Medicine and Health Sciences Commons^™

Reduction Of Endothelial Nitric Oxide Increases The Adhesiveness Of Constitutive Endothelial Membrane Icam-1 Through Src-Mediated Phosphorylation, Feng Gao, Brandon P. Lucke-Wold, Xiang Li, Aric F. Logsdon, Li-Chong Xu, Sulei Xu, Kyle B. Lapenna, Huaqi Wang, M.A. Hassan Talukder, Christopher A. Siedlecki, Jason D. Huber, Charles L. Rosen, Pingnian He

Faculty & Staff Scholarship

Nitric oxide (NO) is a known anti-adhesive molecule that prevents platelet aggregation and leukocyte adhesion to endothelial cells (ECs). The mechanism has been attributed to its role in the regulation of adhesion molecules on leukocytes and the adhesive properties of platelets. Our previous study conducted in rat venules found that reduction of EC basal NO synthesis caused EC ICAM-1-mediated firm adhesion of leukocytes within 10–30min. This quick response occurred in the absence of alterations of adhesion molecules on leukocytes and also opposes the classical pattern of ICAM-1-mediated leukocyte adhesion that requires protein synthesis and occurs hours after stimulation. The objective …

Permeability Changes And Effect Of Chemotherapy In Brain Adjacent To Tumor In An Experimental Model Of Metastatic Brain Tumor From Breast Cancer, Afroz S. Mohammad, Chris E. Adkins, Neal Shah, Rawaa Aljammal, Jessica I. G. Griffith, Rachel M. Tallman, Katherine L. Jarrell, Paul R. Lockman

Faculty & Staff Scholarship

Abstract

Background: Brain tumor vasculature can be significantly compromised and leakier than that of normal brain blood vessels. Little is known if there are vascular permeability alterations in the brain adjacent to tumor (BAT). Changes in BAT permeability may also lead to increased drug permeation in the BAT, which may exert toxicity on cells of the central nervous system. Herein, we studied permeation changes in BAT using quantitative fluorescent microscopy and autoradiography, while the effect of chemotherapy within the BAT region was determined by staining for activated astrocytes.

Methods: Human metastatic breast cancer cells (MDA-MB-231Br) were injected into left ventricle …

Group Ii Innate Lymphoid Cells And Microvascular Dysfunction From Pulmonary Titanium Dioxide Nanoparticle Exposure, Alaeddin Bashir Abukabda, Carroll Rolland Mcbride, Thomas Paul Batchelor, William Travis Goldsmith, Elizabeth Compton Bowdridge, Krista Lee Garner, Sherri Friend, Timothy Robert Nurkiewicz

Faculty & Staff Scholarship

Background: The cardiovascular effects of pulmonary exposure to engineered nanomaterials (ENM) are poorly understood, and the reproductive consequences are even less understood. Inflammation remains the most frequently explored mechanism of ENM toxicity. However, the key mediators and steps between lung exposure and uterine health remain to be fully defined. The purpose of this study was to determine the uterine inflammatory and vascular effects of pulmonary exposure to titanium dioxide nanoparticles (nano-TiO2). We hypothesized that pulmonary nano-TiO2 exposure initiates a Th2 inflammatory response mediated by Group II innate lymphoid cells (ILC2), which may be associated with an impairment in uterine microvascular …

Exposure To Mild Blast Forces Induces Neuropathological Effects, Neurophysiological Deficits And Biochemical Changes, Adan Hernandez, Chunfeng Tan, Florian Plattner, Aric F. Logsdon, Karine Pozo, Mohammad A. Yousuf, Tanvir Singh, Ryan C. Turner, Brandon P. Luke-Wold, Jason D. Huber, Charles L. Rosen, James A. Bibb

Faculty & Staff Scholarship

Direct or indirect exposure to an explosion can induce traumatic brain injury (TBI) of various severity levels. Primary TBI from blast exposure is commonly characterized by internal injuries, such as vascular damage, neuronal injury, and contusion, without external injuries. Current animal models of blast-induced TBI (bTBI) have helped to understand the deleterious effects of moderate to severe blast forces. However, the neurological effects of mild blast forces remain poorly characterized. Here, we investigated the effects caused by mild blast forces combining neuropathological, histological, biochemical and neurophysiological analysis. For this purpose, we employed a rodent blast TBI model with blast forces …

Experimental Intravascular Hemolysis Induces Hemodynamic And Pathological Pulmonary Hypertension: Association With Accelerated Purine Metabolism, Victor P. Bilan, Frank Schneider, Enrico M. Novelli, Eric E. Kelley, Sruti Shiva, Mark T. Gladwin, Edwin K. Jackson, Stevan P. Tofovic

Faculty & Staff Scholarship

Pulmonary hypertension (PH) is emerging as a serious complication associated with hemolytic disorders, and plexiform lesions (PXL) have been reported in patients with sickle cell disease (SCD). We hypothesized that repetitive hemolysis per se induces PH and angioproliferative vasculopathy and evaluated a new mechanism for hemolysis-associated PH (HA-PH) that involves the release of adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) from erythrocytes. In healthy rats, repetitive admin- istration of hemolyzed autologous blood (HAB) for 10 days produced reversible pulmonary parenchymal injury and vascular remodeling and PH. Moreover, the combination of a single dose of Sugen-5416 (SU, 200mg/kg) and 10-day …

Inhibition Of Phosphodiesterase-4 Reverses Aβ-Induced Memory Impairment By Regulation Of Hpa Axis Related Camp Signaling, Ying Xu, Naping Zhu, Wen Xu, Han Ye, Kaiping Liu, Feiyan Wu, Meixi Zhang, Yun Ding, Chong Zhang, Hanting Zhang, James O'Donnell, Jiangchun Pan

Faculty & Staff Scholarship

Beta amyloid peptides (Aβ) are found to be associated with dysfunction of hypothalamic-pituitary-adrenal axis (HPA axis) that leads to memory and cognitive deficits in patients with Alzheimer’s disease (AD). Phosphodiesterase 4 (PDE4) inhibitors increase the intracellular cAMP activities, which may ameliorate cognitive deficits associated with AD. However, it remains unclear whether PDE4-mediated reversal of cognitive impairment in mouse model of AD is related to HPA axis and downstream cAMP-dependent pathway. The present study investigated the effects of PDE4 inhibitor rolipram on Aβ1-42-induced cognitive dysfunction and its underlying mechanisms. The step-down passive avoidance (PA) and Morris water-maze (MWM) tests were conducted …

Incineration Of Nanoclay Composites Leads To Byproducts With Reduced Cellular Reactivity, Alixandra Wagner, Andrew P. White, Man Chio Tang, Sushant Agarwal, Todd A. Stueckle, Yon Rojanasakul, Rakesh K. Gupta, Carasela Zoica Dinu

Faculty & Staff Scholarship

Addition of nanoclays into a polymer matrix leads to nanocomposites with enhanced properties to be used in plastics for food packaging applications. Because of the plastics’ high stored energy value, such nanocomposites make good candidates for disposal via municipal solid waste plants. However, upon disposal, increased concerns related to nanocomposites’ byproducts potential toxicity arise, especially considering that such byproducts could escape disposal filters to cause inhalation hazards. Herein, we investigated the effects that byproducts of a polymer polylactic acid-based nanocomposite containing a functionalized montmorillonite nanoclay (Cloisite 30B) could pose to human lung epithelial cells, used as a model for inhalation …

Fasudil In Combination With Bone Marrow Stromal Cells (Bmscs) Attenuates Alzheimer’S Disease-Related Changes Through The Regulation Of The Peripheral Immune System, Jiezhong Yu, Yuqing Yan, Qingfang Gu, Gajendra Kumar, Hongqiang Yu, Yijin Zhao, Chunyun Liu, Ye Gao, Zhi Chai, Jasleen Chumber, Bao-Guo Xiao, Guang-Xian Zhang, Han-Ting Zhang, Yuqiang Jiang, Cun-Gen Ma

Faculty & Staff Scholarship

Alzheimer’s disease (AD) is a chronic progressive neurodegenerative disease. Its mechanism is still not clear. Majority of research focused on the central nervous system (CNS) changes, while few studies emphasize on peripheral immune system modulation. Our study aimed to investigate the regulation of the peripheral immune system and its relationship to the severity of the disease after treatment in an AD model of APPswe/PSEN1dE9 transgenic (APP/PS1 Tg) mice. APP/PS1 Tg mice (8 months old) were treated with the ROCK-II inhibitor 1-(5-isoquinolinesulfonyl)- homo-piperazine (Fasudil) (intraperitoneal (i.p.) injections, 25 mg/kg/day), bone marrow stromal cells (BMSCs; caudal vein injections, 1 × 106 BMSCs …

In Utero Gene Expression In The Slc39a8(Neo/Neo) Knockdown Mouse, Jing Chen, Marina Galvez-Peralta, Xiang Zhang, Jingyuan Deng, Zijuan Liu, Daniel W. Nebert

Faculty & Staff Scholarship

Slc39a8 encodes ZIP8, a divalent cation/bicarbonate symporter expressed in pluripotent mouse embryonic stem cells, and therefore ubiquitous in adult tissues; ZIP8 influxes Zn2+, Mn2+ and Fe2+. Slc39a8(neo/neo) knockdown mice exhibit 10–15% of wild-type ZIP8 mRNA and protein levels, and show pleiotropic phenotype of stunted growth, neonatal lethality, multi-organ dysmorphogenesis, and dysregulated hematopoiesis manifested as severe anemia. Herein we performed RNA-seq analysis of gestational day (GD)13.5 yolk sac and placenta, and GD16.5 liver, kidney, lung, heart and cerebellum,comparing Slc39a8(neo/neo) with Slc39a8(+/+) wild-type. Meta-data analysis of differentially- expressed genes revealed 29 unique genes from all tissues — having enriched GO categories associated …

Spontaneous Dna Damage To The Nuclear Genome Promotes Senescence, T Redox Imbalance And Aging, Andria R. Robinson, Matthew J. Yousefzadeh, Tania A. Rozgaja, Jin Wang, Xuesen Li, Jeremy S. Tilstra, Chelsea H. Feldman, Siobhan Q. Gregg, Caroline H. Johnson, Erin M. Skoda, Marie-Celine Frantz, Harris Bell-Temin, Hannah Pope-Varsalona, Aditi U. Gurkar, Luigi A. Nasto, Rena A.S. Robinson, Heike Fuhrmann-Stroissnigg, Jolanta Czerwinska, Sara J. Mcgowan, Nadiezhda Cantu-Madellin, Jamie B. Harris, Salony Maniar, Mark A. Ross, Christy E. Trussoni, Nicholas F. Larusso, Eugenia Cifuentes-Pagano, Patrick J. Pagano, Barbara Tudek, Nam V. Vo, Lora H. Rigatti, Patricia L. Opresko, Donna B. Stolz, Simon C. Watkins, Christin E. Burd, Claudette M. St, Croix, Gary Siuzdak, Nathan A. Yates, Paul D. Robbins, Yinsheng Wang, Peter Wipf, Eric E. Kelley, Laura J. Neidernhofer

Faculty & Staff Scholarship

Accumulation of senescent cells over time contributes to aging and age-related diseases. However, what drives senescence in vivo is not clear. Here we used a genetic approach to determine if spontaneous nuclear DNA damage is sufficient to initiate senescence in mammals. Ercc1-/Δ mice with reduced expression of ERCC1-XPF endonuclease have impaired capacity to repair the nuclear genome. Ercc1-/Δ mice accumulated spontaneous, oxidative DNA damage more rapidly than wild-type (WT) mice. As a consequence, senescent cells accumulated more rapidly in Ercc1-/Δ mice compared to repair-competent animals. However, the levels of DNA damage and senescent cells in Ercc1-/Δ mice never exceeded that …

Wdr5 Supports Colon Cancer Cells By Promoting Methylation Of H3k4 And Suppressing Dna Damage, Beth K. Neilsen, Binita Chakraborty, Jamie L. Mccall, Danielle E. Frodyma, Richard L. Sleightholm, Kurt W. Fisher, Robert E. Lewis

Faculty & Staff Scholarship

Background: KMT2/MLL proteins are commonly overexpressed or mutated in cancer and have been shown to support cancer maintenance. These proteins are responsible for methylating histone 3 at lysine 4 and promoting transcription and DNA synthesis; however, they are inactive outside of a multi-protein complex that requires WDR5. WDR5 has been implicated in cancer for its role in the COMPASS complex and its interaction with Myc; however, the role of WDR5 in colon cancer has not yet been elucidated.

Methods: WDR5 expression was evaluated using RT-qPCR and western blot analysis. Cell viability and colony forming assays were utilized to evaluate the …

Conformational Switching In The Coiled-Coil Domains Of A Proteasomal Atpase Regulates Substrate Processing, Aaron Snoberger, Evan J. Brettrager, David M. Smith

Faculty & Staff Scholarship

Protein degradation in all domains of life requires ATPases that unfold and inject proteins into compartmentalized proteolytic chambers. Proteasomal ATPases in eukaryotes and archaea contain poorly understood N-terminally conserved coiled-coil domains. In this study, we engineer disulfide crosslinks in the coiled-coils of the archaeal proteasomal ATPase (PAN) and report that its three identical coiled-coil domains can adopt three different conforma- tions: (1) in-register and zipped, (2) in-register and partially unzipped, and (3) out-of-register. This conformational heterogeneity conflicts with PAN’s symmetrical OB-coiled-coil crystal structure but resembles the conformational heterogeneity of the 26S proteasomal ATPases’ coiled-coils. Furthermore, we find that one coiled-coil …

Statewide Cross-Sectional Survey Of Emergency Departments’ Adoption And Implementation Of The Ohio Opioid Prescribing Guidelines And Opioid Prescribing Practices, Jonathan Penm, Neil J. Mackinnon, Rebecca Mashni, Michael S. Lyons, Edmond A. Hooker, Erin L. Winstanley, Steve Carlton-Ford, Chloe Connelly, Erica Tolle, Jill Boone, Kathleen Koechlin, Jolene Defiore-Hyrmer

Faculty & Staff Scholarship

study objective: To evaluate the implementation of the Ohio Emergency and Acute Care Facility Opioids and Other Controlled Substances Prescribing Guidelines and their perceived impact on local policies and practice.

Methods: The study design was a cross-sectional survey of emergency department (ED) medical directors, or appropriate person identified by the hospital, perception of the impact of the Ohio ED Opioid Prescribing Guidelines on their departments practice. All hospitals with an ED in Ohio were contacted throughout October and November 2016. Distribution followed Dillman’s Tailored Design Method, augmented with telephone recruitment. Hospital chief executive officers were contacted when necessary to encourage …

Increased Phenacetin Oxidation Upon The L382v Substitution In Cytochrome P450 1a2 Is Associated With Altered Substrate Binding Orientation, Qingbiao Huang, Grazyna D. Szklarz

Faculty & Staff Scholarship

Leucine382 of cytochrome P450 1A2 (CYP1A2) plays an important role in binding and O-dealkylation of phenacetin, with the L382V mutation increasing substrate oxidation (Huang and Szklarz, 2010, Drug Metab. Dispos. 38:1039–1045). This was attributed to altered substrate binding orientation, but no direct experimental evidence had been available. Therefore, in the current studies, we employed nuclear magnetic resonance (NMR) longitudinal (T1) relaxation measurements to investigate phenacetin binding orientations within the active site of CYP1A2 wild type (WT) and mutants. Paramagnetic relaxation time (T1P) for each proton of phenacetin was calculated from the T1 value obtained from the enzymes in ferric and …

A Small Molecule P53 Activator Attenuates Fanconi Anemia Leukemic Stem Cell Proliferation, Wei Du, Xiaoli Li, Andrew F. Wilson, Qishen Pang

Faculty & Staff Scholarship

Although p53 mutations are common in solid tumors, such mutations are found at a lower frequency in hematologic malignancies. In the genetic disorder Fanconi anemia (FA), p53 has been proposed as an important pathophysiological factor for two important hematologic hallmarks of the disease: bone marrow failure and leukemogenesis. Here we show that low levels of the p53 protein enhance the capacity of leukemic stem cells from FA patients to repopulate immunodeficient mice. Furthermore, boosting p53 protein levels with the use of the small molecule Nutlin-3 reduced leukemia burden in recipient mice. These results demonstrate that the level of p53 protein …

Polypharmacy Among Patients With Diabetes: A Cross-Sectional Retrospective Study In A Tertiary Hospital In Saudi Arabia, Monira Alwhaibi, Bander Balkhi, Tariq M. Alhawassi, Hadeel Alkofide, Nouf Alduhaim, Rawan Alabdulali, Hadeel Drweesh, Ursha Sambamoorthi

Faculty & Staff Scholarship

Abstract Patients with diabetes are at high risk for polypharmacy (ie, use of multiple medications) for treatment of diabetes, associated comorbidities and other coexisting conditions. This study aims to estimate the prevalence of polypharmacy and factors associated with polypharmacy among adult patients with diabetes.Methods A cross-sectional retrospective observational study of adults with diabetes, who visited the outpatient clinic of a tertiary teaching hospital in Saudi Arabia, was conducted. Data were extracted from the Electronic Health Record database for a period of 12 months (January– December 2016). Polypharmacy was defined as the cumulative use of five or more medications. Polypharmacy among …

Photoluminescence Mechanism And Applications Of Zn-Doped Carbon Dots, Quan Xu, Wei Cai, Miaoran Zhang, Yingchun Ye, Yeqing Li, Lipeng Zhang, Yongjian Guo, Zhiqiang Yu, Siyu Li, Xun Lin, Yusheng Chen, Yan Lou, Jason Street, Meng Xu

Faculty & Staff Scholarship

Heteroatom-doped carbon dots (CDs) with excellent optical characteristics and negligible toxicity have emerged in many applications including bioimaging, biosensing, photocatalysis, and photothermal therapy. The metal-doping of CDs using various heteroatoms results in an enhancement of the photophysics but also imparts them with multifunctionality. However, unlike nonmetal doping, typical metal doping results in low fluorescence quantum yields (QYs), and an unclear photoluminescence mechanism. In this contribution, we detail results concerning zinc doped CDs (Zn-CDs) with QYs of up to 35%. The zinc ion charges serve as a surface passivating agent and prevent the aggregation of graphene p–p stacking, leading to an …

Pseudomonas Aeruginosa Algr Phosphorylation Status Differentially Regulates Pyocyanin And Pyoverdine Production, Alexander S. Little, Yuta Okkotsu, Alexandria A. Reinhart, Heath Damron, Mariette Barbier, Brandon Barrett, Amanda G. Ogledby-Sherrouse, Joanna B. Goldberg, William L. Cody, Michael J. Schurr, Michael L. Vasil

Faculty & Staff Scholarship

Pseudomonas aeruginosa employs numerous, complex regulatory ele- ments to control expression of its many virulence systems. The P. aeruginosa AlgZR two-component regulatory system controls the expression of several crucial viru- lence phenotypes. We recently determined, through transcriptomic profiling of a PAO1 ΔalgR mutant strain compared to wild-type PAO1, that algZR and hemCD are cotranscribed and show differential iron-dependent gene expression. Previous ex- pression profiling was performed in strains without algR and revealed that AlgR acts as either an activator or repressor, depending on the gene. Thus, examination of P. aeruginosa gene expression from cells locked into different AlgR phosphorylation states …

Theaflavin-3,3′-Digallate Enhances The Inhibitory Effect Of Cisplatin By Regulating The Copper Transporter 1 And Glutathione In Human Ovarian Cancer Cells, Haibo Pan, Eunhye Kim, Gary O. Rankin, Yon Rojanasakul, Youying Tu, Yi Charlie Chen

Faculty & Staff Scholarship

Ovarian cancer has the highest fatality rate among the gynecologic cancers. The side effects, high relapse rate, and drug resistance lead to low long-term survival rate (less than 40%) of patients with advanced ovarian cancer. Theaflavin-3,3′-digallate (TF3), a black tea polyphenol, showed less cytotoxicity to normal ovarian cells than ovarian cancer cells. We aimed to investigate whether TF3 could potentiate the inhibitory effect of cisplatin against human ovarian cancer cell lines. In the present study, combined treatment with TF3 and cisplatin showed a synergistic cytotoxicity against A2780/CP70 and OVCAR3 cells. Treatment with TF3 could increase the intracellular accumulation of platinum …

Impact Of Universal Medical Insurance System On The Accessibility Of Medical Service Supply And Affordability Of Patients In China, Xiaolei Xiong, Zhiguo Zhang, Jing Ren, Jie Zhang, Xiaoyun Pan, Liang Zhang, Shiwei Gong, Si Jin

Faculty & Staff Scholarship

Background

China’s universal medical insurance system (UMIS) is designed to promote social fairness through improving access to medical services and reducing out-of-pocket (OOP) costs for all Chinese. However, it is still not known whether UMIS has a significant impact on the accessibility of medical service supply and the affordability, as well as the seeking-care choice, of patients in China.

Methods

Segmented time-series regression analysis, as a powerful statistical method of interrupted time series design, was used to estimate the changes in the quantity and quality of medical service supply before and after the implementation of UMIS. The rates of catastrophic …

State-Level Variability In Veteran Reliance On Veterans Health Administration And Potentially Preventable Hospitalizations: A Geospatial Analysis, Drew A. Helmer, Mazhgan Rowneki, Xue Feng, Chin-Lin Tseng, Danielle Rose, Orysya Soroka, Dennis Fried, Nisha Jani, Leonard M. Pogach, Usha Sambamoorthi

Faculty & Staff Scholarship

Most Veterans who use the Veterans Health Administration (VHA) also utilize private-sector health care providers. To better inform local and regional health care planning, we assessed the association between reliance on VHA ambulatory care and total and system-specific preventable hospitalization rates (PHRs) at the state level. We conducted a retrospective dynamic cohort study using Veterans with diabetes mellitus, aged 66 years or older, and dually enrolled in VHA and Medicare parts A and B from 2004 to 2010. While controlling for median age and proportion of males, we measured the association between reliance on VHA ambulatory care and PHRs at …

A Functional Signature Ontology (Fusion) Screen Detects An Ampk Inhibitor With Selective Toxicity Toward Human Colon Tumor Cells, Binita Das, Beth K. Neilsen, Kurt W. Fisher, Drew Gehring, Youcai Hu, Deanna J. Volle, Hyun Seok Kim, Jamie L. Mccall, David L. Kelly, John B. Macmillian, Michael A. White, Robert E. Lewis

Faculty & Staff Scholarship

AMPK is a serine threonine kinase composed of a heterotrimer of a catalytic, kinase-containing α and regulatory β and γ subunits. Here we show that individual AMPK subunit expression and requirement for survival varies across colon cancer cell lines. While AMPKα1 expression is relatively consistent across colon cancer cell lines, AMPKα1 depletion does not induce cell death. Conversely, AMPKα2 is expressed at variable levels in colon cancer cells. In high expressing SW480 and moderate expressing HCT116 colon cancer cells, siRNA-mediated depletion induces cell death. These data suggest that AMPK kinase inhibition may be a useful component of future therapeutic strategies. …

Three-Dimensional Imaging Of Kndy Neurons In The Mammalian Brain Using Optical Tissue Clearing And Multiple-Label Immunocytochemistry, Aleisha M. Moore, Kathryn A. Lucas, Robert L. Goodman, Lique M. Coolen, Michael N. Lehman

Faculty & Staff Scholarship

Kisspeptin/Neurokinin B/Dynorphin (KNDy) neurons of the arcuate nucleus (ARC) play a key role in the regulation of fertility. The ability to detect features of KNDy neurons that are essential for fertility may require three-dimensional (3D) imaging of the complete population. Recently developed protocols for optical tissue clearing permits 3D imaging of neuronal populations in un-sectioned brains. However, these techniques have largely been described in the mouse brain. We report 3D imaging of the KNDy cell population in the whole rat brain and sheep hypothalamus using immunolabelling and modification of a solvent-based clearing protocol, iDISCO. This study expands the use of …

Maternal Engineered Nanomaterial Inhalation During Gestation Alters The Fetal Transcriptome, P.A. Stapleton, Q.A. Hathaway, C.E. Nichols, A.B. Abukabda, M.V. Pinti, D.L. Shepherd, C.R. Mcbride, J. Yi, V.C. Castranova, J.M Hollander, Timothy Robert Nurkiewicz

Faculty & Staff Scholarship

Background: The integration of engineered nanomaterials (ENM) is well-established and widespread in clinical, commercial, and domestic applications. Cardiovascular dysfunctions have been reported in adult populations after exposure to a variety of ENM. As the diversity of these exposures continues to increase, the fetal ramifications of maternal exposures have yet to be determined. We, and others, have explored the consequences of ENM inhalation during gestation and identified many cardiovascular and metabolic outcomes in the F1 generation. The purpose of these studies was to identify genetic alterations in the F1 generation of Sprague-Dawley rats that result from maternal ENM inhalation during gestation. …

Macrophage Sensing Of Single- Walled Carbon Nanotubes Via Toll- Like Receptors, Sourav P. Mukherjee, Olesja Bondarenko, Pekka Kohonen, Fernando T. Andon, Tana Brzicova, Isabel Gessner, Sanjay Mathur, Massimo Bottini, Paolo Calligari, Lorenzo Stella, Elena Kisin, Anna Shvedova, Reija Autio, Heli Salminen-Mankonen, Ritta Lahesmaa, Bengt Fadeel

Faculty & Staff Scholarship

Carbon-based nanomaterials including carbon nanotubes (CNTs) have been shown to trigger

inflammation. However, how these materials are ‘sensed’ by immune cells is not known. Here we compared the effects of two carbon-based nanomaterials, single-walled CNTs (SWCNTs) and graphene oxide (GO), on primary human monocyte-derived macrophages. Genome-wide transcriptomics assessment was performed at sub-cytotoxic doses. Pathway analysis of the microarray data revealed pronounced effects on chemokine-encoding genes in macrophages exposed to SWCNTs, but not in response to GO, and these results were validated by multiplex array-based cytokine and chemokine profiling. Conditioned medium from SWCNT-exposed cells acted as a chemoattractant for dendritic cells. …

Absolute Lymphocyte And Neutrophil Counts In Neonatal Ischemic Brain Injury, Jessica M. Povroznik, Elizabeth B. Engler-Chiurazzi, Tania Nanavati, Paola Pergami

Faculty & Staff Scholarship

Objectives: This study aimed to identify differences in absolute neutrophils, lymphocytes, and neutrophil-to-lymphocyte ratio between neonates with two forms of ischemic brain injury, hypoxic-ischemic encephalopathy, and acute ischemic stroke, compared to controls. We also aimed to determine whether this neutrophil/lymphocyte response pattern is associated with disease severity or is a consequence of the effects of total-body cooling, an approved treatment for moderate-to-severe hypoxic-ischemic encephalopathy. Methods: A retrospective chart review of 101 neonates with hypoxic-ischemic encephalopathy + total-body cooling (n = 26), hypoxic-ischemic encephalopathy (n=12), acute ischemic stroke (n=15), and transient tachypnea of the newborn (n=48) was conducted; transient tachypnea of …

Hcn2 Channels In The Ventral Tegmental Area Regulate Behavioral Responses To Chronic Stress, Peng Zhong, Casey R. Vickstrom, Xiaojie Liu, Ying Hu, Laikang Yu, Han-Gang Yu, Qing-Song Liu

Faculty & Staff Scholarship

Dopamine neurons in the ventral tegmental area (VTA) are powerful regulators of depression-related behavior. Dopamine neuron activity is altered in chronic stress-based models of depression, but the underlying mechanisms remain incompletely understood. Here, we show that mice subject to chronic mild unpredictable stress (CMS) exhibit anxiety- and depressive-like behavior, which was associated with decreased VTA dopamine neuron firing in vivo and ex vivo. Dopamine neuron firing is governed by voltage-gated ion channels, in particular hyperpolarization- activated cyclic nucleotide-gated (HCN) channels. Following CMS, HCN-mediated currents were decreased in nucleus accumbens-projecting VTA dopamine neurons. Furthermore, shRNA-mediated HCN2 knockdown in the VTA was …

Prior Exposure To Corticosterone Markedly Enhances And Prolongs The Neuroinflammatory Response To Systemic Challenge With Lps, Kimberly A. Kelly, Lindsay T. Michalovicz, Julie V. Miller, Vincent Castranova, Diane B. Miller, James P. O'Callaghan

Faculty & Staff Scholarship

Systemic exposure to the inflammagen and bacterial endotoxin lipopolysaccharide (LPS) has been widely used to evaluate inflammation and sickness behavior. While many inflam- matory conditions occur in the periphery, it is well established that peripheral inflammation can affect the brain. Neuroinflammation, the elaboration of proinflammatory mediators in the CNS, commonly is associated with behavioral symptoms (e.g., lethargy, anhedonia, anorexia, depression, etc.) termed sickness behavior. Stressors have been shown to inter- act with and alter neuroinflammatory responses and associated behaviors. Here, we exam- ined the effects of the stress hormone, corticosterone (CORT), as a stressor mimic, on neuroinflammation induced with a …

The Humanistic And Economic Burden Associated With Anxiety And Depression Among Adults With Comorbid Diabetes And Hypertension, Kimberly Wallace, Xiaohui Zhao, Ranjita Misra, Usha Sambamoorthi

Faculty & Staff Scholarship

We conducted a retrospective cross-sectional study to estimate the humanistic and economic burden associated with depression and anxiety among adults with comorbid diabetes and hypertension. Pooled data from the 2013 and 2015 Medical Expenditure Panel Survey were used to include adults (≥18 years old) who were alive and diagnosed with both diabetes and hypertension during the observation period. We assessed the humanistic burden with health-related quality of life (HRQoL) and economic burden with the total annual healthcare expenditures. Depending on the presence/absence of depression and anxiety, the study sample was divided into four groups (i.e., no depression/anxiety, depression only, anxiety …