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  1. Long non-coding RNAs in lung cancer: Unraveling the molecular modulators of MAPK signaling
    Hussain MS, Afzal O, Gupta G, Altamimi ASA, Almalki WH, Alzarea SI, et al.
    Pathol Res Pract, 2023 Sep;249:154738.
    PMID: 37595448 DOI: 10.1016/j.prp.2023.154738
    Lung cancer (LC) continues to pose a significant global medical burden, necessitating a comprehensive understanding of its molecular foundations to establish effective treatment strategies. The mitogen-activated protein kinase (MAPK) signaling system has been scientifically associated with LC growth; however, the intricate regulatory mechanisms governing this system remain unknown. Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of diverse cellular activities, including cancer growth. LncRNAs have been implicated in LC, which can function as oncogenes or tumor suppressors, and their dysregulation has been linked to cancer cell death, metastasis, spread, and proliferation. Due to their involvement in critical pathophysiological processes, lncRNAs are gaining attention as potential candidates for anti-cancer treatments. This article aims to elucidate the regulatory role of lncRNAs in MAPK signaling in LC. We provide a comprehensive review of the key components of the MAPK pathway and their relevance in LC, focusing on aberrant signaling processes associated with disease progression. By examining recent research and experimental findings, this article examines the molecular mechanisms through which lncRNAs influence MAPK signaling in lung cancer, ultimately contributing to tumor development.
    Matched MeSH terms: MAP Kinase Signaling System*
  2. Fulltext Lignosus rhinocerotis (Cooke) Ryvarden mimics the neuritogenic activity of nerve growth factor via MEK/ERK1/2 signaling pathway in PC-12 cells
    Seow SL, Eik LF, Naidu M, David P, Wong KH, Sabaratnam V
    Sci Rep, 2015 Nov 06;5:16349.
    PMID: 26542212 DOI: 10.1038/srep16349
    The traditional application of the sclerotium of Lignosus rhinocerotis (tiger's milk mushroom) by the indigenous folks as tonic and remedy to treat a variety of ailments has been documented in Malaysia. Indigenous communities claimed to have consumed the decoction to boost their alertness during hunting. Mental alertness is believed to be related to neuronal health and neuroactivity. In the present study, the cell viability and neuritogenic effects of L. rhinocerotis sclerotium hot aqueous and ethanolic extracts, and crude polysaccharides on rat pheochromocytoma (PC-12) cells were studied. Interestingly, the hot aqueous extract exhibited neuritogenic activity comparable to NGF in PC-12 cells. However, the extracts and crude polysaccharides stimulated neuritogenesis without stimulating the production of NGF in PC-12 cells. The involvements of the TrkA receptor and MEK/ERK1/2 pathway in hot aqueous extract-stimulated neuritogenesis were examined by Trk (K252a) and MEK/ERK1/2 (U0126 and PD98059) inhibitors. There was no significant difference in protein expression in NGF- and hot aqueous extract-treated cells for both total and phosphorylated p44/42 MAPK. The neuritogenic activity in PC-12 cells stimulated by hot aqueous and ethanolic extracts, and crude polysaccharides of L. rhinocerotis sclerotium mimicking NGF activity via the MEK/ERK1/2 signaling pathway is reported for the first time.
    Matched MeSH terms: MAP Kinase Signaling System/drug effects*
  3. JNK signaling in cancer cell survival
    Wu Q, Wu W, Fu B, Shi L, Wang X, Kuca K
    Med Res Rev, 2019 11;39(6):2082-2104.
    PMID: 30912203 DOI: 10.1002/med.21574
    c-Jun N-terminal kinase (JNK) is involved in cancer cell apoptosis; however, emerging evidence indicates that this Janus signaling promotes cancer cell survival. JNK acts synergistically with NF-κB, JAK/STAT, and other signaling molecules to exert a survival function. JNK positively regulates autophagy to counteract apoptosis, and its effect on autophagy is related to the development of chemotherapeutic resistance. The prosurvival effect of JNK may involve an immune evasion mechanism mediated by transforming growth factor-β, toll-like receptors, interferon-γ, and autophagy, as well as compensatory JNK-dependent cell proliferation. The present review focuses on recent advances in understanding the prosurvival function of JNK and its role in tumor development and chemoresistance, including a comprehensive analysis of the molecular mechanisms underlying JNK-mediated cancer cell survival. There is a focus on the specific "Yin and Yang" functions of JNK1 and JNK2 in the regulation of cancer cell survival. We highlight recent advances in our knowledge of the roles of JNK in cancer cell survival, which may provide insight into the distinct functions of JNK in cancer and its potential for cancer therapy.
    Matched MeSH terms: MAP Kinase Signaling System*
  4. Fulltext SA-Mediated Regulation and Control of Abiotic Stress Tolerance in Rice
    Nadarajah K, Abdul Hamid NW, Abdul Rahman NSN
    Int J Mol Sci, 2021 May 25;22(11).
    PMID: 34070465 DOI: 10.3390/ijms22115591
    Environmental or abiotic stresses are a common threat that remains a constant and common challenge to all plants. These threats whether singular or in combination can have devastating effects on plants. As a semiaquatic plant, rice succumbs to the same threats. Here we systematically look into the involvement of salicylic acid (SA) in the regulation of abiotic stress in rice. Studies have shown that the level of endogenous salicylic acid (SA) is high in rice compared to any other plant species. The reason behind this elevated level and the contribution of this molecule towards abiotic stress management and other underlying mechanisms remains poorly understood in rice. In this review we will address various abiotic stresses that affect the biochemistry and physiology of rice and the role played by SA in its regulation. Further, this review will elucidate the potential mechanisms that control SA-mediated stress tolerance in rice, leading to future prospects and direction for investigation.
    Matched MeSH terms: MAP Kinase Signaling System/genetics; MAP Kinase Signaling System/physiology
  5. Fulltext Molecular Dynamics Simulations in Designing DARPins as Phosphorylation-Specific Protein Binders of ERK2
    Gautam V, Nimmanpipug P, Zain SM, Rahman NA, Lee VS
    Molecules, 2021 Jul 27;26(15).
    PMID: 34361694 DOI: 10.3390/molecules26154540
    Extracellular signal-regulated kinases 1 and 2 (ERK1/2) play key roles in promoting cell survival and proliferation through the phosphorylation of various substrates. Remarkable antitumour activity is found in many inhibitors that act upstream of the ERK pathway. However, drug-resistant tumour cells invariably emerge after their use due to the reactivation of ERK1/2 signalling. ERK1/2 inhibitors have shown clinical efficacy as a therapeutic strategy for the treatment of tumours with mitogen-activated protein kinase (MAPK) upstream target mutations. These inhibitors may be used as a possible strategy to overcome acquired resistance to MAPK inhibitors. Here, we report a class of repeat proteins-designed ankyrin repeat protein (DARPin) macromolecules targeting ERK2 as inhibitors. The structural basis of ERK2-DARPin interactions based on molecular dynamics (MD) simulations was studied. The information was then used to predict stabilizing mutations employing a web-based algorithm, MAESTRO. To evaluate whether these design strategies were successfully deployed, we performed all-atom, explicit-solvent molecular dynamics (MD) simulations. Two mutations, Ala → Asp and Ser → Leu, were found to perform better than the original sequence (DARPin E40) based on the associated energy and key residues involved in protein-protein interaction. MD simulations and analysis of the data obtained on these mutations supported our predictions.
    Matched MeSH terms: MAP Kinase Signaling System/drug effects*; MAP Kinase Signaling System/genetics
  6. IL-17A induction of ADAMTS-5 in differentiated THP-1 cells is modulated by the ERK signaling pathway
    Thou EMH, Choo QC, Chew CH
    Eur. Cytokine Netw., 2020 Jun 01;31(2):59-67.
    PMID: 32933893 DOI: 10.1684/ecn.2020.0446
    Atherosclerosis is initiated when lipoproteins are trapped by proteoglycans in the arterial intima. Macrophages play a vital role in this disease, especially in the formation of foam cells and the regulation of pro-inflammatory responses. They also participate in plaque stabilization through the secretion of matrix metalloproteinases. Studies have reported the role of ADAMTS proteases in osteoarthritis and atherosclerotic lesions.In the present study, we have studied the effect of interleukin-17A (IL-17A) on the expression of ADAMTS-5 in the macrophage cell line THP-1. The results show that the mRNA and protein expression levels of ADAMTS-5 were significantly upregulated when differentiated THP-1 cells were treated with 100 ng/mL of IL-17A for 24 h with maximum ADAMTS-5 mRNA expression levels obtained at 8 h of stimulation. Subsequent inhibition studies showed that IL-17A upregulation of ADAMTS-5 was mediated through ERK and JNK pathways in THP-1 cells. Phosphorylation studies revealed that the expression of ADAMTS-5 transcripts was upregulated by IL-17A through the activation of p-c-Raf (S338), p-MEK1/2 (Ser217/221), p-p44/42 MAPK (Thr202/Tyr204), and p-Elk1 (Ser383). ERK1/2 siRNA transfection further confirmed that the ERK pathway is involved in the expression of ADAMTS-5 in IL-17A-stimulated THP-1 cells.
    Matched MeSH terms: MAP Kinase Signaling System
  7. Fulltext Suppression of ERK1/2 and hypoxia pathways by four Phyllanthus species inhibits metastasis of human breast cancer cells
    Lee SH, Jaganath IB, Atiya N, Manikam R, Sekaran SD
    J Food Drug Anal, 2016 10;24(4):855-865.
    PMID: 28911625 DOI: 10.1016/j.jfda.2016.03.010
    Chemotherapies remain far from ideal due to drug resistance; therefore, novel chemotherapeutic agents with higher effectiveness are crucial. The extracts of four Phyllanthus species, namely Phyllanthus niruri, Phyllanthus urinaria, Phyllanthus watsonii, and Phyllanthus amarus, were shown to induce apoptosis and inhibit metastasis of breast carcinoma cells (MCF-7). The main objective of this study was to determine the pathways utilized by these four Phyllanthus species to exert anti-metastatic activities. A cancer 10-pathway reporter was used to investigate the pathways affected by the four Phyllanthus species. Results indicated that these Phyllanthus species suppressed breast carcinoma metastasis and proliferation by suppressing matrix metalloprotein 2 and 9 expression via inhibition of the extracellular signal-related kinase (ERK) pathway. Additionally, inhibition of hypoxia-inducible factor 1-α in the hypoxia pathway caused reduced vascular endothelial growth factor and inducible nitric oxide synthase expression, resulting in anti-angiogenic effects and eventually anti-metastasis. Two-dimensional gel electrophoresis identified numerous proteins suppressed by these Phyllanthus species, including invasion proteins, anti-apoptotic protein, protein-synthesis proteins, angiogenic and mobility proteins, and various glycolytic enzymes. Our results indicated that ERK and hypoxia pathways are the most likely targets of the four Phyllanthus species for the inhibition of MCF-7 metastasis.
    Matched MeSH terms: MAP Kinase Signaling System
  8. Cannabinoids inhibit ethanol-induced activation of liver toxicity in rats through JNK/ERK/MAPK signaling pathways
    Yan L, Luo H, Tang X, Wang H
    J Biochem Mol Toxicol, 2023 Feb;37(2):e23260.
    PMID: 36453646 DOI: 10.1002/jbt.23260
    Cannabinoids (CBs) are psychoactive compounds, with reported anticancer, anti-inflammatory, and anti-neoplastic properties. The study was aimed at assessing the hepatoprotective effects of CB against ethanol (EtOH)-induced liver toxicity in rats. The animals were divided into seven groups: control (Group I) and Group II were treated with 50% ethanol (EtOH 5 mg/kg). Groups III, IV, and VI were treated with (EtOH + CB 10 mg/kg), (EtOH + CB 20 mg/kg), and (EtOH + CB 30 mg/kg), respectively. Groups V and VII consisted of animals treated with 20 and 30 mg/kg, of CB, respectively. Biochemical analysis revealed that Group IV (EtOH + CB 20 mg/kg) had reduced levels of ALT-alanine transferase, AST-aspartate aminotransferase, ALP-alanine peroxidase, MDA-malondialdehyde and increased levels of GSH-reduced glutathione. Histopathological analysis of liver and kidney tissues showed that EtOH + CB (20 and 30 mg/kg) treated animal groups exhibited normal tissue architecture similar to that of the control group. ELISA revealed that the inflammatory markers were reduced in the animal groups that were treated with EtOH + CB 20 mg/kg, in comparison to the animals treated only with EtOH. The mRNA expression levels of COX-2, CD-14, and MIP-2 showed a remarkable decrease in EtOH + CB treated animal groups to control groups. Western blot analysis revealed that CB downregulated p38/JNK/ERK thereby exhibiting its hepatoprotective property by inhibiting mitogen-activated protein kinase pathways. Thus, our findings suggest that CB is a potential candidate for the treatment of alcohol-induced hepatotoxicity.
    Matched MeSH terms: MAP Kinase Signaling System
  9. Fulltext Interleukin-6 is required for pancreatic cancer progression by promoting MAPK signaling activation and oxidative stress resistance
    Zhang Y, Yan W, Collins MA, Bednar F, Rakshit S, Zetter BR, et al.
    Cancer Res, 2013 Oct 15;73(20):6359-74.
    PMID: 24097820 DOI: 10.1158/0008-5472.CAN-13-1558-T
    Pancreatic cancer, one of the deadliest human malignancies, is almost invariably associated with the presence of an oncogenic form of Kras. Mice expressing oncogenic Kras in the pancreas recapitulate the stepwise progression of the human disease. The inflammatory cytokine interleukin (IL)-6 is often expressed by multiple cell types within the tumor microenvironment. Here, we show that IL-6 is required for the maintenance and progression of pancreatic cancer precursor lesions. In fact, the lack of IL-6 completely ablates cancer progression even in presence of oncogenic Kras. Mechanistically, we show that IL-6 synergizes with oncogenic Kras to activate the reactive oxygen species detoxification program downstream of the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling cascade. In addition, IL-6 regulates the inflammatory microenvironment of pancreatic cancer throughout its progression, providing several signals that are essential for carcinogenesis. Thus, IL-6 emerges as a key player at all stages of pancreatic carcinogenesis and a potential therapeutic target.
    Matched MeSH terms: MAP Kinase Signaling System/physiology*
  10. Inhibition of EREG/ErbB/ERK by Astragaloside IV reversed taxol-resistance of non-small cell lung cancer through attenuation of stemness via TGFβ and Hedgehog signal pathway
    Xiu W, Zhang Y, Tang D, Lee SH, Zeng R, Ye T, et al.
    Cell Oncol (Dordr), 2024 Dec;47(6):2201-2215.
    PMID: 39373858 DOI: 10.1007/s13402-024-00999-7
    PURPOSE: Taxol is the first-line chemo-drug for advanced non-small cell lung cancer (NSCLC), but it frequently causes acquired resistance, which leads to the failure of treatment. Therefore, it is critical to screen and characterize the mechanism of the taxol-resistance reversal agent that could re-sensitize the resistant cancer cells to chemo-drug.

    METHOD: The cell viability, sphere-forming and xenografts assay were used to evaluate the ability of ASIV to reverse taxol-resistance. Immunohistochemistry, cytokine application, small-interfering RNA, small molecule inhibitors, and RNA-seq approaches were applied to characterize the molecular mechanism of inhibition of epiregulin (EREG) and downstream signaling by ASIV to reverse taxol-resistance.

    RESULTS: ASIV reversed taxol resistance through suppression of the stemness-associated genes of spheres in NSCLC. The mechanism exploration revealed that ASIV promoted the K48-linked polyubiquitination of EREG along with degradation. Moreover, EREG could be triggered by chemo-drug treatment. Consequently, EREG bound to the ErbB receptor and activated the ERK signal to regulate the expression of the stemness-associated genes. Inhibition of EREG/ErbB/ERK could reverse the taxol-resistance by inhibiting the stemness-associated genes. Finally, it was observed that TGFβ and Hedgehog signaling were downstream of EREG/ErbB/ERK, which could be targeted using inhibitors to reverse the taxol resistance of NSCLC.

    CONCLUSIONS: These findings revealed that inhibition of EREG by ASIV reversed taxol-resistance through suppression of the stemness of NSCLC via EREG/ErbB/ERK-TGFβ, Hedgehog axis.

    Matched MeSH terms: MAP Kinase Signaling System/drug effects
  11. Effects of thyroxine on expression of proteins related to thyroid hormone functions (TR-α, TR-β, RXR and ERK1/2) in uterus during peri-implantation period
    Sayem ASM, Giribabu N, Muniandy S, Salleh N
    Biomed Pharmacother, 2017 Dec;96:1016-1021.
    PMID: 29221723 DOI: 10.1016/j.biopha.2017.11.128
    INTRODUCTION: Thyroid hormone is known to play important role during embryo implantation, however mechanisms underlying its actions in uterus during peri-implantation period has not been fully identified. In this study, we hypothesized that thyroid hormone could affect expression of proteins related to its function, where these could explain mechanisms for its action in uterus during this period.

    METHODS: Female rats, once rendered hypothyroid via oral administration of methimazole (0.03% in drinking water) for twenty-one days were mated with fertile euthyroid male rats at 1:1 ratio. Pregnancy was confirmed by the presence of vaginal plug and this was designated as day-1. Thyroxine (20, 40 and 80 μg/kg/day) was then subcutaneously administered to pregnant, hypothyroid female rats for three days. A day after last injection (day four pregnancy), female rats were sacrificed and expression of thyroid hormone receptors (TR-α and β), retinoid X receptor (RXR) and extracellular signal-regulated kinase (ERK1/2) in uterus were quantified by Western blotting while their distribution in endometrium was visualized by immunofluorescence.

    RESULTS: Expression of TRα-1, TRβ-1 and ERK1/2 proteins in uterus increased with increasing doses of thyroxine however no changes in RXR expression was observed. These proteins were found in the stroma with their distribution levels were relatively higher following thyroxine treatment.

    CONCLUSIONS: Increased expression of TRα-1, TRβ-1 and ERK1/2 at day 4 pregnancy in thyroxine-treated hypothyroid pregnant rats indicate the importance of thyroxine in up-regulating expression of these proteins that could help mediate the uterine changes prior to embryo implantation.

    Matched MeSH terms: MAP Kinase Signaling System/drug effects; MAP Kinase Signaling System/physiology*
  12. Hericium erinaceus (Bull.: Fr) Pers. cultivated under tropical conditions: isolation of hericenones and demonstration of NGF-mediated neurite outgrowth in PC12 cells via MEK/ERK and PI3K-Akt signaling pathways
    Phan CW, Lee GS, Hong SL, Wong YT, Brkljača R, Urban S, et al.
    Food Funct, 2014 Dec;5(12):3160-9.
    PMID: 25288148 DOI: 10.1039/c4fo00452c
    Hericium erinaceus (Bull.: Fr.) Pers. is an edible and medicinal mushroom used traditionally to improve memory. In this study, we investigated the neuritogenic effects of hericenones isolated from H. erinaceus and the mechanisms of action involved. H. erinaceus was cultivated and the secondary metabolites were elucidated by high performance liquid chromatography (HPLC), liquid chromatography-mass spectrometry (LC-MS), and nuclear magnetic resonance (NMR). The secondary metabolites were tested for neurite outgrowth activity (if any). Rat pheochromocytoma (PC12) cells were employed and the nerve growth factor (NGF) level was also determined. The signaling pathways involved in the mushroom-induced neuritogenesis were investigated using several pharmacological inhibitors. Hericenones B-E (1-4), erinacerin A (5) and isohericerin (6) were isolated from the basidiocarps of H. erinaceus. The hericenones did not promote neurite outgrowth but when induced with a low concentration of NGF (5 ng mL(-1)), the neuritogenic activity was comparable to that of the positive control (50 ng mL(-1) of NGF). Hericenone E was able to stimulate NGF secretion which was two-fold higher than that of the positive control. The neuritogenesis process was partially blocked by the tyrosine kinase receptor (Trk) inhibitor, K252a, suggesting that the neuritogenic effect was not solely due to NGF. Hericenone E also increased the phosphorylation of extracellular-signal regulated kinases (ERKs) and protein kinase B (Akt). Taken together, this study suggests that hericenone E potentiated NGF-induced neuritogenesis in PC12 cells via the MEK/ERK and PI3K/Akt pathways.
    Matched MeSH terms: MAP Kinase Signaling System/drug effects*
  13. Molecular mechanisms underlying the potential antiobesity-related diseases effect of cocoa polyphenols
    Ali F, Ismail A, Kersten S
    Mol Nutr Food Res, 2014 Jan;58(1):33-48.
    PMID: 24259381 DOI: 10.1002/mnfr.201300277
    Obesity and related metabolic diseases (e.g., type 2 diabetes, cardiovascular diseases, and hypertension) are the most prevailing nutrition-related issues in the world. An emerging feature of obesity is their relationship with chronic inflammation that begins in white adipose tissue and eventually becomes systemic. One potential dietary strategy to reduce glucose intolerance and inflammation is consumption of polyphenol-rich cocoa-like cocoa or their by-products. In vitro as well as in vivo data indicate that cocoa polyphenols (CPs) may exhibit antioxidant and anti-inflammatory properties. Polyphenols commonly found in cocoa have been reported to regulate lipid metabolism via inducing metabolic gene expression or activating transcription factors that regulate the expression of numerous genes, many of which play an important role in energy metabolism. Currently, several molecular targets (e.g., nuclear factor Kappa B, activated protein-1, peroxisome proliferator-activated receptors, liver X receptors, and adiponectin gene) have been identified, which may explain potential beneficial obesity-associated diseases effects of CPs. Further studies have been performed regarding the protective effects of CPs against metabolic diseases by suppressing transcription factors that antagonize lipid accumulation. Thus, polyphenols-rich cocoa products may diminish obesity-mediated metabolic diseases by multiple mechanisms, thereby attenuating chronic inflammation.
    Matched MeSH terms: MAP Kinase Signaling System/drug effects
  14. 14-Deoxy-11,12-didehydroandrographolide induces DDIT3-dependent endoplasmic reticulum stress-mediated autophagy in T-47D breast carcinoma cells
    Tan HK, Muhammad TST, Tan ML
    Toxicol Appl Pharmacol, 2016 06 01;300:55-69.
    PMID: 27049118 DOI: 10.1016/j.taap.2016.03.017
    14-Deoxy-11,12-didehydroandrographolide (14-DDA), a major diterpenoid isolated from Andrographis paniculata (Burm.f.) Nees, is known to be cytotoxic and elicits a non-apoptotic cell death in T-47D breast carcinoma cells. In this study, the mechanistic toxicology properties of 14-DDA in T-47D cells were further investigated. 14-DDA is found to induce the formation of endoplasmic reticulum (ER) vacuoles and autophagosomes, with concurrent upregulation of LC3-II in the breast carcinoma cells. It stimulated an increase in cytosolic calcium concentration and caused a collapse in mitochondrial membrane potential in these cells. In addition, both DDIT3 and GADD45A, molecules implicated in ER stress pathway, were significantly upregulated. DDIT3 knockdown suppressed the formation of both ER vacuoles and autophagosomes, indicating that 14-DDA-induced ER stress and autophagy is dependent on this transcription factor. Collectively, it is possible that GADD45A/p38 MAPK/DDIT3 pathway is involved in the 14-DDA-induced ER-stress-mediated autophagy in T-47D cells.
    Matched MeSH terms: MAP Kinase Signaling System/physiology
  15. Pro-atherogenic proteoglycanase ADAMTS-1 is down-regulated by lauric acid through PI3K and JNK signaling pathways in THP-1 derived macrophages
    Ong MH, Wong HK, Tengku-Muhammad TS, Choo QC, Chew CH
    Mol Biol Rep, 2019 Jun;46(3):2631-2641.
    PMID: 30989556 DOI: 10.1007/s11033-019-04661-6
    The prevalence of atherosclerosis has increased significantly in the recent years due to sedentary lifestyle and high-fat diet. However, the association between saturated fat intake and the increased risk for atherosclerotic cardiovascular diseases remains heavily debated. Lauric acid belongs to the saturated fatty acid group and its unique medium chain fatty acid properties are proven to be beneficial to humans in many ways. Thus, the aim of this project is to investigate the effect of lauric acid on the expression of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) genes-ADAMTS-1, ADAMTS-4, and ADAMTS-5-in macrophages. These genes encode for proteases that participate in the extracellular matrix remodeling and they play important roles in the vulnerability of atherosclerotic plaque. Here, we show that the treatment of 20 µM of lauric acid successfully reduced both transcriptional and translational expressions of these genes in THP-1 differentiated macrophages after 24-h incubation. Further cell signaling experiments using a panel of kinase inhibitors and phosphorylated antibodies proved that lauric acid down-regulated ADAMTS-1 by reducing the activation of PI3K and JNK at Tyr458 and Tyr185, respectively. Finally, JNK1 siRNA knockdown assay confirmed that ADAMTS-1 was regulated through JNK pathway, and lauric acid interfered with this pathway to down-regulate ADAMTS-1 expression. Although preliminary, this present study indicates that lauric acid has the potential to stabilize atherosclerotic plaque and may prevent thrombosis by interfering with the ADAMTS-1 expression through PI3K/JNK pathways.
    Matched MeSH terms: MAP Kinase Signaling System/drug effects*
  16. Fulltext Phosphorylated and Nonphosphorylated PfMAP2 Are Localized in the Nucleus, Dependent on the Stage of Plasmodium falciparum Asexual Maturation
    Dahalan FA, Sidek HM, Murtey MD, Embi MN, Ibrahim J, Fei Tieng L, et al.
    Biomed Res Int, 2016;2016:1645097.
    PMID: 27525262 DOI: 10.1155/2016/1645097
    Plasmodium falciparum mitogen-activated protein (MAP) kinases, a family of enzymes central to signal transduction processes including inflammatory responses, are a promising target for antimalarial drug development. Our study shows for the first time that the P. falciparum specific MAP kinase 2 (PfMAP2) is colocalized in the nucleus of all of the asexual erythrocytic stages of P. falciparum and is particularly elevated in its phosphorylated form. It was also discovered that PfMAP2 is expressed in its highest quantity during the early trophozoite (ring form) stage and significantly reduced in the mature trophozoite and schizont stages. Although the phosphorylated form of the kinase is always more prevalent, its ratio relative to the nonphosphorylated form remained constant irrespective of the parasites' developmental stage. We have also shown that the TSH motif specifically renders PfMAP2 genetically divergent from the other plasmodial MAP kinase activation sites using Neighbour Joining analysis. Furthermore, TSH motif-specific designed antibody is crucial in determining the location of the expression of the PfMAP2 protein. However, by using immunoelectron microscopy, PPfMAP2 were detected ubiquitously in the parasitized erythrocytes. In summary, PfMAP2 may play a far more important role than previously thought and is a worthy candidate for research as an antimalarial.
    Matched MeSH terms: MAP Kinase Signaling System*
  17. Fulltext A novel benzimidazole derivative, MBIC inhibits tumor growth and promotes apoptosis via activation of ROS-dependent JNK signaling pathway in hepatocellular carcinoma
    Dai X, Wang L, Deivasigamni A, Looi CY, Karthikeyan C, Trivedi P, et al.
    Oncotarget, 2017 Feb 21;8(8):12831-12842.
    PMID: 28086233 DOI: 10.18632/oncotarget.14606
    A prior screening programme carried out using MTT assay by our group identified a series of novel benzimidazole derivatives, among which Methyl 2-(5-fluoro-2-hydroxyphenyl)-1H- benzo[d]imidazole-5-carboxylate (MBIC) showed highest anticancer efficacy compared to that of chemotherapeutic agent, cisplatin. In the present study, we found that MBIC inhibited cell viability in different hepatocellular carcinoma (HCC) cell lines without exerting significant cytotoxic effects on normal liver cells. Annexin V-FITC/PI flow cytometry analysis and Western blotting results indicated that MBIC can induce apoptosis in HCC cells, which was found to be mediated through mitochondria associated proteins ultimately leading to the activation of caspase-3. The exposure to MBIC also resulted in remarkable impairment of HCC cell migration and invasion. In addition, treatment with MBIC led to a rapid generation of reactive oxygen species (ROS) and substantial activation of c-Jun-N-terminal kinase (JNK). The depletion of ROS by N-Acetyl cysteine (NAC) partially blocked MBIC-induced apoptosis and JNK activation in HCC cells. Finally, MBIC significantly inhibited tumor growth at a dose of 25 mg/kg in an orthotopic HCC mouse model. Taken together, these results demonstrate that MBIC may inhibit cell proliferation via ROS-mediated activation of the JNK signaling cascade in HCC cells.
    Matched MeSH terms: MAP Kinase Signaling System/drug effects*
  18. Fulltext Curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65) inhibits interleukin-6 production through suppression of NF-κB and MAPK pathways in histamine-induced human keratinocytes cell (HaCaT)
    Razali NA, Nazarudin NA, Lai KS, Abas F, Ahmad S
    BMC Complement Altern Med, 2018 Jul 16;18(1):217.
    PMID: 30012134 DOI: 10.1186/s12906-018-2223-8
    BACKGROUND: Histamine is a well-known mediator involved in skin allergic responses through up-regulation of pro-inflammatory cytokines. Antihistamines remain the mainstay of allergy treatment, but they were found limited in efficacy and associated with several common side effects. Therefore, alternative therapeutic preferences are derived from natural products in an effort to provide safe yet reliable anti-inflammatory agents. Curcumin and their derivatives are among compounds of interest in natural product research due to numerous pharmacological benefits including anti-inflammatory activities. Here, we investigate the effects of chemically synthesized curcumin derivative, 2,6-bis(2-fluorobenzylidene)cyclohexanone (MS65), in reducing cytokine production in histamine-induced HaCaT cells.

    METHODS: Interleukin (IL)-6 cytokine production in histamine-induced HaCaT cells were measured using enzyme-linked immunosorbent assay (ELISA) and cytotoxicity effects were determined using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Real-time polymerase chain reaction (RT-qPCR) was carried out to determine the inhibitory effects of MS65 on nuclear factor-kappa B (NF-κB) and mitogen activated protein kinase (MAPK) pathways.

    RESULTS: Histamine enhanced IL-6 production in HaCaT cells, with the highest production of IL-6 at 97.41 ± 2.33 pg/mL after 24 h of exposure. MS65 demonstrated a promising anti-inflammatory activity by inhibiting IL-6 production with half maximal inhibitory concentration (IC50) value of 4.91 ± 2.50 μM and median lethal concentration (LC50) value of 28.82 ± 7.56 μM. In gene expression level, we found that MS65 inhibits NF-κB and MAPK pathways through suppression of IKK/IκB/NFκB and c-Raf/MEK/ERK inflammatory cascades.

    CONCLUSION: Taken together, our results suggest that MS65 could be used as a lead compound on developing new medicinal agent for the treatment of allergic skin diseases.

    Matched MeSH terms: MAP Kinase Signaling System/drug effects
  19. Antiproliferation effect of guanosine on HCT 116 cells involves MAPK and AMPK pathways
    Teoh WY, Wahab NA, Sim KS
    Nucleosides Nucleotides Nucleic Acids, 2017 Apr 03;36(4):243-255.
    PMID: 28323520 DOI: 10.1080/15257770.2016.1268693
    This study aims to investigate the mechanisms associated with the antiproliferation effect of guanosine on human colon carcinoma HCT 116 cells. In this study, guanosine induced more drastic cell cycle arrest effect than cell death effect on HCT 116 cells. The cell cycle arrest effect of guanosine on HCT 116 cells appeared to be associated with the increased activation of mitogen-activated protein kinases (MAPK) such as ERK1/2, p38 and JNK. The decrease of AMP-activated protein kinase (AMPK) activation and cyclin D1 expression was also involved. Thus, the antiproliferation of colon cancer cells of guanosine could be mediated by the disruption of MAPK and AMPK pathways.
    Matched MeSH terms: MAP Kinase Signaling System/drug effects
  20. Fulltext RNA-Seq analysis revealed genes associated with UV-induced cell necrosis through MAPK/TNF-α pathways in human dermal fibroblast cells as an inducer of premature photoaging
    Alafiatayo AA, Lai KS, Ahmad S, Mahmood M, Shaharuddin NA
    Genomics, 2020 01;112(1):484-493.
    PMID: 30946891 DOI: 10.1016/j.ygeno.2019.03.011
    Exposing the skin to solar UV radiation induces cascades of signaling pathways and biological alterations such as redox imbalance, suppression of antioxidant genes and programmed cell death. Therefore, the aim of this study was to use RNA-Seq to unravel the effects of UV radiation on Normal Human Adult Fibroblast cells (NHDF). Cells were exposed to UV (20 mJ/cm2 for 3 mins) and incubated for 24 h. Total mRNA from the cells generated libraries of 72,080,648 and 40,750,939 raw reads from UV-treated and control cells respectively. Of the differentially expressed genes (DEGs) produced 2,007 were up-regulated and 2,791 were down-regulated (fold change ≥2, p 
    Matched MeSH terms: MAP Kinase Signaling System/radiation effects
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