Displaying publications 21 - 40 of 68 in total

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  1. 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: Proto-Oncogene Proteins c-akt/metabolism
  2. Fulltext Fibroblast growth factor receptor 4 (FGFR4) and fibroblast growth factor 19 (FGF19) autocrine enhance breast cancer cells survival
    Tiong KH, Tan BS, Choo HL, Chung FF, Hii LW, Tan SH, et al.
    Oncotarget, 2016 Sep 06;7(36):57633-57650.
    PMID: 27192118 DOI: 10.18632/oncotarget.9328
    Basal-like breast cancer is an aggressive tumor subtype with poor prognosis. The discovery of underlying mechanisms mediating tumor cell survival, and the development of novel agents to target these pathways, is a priority for patients with basal-like breast cancer. From a functional screen to identify key drivers of basal-like breast cancer cell growth, we identified fibroblast growth factor receptor 4 (FGFR4) as a potential mediator of cell survival. We found that FGFR4 mediates cancer cell survival predominantly via activation of PI3K/AKT. Importantly, a subset of basal-like breast cancer cells also secrete fibroblast growth factor 19 (FGF19), a canonical ligand specific for FGFR4. siRNA-mediated silencing of FGF19 or neutralization of extracellular FGF19 by anti-FGF19 antibody (1A6) decreases AKT phosphorylation, suppresses cancer cell growth and enhances doxorubicin sensitivity only in the FGFR4+/FGF19+ breast cancer cells. Consistently, FGFR4/FGF19 co-expression was also observed in 82 out of 287 (28.6%) primary breast tumors, and their expression is strongly associated with AKT phosphorylation, Ki-67 staining, higher tumor stage and basal-like phenotype. In summary, our results demonstrated the presence of an FGFR4/FGF19 autocrine signaling that mediates the survival of a subset of basal-like breast cancer cells and suggest that inactivation of this autocrine loop may potentially serve as a novel therapeutic intervention for future treatment of breast cancers.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  3. Bisleuconothine A Induces Autophagosome Formation by Interfering with AKT-mTOR Signaling Pathway
    Wong CP, Seki A, Horiguchi K, Shoji T, Arai T, Nugroho AE, et al.
    J Nat Prod, 2015 Jul 24;78(7):1656-62.
    PMID: 26176165 DOI: 10.1021/acs.jnatprod.5b00258
    We have previously reported that bisleuconothine A (Bis-A), a novel bisindole alkaloid isolated from Leuconotis griffithii, showed cytostatic activity in several cell lines. In this report, the mechanism of Bis-A-induced cytostatic activity was investigated in detail using A549 cells. Bis-A did not cause apoptosis, as indicated by analysis of annexin V and propidium iodide staining. Expression of all tested apoptosis-related proteins was also unaffected by Bis-A treatment. Bis-A was found to increase LC3 lipidation in MCF7 cells as well as A549 cells, suggesting that Bis-A cytostatic activity may be due to induction of autophagy. Subsequent investigation via Western blotting and immunofluorescence staining indicated that Bis-A induced formation but prevented degradation of autophagosomes. Mechanistic studies showed that Bis-A down-regulated phosphorylation of protein kinase B (AKT) and its downstream kinase, PRAS40, which is an mTOR repressor. Moreover, phosphorylation of p70S6K, an mTOR-dependent kinase, was also down-regulated. Down-regulation of these kinases suggests that the increase in LC3 lipidation may be due to mTOR deactivation. Thus, the cytostatic activity shown by Bis-A may be attributed to its induction of autophagosome formation. The Bis-A-induced autophagosome formation was suggested to be caused by its interference with the AKT-mTOR signaling pathway.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  4. Fulltext Current therapies and targets for type 2 diabetes mellitus
    Chellappan DK, Yap WS, Bt Ahmad Suhaimi NA, Gupta G, Dua K
    Panminerva Med, 2018 Sep;60(3):117-131.
    PMID: 29696964 DOI: 10.23736/S0031-0808.18.03455-9
    The prevalence of type 2 diabetes mellitus (T2DM) has been increasing at an alarming rate. With an increased understanding of the pathophysiology and pathogenesis of T2DM, various new therapeutic options have been developed to target different key defects in T2DM. Incremental innovations of existing therapies either through unprecedented drug combinations, modified drug molecules, or improved delivery systems are capable to nullify some of the undesirable side effects of traditional therapies as well as to enhance effectiveness. The existing administration routes include inhalation, nasal, buccal, parenteral and oral. Newer drug targets such as protein kinase B (Akt/PKB), AMP-activated protein kinase (AMPK), sirtuin (SIRT), and others are novel approaches that act via different mechanisms and possibly treating T2DM of distinct variations and aetiologies. Other therapies such as endobarrier, gene therapy, and stem cell technology utilize advanced techniques to treat T2DM, and the potential of these therapies are still being explored. Gene therapy is plausible to fix the underlying pathology of T2DM instead of using traditional reactive treatments, especially with the debut of Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein9 (CRISPR-Cas9) gene editing tool. Molecular targets in T2DM are also being extensively studied as it could target the defects at the molecular level. Furthermore, antibody therapies and vaccinations are also being developed against T2DM; but the ongoing clinical trials are relatively lesser and the developmental progress is slower. Although, there are many therapies designed to cure T2DM, each of them has their own advantages and disadvantages. The preference for the treatment plan usually depends on the health status of the patient and the treatment goal. Therefore, an ideal treatment should take patient's compliance, efficacy, potency, bioavailability, and other pharmacological and non-pharmacological properties into account.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  5. Improvement of mitochondrial function by celastrol in palmitate-treated C2C12 myotubes via activation of PI3K-Akt signaling pathway
    Abu Bakar MH, Tan JS
    Biomed Pharmacother, 2017 Sep;93:903-912.
    PMID: 28715871 DOI: 10.1016/j.biopha.2017.07.021
    Compelling evidences posited that high level of saturated fatty acid gives rise to mitochondrial dysfunction and inflammation in the development of insulin resistance in skeletal muscle. Celastrol is a pentacyclic triterpenoid derived from the root extracts of Tripterygium wilfordii that possesses potent anti-inflammatory properties in a number of animal models with metabolic diseases. However, the cellular mechanistic action of celastrol in alleviating obesity-induced insulin resistance in skeletal muscle remains largely unknown. Therefore, the present investigation evaluated the attributive properties of celastrol at different concentrations (10, 20, 30 and 40nM) on insulin resistance in C2C12 myotubes evoked by palmitate. We demonstrated that celastrol improved mitochondrial functions through significant enhancement of intracellular ATP content, mitochondrial membrane potential, citrate synthase activity and decrease of mitochondrial superoxide productions. Meanwhile, augmented mitochondrial DNA (mtDNA) content with suppressed DNA oxidative damage were observed following celastrol treatment. Celastrol significantly enhanced fatty acid oxidation rate and increased the level of tricarboxylic acid (TCA) cycle intermediates in palmitate-treated cells. Further analysis revealed that the improvement of glucose uptake activity in palmitate-loaded myotubes was partly mediated by celastrol via activation of PI3K-Akt insulin signaling pathway. Collectively, these findings provided evidence for the first time that the protection from palmitate-mediated insulin resistance in C2C12 myotubes by celastrol is likely associated with the improvement of mitochondrial functions-related metabolic activities.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism*
  6. Activation of phosphatidylinositol 3-kinase/Akt signaling by EGF downregulates membranous E-cadherin and β-catenin and enhances invasion in nasopharyngeal carcinoma cells
    Yip WK, Seow HF
    Cancer Lett, 2012 May 28;318(2):162-72.
    PMID: 22182447 DOI: 10.1016/j.canlet.2011.12.018
    Dysregulation of E-cadherin and β-catenin function in cell-cell adhesion is common in nasopharyngeal carcinoma (NPC) and correlates with metastatic disease. In this study, we examined the role of EGF-activated phosphatidylinositol 3-kinase (PI3K)-Akt signaling in E-cadherin and β-catenin regulation. We found that reduced membranous E-cadherin and β-catenin expression was positively correlated with Akt phosphorylation in NPC tissues. EGF treatment disrupted cell-cell adhesion and resulted in mesenchymal morphological features in NPC cell lines (TW01, TW04, and TW06). Western blot analysis showed that the E-cadherin protein level was partially reduced in TW04 cells only and the β-catenin levels were not considerably affected upon EGF treatment. In contrast, quantitative real-time RT-PCR showed that the E-cadherin, but not β-catenin, mRNA levels were markedly reduced by EGF in all cell lines. Immunofluorescent staining revealed that E-cadherin and β-catenin appeared to be markedly reduced on the cell surface and more localized in the cytoplasm. Inhibition of PI3K by LY294002 did not abolish the EGF-induced downregulation of E-cadherin protein or mRNA in TW04 cells but moderately increased the β-catenin protein level in TW01 cells and mRNA level in TW06 cells. However, LY294002 substantially restored or increased cell surface E-cadherin and β-catenin in all EGF-treated cell lines, in concordance with the inhibition of cell morphological changes. Moreover, LY294002 significantly blocked EGF-driven cell invasion, correlating with the elevation of membranous E-cadherin and β-catenin levels. In conclusion, EGF-induced epithelial-to-mesenchymal transition may not be only dependent on downregulation of E-cadherin protein/mRNA but also on mislocalization of E-cadherin and β-catenin. The mechanisms involved may be related, at least in part, to the PI3K-Akt pathway.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism*
  7. Zerumbone suppresses the activation of inflammatory mediators in LPS-stimulated U937 macrophages through MyD88-dependent NF-κB/MAPK/PI3K-Akt signaling pathways
    Haque MA, Jantan I, Harikrishnan H
    Int Immunopharmacol, 2018 Feb;55:312-322.
    PMID: 29310107 DOI: 10.1016/j.intimp.2018.01.001
    Zerumbone (ZER), isolated mainly from the Zingiber zerumbet (Z. zerumbet) rhizomes was found to be effective against numerous inflammatory and immune disorders, however, the molecular and biochemical mechanisms underlying its anti-inflammatory and immunosuppressive properties have not been well studied. This study was carried out to examine the profound effects of ZER on inflammatory mediated MyD88-dependent NF-κB/MAPK/PI3K-Akt signaling pathways in LPS-stimulated U937 human macrophages. ZER significantly suppressed the up-regulation pro-inflammatory mediators, TNF-α, IL-1β, PGE2, and COX-2 protein in LPS-induced human macrophages. Moreover, ZER significantly downregulated the phosphorylation of NF-κB (p65), IκBα, and IKKα/β as well as restored the degradation of IκBα. ZER correspondingly showed remarkable attenuation of the expression of Akt, JNK, ERK, and p38 MAPKs phosphorylation in a concentration-dependent manner. ZER also diminished the expression of upstream signaling molecules TLR4 and MyD88, which are prerequisite for the NF-κB, MAPK and PI3K-Akt activation. Additionally, quantification of relative gene expression of TNF-α, IL-1β, and COX-2 indicated that, at a higher dose (50μM), ZER significantly downregulated the elevated mRNA transcription levels of the stated pro-inflammatory markers in LPS-stimulated U937 macrophages. The strong suppressive effects of ZER on the activation of inflammatory markers in the macrophages via MyD88-dependent NF-κB/MAPK/PI3K-Akt signaling pathways suggest that ZER can be a preventive and potent therapeutic candidate for the management of various inflammatory-mediated immune disorders.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  8. LY294002, a PI3K pathway inhibitor, prevents leptin-induced adverse effects on spermatozoa in Sprague-Dawley rats
    Md Mokhtar AH, Malik IA, Abd Aziz NAA, Almabhouh FA, Durairajanayagam D, Singh HJ
    Andrologia, 2019 Apr;51(3):e13196.
    PMID: 30456785 DOI: 10.1111/and.13196
    This study examined the effects of PI3K and AMPK signalling pathway inhibitors on leptin-induced adverse effects on rat spermatozoa. Sprague-Dawley rats, aged 14-16 weeks, were randomised into control, leptin-, leptin + dorsomorphin (AMPK inhibitor)-, and leptin+LY294002 (PI3K inhibitor)-treated groups with six rats per group. Leptin was given once daily for 14 days via the intraperitoneal (i.p.) route at a dose of 60 ug kg-1 body weight. Rats in the leptin and inhibitor-treated groups received concurrently either dorsomorphin (5 mg kg-1  day-1 ) or LY294002 (1.2 mg kg-1  day-1 ) i.p. for 14 days. Controls received 0.1 ml of normal saline. Upon completion, sperm count, sperm morphology, seminiferous tubular epithelial height (STEH), seminiferous tubular diameter (STD), 8-hydroxy-2-deoxyguanosine (8-OHdG) and phospho-Akt/total Akt ratio were estimated. Data were analysed using ANOVA. Sperm count, STEH and STD were significantly lower, while the percentage of spermatozoa with abnormal morphology and the level of 8-OHdG were significantly higher in rats treated with leptin and leptin + dorsomorphin when compared to those in controls and LY294002-treated rats. Testicular phospho-Akt/total Akt ratio was significantly higher in leptin and leptin + LY294002-treated rats. In conclusion, LY294002 prevents leptin-induced changes in rat sperm parameters, suggesting the potential role of the PI3K signalling pathway in the adverse effects of leptin on sperm parameters.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  9. Caralluma pauciflorabased Ag-NPs activate ROS - induced apoptosis through down-regulation of AKT, mTOR and pI3K signaling in human gastric cancer (AGS) cells
    Navaneethan RD, N C J PL, Ramaiah M, Ravindran R, T AK, Chinnathambi A, et al.
    Nanotechnology, 2024 Feb 21;35(19).
    PMID: 38320329 DOI: 10.1088/1361-6528/ad26d9
    The phytochemicals found inCaralluma pauciflorawere studied for their ability to reduce silver nitrate in order to synthesise silver nanoparticles (AgNPs) and characterise their size and crystal structure. Thunbergol, 1,1,6-trimethyl-3-methylene-2-(3,6,9,13-tetram, Methyl nonadecanoate, Methyl cis-13,16-Docosadienate, and (1R,4aR,5S)-5-[(E)-5-Hydroxy-3-methylpent were the major compounds identified in the methanol extract by gas chromatography-mass spectrum analysis. UV/Vis spectra, Fourier-transform infrared spectroscopy, x-ray diffraction, scanning electron microscope with Energy Dispersive Xâray Analysis (EDAX), Dynamic Light Scattering (DLS) particle size analyser and atomic force microscope (AfM) were used to characterise theCaralluma paucifloraplant extract-based AgNPs. The crystal structure and estimated size of the AgNPs ranged from 20.2 to 43 nm, according to the characterization data. The anti-cancer activity of silver nanoparticles (AgNPs) synthesised fromCaralluma paucifloraextract. The AgNPs inhibited more than 60% of the AGS cell lines and had an IC50 value of 10.9640.318 g, according to the findings. The cells were further examined using fluorescence microscopy, which revealed that the AgNPs triggered apoptosis in the cells. Furthermore, the researchers looked at the levels of reactive oxygen species (ROS) in cells treated with AgNPs and discovered that the existence of ROS was indicated by green fluorescence. Finally, apoptotic gene mRNA expression analysis revealed that three target proteins (AKT, mTOR, and pI3K) were downregulated following AgNP therapy. Overall, the findings imply that AgNPs synthesised from Caralluma pauciflora extract could be used to treat human gastric cancer.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  10. Fulltext Targeting extracellular matrix remodeling in disease: Could resveratrol be a potential candidate?
    Agarwal R, Agarwal P
    Exp Biol Med (Maywood), 2017 Feb;242(4):374-383.
    PMID: 27798117 DOI: 10.1177/1535370216675065
    Disturbances of extracellular matrix homeostasis are associated with a number of pathological conditions. The ability of extracellular matrix to provide contextual information and hence control the individual or collective cellular behavior is increasingly being recognized. Hence, newer therapeutic approaches targeting extracellular matrix remodeling are widely investigated. We reviewed the current literature showing the effects of resveratrol on various aspects of extracellular matrix remodeling. This review presents a summary of the effects of resveratrol on extracellular matrix deposition and breakdown. Mechanisms of action of resveratrol in extracellular matrix deposition involving growth factors and their signaling pathways are discussed. Involvement of phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways and role of transcription factors and sirtuins on the effects of resveratrol on extracellular matrix homeostasis are summarized. It is evident from the literature presented in this review that resveratrol has significant effects on both the synthesis and breakdown of extracellular matrix. The major molecular targets of the action of resveratrol are growth factors and their signaling pathways, phosphoinositol-3-kinase/Akt and mitogen-activated protein kinase pathways, transcription factors, and SIRT-1. The effects of resveratrol on extracellular matrix and the molecular targets appear to be related to experimental models, experimental environment as well as the doses.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism*
  11. Syringin from Tinospora crispa downregulates pro-inflammatory mediator production through MyD88-dependent pathways in lipopolysaccharide (LPS)-induced U937 macrophages
    Arshad L, Haque MA, Harikrishnan H, Ibrahim S, Jantan I
    Mol Biol Rep, 2024 Jul 11;51(1):789.
    PMID: 38990383 DOI: 10.1007/s11033-024-09722-z
    BACKGROUND: Syringin, a phenylpropanoid glycoside, has exhibited numerous biological properties including inhibitory activities against various immune and inflammatory disorders. In this study, syringin isolated from Tinospora crispa was evaluated for its ability to down-regulate activated nuclear factor-kappa B (NF-κB), phosphoinositide-3-kinase-Akt (PI3K-Akt) and mitogen-activated protein kinases (MAPKs) signal transducing networks in U937 macrophages activated by lipopolysaccharide.

    METHODS: The attenuating effects of syringin on the productions of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β), and tumor necrosis factor-α (TNF-α), and the expressions of signaling molecules of the signaling pathways were investigated by using ELISA, Western blot, and qRT-PCR.

    RESULTS: Syringin downregulated the NF-κB, MAPKs, and PI3K-Akt signal networks by significantly reducing PGE2 production in the macrophages via suppression of COX-2 gene and protein expression levels. It also reduced TNF-α and IL-1β secretion and their mRNA expression, suppressed phosphorylation of NF-κB (p65), IKKα/β, and IκBα, and restored ability of IκBα to degrade. Syringin dose-dependently attenuated Akt, p38 MAPKs, JNK, and ERK phosphorylation. Also, the expression of corresponding upstream signaling molecules toll-like receptor 4 (TLR4) and myeloid differentiation primary response gene 88 (MyD88) were down-regulated in response to syringin treatment.

    CONCLUSION: The suppressive effect of syringin on the inflammatory signaling molecules in MyD88-dependent pathways suggested it's potential as a drug candidate for development into an agent for treatment of various immune-mediated inflammatory disorders.

    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  12. Para-phenylenediamine-induces apoptosis via a pathway dependent on PTK-Ras-Raf-JNK activation but independent of the PI3K/Akt pathway in NRK-52E cells
    Kasi RA, Moi CS, Kien YW, Yian KR, Chin NW, Yen NK, et al.
    Mol Med Rep, 2015 Mar;11(3):2262-8.
    PMID: 25411820 DOI: 10.3892/mmr.2014.2979
    para‑Phenylenediamine (p‑PD) is a potential carcinogen, and widely used in marketed hair dye formulations. In the present study, the role of the protein tyrosine kinase (PTK)/Ras/Raf/c‑Jun N‑terminal kinase (JNK) and phosphoinositide 3‑kinase (PI3k)/protein kinase B (Akt) pathways on the growth of NRK‑52E cells was investigated. The results demonstrated that p‑PD reduced cell viability in a dose‑dependent manner. The cell death due to apoptosis was confirmed by cell cycle analysis and an Annexin‑V‑fluorescein isothiocyanate binding assay. Subsequent to staining with 2',7'‑dichlorofluorescin diacetate, the treated cells demonstrated a significant increase in reactive oxygen species (ROS) generation compared with the controls. The effects of p‑PD on the signalling pathways were analysed by western blotting. p‑PD‑treated cells exhibited an upregulated phospho‑stress‑activated protein kinase/JNK protein expression level and downregulated Ras and Raf protein expression levels; however, Akt, Bcl‑2, Bcl‑XL and Bad protein expression levels were not significantly altered compared with the control. In conclusion, p‑PD induced apoptosis by a PTK/Ras/Raf/JNK‑dependent pathway and was independent of the PI3K/Akt pathway in NRK‑52E cells.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  13. Fulltext Leucaena leucocephala fruit aqueous extract stimulates adipogenesis, lipolysis, and glucose uptake in primary rat adipocytes
    Kuppusamy UR, Arumugam B, Azaman N, Jen Wai C
    ScientificWorldJournal, 2014;2014:737263.
    PMID: 25180205 DOI: 10.1155/2014/737263
    Leucaena leucocephala had been traditionally used to treat diabetes. The present study was designed to evaluate in vitro "insulin-like" activities of Leucaena leucocephala (Lam.) deWit. aqueous fruit extract on lipid and glucose metabolisms. The ability of the extract to stimulate adipogenesis, inhibit lipolysis, and activate radio-labeled glucose uptake was assessed using primary rat adipocytes. Quantitative Real-Time RT-PCR was performed to investigate effects of the extract on expression levels of genes (protein kinases B, AKT; glucose transporter 4, GLUT4; hormone sensitive lipase, HSL; phosphatidylinositol-3-kinases, PI3KA; sterol regulatory element binding factor 1, Srebp1) involved in insulin-induced signaling pathways. L. leucocephala aqueous fruit extract stimulated moderate adipogenesis and glucose uptake into adipocytes when compared to insulin. Generally, the extract exerted a considerable level of lipolytic effect at lower concentration but decreased gradually at higher concentration. The findings concurred with RT-PCR analysis. The expressions of GLUT4 and HSL genes were upregulated by twofold and onefold, respectively, whereas AKT, PI3KA, and Srebp1 genes were downregulated. The L. leucocephala aqueous fruit extract may be potentially used as an adjuvant in the treatment of Type 2 diabetes mellitus and weight management due to its enhanced glucose uptake and balanced adipogenesis and lipolysis properties.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  14. Fulltext Induction of apoptosis through oxidative stress-related pathways in MCF-7, human breast cancer cells, by ethyl acetate extract of Dillenia suffruticosa
    Tor YS, Yazan LS, Foo JB, Armania N, Cheah YK, Abdullah R, et al.
    BMC Complement Altern Med, 2014;14:55.
    PMID: 24524627 DOI: 10.1186/1472-6882-14-55
    Breast cancer is one of the most dreading types of cancer among women. Herbal medicine has becoming a potential source of treatment for breast cancer. Herbal plant Dillenia suffruticosa (Griff) Martelli under the family Dilleniaceae has been traditionally used to treat cancerous growth. In this study, the anticancer effect of ethyl acetate extract of D. suffruticosa (EADs) was examined on human breast adenocarcinoma cell line MCF-7 and the molecular pathway involved was elucidated.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  15. Apoptosis induction in MV4-11 and K562 human leukemic cells by Pereskia sacharosa (Cactaceae) leaf crude extract
    Asmaa MJ, Al-Jamal HA, Ang CY, Asan JM, Seeni A, Johan MF
    Asian Pac J Cancer Prev, 2014;15(1):475-81.
    PMID: 24528077
    BACKGROUND: Pereskia sacharosa is a genus of cacti widely used in folk medicine for cancer-related treatment. Anti-proliferative effects have been studied in recent years against colon, breast, cervical and lung cancer cell lines, with promising results. We here extended study of anti-proliferative effects to a blood malignancy, leukemia.

    MATERIALS AND METHODS: Two leukemic cell lines, MV4-11 (acute myeloid leukemia) and K562 (chronic myeloid leukemia), were studied. IC50 concentrations were determined and apoptosis and cell cycle regulation were studied by flow cytometric analysis. The expression of apoptosis and cell-cycle related regulatory proteins was assessed by Western blotting.

    RESULTS: P sacharosa inhibited growth of MV4-11 and K562 cells in a dose-dependent manner. The mode of cell death was via induction of intrinsic apoptotic pathways and cell cycle arrest. There was profound up-regulation of cytochrome c, caspases, p21 and p53 expression and repression of Akt and Bcl-2 expression in treated cells.

    CONCLUSIONS: These results suggest that P sacharosa induces leukemic cell death via apoptosis induction and changes in cell cycle checkpoint, thus deserves further study for anti-leukemic potential.

    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  16. Molecular alterations of Ras-Raf-mitogen-activated protein kinase and phosphatidylinositol 3-kinase-Akt signaling pathways in colorectal cancers from a tertiary hospital at Kuala Lumpur, Malaysia
    Yip WK, Choo CW, Leong VC, Leong PP, Jabar MF, Seow HF
    APMIS, 2013 Oct;121(10):954-66.
    PMID: 23992303 DOI: 10.1111/apm.12152
    Molecular alterations in KRAS, BRAF, PIK3CA, and PTEN have been implicated in designing targeted therapy for colorectal cancer (CRC). The present study aimed to determine the status of these molecular alterations in Malaysian CRCs as such data are not available in the literature. We investigated the mutations of KRAS, BRAF, and PTEN, the gene amplification of PIK3CA, and the protein expression of PTEN and phosphatidylinositol 3-kinase (PI3K) catalytic subunit (p110α) by direct DNA sequencing, quantitative real-time PCR, and immunohistochemistry, respectively, in 49 CRC samples. The frequency of KRAS (codons 12, 13, and 61), BRAF (V600E), and PTEN mutations, and PIK3CA amplification was 25.0% (11/44), 2.3% (1/43), 0.0% (0/43), and 76.7% (33/43), respectively. Immunohistochemical staining demonstrated loss of PTEN protein in 54.5% (24/44) of CRCs and no significant difference in PI3K p110α expression between CRCs and the adjacent normal colonic mucosa (p = 0.380). PIK3CA amplification was not associated with PI3K p110α expression level, but associated with male cases (100% of male cases vs 56% of female cases harbored amplified PIK3CA, p = 0.002). PI3K p110α expression was significantly higher (p = 0.041) in poorly/moderately differentiated carcinoma compared with well-differentiated carcinoma. KRAS mutation, PIK3CA amplification, PTEN loss, and PI3K p110α expression did not correlate with Akt phosphorylation or Ki-67 expression. KRAS mutation, PIK3CA amplification, and PTEN loss were not mutually exclusive. This is the first report on CRC in Malaysia showing comparable frequency of KRAS mutation and PTEN loss, lower BRAF mutation rate, higher PIK3CA amplification frequency, and rare PTEN mutation, as compared with published reports.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  17. Fulltext Cancer-associated fibroblasts promote proliferation of endometrial cancer cells
    Subramaniam KS, Tham ST, Mohamed Z, Woo YL, Mat Adenan NA, Chung I
    PLoS One, 2013;8(7):e68923.
    PMID: 23922669 DOI: 10.1371/journal.pone.0068923
    Endometrial cancer is the most commonly diagnosed gynecologic malignancy worldwide; yet the tumor microenvironment, especially the fibroblast cells surrounding the cancer cells, is poorly understood. We established four primary cultures of fibroblasts from human endometrial cancer tissues (cancer-associated fibroblasts, CAFs) using antibody-conjugated magnetic bead isolation. These relatively homogenous fibroblast cultures expressed fibroblast markers (CD90, vimentin and alpha-smooth muscle actin) and hormonal (estrogen and progesterone) receptors. Conditioned media collected from CAFs induced a dose-dependent proliferation of both primary cultures and cell lines of endometrial cancer in vitro (175%) when compared to non-treated cells, in contrast to those from normal endometrial fibroblast cell line (51%) (P<0.0001). These effects were not observed in fibroblast culture derived from benign endometrial hyperplasia tissues, indicating the specificity of CAFs in affecting endometrial cancer cell proliferation. To determine the mechanism underlying the differential fibroblast effects, we compared the activation of PI3K/Akt and MAPK/Erk pathways in endometrial cancer cells following treatment with normal fibroblasts- and CAFs-conditioned media. Western blot analysis showed that the expression of both phosphorylated forms of Akt and Erk were significantly down-regulated in normal fibroblasts-treated cells, but were up-regulated/maintained in CAFs-treated cells. Treatment with specific inhibitors LY294002 and U0126 reversed the CAFs-mediated cell proliferation (P<0.0001), suggesting for a role of these pathways in modulating endometrial cancer cell proliferation. Rapamycin, which targets a downstream molecule in PI3K pathway (mTOR), also suppressed CAFs-induced cell proliferation by inducing apoptosis. Cytokine profiling analysis revealed that CAFs secrete higher levels of macrophage chemoattractant protein (MCP)-1, interleukin (IL)-6, IL-8, RANTES and vascular endothelial growth factor (VEGF) than normal fibroblasts. Our data suggests that in contrast to normal fibroblasts, CAFs may exhibit a pro-tumorigenic effect in the progression of endometrial cancer, and PI3K/Akt and MAPK/Erk signaling may represent critical regulators in how endometrial cancer cells respond to their microenvironment.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  18. Negletein as a neuroprotectant enhances the action of nerve growth factor and induces neurite outgrowth in PC12 cells
    Phan CW, Sabaratnam V, Bovicelli P, Righi G, Saso L
    Biofactors, 2016 Nov 12;42(6):591-599.
    PMID: 27193378 DOI: 10.1002/biof.1296
    Negletein has been shown to have therapeutic potential for inflammation-associated diseases, but its effect on neurite outgrowth is still unknown. The present study showed that negletein alone did not trigger PC12 cells to differentiate and extend neurites. When compared with the cells in the untreated control, a significant (P Akt), and cAMP response element-binding protein (CREB). The growth associated protein-43 (GAP-43) and the NGF level were also upregulated by negletein (10 µM) and a low dose of NGF (5 ng/mL). Negletein at nanomolar concentration also was found to be sufficient to mediate the survival of serum-deprived PC12 cells up to 72 h. Taken together, negletein might be useful as an efficient bioactive compound to protect neurons from cell death and promote neuritogenesis. © 2016 BioFactors, 42(6):591-599, 2016.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  19. Fulltext Flavokawain C Inhibits Cell Cycle and Promotes Apoptosis, Associated with Endoplasmic Reticulum Stress and Regulation of MAPKs and Akt Signaling Pathways in HCT 116 Human Colon Carcinoma Cells
    Phang CW, Karsani SA, Sethi G, Abd Malek SN
    PLoS One, 2016;11(2):e0148775.
    PMID: 26859847 DOI: 10.1371/journal.pone.0148775
    Flavokawain C (FKC) is a naturally occurring chalcone which can be found in Kava (Piper methysticum Forst) root. The present study evaluated the effect of FKC on the growth of various human cancer cell lines and the underlying associated mechanisms. FKC showed higher cytotoxic activity against HCT 116 cells in a time- and dose-dependent manner in comparison to other cell lines (MCF-7, HT-29, A549 and CaSki), with minimal toxicity on normal human colon cells. The apoptosis-inducing capability of FKC on HCT 116 cells was evidenced by cell shrinkage, chromatin condensation, DNA fragmentation and increased phosphatidylserine externalization. FKC was found to disrupt mitochondrial membrane potential, resulting in the release of Smac/DIABLO, AIF and cytochrome c into the cytoplasm. Our results also revealed that FKC induced intrinsic and extrinsic apoptosis via upregulation of the levels of pro-apoptotic proteins (Bak) and death receptors (DR5), while downregulation of the levels of anti-apoptotic proteins (XIAP, cIAP-1, c-FlipL, Bcl-xL and survivin), resulting in the activation of caspase-3, -8 and -9 and cleavage of poly(ADP-ribose) polymerase (PARP). FKC was also found to cause endoplasmic reticulum (ER) stress, as suggested by the elevation of GADD153 protein after FKC treatment. After the cells were exposed to FKC (60μM) over 18hrs, there was a substantial increase in the phosphorylation of ERK 1/2. The expression of phosphorylated Akt was also reduced. FKC also caused cell cycle arrest in the S phase in HCT 116 cells in a time- and dose-dependent manner and with accumulation of cells in the sub-G1 phase. This was accompanied by the downregulation of cyclin-dependent kinases (CDK2 and CDK4), consistent with the upregulation of CDK inhibitors (p21Cip1 and p27Kip1), and hypophosphorylation of Rb.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
  20. Fulltext Endothelium-Dependent Relaxation Effect of Apocynum venetum Leaf Extract via Src/PI3K/Akt Signalling Pathway
    Lau YS, Ling WC, Murugan D, Kwan CY, Mustafa MR
    Nutrients, 2015 Jul;7(7):5239-53.
    PMID: 26133970 DOI: 10.3390/nu7075220
    Botanical herbs are consumed globally not only as an essential diet but also as medicines or as functional/recreational food supplements. The extract of the Apocynum venetum leaves (AVLE), also known as Luobuma, exerts its antihypertensive effect via dilating the blood vessels in an endothelium- and concentration-dependent manner with optimal effect seen at as low as 10 µg/mL. A commercial Luoboma "antihypertensive tea" is available commercially in the western province of China. The present study seeks to investigate the underlying cellular mechanisms of the nitric oxide (NO)-releasing property of AVLE in rat aortas and human umbilical vein endothelial cells (HUVECs). Endothelium-dependent relaxation induced by AVLE was assessed in organ chambers in the presence or absence of polyethyleneglycol catalase (PP2, 20 µM; inhibitor of Src kinase), wortmannin (30 nM) and LY294002 (20 µM; PI3 (phosphatidylinositol3)-Kinase inhibitor), N(G)-nitro-L-arginine (L-NAME, 100 µM; endothelial NO synthase inhibitor (eNOS)) and ODQ (1 µM; soluble guanylyl cyclase inhibitor). Total nitrite and nitrate (NOx) level and protein expression of p-Akt and p-eNOS were measured. AVLE-induced endothelium-dependent relaxation was reduced by PP2, wortmannin and LY294002 and abolished by L-NAME and ODQ. AVLE significantly increased total NOx level in rat aortas and in HUVECs compared to control. It also instigated phosphorylation of Akt and eNOS in cultured HUVECs in a concentration-dependent manner and this was markedly suppressed by PP2, wortmannin and LY294002. AVLE also inhibited superoxide generated from both NADPH oxidase and xanthine/xanthine oxidase system. Taken together, AVLE causes endothelium-dependent NO mediated relaxations of rat aortas through Src/PI3K/Akt dependent NO signalling pathway and possesses superoxide scavenging activity.
    Matched MeSH terms: Proto-Oncogene Proteins c-akt/metabolism
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