Displaying publications 121 - 132 of 132 in total

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  1. Human renal carcinoma cells respond to Newcastle disease virus infection through activation of the p38 MAPK/NF-κB/IκBα pathway
    Ch'ng WC, Abd-Aziz N, Ong MH, Stanbridge EJ, Shafee N
    Cell Oncol (Dordr), 2015 Aug;38(4):279-88.
    PMID: 25930675 DOI: 10.1007/s13402-015-0229-5
    Newcastle disease virus (NDV) is an oncolytic virus that is known to have a higher preference to cancer cells than to normal cells. It has been proposed that this higher preference may be due to defects in the interferon (IFN) responses of cancer cells. The exact mechanism underlying this process, however, remains to be resolved. In the present study, we examined the antiviral response towards NDV infection of clear cell renal cell carcinoma (ccRCC) cells. ccRCC is associated with mutations of the von Hippel-Lindau tumor suppressor gene VHL, whose protein product is important for eliciting cellular responses to changes in oxygen levels. The most common first line treatment strategy of ccRCC includes IFN. Unfortunately, most ccRCC cases are diagnosed at a late stage and often are resistant to IFN-based therapies. Alternative treatment approaches, including virotherapy using oncolytic viruses, are currently being investigated. The present study was designed to investigate the mechanistic pathways underlying the response of ccRCC cells to oncolytic NDV infection.
    Matched MeSH terms: p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases/metabolism*
  2. Mechanism of the induction of endoplasmic reticulum stress by the anti-cancer agent, di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT): Activation of PERK/eIF2α, IRE1α, ATF6 and calmodulin kinase
    Merlot AM, Shafie NH, Yu Y, Richardson V, Jansson PJ, Sahni S, et al.
    Biochem Pharmacol, 2016 06 01;109:27-47.
    PMID: 27059255 DOI: 10.1016/j.bcp.2016.04.001
    The endoplasmic reticulum (ER) plays a major role in the synthesis, maturation and folding of proteins and is a critical calcium (Ca(2+)) reservoir. Cellular stresses lead to an overwhelming accumulation of misfolded proteins in the ER, leading to ER stress and the activation of the unfolded protein response (UPR). In the stressful tumor microenvironment, the UPR maintains ER homeostasis and enables tumor survival. Thus, a novel strategy for cancer therapeutics is to overcome chronically activated ER stress by triggering pro-apoptotic pathways of the UPR. Considering this, the mechanisms by which the novel anti-cancer agent, Dp44mT, can target the ER stress response pathways were investigated in multiple cell-types. Our results demonstrate that the cytotoxic chelator, Dp44mT, which forms redox-active metal complexes, significantly: (1) increased ER stress-associated pro-apoptotic signaling molecules (i.e., p-eIF2α, ATF4, CHOP); (2) increased IRE1α phosphorylation (p-IRE1α) and XBP1 mRNA splicing; (3) reduced expression of ER stress-associated cell survival signaling molecules (e.g., XBP1s and p58(IPK)); (4) increased cleavage of the transcription factor, ATF6, which enhances expression of its downstream targets (i.e., CHOP and BiP); and (5) increased phosphorylation of CaMKII that induces apoptosis. In contrast to Dp44mT, the iron chelator, DFO, which forms redox-inactive iron complexes, did not affect BiP, p-IRE1α, XBP1 or p58(IPK) levels. This study highlights the ability of a novel cancer therapeutic (i.e., Dp44mT) to target the pro-apoptotic functions of the UPR via cellular metal sequestration and redox stress. Assessment of ER stress-mediated apoptosis is fundamental to the understanding of the pharmacology of chelation for cancer treatment.
    Matched MeSH terms: Calcium-Calmodulin-Dependent Protein Kinases/genetics; Calcium-Calmodulin-Dependent Protein Kinases/metabolism
  3. Fulltext Lactobacillus Strains Alleviated Hyperlipidemia and Liver Steatosis in Aging Rats via Activation of AMPK
    Lew LC, Hor YY, Jaafar MH, Lau AS, Lee BK, Chuah LO, et al.
    Int J Mol Sci, 2020 Aug 16;21(16).
    PMID: 32824277 DOI: 10.3390/ijms21165872
    In this study, we hypothesized that different strains of Lactobacillus can alleviate hyperlipidemia and liver steatosis via activation of 5' adenosine monophosphate-activated protein kinase (AMPK), an enzyme that is involved in cellular energy homeostasis, in aged rats. Male rats were fed with a high-fat diet (HFD) and injected with D-galactose daily over 12 weeks to induce aging. Treatments included (n = 6) (i) normal diet (ND), (ii) HFD, (iii) HFD-statin (lovastatin 2 mg/kg/day), (iv) HFD-Lactobacillus fermentum DR9 (10 log CFU/day), (v) HFD-Lactobacillus plantarum DR7 (10 log CFU/day), and (vi) HFD-Lactobacillus reuteri 8513d (10 log CFU/day). Rats administered with statin, DR9, and 8513d reduced serum total cholesterol levels after eight weeks (p < 0.05), while the administration of DR7 reduced serum triglycerides level after 12 weeks (p < 0.05) as compared to the HFD control. A more prominent effect was observed from the administration of DR7, where positive effects were observed, ranging from hepatic gene expressions to liver histology as compared to the control (p < 0.05); downregulation of hepatic lipid synthesis and β-oxidation gene stearoyl-CoA desaturase 1 (SCD1), upregulation of hepatic sterol excretion genes of ATP-binding cassette subfamily G member 5 and 8 (ABCG5 and ABCG8), lesser degree of liver steatosis, and upregulation of hepatic energy metabolisms genes AMPKα1 and AMPKα2. Taken altogether, this study illustrated that the administration of selected Lactobacillus strains led to improved lipid profiles via activation of energy and lipid metabolisms, suggesting the potentials of Lactobacillus as a promising natural intervention for alleviation of cardiovascular and liver diseases.
    Matched MeSH terms: Protein Kinases/genetics; Protein Kinases/metabolism*
  4. Oleoyl-lysophosphatidylinositol enhances glucagon-like peptide-1 secretion from enteroendocrine L-cells through GPR119
    Arifin SA, Paternoster S, Carlessi R, Casari I, Ekberg JH, Maffucci T, et al.
    Biochim Biophys Acta Mol Cell Biol Lipids, 2018 09;1863(9):1132-1141.
    PMID: 29883799 DOI: 10.1016/j.bbalip.2018.06.007
    The gastrointestinal tract is increasingly viewed as critical in controlling glucose metabolism, because of its role in secreting multiple glucoregulatory hormones, such as glucagon like peptide-1 (GLP-1). Here we investigate the molecular pathways behind the GLP-1- and insulin-secreting capabilities of a novel GPR119 agonist, Oleoyl-lysophosphatidylinositol (Oleoyl-LPI). Oleoyl-LPI is the only LPI species able to potently stimulate the release of GLP-1 in vitro, from murine and human L-cells, and ex-vivo from murine colonic primary cell preparations. Here we show that Oleoyl-LPI mediates GLP-1 secretion through GPR119 as this activity is ablated in cells lacking GPR119 and in colonic primary cell preparation from GPR119-/- mice. Similarly, Oleoyl-LPI-mediated insulin secretion is impaired in islets isolated from GPR119-/- mice. On the other hand, GLP-1 secretion is not impaired in cells lacking GPR55 in vitro or in colonic primary cell preparation from GPR55-/- mice. We therefore conclude that GPR119 is the Oleoyl-LPI receptor, upstream of ERK1/2 and cAMP/PKA/CREB pathways, where primarily ERK1/2 is required for GLP-1 secretion, while CREB activation appears dispensable.
    Matched MeSH terms: Cyclic AMP-Dependent Protein Kinases/genetics; Cyclic AMP-Dependent Protein Kinases/metabolism
  5. Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73
    Wong SW, Tiong KH, Kong WY, Yue YC, Chua CH, Lim JY, et al.
    Breast Cancer Res Treat, 2011 Jul;128(2):301-13.
    PMID: 20686837 DOI: 10.1007/s10549-010-1055-0
    Recent gene expression profiling studies have identified five breast cancer subtypes, of which the basal-like subtype is the most aggressive. Basal-like breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it. Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin, its success is often compromised due to its dose-limiting nephrotoxicity and the development of drug resistance. To overcome this limitation, our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies. Using a validated kinase inhibitor library, we showed that inhibition of the mTOR, TGFβRI, NFκB, PI3K/AKT, and MAPK pathways sensitized basal-like MDA-MB-468 cells to cisplatin treatment. Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basal-like MDA-MB-468, MDA-MB-231, and HCC1937 cells but not in luminal-like T47D or MCF-7 cells. We further showed that the synergistic effect of rapamycin plus cisplatin on basal-like breast cancer cells was mediated through the induction of p73. Depletion of endogenous p73 in basal-like cells abolished these synergistic effects. In conclusion, combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basal-like breast cancers.
    Matched MeSH terms: p38 Mitogen-Activated Protein Kinases/genetics; p38 Mitogen-Activated Protein Kinases/metabolism
  6. Fulltext Inhibition of Egr1 expression underlies the anti-mitogenic effects of cAMP in vascular smooth muscle cells
    Kimura TE, Duggirala A, Hindmarch CC, Hewer RC, Cui MZ, Newby AC, et al.
    J Mol Cell Cardiol, 2014 Jul;72(100):9-19.
    PMID: 24534707 DOI: 10.1016/j.yjmcc.2014.02.001
    AIMS: Cyclic AMP inhibits vascular smooth muscle cell (VSMC) proliferation which is important in the aetiology of numerous vascular diseases. The anti-mitogenic properties of cAMP in VSMC are dependent on activation of protein kinase A (PKA) and exchange protein activated by cAMP (EPAC), but the mechanisms are unclear.

    METHODS AND RESULTS: Selective agonists of PKA and EPAC synergistically inhibited Egr1 expression, which was essential for VSMC proliferation. Forskolin, adenosine, A2B receptor agonist BAY60-6583 and Cicaprost also inhibited Egr1 expression in VSMC but not in endothelial cells. Inhibition of Egr1 by cAMP was independent of cAMP response element binding protein (CREB) activity but dependent on inhibition of serum response element (SRE) activity. SRF binding to the Egr1 promoter was not modulated by cAMP stimulation. However, Egr1 expression was dependent on the SRF co-factors Elk1 and 4 but independent of MAL. Inhibition of SRE-dependent Egr1 expression was due to synergistic inhibition of Rac1 activity by PKA and EPAC, resulting in rapid cytoskeleton remodelling and nuclear export of ERK1/2. This was associated with de-phosphorylation of the SRF co-factor Elk1.

    CONCLUSION: cAMP inhibits VSMC proliferation by rapidly inhibiting Egr1 expression. This occurs, at least in part, via inhibition of Rac1 activity leading to rapid actin-cytoskeleton remodelling, nuclear export of ERK1/2, impaired Elk1-phosphorylation and inhibition of SRE activity. This identifies one of the earliest mechanisms underlying the anti-mitogenic effects of cAMP in VSMC but not in endothelial cells, making it an attractive target for selective inhibition of VSMC proliferation.

    Matched MeSH terms: Cyclic AMP-Dependent Protein Kinases/genetics; Cyclic AMP-Dependent Protein Kinases/metabolism
  7. Fulltext Formononetin: A Review of Its Anticancer Potentials and Mechanisms
    Tay KC, Tan LT, Chan CK, Hong SL, Chan KG, Yap WH, et al.
    Front Pharmacol, 2019;10:820.
    PMID: 31402861 DOI: 10.3389/fphar.2019.00820
    Cancer, a complex yet common disease, is caused by uncontrolled cell division and abnormal cell growth due to a variety of gene mutations. Seeking effective treatments for cancer is a major research focus, as the incidence of cancer is on the rise and drug resistance to existing anti-cancer drugs is major concern. Natural products have the potential to yield unique molecules and combinations of substances that may be effective against cancer with relatively low toxicity/better side effect profile compared to standard anticancer therapy. Drug discovery work with natural products has demonstrated that natural compounds display a wide range of biological activities correlating to anticancer effects. In this review, we discuss formononetin (C16H12O4), which originates mainly from red clovers and the Chinese herb Astragalus membranaceus. The compound comes from a class of 7-hydroisoflavones with a substitution of methoxy group at position 4. Formononetin elicits antitumorigenic properties in vitro and in vivo by modulating numerous signaling pathways to induce cell apoptosis (by intrinsic pathway involving Bax, Bcl-2, and caspase-3 proteins) and cell cycle arrest (by regulating mediators like cyclin A, cyclin B1, and cyclin D1), suppress cell proliferation [by signal transducer and activator of transcription (STAT) activation, phosphatidylinositol 3-kinase/protein kinase-B (PI3K/AKT), and mitogen-activated protein kinase (MAPK) signaling pathway], and inhibit cell invasion [by regulating growth factors vascular endothelial growth factor (VEGF) and Fibroblast growth factor 2 (FGF2), and matrix metalloproteinase (MMP)-2 and MMP-9 proteins]. Co-treatment with other chemotherapy drugs such as bortezomib, LY2940002, U0126, sunitinib, epirubicin, doxorubicin, temozolomide, and metformin enhances the anticancer potential of both formononetin and the respective drugs through synergistic effect. Compiling the evidence thus far highlights the potential of formononetin to be a promising candidate for chemoprevention and chemotherapy.
    Matched MeSH terms: Mitogen-Activated Protein Kinases
  8. Fulltext Molecular and Biochemical Pathways of Catalpol in Alleviating Diabetes Mellitus and Its Complications
    Bhattamisra SK, Koh HM, Lim SY, Choudhury H, Pandey M
    Biomolecules, 2021 02 20;11(2).
    PMID: 33672590 DOI: 10.3390/biom11020323
    Catalpol isolated from Rehmannia glutinosa is a potent antioxidant and investigated against many disorders. This review appraises the key molecular pathways of catalpol against diabetes mellitus and its complications. Multiple search engines including Google Scholar, PubMed, and Science Direct were used to retrieve publications containing the keywords "Catalpol", "Type 1 diabetes mellitus", "Type 2 diabetes mellitus", and "diabetic complications". Catalpol promotes IRS-1/PI3K/AKT/GLUT2 activity and suppresses Phosphoenolpyruvate carboxykinase (PEPCK) and Glucose 6-phosphatase (G6Pase) expression in the liver. Catalpol induces myogenesis by increasing MyoD/MyoG/MHC expression and improves mitochondria function through the AMPK/PGC-1α/PPAR-γ and TFAM signaling in skeletal muscles. Catalpol downregulates the pro-inflammatory markers and upregulates the anti-inflammatory markers in adipose tissues. Catalpol exerts antioxidant properties through increasing superoxide dismutase (sod), catalase (cat), and glutathione peroxidase (gsh-px) activity in the pancreas and liver. Catalpol has been shown to have anti-oxidative, anti-inflammatory, anti-apoptosis, and anti-fibrosis properties that in turn bring beneficial effects in diabetic complications. Its nephroprotective effect is related to the modulation of the AGE/RAGE/NF-κB and TGF-β/smad2/3 pathways. Catalpol produces a neuroprotective effect by increasing the expression of protein Kinase-C (PKC) and Cav-1. Furthermore, catalpol exhibits a cardioprotective effect through the apelin/APJ and ROS/NF-κB/Neat1 pathway. Catalpol stimulates proliferation and differentiation of osteoblast cells in high glucose condition. Lastly, catalpol shows its potential in preventing neurodegeneration in the retina with NF-κB downregulation. Overall, catalpol exhibits numerous beneficial effects on diabetes mellitus and diabetic complications.
    Matched MeSH terms: AMP-Activated Protein Kinases
  9. Fulltext Catalpol Ameliorates Insulin Sensitivity and Mitochondrial Respiration in Skeletal Muscle of Type-2 Diabetic Mice Through Insulin Signaling Pathway and AMPK/SIRT1/PGC-1α/PPAR-γ Activation
    Yap KH, Yee GS, Candasamy M, Tan SC, Md S, Abdul Majeed AB, et al.
    Biomolecules, 2020 09 24;10(10).
    PMID: 32987623 DOI: 10.3390/biom10101360
    Catalpol was tested for various disorders including diabetes mellitus. Numerous molecular mechanisms have emerged supporting its biological effects but with little information towards its insulin sensitizing effect. In this study, we have investigated its effect on skeletal muscle mitochondrial respiration and insulin signaling pathway. Type-2 diabetes (T2DM) was induced in male C57BL/6 by a high fat diet (60% Kcal) and streptozotocin (50 mg/kg, i.p.). Diabetic mice were orally administered with catalpol (100 and 200 mg/kg), metformin (200 mg/kg), and saline for four weeks. Fasting blood glucose (FBG), HbA1c, plasma insulin, oral glucose tolerance test (OGTT), insulin tolerance test (ITT), oxygen consumption rate, gene (IRS-1, Akt, PI3k, AMPK, GLUT4, and PGC-1α) and protein (AMPK, GLUT4, and PPAR-γ) expression in muscle were measured. Catalpol (200 mg/kg) significantly (p < 0.05) reduced the FBG, HbA1C, HOMA_IR index, and AUC of OGTT whereas, improved the ITT slope. Gene (IRS-1, Akt, PI3k, GLUT4, AMPK, and PGC-1α) and protein (AMPK, p-AMPK, PPAR-γ and GLUT4) expressions, as well as augmented state-3 respiration, oxygen consumption rate, and citrate synthase activity in muscle was observed in catalpol treated mice. The antidiabetic activity of catalpol is credited with a marked improvement in insulin sensitivity and mitochondrial respiration through the insulin signaling pathway and AMPK/SIRT1/PGC-1α/PPAR-γ activation in the skeletal muscle of T2DM mice.
    Matched MeSH terms: AMP-Activated Protein Kinases
  10. Celastrol attenuates inflammatory responses in adipose tissues and improves skeletal muscle mitochondrial functions in high fat diet-induced obese rats via upregulation of AMPK/SIRT1 signaling pathways
    Abu Bakar MH, Shariff KA, Tan JS, Lee LK
    Eur J Pharmacol, 2020 Sep 15;883:173371.
    PMID: 32712089 DOI: 10.1016/j.ejphar.2020.173371
    Accumulating evidence indicates that adipose tissue inflammation and mitochondrial dysfunction in skeletal muscle are inextricably linked to obesity and insulin resistance. Celastrol, a bioactive compound derived from the root of Tripterygium wilfordii exhibits a number of attributive properties to attenuate metabolic dysfunction in various cellular and animal disease models. However, the underlying therapeutic mechanisms of celastrol in the obesogenic environment in vivo remain elusive. Therefore, the current study investigated the metabolic effects of celastrol on insulin sensitivity, inflammatory response in adipose tissue and mitochondrial functions in skeletal muscle of the high fat diet (HFD)-induced obese rats. Our study revealed that celastrol supplementation at 3 mg/kg/day for 8 weeks significantly reduced the final body weight and enhanced insulin sensitivity of the HFD-fed rats. Celastrol noticeably improved insulin-stimulated glucose uptake activity and increased expression of plasma membrane GLUT4 protein in skeletal muscle. Moreover, celastrol-treated HFD-fed rats showed attenuated inflammatory responses via decreased NF-κB activity and diminished mRNA expression responsible for classically activated macrophage (M1) polarization in adipose tissues. Significant improvement of muscle mitochondrial functions and enhanced antioxidant defense machinery via restoration of mitochondrial complexes I + III linked activity were effectively exhibited by celastrol treatment. Mechanistically, celastrol stimulated mitochondrial biogenesis attributed by upregulation of the adenosine monophosphate-activated protein kinase (AMPK) and sirtuin 1 (SIRT1) signaling pathways. Together, these results further demonstrate heretofore the conceivable therapeutic mechanisms of celastrol in vivo against HFD-induced obesity mediated through attenuation of inflammatory response in adipose tissue and enhanced mitochondrial functions in skeletal muscle.
    Matched MeSH terms: AMP-Activated Protein Kinases/metabolism*
  11. Newer targets for modulation of intraocular pressure: focus on adenosine receptor signaling pathways
    Agarwal R, Agarwal P
    Expert Opin Ther Targets, 2014 May;18(5):527-39.
    PMID: 24579961 DOI: 10.1517/14728222.2014.888416
    The homeostatic role of adenosine in regulating intraocular pressure (IOP) is now widely recognized, and hence, the drugs targeting adenosine receptors have become the focus of investigation. In this review, we summarize the adenosine receptor signaling pathways, which could be potential therapeutic targets for the management of glaucoma.
    Matched MeSH terms: Protein Kinases/physiology
  12. Cyclic-AMP-dependent proliferation of a human osteoblast cell line (HOS cells) induced by hydroxyapatite: effect of exogenous nitric oxide
    Sosroseno W, Sugiatno E
    Acta Biomed, 2008 Aug;79(2):110-6.
    PMID: 18788505
    BACKGROUND AND AIMS OF THE WORK: Nitric oxide (NO) has been reported to enhance the production of cAMP by hydroxyapatite (HA)-induced a human osteoblast cell line (HOS cells). The aim of the present study was to test the hypothesis that exogenous NO may up-regulate the proliferation of hydroxyapatite (HA)-induced HOS cells via the cyclic-AMP-protein kinase A (PKA) pathway.
    Matched MeSH terms: Cyclic GMP-Dependent Protein Kinases
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