Molecular Mechanisms Behind the Chemopreventive Effects of Anthocyanidins

Anthocyanins are polyphenolic ring-based flavonoids, and are widespread in fruits and vegetables of red-blue color. Epidemiological investigations and animal experiments have indicated that anthocyanins may contribute to cancer chemoprevention. The studies on the mechanism have been done recently at molecular level. This review summarizes current molecular bases for anthocyanidins on several key steps involved in cancer chemoprevention: (i) inhibition of anthocyanidins in cell transformation through targeting mitogen-activated protein kinase (MAPK) pathway and activator protein 1 (AP-1) factor; (ii) suppression of anthocyanidins in inflammation and carcinogenesis through targeting nuclear factorkappaB (NF-κB) pathway andcyclooxygenase2 (COX-2) gene; (iii) apoptotic induction of cancer cells by anthocyanidins through reactive oxygen species (ROS) / c-Jun NH2-terminal kinase (JNK)-mediated caspase activation. These data provide a first molecular view of anthocyanidins contributing to cancer chemoprevention.

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Molecular Mechanisms of Liver Injury and Hepatocarcinogenesis: Focusing on the Role of Stress-Activated MAPK

Pathology Research International ◽

10.1155/2012/172894 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 33

Author(s):

Hayato Nakagawa ◽

Shin Maeda

Keyword(s):

Liver Injury ◽

Molecular Mechanisms ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Cellular Effects ◽

Wide Range ◽

Mitogen Activated Protein ◽

Compensatory Proliferation

Hepatocellular carcinoma (HCC) is the third most common cause of cancer mortality. Short-term prognosis of patients with HCC has improved recently due to advances in early diagnosis and treatment, but long-term prognosis is still unsatisfactory. Therefore, obtaining a further understanding of the molecular carcinogenic mechanisms and the unique pathogenic biology of HCC is important. The most characteristic process in hepatocarcinogenesis is underlying chronic liver injury, which leads to repeated cycles of hepatocyte death, inflammation, and compensatory proliferation and subsequently provides a mitogenic and mutagenic environment leading to the development of HCC. Recent in vivo studies have shown that the stress-activated mitogen-activated protein kinase (MAPK) cascade converging on c-Jun NH2-terminal kinase (JNK) and p38 plays a central role in these processes, and it has attracted considerable attention as a therapeutic target. However, JNK and p38 have complex functions and a wide range of cellular effects. In addition, crosstalk with each other and the nuclear factor-kappaB pathway further complicate these functions. A full understanding is essential to bring these observations into clinical settings. In this paper, we discuss the latest findings regarding the mechanisms of liver injury and hepatocarcinogenesis focusing on the role of the stress-activated MAPK pathway.

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MAPK signalling in cardiovascular health and disease: molecular mechanisms and therapeutic targets

Clinical Science ◽

10.1042/cs20070430 ◽

2008 ◽

Vol 115 (7) ◽

pp. 203-218 ◽

Cited By ~ 262

Author(s):

Anthony J. Muslin

Keyword(s):

Molecular Mechanisms ◽

Cardiovascular Health ◽

Mapk Pathway ◽

Science Research ◽

Pharmacological Therapy ◽

Model Systems ◽

Mitogen Activated Protein Kinase ◽

Extracellular Signal ◽

Mitogen Activated Protein

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

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δ-Tocotrienol, Isolated from Rice Bran, Exerts an Anti-Inflammatory Effect via MAPKs and PPARs Signaling Pathways in Lipopolysaccharide-Stimulated Macrophages

International Journal of Molecular Sciences ◽

10.3390/ijms19103022 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3022 ◽

Cited By ~ 5

Author(s):

Junjun Shen ◽

Tao Yang ◽

Youzhi Xu ◽

Yi Luo ◽

Xinyue Zhong ◽

...

Keyword(s):

Rice Bran ◽

Molecular Mechanisms ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Activator Protein 1 ◽

Peroxisome Proliferator Activated Receptor ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Anti Inflammatory ◽

Inflammatory Effect

δ-Tocotrienol, an important component of vitamin E, has been reported to possess some physiological functions, such as anticancer and anti-inflammation, however their molecular mechanisms are not clear. In this study, δ-tocotrienol was isolated and purified from rice bran. The anti-inflammatory effect and mechanism of δ-tocotrienol against lipopolysaccharides (LPS) activated pro-inflammatory mediator expressions in RAW264.7 cells were investigated. Results showed that δ-tocotrienol significantly inhibited LPS-stimulated nitric oxide (NO) and proinflammatory cytokine (TNF-α, IFN-γ, IL-1β and IL-6) production and blocked the phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases 1/2 (ERK1/2). δ-Tocotrienol repressed the transcriptional activations and translocations of nuclear factor-kappa B (NF-κB) and activator protein-1 (AP-1), which were closely related with downregulated cytokine expressions. Meanwhile, δ-tocotrienol also affected the PPAR signal pathway and exerted an anti-inflammatory effect. Taken together, our data showed that δ-tocotrienol inhibited inflammation via mitogen-activated protein kinase (MAPK) and peroxisome proliferator-activated receptor (PPAR) signalings in LPS-stimulated macrophages.

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The NRP1 gene regulates proliferation, apoptosis, migration, and invasion in T24 and 5637 bladder cancer cells

10.21203/rs.2.21110/v1 ◽

2020 ◽

Author(s):

Conghui Han ◽

Yang Dong ◽

Lin Hao ◽

Kun Pang ◽

Xiaoying Zhang ◽

...

Keyword(s):

Cell Lines ◽

Molecular Mechanisms ◽

Biological Function ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Migration And Invasion ◽

Mapk Signalling Pathway ◽

Neuropilin 1 ◽

Mitogen Activated Protein

Abstract Background Bladder urothelial carcinoma (BC) is a fatal invasive malignancy and the most common malignancy of the urinary system. In the current study, we investigate the function and mechanisms of Neuropilin-1 (NRP1), the co-receptor for vascular endothelial growth factor, in BC pathogenesis and progression. Methods The expression of NRP1 was assessed in several BC cell lines. Additionally, the biological function of NRP1 in proliferation, apoptosis, angiogenesis, migration, and invasion of BC were validated in vitro by silencing NRP1. Moreover, gene expression profiling chip analysis was conducted, and the related signalling pathways were confirmed by Western blot to reveal the potential molecular mechanisms by which NRP1 promotes the malignant progression of BC. Results Overexpression of NRP1 was observed in several human BC cell lines. NRP1 knockdown inhibited cell proliferation, promoted apoptosis, and decreased angiogenesis, migration, and invasion in T24 and 5637 human BC cells. Microarray analysis results indicated that the expression of NRP1 was correlated with the levels of cyclin dependent kinase (CDK) 4, baculoviral IAP repeat containing 3, Cyclin E 2, CDK2, and AP-1 transcription factor subunit in BC. We also demonstrated that the biological function of NRP1was associated with activation of the mitogen-activated protein kinase (MAPK) signalling pathway. Conclusions Our findings provide evidence that NRP1, as a potential tumour promoter, contributes to the metastasis and invasion of BC, which is associated with the activation of the MAPK pathway. Targeting NRP1 has the potential to become a new therapeutic strategy to benefit more patients with BC or other cancers.

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Evaluation of the Inhibitory Effects of Genipin on the Fluoxetine-Induced Invasive and Metastatic Model in Human HepG2 Cells

Molecules ◽

10.3390/molecules23123327 ◽

2018 ◽

Vol 23 (12) ◽

pp. 3327 ◽

Cited By ~ 7

Author(s):

Yu-Syuan Tian ◽

Kuan-Chou Chen ◽

Nor Diana Zulkefli ◽

Rida S. Maner ◽

Chiu-Lan Hsieh

Keyword(s):

Protein Kinase ◽

Hepg2 Cells ◽

Molecular Mechanisms ◽

Cell Model ◽

The United States ◽

Mitogen Activated Protein Kinase ◽

Pathological Examination ◽

Activator Protein 1 ◽

Gardenia Jasminoides ◽

Mitogen Activated Protein

Metastasis of hepatocellular carcinoma (HCC) is usually unrecognized before any pathological examination, resulting in time-taking treatment and poor prognosis. As a consequence, HCC patients usually show symptoms of depression. In order to suppress such psychiatric disorders and to facilitate better treatment outcome, antidepressants are prescribed. Up to present, information about the effect of antidepressants on HCC is still lacking. Therefore, we chose fluoxetine (FXT), one of the top five psychiatric prescriptions in the United States, together with the HepG2 cell model to explore its effect on HCC. Our study found that FXT (5 µM) increased the migratory distance of HepG2 cells by a factor of nearly 1.7 compared to control. In addition, our study also investigated the effect of genipin (GNP), which is an active compound from Gardenia jasminoides Ellis fruit (family Rubiaceae), on the FXT-induced HepG2 cells. Our study found that 30 and 60 µM GNP reduced the migratory distance by 42% and 74% respectively, compared to FXT treatment alone. Furthermore, we also found that FXT upregulated matrix metalloproteinases (MMPs) genes, increased the protein expression of MMPs, urokinase-type plasminogen activator (uPA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB), activator protein 1 (AP-1), phosphorylated mitogen-activated protein kinase (P-p38), phosphorylated protein kinase B (P-Akt), downregulated tissue inhibitor metalloproteinases (TIMPs) genes and decreased the TIMPs proteins expression whereas, GNP fully counteracted the action of FXT. Conclusively, this study has provided valuable information regarding the possible molecular mechanisms through which FXT affects the metastatic invasiveness of HepG2 cells and evidences to support that GNP counteracts such effect via the same molecular mechanisms.

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Large-Scale Analysis of Cell Death Phenotypic Heterogeneity

10.1101/2020.02.28.970079 ◽

2020 ◽

Author(s):

Zintis Inde ◽

Giovanni C. Forcina ◽

Kyle Denton ◽

Scott J. Dixon

Keyword(s):

Cell Death ◽

Large Scale ◽

Molecular Mechanisms ◽

Mapk Pathway ◽

Time Lapse ◽

Phenotypic Heterogeneity ◽

Mitogen Activated Protein Kinase ◽

Large Scale Analysis ◽

Mitogen Activated Protein ◽

Time Lapse Imaging

SUMMARYIndividual cancer cells within a population can exhibit substantial phenotypic heterogeneity such that exposure to a lethal agent will kill only a fraction of cells at a given time. Whether common molecular mechanisms govern this fractional killing in response to different lethal stimuli is poorly understood. In part, this is because it is difficult to compare fractional killing between conditions using existing approaches. Here, we show that fractional killing can be quantified and compared for hundreds of populations in parallel using high-throughput time-lapse imaging. We find that fractional killing is highly variable between lethal agents and between cell lines. At the molecular level, we find that the antiapoptotic protein MCL1 is an important determinant of fractional killing in response to mitogen activated protein kinase (MAPK) pathway inhibitors but not other lethal stimuli. These studies lay the foundation for the large-scale, quantitative analysis of cell death phenotypic heterogeneity.

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An interplay between the p38 MAPK pathway and AUBPs regulates c-fos mRNA stability during mitogenic stimulation

Biochemical Journal ◽

10.1042/bj20141100 ◽

2015 ◽

Vol 467 (1) ◽

pp. 77-90 ◽

Cited By ~ 14

Author(s):

Maria Sol Degese ◽

Tamara Tanos ◽

Julian Naipauer ◽

Tim Gingerich ◽

Diego Chiappe ◽

...

Keyword(s):

P38 Mapk ◽

Mrna Stability ◽

Regulatory Networks ◽

Mapk Pathway ◽

Nuclear Gene ◽

Regulatory Elements ◽

Mitogen Activated Protein Kinase ◽

Activator Protein 1 ◽

Mitogen Activated Protein ◽

Protein Phosphatase 2

Mitogen-activated protein kinase (MAPK) pathways constitute key regulatory elements linking extracellular stimuli to nuclear gene expression. Immediate-early responsive genes (IEGs) of the activator protein 1 (AP-1) family, such as fos, achieve peak expression levels shortly after cells are stimulated with growth factors and sharply decrease thereafter. Several AU-rich binding proteins (AUBPs), including HuR (Hu-antigen R, Elav-like protein 1, ELAVL1) and KSRP (far upstream element-binding protein 2, KHSRP) bind to a fos AU-rich element (ARE) present in the 3′-UTR (untranslated region) of fos mRNA regulating its stability by a still poorly defined mechanism. We show in the present study that, whereas HuR binds and stabilizes transcribed reporter mRNAs bearing the fos 3′-UTR, KSRP counteracts this effect. Furthermore, we found that fos mRNA stability and HuR phosphorylation status are dependent on the activity of p38 MAPK in both epithelial cells and fibroblasts upon proliferative stimulation. Analysing PPI (protein–protein interaction) networks, we performed a thorough query of interacting proteins for p38 MAPKs, HuR and other AUBPs upon growth factor stimulation. This revealed novel HuR interactors including inhibitors of protein phosphatase 2 (PP2A) activity. Over-expression of two of these interactors, pp32 and APRIL (acidic leucine-rich nuclear phosphoprotein 32 family member B, ANP32B) and pharmacological inhibition of PP2A stabilized a fos reporter mRNA. Our results indicate that p38 MAPK regulates fos mRNA decay by affecting the state of phosphorylation of HuR while controlling yet to be fully elucidated PP regulatory networks.

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Polygonum multiflorum Thunb. Extract Stimulates Melanogenesis by Induction of COX2 Expression through the Activation of p38 MAPK in B16F10 Mouse Melanoma Cells

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2020/7642019 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Donghee Kim ◽

Hyo-Jin Kim ◽

Hee-Sook Jun

Keyword(s):

P38 Mapk ◽

Molecular Mechanisms ◽

Mapk Pathway ◽

Ethanolic Extract ◽

Tyrosinase Activity ◽

Mitogen Activated Protein Kinase ◽

Polygonum Multiflorum ◽

B16f10 Cells ◽

Mitogen Activated Protein ◽

Cox2 Expression

Polygonum multiflorum Thunb. (PM) root extracts have been used for treating graying hair in Oriental medicine; however, the molecular mechanisms underlying the melanogenic effects of PM root have not been fully understood. In the present study, we investigated the melanogenic effects of an ethanolic extract of PM root (PME) and the mechanisms involved. We examined the effects of PME on cell viability, cellular melanin content, and tyrosinase activity in B16F10 cells. The melanogenic mechanism of PME was explored using signaling inhibitors and examining the expression of melanogenic genes and signaling molecules by western blot and RT-qPCR analyses. PME did not exhibit any cytotoxicity in B16F10 cells compared to that in control cells. PME treatment significantly increased melanin production and tyrosinase activity. In addition, PME induced the expression of cyclooxygenase-2 (COX2) as well as that of melanogenic genes, such as microphthalmia-associated transcription factor (MiTF), tyrosinase-related protein (Trp) 1, Trp2, and tyrosinase, in B16F10 cells. PME treatment increased the level of phosphorylated p38 mitogen-activated protein kinase (MAPK), and pretreatment with SB 203580, a p38 MAPK inhibitor, significantly suppressed this PME-induced increase in the expression of COX2 and melanogenic genes. These results indicate that PME induced the expression of melanogenic genes by inducing COX2 expression via the activation of the p38 MAPK pathway, thereby contributing to the enhancement of melanogenesis.

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The Genomic Landscape of Thyroid Cancer Tumourigenesis and Implications for Immunotherapy

Cells ◽

10.3390/cells10051082 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1082

Author(s):

Amandeep Singh ◽

Jeehoon Ham ◽

Joseph William Po ◽

Navin Niles ◽

Tara Roberts ◽

...

Keyword(s):

Thyroid Cancer ◽

Mapk Pathway ◽

Treatment Options ◽

Metastatic Potential ◽

Pi3k Pathway ◽

Mitogen Activated Protein Kinase ◽

Sequencing Data ◽

Genetic Aberrations ◽

Progression Model ◽

Mitogen Activated Protein

Thyroid cancer is the most prevalent endocrine malignancy that comprises mostly indolent differentiated cancers (DTCs) and less frequently aggressive poorly differentiated (PDTC) or anaplastic cancers (ATCs) with high mortality. Utilisation of next-generation sequencing (NGS) and advanced sequencing data analysis can aid in understanding the multi-step progression model in the development of thyroid cancers and their metastatic potential at a molecular level, promoting a targeted approach to further research and development of targeted treatment options including immunotherapy, especially for the aggressive variants. Tumour initiation and progression in thyroid cancer occurs through constitutional activation of the mitogen-activated protein kinase (MAPK) pathway through mutations in BRAF, RAS, mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway and/or receptor tyrosine kinase fusions/translocations, and other genetic aberrations acquired in a stepwise manner. This review provides a summary of the recent genetic aberrations implicated in the development and progression of thyroid cancer and implications for immunotherapy.

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Review of treatment and therapeutic targets in brain arteriovenous malformation

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211026771 ◽

2021 ◽

pp. 0271678X2110267

Author(s):

Peipei Pan ◽

Shantel Weinsheimer ◽

Daniel Cooke ◽

Ethan Winkler ◽

Adib Abla ◽

...

Keyword(s):

Animal Models ◽

De Novo ◽

Mapk Pathway ◽

Treatment Options ◽

Therapeutic Targets ◽

Current Treatment ◽

Mitogen Activated Protein Kinase ◽

De Novo Mutations ◽

Genetic Syndromes ◽

Mitogen Activated Protein

Brain arteriovenous malformations (bAVM) are an important cause of intracranial hemorrhage (ICH), especially in younger patients. The pathogenesis of bAVM are largely unknown. Current understanding of bAVM etiology is based on studying genetic syndromes, animal models, and surgically resected specimens from patients. The identification of activating somatic mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene and other mitogen-activated protein kinase ( MAPK) pathway genes has opened up new avenues for bAVM study, leading to a paradigm shift to search for somatic, de novo mutations in sporadic bAVMs instead of focusing on inherited genetic mutations. Through the development of new models and understanding of pathways involved in maintaining normal vascular structure and functions, promising therapeutic targets have been identified and safety and efficacy studies are underway in animal models and in patients. The goal of this paper is to provide a thorough review or current diagnostic and treatment tools, known genes and key pathways involved in bAVM pathogenesis to summarize current treatment options and potential therapeutic targets uncovered by recent discoveries.

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