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Tang F.R.,National University of Singapore | Loke W.K.,Defence Medical and Environmental Research Institute
International Journal of Radiation Biology | Year: 2015

Purposes: To review research progress on the molecular mechanisms of low dose ionizing radiation (LDIR)-induced hormesis, adaptive responses, radioresistance, bystander effects, and genomic instability in order to provide clues for therapeutic approaches to enhance biopositive effects (defined as radiation-induced beneficial effects to the organism), and control bionegative effects (defined as radiation-induced harmful effects to the organism) and related human diseases. Conclusions: Experimental studies have indicated that Ataxia telangiectasia-mutated (ATM), extracellular signal-related kinase (ERK), mitogen-activated protein kinase (MAPK), phospho-c-Jun NH2-terminal kinase (JNK) and protein 53 (P53)-related signal transduction pathways may be involved in LDIR-induced hormesis; MAPK, P53 may be important for adaptive response; ATM, cyclooxygenase-2 (COX-2), ERK, JNK, reactive oxygen species (ROS), P53 for radioresistance; COX-2, ERK, MAPK, ROS, tumor necrosis factor receptor alpha (TNFα) for LDIR-induced bystander effect; whereas ATM, ERK, MAPK, P53, ROS, TNFα-related signal transduction pathways are involved in LDIR-induced genomic instability. These results suggest that different manifestations of LDIR-induced cellular responses may have different signal transduction pathways. On the other hand, LDIR-induced different responses may also share the same signal transduction pathways. For instance, P53 has been involved in LDIR-induced hormesis, adaptive response, radioresistance and genomic instability. Current data therefore suggest that caution should be taken when designing therapeutic approaches using LDIR to induce beneficial effects in humans. © 2014 Informa UK, Ltd.


Puneet P.,National University of Singapore | Yap C.T.,National University of Singapore | Wong L.,National University of Singapore | Yulin L.,National University of Singapore | And 6 more authors.
Science | Year: 2010

During sepsis, activation of phagocytes leads to the overproduction of proinflammatory cytokines, causing systemic inflammation. Despite substantial information regarding the underlying molecular mechanisms that lead to sepsis, several elements in the pathway remain to be elucidated. We found that the enzyme sphingosine kinase 1 (SphK1 is up-regulated in stimulated human phagocytes and in peritoneal phagocytes of patients with severe sepsis. Blockade of SphK1 inhibited phagocyte production of endotoxin-induced proinflammatory cytokines. We observed protection against sepsis in mice treated with a specific SphK1inhibitor that was enhanced by treatment with a broad-spectrum antibiotic. These results demonstrated a critical role for SphK1in endotoxin signaling and sepsis-induced inflammatory responses and suggest that inhibition of SphK1is a potential therapy for septic shock.


Gao L.,National University of Singapore | Uttamchandani M.,National University of Singapore | Uttamchandani M.,Defence Medical and Environmental Research Institute | Yao S.Q.,National University of Singapore
Chemical Communications | Year: 2012

A library of 176 human phosphotyrosine-containing peptides was used to establish cell lysate binding profiles in a two colour microarray format. The resulting hits led to the pull-down and identification of biomarkers associated with cancer states. © 2012 The Royal Society of Chemistry.


Koh S.X.T.,National University of Singapore | Lee J.K.W.,National University of Singapore | Lee J.K.W.,Defence Medical and Environmental Research Institute | Lee J.K.W.,Nanyang Technological University
Sports Medicine | Year: 2014

Background: S100B level in the blood has been used as a marker for brain damage and blood-brain barrier (BBB) disruption. Elevations of S100B levels after exercise have been observed, suggesting that the BBB may be compromised during exercise. However, an increase in S100B levels may be confounded by other variables. Objectives: The primary objective of this review was to compile findings on the relationship between S100B and exercise in order to determine if this protein is a valid marker for BBB disruptions during exercise. The secondary objective was to consolidate known factors causing S100B increases that may give rise to inaccurate interpretations of S100B levels. Data Sources and Study Selection: PubMed, Web of Science and ScienceDirect were searched for relevant studies up to January 2013, in which S100B measurements were taken after a bout of exercise. Animal studies were excluded. Variables of interest such as the type of activity, exercise intensities, duration, detection methods, presence and extent of head trauma were examined and compiled. Results: This review included 23 studies; 15 (65 %) reported S100B increases after exercise, and among these, ten reported S100B increases regardless of intervention, while five reported increases in only some trials but not others. Eight (35 %) studies reported no increases in S100B levels across all trials. Most baseline S100B levels fall below 0.16 μg/L, with an increase in S100B levels of less than 0.07 μg/L following exercise. Factors that are likely to affect S100B levels include exercise intensity, and duration, presence and extent of head trauma. Several other probable factors influencing S100B elevations are muscle breakdown, level of training and oxidative stress, but current findings are still weak and inconclusive. Conclusions: Elevated S100B levels have been recorded following exercise and are mostly attributed to either an increase in BBB permeability or trauma to the head. However, even in the absence of head trauma, it appears that the BBB may be compromised following exercise, with the severity dependent on exercise intensity. © 2013 Springer International Publishing Switzerland.


Jadhav S.P.,National University of Singapore | Kamath S.P.,National University of Singapore | Choolani M.,National University of Singapore | Lu J.,Defence Medical and Environmental Research Institute | Dheen S.T.,National University of Singapore
Journal of Neurochemistry | Year: 2014

Chronic activation of microglia, the macrophages of the CNS, has been shown to enhance neuronal damage because of excessive release of proinflammatory cytokines and neurotoxic molecules in a number of neurodegenerative diseases. Recent reports showed altered microRNA (miRNA) expression in immune-mediated pathologies, thus suggesting that miRNAs modulate expression of genes involving immune responses. This study demonstrates that miRNA-200b is expressed in microglia and modulates inflammatory response of microglia by regulating mitogen-activated protein kinase pathway. miRNA-200b expression was found to be down-regulated in activated microglia in vivo (traumatic brain injury rat model) and in vitro. A luciferase assay and loss- and gain-of-function studies revealed c-Jun, the transcription factor of cJun-N terminal kinase (JNK) mitogen-activated protein kinase pathway to be the target of miR-200b. Knockdown of miR-200b in microglia increased JNK activity along with an increase in pro-inflammatory cytokines, inducible nitric oxide synthase expression and nitric oxide (NO) production. Conversely, over-expression of miRNA-200b in microglia resulted in a decrease in JNK activity, inducible nitric oxide synthase expression, NO production and migratory potential of activated microglia. Furthermore, miR-200b inhibition resulted in increased neuronal apoptosis after treatment of neuronal cells with conditioned medium obtained from microglial culture. Taken together, these results indicate that miRNA-200b modulates microglial inflammatory process including cytokine secretion, NO production, migration and neuronal survival. © 2014 International Society for Neurochemistry.

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