Medicine and Health Sciences Commons^™

Small Molecules That Inhibit Tnf Signalling By Stabilising An Asymmetric Form Of The Trimer, James O'Connell, John Porter, Boris Kroeplien, Tim Norman, Stephen Rapecki, Rachel E. Davis, David Mcmillan, Tracy Arakaki, Alex Burgin, David Fox Iii, Tom Ceska, Fabien Lecomte, Alison Maloney, Alex Vugler, Bruce Carrington, Benjamin P. Cossins, Tim Bourne, Alastair Lawson

Faculty Publications

Tumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn's disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for …

Chronic Muscle Weakness And Mitochondrial Dysfunction In The Absence Of Sustained Atrophy In A Preclinical Sepsis Model, Allison M. Owen, Samir P. Patel, Jeffrey D. Smith, Beverly K. Balasuriya, Stephanie F. Mori, Gregory S. Hawk, Arnold J. Stromberg, Naohide Kuriyama, Masao Kaneki, Alexander G. Rabchevsky, Timothy A. Butterfield, Karyn A. Esser, Charlotte A. Peterson, Marlene E. Starr, Hiroshi Saito

Physiology Faculty Publications

Chronic critical illness is a global clinical issue affecting millions of sepsis survivors annually. Survivors report chronic skeletal muscle weakness and development of new functional limitations that persist for years. To delineate mechanisms of sepsis-induced chronic weakness, we first surpassed a critical barrier by establishing a murine model of sepsis with ICU-like interventions that allows for the study of survivors. We show that sepsis survivors have profound weakness for at least 1 month, even after recovery of muscle mass. Abnormal mitochondrial ultrastructure, impaired respiration and electron transport chain activities, and persistent protein oxidative damage were evident in the muscle of …

Interleukin 1 Alpha Administration Is Neuroprotective And Neuro-Restorative Following Experimental Ischemic Stroke, Kathleen E. Salmeron, Michael E. Maniskas, Danielle N. Edwards, Raymond Wong, Ivana Rajkovic, Amanda L. Trout, Abir A. Rahman, Samantha Hamilton, Justin F. Fraser, Emmanuel Pinteaux, Gregory J. Bix

Sanders-Brown Center on Aging Faculty Publications

BACKGROUND: Stroke remains a leading cause of death and disability worldwide despite recent treatment breakthroughs. A primary event in stroke pathogenesis is the development of a potent and deleterious local and peripheral inflammatory response regulated by the pro-inflammatory cytokine interleukin-1 (IL-1). While the role of IL-1β (main released isoform) has been well studied in stroke, the role of the IL-1α isoform remains largely unknown. With increasing utilization of intravenous tissue plasminogen activator (t-PA) or thrombectomy to pharmacologically or mechanically remove ischemic stroke causing blood clots, respectively, there is interest in pairing successful cerebrovascular recanalization with neurotherapeutic pharmacological interventions (Fraser et …

Sirna Targeting And Treatment Of Gastrointestinal Diseases., Rachel Chevalier

Manuscripts, Articles, Book Chapters and Other Papers

RNA interference via small interfering RNA (siRNA) offers opportunities to precisely target genes that contribute to gastrointestinal (GI) pathologies, such as inflammatory bowel disease, celiac, and esophageal scarring. Delivering the siRNA to the GI tract proves challenging as the harsh environment of the intestines degrades the siRNA before it can reach its target or blocks its entry into its site of action in the cytoplasm. Additionally, the GI tract is large and disease is often localized to a specific site. This review discusses polymer and lipid-based delivery systems for protection and targeting of siRNA therapies to the GI tract to …

Cis-Regulatory Basis Of Sister Cell Type Divergence In The Vertebrate Retina, Daniel P Murphy, Andrew Eo Hughes, Karen A Lawrence, Connie A Myers, Joseph C Corbo

2010-2019 OA Pubs

Multicellular organisms evolved via repeated functional divergence of transcriptionally related sister cell types, but the mechanisms underlying sister cell type divergence are not well understood. Here, we study a canonical pair of sister cell types, retinal photoreceptors and bipolar cells, to identify the key

Dormant Pathogenic Cd4(+) T Cells Are Prevalent In The Peripheral Repertoire Of Healthy Mice, Anna Cebula, Michal Kuczma, Edyta Szurek, Maciej Pietrzak, Natasha Savage, Wessam R. Elhefnawy, Grzegorz Rempala, Piotr Kraj, Leszek Ignatowicz

Computer Science Faculty Publications

Thymic central tolerance eliminates most immature T cells with autoreactive T cell receptors (TCR) that recognize self MHC/peptide complexes. Regardless, an unknown number of autoreactive CD4+Foxp3⁻ T cells escape negative selection and in the periphery require continuous suppression by CD4+Foxp3⁺ regulatory cells (Tregs). Here, we compare immune repertoires of Treg-deficient and Treg-sufficient mice to find Tregs continuously constraining one-third of mature CD4⁺Foxp3⁻ cells from converting to pathogenic effectors in healthy mice. These dormant pathogenic clones frequently express TCRs activatable by ubiquitous autoantigens presented by class II MHCs on conventional dendritic cells, including selfpeptides that select …

Sciatic Nerve Cut And Repair Using Fibrin Glue In Adult Mice, Erica T. Akhter, Travis M. Rotterman, Arthur W. English, Francisco J. Alvarez

Neuroscience, Cell Biology & Physiology Faculty Publications

Peripheral nerve injury (PNI) is an excellent model for studying neural responses to injury and elucidating the mechanisms that can facilitate axon regeneration. As such, several animal models have been employed to study regenerative mechanisms after PNI, including Aplysia, zebrafish, rabbits, cats and rodents. This protocol describes how to perform a sciatic nerve injury and repair in mice, one of the most frequently used models to study mechanisms that facilitate recovery after PNI, and that takes advantage of the availability of many genetic models. In this protocol, we describe a method for using fibrin glue to secure the proximal …

Multispectral Tracing In Densely Labeled Mouse Brain With Ntracer, Douglas H Roossien, John M Webb, Cristina Mazuski, Erik D Herzog, Et Al.

2010-2019 OA Pubs

SUMMARY: This note describes nTracer, an ImageJ plug-in for user-guided, semi-automated tracing of multispectral fluorescent tissue samples. This approach allows for rapid and accurate reconstruction of whole cell morphology of large neuronal populations in densely labeled brains.

AVAILABILITY AND IMPLEMENTATION: nTracer was written as a plug-in for the open source image processing software ImageJ. The software, instructional documentation, tutorial videos, sample image and sample tracing results are available at https://www.cai-lab.org/ntracer-tutorial.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Developing Drug Therapies: Cognitive Damage In Mice Following Brain Radiation, Rachel Yuska

The Journal of Purdue Undergraduate Research

Pediatric brain cancer patients are at a high risk for radiation-induced cognitive impairment due to white matter changes in the brain. Half of six-month radiotherapy survivors develop significant changes in white matter. Previous research has shown that a mouse model can be used to show similar cognitive and behavioral deficits in human patients. The purpose of this work is to evaluate the effectiveness of two drug therapies, Donepezil and 3,3-Diindolylmethane (DIM), that could be used to either protect the brain from radiation injury or cure the cognitive injury and behavioral deficits that result from whole-brain irradiation. This project consisted of …

Imaging Of Glucose Metabolism By 13c-Mri Distinguishes Pancreatic Cancer Subtypes In Mice, Shun Kishimoto, Jeffrey R. Brender, Daniel R. Crooks, Shingo Matsumoto, Tomohiro Seki, Nobu Oshima, Hellmut Merkle, Penghui Lin, Galen Reed, Albert P. Chen, Jan Henrik Ardenkjaer-Larsen, Jeeva Munasinghe, Keita Saito, Kazutoshi Yamamoto, Peter L. Choyke, James Mitchell, Andrew N. Lane, Teresa W. M. Fan, W. Marston Linehan, Murali C. Krishna

Center for Environmental and Systems Biochemistry Faculty Publications

Metabolic differences among and within tumors can be an important determinant in cancer treatment outcome. However, methods for determining these differences non-invasively in vivo is lacking. Using pancreatic ductal adenocarcinoma as a model, we demonstrate that tumor xenografts with a similar genetic background can be distinguished by their differing rates of the metabolism of 13C labeled glucose tracers, which can be imaged without hyperpolarization by using newly developed techniques for noise suppression. Using this method, cancer subtypes that appeared to have similar metabolic profiles based on steady state metabolic measurement can be distinguished from each other. The metabolic maps from …

Understanding The Axonal Response To Injury By In Vivo Imaging In The Mouse Spinal Cord: A Tale Of Two Branches., Binhai Zheng, Ariana O Lorenzana, Le Ma

Department of Neuroscience Faculty Papers

Understanding the basic properties of how axons respond to injury in the mammalian central nervous system (CNS) is of fundamental value for developing strategies to promote neural repair. Axons possess complex morphologies with stereotypical branching patterns. However, current knowledge of the axonal response to injury gives little consideration to axonal branches, nor do strategies to promote axon regeneration. This article reviews evidence from in vivo spinal cord imaging that axonal branches markedly impact the degenerative and regenerative responses to injury. At a major bifurcation point, depending on whether one or both axonal branches are injured, neurons may choose either a …

In Vivo Effectiveness And Safety Of Probiotics On Prophylaxis And Treatment Of Oral Candidiasis: A Systematic Review And Meta-Analysis, Lijun Hu, Mimi Zhou, Andrew L. Young, Weiwei Zhao, Zhimin Yan

All Dugoni School of Dentistry Faculty Articles

BACKGROUND: To systematically review and assess the in vivo effectiveness and safety of probiotics for prophylaxis and treating oral candidiasis.

METHODS: A literature search for studies published in English until August 1, 2018 was conducted in the following databases: PubMed, EMBASE, Cochrane Library, and Web of Science. Randomized controlled clinical trials and experimental mouse animal model studies comparing probiotics (at any dosage and in any form) with control groups (placebo, blank control or other agents) and reporting outcomes of the prophylactic and therapeutic effects were considered for inclusion. A descriptive study and, potentially, a meta-analysis were planned.

RESULTS: Six randomized …

Pathologic Gene Network Rewiring Implicates Ppp1r3a As A Central Regulator In Pressure Overload Heart Failure., Pablo Cordero, Victoria N Parikh, Elizabeth T Chin, Ayca Erbilgin, Michael J Gloudemans, Ching Shang, Yong Huang, Alex C Chang, Kevin S Smith, Frederick Dewey, Kathia Zaleta, Michael Morley, Jeff Brandimarto, Nicole Glazer, Daryl Waggott, Aleksandra Pavlovic, Mingming Zhao, Christine S Moravec, W H Wilson Tang, Jamie Skreen, Christine Malloy, Sridhar Hannenhalli, Hongzhe Li, Scott Ritter, Mingyao Li, Daniel Bernstein, Andrew Connolly, Hakon Hakonarson, Aldons J Lusis, Kenneth B Margulies, Anna A Depaoli-Roach, Stephen B Montgomery, Matthew T Wheeler, Thomas Cappola, Euan A Ashley

Articles, Abstracts, and Reports

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and …

Preoperative Stimulation Of Resolution And Inflammation Blockade Eradicates Micrometastases., Dipak Panigrahy, Allison Gartung, Jun Yang, Haixia Yang, Molly M Gilligan, Megan L Sulciner, Swati S Bhasin, Diane R Bielenberg, Jaimie Chang, Birgitta A Schmidt, Julia Piwowarski, Anna Fishbein, Dulce Soler-Ferran, Matthew A Sparks, Steven J Staffa, Vidula Sukhatme, Bruce D Hammock, Mark W Kieran, Sui Huang, Manoj Bhasin, Charles N Serhan, Vikas P Sukhatme

Articles, Abstracts, and Reports

Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 …

Xx Sex Chromosome Complement Promotes Atherosclerosis In Mice, Yasir Alsiraj, Xuqi Chen, Sean E. Thatcher, Ryan E. Temel, Lei Cai, Eric M. Blalock, Wendy Katz, Heba M. Ali, Michael C. Petriello, Pan Deng, Andrew J. Morris, Xuping Wang, Aldons J. Lusis, Arthur P. Arnold, Karen Reue, Katherine L. Thompson, Patrick Tso, Lisa A. Cassis

Pharmacology and Nutritional Sciences Faculty Publications

Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown. Here, we use mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We assess atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating …

Cyclin C Regulated Oxidative Stress Responsive Transcriptome In Mus Musculus Embryonic Fibroblasts, David C Stieg, Kai-Ti Chang, Katrina F Cooper, Randy Strich

Rowan-Virtua School of Osteopathic Medicine Faculty Scholarship

The transcriptional changes that occur in response to oxidative stress help direct the decision to maintain cell viability or enter a cell death pathway. Cyclin C-Cdk8 is a conserved kinase that associates with the RNA polymerase II Mediator complex that stimulates or represses transcription depending on the locus. In response to oxidative stress, cyclin C, but not Cdk8, displays partial translocation into the cytoplasm. These findings open the possibility that cyclin C relocalization is a regulatory mechanism governing oxidative stress-induced transcriptional changes. In the present study, the cyclin C-dependent transcriptome was determined and compared to transcriptional changes occurring in oxidatively …

Altered Detrusor Contractility And Voiding Patterns In Mice Lacking The Mechanosensitive Trek-1 Channel., Ricardo H. Pineda, Joseph Hypolite, Sanghee Lee, Alonso Carrasco, Nao Iguchi, Randall B. Meacham, Anna P. Malykhina

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Previously published results from our laboratory identified a mechano-gated two-pore domain potassium channel, TREK-1, as a main mechanosensor in the smooth muscle of the human urinary bladder. One of the limitations of in vitro experiments on isolated human detrusor included inability to evaluate in vivo effects of TREK-1 on voiding function, as the channel is also expressed in the nervous system, and may modulate micturition via neural pathways. Therefore, in the present study, we aimed to assess the role of TREK-1 channel in bladder function and voiding patterns in vivo by using TREK-1 knockout (KO) mice.

METHODS: Adult C57BL/6 …

A High-Throughput Screen Indicates Gemcitabine And Jak Inhibitors May Be Useful For Treating Pediatric Aml, Christina D. Drenberg, Anang Shelat, Jinjun Dang, Anitria Cotton, Shelley J. Orwick, Mengyu Li, Jae Yoon Jeon, Qiang Fu, Daelynn R. Buelow, Marissa Pioso, Shuiying Hu, Hiroto Inaba, Raul C. Ribeiro, Jeffrey E. Rubnitz, Tanja A. Gruber, R. Kiplin Guy, Sharyn D. Baker

Pharmaceutical Sciences Faculty Publications

Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates < 40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML.

Gasdermin Pores Permeabilize Mitochondria To Augment Caspase-3 Activation During Apoptosis And Inflammasome Activation., Corey Rogers, Dan A. Erkes, Alexandria Nardone, Andrew E. Aplin, Teresa Fernandes-Alnemri, Emad S. Alnemri

Department of Biochemistry and Molecular Biology Faculty Papers

Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis by forming pores in the plasma membrane. Here we show that GSDME-N also permeabilizes the mitochondrial membrane, releasing cytochrome c and activating the apoptosome. Cytochrome c release and caspase-3 activation in response to intrinsic and extrinsic apoptotic stimuli are significantly reduced in GSDME-deficient cells comparing with wild type cells. GSDME deficiency also accelerates cell growth in culture and in a mouse model of melanoma. Phosphomimetic mutation of the highly conserved phosphorylatable Thr6 residue of GSDME, inhibits its pore-forming activity, thus uncovering a potential mechanism by which GSDME …

Proteomic Alterations Of Hdl In Youth With Type 1 Diabetes And Their Associations With Glycemic Control: A Case-Control Study, Evgenia Gourgari, Junfeng Ma, Martin P. Playford, Nehal N. Mehta, Radoslav Goldman, Alan T. Remaley, Scott M. Gordon

Saha Cardiovascular Research Center Faculty Publications

Background: Patients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition.

Methods: This was a cross-sectional case–control study. Blood samples were obtained from patients with T1DM and …

Alterations In Phosphorylation Of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection., Elizabeth K K Glennon, Laura S Austin, Nadia Arang, Heather S Kain, Fred D Mast, Kamalakannan Vijayan, John D Aitchison, Stefan H I Kappe, Alexis Kaushansky

Articles, Abstracts, and Reports

Plasmodium parasites are highly selective when infecting hepatocytes and induce many changes within the host cell upon infection. While several host cell factors have been identified that are important for liver infection, our understanding of what facilitates the maintenance of infection remains incomplete. Here, we describe a role for phosphorylated ribosomal protein S6 (Ser235/236) (p-RPS6) in Plasmodium yoelii-infected hepatocytes. Blocking RPS6 phosphorylation prior to infection decreases the number of liver stage parasites within 24 h. Infected hepatocytes exhibit elevated levels of p-RPS6 while simultaneously abrogating the induction of phosphorylation of RPS6 in response to insulin stimulation. This is in contrast …

H3k27m Induces Defective Chromatin Spread Of Prc2-Mediated Repressive H3k27me2/Me3 And Is Essential For Glioma Tumorigenesis., Ashot S. Harutyunyan, Brian Krug, Haifen Chen, Simon Papillon-Cavanagh, Michele Zeinieh, Nicolas De Jay, Shriya Deshmukh, Carol C L Chen, Jad Belle, Leonie G. Mikael, Dylan M. Marchione, Rui Li, Hamid Nikbakht, Bo Hu, Gael Cagnone, Warren A. Cheung, Abdulshakour Mohammadnia, Denise Bechet, Damien Faury, Melissa K. Mcconechy, Manav Pathania, Siddhant U. Jain, Benjamin Ellezam, Alexander G. Weil, Alexandre Montpetit, Paolo Salomoni, Tomi Pastinen, Chao Lu, Peter W. Lewis, Benjamin A. Garcia, Claudia L. Kleinman, Nada Jabado, Jacek Majewski

Manuscripts, Articles, Book Chapters and Other Papers

Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on …

Development And Validation Of A Rapid Method For The Detection Of Latrunculol A In Plasma., Jiajiu Shaw, Frederick A. Valeriote, Joseph Media, Tyler A. Johnson, Taro Amagata, Karen Tenney, Phillip Crews

Tyler Johnson

Latrunculol A is a recently discovered 6,7-dihydroxy analog of the potent actin inhibitor latrunculin A. Latrunculol A has exhibited greater cytotoxicity than latrunculin A against both murine and human colon tumor cell lines in vitro. Currently, there are no reports regarding the bioavailability of latrunculol A in vivo. This study was undertaken as a prelude to pharmacokinetic assessments and it is the first work where bioavailability of latrunculol A was studied. In the present work, a simple plasma preparation and a rapid HPLC method have been developed. Mouse plasma containing latrunculol A was first treated by acetonitrile and then centrifuged …

Stress-Induced Epinephrine Enhances Lactate Dehydrogenase A And Promotes Breast Cancer Stem-Like Cells, Bai Cui, Yuanyuan Luo, Pengfei Tian, Fei Peng, Jinxin Lu, Yongliang Yang, Qitong Su, Bing Liu, Jiachuan Yu, Xi Luo, Liu Yin, Wei Cheng, Fan An, Bin He, Dapeng Liang, Sijin Wu, Peng Chu, Luyao Song, Xinyu Liu, Huandong Luo, Binhua P. Zhou

Molecular and Cellular Biochemistry Faculty Publications

Chronic stress triggers activation of the sympathetic nervous system and drives malignancy. Using an immunodeficient murine system, we showed that chronic stress–induced epinephrine promoted breast cancer stem-like properties via lactate dehydrogenase A–dependent (LDHA-dependent) metabolic rewiring. Chronic stress–induced epinephrine activated LDHA to generate lactate, and the adjusted pH directed USP28-mediated deubiquitination and stabilization of MYC. The SLUG promoter was then activated by MYC, which promoted development of breast cancer stem-like traits. Using a drug screen that targeted LDHA, we found that a chronic stress–induced cancer stem-like phenotype could be reversed by vitamin C. These findings demonstrated the critical importance of psychological …

A Cleft Lip And Palate Gene, Irf6, Is Involved In Osteoblast Differentiation Of Craniofacial Bone, Jake Thompson, Fabian Mendoza, Ethan Tan, Jessica Wildgrube Bertol, Arju S. Gaggar, Goo Jun, Cláudia Cristina Biguetti, Walid Fakhouri

School of Podiatric Medicine Publications and Presentations

Background:

Interferon Regulatory Factor 6 (IRF6) plays a critical role in embryonic tissue development including differentiation of epithelial cells. Besides orofacial clefting due to haploinsufficiency of IRF6, recent human genetic studies indicated that mutations in IRF6 are linked to small mandible and digit abnormalities. The function of IRF6 has been well studied in oral epithelium, however its role in craniofacial skeletal formation remains unknown. In this study, we investigated the role of Irf6 in craniofacial bone development using comparative analyses between wild-type and Irf6-null littermate mice

Results:

Immunostaining revealed the expression of IRF6 in hypertrophic chondrocytes, osteocytes …

Neoantigen Screening Identifies Broad Tp53 Mutant Immunogenicity In Patients With Epithelial Cancers., Parisa Malekzadeh, Anna Pasetto, Paul F Robbins, Maria R Parkhurst, Biman C Paria, Li Jia, Jared J Gartner, Victoria Hill, Zhiya Yu, Nicholas P Restifo, Abraham Sachs, Eric Tran, Winifred Lo, Robert Pt Somerville, Steven A Rosenberg, Drew C Deniger

Articles, Abstracts, and Reports

No abstract provided.

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

Tyler Johnson

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 …

Lipophilic Stinging Nettle Extracts Possess Potent Anti-Inflammatory Activity, Are Not Cytotoxic And May Be Superior To Traditional Tinctures For Treating Inflammatory Disorders., Tyler A. Johnson, Johann Sohn, Wayne D Inman, Leonard F Bjeldanes, Keith Rayburn

Tyler Johnson

Extracts of four plant portions (roots, stems, leaves and flowers) of Urtica dioica (the stinging nettle) were prepared using accelerated solvent extraction (ASE) involving water, hexanes, methanol and dichloromethane. The extracts were evaluated for their anti-inflammatory and cytotoxic activities in an NF-κB luciferase and MTT assay using macrophage immune (RAW264.7) cells. A standardized commercial ethanol extract of nettle leaves was also evaluated. The methanolic extract of the flowering portions displayed significant anti-inflammatory activity on par with a standard compound celastrol (1) but were moderately cytotoxic. Alternatively, the polar extracts (water, methanol, ethanol) of the roots, stems and leaves displayed moderate …

Pretreatment With A Heat-Killed Probiotic Modulates The Nlrp3 Inflammasome And Attenuates Colitis-Associated Colorectal Cancer In Mice., I-Che Chung, Chun-Nan Ouyang, Sheng-Ning Yuan, Hsin-Chung Lin, Kuo-Yang Huang, Pao-Shu Wu, Chia-Yuan Liu, Kuen-Jou Tsai, Lai-Keng Loi, Yu-Jen Chen, An-Ko Chung, David M. Ojcius, Yu-Sun Chang, Lih-Chyang Chen

All Dugoni School of Dentistry Faculty Articles

Colorectal cancer (CRC) is one of the most common malignancies worldwide. Inflammation contributes to cancer development and inflammatory bowel disease is an important risk factor for CRC. The aim of this study is to assess whether a widely used probiotic Enterococcus faecalis can modulate the NLRP3 inflammasome and protect against colitis and colitis-associated CRC. We studied the effect of heat-killed cells of E. faecalis on NLRP3 inflammasome activation in THP-1-derived macrophages. Pretreatment of E. faecalis or NLRP3 siRNA can inhibit NLRP3 inflammasome activation in macrophages in response to fecal content or commensal microbes, P. mirabilis or E. coli, according …

Discovery Of Selective Toxoplasma Gondii Dihydrofolate Reductase Inhibitors For The Treatment Of Toxoplasmosis, Allen T Hopper, Adam Brockman, Andy Wise, Julie Gould, Jennifer Barks, Joshua B Radke, L. David Sibley, Yongmao Zou, Stephen Thomas

2010-2019 OA Pubs

A safer treatment for toxoplasmosis would be achieved by improving the selectivity and potency of dihydrofolate reductase (DHFR) inhibitors, such as pyrimethamine (1), for Toxoplasma gondii DHFR ( TgDHFR) relative to human DHFR ( hDHFR). We previously reported on the identification of meta-biphenyl analog 2, designed by in silico modeling of key differences in the binding pocket between TgDHFR and hDHFR. Compound 2 improves TgDHFR selectivity 6.6-fold and potency 16-fold relative to 1. Here, we report on the optimization and structure-activity relationships of this arylpiperazine series leading to the discovery of 5-(4-(3-(2-methoxypyrimidin-5-yl)phenyl)piperazin-1-yl)pyrimidine-2,4-diamine 3. Compound 3 has a TgDHFR IC