Displaying publications 1 - 20 of 58 in total

Abstract:
Sort:
  1. Nitric oxide, human diseases and the herbal products that affect the nitric oxide signalling pathway
    Achike FI, Kwan CY
    Clin Exp Pharmacol Physiol, 2003 Sep;30(9):605-15.
    PMID: 12940876
    1. Nitric oxide (NO) is formed enzymatically from l-arginine in the presence of nitric oxide synthase (NOS). Nitric oxide is generated constitutively in endothelial cells via sheer stress and blood-borne substances. Nitric oxide is also generated constitutively in neuronal cells and serves as a neurotransmitter and neuromodulator in non-adrenergic, non-cholinergic nerve endings. Furthermore, NO can also be formed via enzyme induction in many tissues in the presence of cytokines. 2. The ubiquitous presence of NO in the living body suggests that NO plays an important role in the maintenance of health. Being a free radical with vasodilatory properties, NO exerts dual effects on tissues and cells in various biological systems. At low concentrations, NO can dilate the blood vessels and improve the circulation, but at high concentrations it can cause circulatory shock and induce cell death. Thus, diseases can arise in the presence of the extreme ends of the physiological concentrations of NO. 3. The NO signalling pathway has, in recent years, become a target for new drug development. The high level of flavonoids, catechins, tannins and other polyphenolic compounds present in vegetables, fruits, soy, tea and even red wine (from grapes) is believed to contribute to their beneficial health effects. Some of these compounds induce NO formation from the endothelial cells to improve circulation and some suppress the induction of inducible NOS in inflammation and infection. 4. Many botanical medicinal herbs and drugs derived from these herbs have been shown to have effects on the NO signalling pathway. For example, the saponins from ginseng, ginsenosides, have been shown to relax blood vessels (probably contributing to the antifatigue and blood pressure-lowering effects of ginseng) and corpus cavernosum (thus, for the treatment of men suffering from erectile dysfunction; however, the legendary aphrodisiac effect of ginseng may be an overstatement). Many plant extracts or purified drugs derived from Chinese medicinal herbs with proposed actions on NO pathways are also reviewed.
    Matched MeSH terms: Signal Transduction/physiology*
  2. Host evasion by emerging paramyxoviruses: Hendra virus and Nipah virus v proteins inhibit interferon signaling
    Rodriguez JJ, Horvath CM
    Viral Immunol, 2004;17(2):210-9.
    PMID: 15279700
    Interferon (IFN) can activate Signal Transducer and Activator of Transcription (STAT) proteins to establish a cellular antiviral response and inhibit virus replication. Many viruses have evolved strategies to inhibit this antiviral mechanism, but paramyxoviruses are unique in their abilities to directly target the IFN-responsive STAT proteins. Hendra virus and Nipah virus (Henipaviruses) are recently emerged paramyxoviruses that are the causative agents of fatal disease outbreaks in Australia and peninsular Malaysia. Similar to other paramyxoviruses, Henipaviruses inhibit IFN signal transduction through a virus-encoded protein called V. Recent studies have shown that Henipavirus V proteins target STAT proteins by inducing the formation of cytoplasmically localized high molecular weight STAT-containing complexes. This sequestration of STAT1 and STAT2 prevents STAT activation and blocks antiviral IFN signaling. As the V proteins are important factors for host evasion, they represent logical targets for therapeutics directed against Henipavirus epidemics.
    Matched MeSH terms: Signal Transduction/physiology
  3. 6th COSTAM/SFRR (ASEAN/Malaysia) International Workshop on Micronutrients, Oxidative Stress, and the Environment
    Nesaretnam K, Sies H
    Antioxid Redox Signal, 2006 10 13;8(11-12):2175-7.
    PMID: 17034360
    The 6(th) COSTAM/SFRR (ASEAN/Malaysia) workshop, "Micronutrients, Oxidative Stress, and the Environment," was held from June 29 to July 2 at Holiday Inn Damai Beach Resort in Kuching, Sarawak. Two hundred twenty participants from 17 countries presented recent advances on natural antioxidants in the area of oxidative stress and molecular aspects of nutrition. Natural products and research are an important program in academic institutions and are experiencing unprecedented interest and growth by the scientific community and public health authorities. Progress is being driven by better understanding of the molecular mechanisms of the relation between oxidative stress and micronutrient action. The gathering of scientists from around the world was fruitful, and we hope that future work will be developed by the formal and informal interactions that took place in this beautiful tropical setting.
    Matched MeSH terms: Signal Transduction/physiology
  4. Fulltext 9th Workshop on the Neurobiology of Epilepsy (WONOEP IX): the transition from the interictal to the ictal state (Teluk Nibong, Langkawi Island, Malaysia, July 4-7, 2007)
    de Curtis M, Murashima Y, Sankar R
    Epilepsia, 2008 Aug;49(8):1475-9.
    PMID: 18754944 DOI: 10.1111/j.1528-1167.2008.01618_1.x
    Matched MeSH terms: Signal Transduction/physiology
  5. Is vitamin E toxic to neuron cells?
    Then SM, Mazlan M, Mat Top G, Wan Ngah WZ
    Cell Mol Neurobiol, 2009 Jun;29(4):485-96.
    PMID: 19172392 DOI: 10.1007/s10571-008-9340-8
    Besides acting as potent free radical scavengers, tocopherols and tocotrienols have been known to have non-antioxidant properties such as the involvement of alpha-tocopherol (alphaT) in PKC pathway and the anti-cancer properties of gamma-tocotrienol (gammaT3). This study aims to elucidate whether protective effects shown by alphaT and gammaT3 in H(2)O(2)-induced neuron cultures have anti-apoptotic or pro-apoptotic tendency toward the initiation of neuronal apoptosis. H(2)O(2) is used to induce apoptosis in primary cerebellar neuron cultures which is attenuated by pretreatment of alphaT or gammaT3 at concentrations < or =10 microM. Similar to our previous work, gammaT3 was found to be neurotoxic at concentrations > or =100 microM, whereas alphaT showed no neurotoxicity. Cellular uptake of gammaT3 was higher than that of alphaT. Treating cells simultaneously with either gammaT3 or alphaT and with then H(2)O(2) led to higher expression of Bax and Bcl-2 than in neurons exposed to H(2)O(2) alone. Analysis of Bcl-2/Bax ratio as 'survival index' showed that both pretreatment of gammaT3 and alphaT followed by H(2)O(2) increase the 'survival index' of Bcl-2/Bax ratio compared to H(2)O(2)-treated cells, while treatment of gammaT3 alone decrease the ratio compared to unchanged Bcl2/Bax ratio of similar treatment with alphaT alone. Similar treatment of gammaT3 decreased p53 expression and activates p38 MAPK phosphorylation, whereas alphaT did not alter its expression compared to H(2)O(2)-treated cells. Treating neurons with only gammaT3 or alphaT increased the expression of Bax, Bcl-2, p53, and p38 MAPK compared to control with gammaT3 exerting stronger expression for proteins involved than alphaT. In conclusion, low doses of gammaT3 and alphaT confer neuroprotection to H(2)O(2)-treated neurons via their antioxidant mechanism but gammaT3 has stronger pro-apoptosis tendency than alphaT by activating molecules involved in the neuronal apoptotic pathway in the absence of H(2)O(2).
    Matched MeSH terms: Signal Transduction/physiology
  6. Apoptotic effects of Physalis minima L. chloroform extract in human breast carcinoma T-47D cells mediated by c-myc-, p53-, and caspase-3-dependent pathways
    Ooi KL, Tengku Muhammad TS, Lim CH, Sulaiman SF
    Integr Cancer Ther, 2010 Mar;9(1):73-83.
    PMID: 20150224 DOI: 10.1177/1534735409356443
    The chloroform extract of Physalis minima produced a significant growth inhibition against human T-47D breast carcinoma cells as compared with other extracts with an EC(50) value of 3.8 microg/mL. An analysis of cell death mechanisms indicated that the extract elicited an apoptotic cell death. mRNA expression analysis revealed the coregulation of apoptotic genes, that is, c-myc , p53, and caspase-3. The c-myc was significantly induced by the chloroform extract at the earlier phase of treatment, followed by p53 and caspase-3. Biochemical assay and ultrastructural observation displayed typical apoptotic features in the treated cells, including DNA fragmentation, blebbing and convolution of cell membrane, clumping and margination of chromatin, and production of membrane-bound apoptotic bodies. The presence of different stages of apoptotic cell death and phosphatidylserine externalization were further reconfirmed by annexin V and propidium iodide staining. Thus, the results from this study strongly suggest that the chloroform extract of P. minima induced apoptotic cell death via p53-, caspase-3-, and c-myc-dependent pathways.
    Matched MeSH terms: Signal Transduction/physiology
  7. Immunohistochemical detection of phospho-Akt, phospho-BAD, HER2 and oestrogen receptors alpha and beta in Malaysian breast cancer patients
    Seow HF, Yip WK, Loh HW, Ithnin H, Por P, Rohaizak M
    Pathol Oncol Res, 2010 Jun;16(2):239-48.
    PMID: 19882362 DOI: 10.1007/s12253-009-9216-3
    Activation of Akt signaling pathway has been documented in various human malignancies, including breast carcinoma. The objective of this study is to determine the incidence of Akt phosphorylation in breast tumours and its relationship with expression of ER-alpha, ER-beta, HER2, Ki-67 and phosphorylated Bcl-2 associated death domain (p-BAD). Immunohistochemical staining was performed to detect these molecules on 43 paraffin-embedded breast tumour tissues with commercially available antibodies. Eighteen (41.9%), 3 (7.0%), 23 (53.5%), 35 (81.4%), 21 (48.8%), 29 (67.4%), and 34 (81.0%) of breast tumours were positive for nuclear ER-alpha, nuclear ER-beta, membranous HER2, cytonuclear p-Akt (Thr308), p-Akt (Ser473), p-BAD and Ki-67, respectively. ER-alpha expression was inversely correlated with HER2 and Ki-67 (P = 0.041 and P = 0.040, respectively). The p-Akt (Ser473) was correlated with increased level of p-BAD (Ser136) (P = 0.012). No relationship of Akt phosphorylation with HER2, ER-alpha or ER-beta was found. The p-Akt (Ser473) immunoreactivity was significantly higher in stage IV than in stage I or II (P = 0.036 or P = 0.009). The higher Ki-67 and lower ER-alpha expression showed an association with patient age of <50 years (P = 0.004) and with positive nodal status (P = 0.033), respectively. Our data suggest that the Akt phosphorylation and inactivation of its downstream target, BAD may play a role in survival of breast cancer cell. This study does not support the simple model of linear HER2/PI3K/Akt pathway in breast cancer.
    Matched MeSH terms: Signal Transduction/physiology
  8. Neonatal dexamethasone exposure down-regulates GnRH expression through the GnIH pathway in female mice
    Soga T, Dalpatadu SL, Wong DW, Parhar IS
    Neuroscience, 2012 Aug 30;218:56-64.
    PMID: 22626647 DOI: 10.1016/j.neuroscience.2012.05.023
    Synthetic glucocorticoid (dexamethasone; DEX) treatment during the neonatal stage is known to affect reproductive activity. However, it is still unknown whether neonatal stress activates gonadotropin-inhibitory hormone (GnIH) synthesizing cells in the dorsomedial hypothalamus (DMH), which could have pronounced suppressive action on gonadotropin-releasing hormone (GnRH) neurons, leading to delayed pubertal onset. This study was designed to determine the effect of neonatal DEX (1.0mg/kg) exposure on reproductive maturation. Therefore, GnRH, GnIH and GnIH receptors, G-protein coupled receptors (GPR) 147 and GPR74 mRNA levels were measured using quantitative real-time PCR in female mice at postnatal (P) days 21, 30 and in estrus stage mice, aged between P45-50. DEX-treated females of P45-50 had delayed vaginal opening, and irregular estrus cycles and lower GnRH expression in the preoptic area (POA) when compared with age-matched controls. The expression levels of GPR147 and GPR74 mRNA in the POA increased significantly in DEX-treated female mice of P21 and P45-50 compared to controls. In addition, GPR147 and GPR74 mRNA expression was observed in laser captured single GnRH neurons in the POA. Although there was no difference in GnIH mRNA expression in the DMH, immunostained GnIH cell numbers in the DMH increased in DEX-treated females of P45-50 compared to controls. Taken together, the results show that the delayed pubertal onset could be due to the inhibition of GnRH gene expression after neonatal DEX treatment, which may be accounted for in part by the inhibitory signals from the up-regulated GnIH-GnIH receptor pathway to the POA.
    Matched MeSH terms: Signal Transduction/physiology
  9. Comparative aspects of kisspeptin gene regulation
    Kitahashi T, Parhar IS
    Gen Comp Endocrinol, 2013 Jan 15;181:197-202.
    PMID: 23089246 DOI: 10.1016/j.ygcen.2012.10.003
    Kisspeptin plays an important role in the onset of puberty through stimulation of gonadotropin-releasing hormone (GnRH), a master molecule of reproduction. Furthermore, the existence of multiple kisspeptins is evident in most vertebrate species. Therefore, elucidating the regulatory mechanisms of the kisspeptin genes is important to understand the functions of multiple kisspeptin forms in the brain. This review focuses on the comparative aspects of kisspeptin gene regulation with an emphasis on the role of environmental signals including gonadal steroids, photoperiods and metabolic signals. These environmental signals differently regulate the kisspeptin genes distinctively in each species. In addition, photoperiodic regulation of the kisspeptin genes alters during sexual maturational, suggesting interactions between the gonadal hormone pathway and the photoperiod pathway. Further studies of the regulatory mechanisms of kisspeptin genes especially in teleosts which possess multiple kisspeptin/kisspeptin receptor systems will help to understand the precise role of multiple kisspeptin forms in different species.
    Matched MeSH terms: Signal Transduction/physiology
  10. Dental stem cells as an alternative source for cardiac regeneration
    Xin LZ, Govindasamy V, Musa S, Abu Kasim NH
    Med Hypotheses, 2013 Oct;81(4):704-6.
    PMID: 23932760 DOI: 10.1016/j.mehy.2013.07.032
    Dental tissues contains stem cells or progenitors that have high proliferative capacity, are clonogenic in vitro and demonstrate the ability to differentiate to multiple type cells involving neurons, bone, cartilage, fat and smooth muscle. Numerous experiments have demonstrated that the multipotent stem cells are not rejected by immune system and therefore it may be possible to use these cells in allogeneic settings. In addition, these remarkable cells are easily abundantly available couple with less invasive procedure in isolating comparing to bone marrow aspiration. Here we proposed dental stem cells as candidate for cardiac regeneration based on its immature characteristic and propensity towards cardiac lineage via PI3-Kinase/Aktsignalling pathway.
    Matched MeSH terms: Signal Transduction/physiology
  11. Fulltext Interleukin-6 and intercellular cell adhesion molecule-1 expression remains elevated in revived live endothelial cells following spaceflight
    Muid S, Froemming GR, Ali AM, Nawawi H
    Malays J Pathol, 2013 Dec;35(2):165-76.
    PMID: 24362480 MyJurnal
    The effects of spaceflight on cardiovascular health are not necessarily seen immediately after astronauts have returned but can be delayed. It is important to investigate the long term effects of spaceflight on protein and gene expression of inflammation and endothelial activation as a predictor for the development of atherosclerosis and potential cardiovascular problems. The objectives of this study were to investigate the (a) protein and gene expression of inflammation and endothelial activation, (b) expression of nuclear factor kappa B (NFκB), signal transducer and activator of transcription-3 (STAT-3) and endothelial nitric oxide synthase (eNOS) in human umbilical vein endothelial cells (HUVEC) 3 months post-space flight travel compared to ground controls. HUVEC cultured on microcarriers in fluid processing apparatus were flown to the International Space Station (ISS) by the Soyuz TMA-11 rocket. After landing, the cells were detached from microcarriers and recultured in T-25 cm(2) culture flasks (Revived HUVEC). Soluble protein expression of IL-6, TNF-α, ICAM-1, VCAM-1 and e-selectin were measured by ELISA. Gene expression of these markers and in addition NFκB, STAT-3 and eNOS were measured. Spaceflight induced IL-6 and ICAM-1 remain elevated even after 3 months post spaceflight travel and this is mediated via STAT-3 pathway. The downregulation of eNOS expression in revived HUVEC cells suggests a reduced protection of the cells and the surrounding vessels against future insults that may lead to atherosclerosis. It would be crucial to explore preventive measures, in relation to atherosclerosis and its related complications.
    Matched MeSH terms: Signal Transduction/physiology*
  12. Dietary repletion with ω3 fatty acid or with COX inhibition reverses cognitive effects in F3 ω3 fatty-acid-deficient mice
    Hafandi A, Begg DP, Premaratna SD, Sinclair AJ, Jois M, Weisinger RS
    Comp. Med., 2014 Apr;64(2):106-9.
    PMID: 24674584
    Dietary deficiency of ω3 fatty acid during development leads to impaired cognitive function. However, the effects of multiple generations of ω3 fatty-acid deficiency on cognitive impairment remain unclear. In addition, we sought to test the hypothesis that the cognitive impairments of ω3 fatty-acid-deficient mice are mediated through the arachidonic acid-cyclooxygenase (COX) pathway. To address these issues, C57BL/6J mice were bred for 3 generations and fed diets either deficient (DEF) or sufficient (SUF) in ω3 fatty acids. At postnatal day 21, the F3 offspring remained on the dam's diet or were switched to the opposite diet, creating 4 groups. In addition, 2 groups that remained on the dam's diet were treated with a COX inhibitor. At 19 wk of age, spatial-recognition memory was tested on a Y-maze. Results showed that 16 wk of SUF diet reversed the cognitive impairment of F3 DEF mice. However, 16 wk of ω3 fatty-acid-deficient diet impaired the cognitive performance of the F3 SUF mice, which did not differ from that of the F3 DEF mice. These findings suggest that the cognitive deficits after multigenerational maintenance on ω3 fatty-acid-deficient diet are not any greater than are those after deficiency during a single generation. In addition, treatment with a COX inhibitor prevented spatial-recognition deficits in F3 DEF mice. Therefore, cognitive impairment due to dietary ω3 fatty-acid deficiency appears to be mediated by the arachidonic acid-COX pathway and can be prevented by 16 wk of dietary repletion with ω3 fatty acids or COX inhibition.
    Matched MeSH terms: Signal Transduction/physiology*
  13. Crosstalk between insulin and Toll-like receptor signaling pathways in the central nervous system
    Hemmati F, Ghasemi R, Mohamed Ibrahim N, Dargahi L, Mohamed Z, Raymond AA, et al.
    Mol Neurobiol, 2014 Dec;50(3):797-810.
    PMID: 24464263 DOI: 10.1007/s12035-013-8631-3
    Neuroinflammation is known as a key player in a variety of neurodegenerative and/or neurological diseases. Brain Toll-like receptors (TLRs) are leading elements in the initiation and progression of neuroinflammation and the development of different neuronal diseases. Furthermore, TLR activation is one of the most important elements in the induction of insulin resistance in different organs such as the central nervous system. Involvement of insulin signaling dysregulation and insulin resistance are also shown to contribute to the pathology of neurological diseases. Considering the important roles of TLRs in neuroinflammation and central insulin resistance and the effects of these processes in the initiation and progression of neurodegenerative and neurological diseases, here we are going to review current knowledge about the potential crosstalk between TLRs and insulin signaling pathways in neuroinflammatory disorders of the central nervous system.
    Matched MeSH terms: Signal Transduction/physiology*
  14. Wnt5A regulates ABCB1 expression in multidrug-resistant cancer cells through activation of the non-canonical PKA/β-catenin pathway
    Hung TH, Hsu SC, Cheng CY, Choo KB, Tseng CP, Chen TC, et al.
    Oncotarget, 2014 Dec 15;5(23):12273-90.
    PMID: 25401518
    Multidrug resistance in cancer cells arises from altered drug permeability of the cell. We previously reported activation of the Wnt pathway in ABCB1-overexpressed human uterus sarcoma drug-resistant MES-SA/Dx5 cells through active β-catenin and associated transactivation activities, and upregulation of Wnt-targeting genes. In this study, Wnt5A was found to be significantly upregulated in MES-SA/Dx5 and MCF7/ADR2 cells, suggesting an important role for the Wnt5A signaling pathway in cancer drug resistance. Higher cAMP response elements and Tcf/Lef transcription activities were shown in the drug-resistant cancer cells. However, expression of Wnt target genes and CRE activities was downregulated in Wnt5A shRNA stably-transfected MES-SA/Dx5 cells. Cell viability of the drug-resistant cancer cells was also reduced by doxorubicin treatment and Wnt5A shRNA transfection, or by Wnt5A depletion. The in vitro data were supported by immunohistochemical analysis of 24 paired breast cancer biopsies obtained pre- and post-chemotherapeutic treatment. Wnt5A, VEGF and/or ABCB1 were significantly overexpressed after treatment, consistent with clinical chemoresistance. Taken together, the Wnt5A signaling pathway was shown to contribute to regulating the drug-resistance protein ABCB1 and β-catenin-related genes in antagonizing the toxic effects of doxorubicin in the MDR cell lines and in clinical breast cancer samples.
    Matched MeSH terms: Signal Transduction/physiology
  15. Fulltext Labrenzia sp. BM1: a quorum quenching bacterium that degrades N-acyl homoserine lactones via lactonase activity
    Ghani NA, Norizan SN, Chan XY, Yin WF, Chan KG
    Sensors (Basel), 2014;14(7):11760-9.
    PMID: 24995373 DOI: 10.3390/s140711760
    We report the degradation of quorum sensing N-acylhomoserine lactone molecules by a bacterium isolated from a Malaysian marine water sample. MALDI-TOF and phylogenetic analysis indicated this isolate BM1 clustered closely to Labrenzia sp. The quorum quenching activity of this isolate was confirmed by using a series of bioassays and rapid resolution liquid chromatography analysis. Labrenzia sp. degraded a wide range of N-acylhomoserine lactones namely N-(3-hexanoyl)-L-homoserine lactone (C6-HSL), N-(3-oxohexanoyl)-L-homoserine lactone (3-oxo-C6-HSL) and N-(3-hydroxyhexanoyl)-L-homoserine lactone (3-hydroxy-C6-HSL). Re-lactonisation bioassays confirmed Labrenzia sp. BM1 degraded these signalling molecules efficiently via lactonase activity. To the best of our knowledge, this is the first documentation of a Labrenzia sp. capable of degrading N-acylhomoserine lactones and confirmation of its lactonase-based mechanism of action.
    Matched MeSH terms: Signal Transduction/physiology*
  16. Down-regulation of LPA receptor 5 contributes to aberrant LPA signalling in EBV-associated nasopharyngeal carcinoma
    Yap LF, Velapasamy S, Lee HM, Thavaraj S, Rajadurai P, Wei W, et al.
    J Pathol, 2015 Feb;235(3):456-65.
    PMID: 25294670 DOI: 10.1002/path.4460
    Undifferentiated nasopharyngeal carcinoma (NPC) is a highly metastatic disease that is consistently associated with Epstein-Barr virus (EBV) infection. In this study, we have investigated the contribution of lysophosphatidic acid (LPA) signalling to the pathogenesis of NPC. Here we demonstrate two distinct functional roles for LPA in NPC. First, we show that LPA enhances the migration of NPC cells and second, that it can inhibit the activity of EBV-specific cytotoxic T cells. Focusing on the first of these phenotypes, we show that one of the LPA receptors, LPA receptor 5 (LPAR5), is down-regulated in primary NPC tissues and that this down-regulation promotes the LPA-induced migration of NPC cell lines. Furthermore, we found that EBV infection or ectopic expression of the EBV-encoded LMP2A was sufficient to down-regulate LPAR5 in NPC cell lines. Our data point to a central role for EBV in mediating the oncogenic effects of LPA in NPC and identify LPA signalling as a potential therapeutic target in this disease.
    Matched MeSH terms: Signal Transduction/physiology*
  17. Fulltext Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans
    Yan EB, Frugier T, Lim CK, Heng B, Sundaram G, Tan M, et al.
    J Neuroinflammation, 2015 May 30;12:110.
    PMID: 26025142 DOI: 10.1186/s12974-015-0328-2
    During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims. Acute QUIN levels were further correlated with outcome scores to explore its prognostic value in TBI recovery.

    METHODS: Twenty-eight patients with severe TBI (GCS ≤ 8, three patients had initial GCS = 9-10, but rapidly deteriorated to ≤8) were recruited. CSF was collected from admission to day 5 post-injury. TRP, kynurenine (KYN), kynurenic acid (KYNA), QUIN, anthranilic acid (AA) and 3-hydroxyanthranilic acid (3HAA) were measured in CSF. The Glasgow Outcome Scale Extended (GOSE) score was assessed at 6 months post-TBI. Post-mortem brains were obtained from the Australian Neurotrauma Tissue and Fluid Bank and used in qPCR for quantitating expression of KP enzymes (indoleamine 2,3-dioxygenase-1 (IDO1), kynurenase (KYNase), kynurenine amino transferase-II (KAT-II), kynurenine 3-monooxygenase (KMO), 3-hydroxyanthranilic acid oxygenase (3HAO) and quinolinic acid phosphoribosyl transferase (QPRTase) and IDO1 immunohistochemistry.

    RESULTS: In CSF, KYN, KYNA and QUIN were elevated whereas TRP, AA and 3HAA remained unchanged. The ratios of QUIN:KYN, QUIN:KYNA, KYNA:KYN and 3HAA:AA revealed that QUIN levels were significantly higher than KYN and KYNA, supporting increased neurotoxicity. Amplified IDO1 and KYNase mRNA expression was demonstrated on post-mortem brains, and enhanced IDO1 protein coincided with overt tissue damage. QUIN levels in CSF were significantly higher in patients with unfavourable outcome and inversely correlated with GOSE scores.

    CONCLUSION: TBI induced a striking activation of the KP pathway with sustained increase of QUIN. The exceeding production of QUIN together with increased IDO1 activation and mRNA expression in brain-injured areas suggests that TBI selectively induces a robust stimulation of the neurotoxic branch of the KP pathway. QUIN's detrimental roles are supported by its association to adverse outcome potentially becoming an early prognostic factor post-TBI.

    Matched MeSH terms: Signal Transduction/physiology*
  18. Glycogen synthase kinase-3 beta (GSK-3β) signaling: Implications for Parkinson's disease
    Golpich M, Amini E, Hemmati F, Ibrahim NM, Rahmani B, Mohamed Z, et al.
    Pharmacol Res, 2015 Jul;97:16-26.
    PMID: 25829335 DOI: 10.1016/j.phrs.2015.03.010
    Glycogen synthase kinase 3 (GSK-3) dysregulation plays an important role in the pathogenesis of numerous disorders, affecting the central nervous system (CNS) encompassing both neuroinflammation and neurodegenerative diseases. Several lines of evidence have illustrated a key role of the GSK-3 and its cellular and molecular signaling cascades in the control of neuroinflammation. Glycogen synthase kinase 3 beta (GSK-3β), one of the GSK-3 isomers, plays a major role in neuronal apoptosis and its inhibition decreases expression of alpha-Synuclein (α-Synuclein), which make this kinase an attractive therapeutic target for neurodegenerative disorders. Parkinson's disease (PD) is a chronic neurodegenerative movement disorder characterized by the progressive and massive loss of dopaminergic neurons by neuronal apoptosis in the substantia nigra pars compacta and depletion of dopamine in the striatum, which lead to pathological and clinical abnormalities. Thus, understanding the role of GSK-3β in PD will enhance our knowledge of the basic mechanisms underlying the pathogenesis of this disorder and facilitate the identification of new therapeutic avenues. In recent years, GSK-3β has been shown to play essential roles in modulating a variety of cellular functions, which have prompted efforts to develop GSK-3β inhibitors as therapeutics. In this review, we summarize GSK-3 signaling pathways and its association with neuroinflammation. Moreover, we highlight the interaction between GSK-3β and several cellular processes involved in the pathogenesis of PD, including the accumulation of α-Synuclein aggregates, oxidative stress and mitochondrial dysfunction. Finally, we discuss about GSK-3β inhibitors as a potential therapeutic strategy in PD.
    Matched MeSH terms: Signal Transduction/physiology*
  19. Inhibition of activin A signalling in a mouse model of pre-eclampsia
    Lim R, Adhikari S, Gurusinghe S, Leaw B, Acharya R, Rahman R, et al.
    Placenta, 2015 Aug;36(8):926-31.
    PMID: 26138362 DOI: 10.1016/j.placenta.2015.06.004
    Pre-eclampsia remains a major cause of maternal and fetal morbidity and mortality. Despite intensive research over the last 50 years, significant therapeutic advances have yet to be realised. We recently reported on the role of activin A in the pathophysiology of pre-eclampsia, whereby a pre-eclampsia-like disease state was induced in pregnant mice through activin A infusion. Using the same animal model, the effects of inhibiting activin A signalling on this pre-eclampsia-like disease state have now been assessed with low molecular weight compounds structurally related to activin-receptor-like kinase (ALK) inhibitors.
    Matched MeSH terms: Signal Transduction/physiology*
  20. Fulltext Osteoimmunology: Major and Costimulatory Pathway Expression Associated with Chronic Inflammatory Induced Bone Loss
    Crotti TN, Dharmapatni AA, Alias E, Haynes DR
    J Immunol Res, 2015;2015:281287.
    PMID: 26064999 DOI: 10.1155/2015/281287
    The field of osteoimmunology has emerged in response to the range of evidences demonstrating the close interrelationship between the immune system and bone metabolism. This is pertinent to immune-mediated diseases, such as rheumatoid arthritis and periodontal disease, where there are chronic inflammation and local bone erosion. Periprosthetic osteolysis is another example of chronic inflammation with associated osteolysis. This may also involve immune mediation when occurring in a patient with rheumatoid arthritis (RA). Similarities in the regulation and mechanisms of bone loss are likely to be related to the inflammatory cytokines expressed in these diseases. This review highlights the role of immune-related factors influencing bone loss particularly in diseases of chronic inflammation where there is associated localized bone loss. The importance of the balance of the RANKL-RANK-OPG axis is discussed as well as the more recently appreciated role that receptors and adaptor proteins involved in the immunoreceptor tyrosine-based activation motif (ITAM) signaling pathway play. Although animal models are briefly discussed, the focus of this review is on the expression of ITAM associated molecules in relation to inflammation induced localized bone loss in RA, chronic periodontitis, and periprosthetic osteolysis, with an emphasis on the soluble and membrane bound factor osteoclast-associated receptor (OSCAR).
    Matched MeSH terms: Signal Transduction/physiology*
Related Terms
Filters
Contact Us

Please provide feedback to Administrator (afdal@afpm.org.my)

External Links