Soumen Paul - Academia.edu (original) (raw)
Papers by Soumen Paul
Scientific reports, 2015
Atypical Protein Kinase C zeta (PKCζ) forms Partitioning-defective (PAR) polarity complex for api... more Atypical Protein Kinase C zeta (PKCζ) forms Partitioning-defective (PAR) polarity complex for apico-basal distribution of membrane proteins essential to maintain normal cellular junctional complexes and tissue homeostasis. Consistently, tumor suppressive role of PKCζ has been established for multiple human cancers. However, recent studies also indicate pro-oncogenic function of PKCζ without firm understanding of detailed molecular mechanism. Here we report a possible mechanism of oncogenic PKCζ signaling in the context of breast cancer. We observed that depletion of PKCζ promotes epithelial morphology in mesenchymal-like MDA-MB-231 cells. The induction of epithelial morphology is associated with significant upregulation of adherens junction (AJ) protein E-cadherin and tight junction (TJ) protein Zonula Occludens-1 (ZO-1). Functionally, depletion of PKCζ significantly inhibits invasion and metastatic progression. Consistently, we observed higher expression and activation of PKCζ sign...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2014
NeuroImage, 2014
Adenosine A 1 receptors (A1Rs) are implied in the modulation of neuroinflammation. Activation of ... more Adenosine A 1 receptors (A1Rs) are implied in the modulation of neuroinflammation. Activation of cerebral A1Rs acts as a brake on the microglial response after traumatic brain injury and has neuroprotective properties in animal models of Parkinson's disease and multiple sclerosis. Neuroinflammatory processes in turn may affect the expression of A1Rs, but the available data is limited and inconsistent. Here, we applied an animal model of encephalitis to assess how neuroinflammation affects the expression of A1Rs. Two groups of animals were studied: Infected rats (n = 7) were intranasally inoculated with herpes simplex virus-1 (HSV-1, 1 × 10 7 plaque forming units), sham-infected rats (n = 6) received only phosphate-buffered saline. Six or seven days later, microPET scans (60 min with arterial blood sampling) were made using the tracer 8-dicyclopropyl-1-11 Cmethyl-3-propyl-xanthine ( 11 C-MPDX). Tracer clearance from plasma and partition coefficient (K 1 /k 2 estimated from a 2-tissue compartment model fit) were not significantly altered after virus infection. PET tracer distribution volume calculated from a Logan plot was significantly increased in the hippocampus (+ 37%) and medulla (+27%) of virus infected rats. Tracer binding potential (k 3 /k 4 estimated from the model fit) was significantly increased in the cerebellum (+87%) and the medulla (+148%) which may indicate increased A1R expression. This was confirmed by immunohistochemical analysis showing a strong increase of A1R immunoreactivity in the cerebellum of HSV-1-infected rats. Both the quantitative PET data and immunohistochemical analysis indicate that A1Rs are upregulated in brain areas where active virus is present.
Journal of Nuclear Medicine, 2011
Activation of adenosine A 1 receptors (A 1 R) in the brain causes sedation, reduces anxiety, inhi... more Activation of adenosine A 1 receptors (A 1 R) in the brain causes sedation, reduces anxiety, inhibits seizures, and promotes neuroprotection. Cerebral A 1 R can be visualized using 8dicyclopropylmethyl-1-11 C-methyl-3-propyl-xanthine ( 11 C-MPDX) and PET. This study aims to test whether 11 C-MPDX can be used for quantitative studies of cerebral A 1 R in rodents. Methods: 11 C-MPDX was injected (intravenously) into isoflurane-anesthetized male Wistar rats (300 g). A dynamic scan of the central nervous system was obtained, using a small-animal PET camera. A cannula in a femoral artery was used for blood sampling. Three groups of animals were studied: group 1, controls (saline-treated); group 2, animals pretreated with the A 1 R antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 1 mg, intraperitoneally); and group 3, animals pretreated (intraperitoneally) with a 20% solution of ethanol in saline (2 mL) plus the adenosine kinase inhibitor 4amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d] pyrimidine dihydrochloride (ABT-702) (1 mg). DPCPX is known to occupy cerebral A 1 R, whereas ethanol and ABT-702 increase extracellular adenosine. Results: In groups 1 and 3, the brain was clearly visualized. High uptake of 11 C-MPDX was noted in striatum, hippocampus, and cerebellum. In group 2, tracer uptake was strongly suppressed and regional differences were abolished. The treatment of group 3 resulted in an unexpected 40%-45% increase of the cerebral uptake of radioactivity as indicated by increases of PET standardized uptake value, distribution volume from Logan plot, nondisplaceable binding potential from 2tissue-compartment model fit, and standardized uptake value from a biodistribution study performed after the PET scan. The partition coefficient of the tracer (K 1 /k 2 from the model fit) was not altered under the study conditions. Conclusion: 11 C-MPDX shows a regional distribution in rat brain consistent with binding to A 1 R. Tracer binding is blocked by the selective A 1 R antagonist DPCPX. Pretreatment of animals with ethanol and adenosine kinase inhibitor increases 11 C-MPDX uptake. This increase may reflect an increased availability of A 1 R after acute exposure to ethanol.
Journal of Nuclear Medicine, 2014
Adenosine A 1 receptors (A 1 Rs) in human and rodent brains can be visualized with the radioligan... more Adenosine A 1 receptors (A 1 Rs) in human and rodent brains can be visualized with the radioligand 8-dicyclopropylmethyl-1-11 C-methyl-3-propylxanthine ( 11 C-MPDX) and PET. Here we investigated whether A 1 R occupancy by nonradioactive agonists and antagonists can be assessed with this technique. Methods: Small-animal PET scans with arterial blood sampling were obtained for 4 groups of isoflurane-anesthetized Wistar rats: controls (n 5 7); pretreated with a centrally active A 1 R agonist, N 6 -cyclopentyladenosine (CPA; 0.25 mg/kg intraperitoneally; dissociation constant, 0.48 nM; n 5 7); pretreated with a moderate dose of caffeine (antagonist for A 1 Rs and adenosine A 2A receptors; 4 mg/kg intraperitoneally; dissociation constant, 11 mM; n 5 6); and pretreated with a high dose of caffeine (40 mg/kg intraperitoneally; n 5 6). Results: The administration of CPA resulted in a strong reduction (.50%) in the heart rate, and caffeine administration resulted in a small increase (10%-15%). A caffeine dose of 4 mg/kg (n 5 6) resulted in 65.9% A 1 R occupancy, and a dose of 40 mg/kg (n 5 6) resulted in 98.5% occupancy (calculated from a modified Lassen plot). However, the administration of CPA resulted in an increase in 11 C-MPDX binding in the brain. Conclusion: Small-animal PET with 11 C-MPDX can be used to assess antagonist but not agonist binding at A 1 Rs. Changes in tracer uptake after the administration of CPA resembled previously reported changes induced by treatment of rats with ethanol and an adenosine kinase inhibitor (ABT702). Thus, the administration of an exogenous agonist or increasing the level of an endogenous agonist have similar effects. Agonists and antagonists may bind to different sites on the A 1 R protein having allosteric interactions.
![Research paper thumbnail of Development of [ 18 F]-Labeled Pyrazolo[4,3- e ]-1,2,4- triazolo[1,5- c ]pyrimidine (SCH442416) Analogs for the Imaging of Cerebral Adenosine A 2A Receptors with Positron Emission Tomography](https://attachments.academia-assets.com/40206527/thumbnails/1.jpg)
](Journal of Medicinal Chemistry, 2014
Cerebral adenosine A 2A receptors (A 2A Rs) are attractive therapeutic targets for the treatment ... more Cerebral adenosine A 2A receptors (A 2A Rs) are attractive therapeutic targets for the treatment of neurodegenerative and psychiatric disorders. We developed high affinity and selective compound 8 (SCH442416) analogs as in vivo probes for A 2A Rs using PET. We observed the A 2A R-mediated accumulation of [ 18 F]fluoropropyl ([ 18 F]-10b) and [ 18 F]fluoroethyl ([ 18 F]-10a) derivatives of 8 in the brain. The striatum was clearly visualized in PET and in vitro autoradiography images of control animals and was no longer visible after pretreatment with the A 2A R subtype-selective antagonist KW6002. In vitro and in vivo metabolite analyses indicated the presence of hydrophilic (radio)metabolite(s), which are not expected to cross the blood-brainbarrier. [ 18 F]-10b and [ 18 F]-10a showed comparable striatum-to-cerebellum ratios (4.6 at 25 and 37 min post injection, respectively) and reversible binding in rat brains. We concluded that these compounds performed equally well, but their kinetics were slightly different. These molecules are potential tools for mapping cerebral A 2A Rs with PET.
Scientific reports, 2015
Atypical Protein Kinase C zeta (PKCζ) forms Partitioning-defective (PAR) polarity complex for api... more Atypical Protein Kinase C zeta (PKCζ) forms Partitioning-defective (PAR) polarity complex for apico-basal distribution of membrane proteins essential to maintain normal cellular junctional complexes and tissue homeostasis. Consistently, tumor suppressive role of PKCζ has been established for multiple human cancers. However, recent studies also indicate pro-oncogenic function of PKCζ without firm understanding of detailed molecular mechanism. Here we report a possible mechanism of oncogenic PKCζ signaling in the context of breast cancer. We observed that depletion of PKCζ promotes epithelial morphology in mesenchymal-like MDA-MB-231 cells. The induction of epithelial morphology is associated with significant upregulation of adherens junction (AJ) protein E-cadherin and tight junction (TJ) protein Zonula Occludens-1 (ZO-1). Functionally, depletion of PKCζ significantly inhibits invasion and metastatic progression. Consistently, we observed higher expression and activation of PKCζ sign...
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 2014
NeuroImage, 2014
Adenosine A 1 receptors (A1Rs) are implied in the modulation of neuroinflammation. Activation of ... more Adenosine A 1 receptors (A1Rs) are implied in the modulation of neuroinflammation. Activation of cerebral A1Rs acts as a brake on the microglial response after traumatic brain injury and has neuroprotective properties in animal models of Parkinson's disease and multiple sclerosis. Neuroinflammatory processes in turn may affect the expression of A1Rs, but the available data is limited and inconsistent. Here, we applied an animal model of encephalitis to assess how neuroinflammation affects the expression of A1Rs. Two groups of animals were studied: Infected rats (n = 7) were intranasally inoculated with herpes simplex virus-1 (HSV-1, 1 × 10 7 plaque forming units), sham-infected rats (n = 6) received only phosphate-buffered saline. Six or seven days later, microPET scans (60 min with arterial blood sampling) were made using the tracer 8-dicyclopropyl-1-11 Cmethyl-3-propyl-xanthine ( 11 C-MPDX). Tracer clearance from plasma and partition coefficient (K 1 /k 2 estimated from a 2-tissue compartment model fit) were not significantly altered after virus infection. PET tracer distribution volume calculated from a Logan plot was significantly increased in the hippocampus (+ 37%) and medulla (+27%) of virus infected rats. Tracer binding potential (k 3 /k 4 estimated from the model fit) was significantly increased in the cerebellum (+87%) and the medulla (+148%) which may indicate increased A1R expression. This was confirmed by immunohistochemical analysis showing a strong increase of A1R immunoreactivity in the cerebellum of HSV-1-infected rats. Both the quantitative PET data and immunohistochemical analysis indicate that A1Rs are upregulated in brain areas where active virus is present.
Journal of Nuclear Medicine, 2011
Activation of adenosine A 1 receptors (A 1 R) in the brain causes sedation, reduces anxiety, inhi... more Activation of adenosine A 1 receptors (A 1 R) in the brain causes sedation, reduces anxiety, inhibits seizures, and promotes neuroprotection. Cerebral A 1 R can be visualized using 8dicyclopropylmethyl-1-11 C-methyl-3-propyl-xanthine ( 11 C-MPDX) and PET. This study aims to test whether 11 C-MPDX can be used for quantitative studies of cerebral A 1 R in rodents. Methods: 11 C-MPDX was injected (intravenously) into isoflurane-anesthetized male Wistar rats (300 g). A dynamic scan of the central nervous system was obtained, using a small-animal PET camera. A cannula in a femoral artery was used for blood sampling. Three groups of animals were studied: group 1, controls (saline-treated); group 2, animals pretreated with the A 1 R antagonist 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX, 1 mg, intraperitoneally); and group 3, animals pretreated (intraperitoneally) with a 20% solution of ethanol in saline (2 mL) plus the adenosine kinase inhibitor 4amino-5-(3-bromophenyl)-7-(6-morpholino-pyridin-3-yl)pyrido [2,3-d] pyrimidine dihydrochloride (ABT-702) (1 mg). DPCPX is known to occupy cerebral A 1 R, whereas ethanol and ABT-702 increase extracellular adenosine. Results: In groups 1 and 3, the brain was clearly visualized. High uptake of 11 C-MPDX was noted in striatum, hippocampus, and cerebellum. In group 2, tracer uptake was strongly suppressed and regional differences were abolished. The treatment of group 3 resulted in an unexpected 40%-45% increase of the cerebral uptake of radioactivity as indicated by increases of PET standardized uptake value, distribution volume from Logan plot, nondisplaceable binding potential from 2tissue-compartment model fit, and standardized uptake value from a biodistribution study performed after the PET scan. The partition coefficient of the tracer (K 1 /k 2 from the model fit) was not altered under the study conditions. Conclusion: 11 C-MPDX shows a regional distribution in rat brain consistent with binding to A 1 R. Tracer binding is blocked by the selective A 1 R antagonist DPCPX. Pretreatment of animals with ethanol and adenosine kinase inhibitor increases 11 C-MPDX uptake. This increase may reflect an increased availability of A 1 R after acute exposure to ethanol.
Journal of Nuclear Medicine, 2014
Adenosine A 1 receptors (A 1 Rs) in human and rodent brains can be visualized with the radioligan... more Adenosine A 1 receptors (A 1 Rs) in human and rodent brains can be visualized with the radioligand 8-dicyclopropylmethyl-1-11 C-methyl-3-propylxanthine ( 11 C-MPDX) and PET. Here we investigated whether A 1 R occupancy by nonradioactive agonists and antagonists can be assessed with this technique. Methods: Small-animal PET scans with arterial blood sampling were obtained for 4 groups of isoflurane-anesthetized Wistar rats: controls (n 5 7); pretreated with a centrally active A 1 R agonist, N 6 -cyclopentyladenosine (CPA; 0.25 mg/kg intraperitoneally; dissociation constant, 0.48 nM; n 5 7); pretreated with a moderate dose of caffeine (antagonist for A 1 Rs and adenosine A 2A receptors; 4 mg/kg intraperitoneally; dissociation constant, 11 mM; n 5 6); and pretreated with a high dose of caffeine (40 mg/kg intraperitoneally; n 5 6). Results: The administration of CPA resulted in a strong reduction (.50%) in the heart rate, and caffeine administration resulted in a small increase (10%-15%). A caffeine dose of 4 mg/kg (n 5 6) resulted in 65.9% A 1 R occupancy, and a dose of 40 mg/kg (n 5 6) resulted in 98.5% occupancy (calculated from a modified Lassen plot). However, the administration of CPA resulted in an increase in 11 C-MPDX binding in the brain. Conclusion: Small-animal PET with 11 C-MPDX can be used to assess antagonist but not agonist binding at A 1 Rs. Changes in tracer uptake after the administration of CPA resembled previously reported changes induced by treatment of rats with ethanol and an adenosine kinase inhibitor (ABT702). Thus, the administration of an exogenous agonist or increasing the level of an endogenous agonist have similar effects. Agonists and antagonists may bind to different sites on the A 1 R protein having allosteric interactions.
Journal of Medicinal Chemistry, 2014
Cerebral adenosine A 2A receptors (A 2A Rs) are attractive therapeutic targets for the treatment ... more Cerebral adenosine A 2A receptors (A 2A Rs) are attractive therapeutic targets for the treatment of neurodegenerative and psychiatric disorders. We developed high affinity and selective compound 8 (SCH442416) analogs as in vivo probes for A 2A Rs using PET. We observed the A 2A R-mediated accumulation of [ 18 F]fluoropropyl ([ 18 F]-10b) and [ 18 F]fluoroethyl ([ 18 F]-10a) derivatives of 8 in the brain. The striatum was clearly visualized in PET and in vitro autoradiography images of control animals and was no longer visible after pretreatment with the A 2A R subtype-selective antagonist KW6002. In vitro and in vivo metabolite analyses indicated the presence of hydrophilic (radio)metabolite(s), which are not expected to cross the blood-brainbarrier. [ 18 F]-10b and [ 18 F]-10a showed comparable striatum-to-cerebellum ratios (4.6 at 25 and 37 min post injection, respectively) and reversible binding in rat brains. We concluded that these compounds performed equally well, but their kinetics were slightly different. These molecules are potential tools for mapping cerebral A 2A Rs with PET.