Displaying publications 1 - 20 of 62 in total

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  1. Fulltext The ERBB2 Exonic Variant Pro1170Ala Modulates Mitogen-Activated Protein Kinase Signaling Cascades and Associates with Allergic Asthma
    Sio YY, Gan WL, Ng WS, Matta SA, Say YH, Teh KF, et al.
    Int Arch Allergy Immunol, 2023;184(10):1010-1021.
    PMID: 37336194 DOI: 10.1159/000530960
    INTRODUCTION: Previous studies have indicated the ERBB2 genetic variants in the 17q12 locus might be associated with asthma; however, the functional effects of these variants on asthma risk remain inconclusive. This study aimed to characterize the functional roles of asthma-associated ERBB2 single nucleotide polymorphisms (SNPs) in asthma pathogenesis by performing genetic association and functional analysis studies.

    METHODS: This study belongs to a part of an ongoing Singapore/Malaysia cross-sectional genetics and epidemiological study (SMCSGES). Genotype-phenotype associations were assessed by performing a genotyping assay on n = 4,348 ethnic Chinese individuals from the SMCSGES cohort. The phosphorylation levels of receptors and signaling proteins in the MAPK signaling cascades, including ErbB2, EGFR, and ERK1/2, were compared across the genotypes of asthma-associated SNPs through in vitro and ex vivo approaches.

    RESULTS: The ERBB2 tag-SNP rs1058808 was significantly associated with allergic asthma, with the allele "G" identified as protective against the disease (adjusted logistic p = 6.56 × 10-9, OR = 0.625, 95% CI: 0.544-0.718). The allele "G" of rs1058808 resulted in a Pro1170Ala mutation that results in lower phosphorylation levels of ErbB2 in HaCat cells (p < 0.001), whereas the overall ERBB2 mRNA expression and the phosphorylation levels of EGFR remained unaffected. In the SMCSGES cohort, individuals carrying the genotype "GG" of rs1058808 had lower phosphorylated ERK1/2 proteins in the MAPK signaling cascade. A lower phosphorylation level of ERK1/2 was also associated with reduced asthma risk.

    CONCLUSIONS: The present findings highlighted the involvement of a functional exonic variant of ERBB2 in asthma development via modulating the MAPK signaling cascade.

    Matched MeSH terms: Mitogen-Activated Protein Kinases/genetics; Mitogen-Activated Protein Kinases/metabolism
  2. Fulltext Thymoquinone regulates gene expression levels in the estrogen metabolic and interferon pathways in MCF7 breast cancer cells
    Motaghed M, Al-Hassan FM, Hamid SS
    Int J Mol Med, 2014 Jan;33(1):8-16.
    PMID: 24270600 DOI: 10.3892/ijmm.2013.1563
    New drugs are continuously being developed for the treatment of patients with estrogen receptor-positive breast cancer. Thymoquinone is one of the drugs that exhibits anticancer characteristics based on in vivo and in vitro models. This study further investigates the effects of thymoquinone on human gene expression using cDNA microarray technology. The quantification of RNA samples was carried out using an Agilent 2100 Bioanalyser to determine the RNA integrity number (RIN). The Agilent Low Input Quick Amplification Labelling kit was used to generate cRNA in two-color microarray analysis. Samples with RIN >9.0 were used in this study. The universal human reference RNA was used as the common reference. The samples were labelled with cyanine-3 (cye-3) CTP dye and the universal human reference was labelled with cyanine-5 (cye-5) CTP dye. cRNA was purified with the RNeasy Plus Mini kit and quantified using a NanoDrop 2000c spectrophotometer. The arrays were scanned data analysed using Feature Extraction and GeneSpring software. Two-step qRT-PCR was selected to determine the relative gene expression using the High Capacity RNA-to-cDNA kit. The results from Gene Ontology (GO) analysis, indicated that 8 GO terms were related to biological processes (84%) and molecular functions (16%). A total of 577 entities showed >2-fold change in expression. Of these entities, 45.2% showed an upregulation and 54.7% showed a downregulation in expression. The interpretation of single experiment analysis (SEA) revealed that the cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1) and UDP glucuronosyltransferase 1 family, polypeptide A8 (UGT1A8) genes in the estrogen metabolic pathway were downregulated significantly by 43- and 11‑fold, respectively. The solute carrier family 7 (anionic amino acid transporter light chain, xc-system), member 11 (SLC7A11) gene in the interferon pathway, reported to be involved in the development of chemoresistance, was downregulated by 15‑fold. The interferon-induced protein with tetratricopeptide repeats (IFIT)1, IFIT2, IFIT3, interferon, α-inducible protein (IFI)6 (also known as G1P3), interferon regulatory factor 9 (IRF9, ISGF3), 2'-5'-oligoadenylate synthetase 1, 40/46 kDa (OAS1) and signal transducer and activator of transcription 1 (STAT1) genes all showed changes in expression following treatment with thymoquinone. The caspase 10, apoptosis-related cysteine peptidase (CASP10) gene was activated and the protein tyrosine phosphatase, receptor type, R (PTPRR) and myocyte enhancer factor 2C (MEF2C) genes were upregulated in the classical MAPK and p38 MAPK pathways. These findings indicate that thymquinone targets specific genes in the estrogen metabolic and interferon pathways.
    Matched MeSH terms: p38 Mitogen-Activated Protein Kinases/genetics; p38 Mitogen-Activated Protein Kinases/metabolism
  3. Fulltext Hydroxychavicol, a polyphenol from Piper betle leaf extract, induces cell cycle arrest and apoptosis in TP53-resistant HT-29 colon cancer cells
    Rajedadram A, Pin KY, Ling SK, Yan SW, Looi ML
    J Zhejiang Univ Sci B, 2021 Feb 15;22(2):112-122.
    PMID: 33615752 DOI: 10.1631/jzus.B2000446
    This study aims to elucidate the antiproliferative mechanism of hydroxychavicol (HC). Its effects on cell cycle, apoptosis, and the expression of c-Jun N-terminal kinase (JNK) and P38 mitogen-activated protein kinase (MAPK) in HT-29 colon cancer cells were investigated. HC was isolated from Piper betle leaf (PBL) and verified by high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR), and gas chromatography-mass spectrometry (GC-MS). The cytotoxic effects of the standard drug 5-fluorouracil (5-FU), PBL water extract, and HC on HT-29 cells were measured after 24, 48, and 72 h of treatment. Cell cycle and apoptosis modulation by 5-FU and HC treatments were investigated up to 30 h. Changes in phosphorylated JNK (pJNK) and P38 (pP38) MAPK expression were observed up to 18 h. The half maximal inhibitory concentration (IC50) values of HC (30 μg/mL) and PBL water extract (380 μg/mL) were achieved at 24 h, whereas the IC50 of 5-FU (50 μmol/L) was obtained at 72 h. Cell cycle arrest at the G0/G1 phase in HC-treated cells was observed from 12 h onwards. Higher apoptotic cell death in HC-treated cells compared to 5-FU-treated cells (P<0.05) was observed. High expression of pJNK and pP38 MAPK was observed at 12 h in HC-treated cells, but not in 5-FU-treated HT-29 cells (P<0.05). It is concluded that HC induces cell cycle arrest and apoptosis of HT-29 cells, with these actions possibly mediated by JNK and P38 MAPK.
    Matched MeSH terms: Mitogen-Activated Protein Kinases; JNK Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases
  4. Fulltext The Role of Inflammation in the Pathogenesis of Osteoarthritis
    Chow YY, Chin KY
    Mediators Inflamm, 2020;2020:8293921.
    PMID: 32189997 DOI: 10.1155/2020/8293921
    A joint is the point of connection between two bones in our body. Inflammation of the joint leads to several diseases, including osteoarthritis, which is the concern of this review. Osteoarthritis is a common chronic debilitating joint disease mainly affecting the elderly. Several studies showed that inflammation triggered by factors like biomechanical stress is involved in the development of osteoarthritis. This stimulates the release of early-stage inflammatory cytokines like interleukin-1 beta (IL-1β), which in turn induces the activation of signaling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/AKT), and mitogen-activated protein kinase (MAPK). These events, in turn, generate more inflammatory molecules. Subsequently, collagenase like matrix metalloproteinases-13 (MMP-13) will degrade the extracellular matrix. As a result, anatomical and physiological functions of the joint are altered. This review is aimed at summarizing the previous studies highlighting the involvement of inflammation in the pathogenesis of osteoarthritis.
    Matched MeSH terms: Mitogen-Activated Protein Kinases/genetics; Mitogen-Activated Protein Kinases/metabolism
  5. 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: Mitogen-Activated Protein Kinases/genetics; Mitogen-Activated Protein Kinases/metabolism*
  6. DeepPSP: A Global-Local Information-Based Deep Neural Network for the Prediction of Protein Phosphorylation Sites
    Guo L, Wang Y, Xu X, Cheng KK, Long Y, Xu J, et al.
    J Proteome Res, 2021 01 01;20(1):346-356.
    PMID: 33241931 DOI: 10.1021/acs.jproteome.0c00431
    Identification of phosphorylation sites is an important step in the function study and drug design of proteins. In recent years, there have been increasing applications of the computational method in the identification of phosphorylation sites because of its low cost and high speed. Most of the currently available methods focus on using local information around potential phosphorylation sites for prediction and do not take the global information of the protein sequence into consideration. Here, we demonstrated that the global information of protein sequences may be also critical for phosphorylation site prediction. In this paper, a new deep neural network model, called DeepPSP, was proposed for the prediction of protein phosphorylation sites. In the DeepPSP model, two parallel modules were introduced to extract both local and global features from protein sequences. Two squeeze-and-excitation blocks and one bidirectional long short-term memory block were introduced into each module to capture effective representations of the sequences. Comparative studies were carried out to evaluate the performance of DeepPSP, and four other prediction methods using public data sets The F1-score, area under receiver operating characteristic curves (AUROC), and area under precision-recall curves (AUPRC) of DeepPSP were found to be 0.4819, 0.82, and 0.50, respectively, for S/T general site prediction and 0.4206, 0.73, and 0.39, respectively, for Y general site prediction. Compared with the MusiteDeep method, the F1-score, AUROC, and AUPRC of DeepPSP were found to increase by 8.6, 2.5, and 8.7%, respectively, for S/T general site prediction and by 20.6, 5.8, and 18.2%, respectively, for Y general site prediction. Among the tested methods, the developed DeepPSP method was also found to produce best results for different kinase-specific site predictions including CDK, mitogen-activated protein kinase, CAMK, AGC, and CMGC. Taken together, the developed DeepPSP method may offer a more accurate phosphorylation site prediction by including global information. It may serve as an alternative model with better performance and interpretability for protein phosphorylation site prediction.
    Matched MeSH terms: Mitogen-Activated Protein Kinases
  7. Infeksi Plasmodium berghei dan kesannya ke atas pengisyaratan MAP kinase eritrosit perumah
    Mohd Fakharul Zaman Raja Yahya, Hasidah Mohd Sidek
    Sains Malaysiana, 2009;38.
    Kajian ini melibatkan pemantauan perkembangan parasitemia dan taburan morfologi Plasmodium berghei sewaktu infeksi parasit dalam mencit, serta penentuan kesan infeksi P. berghei ke atas pengisyaratan MAP kinase eritrosit perumah. Analisis mikroskop ke atas slaid calitan darah terwarna-Giemsa yang disediakan daripada mencit terinfeksi-P. berghei (strain PZZ1/00) menunjukkan darjah parasitemia mencapai sehingga 70% dalam masa dua minggu selepas penyuntikan parasit. Morfologi cecincin dan trofozoit parasit dicerap dengan jelas sepanjang tempoh infeksi manakala morfologi skizon parasit hanya dicerap dengan ketara selepas hari ketiga selepas penyuntikan parasit. Pemblotan Western [antibodi primer: anti-MAP kinase (ERK-1/2 tak terfosfat) monoklon; antibodi sekunder: anti-IgG, poliklon terkonjugat-HRP] ke atas protein sitosol eritrosit terinfeksi-P. berghei (70% parasitemia) susulan pemisahan SDS-PAGE menunjukkan bahawa keamatan protein imunoreaktif-MAP kinase eritrosit berberat molekul 42 dan 44 kDa didapati meningkat secara signifikan (p<0.05) pada 70% iaitu peningkatan sebanyak 21.5% dan 22.3% masing-masing berbanding sampel kawalan tanpa infeksi. Samada kesan infeksi P. berghei (70% parasitemia) ke atas pengisyaratan MAP kinase perumah ini berkaitan dengan pengaktifan enzim ini perlu dikaji dengan lebih lanjut.
    Matched MeSH terms: Mitogen-Activated Protein Kinases
  8. 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: JNK Mitogen-Activated Protein Kinases/metabolism*
  9. Fulltext A Central Bioactive Region of LTBP-2 Stimulates the Expression of TGF-β1 in Fibroblasts via Akt and p38 Signalling Pathways
    Sideek MA, Smith J, Menz C, Adams JRJ, Cowin AJ, Gibson MA
    Int J Mol Sci, 2017 Oct 09;18(10).
    PMID: 28991210 DOI: 10.3390/ijms18102114
    Latent transforming growth factor-β-1 binding protein-2 (LTBP-2) belongs to the LTBP-fibrillin superfamily of extracellular proteins. Unlike other LTBPs, LTBP-2 does not covalently bind transforming growth factor-β1 (TGF-β1) but appears to be implicated in the regulation of TGF-β1 bioactivity, although the mechanisms are largely unknown. In experiments originally designed to study the displacement of latent TGF-β1 complexes from matrix storage, we found that the addition of exogenous LTBP-2 to cultured human MSU-1.1 fibroblasts caused an increase in TGF-β1 levels in the medium. However, the TGF-β1 increase was due to an upregulation of TGF-β1 expression and secretion rather than a displacement of matrix-stored TGF-β1. The secreted TGF-β1 was mainly in an inactive form, and its concentration peaked around 15 h after addition of LTBP-2. Using a series of recombinant LTBP-2 fragments, the bioactivity was identified to a small region of LTBP-2 consisting of an 8-Cys motif flanked by four epidermal growth factor (EGF)-like repeats. The LTBP-2 stimulation of TGF-β expression involved the phosphorylation of both Akt and p38 mitogen-activated protein kinase (MAPK) signalling proteins, and specific inactivation of each protein individually blocked TGF-β1 increase. The search for the cell surface receptor mediating this LTBP-2 activity proved inconclusive. Inhibitory antibodies to integrins β1 and αVβ5 showed no reduction of LTBP-2 stimulation of TGF-β1. However, TGF-β1 upregulation was partially inhibited by anti-αVβ3 integrin antibodies, suggestive of a direct or indirect role for this integrin. Overall, the study indicates that LTBP-2 can directly upregulate cellular TGF-β1 expression and secretion by interaction with cells via a short central bioactive region. This may be significant in connective tissue disorders involving aberrant TGF-β1 signalling.
    Matched MeSH terms: p38 Mitogen-Activated Protein Kinases/metabolism*
  10. Flavonoid diversity and roles in the lipopolysaccharide-mediated inflammatory response of monocytes and macrophages
    Rullah K, Shamsudin NF, Koeberle A, Tham CL, Fasihi Mohd Aluwi MF, Leong SW, et al.
    Future Med Chem, 2024 Jan;16(1):75-99.
    PMID: 38205612 DOI: 10.4155/fmc-2023-0174
    Targeting lipopolysaccharide (LPS)/toll-like receptor 4 signaling in mononuclear phagocytes has been explored for the treatment of inflammation and inflammation-related disorders. However, only a few key targets have been translated into clinical applications. Flavonoids, a class of ubiquitous plant secondary metabolites, possess a privileged scaffold which serves as a valuable template for designing pharmacologically active compounds directed against diseases with inflammatory components. This perspective provides a general overview of the diversity of flavonoids and their multifaceted mechanisms that interfere with LPS-induced signaling in monocytes and macrophages. Focus is placed on flavonoids targeting MD-2, IκB kinases, c-Jun N-terminal kinases, extracellular signal-regulated kinase, p38 MAPK and PI3K/Akt or modulating LPS-related gene expression.
    Matched MeSH terms: p38 Mitogen-Activated Protein Kinases/metabolism
  11. 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: Mitogen-Activated Protein Kinases/metabolism*; Mitogen-Activated Protein Kinases/pharmacokinetics
  12. Cgl-SLT2 is required for appressorium formation, sporulation and pathogenicity in Colletotrichum gloeosporioides
    Yong HY, Bakar FD, Illias RM, Mahadi NM, Murad AM
    Braz J Microbiol, 2013 Dec;44(4):1241-50.
    PMID: 24688518
    The mitogen-activated protein (MAP) kinase pathways has been implicated in the pathogenicity of various pathogenic fungi and plays important roles in regulating pathogenicity-related morphogenesis. This work describes the isolation and characterization of MAP kinase gene, Cgl-SLT2, from Colletotrichum gloeosporioides. A DNA sequence, including 1,633 bp of Cgl-SLT2 open-reading frame and its promoter and terminator regions, was isolated via DNA walking and cloned. To analyze gene function, a gene disruption cassette containing hygromycin-resistant gene was constructed, and Cgl-SLT2 was inactivated via gene deletion. Analysis on Cgl-slt2 mutant revealed a defect in vegetative growth and sporulation as compared to the wild-type strain. When grown under nutrient-limiting conditions, hyperbranched hyphal morphology was observed in the mutant. Conidia induction for germination on rubber wax-coated hard surfaces revealed no differences in the percentage of conidial germination between the wild-type and Cgl-slt2 mutant. However, the percentage of appressorium formation in the mutant was greatly reduced. Bipolar germination in the mutant was higher than in the wild-type at 8-h post-induction. A pathogenicity assay revealed that the mutant was unable to infect either wounded or unwounded mangoes. These results suggest that the Cgl-SLT2 MAP kinase is required for C. gloeosporioides conidiation, polarized growth, appressorium formation and pathogenicity.
    Matched MeSH terms: Mitogen-Activated Protein Kinases/genetics; Mitogen-Activated Protein Kinases/metabolism*
  13. Fulltext The Epstein-Barr virus encoded LMP1 oncoprotein modulates cell adhesion via regulation of activin A/TGFβ and β1 integrin signalling
    Morris MA, Dawson CW, Laverick L, Davis AM, Dudman JP, Raveenthiraraj S, et al.
    Sci Rep, 2016;6:19533.
    PMID: 26782058 DOI: 10.1038/srep19533
    Approximately 20% of global cancer incidence is causally linked to an infectious agent. Epstein-Barr virus (EBV) accounts for around 1% of all virus-associated cancers and is associated with nasopharyngeal carcinoma (NPC). Latent membrane protein 1 (LMP1), the major oncoprotein encoded by EBV, behaves as a constitutively active tumour necrosis factor (TNF) receptor activating a variety of signalling pathways, including the three classic MAPKs (ERK-MAPK, p38 MAPK and JNK/SAPK). The present study identifies novel signalling properties for this integral membrane protein via the induction and secretion of activin A and TGFβ1, which are both required for LMP1's ability to induce the expression of the extracellular matrix protein, fibronectin. However, it is evident that LMP1 is unable to activate the classic Smad-dependent TGFβ signalling pathway, but rather elicits its effects through the non-Smad arm of TGFβ signalling. In addition, there is a requirement for JNK/SAPK signalling in LMP1-mediated fibronectin induction. LMP1 also induces the expression and activation of the major fibronectin receptor, α5β1 integrin, an effect that is accompanied by increased focal adhesion formation and turnover. Taken together, these findings support the putative role for LMP1 in the pathogenesis of NPC by contributing to the metastatic potential of epithelial cells.
    Matched MeSH terms: p38 Mitogen-Activated Protein Kinases
  14. Targeted RNAi of the mitogen-activated protein kinase pathway genes in acute myeloid leukemia cells
    M.R. Mohd Hafiz, M.Z. Mazatulikhma, F.A. Mohd Faiz, M.S. Mohamed Saifulaman
    Sains Malaysiana, 2013;42:1131-1137.
    In this study, RNA interference (RNAi) was carried out as an experimental technique to knockdown three mitogen-activated protein kinase (MAPK) pathway genes, raf-1, mekk1 and mlk3 in acute myeloid leukemia (AML) cells. Conventionally, RNAi knockdown experiments target a single gene for functional studies or therapeutic purposes. We wanted to explore the potential differences or similarities between targeting single targets or multiple target genes in a single application. We achieved knockdown of gene expression levels of between 40 and 60% for the RNAi experiments, with better knockdown observed in single target gene experiments in comparison with the multiple target gene experiment. Microarray analysis indicated that the transfection process had most likely induced the immune response from the cells in every RNAi treatment. This might indicate that when the MAPK signaling pathway is partially blocked, in tandem with the immune response, the cells will begin signaling for apoptosis leading to cellular death of the leukemic cells.
    Matched MeSH terms: Mitogen-Activated Protein Kinases
  15. Apoptosis transcriptional mechanism of feline infectious peritonitis virus infected cells
    Shuid AN, Safi N, Haghani A, Mehrbod P, Haron MS, Tan SW, et al.
    Apoptosis, 2015 Nov;20(11):1457-70.
    PMID: 26386572 DOI: 10.1007/s10495-015-1172-7
    Apoptosis has been postulated to play an important role during feline infectious peritonitis virus (FIPV) infection; however, its mechanism is not well characterized. This study is focused on apoptosis and transcriptional profiling of FIPV-infected cells following in vitro infection of CRFK cells with FIPV 79-1146 WSU. Flow cytometry was used to determine mode of cell death in first 42 h post infection (hpi). FIPV infected cells underwent early apoptosis at 9 hpi (p protein concentration were analyzed by RT-qPCR and ELISA, respectively, at different time-points. Up-regulations of both pro-apoptotic (i.e. PDCD5) and anti-apoptotic (i.e. TRAF2) were detected from first hpi and continuing to deregulate during apoptosis process in the infected cells.
    Matched MeSH terms: p38 Mitogen-Activated Protein Kinases/genetics
  16. Fulltext Standardized ethanol extract of Tinospora crispa upregulates pro-inflammatory mediators release in LPS-primed U937 human macrophages through stimulation of MAPK, NF-κB and PI3K-Akt signaling networks
    Haque MA, Jantan I, Harikrishnan H, Ahmad W
    BMC Complement Med Ther, 2020 Aug 06;20(1):245.
    PMID: 32762741 DOI: 10.1186/s12906-020-03039-7
    BACKGROUND: Immunomodulatory effects of Tinospora crispa have been investigated due to its traditional use to treat several inflammatory disorders associated to the immune system. The present study reports the underlying mechanisms involved in the stimulation of 80% ethanol extract of T. crispa stems on pro-inflammatory mediators release in lipopolysaccharide (LPS)-primed U937 human macrophages via MyD88-dependent pathways.

    METHODS: Release of interleukin (IL)-1β and tumor necrosis factor (TNF)-α, and production of prostaglandin E2 (PGE2) were determined by using enzyme-linked immunosorbent assay (ELISA). Immunoblot technique was executed to determine the activation of MAPKs molecules, NF-κB, PI3K-Akt and cyclooxygenase-2 (COX-2) protein. Determination of pro-inflammatory cytokines and COX-2 relative gene expression levels was by performing the real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). A reversed-phase HPLC method was developed and validated to standardize the T. crispa extract and chemical profiling of its secondary metabolites was performed by LC-MS/MS.

    RESULTS: Qualitative and quantitative analyses of chromatographic data indicated that syringin and magnoflorine were found as the major components of the extract. T. crispa-treatment prompted activation of NF-κB by enhancing IKKα/β and NF-κB (p65) phosphorylation, and degradation of IκBα. The extract upregulated COX-2 protein expression, release of pro-inflammatory mediators and MAPKs (ERK, p38 and JNK) phosphorylation as well as Akt dose-dependently. T. crispa extract also upregulated the upstream signaling adaptor molecules, toll-like receptor 4 (TLR4) and MyD88. T. crispa-treatment also upregulated the pro-inflammatory markers mRNA expression.

    CONCLUSION: The results suggested that T. crispa extract stimulated the MyD88-dependent signaling pathways by upregulating the various immune inflammatory related parameters.

    Matched MeSH terms: Mitogen-Activated Protein Kinases/metabolism*
  17. Apoptosis induced by para-phenylenediamine involves formation of ROS and activation of p38 and JNK in chang liver cells
    Chye SM, Tiong YL, Yip WK, Koh RY, Len YW, Seow HF, et al.
    Environ Toxicol, 2014 Sep;29(9):981-90.
    PMID: 23172806 DOI: 10.1002/tox.21828
    para-Phenylenediamine (p-PD) is a suspected carcinogen, but it has been widely used as a component in permanent hair dyes. In this study, the mechanism of p-PD-induced cell death in normal Chang liver cells was investigated. The results demonstrated that p-PD decreased cell viability in a dose-dependent manner. Cell death via apoptosis was confirmed by enhanced DNA damage and increased cell number in the sub-G1 phase of the cell cycle, using Hoechst 33258 dye staining and flow cytometry analysis. Apoptosis via reactive oxygen species generation was detected by the dichlorofluorescin diacetate staining method. Mitogen-activated protein kinase (MAPK) activation was assessed by western blot analysis and revealed that p-PD activated not only stress-activated protein kinase (SAPK)/c-Jun N-terminal kinases (JNK) and p38 MAPK but also extracellular signal-regulated kinase (ERK). Cytotoxicity and apoptosis induced by p-PD were markedly enhanced by ERK activation and selectively inhibited by ERK inhibitor PD98059, thus indicating a negative role of ERK. In contrast, inhibition of p38 MAPK activity with the p38-specific inhibitor SB203580 moderately inhibited cytotoxicity and apoptosis induction by p-PD. Similarly, SP600125, an inhibitor of SAPK/JNK, moderately inhibited cytotoxicity and apoptosis induced by p-PD, thus implying that p38 MAPK and SAPK/JNK had a partial role in p-PD-induced apoptosis. Western blot analysis revealed that p-PD significantly increased phosphorylation of p38 and SAPK/JNK and decreased phosphorylation of ERK. In conclusion, the results demonstrated that SAPK/JNK and p38 cooperatively participate in apoptosis induced by p-PD and that a decreased ERK signal contributes to growth inhibition or apoptosis.
    Matched MeSH terms: p38 Mitogen-Activated Protein Kinases/metabolism*
  18. Interferon-γ induces biphasic changes in caldesmon localization as well as adherens junction organization and expression in HUVECs
    Ng CT, Fong LY, Yong YK, Hakim MN, Ahmad Z
    Cytokine, 2018 11;111:541-550.
    PMID: 29909980 DOI: 10.1016/j.cyto.2018.06.010
    Endothelial barrier dysfunction leads to increased endothelial permeability and is an early step in the development of vascular inflammatory diseases such as atherosclerosis. Interferon-γ (IFN-γ), a proinflammatory cytokine, is known to cause increased endothelial permeability. However, the mechanisms by which IFN-γ disrupts the endothelial barrier have not been clarified. This study aimed to investigate how IFN-γ impairs the endothelial barrier integrity by specifically examining the roles of caldesmon, adherens junctions (AJs) and p38 mitogen-activated protein (MAP) kinase in IFN-γ-induced endothelial barrier dysfunction. IFN-γ exhibited a biphasic effect on caldesmon localization and both the structural organization and protein expression of AJs. In the early phase (4-8 h), IFN-γ induced the formation of peripheral caldesmon bands and discontinuous AJs, while AJ protein expression was unchanged. Interestingly, IFN-γ also stimulated caldesmon phosphorylation, resulting in actin dissociation from caldesmon at 8 h. Conversely, changes seen in the late phase (16-24 h) included cytoplasmic caldesmon dispersal, AJ linearization and junctional area reduction, which were associated with reduced membrane, cytoskeletal and total AJ protein expression. In addition, IFN-γ enhanced myosin binding to caldesmon at 12 h and persisted up to 24 h. Furthermore, inhibition of p38 MAP kinase by SB203580 did not reverse either the early or late phase changes observed. These data suggest that IFN-γ may activate signaling molecules other than p38 MAP kinase. In conclusion, our findings enhance the current understanding of how IFN-γ disrupts endothelial barrier function and reveal potential therapeutic targets, such as caldesmon and AJs, for the treatment of IFN-γ-associated vascular inflammatory diseases.
    Matched MeSH terms: p38 Mitogen-Activated Protein Kinases/metabolism
  19. A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells
    Dyari HRE, Rawling T, Chen Y, Sudarmana W, Bourget K, Dwyer JM, et al.
    FASEB J, 2017 12;31(12):5246-5257.
    PMID: 28798154 DOI: 10.1096/fj.201700033R
    A saturated analog of the cytochrome P450-mediated ω-3-17,18-epoxide of ω-3-eicosapentaenoic acid (C20E) activated apoptosis in human triple-negative MDA-MB-231 breast cancer cells. This study evaluated the apoptotic mechanism of C20E. Increased cytosolic cytochrome c expression and altered expression of pro- and antiapoptotic B-cell lymphoma-2 proteins indicated activation of the mitochondrial pathway. Caspase-3 activation by C20E was prevented by pharmacological inhibition and silencing of the JNK and p38 MAP kinases (MAPK), upstream MAPK kinases MKK4 and MKK7, and the upstream MAPK kinase kinase apoptosis signal-regulating kinase 1 (ASK1). Silencing of the death receptor TNF receptor 1 (TNFR1), but not Fas, DR4, or DR5, and the adapters TRADD and TNF receptor-associated factor 2, but not Fas-associated death domain, prevented C20E-mediated apoptosis. B-cell lymphoma-2 homology 3-interacting domain death agonist (Bid) cleavage by JNK/p38 MAPK linked the extrinsic and mitochondrial pathways of apoptosis. In further studies, an antibody against the extracellular domain of TNFR1 prevented apoptosis by TNF-α but not C20E. These findings suggest that C20E acts intracellularly at TNFR1 to activate ASK1-MKK4/7-JNK/p38 MAPK signaling and to promote Bid-dependent mitochondrial disruption and apoptosis. Inin vivostudies, tumors isolated from C20E-treated nu/nu mice carrying MDA-MB-231 xenografts showed increased TUNEL staining and decreased Ki67 staining, reflecting increased apoptosis and decreased proliferation, respectively. ω-3-Epoxy fatty acids like C20E could be incorporated into treatments for triple-negative breast cancers.-Dyari, H. R. E., Rawling, T., Chen, Y., Sudarmana, W., Bourget, K., Dwyer, J. M., Allison, S. E., Murray, M. A novel synthetic analogue of ω-3 17,18-epoxyeicosatetraenoic acid activates TNF receptor-1/ASK1/JNK signaling to promote apoptosis in human breast cancer cells.
    Matched MeSH terms: JNK Mitogen-Activated Protein Kinases/genetics; JNK Mitogen-Activated Protein Kinases/metabolism*; p38 Mitogen-Activated Protein Kinases/metabolism
  20. Fulltext Inhibitory action of gonadotropin-inhibitory hormone on the signaling pathways induced by kisspeptin and vasoactive intestinal polypeptide in GnRH neuronal cell line, GT1-7
    Son YL, Ubuka T, Soga T, Yamamoto K, Bentley GE, Tsutsui K
    FASEB J, 2016 06;30(6):2198-210.
    PMID: 26929433 DOI: 10.1096/fj.201500055
    Gonadotropin-inhibitory hormone (GnIH) acts as a negative regulator of reproduction by acting on gonadotropes and gonadotropin-releasing hormone (GnRH) neurons. Despite its functional significance, the molecular mechanism of GnIH action in the target cells has not been fully elucidated. To expand our previous study on GnIH actions in gonadotropes, we investigated the potential signal transduction pathway that conveys the inhibitory action of GnIH in GnRH neurons by using the GnRH neuronal cell line, GT1-7. We examined whether GnIH inhibits the action of kisspeptin and vasoactive intestinal polypeptide (VIP), positive regulators of GnRH neurons. Although GnIH significantly suppressed the stimulatory effect of kisspeptin on GnRH release in hypothalamic culture, GnIH had no inhibitory effect on kisspeptin stimulation of serum response element and nuclear factor of activated T-cell response element activities and ERK phosphorylation, indicating that GnIH may not directly inhibit kisspeptin signaling in GnRH neurons. On the contrary, GnIH effectively eliminated the stimulatory effect of VIP on p38 and ERK phosphorylation, c-Fos mRNA expression, and GnRH release. The use of pharmacological modulators strongly demonstrated the specific inhibitory action of GnIH on the adenylate cyclase/cAMP/protein kinase A pathway, suggesting a common inhibitory mechanism of GnIH action in GnRH neurons and gonadotropes.-Son, Y. L., Ubuka, T., Soga, T., Yamamoto, K., Bentley, G. E., Tsutsui, K. Inhibitory action of gonadotropin-inhibitory hormone on the signaling pathways induced by kisspeptin and vasoactive intestinal polypeptide in GnRH neuronal cell line, GT1-7.
    Matched MeSH terms: p38 Mitogen-Activated Protein Kinases/genetics; p38 Mitogen-Activated Protein Kinases/metabolism
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