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Search Results: 1 - 10 of 90 matches for " Subbiah Pugazhenthi "
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Modulation of Apoptosis Pathways by Oxidative Stress and Autophagy in β Cells
Maorong Wang,Mia Crager,Subbiah Pugazhenthi
Experimental Diabetes Research , 2012, DOI: 10.1155/2012/647914
Abstract: Human islets isolated for transplantation are exposed to multiple stresses including oxidative stress and hypoxia resulting in significant loss of functional β cell mass. In this study we examined the modulation of apoptosis pathway genes in islets exposed to hydrogen peroxide, peroxynitrite, hypoxia, and cytokines. We observed parallel induction of pro- and antiapoptotic pathways and identified several novel genes including BFAR, CARD8, BNIP3, and CIDE-A. As BNIP3 is an inducer of autophagy, we examined this pathway in MIN6 cells, a mouse beta cell line and in human islets. Culture of MIN6 cells under low serum conditions increased the levels of several proteins in autophagy pathway, including ATG4, Beclin 1, LAMP-2, and UVRAG. Amino acid deprivation led to induction of autophagy in human islets. Preconditioning of islets with inducers of autophagy protected them from hypoxia-induced apoptosis. However, induction of autophagy during hypoxia exacerbated apoptotic cell death. ER stress led to induction of autophagy and apoptosis in β cells. Overexpression of MnSOD, an enzyme that scavenges free radicals, resulted in protection of MIN6 cells from cytokine-induced apoptosis. Ceramide, a mediator of cytokine-induced injury, reduced the active phosphorylated form of Akt and downregulated the promoter activity of the antiapoptotic gene bcl-2. Furthermore, cytokine-stimulated JNK pathway downregulated the bcl-2 promoter activity which was reversed by preincubation with SP600125, a JNK inhibitor. Our findings suggest that β cell apoptosis by multiple stresses in islets isolated for transplantation is the result of orchestrated gene expression in apoptosis pathway.
Islet Cell Biology, Regeneration, and Transplantation
A. N. Balamurugan,Velayutham Kumaravel,Subbiah Pugazhenthi,Bashoo Naziruddin
International Journal of Endocrinology , 2012, DOI: 10.1155/2012/139787
Induction of an Inflammatory Loop by Interleukin-1β and Tumor Necrosis Factor-α Involves NF-kB and STAT-1 in Differentiated Human Neuroprogenitor Cells
Subbiah Pugazhenthi, Yuji Zhang, Ron Bouchard, Gregory Mahaffey
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0069585
Abstract: Proinflammatory cytokines secreted from microglia are known to induce a secondary immune response in astrocytes leading to an inflammatory loop. Cytokines also interfere with neurogenesis during aging and in neurodegenerative diseases. The present study examined the mechanism of induction of inflammatory mediators at the transcriptional level in human differentiated neuroprogenitor cells (NPCs). Interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) induced the expression of cytokines and chemokines in differentiated human NPCs as shown by an immune pathway-specific array. Network motif (NM) analysis of these genes revealed 118 three-node NMs, suggesting complex interactions between inflammatory mediators and transcription factors. Immunofluorescent staining showed increases in the levels of IL-8 and CXCL10 proteins in neurons and glial cells. Findings from Taqman low density array suggested the synergistic actions of IL-1β and TNF-α in the induction of a majority of inflammatory genes by a mechanism involving NF-kB and STAT-1. Nuclear localization of these transcription factors in differentiated NPCs was observed following exposure to IL-1α and TNF-α. Further studies on CXCL10, a chemokine known to be elevated in the Alzheimer's brain, showed that TNF-α is a stronger inducer of CXCL10 promoter when compared to IL-1β. The synergy between these cytokines was lost when ISRE or kB elements in CXCL10 promoter were mutated. Our findings suggest that the activation of inflammatory pathways in neurons and astrocytes through transcription factors including NF-kB and STAT-1 play important roles in neuroglial interactions and in sustaining the vicious cycle of inflammatory response.
Islet Cell Biology, Regeneration, and Transplantation
A. N. Balamurugan,Velayutham Kumaravel,Subbiah Pugazhenthi,Bashoo Naziruddin
International Journal of Endocrinology , 2012, DOI: 10.1155/2012/139787
Downregulation of CREB expression in Alzheimer's brain and in Aβ-treated rat hippocampal neurons
Subbiah Pugazhenthi, Maorong Wang, Serena Pham, Chun-I Sze, Christopher B Eckman
Molecular Neurodegeneration , 2011, DOI: 10.1186/1750-1326-6-60
Abstract: Laser Capture Microdissection of hippocampal neurons from Tg2576 mouse brain revealed decreases in the mRNA levels of CREB and its target, BDNF. Immunohistochemical analysis of Tg2576 mouse brain showed decreases in CREB levels in hippocampus and cortex. Markers of oxidative stress were detected in transgenic mouse brain and decreased CREB staining was observed in regions showing abundance of astrocytes. There was also an inverse correlation between SDS-extracted Aβ and CREB protein levels in Alzheimer's post-mortem hippocampal samples. The levels of CREB-regulated BDNF and BIRC3, a caspase inhibitor, decreased and the active cleaved form of caspase-9, a marker for the intrinsic pathway of apoptosis, was elevated in these samples. Exposure of rat primary hippocampal neurons to Aβ fibrils decreased CREB promoter activity. Decrease in CREB mRNA levels in Aβ-treated neurons was reversed by the antioxidant, N-acetyl cysteine. Overexpression of CREB by adenoviral transduction led to significant protection against Aβ-induced neuronal apoptosis.Our findings suggest that chronic downregulation of CREB-mediated transcription results in decrease of CREB content in the hippocampal neurons of AD brain which may contribute to exacerbation of disease progression.Cyclic AMP response element binding protein (CREB) is a constitutively expressed nuclear transcription factor that regulates the expression of genes involved in neuronal survival and function [1-3]. CREB is essential for the formation and retention of memory in several species [4,5]. CREB-mediated gene expression is increased in the hippocampus during LTP [6]. Spatial learning deficits in rats are observed after intra-hippocampal infusion of CREB antisense oligos [7]. CREB is also an important nuclear target that couples neurotrophin-mediated signaling to neuronal survival [8]. CREB undergoes phosphorylation at serine 133 in response to multiple signaling pathways [9,10]. The phosphorylated form of CREB binds to the coact
A 2D Finite Element Study on the Flow Pattern and Temperature Distribution for an Isothermal Spherical Furnace with the Aperture  [PDF]
Sudhakar Matle, Subbiah Sundar
Open Journal of Applied Sciences (OJAppS) , 2012, DOI: 10.4236/ojapps.2012.24046
Abstract: Calibration of radiation thermometers is one of the important research activities in the field of metrology. Many researchers in recent times have conducted numerical simulations on the calibration furnace to understand and overcome the experiment limitations. This paper presents a 2D numerical free convective study on the calibration furnace with the aperture using finite element method. The focused issues here are: aspect ratio effect on the flow pattern and temperature fields, heat transfer mechanism in the aperture zone as well as in hump regime. It is concluded that flow and temperature fields follow the same behavior in the hump regime as well as in the aperture zone. Also, it concluded that penetrative convection is more dominant for the enclosure of high aspect ratio.
A Simple Computational Approach for the Texture Analysis of CT Scan Images Using Orthogonal Moments  [PDF]
Nallasivan Gomathinayagam, Janakiraman Subbiah
Circuits and Systems (CS) , 2016, DOI: 10.4236/cs.2016.78163
Abstract: This paper is a study on texture analysis of Computer Tomography (CT) liver images using orthogonal moment features. Orthogonal moments are used as image feature representation in many applications like invariant pattern recognition of images. Orthogonal moments are proposed here for the diagnosis of any abnormalities on the CT images. The objective of the proposed work is to carry out the comparative study of the performance of orthogonal moments like Zernike, Racah and Legendre moments for the detection of abnormal tissue on CT liver images. The Region of Interest (ROI) based segmentation and watershed segmentation are applied to the input image and the features are extracted with the orthogonal moments and analyses are made with the combination of orthogonal moment with segmentation that provides better accuracy while detecting the tumor. This computational model is tested with many inputs and the performance of the orthogonal moments with segmentation for the texture analysis of CT scan images is computed and compared.
The Time Course of D1 Agonist Induced Striatonigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease  [PDF]
Cicely Moreno, Subbiah P. Sivam
Journal of Behavioral and Brain Science (JBBS) , 2012, DOI: 10.4236/jbbs.2012.21001
Abstract: Using a rat model of hemiparkinsonism, we examined the time-course of D1 agonist, SKF-38393-induced changes in extracellular signaling regulated kinases 1/2 (ERK1/2) phosphorylation in the striatum and substantia nigra (SN). We unilaterally lesioned the rat median forebrain bundle with 6-hydroxydopamine. Dopaminergic lesioned rats were administered with SKF-38393 and perfused at 15, 30, 60, or 120 minutes after the drug. Immunohistochemical analysis of striatum and SN revealed, as expected, a loss of tyrosine hydroxylase and a decrease of substance P in lesioned rats. SKF-38393 induced a robust increase in phospho-ERK1/2 levels in the lesioned striatum, which peaked at 15 min and substantially declined by 120 min. We report for the first time that similar changes were observed in the SN. The time-dependent ERK 1/2 activation in the striatonigral neurons may play a role in the therapeutic and/or side effects such as dyskinesias related to the dopamine agonist treatment for Parkinson’s disease.
GABA Attenuates L-DOPA-Induced Striatal and Nigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease  [PDF]
Sarah Lynch, Subbiah P. Sivam
Journal of Behavioral and Brain Science (JBBS) , 2013, DOI: 10.4236/jbbs.2013.33032
Abstract: L-DOPA is the primary drug used to treat Parkinson’s disease (PD) symptoms, but motor side effects limit its long term use. Previous experimental studies show that L-DOPA acts on supersensitive D1 receptors in the basal ganglia to induce extracellular signal-regulated kinases 1 and 2 (ERK1/2), a pair of MAP-kinase proteins that may be involved in induction of motor side effects. Since GABA is known to be intimately involved in basal ganglia function, we investigated whether elevating GABA levels via a GABA-transaminase (GABA-T) inhibitor affects the L-DOPA-induced ERK1/2 phosphorylation in the striatum and substantia nigra (SN) using a rat model of PD. Unilateral dopaminergic lesions of median forebrain bundle neurons were done using the neurotoxin 6-hydroxydopamine. Rats were prescreened for the extent of the lesion by apomorphine-induced rotation test. Lesioned rats were treated with aminooxyacetic acid (AOAA, a GABA-T inhibitor), L-DOPA, or in combination. Immunohistochemistry of tyrosine hydroxylase (TH, a direct indicator of dopaminergic lesion), substance P (SP, an indirect marker that decreases after lesion), and phospho-ERK1/2 was done using slices at the level of striatum and SN. Unilateral dopaminergic lesioned rats, as expected, exhibited >90% TH loss and a modest SP loss in the striatum and SN. L-DOPA alone induced a 343% and 330% increase in phospho-ERK1/2 in the striatum and SN, respectively. We report here a novel finding that pretreatment with AOAA attenuated the L-DOPA induced increase in phospho-ERK1/2 by 62% and 68% in the striatum and SN, respectively, suggesting a DA-GABA-ERK1/2 link in the therapeutic and/or side effects of L-DOPA.
Dopamine and GABA Interaction in Basal Ganglia: GABA-A or GABA-B Receptor Stimulation Attenuates L-DOPA-Induced Striatal and Nigral ERK1/2 Signaling in a Rat Model of Parkinson’s Disease  [PDF]
Sarah Lynch, Subbiah P. Sivam
Journal of Behavioral and Brain Science (JBBS) , 2013, DOI: 10.4236/jbbs.2013.36050

Parkinson’s disease (PD) is characterized by degeneration of nigrostriatal dopamine (DA) neurons. The primary drug used to treat PD symptoms is L-DOPA, but side effects such as dyskinesias limit its use. Previous findings show that L-DOPA treatment induces extracellular signal-regulated kinase (ERK1/2), a MAP-kinase protein. γ-aminobutyric acid (GABA) is intimately involved in basal ganglia function. Our previous study using a unilaterally lesioned rat model of PD indicated that elevating GABA levels by GABA transaminase inhibitor, aminooxyacetic acid significantly attenuated L-DOPA-induced ERK phosphorylation in the striatum and substantia nigra (SN). The aim of the present study was to assess the role of GABA-A and GABA-B receptor by using a selective agonists, muscimol and baclofen respectively, on L-DOPA-induced ERK phosphorylation in the striatum and SN. Unilaterally 6-OHDA-lesioned rats were prescreened by apomorphine induced rotation test for the extent of DA loss. Lesioned rats were treated with L-DOPA alone or after muscimol or baclofen pretreatment. Appropriate control groups were used. Phospho-ERK levels, tyrosine hydroxylase (to ascertain DA loss) and substance P (an indirect marker for DA loss) levels were assessed by immunohistochemistry using coronal slices at the level of striatum and SN. L-DOPA administration induced a robust increase (>300%) in phospho-ERK1/2 levels in the striatum and SN. Muscimol as well as baclofen pretreatment attenuated the L-DOPA-induced increase in phospho-ERK1/2 levels by >60% in the striatum and SN. Muscimol and baclofen pretreatment also greatly reduced the number of L-DOPA induced phospho-ERK1/2 stained cells in the striatum as well as the contralateral rotational behavior. The present data taken together with our previous study indicate that the L-DOPA induced increase in ERK1/2 is attenuated by GABA via a GABA-A and GABA-B receptor linked mechanism. The study provides further insight into a dopamine-GABA-ERK interaction in the therapeutic and/or side effects

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