scholarly journals Targeting ERK-Hippo Interplay in Cancer Therapy

2020 ◽  
Vol 21 (9) ◽  
pp. 3236 ◽  
Author(s):  
Karel Vališ ◽  
Petr Novák
Keyword(s):  
Cancer Therapy ◽  
Signaling Pathways ◽  
Signaling Pathway ◽  
Cross Talk ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Therapies ◽  
Anti Cancer ◽  
Targeted Inhibition

Extracellular signal-regulated kinase (ERK) is a part of the mitogen-activated protein kinase (MAPK) signaling pathway which allows the transduction of various cellular signals to final effectors and regulation of elementary cellular processes. Deregulation of the MAPK signaling occurs under many pathological conditions including neurodegenerative disorders, metabolic syndromes and cancers. Targeted inhibition of individual kinases of the MAPK signaling pathway using synthetic compounds represents a promising way to effective anti-cancer therapy. Cross-talk of the MAPK signaling pathway with other proteins and signaling pathways have a crucial impact on clinical outcomes of targeted therapies and plays important role during development of drug resistance in cancers. We discuss cross-talk of the MAPK/ERK signaling pathway with other signaling pathways, in particular interplay with the Hippo/MST pathway. We demonstrate the mechanism of cell death induction shared between MAPK/ERK and Hippo/MST signaling pathways and discuss the potential of combination targeting of these pathways in the development of more effective anti-cancer therapies.

scholarly journals Bu Shen Zhu Yun Decoction Improves Endometrial Receptivity via VEGFR-2-Mediated Angiogenesis

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Li Li ◽  
Huabo Jiang ◽  
Xuecong Wei ◽  
Dandan Geng ◽  
Ming He ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Embryo Implantation ◽  
Mapk Signaling ◽  
Endometrial Receptivity ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cell Counting ◽  
Nuclear Antigen ◽  
Vitro Fertilization

Vascular endothelial growth factor receptor-2 (VEGFR-2) regulates the mitogen-activated protein kinase (MAPK) signaling pathway and plays an important role in angiogenesis. Bu Shen Zhu Yun decoction (BSZYD) can improve endometrial receptivity and embryo implantation rates in patients undergoing in vitro fertilization. However, whether BSZYD improves endometrial receptivity via angiogenesis remains unclear. Here, we investigated the effects of BSZYD on the proliferation, migration, and angiogenesis of human endometrial microvascular endothelial cells (HEMECs) and found that BSZYD upregulated the expression of cyclin D1, matrix metalloproteinase 9 (MMP9), and proliferating cell nuclear antigen (PCNA) in HEMECs. Cell Counting Kit 8 assay, scratch-wound assay, and Tube Formation Assay results showed that BSZYD promoted the proliferation, migration, and angiogenesis of HEMECs. Western blot analysis results revealed the activation of the MAPK signaling pathway by BSZYD through the upregulation of VEGF and VEGFR-2 expression. Together, these findings highlight the novel mechanism underlying BSZYD-mediated improvement in endometrial receptivity through the MAPK signaling pathway.

scholarly journals The oxygenated products of cryptotanshinone by biotransformation with Cunninghamella elegans exerting anti-neuroinflammatory effects by inhibiting TLR 4-mediated MAPK signaling pathway

2020 ◽  
Author(s):  
Jing-Shuai Wu ◽  
Qin-Yu Meng ◽  
Xiao-Hui Shi ◽  
Zhen-Kun Zhang ◽  
Hua-Shi Guan ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Transcriptome Analysis ◽  
Salvia Miltiorrhiza ◽  
Underlying Mechanism ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Cunninghamella Elegans ◽  
Chinese Medicinal Herb ◽  
Oxygenated Products

Abstract Background: Neuroinflammatory processes are critical in the development and progression of Alzheimer's disease (AD). The potent anti-neuroinflammatory inhibitors are expected as the candidates to treat AD. Cryptotanshinone (1), a major bioactive constituent in the traditional Chinese medicinal herb Dan-Shen Salvia miltiorrhiza Bunge, has been reported to possess remarkable pharmacological activities, especially anti-oxidation and anti-inflammation. Methods: Cryptotanshinone (1) was biotransformed with the fungus Cunninghamella elegans AS3.2028 to improve its bioactivities and physicochemical properties. The structures of transformed products were elucidated by comprehensive spectroscopic analysis including HRESIMS, NMR and ECD data. Their anti-neuroinflammatory activities were assessed by ELISA, transcriptome analysis, western blot, and immunofluorescence methods. Results: Three oxygenated products (2–4) at C-3 of cryptotanshinone (1) were obtained, among them 2 was a new compound. All of the biotransformed products (2–4) were found to inhibit significantly lipopolysaccharide-induced nitric oxide production in BV2 microglia cells with the IC50 values of 0.16‒1.16 μM, approximately 2‒20 folds stronger than the substrate (1). These biotransformed products also displayed remarkably improved inhibitory effects on the production of inflammatory cytokines (IL-1β, IL-6, TNF-α, COX-2 and iNOS) in BV-2 cells via targeting TLR4 compared to substrate (1). The underlying mechanism of 2 was elucidated by comparative transcriptome analysis, which suggested that it reduced neuroinflammatory mainly through mitogen-activated protein kinase (MAPK) signaling pathway. Western blotting results revealed that 2 downregulated LPS-induced phosphorylation of JNK, ERK, and p38 in MAPK signaling pathway. Conclusion: The biotransformed products of cryptotanshinone exhibit potent anti-neuroinflammatory activities. These findings provide a basal material for the discovery of candidates in treating AD.

scholarly journals MKP-1 reduces Aβ generation and alleviates cognitive impairments in Alzheimer’s disease models

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Yehong Du ◽  
Yexiang Du ◽  
Yun Zhang ◽  
Zhilin Huang ◽  
Min Fu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Signaling Pathway ◽  
Amyloid Β ◽  
Gene Promoter ◽  
Long Term Potentiation ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase

AbstractMitogen-activated protein kinase (MAPK) phosphatase 1 (MKP-1) is an essential negative regulator of MAPKs by dephosphorylating MAPKs at both tyrosine and threonine residues. Dysregulation of the MAPK signaling pathway has been associated with Alzheimer’s disease (AD). However, the role of MKP-1 in AD pathogenesis remains elusive. Here, we report that MKP-1 levels were decreased in the brain tissues of patients with AD and an AD mouse model. The reduction in MKP-1 gene expression appeared to be a result of transcriptional inhibition via transcription factor specificity protein 1 (Sp1) cis-acting binding elements in the MKP-1 gene promoter. Amyloid-β (Aβ)-induced Sp1 activation decreased MKP-1 expression. However, upregulation of MKP-1 inhibited the expression of both Aβ precursor protein (APP) and β-site APP-cleaving enzyme 1 by inactivating the extracellular signal-regulated kinase 1/2 (ERK)/MAPK signaling pathway. Furthermore, upregulation of MKP-1 reduced Aβ production and plaque formation and improved hippocampal long-term potentiation (LTP) and cognitive deficits in APP/PS1 transgenic mice. Our results demonstrate that MKP-1 impairment facilitates the pathogenesis of AD, whereas upregulation of MKP-1 plays a neuroprotective role to reduce Alzheimer-related phenotypes. Thus, this study suggests that MKP-1 is a novel molecule for AD treatment.

Inhibition of miR-200c Expression Promotes Activation of Extracellular Signal-Regulated Kinase (ERK)/ Mitogen-Activated Protein Kinase (MAPK) Signaling Pathway and Inhibits Osteogenic Differentiation in Osteoporosis Mice

2020 ◽  
Vol 10 (2) ◽  
pp. 163-168
Author(s):  
Sheng Wang ◽  
Zhonghan Min ◽  
Run Gu ◽  
Zhongwei Yu ◽  
Pingquan Chen ◽  
...  
Keyword(s):  
Osteogenic Differentiation ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Bone Diseases ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Erk Mapk ◽  
Mitogen Activated Protein ◽  
Marrow Mesenchymal Stem Cells ◽  
Sirna Group

During OP bone metabolism, activated MAPK signaling can promote the proliferation and differentiation of osteoclasts. miRNAs involve in bone diseases. Our study aimed to evaluate miR-200c’s effect on ERK/MAPK signaling pathway in OP. miR-200c expression in OP mice and normal mice was detected by qPCR. BMSCs were cultured and transfected with siRNA to establish a miR-200c knockout model. Flow cytometry was used to detect cell apoptosis and ERK/MAPK signaling protein was detected by Western blot. miR-200c expression in OP mice was significantly lower than that in normal mice. Bone marrow mesenchymal stem cells (BMSCs) contain a large amount of siRNA particles under a fluorescence microscope. siRNA transfection can effectively inhibit miR-200c expression without difference of BMSCs apoptosis between miR-200c siRNA group and NC group. However, ERK1/2 and P38 expression in experimental group were significantly higher than those in NC siRNA group with reduced ALP activity. In addition, BMSCs osteogenic differentiation was further diminished when miR-200c expression was inhibited. miR-200c expression is lower in OP mice. miR-200c siRNA inhibits BMSCs osteogenic differentiation via ERK/MAPK signaling, thereby promoting OP progression.

scholarly journals Aloesin Suppresses Cell Growth and Metastasis in Ovarian Cancer SKOV3 Cells through the Inhibition of the MAPK Signaling Pathway

2017 ◽  
Vol 2017 ◽  
pp. 1-9 ◽  
Author(s):  
Li-qian Zhang ◽  
Rong-wei Lv ◽  
Xiang-dong Qu ◽  
Xian-jun Chen ◽  
Hong-sheng Lu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Growth ◽  
Signaling Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Migration And Invasion ◽  
Therapeutic Drug ◽  
Dependent Manner ◽  
Skov3 Cells

Aloesin is an active constituent of the herb aloe vera and plays a crucial role in anti-inflammatory activity, ultraviolet protection, and antibacterium. We investigated the role and possible mechanisms of aloesin in the cell growth and metastasis of ovarian cancer. It was found that aloesin inhibited cell viability and cell clonality in a dose-dependent manner. It arrests the cell cycle at the S-phase and induced apoptosis in SKOV3 cells. In an in vivo experiment, it was observed that aloesin inhibited tumor growth. Moreover, it inhibited migration and invasion of cancer in SKOV3 cells. Interestingly, members from the mitogen-activated protein kinase (MAPK) signaling family became less phosphorylated as the aloesin dose increased. This suggests that aloesin exerts its anticancer effect through the MAPK signaling pathway. Our data also highlights the possibility of using aloesin as a novel therapeutic drug for ovarian cancer treatment.

scholarly journals Silencing of SPARC represses heterotopic ossification via inhibition of the MAPK signaling pathway

2019 ◽  
Vol 39 (11) ◽  
Author(s):  
Qianjun Wang ◽  
Qianqian Yang ◽  
Ali Zhang ◽  
Zhiqiang Kang ◽  
Yingsheng Wang ◽  
...  
Keyword(s):  
Heterotopic Ossification ◽  
Signaling Pathway ◽  
Molecular Mechanisms ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Loss Of Function ◽  
Alp Activity ◽  
Mechanistic Investigation

Abstract Heterotopic ossification (HO), the pathologic formation of extraskeletal bone, can be disabling and lethal. However, the underlying molecular mechanisms were largely unknown. The present study aimed to clarify the involvement of secreted protein acidic and rich in cysteine (SPARC) and the underlying mechanism in rat model of HO. The mechanistic investigation on roles of SPARC in HO was examined through gain- and loss-of-function approaches of SPARC, with alkaline-phosphatase (ALP) activity, mineralized nodules, and osteocalcin (OCN) content measured. To further confirm the regulatory role of SPARC, levels of mitogen-activated protein kinase (MAPK) signaling pathways-related proteins (extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK), p38, nuclear factor κ-B (NF-κB), and IkB kinase β (IKKβ)) were determined. Bone marrow mesenchymal stem cells were treated with pathway inhibitor to investigate the relationship among SPARC, MAPK signaling pathway, and HO. The results suggested that SPARC expression was up-regulated in Achilles tendon tissues of HO rats. Silencing of SPARC could decrease phosphorylation of ERK, JNK, p38, NF-κB, and IKKβ. Additionally, silencing of SPARC or inhibition of MAPK signaling pathway could reduce the ALP activity, the number of mineralized nodules, and OCN content, thus impeding HO. To sum up, our study identifies the inhibitory role of SPARC gene silencing in HO via the MAPK signaling pathway, suggesting SPARC presents a potential target for HO therapy.

scholarly journals Cardiovascular protective effects of GLP-1:A focus on the MAPK signaling pathway

2021 ◽  
Author(s):  
Yu-Yan Zhao ◽  
Lin-Hui Chen ◽  
Liang Huang ◽  
Yong-Zhen Li ◽  
Chen Yang ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Metabolic Diseases ◽  
Mapk Pathway ◽  
Signal Transduction Pathway ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Protective Effects ◽  
Glucagon Like Peptide 1 ◽  
Common Signal

Cardiovascular and related metabolic diseases are significant global health challenges. Glucagon-like peptide 1 (GLP-1) is a brain-gut peptide secreted by ileal endocrine that is now an established drug target in type 2 diabetes (T2DM). GLP-1 targeting agents have been shown not only to treat T2DM, but also to exert cardiovascular protective effects through regulating multiple signaling pathways. The mitogen-activated protein kinase (MAPK) pathway, a common signal transduction pathway for transmitting extracellular signals to downstream effector molecules, is involved in regulating diverse cell physiological processes, including cell proliferation, differentiation, stress, inflammation, functional synchronization, transformation and apoptosis. The purpose of this review is to highlight the relationship between GLP-1 and cardiovascular disease (CVD), and discuss how GLP-1 exerts cardiovascular protective effects through MAPK signaling pathway. This review also discusses the future challenges in fully characterizing and evaluating the CVD protective effects of GLP-1 receptor agonists (GLP-1RA) at the cellular and molecular level. A better understanding of MAPK signaling pathway that are disregulated in CVD may aid in the design and development of promising GLP-1RA.

scholarly journals Chicken avian β-defensin 8 modulates immune response via the mitogen-activated protein kinase signaling pathways in a chicken macrophage cell line

2019 ◽  
Author(s):  
Yeojin Hong ◽  
Thu Thao Pham ◽  
Jiae Lee ◽  
Hyun S. Lillehoj ◽  
Yeong Ho Hong
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Proinflammatory Cytokines ◽  
Interferon Γ ◽  
Mapk Signaling ◽  
Mapk Signaling Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Macrophage Cell ◽  
Mitogen Activated Protein ◽  
Chicken Macrophage

Abstract Background Defensins are antimicrobial peptides composed of three conserved disulfide bridges, a β-sheet, and both hydrophobic and cationic amino acids. In this study, we aimed to demonstrate the immunomodulation role of avian β-defensin 8 (AvBD8) in a chicken macrophage cell line.Results Chicken AvBD8 stimulated the expression of proinflammatory cytokines (interleukin (IL)-1β, interferon-γ, and IL-12p40) and chemokines (CCL4, CXCL13, and CCL20) in macrophages. Furthermore, by western blotting and immunocytochemistry, we confirmed that AvBD8 activated the mitogen-activated protein kinase (MAPK) signaling pathway via extracellular regulated kinases 1/2 (ERK1/2) and p38 signaling molecules.Conclusion Overall, AvBD8 plays a crucial role in host defense as not only an antimicrobial peptide, but also an immunomodulator by activating the MAPK signaling pathway and inducing the expression of proinflammatory cytokines and chemokines.

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