Displaying publications 341 - 360 of 701 in total

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  1. Trek2a regulates gnrh3 expression under control of melatonin receptor Mt1 and α2-adrenoceptor
    Loganathan K, Moriya S, Parhar IS
    Biochem Biophys Res Commun, 2018 02 12;496(3):927-933.
    PMID: 29395088 DOI: 10.1016/j.bbrc.2018.01.117
    Gonadotrophin-releasing hormone (GnRH) expression is associated with the two-pore domain potassium ion (K+) channel-related K+ (TREK) channel trek2a expression and melatonin levels. We aimed to investigate correlation of trek2a expression with gnrh3 expression, and regulatory mechanisms of trek2a expression by the melatonin receptor Mt1 and α2-adrenoceptor which are regulated by melatonin. trek2a specific siRNA, Mt1 antagonist luzindole and α2-adrenoceptor antagonist prazosin were administered into the adult zebrafish brain and gene expressions were examined by real-time PCR. trek2a specific siRNA administration significantly reduced expression levels of trek2a, gnrh3 and mt1. Luzindole administration suppressed trek2a and gnrh3 expressions. Prazosin administration reduced trek2a and gnrh3 expressions. It is suggested that Trek2a regulates gnrh3 expression under the control of Mt1 and α2-adrenoceptor.
    Matched MeSH terms: Signal Transduction/physiology
  2. Plagioneurin B, a potent isolated compound induces apoptotic signalling pathways and cell cycle arrest in ovarian cancer cells
    Nordin N, Majid NA, Othman R, Omer FAA, Nasharuddin MNA, Hashim NM
    Apoptosis, 2018 02;23(2):152-169.
    PMID: 29430581 DOI: 10.1007/s10495-018-1447-x
    Plagioneurin B belongs to acetogenin group has well-established class of compounds. Acetogenin group has attracted worldwide attention in the past few years due their biological abilities as inhibitors for several types of tumour cells. Plagioneurin B was isolated via conventional chromatography and tested for thorough mechanistic apoptosis activity on human ovarian cancer cells (CAOV-3). Its structure was also docked at several possible targets using Autodock tools software. Our findings showed that plagioneurin B successfully inhibits the growth of CAOV-3 cells at IC50 of 0.62 µM. The existence of apoptotic bodies, cell membrane blebbing and chromatin condensation indicated the hallmark of apoptosis. Increase of Annexin V-FITC bound to phosphatidylserine confirmed the apoptosis induction in the cells. The apoptosis event was triggered through the extrinsic and intrinsic pathways via activation of caspases 8 and 9, respectively. Stimulation of caspase 3 and the presence of DNA ladder suggested downstream apoptotic signalling were initiated. Further confirmation of apoptosis was conducted at the molecular levels where up-regulation in Bax, as well as down-regulation of Bcl-2, Hsp-70 and survivin were observed. Plagioneurin B was also seen to arrest CAOV-3 cells cycle at the G2/M phase. Docking simulation of plagioneurin B with CD95 demonstrated that the high binding affinity and hydrogen bonds formation may explain the capability of plagioneurin B to trigger apoptosis. This study is therefore importance in finding the effective compound that may offer an alternative drug for ovarian cancer treatment.
    Matched MeSH terms: Signal Transduction/drug effects*
  3. Evaluating the Protective Effects and Mechanisms of Diallyl Disulfide on Interlukin-1β-Induced Oxidative Stress and Mitochondrial Apoptotic Signaling Pathways in Cultured Chondrocytes
    Hosseinzadeh A, Jafari D, Kamarul T, Bagheri A, Sharifi AM
    J Cell Biochem, 2017 Jul;118(7):1879-1888.
    PMID: 28169456 DOI: 10.1002/jcb.25907
    The protective effects and mechanisms of DADS on IL-1β-mediated oxidative stress and mitochondrial apoptosis were investigated in C28I2 human chondrocytes. The effect of various concentrations of DADS (1, 5 10, 25, 50, and 100 μM) on C28I2 cell viability was evaluated in different times (2, 4, 8, 16, and 24 h) to obtain the non-cytotoxic concentrations of drug by MTT-assay. The protective effect of non-toxic concentrations of DADS on experimentally induced oxidative stress and apoptosis by IL-1β in C28I2 was evaluated. The effects of DADS on IL-1β-induced intracellular ROS production and lipid peroxidation were detected and the proteins expression of Nrf2, Bax, Bcl-2, caspase-3, total and phosphorylated JNK, and P38 MAPKs were analyzed by Western blotting. The mRNA expression of detoxifying phase II/antioxidant enzymes including heme oxygenase-1, NAD(P)H quinine oxidoreductase, glutathione S-transferase-P1, catalase, superoxide dismutase-1, glutathione peroxidase-1, -3, -4 were evaluated by reverse transcription-polymerase chain reaction. DADS in 1, 5, 10, and 25 μM concentrations had no cytotoxic effect after 24 h. Pretreatment with DADS remarkably increased Nrf2 nuclear translocation as well as the genes expression of detoxifying phase II/antioxidant enzymes and reduced IL-1β-induced elevation of ROS, lipid peroxidation, Bax/Bcl-2 ratio, caspase-3 activation, and JNK and P38 phosphorylation. DADS could considerably reduce IL-1β-induced oxidative stress and consequent mitochondrial apoptosis, as the major mechanisms of chondrocyte cell death in an experimental model of osteoarthritis. It may be considered as natural product in protecting OA-induced cartilage damage in clinical setting. J. Cell. Biochem. 118: 1879-1888, 2017. © 2017 Wiley Periodicals, Inc.
    Matched MeSH terms: Signal Transduction/drug effects
  4. Fulltext Comparing the effects of vitamin E tocotrienol-rich fraction supplementation and α-tocopherol supplementation on gene expression in healthy older adults
    Ghani SMA, Goon JA, Azman NHEN, Zakaria SNA, Hamid Z, Ngah WZW
    Clinics (Sao Paulo), 2019 03 07;74:e688.
    PMID: 30864639 DOI: 10.6061/clinics/2019/e688
    OBJECTIVES: This study aims to compare the differential gene expression resulting from tocotrienol-rich fraction and α-tocopherol supplementation in healthy older adults.

    METHODS: A total of 71 eligible subjects aged 50 to 55 years from Gombak and Kuala Lumpur, Malaysia, were divided into three groups and supplemented with placebo (n=23), α-tocopherol (n=24) or tocotrienol-rich fraction (n=24). Blood samples were collected at baseline and at 3 and 6 months of supplementation for microarray analysis.

    RESULTS: The number of genes altered by α-tocopherol was higher after 6 months (1,410) than after 3 months (273) of supplementation. α-Tocopherol altered the expression of more genes in males (952) than in females (731). Similarly, tocotrienol-rich fraction modulated the expression of more genes after 6 months (1,084) than after 3 months (596) and affected more genes in males (899) than in females (781). α-Tocopherol supplementation modulated pathways involving the response to stress and stimuli, the immune response, the response to hypoxia and bacteria, the metabolism of toxins and xenobiotics, mitosis, and synaptic transmission as well as activated the mitogen-activated protein kinase and complement pathways after 6 months. However, tocotrienol-rich fraction supplementation affected pathways such as the signal transduction, apoptosis, nuclear factor kappa B kinase, cascade extracellular signal-regulated kinase-1 and extracellular signal-regulated kinase-2, immune response, response to drug, cell adhesion, multicellular organismal development and G protein signaling pathways.

    CONCLUSION: Supplementation with either α-tocopherol or tocotrienol-rich fraction affected the immune and drug response and the cell adhesion and signal transduction pathways but modulated other pathways differently after 6 months of supplementation, with sex-specific responses.

    Matched MeSH terms: Signal Transduction/drug effects
  5. Fulltext Current Status of Endoplasmic Reticulum Stress in Type II Diabetes
    Mustapha S, Mohammed M, Azemi AK, Jatau AI, Shehu A, Mustapha L, et al.
    Molecules, 2021 Jul 19;26(14).
    PMID: 34299638 DOI: 10.3390/molecules26144362
    The endoplasmic reticulum (ER) plays a multifunctional role in lipid biosynthesis, calcium storage, protein folding, and processing. Thus, maintaining ER homeostasis is essential for cellular functions. Several pathophysiological conditions and pharmacological agents are known to disrupt ER homeostasis, thereby, causing ER stress. The cells react to ER stress by initiating an adaptive signaling process called the unfolded protein response (UPR). However, the ER initiates death signaling pathways when ER stress persists. ER stress is linked to several diseases, such as cancer, obesity, and diabetes. Thus, its regulation can provide possible therapeutic targets for these. Current evidence suggests that chronic hyperglycemia and hyperlipidemia linked to type II diabetes disrupt ER homeostasis, thereby, resulting in irreversible UPR activation and cell death. Despite progress in understanding the pathophysiology of the UPR and ER stress, to date, the mechanisms of ER stress in relation to type II diabetes remain unclear. This review provides up-to-date information regarding the UPR, ER stress mechanisms, insulin dysfunction, oxidative stress, and the therapeutic potential of targeting specific ER stress pathways.
    Matched MeSH terms: Signal Transduction*
  6. Fulltext Mechanistic Understanding of Curcumin's Therapeutic Effects in Lung Cancer
    Wan Mohd Tajuddin WNB, Lajis NH, Abas F, Othman I, Naidu R
    Nutrients, 2019 Dec 06;11(12).
    PMID: 31817718 DOI: 10.3390/nu11122989
    Lung cancer is among the most common cancers with a high mortality rate worldwide. Despite the significant advances in diagnostic and therapeutic approaches, lung cancer prognoses and survival rates remain poor due to late diagnosis, drug resistance, and adverse effects. Therefore, new intervention therapies, such as the use of natural compounds with decreased toxicities, have been considered in lung cancer therapy. Curcumin, a natural occurring polyphenol derived from turmeric (Curcuma longa) has been studied extensively in recent years for its therapeutic effects. It has been shown that curcumin demonstrates anti-cancer effects in lung cancer through various mechanisms, including inhibition of cell proliferation, invasion, and metastasis, induction of apoptosis, epigenetic alterations, and regulation of microRNA expression. Several invitro and invivo studies have shown that these mechanisms are modulated by multiple molecular targets such as STAT3, EGFR, FOXO3a, TGF-β, eIF2α, COX-2, Bcl-2, PI3KAkt/mTOR, ROS, Fas/FasL, Cdc42, E-cadherin, MMPs, and adiponectin. In addition, limitations, strategies to overcome curcumin bioavailability, and potential side effects as well as clinical trials were also reviewed.
    Matched MeSH terms: Signal Transduction/drug effects
  7. 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: Signal Transduction/drug effects
  8. Fulltext The E-Cadherin and N-Cadherin Switch in Epithelial-to-Mesenchymal Transition: Signaling, Therapeutic Implications, and Challenges
    Loh CY, Chai JY, Tang TF, Wong WF, Sethi G, Shanmugam MK, et al.
    Cells, 2019 Sep 20;8(10).
    PMID: 31547193 DOI: 10.3390/cells8101118
    Epithelial-to-Mesenchymal Transition (EMT) has been shown to be crucial in tumorigenesis where the EMT program enhances metastasis, chemoresistance and tumor stemness. Due to its emerging role as a pivotal driver of tumorigenesis, targeting EMT is of great therapeutic interest in counteracting metastasis and chemoresistance in cancer patients. The hallmark of EMT is the upregulation of N-cadherin followed by the downregulation of E-cadherin, and this process is regulated by a complex network of signaling pathways and transcription factors. In this review, we summarized the recent understanding of the roles of E- and N-cadherins in cancer invasion and metastasis as well as the crosstalk with other signaling pathways involved in EMT. We also highlighted a few natural compounds with potential anti-EMT property and outlined the future directions in the development of novel intervention in human cancer treatments. We have reviewed 287 published papers related to this topic and identified some of the challenges faced in translating the discovery work from bench to bedside.
    Matched MeSH terms: Signal Transduction/genetics
  9. Fulltext The endogenous antimicrobial cathelicidin LL37 induces platelet activation and augments thrombus formation
    Salamah MF, Ravishankar D, Kodji X, Moraes LA, Williams HF, Vallance TM, et al.
    Blood Adv, 2018 Nov 13;2(21):2973-2985.
    PMID: 30413433 DOI: 10.1182/bloodadvances.2018021758
    Platelet-associated complications including thrombosis, thrombocytopenia, and hemorrhage are commonly observed during various inflammatory diseases such as sepsis, inflammatory bowel disease, and psoriasis. Despite the reported evidence on numerous mechanisms/molecules that may contribute to the dysfunction of platelets, the primary mechanisms that underpin platelet-associated complications during inflammatory diseases are not fully established. Here, we report the discovery of formyl peptide receptor 2, FPR2/ALX, in platelets and its primary role in the development of platelet-associated complications via ligation with its ligand, LL37. LL37 acts as a powerful endogenous antimicrobial peptide, but it also regulates innate immune responses. We demonstrate the impact of LL37 in the modulation of platelet reactivity, hemostasis, and thrombosis. LL37 activates a range of platelet functions, enhances thrombus formation, and shortens the tail bleeding time in mice. By utilizing a pharmacological inhibitor and Fpr2/3 (an ortholog of human FPR2/ALX)-deficient mice, the functional dependence of LL37 on FPR2/ALX was determined. Because the level of LL37 is increased in numerous inflammatory diseases, these results point toward a critical role for LL37 and FPR2/ALX in the development of platelet-related complications in such diseases. Hence, a better understanding of the clinical relevance of LL37 and FPR2/ALX in diverse pathophysiological settings will pave the way for the development of improved therapeutic strategies for a range of thromboinflammatory diseases.
    Matched MeSH terms: Signal Transduction/drug effects
  10. Genetic polymorphisms in the one-carbon metabolism pathway genes and susceptibility to non-Hodgkin lymphoma
    Suthandiram S, Gan GG, Mohd Zain S, Bee PC, Lian LH, Chang KM, et al.
    Tumour Biol., 2015 Mar;36(3):1819-34.
    PMID: 25384508 DOI: 10.1007/s13277-014-2785-0
    Corroborating evidence related to the role of aberrations on one-carbon metabolism (OCM) genes has been inconsistent. We evaluated the association between polymorphisms in 12 single nucleotide polymorphisms (SNPs) in 8 OCM genes (CBS, FPGS, FTHFD, MTRR, SHMT1, SLC19A1, TCN1, and TYMS), and non-Hodgkin lymphoma (NHL) risk in a multi-ethnic population which includes Malay, Chinese and Indian ethnic subgroups. Cases (N = 372) and controls (N = 722) were genotyped using the Sequenom MassARRAY platform. Our results of the pooled subjects showed a significantly enhanced NHL risk for CBS Ex9 + 33C > T (T versus C: OR 1.55, 95% CI 1.22-1.96, P = 0.0003), CBS Ex18-319G > A (A versus G: OR 1.15, 95% CI 1.14-1.83; P = 0.002), SHMT1 Ex12 + 236 T > C (T versus C: OR 1.44, 95% CI 1.15-1.81, P = 0.002), and TYMS Ex8 + 157C > T (T versus C: OR 1.29, 95% CI 1.06-1.57, P = 0.01). Haplotype analysis for CBS SNPs showed a significantly decreased risk of NHL in subjects with haplotype CG (OR 0.69, 95% CI 0.56-0.86, P = <0.001). The GG haplotype for the FTHFD SNPs showed a significant increased risk of NHL (OR 1.40, 95% CI 1.12-1.76, P = 0.002). For the TYMS gene, haplotype CAT at TYMS (OR 0.67, 95% CI 0.49-0.90, P = 0.007) was associated with decreased risk of NHL, while haplotype TAC (OR 1.29, 95% CI 1.05-1.58, P = 0.01) was found to confer increased risk of NHL. Our study suggests that variation in several OCM genes (CBS, FTHFD, SHMT1, TCN1, and TYMS) may influence susceptibility to NHL.
    Matched MeSH terms: Signal Transduction
  11. Fulltext Understanding the shoot apical meristem regulation: a study of the phytohormones, auxin and cytokinin, in rice
    Azizi P, Rafii MY, Maziah M, Abdullah SN, Hanafi MM, Latif MA, et al.
    Mech. Dev., 2015 Feb;135:1-15.
    PMID: 25447356 DOI: 10.1016/j.mod.2014.11.001
    Auxin and cytokinin regulate different critical processes involved in plant growth and environmental feedbacks. These plant hormones act either synergistically or antagonistically to control the organisation, formation and maintenance of meristem. Meristem cells can be divided to generate new tissues and organs at the locations of plant postembryonic development. The aboveground plant organs are created by the shoot apical meristem (SAM). It has been proposed that the phytohormone, cytokinin, plays a positive role in the shoot meristem function, promotes cell expansion and promotes an increasing size of the meristem in Arabidopsis, whereas it has the reverse effects in the root apical meristem (RAM). Over the last few decades, it has been believed that the apically derived auxin suppresses the shoot branching by inactivating the axillary buds. However, it has recently become clear that the mechanism of action of auxinis indirect and multifaceted. In higher plants, the regulatory mechanisms of the SAM formation and organ separation are mostly unknown. This study reviews the effects and functions of cytokinin and auxin at the shoot apical meristem. This study also highlights the merger of the transcription factor activity with the actions of cytokinin/auxin and their complex interactions with the shoot meristem in rice.
    Matched MeSH terms: Signal Transduction
  12. Functional features and protein network of human sperm-egg interaction
    Sabetian S, Shamsir MS, Abu Naser M
    Syst Biol Reprod Med, 2014 Dec;60(6):329-37.
    PMID: 25222562 DOI: 10.3109/19396368.2014.955896
    Elucidation of the sperm-egg interaction at the molecular level is one of the unresolved problems in sexual reproduction, and understanding the molecular mechanism is crucial in solving problems in infertility and failed in vitro fertilization (IVF). Many molecular interactions in the form of protein-protein interactions (PPIs) mediate the sperm-egg membrane interaction. Due to the complexity of the problem such as difficulties in analyzing in vivo membrane PPIs, many efforts have failed to comprehensively elucidate the fusion mechanism and the molecular interactions that mediate sperm-egg membrane fusion. The main purpose of this study was to reveal possible protein interactions and associated molecular function during sperm-egg interaction using a protein interaction network approach. Different databases have been used to construct the human sperm-egg interaction network. The constructed network revealed new interactions. These included CD151 and CD9 in human oocyte that interact with CD49 in sperm, and CD49 and ITGA4 in sperm that interact with CD63 and CD81, respectively, in the oocyte. These results showed that the different integrins in sperm may be involved in human sperm-egg interaction. It was also suggested that sperm ADAM2 plays a role as a protein candidate involved in sperm-egg membrane interaction by interacting with CD9 in the oocyte. Interleukin-4 receptor activity, receptor signaling protein tyrosine kinase activity, and manganese ion transmembrane transport activity are the major molecular functions in sperm-egg interaction protein network. The disease association analysis indicated that sperm-egg interaction defects are also reflected in other disease networks such as cardiovascular, hematological, and breast cancer diseases. By analyzing the network, we identified the major molecular functions and disease association genes in sperm-egg interaction protein. Further experimental studies will be required to confirm the significance of these new computationally resolved interactions and the genetic links between sperm-egg interaction abnormalities and the associated disease.
    Matched MeSH terms: Signal Transduction
  13. Fulltext Lack of clinical manifestations in asymptomatic dengue infection is attributed to broad down-regulation and selective up-regulation of host defence response genes
    Yeo AS, Azhar NA, Yeow W, Talbot CC, Khan MA, Shankar EM, et al.
    PLoS One, 2014;9(4):e92240.
    PMID: 24727912 DOI: 10.1371/journal.pone.0092240
    Dengue represents one of the most serious life-threatening vector-borne infectious diseases that afflicts approximately 50 million people across the globe annually. Whilst symptomatic infections are frequently reported, asymptomatic dengue remains largely unnoticed. Therefore, we sought to investigate the immune correlates conferring protection to individuals that remain clinically asymptomatic.
    Matched MeSH terms: Signal Transduction
  14. Fulltext The effect of relaxin on the musculoskeletal system
    Dehghan F, Haerian BS, Muniandy S, Yusof A, Dragoo JL, Salleh N
    Scand J Med Sci Sports, 2014 Aug;24(4):e220-9.
    PMID: 24283470 DOI: 10.1111/sms.12149
    Relaxin is a hormone structurally related to insulin and insulin-like growth factor, which exerts its regulatory effect on the musculoskeletal and other systems through binding to its receptor in various tissues, mediated by different signaling pathways. Relaxin alters the properties of cartilage and tendon by activating collagenase. This hormone is also involved in bone remodeling and healing of injured ligaments and skeletal muscle. In this review, we have summarized the literature on the effect of relaxin in musculoskeletal system to provide a broad perspective for future studies in this field.
    Matched MeSH terms: Signal Transduction
  15. PIK3CA gene mutations in breast carcinoma in Malaysian patients
    Ching-Shian Leong V, Jabal MF, Leong PP, Abdullah MA, Gul YA, Seow HF
    Cancer Genet. Cytogenet., 2008 Dec;187(2):74-9.
    PMID: 19027487 DOI: 10.1016/j.cancergencyto.2008.07.005
    Somatic mutations of phosphoinositide-3-kinase, catalytic, alpha; PIK3CA gene have been reported in several types of human cancers. The majority of the PIK3CA mutations map to the three "hot spots" - E542 K and E545 K in the helical (exon 9) and H1047R in the kinase (exon 20) domains of the p110alpha. These hot spot mutations lead to a gain of function in PI3 K signaling. We aimed to determine the frequency of PIK3CA mutations in the three most common Malaysian cancers. In this study, we assessed the genetic alterations in the PIK3CA gene in a series of 20 breast carcinomas, 24 colorectal carcinomas, 27 nasopharyngeal carcinomas (NPC), and 5 NPC cell lines. We performed mutation analysis of the PIK3CA gene by genomic polymerase chain reaction (PCR) and followed by DNA direct sequencing in exons 9 and 20. No mutations were detected in any of the 24 colorectal and 27 NPC samples, but one hot spot mutation located at exon 20 was found in a NPC cell line, SUNE1. Interestingly, PIK3CA somatic mutations were present in 6/20 (30%) breast carcinomas. Two of the six mutations, H1047R, have been reported previously as a hot spot mutation. Only one out of three hot spot mutations were identified in breast tumor samples. The remaining four mutations were novel. Our data showed that a higher incidence rate of PIK3CA mutations was present in Malaysian breast cancers as compared to colorectal and nasopharyngeal tumor tissues. Our findings also indicate that PIK3CA mutations play a pivotal role in activation of the PI3 K signaling pathway in breast cancer, and specific inhibitors of PIK3CA could be useful for breast cancer treatment in Malaysia.
    Matched MeSH terms: Signal Transduction
  16. Fulltext An evolutionary firefly algorithm for the estimation of nonlinear biological model parameters
    Abdullah A, Deris S, Anwar S, Arjunan SN
    PLoS One, 2013;8(3):e56310.
    PMID: 23469172 DOI: 10.1371/journal.pone.0056310
    The development of accurate computational models of biological processes is fundamental to computational systems biology. These models are usually represented by mathematical expressions that rely heavily on the system parameters. The measurement of these parameters is often difficult. Therefore, they are commonly estimated by fitting the predicted model to the experimental data using optimization methods. The complexity and nonlinearity of the biological processes pose a significant challenge, however, to the development of accurate and fast optimization methods. We introduce a new hybrid optimization method incorporating the Firefly Algorithm and the evolutionary operation of the Differential Evolution method. The proposed method improves solutions by neighbourhood search using evolutionary procedures. Testing our method on models for the arginine catabolism and the negative feedback loop of the p53 signalling pathway, we found that it estimated the parameters with high accuracy and within a reasonable computation time compared to well-known approaches, including Particle Swarm Optimization, Nelder-Mead, and Firefly Algorithm. We have also verified the reliability of the parameters estimated by the method using an a posteriori practical identifiability test.
    Matched MeSH terms: Signal Transduction
  17. Fulltext Human IFNAR2 deficiency: Lessons for antiviral immunity
    Duncan CJ, Mohamad SM, Young DF, Skelton AJ, Leahy TR, Munday DC, et al.
    Sci Transl Med, 2015 Sep 30;7(307):307ra154.
    PMID: 26424569 DOI: 10.1126/scitranslmed.aac4227
    Type I interferon (IFN-α/β) is a fundamental antiviral defense mechanism. Mouse models have been pivotal to understanding the role of IFN-α/β in immunity, although validation of these findings in humans has been limited. We investigated a previously healthy child with fatal encephalitis after inoculation of the live attenuated measles, mumps, and rubella (MMR) vaccine. By targeted resequencing, we identified a homozygous mutation in the high-affinity IFN-α/β receptor (IFNAR2) in the proband, as well as a newborn sibling, that rendered cells unresponsive to IFN-α/β. Reconstitution of the proband's cells with wild-type IFNAR2 restored IFN-α/β responsiveness and control of IFN-attenuated viruses. Despite the severe outcome of systemic live vaccine challenge, the proband had previously shown no evidence of heightened susceptibility to respiratory viral pathogens. The phenotype of IFNAR2 deficiency, together with similar findings in STAT2-deficient patients, supports an essential but narrow role for IFN-α/β in human antiviral immunity.
    Matched MeSH terms: Signal Transduction
  18. Fulltext Lignosus rhinocerotis (Cooke) Ryvarden mimics the neuritogenic activity of nerve growth factor via MEK/ERK1/2 signaling pathway in PC-12 cells
    Seow SL, Eik LF, Naidu M, David P, Wong KH, Sabaratnam V
    Sci Rep, 2015 Nov 06;5:16349.
    PMID: 26542212 DOI: 10.1038/srep16349
    The traditional application of the sclerotium of Lignosus rhinocerotis (tiger's milk mushroom) by the indigenous folks as tonic and remedy to treat a variety of ailments has been documented in Malaysia. Indigenous communities claimed to have consumed the decoction to boost their alertness during hunting. Mental alertness is believed to be related to neuronal health and neuroactivity. In the present study, the cell viability and neuritogenic effects of L. rhinocerotis sclerotium hot aqueous and ethanolic extracts, and crude polysaccharides on rat pheochromocytoma (PC-12) cells were studied. Interestingly, the hot aqueous extract exhibited neuritogenic activity comparable to NGF in PC-12 cells. However, the extracts and crude polysaccharides stimulated neuritogenesis without stimulating the production of NGF in PC-12 cells. The involvements of the TrkA receptor and MEK/ERK1/2 pathway in hot aqueous extract-stimulated neuritogenesis were examined by Trk (K252a) and MEK/ERK1/2 (U0126 and PD98059) inhibitors. There was no significant difference in protein expression in NGF- and hot aqueous extract-treated cells for both total and phosphorylated p44/42 MAPK. The neuritogenic activity in PC-12 cells stimulated by hot aqueous and ethanolic extracts, and crude polysaccharides of L. rhinocerotis sclerotium mimicking NGF activity via the MEK/ERK1/2 signaling pathway is reported for the first time.
    Matched MeSH terms: Signal Transduction
  19. Fulltext Conflict of interest and signal interference lead to the breakdown of honest signaling
    Popat R, Pollitt EJ, Harrison F, Naghra H, Hong KW, Chan KG, et al.
    Evolution, 2015 Sep;69(9):2371-83.
    PMID: 26282874 DOI: 10.1111/evo.12751
    Animals use signals to coordinate a wide range of behaviors, from feeding offspring to predator avoidance. This poses an evolutionary problem, because individuals could potentially signal dishonestly to coerce others into behaving in ways that benefit the signaler. Theory suggests that honest signaling is favored when individuals share a common interest and signals carry reliable information. Here, we exploit the opportunities offered by bacterial signaling to test these predictions with an experimental evolution approach. We show that: (1) reduced relatedness leads to the relative breakdown of signaling, (2) signaling breaks down by the invasion of mutants that show both reduced signaling and reduced response to signal, (3) the genetic route to signaling breakdown is variable, and (4) the addition of artificial signal, to interfere with signal information, also leads to reduced signaling. Our results provide clear support for signaling theory, but we did not find evidence for previously predicted coercion at intermediate relatedness, suggesting that mechanistic details can alter the qualitative nature of specific predictions. Furthermore, populations evolved under low relatedness caused less mortality to insect hosts, showing how signal evolution in bacterial pathogens can drive the evolution of virulence in the opposite direction to that often predicted by theory.
    Matched MeSH terms: Signal Transduction
  20. Fulltext Expression of fibroblast growth factor receptor 4 (FGFR-4) in nasopharyngeal carcinoma (NPC) cell lines and its potential as therapeutic target
    Hooi Yeen Yap, Jack Bee Chook, Sin Yeang Teow
    Malaysian Journal of Medicine and Health Sciences, 2019;15(108):49-49.
    MyJurnal
    ntroduction: Nasopharyngeal carcinoma (NPC) is a prevalent cancer among human population in Southern China, Hong Kong and Southeast Asia. In Malaysia, NPC is the fourth most common cancer in both sexes, predominantly in the Chinese. Epstein-Barr virus (EBV) infection is known to be highly associated with NPC. Fibroblast growth factor receptor-4 (FGFR4) is part of the family of tyrosine kinase receptors that regulate cell survival, differentiation and pro-liferation. The binding of FGFR4 ligands such as fibroblasts growth factors (FGFs) has been shown to activate various oncogenic signalling pathway including MAPK, Ras and PI3K-Akt pathways. In the past, FGFR4 has been shown to promote tumorigenesis and tumour progression in various cancers such as liver, colon, breast and pancreatic and gastric cancers. However, its role in NPC establishment and pathogenesis is under-explored. This study aimed to evaluate the FGFR4 expression in NPC using various cell lines and its potential as a therapeutic target for NPC treat-ment by gene silencing. Methods: The basal FGFR4 level of NPC (EBV-positive: C666-1 and EBV-negative: HONE1 and HK1) and nasopharyngeal epithelial (NPE) normal (NP69 and NP460) cell lines was determined by western blot analysis and RT-qPCR. FGFR4 level at different time points (0, 24, 48, and 72 hours) in HONE1 and C666-1 cell lines were determined by western blot analysis. Luminescence-based assay was performed to determine the cell prolifer-ation of NPC cells in correlation with the FGFR4 expression. NPC cells were then treated with the optimised FGFR4 siRNA or FGFR inhibitor, BLU-9931 and the silencing/ inhibition of FGFR4 expression was confirmed by western blot analysis. The effect of FGFR4 inhibition on the cell proliferation and aggressiveness of NPC cells was then investigat-ed through wound healing assay and invasion marker analysis. Results: Out of the five tested cell lines, HONE1 and C666-1 highly expressed FGFR4, NP69 showed very low expression while HK1 and NP460 did not express FGFR4. In the time-point study, the FGFR4 level of HONE1 and C666-1 peaked at 24-48 hours which is the exponential phase of cells. Following that, the FGFR4 level decreased corresponding to the decreased cell growth rate due to the nutrient deprivation. siRNA experiments showed that 6.25nM of four siRNAs (5, 6, 9 and 10) could effectively target and silence the FGFR4 expression of HONE1, but not in C666-1 even up to 250nM was tested. When BLU-9931 was used, only modest inhibition was observed in both cells at 3uM. Compared to the untreated control, FGFR4-inhibited HONE1 exhibited decreased cell proliferation rate. Cell migration and invasion capabilities of HONE1 were also significantly reduced following the FGFR4 silencing, suggesting the potential of utilising FGFR4 as the therapeutic target. Conclusion: FGFR4 is highly expressed in C666-1 (EBV-positive) and HONE1 (initially EBV-positive, but lost EBV genome in subsequent in vitro passage) NPC cells, but not in EBV-negative HK1 NPC cell and normal NPE cells. FGFR4 gene silencing effectively inhibited the cell proliferation, migration and invasive potentials of NPC cell line. These findings highlight the therapeutic value of targeting FGFR4 for NPC treatment. Further investigations are war-ranted to reveal the molecular mechanism and the possible role of EBV in regulating FGFR4 pathway.
    Matched MeSH terms: Signal Transduction
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