Digital Commons Network^™

The P2y(12) Antagonists, 2mesamp And Cangrelor, Inhibit Platelet Activation Through P2y(12)/G(I)-Dependent Mechanism, Binggang Xiang, Guoying Zhang, Hongmei Ren, Manjula Sunkara, Andrew J. Morris, T. Kent Gartner, Susan S. Smyth, Zhenyu Li

Saha Cardiovascular Research Center Faculty Publications

BACKGROUND: ADP is an important physiological agonist that induces integrin activation and platelet aggregation through its receptors P2Y(1) (Gα(q)-coupled) and P2Y(12) (Gα(i)-coupled). P2Y(12) plays a critical role in platelet activation and thrombosis. Adenosine-based P2Y(12) antagonists, 2-methylthioadenosine 5'-monophosphate triethylammonium salt hydrate (2MeSAMP) and Cangrelor (AR-C69931MX) have been widely used to demonstrate the role of P2Y(12) in platelet function. Cangrelor is being evaluated in clinical trials of thrombotic diseases. However, a recent study reported that both 2MeSAMP and Cangrelor raise intra-platelet cAMP levels and inhibit platelet aggregation through a P2Y(12)-independent mechanism.

METHODOLOGY/PRINCIPAL FINDINGS: The present work, using P2Y(12) deficient mice, sought to …

Fak Is A Critical Regulator Of Neuroblastoma Liver Metastasis, Sora Lee, Jingbo Qiao, Pritha Paul, Kathleen L. O'Connor, B. Mark Evers, Dai H. Chung

Surgery Faculty Publications

Neuroblastomas express increased levels of gastrin-releasing peptide receptor (GRP-R). However, the exact molecular mechanisms involved in GRP-R-mediated cell signaling in neuroblastoma growth and metastasis are unknown. Here, we report that focal adhesion kinase (FAK), as a critical downstream target of GRP-R, is an important regulator of neuroblastoma tumorigenicity. We found that FAK expression correlates with GRP-R expression in human neuroblastoma sections and cell lines. GRP-R overexpression in SK-N-SH cells increased FAK, integrin α3 and β1 expressions and cell migration. These cells demonstrated flatter cell morphology with broad lamellae, in which intense FAK expression was localized to the leading edges of …

Necrostatin-1 Analogues: Critical Issues On The Specificity, Activity And In Vivo Use In Experimental Disease Models., N Takahashi, L Duprez, S Grootjans, A Cauwels, W Nerinckx, J B Duhadaway, V Goossens, R Roelandt, F Van Hauwermeiren, C Libert, W Declercq, N Callewaert, G C Prendergast, A Degterev, J Yuan, P Vandenabeele

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Necrostatin-1 (Nec-1) is widely used in disease models to examine the contribution of receptor-interacting protein kinase (RIPK) 1 in cell death and inflammation. We studied three Nec-1 analogs: Nec-1, the active inhibitor of RIPK1, Nec-1 inactive (Nec-1i), its inactive variant, and Nec-1 stable (Nec-1s), its more stable variant. We report that Nec-1 is identical to methyl-thiohydantoin-tryptophan, an inhibitor of the potent immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO). Both Nec-1 and Nec-1i inhibited human IDO, but Nec-1s did not, as predicted by molecular modeling. Therefore, Nec-1s is a more specific RIPK1 inhibitor lacking the IDO-targeting effect. Next, although Nec-1i was ∼100 × …

Zinc Modifies The Effect Of Phyto-Oestrogens On Osteoblast And Osteoclast Differentiation In Vitro., S Karieb, Sw Fox

School of Biomedical Sciences

Osteoblast and osteoclast activity is disrupted in post-menopausal osteoporosis. Thus, to fully address this imbalance, therapies should reduce bone resorption and promote bone formation. Dietary factors such as phyto-oestrogens and Zn have beneficial effects on osteoblast and osteoclast activity. However, the effect of combinations of these factors has not been widely studied. We therefore examined the effect of coumestrol, daidzein and genistein in the presence or absence of zinc sulphate (Zn) on osteoclast and osteoblast activity. Osteoclast differentiation and bone resorption were significantly reduced by coumestrol (10- 7 m), daidzein (10- 5 m) and genistein (10- 7 m); and this …

Open Release Of Male Mosquitoes Infected With A Wolbachia Biopesticide: Field Performance And Infection Containment, Linda O'Connor, Catherine Plichart, Ayo Cheong Sang, Corey L. Brelsfoard, Hervé C. Bossin, Stephen L. Dobson

Entomology Faculty Publications

BACKGROUND: Lymphatic filariasis (LF) is a globally significant disease, with 1.3 billion persons in 83 countries at risk. A coordinated effort of administering annual macrofilaricidal prophylactics to the entire at-risk population has succeeded in impacting and eliminating LF transmission in multiple regions. However, some areas in the South Pacific are predicted to persist as transmission sites, due in part to the biology of the mosquito vector, which has led to a call for additional tools to augment drug treatments. Autocidal strategies against mosquitoes are resurging in the effort against invasive mosquitoes and vector borne disease, with examples that include field …

Toward The Beginning Of Time: Circadian Rhythms In Metabolism Precede Rhythms In Clock Gene Expression In Mouse Embryonic Stem Cells, Jiffin K. Paulose, Edmund B. Rucker Iii, Vincent M. Cassone

Biology Faculty Publications

The appearance, progression, and potential role for circadian rhythms during early development have previously focused mainly on the suprachiasmatic nucleus (SCN) and peri- and postnatal expression of canonical clock genes. More recently, gene expression studies in embryonic stem cells have shown that some clock genes are expressed in undifferentiated cells; however rhythmicity was only established when cells are directed toward a neural fate. These studies also concluded that a functional clock is not present in ESCs, based solely on their gene expression. The null hypothesis underlying the present study is that embryonic stem cells become rhythmic in both clock gene …

Multifactorial Patterns Of Gene Expression In Colonic Epithelial Cells Predict Disease Phenotypes In Experimental Colitis, Aubrey Leigh Frantz, Maria E. C. Bruno, Eric William Rogier, Halide Tuna, Donald A. Cohen, Subbarao Bondada, Ralph Lakshman Chelvarajan, J. Anthony Brandon, C. Darrell Jennings, Charlotte S. Kaetzel

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Background— The pathogenesis of inflammatory bowel disease (IBD) is complex and the need to identify molecular biomarkers is critical. Epithelial cells play a central role in maintaining intestinal homeostasis. We previously identified five “signature” biomarkers in colonic epithelial cells (CEC) that are predictive of disease phenotype in Crohn's disease. Here we investigate the ability of CEC biomarkers to define the mechanism and severity of intestinal inflammation.

Methods— We analyzed the expression of RelA, A20, pIgR, tumor necrosis factor (TNF), and macrophage inflammatory protein (MIP)-2 in CEC of mice with dextran sodium sulfate (DSS) acute colitis or T-cell-mediated chronic colitis. …

Mucin (Muc) Expression During Pancreatic Cancer Progression In Spontaneous Mouse Model: Potential Implications For Diagnosis And Therapy., Satyanarayana Rachagani, María P Torres, Sushil Kumar, Dhanya Haridas, Michael J. Baine, Muzafar A. Macha, Sukhwinder Kaur, Moorthy P. Ponnusamy, Parama Dey, Parthasarathy Seshacharyulu, Sonny L. Johansson, Maneesh Jain, Kay-Uwe Wagner, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Pancreatic cancer (PC) is a lethal malignancy primarily driven by activated Kras mutations and characterized by the deregulation of several genes including mucins. Previous studies on mucins have identified their significant role in both benign and malignant human diseases including PC progression and metastasis. However, the initiation of MUC expression during PC remains unknown because of lack of early stage tumor tissues from PC patients.

METHODS: In the present study, we have evaluated stage specific expression patterns of mucins during mouse PC progression in (Kras(G12D);Pdx1-Cre (KC)) murine PC model from pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC) …

Severe Stress Switches Crf Action In The Nucleus Accumbens From Appetitive To Aversive., Julia C Lemos, Matthew J Wanat, Jeffrey S Smith, Beverly A S Reyes, Nick G Hollon, Elisabeth J Van Bockstaele, Charles Chavkin, Paul E M Phillips

Farber Institute for Neuroscience Faculty Papers

Stressors motivate an array of adaptive responses ranging from 'fight or flight' to an internal urgency signal facilitating long-term goals. However, traumatic or chronic uncontrollable stress promotes the onset of major depressive disorder, in which acute stressors lose their motivational properties and are perceived as insurmountable impediments. Consequently, stress-induced depression is a debilitating human condition characterized by an affective shift from engagement of the environment to withdrawal. An emerging neurobiological substrate of depression and associated pathology is the nucleus accumbens, a region with the capacity to mediate a diverse range of stress responses by interfacing limbic, cognitive and motor circuitry. …

Gene Expression Analysis Of A Murine Model With Pulmonary Vascular Remodeling Compared To End-Stage Ipah Lungs, Kayoko Shimodaira, Yoichiro Okubo, Eri Ochiai, Haruo Nakayama, Harutaka Katano, Megumi Wakayama, Minoru Shinozaki, Takao Ishiwatari, Daisuke Sasai, Naobumi Tochigi, Tetsuo Nemoto, Tsutomu Saji, Katsuhiko Kamei, Kazutoshi Shibuya

Microbiology, Immunology, and Molecular Genetics Faculty Publications

BACKGROUND: Idiopathic pulmonary arterial hypertension (IPAH) continues to be one of the most serious intractable diseases that might start with activation of several triggers representing the genetic susceptibility of a patient. To elucidate what essentially contributes to the onset and progression of IPAH, we investigated factors playing an important role in IPAH by searching discrepant or controversial expression patterns between our murine model and those previously published for human IPAH. We employed the mouse model, which induced muscularization of pulmonary artery leading to hypertension by repeated intratracheal injection of Stachybotrys chartarum, a member of nonpathogenic and ubiquitous fungus in our …

Quantifying The Cdk Inhibitor Vmy-1-103'S Activity And Tissue Levels In An In Vivo Tumor Model By Lc-Ms/Ms And By Mri., Paul Sirajuddin, Sudeep Das, Lymor Ringer, Olga C Rodriguez, Angiela Sivakumar, Yi-Chien Lee, Aykut Üren, Stanley T Fricke, Brian Rood, Alpay Ozcan, Sean S Wang, Sana Karam, Venkata Yenugonda, Patricia Salinas, Emanuel Petricoin, Michael Pishvaian, Michael P Lisanti, Yue Wang, Richard Schlegel, Bahram Moasser, Chris Albanese

Kimmel Cancer Center Faculty Papers

The development of new small molecule-based therapeutic drugs requires accurate quantification of drug bioavailability, biological activity and treatment efficacy. Rapidly measuring these endpoints is often hampered by the lack of efficient assay platforms with high sensitivity and specificity. Using an in vivo model system, we report a simple and sensitive liquid chromatography-tandem mass spectrometry assay to quantify the bioavailability of a recently developed novel cyclin-dependent kinase inhibitor VMY-1-103, a purvalanol B-based analog whose biological activity is enhanced via dansylation. We developed a rapid organic phase extraction technique and validated wide and functional VMY-1-103 distribution in various mouse tissues, consistent with …

Cross-Ontology Multi-Level Association Rule Mining In The Gene Ontology., Prashanti Manda, Seval Ozkan, Hui Wang, Fiona M. Mccarthy, Susan M. Bridges

BCoE Publications

The Gene Ontology (GO) has become the internationally accepted standard for representing function, process, and location aspects of gene products. The wealth of GO annotation data provides a valuable source of implicit knowledge of relationships among these aspects. We describe a new method for association rule mining to discover implicit co-occurrence relationships across the GO sub-ontologies at multiple levels of abstraction. Prior work on association rule mining in the GO has concentrated on mining knowledge at a single level of abstraction and/or between terms from the same sub-ontology. We have developed a bottom-up generalization procedure called Cross-Ontology Data Mining-Level by …

Cross-Ontology Multi-Level Association Rule Mining In The Gene Ontology., Prashanti Manda, Seval Ozkan, Hui Wang, Fiona M. Mccarthy, Susan M. Bridges

FWRC Publications

The Gene Ontology (GO) has become the internationally accepted standard for representing function, process, and location aspects of gene products. The wealth of GO annotation data provides a valuable source of implicit knowledge of relationships among these aspects. We describe a new method for association rule mining to discover implicit co-occurrence relationships across the GO sub-ontologies at multiple levels of abstraction. Prior work on association rule mining in the GO has concentrated on mining knowledge at a single level of abstraction and/or between terms from the same sub-ontology. We have developed a bottom-up generalization procedure called Cross-Ontology Data Mining-Level by …

Cdk Inhibitors (P16/P19/P21) Induce Senescence And Autophagy In Cancer-Associated Fibroblasts, "Fueling" Tumor Growth Via Paracrine Interactions, Without An Increase In Neo-Angiogenesis., Claudia Capparelli, Barbara Chiavarina, Diana Whitaker-Menezes, Timothy G Pestell, Richard Pestell, James Hulit, Sebastiano Andò, Anthony Howell, Ubaldo E. Martinez-Outshoorn, Federica Sotgia, Michael P. Lisanti

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Here, we investigated the compartment-specific role of cell cycle arrest and senescence in breast cancer tumor growth. For this purpose, we generated a number of hTERT-immortalized senescent fibroblast cell lines overexpressing CDK inhibitors, such as p16(INK4A), p19(ARF) or p21(WAF1/CIP1). Interestingly, all these senescent fibroblast cell lines showed evidence of increased susceptibility toward the induction of autophagy (either at baseline or after starvation), as well as significant mitochondrial dysfunction. Most importantly, these senescent fibroblasts also dramatically promoted tumor growth (up to ~2-fold), without any comparable increases in tumor angiogenesis. Conversely, we generated human breast cancer cells (MDA-MB-231 cells) overexpressing CDK inhibitors, …

The Alternative Crosstalk Between Rage And Nitrative Thioredoxin Inactivation During Diabetic Myocardial Ischemia-Reperfusion Injury., Yi Liu, Yan Qu, Rutao Wang, Yanzhuo Ma, Chenhai Xia, Chao Gao, Jingyi Liu, Kun Lian, Aibing Xu, Xiaoyan Lu, Lu Sun, Lu Yang, Wayne B. Lau, Erhe Gao, Walter Koch, Haichang Wang, Ling Tao

Department of Emergency Medicine Faculty Papers

The receptor for advanced glycation end products (RAGE) and thioredoxin (Trx) play opposing roles in diabetic myocardial ischemia-reperfusion (MI/R) injury. We recently demonstrated nitrative modification of Trx leads to its inactivation and loss of cardioprotection. The present study is to determine the relationship between augmented RAGE expression and diminished Trx activity pertaining to exacerbated MI/R injury in the diabetic heart. The diabetic state was induced in mice by multiple intraperitoneal low-dose streptozotocin injections. RAGE small-interfering RNA (siRNA) or soluble RAGE (sRAGE, a RAGE decoy) was via intramyocardial and intraperitoneal injection before MI/R, respectively. Mice were subjected to 30 min of …

Latexin Is Down-Regulated In Hematopoietic Malignancies And Restoration Of Expression Inhibits Lymphoma Growth, Yi Liu, Dianna Howard, Kyle Rector, Carol Swiderski, Jason Brandon, Lawrence Schook, Jayesh Mehta, J. Scott Bryson, Subbarao Bondada, Ying Liang

Internal Medicine Faculty Publications

Latexin is a negative regulator of hematopoietic stem cell number in mice. Its dysregulated expression in other tumors led us to hypothesize that latexin may have tumor suppressor properties in hematological malignancies. We found that latexin was down-regulated in a variety of leukemia and lymphoma cell lines as well as in CD34+ cells from the blood and marrow of patients with these malignancies. 5-aza-2'-deoxycytodine treatment and bisulfite sequencing revealed hypermethylation of latexin promoter in tumor cells. Retrovirus-mediated latexin overexpression in A20 mouse lymphoma cells inhibited their in vitro growth by 16 fold and in vivo tumor volume by 2 fold. …

Perlecan Domain V Induces Vegf Secretion In Brain Endothelial Cells Through Integrin Α5Β1 And Erk-Dependent Signaling Pathways, Douglas N. Clarke, Abraham Al Ahmad, Boyeon Lee, Christi Parham, Lisa Auckland, Andrezj Fertala, Michael Kahle, Courtney S. Shaw, Jill Roberts, Gregory J. Bix

Sanders-Brown Center on Aging Faculty Publications

Perlecan Domain V (DV) promotes brain angiogenesis by inducing VEGF release from brain endothelial cells (BECs) following stroke. In this study, we define the specific mechanism of DV interaction with the α(5)β(1) integrin, identify the downstream signal transduction pathway, and further investigate the functional significance of resultant VEGF release. Interestingly, we found that the LG3 portion of DV, which has been suggested to possess most of DV's angio-modulatory activity outside of the brain, binds poorly to α(5)β(1) and induces less BEC proliferation compared to full length DV. Additionally, we implicate DV's DGR sequence as an important element for the interaction …

Perlecan Domain V Induces Vegf Secretion In Brain Endothelial Cells Through Integrin Α5Β1 And Erk-Dependent Signaling Pathways., Douglas N Clarke, Abraham Al Ahmad, Boyeon Lee, Christi Parham, Lisa Auckland, Andrezj Fertala, Michael Kahle, Courtney S Shaw, Jill Roberts, Gregory J Bix

Department of Dermatology and Cutaneous Biology Faculty Papers

Perlecan Domain V (DV) promotes brain angiogenesis by inducing VEGF release from brain endothelial cells (BECs) following stroke. In this study, we define the specific mechanism of DV interaction with the α(5)β(1) integrin, identify the downstream signal transduction pathway, and further investigate the functional significance of resultant VEGF release. Interestingly, we found that the LG3 portion of DV, which has been suggested to possess most of DV's angio-modulatory activity outside of the brain, binds poorly to α(5)β(1) and induces less BEC proliferation compared to full length DV. Additionally, we implicate DV's DGR sequence as an important element for the interaction …

Metabolic Remodeling Of The Tumor Microenvironment: Migration Stimulating Factor (Msf) Reprograms Myofibroblasts Toward Lactate Production, Fueling Anabolic Tumor Growth., Valentina Carito, Gloria Bonuccelli, Ubaldo E Martinez-Outschoorn, Diana Whitaker-Menezes, Maria Cristina Caroleo, Erika Cione, Anthony Howell, Richard G Pestell, Michael P. Lisanti, Federica Sotgia

Department of Stem Cell Biology and Regenerative Medicine Faculty Papers & Presentations

Migration stimulating factor (MSF) is a genetically truncated N-terminal isoform of fibronectin that is highly expressed during mammalian development in fetal fibroblasts, and during tumor formation in human cancer-associated myofibroblasts. However, its potential functional role in regulating tumor metabolism remains unexplored. Here, we generated an immortalized fibroblast cell line that recombinantly overexpresses MSF and studied their properties relative to vector-alone control fibroblasts. Our results indicate that overexpression of MSF is sufficient to confer myofibroblastic differentiation, likely via increased TGF-b signaling. In addition, MSF activates the inflammation-associated transcription factor NFκB, resulting in the onset of autophagy/mitophagy, thereby driving glycolytic metabolism (L-lactate …

Investigation Of The Role Of Tnf-A Converting Enzyme (Tace) In The Inhibition Of Cell Surface And Soluble Tnf-A Production By Acute Ethanol Exposure., Kristine Von Maltzan, Wei Tan, Stephen B. Pruett

CVM Publications

Toll-like receptors (TLRs) play a fundamental role in the immune system by detecting pathogen associated molecular patterns (PAMPs) to sense host infection. Ethanol at doses relevant for humans inhibits the pathogen induced cytokine response mediated through TLRs. The current study was designed to investigate the mechanisms of this effect by determining whether ethanol inhibits TLR3 and TLR4 mediated TNF-? secretion through inhibition of transcription factor activation or post-transcriptional effects. In NF-?B reporter mice, activation of NF-?B in vivo by LPS was inhibited by ethanol (LPS alone yielded 170,000?35,300 arbitrary units of light emission; LPS plus ethanol yielded 56,120?16880, p = …

Global Cellular Regulation Including Cardiac Function By Post-Translational Protein Arginylation., Hideko Kaji, Akira Kaji

Department of Biochemistry and Molecular Biology Faculty Papers

In this issue a very significant contribution to cardiology describing critical roles of ATE1 appears by Kurosaka et al. [1]. In view of this paper, as the discoverers of ATE1, we have been asked to contribute an article (editorial) regarding ATE1 (enzyme which transfers arginine from arginyl tRNA to protein acceptors). This short article consists of three sections: 1) a historical anecdote describing how ATE1 was discovered; 2) its possible role in aging and cellular transformation, and most importantly; 3) its role in the development and maintenance of cardiac activity. The last section has direct bearing to the Kurosaka …

Mammalian Alteration/Deficiency In Activation 3 (Ada3) Is Essential For Embryonic Development And Cell Cycle Progression., Shakur Mohibi, Channabasavaiah B. Gurumurthy, Alo Nag, Jun Wang, Sameer Mirza, Yousaf Mian, Meghan Quinn, Bryan J. Katafiasz, James D. Eudy, Sanjit Pandey, Chittibabu Guda, Mayumi Naramura, Hamid Band, Vimla Band

Journal Articles: Genetics, Cell Biology & Anatomy

Ada3 protein is an essential component of histone acetyl transferase containing coactivator complexes conserved from yeast to human. We show here that germline deletion of Ada3 in mouse is embryonic lethal, and adenovirus-Cre mediated conditional deletion of Ada3 in Ada3(FL/FL) mouse embryonic fibroblasts leads to a severe proliferation defect which was rescued by ectopic expression of human Ada3. A delay in G(1) to S phase of cell cycle was also seen that was due to accumulation of Cdk inhibitor p27 which was an indirect effect of c-myc gene transcription control by Ada3. We further showed that this defect could be …

Tryptophan Hydroxylase-1 Regulates Immune Tolerance And Inflammation, Elizabeth C. Nowak, Victor C. De Vries, Anna Wasiuk, Cory Ahonen, Kathryn A. Bennett, Isabelle Le Mercier, Dae-Gon Ha, Randolph J. Noelle

Dartmouth Scholarship

Nutrient deprivation based on the loss of essential amino acids by catabolic enzymes in the microenvironment is a critical means to control in ammatory responses and immune tolerance. Here we report the novel nding that Tph-1 (tryptophan hydroxylase-1), a synthase which catalyses the conversion of tryptophan to serotonin and exhausts tryptophan, is a potent regulator of immunity. In models of skin allograft tolerance, tumor growth, and experimental autoimmune encephalomyelitis, Tph-1 de ciency breaks allograft tolerance, induces tumor remission, and intensi es neuroin ammation, respectively. All of these effects of Tph-1 de ciency are independent of its downstream product serotonin. Because …

Coronary Artery Remodeling In A Model Of Left Ventricular Pressure Overload Is Influenced By Platelets And Inflammatory Cells, Fanmuyi Yang, Anping Dong, Paul Mueller, Jessica Caicedo, Alyssa Moore Sutton, Juliana Odetunde, Cordelia J. Barrick, Yuri M. Klyachkin, Ahmed Abdel-Latif, Susan S. Smyth

Internal Medicine Faculty Publications

Left ventricular hypertrophy (LVH) is usually accompanied by intensive interstitial and perivascular fibrosis, which may contribute to arrhythmogenic sudden cardiac death. The mechanisms underlying the development of cardiac fibrosis are incompletely understood. To investigate the role of perivascular inflammation in coronary artery remodeling and cardiac fibrosis during hypertrophic ventricular remodeling, we used a well-established mouse model of LVH (transverse aortic constriction [TAC]). Three days after pressure overload, macrophages and T lymphocytes accumulated around and along left coronary arteries in association with luminal platelet deposition. Consistent with these histological findings, cardiac expression of IL-10 was upregulated and in the systemic circulation, …

Genomics Of Mature And Immature Olfactory Sensory Neurons, Melissa D. Nickell, Patrick Breheny, Arnold J. Stromberg, Timothy S. Mcclintock

Physiology Faculty Publications

The continuous replacement of neurons in the olfactory epithelium provides an advantageous model for investigating neuronal differentiation and maturation. By calculating the relative enrichment of every mRNA detected in samples of mature mouse olfactory sensory neurons (OSNs), immature OSNs, and the residual population of neighboring cell types, and then comparing these ratios against the known expression patterns of >300 genes, enrichment criteria that accurately predicted the OSN expression patterns of nearly all genes were determined. We identified 847 immature OSN-specific and 691 mature OSN-specific genes. The control of gene expression by chromatin modification and transcription factors, and neurite growth, protein …

Early Stage Drug Treatment That Normalizes Proinflammatory Cytokine Production Attenuates Synaptic Dysfunction In A Mouse Model That Exhibits Age-Dependent Progression Of Alzheimer's Disease-Related Pathology, Adam D. Bachstetter, Christopher M. Norris, Pradoldej Sompol, Donna M. Wilcock, Danielle Goulding, Janna H. Neltner, Daret St. Clair, D. Martin Watterson, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Overproduction of proinflammatory cytokines in the CNS has been implicated as a key contributor to pathophysiology progression in Alzheimer's disease (AD), and extensive studies with animal models have shown that selective suppression of excessive glial proinflammatory cytokines can improve neurologic outcomes. The prior art, therefore, raises the logical postulation that intervention with drugs targeting dysregulated glial proinflammatory cytokine production might be effective disease-modifying therapeutics if used in the appropriate biological time window. To test the hypothesis that early stage intervention with such drugs might be therapeutically beneficial, we examined the impact of intervention with MW01-2-151SRM (MW-151), an experimental therapeutic that …

Secreted Semaphorin 5a Suppressed Pancreatic Tumour Burden But Increased Metastasis And Endothelial Cell Proliferation., A Sadanandam, S S. Sidhu, S Wullschleger, S Singh, M L. Varney, C-S Yang, A E. Ashour, Surinder K. Batra, Rakesh Singh

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Our earlier reports demonstrated that membrane-bound semaphorin 5A (SEMA5A) is expressed in aggressive pancreatic cancer cells and tumours, and promotes tumour growth and metastasis. In this study, we examine whether (1) pancreatic cancer cells secrete SEMA5A and (2) that secreted SEMA5A modulates certain phenotypes associated with tumour progression, angiogenesis and metastasis through various other molecular factors and signalling proteins.

METHODS AND RESULTS: In this study, we show that human pancreatic cancer cell lines secrete the extracellular domain (ECD) of SEMA5A (SEMA5A-ECD) and overexpression of mouse Sema5A-ECD in Panc1 cells (not expressing SEMA5A; Panc1-Sema5A-ECD; control cells - Panc1-control) significantly increases …

I(A) Channels Encoded By Kv1.4 And Kv4.2 Regulate Neuronal Firing In The Suprachiasmatic Nucleus And Circadian Rhythms In Locomotor Activity, Daniel Granados-Fuentes, Aaron J. Norris, Yarimar Carrasquillo, Jeanne M. Nerbonne, Erik D. Herzog

Open Access Publications

Neurons in the suprachiasmatic nucleus (SCN) display coordinated circadian changes in electrical activity that are critical for daily rhythms in physiology, metabolism, and behavior. SCN neurons depolarize spontaneously and fire repetitively during the day and hyperpolarize, drastically reducing firing rates, at night. To explore the hypothesis that rapidly activating and inactivating A-type (I(A)) voltage-gated K(+) (Kv) channels, which are also active at subthreshold membrane potentials, are critical regulators of the excitability of SCN neurons, we examined locomotor activity and SCN firing in mice lacking Kv1.4 (Kv1.4(-/-)), Kv4.2 (Kv4.2(-/-)), or Kv4.3 (Kv4.3(-/-)), the pore-forming (α) subunits of I(A) channels. Mice lacking …

Myxobacteria Versus Sponge-Derived Alkaloids: The Bengamide Family Identified As Potent Immune Modulating Agents By Scrutiny Of Lc-Ms/Elsd Libraries., Tyler A. Johnson, Johann Sohn, Yvette M. Vaske, Kimberly N. White, Tanya L. Cohen, Helene C. Vervoort, Karen Tenney, Frederick A. Valeriote, Leonard F. Bjeldanes, Phillip Crews

Natural Sciences and Mathematics | Faculty Scholarship

A nuclear factor-κB (NF-κB) luciferase assay has been employed to identify the bengamides, previously known for their anti-tumor activity, as a new class of immune modulators. A unique element of this study was that the bengamide analogs were isolated from two disparate sources, Myxococcus virescens (bacterium) and Jaspis coriacea (sponge). Comparative LC-MS/ELSD and NMR analysis facilitated the isolation of M. viriscens derived samples of bengamide E (8) and two congeners, bengamide E' (13) and F' (14) each isolated as an insperable mixture of diastereomers. Additional compounds drawn from the UC, Santa Cruz repository allowed expansion of the structure activity relationship …

Acute And Subchronic Toxicity Study Of Ardisia Ellipica Thunb. Fruit Extract, Nalinphat Saktiyasunthorn, Songpol Chivapat, Pornchai Sincharoenpokai, Anudep Rungsipipat, Nongnuth Maneechai, Boonyanee Suphaphon, Aussavashai Shuayprom

The Thai Journal of Veterinary Medicine

Several plants species in the genus Ardisia contained various biologically active compounds. Ram Yai orPilangkasa (Ardisia elliptica Thunb.) has been used in traditional medicines. The objective of this study was to evaluatethe safety of ethanolic extract of A. elliptica fruit in animal models by oral administration. Acute toxicity test in miceby gavage the extract at each dose of 2.5 g/kg twice revealed no abnormal signs, mortality and gross lesion of vitalorgans. Subchronic toxicity study was investigated in one hundred Wistar rats separated into five groups, each oftwenty (ten males and ten females). Two control groups received distilled water and 0.5% …