Recent Research Articles from UNTHSC

Recent research articles indexed in PubMed from authors affiliated with the UNT Health Science Center.

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Updated: 2 hours 41 min ago

Negative regulation of Smad1 pathway and collagen IV expression by store-operated Ca2+ entry in glomerular mesangial cells.

Fri, 03/17/2017 - 16:36
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Negative regulation of Smad1 pathway and collagen IV expression by store-operated Ca2+ entry in glomerular mesangial cells.

Am J Physiol Renal Physiol. 2017 Mar 15;:ajprenal.00642.2016

Authors: Wu P, Ren Y, Ma Y, Wang Y, Jiang H, Chaudhari S, Davis ME, Zuckerman JE, Ma R

Abstract
Collagen IV (Col IV) is a major component of expanded glomerular extracellular matrix in diabetic nephropathy and Smad1 is a key molecule regulating Col IV expression in mesangial cells (MCs). The present study was conducted to determine if Smad1 pathway and Col IV protein abundance were regulated by store-operated Ca2+ entry (SOCE). In cultured human MCs, pharmacological inhibition of SOCE significantly increased the total amount of Smad1 protein. Activation of SOCE blunted high glucose-increased Smad1 protein content. Treating human MCs with angiotensin II at 1 µM for 15 min, or high glucose for 3 days, or TGF-β1 at 5 ng/ml for 30 min increased the level of phosphorylated Smad1. However, the phosphorylation of Smad1 by those stimuli was significantly attenuated by activation of SOCE. Knocking down Smad1 reduced, but expressing Smad1 increased the amount of Col IV protein. Furthermore, activation of SOCE significantly attenuated high glucose-induced Col IV protein production and blockade of SOCE substantially increased the abundance of Col IV. To further verify those in vitro findings, we downregulated SOCE specifically in MCs in mice using siRNA against Orai1 (the channel protein mediating SOCE) delivered by the targeted nanoparticle delivery system. Immunohistochemical examinations showed that expression of both Smad1 and Col IV proteins were significantly greater in the glomeruli with positively-transfected Orai1 siRNA compared to the glomeruli from the mice without Orai1 siRNA treatment. Taken together, our results indicate that SOCE negatively regulates the Smad1 signaling pathway and inhibits Col IV protein production in MCs.

PMID: 28298362 [PubMed - as supplied by publisher]

Analysis of DNA from post-blast pipe bomb fragments for identification and determination of ancestry.

Thu, 03/16/2017 - 10:44
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Analysis of DNA from post-blast pipe bomb fragments for identification and determination of ancestry.

Forensic Sci Int Genet. 2017 Mar 01;28:195-202

Authors: Tasker E, LaRue B, Beherec C, Gangitano D, Hughes-Stamm S

Abstract
Improvised explosive devices (IEDs) such as pipe bombs are weapons used to detrimentally affect people and communities. A readily accessible brand of exploding targets called Tannerite® has been identified as a potential material for abuse as an explosive in pipe bombs. The ability to recover and genotype DNA from such weapons may be vital in the effort to identify suspects associated with these devices. While it is possible to recover DNA from post-blast fragments using short tandem repeat markers (STRs), genotyping success can be negatively affected by low quantities of DNA, degradation, and/or PCR inhibitors. Alternative markers such as insertion/null (INNULs) and single nucleotide polymorphisms (SNPs) are bi-allelic genetic markers that are shorter genomic targets than STRs for amplification, which are more likely to resist degradation. In this study, we constructed pipe bombs that were spiked with known amounts of biological material to: 1) recover "touch" DNA from the surface of the device, and 2) recover traces of blood from the ends of wires (simulated finger prick). The bombs were detonated with the binary explosive Tannerite® using double-base smokeless powder to initiate the reaction. DNA extracted from the post-blast fragments was quantified with the Quantifiler® Trio DNA Quantification Kit. STR analysis was conducted using the GlobalFiler® Amplification Kit, INNULs were amplified using an early-access version of the InnoTyper™ 21 Kit, and SNP analysis via massively parallel sequencing (MPS) was performed using the HID-Ion Ampliseq™ Identity and Ancestry panels using the Ion Chef and Ion PGM sequencing system. The results of this study showed that INNUL markers resulted in the most complete genetic profiles when compared to STR and SNP profiles. The random match probabilities calculated for samples using INNULs were lower than with STRs when less than 14 STR alleles were reported. These results suggest that INNUL analysis may be well suited for low-template and/or degraded DNA samples, and may be used to supplement incomplete or failed STR analysis. Human identification using SNP analysis via MPS showed variable success with low-level post-blast samples in this study (<150pg). While neat DNA samples (6μL input as recommended) resulted in <50% of SNP calls, samples that were concentrated from 15μL to 6μL (15μL was added for STR and INNUL typing) resulted in more complete SNP profiles. Five out of six blood samples recovered from the wires attached to the pipe-bombs resulted in the correct ancestry predictions.

PMID: 28292727 [PubMed - as supplied by publisher]

Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.

Thu, 03/16/2017 - 10:44
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Practical Strategies and Concepts in GPCR Allosteric Modulator Discovery: Recent Advances with Metabotropic Glutamate Receptors.

Chem Rev. 2016 06 08;116(11):6707-41

Authors: Lindsley CW, Emmitte KA, Hopkins CR, Bridges TM, Gregory KJ, Niswender CM, Conn PJ

Abstract
Allosteric modulation of GPCRs has initiated a new era of basic and translational discovery, filled with therapeutic promise yet fraught with caveats. Allosteric ligands stabilize unique conformations of the GPCR that afford fundamentally new receptors, capable of novel pharmacology, unprecedented subtype selectivity, and unique signal bias. This review provides a comprehensive overview of the basics of GPCR allosteric pharmacology, medicinal chemistry, drug metabolism, and validated approaches to address each of the major challenges and caveats. Then, the review narrows focus to highlight recent advances in the discovery of allosteric ligands for metabotropic glutamate receptor subtypes 1-5 and 7 (mGlu1-5,7) highlighting key concepts ("molecular switches", signal bias, heterodimers) and practical solutions to enable the development of tool compounds and clinical candidates. The review closes with a section on late-breaking new advances with allosteric ligands for other GPCRs and emerging data for endogenous allosteric modulators.

PMID: 26882314 [PubMed - indexed for MEDLINE]

The Impact of Rurality on 30-Day Preventable Readmission, Illness Severity, and Risk of Mortality for Heart Failure Medicare Home Health Beneficiaries.

Thu, 03/16/2017 - 10:44
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The Impact of Rurality on 30-Day Preventable Readmission, Illness Severity, and Risk of Mortality for Heart Failure Medicare Home Health Beneficiaries.

J Rural Health. 2016;32(2):176-87

Authors: Chen HF, Carlson E, Popoola T, Suzuki S

Abstract
PURPOSE: To examine the impact of rurality on 30-day preventable readmission, and the illness severity and risk of mortality for 30-day preventable readmissions.
METHODS: We analyzed heart failure Medicare beneficiaries who received home health services for postacute care after hospital discharge in 2009. The study was a cross-sectional design with the unit of analysis as the home health episode for postacute care. Data sources included the following: Medicare Beneficiary Summary File, Medicare Provider Analysis Review, Outcome Assessment Information Set, Home Health Agency Research Identifiable File, and Area Health Resources File. The dependent variables were 30-day preventable readmission, and the extreme/major level of illness severity and of risk of mortality for a 30-day preventable readmission. The key independent variable was rurality defined as remote rural, adjacent rural, and micropolitan areas, with urban areas in the reference group.
FINDINGS: Home health beneficiaries in remote rural areas had 27% lower 30-day preventable readmission than those in urban areas. Home health beneficiaries in adjacent rural areas were 33% less likely to have high illness severity at readmission due to a preventable condition than those in urban areas.
CONCLUSIONS: Geographical location affects preventable readmission and illness severity of preventable readmission. Patients' geographic location along with patients' risk factors should be taken into consideration in the risk adjustment model for the financial incentive program that penalizes home health agencies with high preventable readmissions.

PMID: 26348123 [PubMed - indexed for MEDLINE]

A Precision Medicine Initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling.

Tue, 03/14/2017 - 07:39

A Precision Medicine Initiative for Alzheimer's disease: the road ahead to biomarker-guided integrative disease modeling.

Climacteric. 2017 Apr;20(2):107-118

Authors: Hampel H, O'Bryant SE, Durrleman S, Younesi E, Rojkova K, Escott-Price V, Corvol JC, Broich K, Dubois B, Lista S, Alzheimer Precision Medicine Initiative

Abstract
After intense scientific exploration and more than a decade of failed trials, Alzheimer's disease (AD) remains a fatal global epidemic. A traditional research and drug development paradigm continues to target heterogeneous late-stage clinically phenotyped patients with single 'magic bullet' drugs. Here, we propose that it is time for a paradigm shift towards the implementation of precision medicine (PM) for enhanced risk screening, detection, treatment, and prevention of AD. The overarching structure of how PM for AD can be achieved will be provided through the convergence of breakthrough technological advances, including big data science, systems biology, genomic sequencing, blood-based biomarkers, integrated disease modeling and P4 medicine. It is hypothesized that deconstructing AD into multiple genetic and biological subsets existing within this heterogeneous target population will provide an effective PM strategy for treating individual patients with the specific agent(s) that are likely to work best based on the specific individual biological make-up. The Alzheimer's Precision Medicine Initiative (APMI) is an international collaboration of leading interdisciplinary clinicians and scientists devoted towards the implementation of PM in Neurology, Psychiatry and Neuroscience. It is hypothesized that successful realization of PM in AD and other neurodegenerative diseases will result in breakthrough therapies, such as in oncology, with optimized safety profiles, better responder rates and treatment responses, particularly through biomarker-guided early preclinical disease-stage clinical trials.

PMID: 28286989 [PubMed - in process]

Treadmill exercise within lower body negative pressure protects leg lean tissue mass and extensor strength and endurance during bed rest.

Tue, 03/14/2017 - 07:39
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Treadmill exercise within lower body negative pressure protects leg lean tissue mass and extensor strength and endurance during bed rest.

Physiol Rep. 2016 08;4(15):

Authors: Schneider SM, Lee SM, Feiveson AH, Watenpaugh DE, Macias BR, Hargens AR

Abstract
Leg muscle mass and strength are decreased during reduced activity and non-weight-bearing conditions such as bed rest (BR) and spaceflight. Supine treadmill exercise within lower body negative pressure (LBNPEX) provides full-body weight loading during BR and may prevent muscle deconditioning. We hypothesized that a 40-min interval exercise protocol performed against LBNPEX 6 days week(-1) would attenuate losses in leg lean mass (LLM), strength, and endurance during 6° head-down tilt BR, with similar benefits for men and women. Fifteen pairs of healthy monozygous twins (8 male and 7 female pairs) completed 30 days of BR with one sibling of each twin pair assigned randomly as the non-exercise control (CON) and the other twin as the exercise subject (EX). Before and after BR, LLM and isokinetic leg strength and endurance were measured. Mean knee and ankle extensor and flexor strength and endurance and LLM decreased from pre- to post-BR in the male CON subjects (P < 0.01), but knee extensor strength and endurance, ankle extensor strength, and LLM were maintained in the male EX subjects. In contrast, no pre- to post-BR changes were significant in the female subjects, either CON or EX, likely due to their lower pre-BR values. Importantly, the LBNPEX countermeasure prevents or attenuates declines in LLM as well as extensor leg strength and endurance. Individuals who are stronger, have higher levels of muscular endurance, and/or have greater LLM are likely to experience greater losses during BR than those who are less fit.

PMID: 27495299 [PubMed - indexed for MEDLINE]

Tuberculosis hospitalization expenditures per patient from private health insurance claims data, 2010-2014.

Mon, 03/13/2017 - 07:31

Tuberculosis hospitalization expenditures per patient from private health insurance claims data, 2010-2014.

Int J Tuberc Lung Dis. 2017 Apr 01;21(4):398-404

Authors: Owusu-Edusei K, Marks SM, Miramontes R, Stockbridge EL, Winston CA

Abstract
OBJECTIVE: To determine hospitalization expenditures for tuberculosis (TB) disease among privately insured patients in the United States.
METHODS: We extracted TB hospital admissions data from the 2010-2014 MarketScan® commercial database using International Classification of Diseases version 9 codes for TB (011.0-018.96) as the principal diagnosis. We estimated adjusted average expenditures (in 2014 USD) using regression analyses controlling for patient and claim characteristics. We also estimated the total expenditure paid by enrollee and insurance, and extrapolated it to the entire US employer-based privately insured population.
RESULTS: We found 892 TB hospitalizations representing 825 unique enrollees over the 5-year period. The average hospitalization expenditure per person (including multiple hospitalizations) was US$33 085 (95%CI US$31 606- US$34 565). Expenditures for central nervous system TB (US$73 065, 95%CI US$59 572-US$86 558), bone and joint TB (US$56 842, 95%CI US$39 301-US$74 383), and miliary/disseminated TB (US$55 487, 95%CI US$46 101-US$64 873) were significantly higher than those for pulmonary TB (US$28 058, 95%CI US$26 632-US$29 484). The overall total expenditure for hospitalizations for TB disease over the period (2010-2014) was US$38.4 million; it was US$154 million when extrapolated to the entire employer-based privately insured population in the United States.
CONCLUSIONS: Hospitalization expenditures for some forms of extra-pulmonary TB were substantially higher than for pulmonary TB.

PMID: 28284254 [PubMed - in process]

Kienböck Disease: Moving Forward.

Sat, 03/11/2017 - 07:34
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Kienböck Disease: Moving Forward.

J Hand Surg Am. 2016 May;41(5):630-8

Authors: Lichtman DM, Pientka WF, Bain GI

Abstract
Over the past decade, a plethora of new information has been reported regarding etiology, natural history, classification, and treatment options for lunate osteonecrosis. New disease classifications have been described based on advanced imaging determination of lunate viability as well as a cartilage-based arthroscopic classification. Here we review the newest literature regarding Kienböck disease and present a new treatment algorithm that incorporates the traditional osseous classification system with a perfusion/viability classification and an articular cartilage-based classification.

PMID: 27055625 [PubMed - indexed for MEDLINE]

The health action process approach applied to African American breast cancer survivors.

Sat, 03/11/2017 - 07:34
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The health action process approach applied to African American breast cancer survivors.

Psychooncology. 2016 06;25(6):648-55

Authors: Paxton RJ

Abstract
BACKGROUND: The health action process approach (HAPA) is a relevant model for understanding physical activity (PA), yet it has not been examined in cancer survivors or minorities. In this study, we assessed the HAPA in African American breast cancer survivors using covariance modeling.
METHODS: A total of 304 African American breast cancer survivors (mean age = 54 years) participated in a Web-based survey assessing demographic and medical characteristics as well as constructs of the HAPA. A two-step covariance modeling approach was used to assess the structural relationships among the constructs.
RESULTS: The hypothesized measurement model fit the data; however, general severity was not significantly associated with the remaining constructs. General severity was removed, and the fit did not change significantly. The final adjusted model provided a reasonable fit to the data and accounted for significant variance in intentions (49%) and PA (42%). Action (β = 0.1, p < 0.01) and coping (β = 0.3, p < 0.01) planning mediated the relationship between intentions and behavior.
CONCLUSIONS: The HAPA appears to be a relevant model for understanding PA in African American breast cancer survivors. However, more work is needed to determine whether these relationships can be replicated in other breast cancer survivors. Copyright © 2015 John Wiley & Sons, Ltd.

PMID: 26058382 [PubMed - indexed for MEDLINE]

The factor of 10 in forensic DNA match probabilities.

Thu, 03/09/2017 - 07:34

The factor of 10 in forensic DNA match probabilities.

Forensic Sci Int Genet. 2017 Feb 16;28:178-187

Authors: Gittelson S, Moretti TR, Onorato AJ, Budowle B, Weir BS, Buckleton J

Abstract
An update was performed of the classic experiments that led to the view that profile probability assignments are usually within a factor of 10 of each other. The data used in this study consist of 15 Identifiler loci collected from a wide range of forensic populations. Following Budowle et al. [1], the terms cognate and non-cognate are used. The cognate database is the database from which the profiles are simulated. The profile probability assignment was usually larger in the cognate database. In 44%-65% of the cases, the profile probability for 15 loci in the non-cognate database was within a factor of 10 of the profile probability in the cognate database. This proportion was between 60% and 80% when the FBI and NIST data were used as the non-cognate databases. A second experiment compared the match probability assignment using a generalised database and recommendation 4.2 from NRC II (the 4.2 assignment) with a proxy for the matching proportion developed using subpopulation allele frequencies and the product rule. The findings support that the 4.2 assignment has a large conservative bias. These results are in agreement with previous research results.

PMID: 28273509 [PubMed - as supplied by publisher]

Flanking region variation of ForenSeq™ DNA Signature Prep Kit STR and SNP loci in Yavapai Native Americans.

Thu, 03/09/2017 - 07:34

Flanking region variation of ForenSeq™ DNA Signature Prep Kit STR and SNP loci in Yavapai Native Americans.

Forensic Sci Int Genet. 2017 Feb 27;28:146-154

Authors: Wendt FR, King JL, Novroski NM, Churchill JD, Ng J, Oldt RF, McCulloh KL, Weise JA, Smith DG, Kanthaswamy S, Budowle B

Abstract
Massively parallel sequencing (MPS) offers advantages over current capillary electrophoresis-based analysis of short tandem repeat (STR) loci for human identification testing. In particular STR repeat motif sequence information can be obtained, thereby increasing the discrimination power of some loci. While sequence variation within the repeat region is observed relatively frequently in some of the commonly used STRs, there is an additional degree of variation found in the flanking regions adjacent to the repeat motif. Repeat motif and flanking region sequence variation have been described for major population groups, however, not for more isolated populations. Flanking region sequence variation in STR and single nucleotide polymorphism (SNP) loci in the Yavapai population was analyzed using the ForenSeq™ DNA Signature Prep Kit and STRait Razor v2s. Seven and 14 autosomal STRs and identity-informative single nucleotide polymorphisms (iiSNPs), respectively, had some degree of flanking region variation. Three and four of these identity-informative loci, respectively, showed ≥5% increase in expected heterozygosity. The combined length- and sequence-based random match probabilities (RMPs) for 27 autosomal STRs were 6.11×10(-26) and 2.79×10(-29), respectively. When combined with 94 iiSNPs (a subset of which became microhaplotypes) the combined RMP was 5.49×10(-63). Analysis of length-based and sequence-based autosomal STRs in STRUCTURE indicated that the Yavapai are most similar to the Hispanic population. While producing minimal increase in X- and Y-STR discrimination potential, access to flanking region data enabled identification of one novel X-STR and three Y-STR alleles relative to previous reports. Five ancestry-informative SNPs (aiSNPs) and two phenotype-informative SNPs (piSNPs) exhibited notable flanking region variation.

PMID: 28273507 [PubMed - as supplied by publisher]

Enzymatic Debridement of Chronic Nonischemic Diabetic Foot Ulcers: Results of a Randomized, Controlled Trial.

Wed, 03/08/2017 - 07:35
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Enzymatic Debridement of Chronic Nonischemic Diabetic Foot Ulcers: Results of a Randomized, Controlled Trial.

Wounds. 2017 Feb 27;:

Authors: Jimenez JC, Agnew PS, Mayer P, Clements JR, Caporusso JM, Lange DL, Dickerson JE, Slade HB

Abstract
OBJECTIVE: The aim of this randomized, controlled multicenter trial was to evaluate the clinical outcomes associated with the use of clostridial collagenase ointment (CCO) for up to 12 weeks in 215 patients with type 1 or type 2 diabetes mellitus and a neuropathic, nonischemic diabetic foot ulcer (DFU).
MATERIALS AND METHODS: Patients were randomized into either a group receiving CCO applied once daily at a thickness of ~2 mm or a group receiving standard care (SC) consisting of a daily application of a hydrogel as needed to maintain a moist ulcer environment. All ulcers were covered with a nonadherent foam dressing that was changed once daily, and sharp debridement was allowed when the investigators deemed it medically warranted. Outcome measures included the percent change in ulcer area and the effect of baseline wound microbiota on subsequent healing. Patients with ulcers that showed no decrease in size after 4 weeks were crossed over to the other treatment group.
RESULTS: The wound area decreased relative to baseline for both the CCO group (-60%, P < .0001; -65%, P < .0001) and the control group (-50%, P = .0001; -51%, P = .0001) after 6 and 12 weeks, respectively. While the intergroup differences at 6 and 12 weeks did not reach statistical significance (P = .3801; P = .3606), mean percent reductions for the CCO group were greater than the control at all 12 time points (averages: -55%; -41%, respectively). Overall closure rate was 21% and 41% (weeks 6 and 12, P = .3705; P = .2358) with no significant differences between groups. However, the DFUs that showed no improvement at 4 weeks (N = 24, 12/group) were crossed over to the other treatment group. A numerically greater proportion of subjects who switched to CCO achieved closure (33%) than for those who switched to SC (8%). Baseline biopsy showed that despite the absence of clinical signs of infection, all ulcers were heavily colonized by 1 to 5 species of bacteria. No adverse events were assessed by the investigators as related to either treatment.
CONCLUSION: These results confirm observations from previous studies demonstrating positive outcomes associated with enzymatic debridement with CCO following 6 weeks of treatment.

PMID: 28267678 [PubMed - as supplied by publisher]

Superparamagnetic reconstituted high-density lipoprotein nanocarriers for magnetically guided drug delivery.

Tue, 03/07/2017 - 07:36
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Superparamagnetic reconstituted high-density lipoprotein nanocarriers for magnetically guided drug delivery.

Int J Nanomedicine. 2017;12:1453-1464

Authors: Sabnis S, Sabnis NA, Raut S, Lacko AG

Abstract
Current cancer chemotherapy is frequently associated with short- and long-term side effects, affecting the quality of life of cancer survivors. Because malignant cells are known to overexpress specific surface antigens, including receptors, targeted drug delivery is often utilized to reduce or overcome side effects. The current study involves a novel targeting approach using specifically designed nanoparticles, including encapsulation of the anti-cancer drug valrubicin into superparamagnetic iron oxide nanoparticle (SPION) containing reconstituted high-density lipoprotein (rHDL) nanoparticles. Specifically, rHDL-SPION-valrubicin hybrid nanoparticles were assembled and characterized with respect to their physical and chemical properties, drug entrapment efficiency and receptor-mediated release of the drug valrubicin from the nanoparticles to prostate cancer (PC-3) cells. Prussian blue staining was used to assess nanoparticle movement in a magnetic field. Measurements of cytotoxicity toward PC-3 cells showed that rHDL-SPION-valrubicin nanoparticles were up to 4.6 and 31 times more effective at the respective valrubicin concentrations of 42.4 µg/mL and 85 µg/mL than the drug valrubicin alone. These studies showed, for the first time, that lipoprotein drug delivery enhanced via magnetic targeting could be an effective chemotherapeutic strategy for prostate cancer.

PMID: 28260891 [PubMed - in process]

Glucocorticoid therapy and ocular hypertension.

Tue, 03/07/2017 - 07:36
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Glucocorticoid therapy and ocular hypertension.

Eur J Pharmacol. 2016 Sep 15;787:57-71

Authors: Dibas A, Yorio T

Abstract
The projected number of people who will develop age-related macular degeneration in estimated at 2020 is 196 million and is expected to reach 288 million in 2040. Also, the number of people with Diabetic retinopathy will grow from 126.6 million in 2010 to 191.0 million by 2030. In addition, it is estimated that there are 2.3 million people suffering from uveitis worldwide. Because of the anti-inflammatory properties of glucocorticoids (GCs), they are often used topically and/or intravitreally to treat ocular inflammation conditions or edema associated with macular degeneration and diabetic retinopathy. Unfortunately, ocular GC therapy can lead to severe side effects. Serious and sometimes irreversible eye damage can occur as a result of the development of GC-induced ocular hypertension causing secondary open-angle glaucoma. According to the world health organization, glaucoma is the second leading cause of blindness in the world and it is estimated that 80 million will suffer from glaucoma by 2020. In the current review, mechanisms of GC-induced damage in ocular tissue, GC-resistance, and enhancing GC therapy will be discussed.

PMID: 27388141 [PubMed - indexed for MEDLINE]

4-Chlorophenylguanidine is an ASIC3 agonist and positive allosteric modulator.

Mon, 03/06/2017 - 07:35

4-Chlorophenylguanidine is an ASIC3 agonist and positive allosteric modulator.

J Pharmacol Sci. 2017 Feb 17;:

Authors: Agharkar AS, Gonzales EB

Abstract
Acid-sensing ion channels (ASICs) are proton-sensitive sodium channels that open in response to lowered extracellular pH and are expressed in the central and peripheral nervous systems. The ASIC3 subtype is found primarily in the periphery where the channel mediates pain signals caused by ischemia and inflammation. Here, we provide identify 4-chlorophenylguanidine (4-CPG) as an ASIC3 positive allosteric modulator and newest member of the growing group of guanidine modulators of ASICs. Furthermore, the 4-CPG reversed the effects of ASIC3 desensitization. The molecule 4-CPG offers a novel chemical backbone for the design of new ASIC3 ligands to study ASIC3 in vivo.

PMID: 28259560 [PubMed - as supplied by publisher]

Stroke Cytoprotection: Can Repeating History with New Expectations Really Be the Path to Success in Stroke Research?

Fri, 03/03/2017 - 07:31
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Stroke Cytoprotection: Can Repeating History with New Expectations Really Be the Path to Success in Stroke Research?

Transl Stroke Res. 2017 Mar 01;:

Authors: Lapchak PA, Uteshev VV

PMID: 28251583 [PubMed - as supplied by publisher]

Fluorocycline TP-271 Is Potent against Complicated Community-Acquired Bacterial Pneumonia Pathogens.

Fri, 03/03/2017 - 07:31
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Fluorocycline TP-271 Is Potent against Complicated Community-Acquired Bacterial Pneumonia Pathogens.

mSphere. 2017 Jan-Feb;2(1):

Authors: Grossman TH, Fyfe C, O'Brien W, Hackel M, Minyard MB, Waites KB, Dubois J, Murphy TM, Slee AM, Weiss WJ, Sutcliffe JA

Abstract
TP-271 is a novel, fully synthetic fluorocycline antibiotic in clinical development for the treatment of respiratory infections caused by susceptible and multidrug-resistant pathogens. TP-271 was active in MIC assays against key community respiratory Gram-positive and Gram-negative pathogens, including Streptococcus pneumoniae (MIC90 = 0.03 µg/ml), methicillin-sensitive Staphylococcus aureus (MSSA; MIC90 = 0.25 µg/ml), methicillin-resistant S. aureus (MRSA; MIC90 = 0.12 µg/ml), Streptococcus pyogenes (MIC90 = 0.03 µg/ml), Haemophilus influenzae (MIC90 = 0.12 µg/ml), and Moraxella catarrhalis (MIC90 ≤0.016 µg/ml). TP-271 showed activity (MIC90 = 0.12 µg/ml) against community-acquired MRSA expressing Panton-Valentine leukocidin (PVL). MIC90 values against Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae were 0.004, 1, and 4 µg/ml, respectively. TP-271 was efficacious in neutropenic and immunocompetent animal pneumonia models, generally showing, compared to the burden at the start of dosing, ~2 to 5 log10 CFU reductions against MRSA, S. pneumoniae, and H. influenzae infections when given intravenously (i.v.) and ~1 to 4 log10 CFU reductions when given orally (p.o.). TP-271 was potent against key community-acquired bacterial pneumonia (CABP) pathogens and was minimally affected, or unaffected, by tetracycline-specific resistance mechanisms and fluoroquinolone or macrolide drug resistance phenotypes. IMPORTANCE Rising resistance rates for macrolides, fluoroquinolones, and β-lactams in the most common pathogens associated with community-acquired bacterial pneumonia (CABP) are of concern, especially for cases of moderate to severe infections in vulnerable populations such as the very young and the elderly. New antibiotics that are active against multidrug-resistant Streptococcus pneumoniae and Staphylococcus aureus are needed for use in the empirical treatment of the most severe forms of this disease. TP-271 is a promising new fluorocycline antibiotic demonstrating in vitro potency and nonclinical efficacy by intravenous and oral administration against the major pathogens associated with moderate to severe CABP.

PMID: 28251179 [PubMed - in process]

Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma.

Fri, 03/03/2017 - 07:31
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Upregulation of the endothelin A (ETA) receptor and its association with neurodegeneration in a rodent model of glaucoma.

BMC Neurosci. 2017 Mar 01;18(1):27

Authors: McGrady NR, Minton AZ, Stankowska DL, He S, Jefferies HB, Krishnamoorthy RR

Abstract
BACKGROUND: Primary open angle glaucoma is a heterogeneous group of optic neuropathies that results in optic nerve degeneration and a loss of retinal ganglion cells (RGCs) ultimately causing blindness if allowed to progress. Elevation of intraocular pressure (IOP) is the most attributable risk factor for developing glaucoma and lowering of IOP is currently the only available therapy. However, despite lowering IOP, neurodegenerative effects persist in some patients. Hence, it would be beneficial to develop approaches to promote neuroprotection of RGCs in addition to IOP lowering therapies. The endothelin system is a key target for intervention against glaucomatous neurodegeneration. The endothelin family of peptides and receptors, particularly endothelin-1 (ET-1) and endothelin B (ETB) receptor, has been shown to have neurodegenerative roles in glaucoma. The purpose of this study was to examine changes in endothelin A (ETA) receptor protein expression in the retinas of adult male Brown Norway rats following IOP elevation by the Morrison's model of ocular hypertension and the impact of ETA receptor overexpression on RGC viability in vitro.
RESULTS: IOP elevation was carried out in one eye of Brown Norway rats by injection of hypertonic saline through episcleral veins. After 2 weeks of IOP elevation, immunohistochemical analysis of retinal sections from rat eyes showed an increasing trend in immunostaining for ETA receptors in multiple retinal layers including the inner plexiform layer, ganglion cell layer and outer plexiform layer. Following 4 weeks of IOP elevation, a significant increase in immunostaining for ETA receptor expression was found in the retina, primarily in the inner plexiform layer and ganglion cells. A modest increase in staining for ETA receptors was also found in the outer plexiform layer in the retina of rats with IOP elevation. Cell culture studies showed that overexpression of ETA receptors in 661W cells as well as primary RGCs decreases cell viability, compared to empty vector transfected cells. Adeno-associated virus mediated overexpression of the ETA receptor produced an increase in the ETB receptor in primary RGCs.
CONCLUSIONS: Elevated IOP results in an appreciable change in ETA receptor expression in the retina. Overexpression of the ETA receptor results in an overall decrease in cell viability, accompanied by an increase in ETB receptor levels, suggesting the involvement of both ETA and ETB receptors in mediating cell death. These findings raise possibilities for the development of ETA/ETB dual receptor antagonists as neuroprotective treatments for glaucomatous neuropathy.

PMID: 28249604 [PubMed - in process]

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