Antiproliferative Activity of Hinokitiol, a Tropolone Derivative, Is Mediated via the Inductions of p-JNK and p-PLCγ1 Signaling in PDGF-BB-Stimulated Vascular Smooth Muscle Cells

Yang, Po Sheng; Wang, Meng Jiy; Jayakumar, Thanasekaran; Chou, Duen Suey; Ko, Ching Ya; Hsu, Ming Jen; Hsieh, Cheng Ying

doi:10.3390/molecules20058198

Cited by 16 publications

(15 citation statements)

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“…JNK transcription is required for the activation of NGF-responsive genes to achieve proper development and function during peripheral nerve regeneration [ 96 ]. PDGF stimulates angiogenesis, vascular smooth muscle cell migration, axonal outgrowth, regeneration and peripheral target innervation via activation of c-JNK and Akt phosphorylation [ 97 , 98 ]. FGF-2 has also consistently been shown to induce angiogenesis and enhance neural regrowth, branching and plasticity through the activation of JNK/c-Jun signaling after sciatic nerve transection in adult rats [ 99 , 100 ].…”

Section: Gf Signaling Mechanisms That Regulate Nerve Regenerationmentioning

confidence: 99%

Growth factors-based therapeutic strategies and their underlying signaling mechanisms for peripheral nerve regeneration

et al. 2020

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Peripheral nerve injury (PNI), one of the most common concerns following trauma, can result in a significant loss of sensory or motor function. Restoration of the injured nerves requires a complex cellular and molecular response to rebuild the functional axons so that they can accurately connect with their original targets. However, there is no optimized therapy for complete recovery after PNI. Supplementation with exogenous growth factors (GFs) is an emerging and versatile therapeutic strategy for promoting nerve regeneration and functional recovery. GFs activate the downstream targets of various signaling cascades through binding with their corresponding receptors to exert their multiple effects on neurorestoration and tissue regeneration. However, the simple administration of GFs is insufficient for reconstructing PNI due to their short half-life and rapid deactivation in body fluids. To overcome these shortcomings, several nerve conduits derived from biological tissue or synthetic materials have been developed. Their good biocompatibility and biofunctionality made them a suitable vehicle for the delivery of multiple GFs to support peripheral nerve regeneration. After repairing nerve defects, the controlled release of GFs from the conduit structures is able to continuously improve axonal regeneration and functional outcome. Thus, therapies with growth factor (GF) delivery systems have received increasing attention in recent years. Here, we mainly review the therapeutic capacity of GFs and their incorporation into nerve guides for repairing PNI. In addition, the possible receptors and signaling mechanisms of the GF family exerting their biological effects are also emphasized.

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Section: Gf Signaling Mechanisms That Regulate Nerve Regenerationmentioning

confidence: 99%

Growth factors-based therapeutic strategies and their underlying signaling mechanisms for peripheral nerve regeneration

et al. 2020

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“…Our recent study shown that hinokitiol inhibits in vitro melanoma cell migration via inhibiting MMP-1 followed by suppressing NF-κB/MAPKs signaling pathways and in vivo tumor nodule formation [20]. A recent our study also shown hinokitiol inhibits VSMC proliferation via JNK1/2 and PLC-γ1 phosphorylation and limits the synthesis of specific cell cycle enzyme, PCNA [21]. With this background, in this study we aimed to evaluate the anticancer effects of hinokitiol against B16-F10 melanoma by assessing the status of tumor invasion factor-MMPs 2 and 9 along with the levels of intracellular antioxidant enzymes.…”

Section: Introductionmentioning

confidence: 99%

Hinokitiol Exerts Anticancer Activity through Downregulation of MMPs 9/2 and Enhancement of Catalase and SOD Enzymes: In Vivo Augmentation of Lung Histoarchitecture

et al. 2015

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Melanoma is extremely resistant to chemotherapy and the death rate is increasing hastily worldwide. Extracellular matrix promotes the migration and invasion of tumor cells through the production of matrix metalloproteinase (MMP)-2 and -9. Evidence has shown that natural dietary antioxidants are capable of inhibiting cancer cell growth. Our recent studies showed that hinokitiol, a natural bioactive compound, inhibited vascular smooth muscle cell proliferation and platelets aggregation. The present study is to investigate the OPEN ACCESSMolecules 2015, 20 17721 anticancer efficacy of hinokitiol against B16-F10 melanoma cells via modulating tumor invasion factors MMPs, antioxidant enzymes in vitro. An in vivo mice model of histological investigation was performed to study the patterns of elastic and collagen fibers. Hinokitiol inhibited the expression and activity of MMPs-2 and -9 in B16-F10 melanoma cells, as measured by western blotting and gelatin zymography, respectively. An observed increase in protein expression of MMPs 2/9 in melanoma cells was significantly inhibited by hinokitiol. Notably, hinokitiol (1-5 μM) increased the activities of antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) from the reduction in melanoma cells. Also, hinokitiol (2-10 µM) concentration dependently reduced in vitro Fenton reaction induced hydroxyl radical (OH·) formation. An in vivo study showed that hinokitiol treatment increased elastic fibers (EF), collagens dispersion, and improved alveolar alterations in the lungs of B16/F10 injected mice. Overall, our findings propose that hinokitiol may be a potent anticancer candidate through down regulation of MMPs 9/2, reduction of OH· production and enhancement of antioxidant enzymes SOD and CAT.

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“…We identified several kinases and phosphatases that have been implicated in the promotion of VSMC proliferation, which gives biological credibility to our results. Kinases and phosphatases possibly promoting the mechanisms by which α 2B -adrenoceptor activation leads to increased proliferation of A7r5 VSMCs included calcineurin [ 61 , 173 – 175 ], protein kinase CK2 (casein kinase) [ 176 ], Src kinases [ 177 – 182 ], JNK [ 183 , 184 ], p38 MAP kinase [ 185 – 187 ], Cdk1/2 [ 85 , 188 – 191 ], PI3-kinases [ 173 , 192 – 195 ], EGFR [ 179 , 196 – 199 ] and Raf-1 kinase [ 37 , 177 , 200 ]. A more detailed description of the effects of these kinases on VSMC proliferation is summarized in Additional file 5 .…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiles and signaling mechanisms in α2B-adrenoceptor-evoked proliferation of vascular smooth muscle cells

Huhtinen

Hongisto²,

Laiho

et al. 2017

BMC Syst Biol

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Backgroundα2-adrenoceptors are important regulators of vascular tone and blood pressure. Regulation of cell proliferation is a less well investigated consequence of α2-adrenoceptor activation. We have previously shown that α2B-adrenoceptor activation stimulates proliferation of vascular smooth muscle cells (VSMCs). This may be important for blood vessel development and plasticity and for the pathology and therapeutics of cardiovascular disorders. The underlying cellular mechanisms have remained mostly unknown. This study explored pathways of regulation of gene expression and intracellular signaling related to α2B-adrenoceptor-evoked VSMC proliferation.ResultsThe cellular mechanisms and signaling pathways of α2B-adrenoceptor-evoked proliferation of VSMCs are complex and include redundancy. Functional enrichment analysis and pathway analysis identified differentially expressed genes associated with α2B-adrenoceptor-regulated VSMC proliferation. They included the upregulated genes Egr1, F3, Ptgs2 and Serpine1 and the downregulated genes Cx3cl1, Cav1, Rhoa, Nppb and Prrx1. The most highly upregulated gene, Lypd8, represents a novel finding in the VSMC context. Inhibitor library screening and kinase activity profiling were applied to identify kinases in the involved signaling pathways. Putative upstream kinases identified by two different screens included PKC, Raf-1, Src, the MAP kinases p38 and JNK and the receptor tyrosine kinases EGFR and HGF/HGFR. As a novel finding, the Src family kinase Lyn was also identified as a putative upstream kinase.Conclusionsα2B-adrenoceptors may mediate their pro-proliferative effects in VSMCs by promoting the activity of bFGF and PDGF and the growth factor receptors EGFR, HGFR and VEGFR-1/2. The Src family kinase Lyn was also identified as a putative upstream kinase. Lyn is known to be expressed in VSMCs and has been identified as an important regulator of GPCR trafficking and GPCR effects on cell proliferation. Identified Ser/Thr kinases included several PKC isoforms and the β-adrenoceptor kinases 1 and 2. Cross-talk between the signaling mechanisms involved in α2B-adrenoceptor-evoked VSMC proliferation thus appears to involve PKC activation, subsequent changes in gene expression, transactivation of EGFR, and modulation of kinase activities and growth factor-mediated signaling. While many of the identified individual signals were relatively small in terms of effect size, many of them were validated by combining pathway analysis and our integrated screening approach.Electronic supplementary materialThe online version of this article (doi:10.1186/s12918-017-0439-8) contains supplementary material, which is available to authorized users.

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Antiproliferative Activity of Hinokitiol, a Tropolone Derivative, Is Mediated via the Inductions of p-JNK and p-PLCγ1 Signaling in PDGF-BB-Stimulated Vascular Smooth Muscle Cells

Cited by 16 publications

References 38 publications

Growth factors-based therapeutic strategies and their underlying signaling mechanisms for peripheral nerve regeneration

Growth factors-based therapeutic strategies and their underlying signaling mechanisms for peripheral nerve regeneration

Hinokitiol Exerts Anticancer Activity through Downregulation of MMPs 9/2 and Enhancement of Catalase and SOD Enzymes: In Vivo Augmentation of Lung Histoarchitecture

Gene expression profiles and signaling mechanisms in α2B-adrenoceptor-evoked proliferation of vascular smooth muscle cells

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