cancer, is a common cause of cancer-related death worldwide. Signal transducer and activator of transcription 3 (STAT3) signaling is constantly activated in HCC and has been proposed as a chemotherapeutic target for HCC. Antrodia camphorata (AC), a medicinal mushroom unique to Taiwan, is traditionally used for treating HCC. Whereas natural AC is scarce, cultured AC mycelia are becoming alternatives. In this study, we investigated the anti-HCC effects of the ethyl acetate fraction of an ethanolic extract of AC mycelia (EEAC), particularly exploring the involvement of STAT3 signaling in these effects. We found that EEAC reduced cell viability, induced apoptosis, and retarded migration and invasion in cultured HepG2 and SMMC-7721 cells. Immunoblotting results showed that EEAC downregulated protein levels of phosphorylated and total STAT3 and JAK2 (an upstream kinase of STAT3) in HCC cells. Real-time PCR analyses showed that STAT3, but not JAK2, mRNA levels were decreased by EEAC. EEAC also lowered the protein level of nuclear STAT3, decreased the transcriptional activity of STAT3, and downregulated protein levels of STAT3-targeted molecules, including anti-apoptotic proteins Bcl-xL and Bcl-2, and invasion-related proteins MMP-2 and MMP-9. Over-activation of STAT3 in HCC cells diminished the cytotoxic effects of EEAC. In SMMC-7721 cell-bearing mice, EEAC (100 mg/kg, i.g. for 18 days) significantly inhibited tumor growth. Consistent with our in vitro data, EEAC induced apoptosis and suppressed JAK2/STAT3 activation/phosphorylation in the tumors. Taken together, EEAC exerts anti-HCC effects both in vitro and in vivo; and inhibition of STAT3 signaling is, at least in part, responsible for these effects. We did not observe significant toxicity of EEAC in normal human liver-derived cells, nude mice and rats. Our results provide a pharmacological basis for developing EEAC as a safe and effective agent for HCC management.

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Zhankuic acid A as a novel JAK2 inhibitor for the treatment of concanavalin A-induced hepatitis

Cited by 9 publications

References 52 publications

Direct Inhibition of IRF-Dependent Transcriptional Regulatory Mechanisms Associated With Disease

Direct Inhibition of IRF-Dependent Transcriptional Regulatory Mechanisms Associated With Disease

Protectin D1 reduces concanavalin A-induced liver injury by inhibiting NF-κB-mediated CX3CL1/CX3CR1 axis and NLR family, pyrin domain containing 3 inflammasome activation

Antrodia camphorata Mycelia Exert Anti-liver Cancer Effects and Inhibit STAT3 Signaling in vitro and in vivo

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