Although strokes are frequent and severe, treatment options are scarce. Plasminogen activators, the only FDA-approved agents for clot treatment (tissue plasminogen activators (tPAs)), are used in a limited patient group. Moreover, there are few approaches for handling the brain's inflammatory reactions to a stroke.
View Article and Find Full Text PDFAn amendment to this paper has been published and can be accessed via a link at the top of the paper.
View Article and Find Full Text PDFTobacco smoking is common in HIV-infected patients, and is prevalent among intravenous opiate abusers. Conversely, intravenous opiate abusers are more likely HIV-infected, and opiate abuse is associated with more severe neuroinflammation. Given the coincident use of tobacco smoking among HIV-infected intravenous drug users (IVDUs), we set out to study the effects of smoke exposure, chronic morphine administration, and HIV infection using the NSG humanized mouse model.
View Article and Find Full Text PDFDespite combined antiretroviral therapy (ART) achieving efficient HIV replication control, HIV-associated neurocognitive disorders (HAND) continue to be highly prevalent in HIV-infected patients. Diabetes mellitus (DM) is a well-known comorbidity of HAND in HIV-infected patients. Blood brain barrier (BBB) dysfunction has been linked recently to dementia development, specifically in DM patients.
View Article and Find Full Text PDFCognitive impairment is a well-known complication of diabetes mellitus (DM). Microvascular compromise was described one DM complication. Recently we showed blood brain barrier (BBB) permeability and memory loss are associated with diminution of tight junctions (TJ) in brain endothelium and pericyte coverage and inflammation in cerebral microvessels and brain tissue paralleling hyperglycemia in mice of both DM types.
View Article and Find Full Text PDFElectronic cigarette (e-cigarette) use has grown substantially since inception, particularly among adolescents and combustible tobacco users. Several cigarette smoke constituents with known neurovascular effect are present in e-cigarette liquids or formed during the vapor generation. The present study establishes inhaled models of cigarette and e-cigarette use with normalized nicotine delivery, then characterizes the impact on blood-brain barrier (BBB) function.
View Article and Find Full Text PDFStroke is a debilitating disease, accounting for almost 20% of all hospital visits, and 8% of all fatalities in the United States in 2017. Following an ischemic attack, inflammatory processes originating from endothelial cells within the brain microvasculature can induce many toxic effects into the impacted area, from both sides of the blood brain barrier (BBB). In addition to increased BBB permeability, impacted brain microvascular endothelial cells can recruit macrophages and other immune cells from the periphery and can also trigger the activation of microglia and astrocytes within the brain.
View Article and Find Full Text PDFMost neurological diseases, including stroke, lead to some degree of blood-brain barrier (BBB) dysfunction. A significant portion of BBB injury is caused by inflammation, due to pro-inflammatory factors produced in the brain, and by leukocyte engagement of the brain endothelium. Recently, microRNAs (miRNAs) have appeared as major regulators of inflammation-induced changes to gene expression in the microvascular endothelial cells (BMVEC) that comprise the BBB.
View Article and Find Full Text PDFNew neurons are continuously produced by neural stem cells (NSCs) within the adult hippocampus. Numerous diseases, including major depressive disorder and HIV-1 associated neurocognitive disorder, are associated with decreased rates of adult neurogenesis. A hallmark of these conditions is a chronic release of neuroinflammatory mediators by activated resident glia.
View Article and Find Full Text PDFEnd organ injury in diabetes mellitus (DM) is driven by microvascular compromise (including diabetic retinopathy and nephropathy). Cognitive impairment is a well-known complication of DM types 1 and 2; however, its mechanism(s) is(are) not known. We hypothesized that blood-brain barrier (BBB) compromise plays a key role in cognitive decline in DM.
View Article and Find Full Text PDFBackground And Purpose: The cannabinoid system exerts functional regulation of neural stem cell (NSC) proliferation and adult neurogenesis, yet not all effects of cannabinoid-like compounds seen can be attributed to the cannabinoid 1 (CB ) or CB receptor. The recently de-orphaned GPR55 has been shown to be activated by numerous cannabinoid ligands suggesting that GPR55 is a third cannabinoid receptor. Here, we examined the role of GPR55 activation in NSC proliferation and early adult neurogenesis.
View Article and Find Full Text PDFBackground: Secoisolariciresinol diglucoside (SDG), the main lignan in flaxseed, is known for its beneficial effects in inflammation, oxidative stress, heart disease, tumor progression, atherosclerosis, and diabetes. SDG might be an attractive natural compound that protects against neuroinflammation. Yet, there are no comprehensive studies to date investigating the effects of SDG on brain endothelium using relevant in vivo and in vitro models.
View Article and Find Full Text PDFLoss of function mutations in Kelch-like ECH Associated Protein 1 (KEAP1), or gain-of-function mutations in nuclear factor erythroid 2-related factor 2 (NRF2), are common in non-small cell lung cancer (NSCLC) and associated with therapeutic resistance. To discover novel NRF2 inhibitors for targeted therapy, we conducted a quantitative high-throughput screen using a diverse set of ∼400 000 small molecules (Molecular Libraries Small Molecule Repository Library, MLSMR) at the National Center for Advancing Translational Sciences. We identified ML385 as a probe molecule that binds to NRF2 and inhibits its downstream target gene expression.
View Article and Find Full Text PDFBackground: Blood-brain barrier (BBB) dysfunction/disruption followed by leukocyte infiltration into the brain causes neuroinflammation and contributes to morbidity in multiple sclerosis, encephalitis, traumatic brain injury, and stroke. The identification of pathways that decreases the inflammatory potential of leukocytes would prevent such injury. Poly(ADP-ribose) polymerase 1 (PARP) controls various genes via its interaction with myriad transcription factors.
View Article and Find Full Text PDFAm J Physiol Lung Cell Mol Physiol
July 2015
Asthma development and pathogenesis are influenced by the interactions of airway epithelial cells and innate and adaptive immune cells in response to allergens. Oxidative stress is an important mediator of asthmatic phenotypes in these cell types. Nuclear erythroid 2-related factor 2 (Nrf2) is a redox-sensitive transcription factor that is the key regulator of the response to oxidative and environmental stress.
View Article and Find Full Text PDFElectronic cigarettes (E-cigs) have experienced sharp increases in popularity over the past five years due to many factors, including aggressive marketing, increased restrictions on conventional cigarettes, and a perception that E-cigs are healthy alternatives to cigarettes. Despite this perception, studies on health effects in humans are extremely limited and in vivo animal models have not been generated. Presently, we determined that E-cig vapor contains 7 x 10(11) free radicals per puff.
View Article and Find Full Text PDFAm J Respir Cell Mol Biol
February 2012
MUC1 (or Muc1 in nonhuman species) is a membrane-tethered mucin expressed on the apical surface of mucosal epithelia (including those of the airways) that suppresses Toll-like receptor (TLR) signaling. We sought to determine whether the anti-inflammatory effect of MUC1 is operative during infection with nontypeable Haemophilus influenzae (NTHi), and if so, which TLR pathway was affected. Our results showed that: (1) a lysate of NTHi increased the early release of IL-8 and later production of MUC1 protein by A549 cells in dose-dependent and time-dependent manners, compared with vehicle control; (2) both effects were attenuated after transfection of the cells with a TLR2-targeting small interfering (si) RNA, compared with a control siRNA; (3) the NTHi-induced release of IL-8 was suppressed by an overexpression of MUC1, and was enhanced by the knockdown of MUC1; (4) the TNF-α released after treatment with NTHi was sufficient to up-regulate MUC1, which was completely inhibited by pretreatment with a soluble TNF-α receptor; and (5) primary murine tracheal surface epithelial (MTSE) cells from Muc1 knockout mice exhibited an increased in vitro production of NTHi-stimulated keratinocyte chemoattractant compared with MTSE cells from Muc1-expressing animals.
View Article and Find Full Text PDFThe goal of the study was to investigate bone morphogenetic protein 2 (BMP-2) and transforming growth factor beta (TGF-beta) control of the expression of beta1,3-glucuronosyl transferase 1 (GlcAT-1), an important regulator of chondroitin sulfate synthesis in cells of the nucleus pulposus. Treatment with both growth factors resulted in induction of GlcAT-1 expression and promoter activity. Deletion analysis indicated that promoter constructs lacking AP1 and TonE sites were unresponsive to growth factor treatment.
View Article and Find Full Text PDFThe goal of the investigation was to test the hypothesis that the phosphoinositide-3 kinase (PI3K)/AKT signaling pathway regulates the expression of the major extracellular matrix component of the intervertebral disc, aggrecan, in nucleus pulposus cells. Primary rat nucleus pulposus cells were treated with PI3K inhibitor to measure changes in gene and protein expression. In addition, cells were transfected with various luciferase reporter plasmids to investigate mechanisms of regulation of aggrecan gene expression.
View Article and Find Full Text PDFThe goal of this investigation was to study the expression and regulation of beta1,3-Glucuronosyltransferase-I (GlcAT-I), a key enzyme regulating GAG synthesis in cells of the intervertebral disc. There was a robust expression of GlcAT-I in the nucleus pulposus in vivo. Treatment with the calcium ionophore ionomycin resulted in increased GlcAT-I expression, whereas GlcAT-I promoter constructs lacking TonE site or a mutant TonE were unresponsive to the ionophore.
View Article and Find Full Text PDFThe goal of this study was to examine the expression and regulation of aquaporin2 (AQP2), a tonicity-sensitive water channel in nucleus pulposus cells of the intervertebral disc. We found that AQP2 protein was expressed in vivo in both rat and human discs. We determined whether AQP2 promoter expression was regulated by osmolarity in a tonicity enhancer binding protein (TonEBP)-dependent manner.
View Article and Find Full Text PDFObjective: To determine whether nucleus pulposus cells of the intervertebral disc express hypoxia-inducible factor 2alpha (HIF-2alpha), and to assess the role of HIF-1 and HIF-2 in controlling cited2 and vascular endothelial growth factor (VEGF) expression.
Methods: Rat cells were cultured under normoxic (21% O2) or hypoxic (2% O2) conditions, and expression and promoter activity of HIF-2 target genes were evaluated. Gain- or loss-of-function experiments were performed to investigate the contribution of HIF isoforms to cited2 activity as well as the role of cited2 in regulating VEGF expression.
The goal of this investigation was to study the regulation of acid-sensing ion channel (ASIC)3 expression by TGFbeta in the nucleus pulposus cells of the intervertebral disc. Analysis of human nucleus pulposus tissue indicated decreased ASIC3 and elevated TGFbeta expression in the degenerate state. In a parallel study, treatment of nucleus pulposus cells with TGFbeta resulted in decreased expression of ASIC3 mRNA and protein.
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