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1.
CNS Neurosci Ther ; 30(2): e14600, 2024 02.
Article in English | MEDLINE | ID: mdl-38357857

ABSTRACT

AIM: Characterize Growth Differentiation Factor 15 (GDF15) as a secreted biomarker of the integrated stress response (ISR) within the central nervous system (CNS). METHODS: We determined GDF15 levels utilizing in vitro and in vivo neuronal systems wherein the ISR was activated. Primarily, we used the murine model of vanishing white matter disease (VWMD), a neurological disease driven by persistent ISR in the CNS, to establish a link between levels of GDF15 in the cerebrospinal fluid (CSF) and ISR gene expression signature in the CNS. GDF15 was also determined in the CSF of VWM patients. RESULTS: GDF15 expression was increased concomitant to ISR activation in stress-induced primary astrocytes as well as in retinal ganglion cells following optic nerve crush, while treatment with 2Bact, a specific eIF2B activator, suppressed both the ISR and GDF15. In the VWMD model, CSF GDF15 levels corresponded with the magnitude of the ISR and were reduced by 2BAct. In VWM patients, mean CSF GDF15 was elevated >20-fold as compared to healthy controls, whereas plasma GDF15 was undifferentiated. CONCLUSIONS: These data suggest that CSF GDF15 is a dynamic marker of ISR activation in the CNS and may serve as a pharmacodynamic biomarker for ISR-modulating therapies.


Subject(s)
Growth Differentiation Factor 15 , Leukoencephalopathies , Humans , Mice , Animals , Growth Differentiation Factor 15/genetics , Leukoencephalopathies/genetics , Central Nervous System/metabolism , Eukaryotic Initiation Factor-2B/genetics , Eukaryotic Initiation Factor-2B/metabolism , Biomarkers
2.
Laryngoscope ; 132(2): 290-297, 2022 02.
Article in English | MEDLINE | ID: mdl-34272876

ABSTRACT

OBJECTIVES/HYPOTHESIS: Olfactory neuroblastoma (ONB) is a rare sinonasal malignant neoplasm that is known to develop late recurrence. The aim of this study is to evaluate the long-term outcomes of patients with ONB and to determine the factors associated with prognosis. STUDY DESIGN: Retrospective study. METHODS: A retrospective review of the medical records of 139 patients diagnosed with ONB at MD Anderson Cancer Center was performed between 1991 and 2016. Descriptive statistics were calculated, and Kaplan-Meier curves were utilized to assess survival. RESULTS: Median follow-up time was 75 months. Overall, 129 patients (92.8%) had surgery as part of their treatment and 82 (58.9%) patients received postoperative radiation therapy (PORT) or concurrent chemoradiotherapy. Endoscopic approaches were utilized for 72 patients, 69.4% of whom had pure endoscopic endonasal approaches. Five-year overall survival and disease-specific survival were 85.6% and 93.4%, respectively. Recurrence rate was 39.6% with a median time to recurrence of 42 months. Among the 31 patients who received elective nodal irradiation (ENI), two patients developed neck recurrence (6.4%) compared with 20 who developed neck recurrence when ENI was omitted (34.4%) (P = .003). Advanced Kadish stage, orbital invasion, intracranial invasion, and presence of cervical lymphadenopathy at the time of presentation were significantly associated with poor survival. CONCLUSION: ONB has an excellent survival. Surgical resection with PORT when indicated is the mainstay of treatment. Endoscopic approaches can be used as a good tool. Elective neck irradiation reduces the risk of nodal recurrence among patients with clinically N0 neck. Despite the excellent survival, recurrence rate remains high and delayed, highlighting the need for long-term surveillance. LEVEL OF EVIDENCE: Level 4 Laryngoscope, 132:290-297, 2022.


Subject(s)
Esthesioneuroblastoma, Olfactory/therapy , Nasal Cavity , Nose Neoplasms/therapy , Esthesioneuroblastoma, Olfactory/mortality , Humans , Nose Neoplasms/mortality , Prognosis , Retrospective Studies , Survival Rate , Time Factors , Treatment Outcome
3.
J Transl Autoimmun ; 4: 100079, 2021.
Article in English | MEDLINE | ID: mdl-33490940

ABSTRACT

Nuclear factor (erythroid-derived 2) like 2 (NRF2) is a nuclear transcription factor activated in response to oxidative stress that induces a gene program that dampens inflammation and can limit cell damage that perpetuates the inflammatory response. We have identified A-1396076, a potent and selective NRF2 activator with demonstrated KEAP1 binding and modulation of cellular NRF2 mediated effects. In vivo administration of A-1396076 inhibits inflammation across several rodent models of autoimmunity when administered at or before the time of antigen challenge while also inducing NRF2 modulated gene transcription in the liver of the animals. It was not effective when administered after the time of antigen challenge or in a T cell independent model of arthritis induced by passive transfer of anti-collagen antibodies. A-1396076 inhibited antigen dependent T cell activation as measured by IFN-γ production in an ex vivo re-stimulation assay and following anti-CD3 challenge of MOG-sensitized mice. A-1396076 reduced costimulatory molecule expression on dendritic cells in the lungs of OVA LPS challenged mice suggesting that the mechanism of T cell inhibition was mediated at least partially by interfering with antigen presentation. These data suggest that NRF2 activation may be an effective strategy to dampen inflammation for treatment of autoimmune disease.

4.
J Med Chem ; 64(1): 417-429, 2021 01 14.
Article in English | MEDLINE | ID: mdl-33378180

ABSTRACT

Tumor necrosis factor α (TNFα) is a soluble cytokine that is directly involved in systemic inflammation through the regulation of the intracellular NF-κB and MAPK signaling pathways. The development of biologic drugs that inhibit TNFα has led to improved clinical outcomes for patients with rheumatoid arthritis and other chronic autoimmune diseases; however, TNFα has proven to be difficult to drug with small molecules. Herein, we present a two-phase, fragment-based drug discovery (FBDD) effort in which we first identified isoquinoline fragments that disrupt TNFα ligand-receptor binding through an allosteric desymmetrization mechanism as observed in high-resolution crystal structures. The second phase of discovery focused on the de novo design and optimization of fragments with improved binding efficiency and drug-like properties. The 3-indolinone-based lead presented here displays oral, in vivo efficacy in a mouse glucose-6-phosphate isomerase (GPI)-induced paw swelling model comparable to that seen with a TNFα antibody.


Subject(s)
Biological Products/chemical synthesis , Drug Design , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Administration, Oral , Allosteric Regulation , Animals , Arthritis, Rheumatoid/drug therapy , Autoimmune Diseases/drug therapy , Biological Products/pharmacology , Biological Products/therapeutic use , Ligands , Mice , Tumor Necrosis Factor-alpha/metabolism
5.
ACS Chem Biol ; 15(12): 3262-3274, 2020 12 18.
Article in English | MEDLINE | ID: mdl-33270420

ABSTRACT

Alzheimer's Disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia. The current treatment options for AD are limited to ameliorating cognitive decline temporarily and not reversing or preventing the progression of dementia. Hence, more effective therapeutic strategies are needed to combat this devastating disease. The low-density lipoprotein receptor has been shown to modulate the neuronal metabolism of cholesterol and apolipoprotein E, a major genetic risk factor for AD. LDLR overexpression in mice has been shown to increase amyloid-ß clearance and reduce amyloid deposition. We conducted a phenotypic screen to identify novel signaling pathways and targets that regulate LDLR expression in glial cells using an annotated compound library of approximately 29 000 compounds. The screen identified novel targets such as polo like kinase 1 (PLK1), activin receptor like kinase 5 (ALK5), and serotonin transporter (SERT). We used genetic, chemical biology and pathway analysis to confirm the target hypothesis. This work highlights that phenotypic screening is a promising strategy to identify novel mechanisms and targets for therapeutic intervention of complex neurodegenerative disorders.


Subject(s)
Receptors, LDL/drug effects , Small Molecule Libraries/pharmacology , Alzheimer Disease/pathology , Gene Knockdown Techniques , Humans , RNA, Small Interfering/genetics , Receptors, LDL/metabolism , Reproducibility of Results
6.
J Dermatol ; 46(6): 482-497, 2019 Jun.
Article in English | MEDLINE | ID: mdl-31062408

ABSTRACT

The interleukin (IL)-23/IL-17 axis plays a central role in the pathogenesis of psoriasis and is elevated in lesional psoriatic skin. Different murine models have been developed to mimic this pathophysiology each carrying specific merits and limitations. In an attempt to address some of these limitations, B10.RIII mice received a single hydrodynamic injection of IL-23 minicircles (MC) to induce hepatic transcription and the endogenous production of IL-23. Plasma and ear IL-23 levels were dose-dependently (0.3-3 µg) increased in MC injected mice and were sustained over the 14-day study duration. Beginning on day 7 post-injection, mice developed dose-related ear inflammation, histologically confirmed increases in epidermal and dermal area, as well as enhanced neutrophil and macrophage content. Flow cytometry demonstrated increased levels of granulocytes, T cells and monocytes/macrophages in the ear skin, with T cells identified as the main cellular source of IL-17A. Evaluation of mRNA and protein showed time-dependent, increased levels of the IL-23/IL-17 pathway and inflammatory/microbial cytokines/chemokines in the ear which differed kinetically from circulating levels. An anti-IL-23p40 antibody was assessed following both prophylactic administration and administration once the disease was established. Prophylactic dosing completely prevented the development of the ear phenotype across endpoints. Treatment administration showed a dose-related response, with a maximum inhibition of 64-94%, depending on endpoint. These data demonstrate that the IL-23 MC model is a useful approach to study IL-23/IL-17-driven skin inflammation and may facilitate preclinical assessment of novel therapies.


Subject(s)
Antibodies, Monoclonal/administration & dosage , Interleukin-17/immunology , Interleukin-23/immunology , Psoriasis/immunology , Animals , DNA, Circular/administration & dosage , DNA, Circular/genetics , Disease Models, Animal , Dose-Response Relationship, Drug , Gene Transfer Techniques , Humans , Interleukin-17/metabolism , Interleukin-23/antagonists & inhibitors , Interleukin-23/genetics , Male , Mice , Psoriasis/blood , Psoriasis/drug therapy , Psoriasis/pathology , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Skin/immunology , Skin/pathology , Treatment Outcome
7.
ACS Chem Biol ; 14(5): 857-872, 2019 05 17.
Article in English | MEDLINE | ID: mdl-30938974

ABSTRACT

Interleukin-17A (IL17A) plays a critical role in the development of numerous autoimmune diseases, including psoriasis. The clinical success of IL17A neutralizing biologics in psoriasis has underlined its importance as a drug discovery target. While many studies have focused on the differentiation and trafficking of IL17A producing T-helper 17 cells, less is known about IL17A-initiated signaling events in stromal and parenchymal cells leading to psoriatic phenotypes. We sought to discover signaling nodes downstream of IL17A contributing to disease pathogenesis. Using IL17A and tumor necrosis factor α (TNF) to stimulate primary human epidermal keratinocytes, we employed two different phenotypic screening approaches. First, a library of ∼22000 annotated compounds was screened for reduced secretion of the pro-inflammatory chemokine IL8. Second, a library of 729 kinases was screened in a pooled format by utilizing CRISPR-Cas9 and monitoring IL8 intracellular staining. The highest-ranking novel hits identified in both screens were the bromodomain and extra-terminal domain (BET) family proteins and bromodomain-containing protein 2 (BRD2), respectively. Comparison of BRD2, BRD3, and BRD4 silencing with siRNA and CRISPR confirmed that BRD2 was responsible for mediating IL8 production. Pan-BRD inhibitors and BRD2 knockout also reduced IL17A/TNF-mediated CXC motif chemokines 1/2/6 (CXCL1/2/6) and granulocyte colony stimulating factor (G-CSF) production. In RNA-Seq analysis, 438 IL17A/TNF dependent genes were reduced in BRD2-deficient primary keratinocytes. KEGG pathway analysis of these genes showed enrichment in TNF signaling and rheumatoid arthritis relevant genes. Moreover, a number of genes important for keratinocyte homeostasis and cornification were dysregulated in BRD2-deficient keratinocytes. In IL17A/TNF/IL22 stimulated three-dimensional organotypic raft cultures, pan-BRD inhibition reduced inflammatory factor production but elicited aberrant cornification, consistent with RNA-Seq analysis. These studies highlight a novel role for BRDs and BRD2 in particular in IL17A-mediated inflammatory signaling.


Subject(s)
Clustered Regularly Interspaced Short Palindromic Repeats , Inflammation/metabolism , Interleukin-17/metabolism , Keratinocytes/metabolism , Signal Transduction , Small Molecule Libraries/metabolism , Transcription Factors/metabolism , Cell Differentiation , Cells, Cultured , Gene Knockdown Techniques , Homeostasis , Humans , Keratinocytes/cytology , RNA, Small Interfering/genetics , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Tumor Necrosis Factor-alpha/metabolism
8.
Elife ; 82019 01 09.
Article in English | MEDLINE | ID: mdl-30624206

ABSTRACT

The integrated stress response (ISR) attenuates the rate of protein synthesis while inducing expression of stress proteins in cells. Various insults activate kinases that phosphorylate the GTPase eIF2 leading to inhibition of its exchange factor eIF2B. Vanishing White Matter (VWM) is a neurological disease caused by eIF2B mutations that, like phosphorylated eIF2, reduce its activity. We show that introduction of a human VWM mutation into mice leads to persistent ISR induction in the central nervous system. ISR activation precedes myelin loss and development of motor deficits. Remarkably, long-term treatment with a small molecule eIF2B activator, 2BAct, prevents all measures of pathology and normalizes the transcriptome and proteome of VWM mice. 2BAct stimulates the remaining activity of mutant eIF2B complex in vivo, abrogating the maladaptive stress response. Thus, 2BAct-like molecules may provide a promising therapeutic approach for VWM and provide relief from chronic ISR induction in a variety of disease contexts.


Subject(s)
Brain Diseases/etiology , Eukaryotic Initiation Factor-2B/metabolism , Stress, Psychological/complications , White Matter/pathology , Animals , Astrocytes/pathology , Brain Diseases/pathology , Brain Diseases/prevention & control , Chronic Disease , Eukaryotic Initiation Factor-2B/genetics , Humans , Male , Mice , Mutation , Nerve Tissue Proteins/metabolism , Oligodendroglia/pathology , Phosphorylation , Protein Biosynthesis , Proteome , Weight Gain
9.
J Pharmacol Toxicol Methods ; 94(Pt 1): 34-43, 2018.
Article in English | MEDLINE | ID: mdl-29684554

ABSTRACT

INTRODUCTION: The adenine model of kidney disease typically involves dietary delivery of adenine over several weeks. This model can be variable in its disease progression and can result in significant mortality. In the current study, the amount of adenine delivered to rats was controlled by utilizing oral gavage administration over a short period in an attempt to induce robust renal pathology while addressing variability and viability of the animals. METHODS: Adenine (150 or 200 mg/kg) was administered via oral gavage for 10 consecutive days, and assessed over a total of 20 days. RESULTS: Both adenine dose groups manifested pathophysiological features of kidney disease such as proteinuria, elevated serum creatinine and BUN, and tubulointerstitial fibrosis. The animals also displayed a decline in glomerular filtration rate. Renal mRNA expression of genes associated with injury, inflammation, and fibrosis (i.e., Col1a1, Acta2, Serpine1, Timp1, Fn-Eda, Tgfb1, Ccl2, Nlrp3, Aqp1 and Ccnd1) were elevated as were urinary biomarkers that have translational utility (i.e., clusterin, KIM-1, MCP-1, OPN, NGAL, B2M, calbindin, and cystatin C). All disease endpoints were more pronounced in the 200 mg/kg group, however, while measures of tissue fibrosis were sustained, there was partial recovery by day 20 in functional readouts. No mortality was observed in either dose group. DISCUSSION: Short-term delivery of adenine via precise gavage delivery induced a robust model with hallmarks of fibrotic kidney disease, had limited variance between animals, and no animal morbidity within the 20 days studied. This model represents a methodical alternative to long-term dietary dosing of adenine.


Subject(s)
Adenine/administration & dosage , Fibrosis/chemically induced , Kidney Diseases/chemically induced , Kidney/drug effects , Administration, Oral , Animals , Biomarkers/urine , Fibrosis/metabolism , Fibrosis/urine , Glomerular Filtration Rate/drug effects , Inflammation/chemically induced , Inflammation/metabolism , Inflammation/urine , Kidney/metabolism , Kidney Diseases/metabolism , Kidney Diseases/urine , Male , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley
10.
J Basic Clin Physiol Pharmacol ; 29(3): 281-290, 2018 Jun 27.
Article in English | MEDLINE | ID: mdl-29397387

ABSTRACT

BACKGROUND: Losartan, a blocker of the angiotensin II type I receptor, is an important part of the standard of care for diabetic nephropathy (DN). The obese ZSF-1 rats display many aspects of the clinical features of human Type II DN. The current study was designed to examine the treatment effects of losartan on obese ZSF-1 rats and to evaluate the impact of the onset of dosing on efficacy. METHODS: The rats (7-10 weeks) underwent a right uninephrectomy (Unx) or sham surgery. Losartan (3, 10, 30 mg/kg) was dosed 3 or 9 weeks post-Unx and continued for 12 weeks. RESULTS: Treatment with losartan reduced urinary protein excretion and blood lipids (triglyceride and cholesterol) dose-dependently in both studies. The glomerular filtration rate (GFR) was significantly lower in obese ZSF-1 rats compared with those in lean rats, and losartan was efficacious against this endpoint, in particular with the earlier onset of treatment. Losartan also decreased tubulointerstitial fibrosis, and similar to GFR, earlier treatment conferred beneficial actions even at the lowest dose of 3 mg/kg. Several urinary biomarkers were elevated in the obese ZSF-1 rats, but the levels of sTNFR1, TIMP-1, L-FABP and KIM-1 were the only markers decreased by losartan. CONCLUSIONS: Losartan was renoprotective in the ZSF-1 rats with DN, improving both the pathological and functional parameters of the disease. Importantly, the data also highlight the importance of treatment at earlier stages of the disease for protecting against decline in the GFR and the development of fibrosis.


Subject(s)
Angiotensin II Type 1 Receptor Blockers/pharmacology , Diabetic Nephropathies/prevention & control , Losartan/pharmacology , Obesity/drug therapy , Angiotensin II Type 1 Receptor Blockers/administration & dosage , Animals , Biomarkers/metabolism , Cholesterol/blood , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Disease Models, Animal , Dose-Response Relationship, Drug , Female , Glomerular Filtration Rate/drug effects , Losartan/administration & dosage , Male , Rats , Triglycerides/blood
11.
Am J Nephrol ; 44(5): 339-353, 2016.
Article in English | MEDLINE | ID: mdl-27736813

ABSTRACT

BACKGROUND: Obese ZSF-1 rats display many features of human type II diabetes including nephropathy (DN). The study aimed to further understand the relevance of this model to DN, for which glomerular filtration rate (GFR), renal fibrosis and several urinary/tissue biomarkers was followed over 24 weeks in ZSF-1 rats. METHODS: Intact/sham or uninephrectomized male and female ZSF-1 rats were studied. GFR was measured by transdermal clearance of fluorescein isothiocyanate-sinistrin. Urine was collected every 2-4 weeks for biomarker analysis. Renal tissue was examined histologically for fibrosis and for levels of inflammatory and fibrotic genes. RESULTS: Male obese ZSF-1 rats demonstrated metabolic syndrome and proteinuria. Female counterparts were hyperlipidemic with delayed proteinuria, but were not hyperglycemic. Kidney hyperfiltration was observed in male obese rats in weeks 2-4 after surgery, and subsequently declined to levels significantly lower than controls. Tubulointerstitial/glomerular fibrosis in male obese rats was significantly elevated by week 12 post surgery and continued to expand in the ensuing weeks, particularly in uninephrectomized rats. Female rats had less severe fibrosis. Except for epidermal growth factor which decreased, the levels of several key inflammatory, injury and fibrotic factors were elevated in both tissue (mRNA) and urine (protein) of male obese rats. CONCLUSION: Male obese ZSF-1 rats represent an important DN model, manifesting key pathophysiological features including metabolic syndrome, proteinuria, progressive tubular and glomerular fibrosis, and transient hyperfiltration followed by progressive decline in renal function. Uninephrectomy significantly accelerated disease progression. Females were less severe in disease manifestation. Several urinary and tissue biomarkers were identified in the male obese rats that tracked with disease progression.


Subject(s)
Diabetic Nephropathies/physiopathology , Disease Models, Animal , Glomerular Filtration Rate , Kidney/pathology , Animals , Biomarkers/urine , Diabetes Mellitus, Experimental/complications , Diabetes Mellitus, Type 2/complications , Diabetic Nephropathies/etiology , Diabetic Nephropathies/metabolism , Diabetic Nephropathies/pathology , Female , Fibrosis , Gene Expression Profiling , Male , Nephrosclerosis/etiology , Nephrosclerosis/pathology , Rats
12.
Laryngoscope ; 126(5): 1187-92, 2016 05.
Article in English | MEDLINE | ID: mdl-26371776

ABSTRACT

OBJECTIVES/HYPOTHESIS: To compare the complication rate for osseointegrated hearing aids (OIHA) in patients with or without irradiation. STUDY DESIGN: Retrospective case review. METHODS: We studied patients with OIHAs implanted between January 1, 2005, and July 15, 2013 in a tertiary university center with a referral otology and neurotology practice. Demographics, history of oncologic surgery, follow-up length after OIHA implantation, radiation history and dosage, postoperative complications, and chronologic relationship between oncologic resection, OIHA implantation, and irradiation were reviewed to collect information. Soft tissue complications were graded according to a modified Holgers classification. RESULTS: The study included 48 patients. Twenty-nine patients (32 implants) did not undergo radiotherapy and 19 patients (19 implants) did. In the radiotherapy group, six patients had OIHAs implanted before radiotherapy, and 13 had OIHAs implanted in irradiated bone. Of these 13 patients, one had OIHA implanted during primary oncologic surgery; 11 had OIHA implanted during secondary surgery; and one patient did not have oncologic surgery. Patients with both OIHA implantation and radiotherapy had more complications than patients without radiotherapy (31.6% vs. 24.1%, P > 0.05) and more major complications than patients without radiotherapy (26.3% vs. 3.4%, P > 0.05). Patients with OIHAs implanted before radiotherapy did not have any complications. There were significantly fewer and less severe complications in patients with OIHAs implanted during primary oncologic resection than in patients with OIHAs implanted secondarily (0/8 vs. 8/11, P < 0.05). CONCLUSIONS: The rate and severity of complications of OIHAs can be minimized by implanting the device before irradiation, ideally at the time of primary oncologic surgery. LEVEL OF EVIDENCE: 4. Laryngoscope, 126:1187-1192, 2016.


Subject(s)
Hearing Aids/adverse effects , Hearing Loss, Conductive/therapy , Osseointegration , Radiotherapy/adverse effects , Temporal Bone/surgery , Aged , Combined Modality Therapy , Female , Humans , Male , Middle Aged , Osseointegration/radiation effects , Postoperative Complications , Retrospective Studies , Temporal Bone/radiation effects
13.
Pharmacol Rev ; 67(4): 1025-73, 2015 Oct.
Article in English | MEDLINE | ID: mdl-26419447

ABSTRACT

Progress in the fields of neuroscience and molecular biology has identified the forebrain cholinergic system as being important in many higher order brain functions. Further analysis of the genes encoding the nicotinic acetylcholine receptors (nAChRs) has highlighted, in particular, the role of α7 nAChRs in these higher order brain functions as evidenced by their peculiar physiologic and pharmacological properties. As this receptor has gained the attention of scientists from academia and industry, our knowledge of its roles in various brain and bodily functions has increased immensely. We have also seen the development of small molecules that have further refined our understanding of the roles of α7 nAChRs, and these molecules have begun to be tested in clinical trials for several indications. Although a large body of data has confirmed a role of α7 nAChRs in cognition, the translation of small molecules affecting α7 nAChRs into therapeutics has to date only progressed to the stage of testing in clinical trials. Notably, however, most recent human genetic and biochemical studies are further underscoring the crucial role of α7 nAChRs and associated genes in multiple organ systems and disease states. The aim of this review is to discuss our current knowledge of α7 nAChRs and their relevance as a target in specific functional systems and disease states.


Subject(s)
Brain/metabolism , alpha7 Nicotinic Acetylcholine Receptor/metabolism , Animals , Cardiovascular Diseases/genetics , Cardiovascular Diseases/physiopathology , Humans , Immune System Diseases/genetics , Immune System Diseases/physiopathology , Nervous System Diseases/genetics , Nervous System Diseases/physiopathology , Polymorphism, Single Nucleotide , Signal Transduction , Structure-Activity Relationship , alpha7 Nicotinic Acetylcholine Receptor/genetics
14.
Biochem Pharmacol ; 97(4): 454-462, 2015 Oct 15.
Article in English | MEDLINE | ID: mdl-26206194

ABSTRACT

Mutations in the progranulin gene cause frontotemporal dementia (FTD), a debilitating neurodegenerative disease that involves atrophy of the frontal and temporal lobes and affects personality, behavior, and language. Progranulin-deficient mouse models of FTD exhibit deficits in compulsive and social behaviors reminiscent of patients with FTD, and develop excessive microgliosis and increased release of inflammatory cytokines. Activation of nicotinic acetylcholine receptors (nAChRs) by nicotine or specific α7 nAChR agonists reduces neuroinflammation. Here, we investigated whether activation of nAChRs by nicotine or α7 agonists improved the excessive inflammatory and behavioral phenotypes of a progranulin-deficient FTD mouse model. We found that treatment with selective α7 agonists, PHA-568487 or ABT-107, strongly suppressed the activation of NF-κB in progranulin-deficient cells. Treatment with ABT-107 also reduced microgliosis, decreased TNFα levels, and reduced compulsive behavior in progranulin-deficient mice. Collectively, these data suggest that targeting activation of the α7 nAChR pathway may be beneficial in decreasing neuroinflammation and reversing some of the behavioral deficits observed in progranulin-deficient FTD.


Subject(s)
Aza Compounds/therapeutic use , Dioxins/therapeutic use , Frontotemporal Dementia/drug therapy , Indoles/therapeutic use , Inflammation/drug therapy , Intercellular Signaling Peptides and Proteins/metabolism , Quinuclidines/therapeutic use , alpha7 Nicotinic Acetylcholine Receptor/agonists , Animals , Behavior, Animal/drug effects , Female , Genes, Reporter , Granulins , Intercellular Signaling Peptides and Proteins/genetics , Macrophages/drug effects , Male , Mice , Mice, Knockout , Microglia/drug effects , Microglia/metabolism , NF-kappa B/metabolism , Progranulins
16.
Am J Public Health ; 104 Suppl 3: S496-503, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24754621

ABSTRACT

OBJECTIVES: We assessed diabetes-related mortality for American Indians and Alaska Natives (AI/ANs) and Whites. METHODS: Study populations were non-Hispanic AI/AN and White persons in Indian Health Service (IHS) Contract Health Service Delivery Area counties; Hispanics were excluded. We used 1990 to 2009 death certificate data linked to IHS patient registration records to identify AI/AN decedents aged 20 years or older. We examined disparities and trends in mortality related to diabetes as an underlying cause of death (COD) and as a multiple COD. RESULTS: After increasing between 1990 and 1999, rates of diabetes as an underlying COD and a multiple COD subsequently decreased in both groups. However, between 2000 and 2009, age-adjusted rates of diabetes as an underlying COD and a multiple COD remained 2.5 to 3.5 times higher among AI/AN persons than among Whites for all age groups (20-44, 45-54, 55-64, 65-74, and ≥ 75 years), both sexes, and every IHS region except Alaska. CONCLUSIONS: Declining trends in diabetes-related mortality in both AI/AN and White populations are consistent with recent improvements in their health status. Reducing persistent disparities in diabetes mortality will require developing effective approaches to not only control but also prevent diabetes among AI/AN populations.


Subject(s)
Diabetes Mellitus/ethnology , Diabetes Mellitus/mortality , Indians, North American/statistics & numerical data , Inuit/statistics & numerical data , Adult , Aged , Aged, 80 and over , Alaska/epidemiology , Alaska/ethnology , Cause of Death , Death Certificates , Female , Humans , Male , Middle Aged , Population Surveillance , Registries , United States/epidemiology , White People/statistics & numerical data
17.
Prev Chronic Dis ; 11: E56, 2014 Apr 10.
Article in English | MEDLINE | ID: mdl-24721216

ABSTRACT

INTRODUCTION: Alaska Native colorectal cancer (CRC) incidence and mortality rates are the highest of any ethnic/racial group in the United States. CRC screening using guaiac-based fecal occult blood tests (gFOBT) are not recommended for Alaska Native people because of false-positive results associated with a high prevalence of Helicobacter pylori-associated hemorrhagic gastritis. This study evaluated whether the newer immunochemical FOBT (iFOBT) resulted in a lower false-positive rate and higher specificity for detecting advanced colorectal neoplasia than gFOBT in a population with elevated prevalence of H. pylori infection. METHODS: We used a population-based sample of 304 asymptomatic Alaska Native adults aged 40 years or older undergoing screening or surveillance colonoscopy (April 2008-January 2012). RESULTS: Specificity differed significantly (P < .001) between gFOBT (76%; 95% CI, 71%-81%) and iFOBT (92%; 95% CI, 89%-96%). Among H. pylori-positive participants (54%), specificity of iFOBT was even higher (93% vs 69%). Overall, sensitivity did not differ significantly (P = .73) between gFOBT (29%) and iFOBT (36%). Positive predictive value was 11% for gFOBT and 32% for iFOBT. CONCLUSION: The iFOBT had a significantly higher specificity than gFOBT, especially in participants with current H. pylori infection. The iFOBT represents a potential strategy for expanding CRC screening among Alaska Native and other populations with elevated prevalence of H. pylori, especially where access to screening endoscopy is limited.


Subject(s)
Colorectal Neoplasms/diagnosis , Feces/chemistry , Helicobacter Infections/epidemiology , Helicobacter pylori , Indians, North American , Occult Blood , Adult , Alaska , Early Detection of Cancer/methods , Female , Helicobacter Infections/complications , Helicobacter Infections/microbiology , Humans , Male , Middle Aged
18.
Am J Public Health ; 104 Suppl 3: S286-94, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24754557

ABSTRACT

OBJECTIVES: We describe methods used to mitigate the effect of race misclassification in mortality records and the data sets used to improve mortality estimates for American Indians and Alaska Natives (AI/ANs). METHODS: We linked US National Death Index (NDI) records with Indian Health Service (IHS) registration records to identify AI/AN deaths misclassified as non-AI/AN deaths. Analyses excluded decedents of Hispanic origin and focused on Contract Health Service Delivery Area (CHSDA) counties. We compared death rates for AI/AN persons and Whites across 6 US regions. RESULTS: IHS registration records merged to 176,137 NDI records. Misclassification of AI/AN race in mortality data ranged from 6.3% in the Southwest to 35.6% in the Southern Plains. From 1999 to 2009, the all-cause death rate in CHSDA counties for AI/AN persons varied by geographic region and was 46% greater than that for Whites. Analyses for CHSDA counties resulted in higher death rates for AI/AN persons than in all counties combined. CONCLUSIONS: Improving race classification among AI/AN decedents strengthens AI/AN mortality data, and analyzing deaths by geographic region can aid in planning, implementation, and evaluation of efforts to reduce health disparities in this population.


Subject(s)
Data Collection/standards , Indians, North American/statistics & numerical data , Inuit/statistics & numerical data , Mortality/trends , Adolescent , Adult , Aged , Aged, 80 and over , Alaska , Cause of Death , Child , Child, Preschool , Death Certificates , Female , Humans , Infant , Male , Middle Aged , Population Surveillance , United States , United States Indian Health Service
20.
Curr Protoc Pharmacol ; Chapter 9: Unit 9.15., 2012 Jun.
Article in English | MEDLINE | ID: mdl-22684723

ABSTRACT

Adenosine triphosphate (ATP) activates two receptor superfamilies, metabotropic P2Y and ionotropic P2X receptors. The P2X receptors are nonselective cation channels that are widely expressed on excitable cells including neurons, glia, and smooth muscle cells. The protocols in this unit are useful for evaluating ligands that interact with P2X receptors on native cells or that are cloned and expressed in recombinant heterologous cell systems. Calcium imaging methods are described for the pharmacological characterization of fast or slowly desensitizing P2X receptors. While these methods are readily applicable to a wide variety of ligand-gated ion channels, the protocols provided herein detail how they can be used to measure activation of homomeric P2X3 (fast desensitizing) and heteromeric P2X2/3 (slowly desensitizing) receptors. Appropriate agonists and/or calcium dyes can be substituted to assess activity at other P2X receptor subtypes. An additional protocol is provided for measuring P2X7 receptor-mediated pore formation in THP-1, a native human acute monocytic leukemia cell line that can be used to study homomeric P2X7 (non-desensitizing) receptors that are expressed on macrophages and microglial cells.


Subject(s)
Calcium/metabolism , Fluorometry/methods , Purinergic P2X Receptor Agonists/pharmacology , Purinergic P2X Receptor Antagonists/pharmacology , Receptors, Purinergic P2X2/metabolism , Astrocytoma/metabolism , Buffers , Humans , Indicators and Reagents/pharmacology , Tumor Cells, Cultured
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