Publications by authors named "Suraj Pradhan"

10 Publications

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Anti-Inflammatory and Neuroprotective Effects of PGE EP4 Signaling in Models of Parkinson's Disease.

J Neuroimmune Pharmacol 2017 06 12;12(2):292-304. Epub 2016 Oct 12.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Inflammation is a ubiquitous factor accompanying normal aging and neurodegeneration, and recent studies indicate a major contribution of inducible cyclooxygenase (COX-2) and its downstream prostaglandin signaling pathways in modulating neuroinflammatory responses and neuronal function. We have previously shown that the prostaglandin PGE receptor EP4 suppresses innate immune responses in models of systemic inflammation. Here we investigated the role of the EP4 receptor in models of Parkinson's disease (PD). Systemic co-administration of the EP4 agonist ONO-AE1-329 with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) prevented loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) without significant changes in glial activation, suggesting a potent neuroprotective effect of EP4 signaling in this acute model of DA neuronal loss. Cell-specific conditional ablation of EP4 in Cd11bCre;EP4 mice exacerbated MPTP-associated glial activation and T-cell infiltration in SNpc, consistent with anti-inflammatory functions of microglial EP4 signaling. In vitro, in primary microglia stimulated with oligomeric α-synuclein, EP4 receptor activation suppressed generation of pro-inflammatory and oxidative stress factors. Taken together, these findings suggest a dual neuroprotective and anti-inflammatory mechanism of action by the EP4 receptor in models of PD.
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http://dx.doi.org/10.1007/s11481-016-9713-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5389937PMC
June 2017

Network-driven plasma proteomics expose molecular changes in the Alzheimer's brain.

Mol Neurodegener 2016 04 26;11:31. Epub 2016 Apr 26.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA, USA.

Background: Biological pathways that significantly contribute to sporadic Alzheimer's disease are largely unknown and cannot be observed directly. Cognitive symptoms appear only decades after the molecular disease onset, further complicating analyses. As a consequence, molecular research is often restricted to late-stage post-mortem studies of brain tissue. However, the disease process is expected to trigger numerous cellular signaling pathways and modulate the local and systemic environment, and resulting changes in secreted signaling molecules carry information about otherwise inaccessible pathological processes.

Results: To access this information we probed relative levels of close to 600 secreted signaling proteins from patients' blood samples using antibody microarrays and mapped disease-specific molecular networks. Using these networks as seeds we then employed independent genome and transcriptome data sets to corroborate potential pathogenic pathways.

Conclusions: We identified Growth-Differentiation Factor (GDF) signaling as a novel Alzheimer's disease-relevant pathway supported by in vivo and in vitro follow-up experiments, demonstrating the existence of a highly informative link between cellular pathology and changes in circulatory signaling proteins.
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http://dx.doi.org/10.1186/s13024-016-0095-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4845325PMC
April 2016

Suppression of inflammation with conditional deletion of the prostaglandin E2 EP2 receptor in macrophages and brain microglia.

J Neurosci 2013 Oct;33(40):16016-32

Departments of Neurology and Neurological Sciences, Molecular and Cellular Physiology, Microbiology and Immunology, and Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, Neurosciences Graduate Program, Stanford University, Stanford, California 94305, and Center for Health Sciences, SRI International, Menlo Park, California 94025.

Prostaglandin E2 (PGE2), a potent lipid signaling molecule, modulates inflammatory responses through activation of downstream G-protein coupled EP(1-4) receptors. Here, we investigated the cell-specific in vivo function of PGE2 signaling through its E-prostanoid 2 (EP2) receptor in murine innate immune responses systemically and in the CNS. In vivo, systemic administration of lipopolysaccharide (LPS) resulted in a broad induction of cytokines and chemokines in plasma that was significantly attenuated in EP2-deficient mice. Ex vivo stimulation of peritoneal macrophages with LPS elicited proinflammatory responses that were dependent on EP2 signaling and that overlapped with in vivo plasma findings, suggesting that myeloid-lineage EP2 signaling is a major effector of innate immune responses. Conditional deletion of the EP2 receptor in myeloid lineage cells in Cd11bCre;EP2(lox/lox) mice attenuated plasma inflammatory responses and transmission of systemic inflammation to the brain was inhibited, with decreased hippocampal inflammatory gene expression and cerebral cortical levels of IL-6. Conditional deletion of EP2 significantly blunted microglial and astrocytic inflammatory responses to the neurotoxin MPTP and reduced striatal dopamine turnover. Suppression of microglial EP2 signaling also increased numbers of dopaminergic (DA) neurons in the substantia nigra independent of MPTP treatment, suggesting that microglial EP2 may influence development or survival of DA neurons. Unbiased microarray analysis of microglia isolated from adult Cd11bCre;EP2(lox/lox) and control mice demonstrated a broad downregulation of inflammatory pathways with ablation of microglial EP2 receptor. Together, these data identify a cell-specific proinflammatory role for macrophage/microglial EP2 signaling in innate immune responses systemically and in brain.
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http://dx.doi.org/10.1523/JNEUROSCI.2203-13.2013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3787507PMC
October 2013

Commentary: Progressive inflammation as a contributing factor to early development of Parkinson's disease.

Exp Neurol 2013 Mar 21;241:148-55. Epub 2012 Dec 21.

Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA 94305, USA.

Parkinson's disease (PD) is a progressive neurodegenerative disorder with three cardinal features of pathology: 1. Aggregation of α-synuclein into intraneuronal structures called Lewy bodies and Lewy neurites. 2. Dysregulated immune activation in the substantia nigra (SN). 3. Degeneration of dopaminergic neurons in the nigrostriatal circuit. The largely correlative nature of evidence in humans has precluded a decisive verdict on the relationship between α-synuclein pathology, inflammation, and neuronal damage. Furthermore, it is unclear whether inflammation plays a role in the early prodromal stages of PD before neuronal damage has occurred and Parkinsonian motor symptoms become apparent. To gain insight into the interaction between the inflammatory response and the development of neuronal pathology in PD, Watson et al. characterized neuroinflammation in a wild-type α-synuclein overexpressing mouse model of prodromal PD. They demonstrate, for the first time, the existence of early and sustained microglial mediated innate inflammation that precedes damage to the nigrostriatal circuit. Additionally they observe the spread of inflammation from the striatum to the SN. This study suggests that early dysregulated inflammation may contribute to progressive nigrostriatal pathology in PD, although the initiating factor that triggers the inflammatory response remains elusive. The novel concept of an early inflammatory response in the development of PD has important implications for preventive and therapeutic strategies for PD.
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http://dx.doi.org/10.1016/j.expneurol.2012.12.008DOI Listing
March 2013

Thrombocytapheresis: managing essential thrombocythemia in a surgical patient.

Ann Thorac Surg 2011 Jul;92(1):e5-6

Department of Cardiac Surgery, The Mission Hospital, Durgapur, West Bengal, India.

A 73-year-old man presented with acute chest pain and shortness of breath suggestive of unstable angina. A detailed investigation revealed essential thrombocythemia and coronary artery pathology. With a baseline platelet count of 2,650×10(3)/μL, coronary artery bypass grafting became nearly impossible. Three therapeutic plateletpheresis procedures successfully lowered the platelet count to 367×10(3)/μL. Thereafter, surgery was performed with no complications. Although a drop and rise in platelet counts were observed postoperatively, the patient could be discharged in stable condition after 14 days. Thus, therapeutic plateletpheresis reduces platelet count rapidly in essential thrombocythemia and relieves patients of acute symptoms.
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http://dx.doi.org/10.1016/j.athoracsur.2011.02.050DOI Listing
July 2011

The prefrontal cortex modulates category selectivity in human extrastriate cortex.

J Cogn Neurosci 2011 Jan;23(1):1-10

University of California, Berkeley, USA.

Different categories of visual objects evoke distinct stimulus-evoked sensory responses in extrastriate visual cortex. Although numerous lines of evidence support a distinct representational neural architecture, the mechanisms underlying the modulation of the category selectivity by top-down influences remains uncertain. In this study, we investigate the causal role of the PFC in the modulation of evoked activity to face and scene stimuli in the extrastriate cortex. We used two experimental approaches to disrupt prefrontal cortical function-repetitive TMS to PFC in healthy participants (Experiment 1) and focal PFC lesions in stroke patients (Experiment 2). After these perturbations to normal PFC function (pre- vs. post-TMS and lesion vs. intact hemisphere), stimulus-evoked activity in extrastriate cortex exhibited less distinct category selectivity to faces and scenes. These two experiments provide convergent evidence highlighting a direct role of PFC in the top-down modulation of bottom-up visual signals.
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http://dx.doi.org/10.1162/jocn.2010.21516DOI Listing
January 2011

Meta-analysis of Drosophila circadian microarray studies identifies a novel set of rhythmically expressed genes.

PLoS Comput Biol 2007 Nov 11;3(11):e208. Epub 2007 Sep 11.

Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois, United States of America.

Five independent groups have reported microarray studies that identify dozens of rhythmically expressed genes in the fruit fly Drosophila melanogaster. Limited overlap among the lists of discovered genes makes it difficult to determine which, if any, exhibit truly rhythmic patterns of expression. We reanalyzed data from all five reports and found two sources for the observed discrepancies, the use of different expression pattern detection algorithms and underlying variation among the datasets. To improve upon the methods originally employed, we developed a new analysis that involves compilation of all existing data, application of identical transformation and standardization procedures followed by ANOVA-based statistical prescreening, and three separate classes of post hoc analysis: cross-correlation to various cycling waveforms, autocorrelation, and a previously described fast Fourier transform-based technique. Permutation-based statistical tests were used to derive significance measures for all post hoc tests. We find application of our method, most significantly the ANOVA prescreening procedure, significantly reduces the false discovery rate relative to that observed among the results of the original five reports while maintaining desirable statistical power. We identify a set of 81 cycling transcripts previously found in one or more of the original reports as well as a novel set of 133 transcripts not found in any of the original studies. We introduce a novel analysis method that compensates for variability observed among the original five Drosophila circadian array reports. Based on the statistical fidelity of our meta-analysis results, and the results of our initial validation experiments (quantitative RT-PCR), we predict many of our newly found genes to be bona fide cyclers, and suggest that they may lead to new insights into the pathways through which clock mechanisms regulate behavioral rhythms.
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http://dx.doi.org/10.1371/journal.pcbi.0030208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2098839PMC
November 2007

Clockwork orange encodes a transcriptional repressor important for circadian-clock amplitude in Drosophila.

Curr Biol 2007 Jun 7;17(12):1082-9. Epub 2007 Jun 7.

Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208, USA.

Gene transcription is a central timekeeping process in animal clocks. In Drosophila, the basic helix-loop helix (bHLH)-PAS transcription-factor heterodimer, CLOCK/CYCLE (CLK/CYC), transcriptionally activates the clock components period (per), timeless (tim), Par domain protein 1 (Pdp1), and vrille (vri), which feed back and regulate distinct features of CLK/CYC function. Microarray studies have identified numerous rhythmically expressed transcripts, some of which are potential direct CLK targets. Here we demonstrate a circadian function for one such target, a bHLH-Orange repressor, CG17100/CLOCKWORK ORANGE (CWO). cwo is rhythmically expressed, and levels are reduced in Clk mutants, suggesting that cwo is CLK activated in vivo. cwo mutants display reduced-amplitude molecular and behavioral rhythms with lengthened periods. Molecular analysis suggests that CWO acts, in part, by repressing CLK target genes. We propose that CWO acts as a transcriptional and behavioral rhythm amplifier.
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http://dx.doi.org/10.1016/j.cub.2007.05.039DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1963421PMC
June 2007

Comparative study of single- and double-patch techniques for sinus venosus atrial septal defect with partial anomalous pulmonary venous connection.

J Thorac Cardiovasc Surg 2007 Mar;133(3):656-9

Department of Pediatric Cardiac Surgery, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India.

Objective: The correction of sinus venosus atrial septal defect with a partial anomalous pulmonary venous connection to the superior vena cava has been associated with obstruction to the venous return and sinus node dysfunction. We present our follow-up of 2 approaches of managing the lesion and compare their postoperative results.

Methods: Forty patients underwent operation between March 1999 and January 2005, of whom 37 patients (aged 3-50 years) are on follow-up. These patients were divided into 2 groups: single-patch repair (group A, 18 patients) and double-patch repair (group B, 19 patients). Echocardiography and electrocardiography were performed 7 days after surgery and during the subsequent follow-up.

Results: The mean duration of follow-up was 22.56 months. There were no postoperative deaths or residual defects. Six patients in group A and 2 patients in group B had turbulence and a significant superior vena cava-right atrium pressure gradient of more than 6 mm Hg. Nine patients in group A had a significant gradient causing turbulence across the right superior pulmonary vein at the level of the patch, whereas no patients in group B had turbulence across the pulmonary vein. Four patients in group A and no patients in group B had postoperative rhythm abnormalities on late follow-up. There was no other complication.

Conclusions: Partial anomalous pulmonary venous connection can be safely managed with multiple techniques with low morbidity. The double-patch technique is technically reproducible and offers better results in terms of superior vena cava narrowing and gradient across the pulmonary vein without any increase in complications.
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http://dx.doi.org/10.1016/j.jtcvs.2006.08.076DOI Listing
March 2007