Medical Sciences Commons^™

The Neuroprotective Role Of Lipoxin A4 In Reinstating Blood Brain Barrier Integrity In Neuroinflammatory Disease Processes, Minjal Patel, Nimish Acharya

Rowan-Virtua Research Day

Background: The blood-brain barrier (BBB), formed by the vascular endothelium, astrocytic foot processes, pericytes, is a highly selective barrier that is responsible for maintaining brain homeostasis and ultimately proper neuronal function. Disruption of the BBB, leading to increased BBB permeability, has been reported in several neurodegenerative diseases, including Alzheimer’s disease (AD) and traumatic brain injury (TBI).¹ Loss of BBB integrity leads to the proliferation of pro-inflammatory cytokines, including TNFɑ, IL-1β, and IL-6.² Moderate inflammation has a beneficial response in the system following an acute injury. However, prolonged inflammation has been known to perturb homeostasis and have …

Metabolic Diversity Of Human Macrophages: Potential Influence On Staphylococcus Aureus Intracellular Survival, Blake P. Bertrand, Dhananjay Shinde, Vinai C. Thomas, Marvin Whiteley, Carolyn B. Ibberson, Tammy Kielian

Journal Articles: Pathology and Microbiology

Staphylococcus aureus is a leading cause of medical device-associated biofilm infections. This is influenced by the ability of S. aureus biofilm to evade the host immune response, which is partially driven by the anti-inflammatory cytokine interleukin-10 (IL-10). Here, we show that treatment of human monocyte-derived macrophages (HMDMs) with IL-10 enhanced biofilm formation, suggesting that macrophage anti-inflammatory programming likely plays an important role during the transition from planktonic to biofilm growth. To identify S. aureus genes that were important for intracellular survival in HMDMs and how this was affected by IL-10, transposon sequencing was performed. The size of the S. aureus …

Sex-Dependent Effects Of Intestinal Microbiome Manipulation In A Mouse Model Of Alzheimer’S Disease, Harpreet Kaur, Suba Nookala, Surjeet Singh, Santhosh Mukundan, Kumi Nagamoto-Combs, Colin K. Combs

Biomedical Sciences Faculty Publications

Mechanisms linking intestinal bacteria and neurodegenerative diseases such as Alzheimer’s disease (AD) are still unclear. We hypothesized that intestinal dysbiosis might potentiate AD, and manipulating the microbiome to promote intestinal eubiosis and immune homeostasis may improve AD-related brain changes. This study assessed sex differences in the effects of oral probiotic, antibiotics, and synbiotic treatments in the AppNL-G-F mouse model of AD. The fecal microbiome demonstrated significant correlations between bacterial genera in AppNL-G-F mice and Aβ plaque load, gliosis, and memory performance. Female and not male AppNL-G-F mice fed probiotic but not synbiotic exhibited a decrease in Aβ plaques, microgliosis, brain …

Hla-Ii Alleles Influence Physical And Behavioral Responses To A Whey Allergen In A Transgenic Mouse Model Of Cow's Milk Allergy, Danielle L. Germundson, Suba Nookala, Nicholas A. Smith, Yassmine Warda, Kumi Nagamoto-Combs

Biomedical Sciences Faculty Publications

The symptoms of food allergies vary significantly between individuals, likely due to genetic determinants. In humans, allergy development is initiated by antigen-presenting cells via class II human leukocyte antigen (HLA-II). The HLA-II gene is highly polymorphic, and its allelic variance is thought to influence the susceptibility of individuals to a particular allergen. However, whether antigen presentation by different HLA-II variants contributes to symptom variation is not clear. We hypothesized that HLA-II allelic variance affects symptom phenotypes, including immediate physical reactions and delayed behavioral changes, in individuals with food hypersensitivity. To test our hypothesis, male and female mice of three transgenic …

Understanding The Journey Of Human Prenatal Cd4+ Plzf+ T Cells To The Small Intestine, Tomi Oyedeji Olaniyan

CMC Senior Theses

The fetal immune system has a variety of needs that differ from those of the adult immune system. One such difference is fetal T cell composition and how they migrate from the thymus to peripheral lymphoid organs and mucosal tissue such as the small intestine (SI). Previous research shows that the majority of memory T cells in the prenatal SI are CD4+ PLZF+ T cells but the mechanisms involved in the homing of these cells in the small intestine have not yet been determined. In our experiment, I found evidence to support the claim that IL-7 drives the acquisition of …

Attenuation Of Relapsing Fever Neuroborreliosis In Mice By Il-17a Blockade, Meihui Cheng, Jingwen Xu, Kaiyun Ding, Jing Zhang, Wei Lu, Jiansheng Liu, Jiahong Gao, Kishore R Alugupalli, Hongqi Liu

Department of Microbiology and Immunology Faculty Papers

Relapsing fever due to Borrelia hermsiiis characterized by recurrent bacteremia episodes. However, infection of B. hermsii, if not treated early, can spread to various organs including the central nervous system (CNS). CNS disease manifestations are commonly referred to as relapsing fever neuroborreliosis (RFNB). In the mouse model of B. hermsiiinfection, we have previously shown that the development of RFNB requires innate immune cells as well as T cells. Here, we found that prior to the onset of RFNB, an increase in the systemic proinflammatory cytokine response followed by sustained levels of IP-10 concurrent with the CNS disease phase. RNA sequencing …

A Study Of Apolipoprotein A1(Apoa1) And Interleukin-10(Il-10) In Diabetes With Foot Ulcers, Rachita Nanda, Suprava Patel, Amritava Ghosh, Asha Ks, Eli Mohapatra

BioMedicine

Background

The high morbidity, mortality and associated economic burden have entailed to identifying early biomarker of diabetic foot ulcers(DFU). Pro-inflammatory and anti-inflammatory molecules play a role in the chronic inflammation associated with diabetic foot ulcers(DFU).

Aim

This study aims to find the association between ApoA1, IL-10, TNF-α and diabetic foot ulcers, and whether their levels can assess the severity of the disease.

Method

Two groups, diabetic mellitus without foot ulcers and diabetes with foot ulcers were recruited for the study. Detailed clinical history was obtained and blood was collected to measure TNF-α, IL-10 and Apo A1. The association between variables …

Tumor Microenvironment Enriches The Stemness Features: The Architectural Event Of Therapy Resistance And Metastasis, Palanisamy Nallasamy, Rama Krishna Nimmakayala, Seema Parte, Abhirup C. Are, Surinder K. Batra, Moorthy P. Ponnusamy

Journal Articles: Biochemistry & Molecular Biology

Cancer divergence has many facets other than being considered a genetic term. It is a tremendous challenge to understand the metastasis and therapy response in cancer biology; however, it postulates the opportunity to explore the possible mechanism in the surrounding tumor environment. Most deadly solid malignancies are distinctly characterized by their tumor microenvironment (TME). TME consists of stromal components such as immune, inflammatory, endothelial, adipocytes, and fibroblast cells. Cancer stem cells (CSCs) or cancer stem-like cells are a small sub-set of the population within cancer cells believed to be a responsible player in the self-renewal, metastasis, and therapy response of …

Proteomics-Derived Basal Biomarker Dna-Pkcs Is Associated With Intrinsic Subtype And Long-Term Clinical Outcomes In Breast Cancer, Karama Asleh, Nazia Riaz, Angela S. Cheng, Dongxia Gao, Samuel C Y. Leung, Meenakshi Anurag, Torsten O. Nielsen

Centre for Regenerative Medicine & Stem Cell Research

Precise biomarkers are needed to guide better diagnostics and therapeutics for basal-like breast cancer, for which DNA-dependent protein kinase catalytic subunit (DNA-PKcs) has been recently reported by the Clinical Proteomic Tumor Analysis Consortium as the most specific biomarker. We evaluated DNA-PKcs expression in clinically-annotated breast cancer tissue microarrays and correlated results with immune biomarkers (training set: n = 300; validation set: n = 2401). Following a pre-specified study design per REMARK criteria, we found that high expression of DNA-PKcs was significantly associated with stromal and CD8 + tumor infiltrating lymphocytes. Within the basal-like subtype, tumors with low DNA-PKcs and high …

Developing A Microdialysis Sampling-Based Biofilm/Macrophage Co-Culture Model, Alda Diaz Perez

Graduate Theses and Dissertations

The host immune system and bacterial cells are known to interact during the human lifetime. Bacteria secrete a wide variety of signaling molecules, known as quorum sensing (QSC) molecules, that modulate the host immune system. While immune-biofilm interactions involve this chemical signaling network, the mechanisms through which this occurs are not well understood. This work aimed to develop a new method that can be used not only in vitro settings but also in vivo. The microdialysis sampling technique has widely been used in in vitro and in vivo settings in humans, mice, and rats for the collection of neuropeptides, cytokines, …

Placenta-Expanded Stromal Cell Therapy In A Rodent Model Of Simulated Weightlessness, Amber M. Paul, Linda Rubinstein, Charles Houseman, Metadel Abegaz, Steffy Tabares Ruiz

Publications

Long duration spaceflight poses potential health risks to astronauts during flight and re-adaptation after return to Earth. There is an emerging need for NASA to provide successful and reliable therapeutics for long duration missions when capability for medical intervention will be limited. Clinically relevant, human placenta-derived therapeutic stromal cells (PLX-PAD) are a promising therapeutic alternative. We found that treatment of adult female mice with PLX-PAD near the onset of simulated weightlessness by hindlimb unloading (HU, 30 d) was well-tolerated and partially mitigated decrements caused by HU. Specifically, PLX-PAD treatment rescued HU-induced thymic atrophy, and mitigated HU-induced changes in percentages of …

Janus Kinase 1 Drives Endoplasmic Reticulum Stress-Induced Transcriptional Reprogramming In Astrocytes, Savannah Graham Sims

Graduate Theses, Dissertations, and Problem Reports

Neurological and neurodegenerative diseases are heterogenous and devastating diseases with limited therapeutic options and no cures. The broad, long-term goal of this project was to elucidate therapeutic targets for neurodegenerative conditions that attenuate damaging inflammation while leaving the beneficial immune response intact and avoiding broad immunosuppression. Inflammation and the accumulation of misfolded proteins are associated with a wide variety of neurological diseases. Here, we have examined how the accumulation of misfolded proteins shapes inflammatory signaling in the glial cell population astrocytes. Astrocytes are the most populous cell in the central nervous system (CNS) and provide physical and trophic support to …

Proteomic Analysis Of Platelet-Rich And Platelet-Poor Plasma, Olga Miroshnychenko, Robert J. Chalkley, Ryan D. Leib, Peter A. Everts, Jason L. Dragoo

Publications and Research

Background

Autologous blood products, such as platelet-rich plasma (PRP) are commercial products broadly used to accelerate healing of tissues after injuries. However, their content is not standardized and significantly varies in composition, which may lead to differences in clinical efficacy. Also, the underlying molecular mechanisms for therapeutic effects are not well understood.

Purpose

A proteomic study was performed to compare the composition of low leukocyte PRP, platelet poor plasma (PPP), and blood plasma. Pathway analysis of the proteomic data was performed to evaluate differences between plasma formulations at the molecular level. Low abundance regulatory proteins in plasma were identified and …

Staphylococcus Aureus Atp Synthase Promotes Biofilm Persistence By Influencing Innate Immunity, Megan E. Bosch, Blake P. Bertrand, Cortney E. Heim, Abdulelah A. Alqarzaee, Sujata S. Chaudhari, Amy L. Aldrich, Paul D. Fey, Vinai C. Thomas, Tammy Kielian

Journal Articles: Pathology and Microbiology

No abstract provided.

Immune-Related Gene Expression And Cytokine Secretion Is Reduced Among African American Colon Cancer Patients, Jenny Paredes, Jovanny Zabaleta, Jone Garai, Ping Ji, Sayed Imtiaz, Marzia Spagnardi, Joussette Alvarado, Li Li, Mubarak Akadri, Kaylene Barrera, Maria Munoz-Sagastibelza, Raavi Gupta, Mohamed Alshal, Maksim Agaronov, Henry Talus, Xuefeng Wang, John M. Carethers, Jennie L. Williams, Laura A. Martello

School of Medicine Faculty Publications

Background: Colorectal cancer is the third most deadly cancer among African Americans (AA). When compared to Caucasian Americans (CA), AA present with more advanced disease and lower survival rates. Here, we investigated if differences in tumor immunology could be contributive to disparities observed between these populations. Methods: We examined gene expression of tumor and non-tumor adjacent tissues from AA and CA by whole transcriptome sequencing, and generated scores for immune cell populations by NanoString. In addition, we utilized “The Cancer Genome Atlas” (TCGA) database from AA and CA as a validation cohort. Finally, we measured the secretion of cytokines characteristic …

Dendritic Cell Development And Function, Vivek Durai

Arts & Sciences Electronic Theses and Dissertations

Dendritic cells (DCs) are a group of immune cells that include both classical dendritic cells (cDCs) and plasmacytoid dendritic cells (pDCs). cDCs are further comprised of two distinct subsets, cDC1s and cDC2s, which play critical roles in the initiation of innate and adaptive immune responses. Understanding how these lineages develop and function is therefore paramount. All DCs require the receptor tyrosine kinase Flt3 and its ligand Flt3L for their development, but the loss of Flt3L in mice leads to a more severe DC deficiency than does the loss of Flt3. This has led to speculation that Flt3L can bind to …

Immune-Endocrine Links To Gregariousness In Wild House Mice, Patricia C. Lopes, Esther H. D. Carlitz, Morgan Kindel, Barbara König

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Social interactions are critically important for survival and impact overall-health, but also impose costs on animals, such as exposure to contagious agents. The immune system can play a critical role in modulating social behavior when animals are sick, as has been demonstrated within the context of “sickness behaviors.” Can immune molecules affect or be affected by social interactions even when animals are not sick, therefore serving a role in mediating pathogen exposure? We tested whether markers of immune function in both the blood and the brain are associated with gregariousness, quantified as number of animals interacted with per day. To …

Expression Of Cytokines And Chemokines As Predictors Of Stroke Outcomes In Acute Ischemic Stroke, Sarah R. Martha, Qiang Cheng, Justin F. Fraser, Liyu Gong, Lisa A. Collier, Stephanie M. Davis, Doug Lukins, Abdulnasser Alhajeri, Stephen Grupke, Keith R. Pennypacker

Institute for Biomedical Informatics Faculty Publications

Introduction: Ischemic stroke remains one of the most debilitating diseases and is the fifth leading cause of death in the US. The ability to predict stroke outcomes within the acute period of stroke would be essential for care planning and rehabilitation. The Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC; clinicaltrials.gov NCT03153683) study collects arterial blood immediately distal and proximal to the intracranial thrombus at the time of mechanical thrombectomy. These blood samples are an innovative resource in evaluating acute gene expression changes at the time of ischemic stroke. The purpose of this study was to identify inflammatory genes and …

Natural Autoantibodies: Origin, Function And Utility For Diagnosis Of Disease, Abhirup Sarkar

Graduate School of Biomedical Sciences Theses and Dissertations

Autoantibodies (aAbs) by the simplest definitions have been described as antibodies against self-antigens and were exclusively associated with autoimmune diseases. Eventually, studies demonstrated that they are abundant in the blood of all human sera, regardless of age, gender, or the presence or absence of disease, and were thus named as ‘natural autoantibodies’. The underlying reason for their ubiquity has remained elusive, but we have hypothesized that they are responsible for clearing blood-borne cell and tissue debris generated under conditions of health and disease. To test this, we chose to use two widely different disease model systems, namely neurodegenerative diseases and …

Deletion Of P38Α Mapk In Microglia Blunts Trauma-Induced Inflammatory Responses In Mice, Josh M. Morganti, Danielle S. Goulding, Linda J. Van Eldik

Sanders-Brown Center on Aging Faculty Publications

Traumatic brain injury (TBI) is a significant cause of morbidity and mortality in the USA and other developed countries worldwide. Following the initial mechanical insult, the brain’s primary innate immune effector, microglia, initiate inflammatory signaling cascades and pathophysiological responses that can lead to chronic neuroinflammation and neurodegenerative sequelae. The p38α MAPK signaling pathway in microglia is a key contributor to inflammatory responses to diverse disease-relevant stressors and injury conditions. Therefore, we tested here whether microglia p38α contributes to acute and persistent inflammatory responses induced by a focal TBI. We generated conditional cell-specific knockout of p38α in microglia using a CX3CR1 …

Neuroprotective Activity Of Leukemia Inhibitory Factor Is Relayed Through Myeloid Zinc Finger-1 In A Rat Model Of Stroke, Stephanie M. Davis, Lisa A. Collier, Elspeth A. Foran, Christopher C. Leonardo, Craig T. Ajmo Jr., Keith R. Pennypacker

Neurology Faculty Publications

The aim of this study was to determine whether leukemia inhibitory factor (LIF) exerts its neuroprotective effects through signal transduction of the transcription factor myeloid zinc finger-1 (MZF-1). According to the hypothesis of this study, MZF-1 mediates LIF-induced neuroprotective signaling during ELVO through increased expression and transcriptional activity. To determine the in vivo role of MZF-1 in LIF-induced neuroprotection, we used Genomatix software was used to MZF-1 sites in the promoter region of the rat superoxide dismutase 3 (SOD3) gene. Stroke was induced via middle cerebral artery occlusion, and animals were administered PBS or 125 μg/kg LIF at …

Efficacy Of Leukemia Inhibitory Factor As A Therapeutic For Permanent Large Vessel Stroke Differs Among Aged Male And Female Rats, Stephanie M. Davis, Lisa A. Collier, Sarah J. Goodwin, Douglas E. Lukins, David K. Powell, Keith R. Pennypacker

Neurology Faculty Publications

Preclinical studies using rodent models of stroke have had difficulty in translating their results to human patients. One possible factor behind this inability is the lack of studies utilizing aged rodents of both sexes. Previously, this lab showed that leukemia inhibitory factor (LIF) promoted recovery after stroke through antioxidant enzyme upregulation. This study examined whether LIF promotes neuroprotection in aged rats of both sexes. LIF did not reduce tissue damage in aged animals, but LIF-treated female rats showed partial motor skill recovery. The LIF receptor (LIFR) showed membrane localization in young male and aged rats of both sexes after stroke. …

Forebrain Cholinergic Signaling Regulates Innate Immune Responses And Inflammation, K. R. Lehner, H. A. Silverman, M. E. Adorissio, A. Roy, A. Al-Onaizi, S. S. Chavan, Y. Al-Abed, C. N. Metz, K. J. Tracey, V. A. Paviov, +6 Additional Authors

Journal Articles

No abstract provided.

The Association Between Levels Of Inflammatory Markers In Autistic Children Compared To Their Unaffected Siblings And Unrelated Healthy Controls, Loai Alzghoul, Sultan Abdelhamid, Ahmad Yanis, Yasmeen Qwaider, Mohammad Aldahabi, Suzan Albdour

Turkish Journal of Medical Sciences

Background/aim: Autism spectrum disorder (ASD) describes a range of neurodevelopmental disabilities that impair behavior and communication. Although it is relatively prevalent, the pathophysiology is still subject to speculation and debate. The aim of this study is to identify a possible association between interleukin-6, -8, -9, and -10 and tumor necrosis factor alpha (TNF- ∝) in autism among Jordanian children by comparing the plasma levels of these cytokines in autistic children with those of their unaffected siblings and unrelated healthy controls. Materials andmethods: In this study, 80 Jordanian children under the age of 12 with diagnosed autism were selected. For comparison, …

Novel Tnf Receptor-1 Inhibitors Identified As Potential Therapeutic Candidates For Traumatic Brain Injury, Rachel K. Rowe, Jordan L. Harrison, Hongtao Zhang, Adam D. Bachstetter, David P. Hesson, Bruce F. O'Hara, Mark I. Greene, Jonathan Lifshitz

Sanders-Brown Center on Aging Faculty Publications

Background: Traumatic brain injury (TBI) begins with the application of mechanical force to the head or brain, which initiates systemic and cellular processes that are hallmarks of the disease. The pathological cascade of secondary injury processes, including inflammation, can exacerbate brain injury-induced morbidities and thus represents a plausible target for pharmaceutical therapies. We have pioneered research on post-traumatic sleep, identifying that injury-induced sleep lasting for 6 h in brain-injured mice coincides with increased cortical levels of inflammatory cytokines, including tumor necrosis factor (TNF). Here, we apply post-traumatic sleep as a physiological bio-indicator of inflammation. We hypothesized the efficacy of novel …

Comparison Of Serum And Cervical Cytokine Levels Throughout Pregnancy Between Preterm And Term Births, Kristin Ashford, Niraj R. Chavan, Amanda T. Wiggins, Molly Malany Sayre, Andrea Mccubbin, Agatha S. Critchfield, John O'Brien

Nursing Faculty Publications

Objective To assess differences in cytokine levels in cervicovaginal fluid (CVF) and serum across trimesters between women with preterm births (PTBs) and full-term births.

Study Design This multicenter study enrolled 302 women with a singleton gestation. CVF and serum cytokines, interleukin 1α (IL-1α), IL-1β, IL-6, IL-8, IL-10, C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and matrix metalloproteinase (MMP)-8, were measured. Women with at least one cytokine assessment and noted PTB status in their medical record were retained in the study (N = 272). Data were analyzed using mixed modeling (main effects of PTBs and time/trimester).

Results For the CVF …

The Role Of The Leukemia Inhibitory Factor Receptor In Neuroprotective Signaling, Stephanie M. Davis, Keith R. Pennypacker

Center for Advanced Translational Stroke Science Faculty Publications

Several neurotropic cytokines relay their signaling through the leukemia inhibitory factor receptor. This 190kDa subunit couples with the 130kDa gp130 subunit to transduce intracellular signaling in neurons and oligodendrocytes that leads to expression of genes associated with neurosurvival. Moreover, activation of this receptor alters the phenotype of immune cells to an anti-inflammatory one. Although cytokines that activate the leukemia inhibitory factor receptor have been studied in the context of neurodegenerative disease, therapeutic targeting of the specific receptor subunit has been understudied in by comparison. This review examines the role of this receptor in the CNS and immune system, and its …

Minocycline Protects Developing Brain Against Ethanol-Induced Damage, Xin Wang, Kai Zhang, Fanmuyi Yang, Zhenhua Ren, Mei Xu, Jacqueline A. Frank, Zun-Ji Ke, Jia Luo

Pharmacology and Nutritional Sciences Faculty Publications

Fetal alcohol spectrum disorders (FASD) are caused by ethanol exposure during the pregnancy and is the leading cause of mental retardation. Ethanol exposure during the development results in the loss of neurons in the developing brain, which may underlie many neurobehavioral deficits associated with FASD. It is important to understand the mechanisms underlying ethanol-induced neuronal loss and develop appropriate therapeutic strategies. One of the potential mechanisms involves neuroimmune activation. Using a third trimester equivalent mouse model of ethanol exposure, we demonstrated that ethanol induced a wide-spread neuroapoptosis, microglial activation, and neuroinflammation in C57BL/6 mice. Minocycline is an antibiotic that inhibits …

Editorial: Neuro-Immune Interactions In Inflammation And Autoimmunity, N. Terrando, V. A. Pavlov

Journal Articles

No abstract provided.

Molecular And Functional Neuroscience In Immunity, V. A. Pavlov, S. S. Chavan, K. J. Tracey

Journal Articles

No abstract provided.