Recent Research Articles from UNTHSC

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Conjunctival Lesions and Vision Impairment After Gastrointestinal Surgery.

Fri, 04/01/2016 - 06:43

Conjunctival Lesions and Vision Impairment After Gastrointestinal Surgery.

JAMA Ophthalmol. 2016 Mar 31;

Authors: Kirkland KA, Swann RE

PMID: 27031091 [PubMed - as supplied by publisher]

Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents.

Thu, 03/31/2016 - 06:31

Locomotor, discriminative stimulus, and place conditioning effects of MDAI in rodents.

Behav Pharmacol. 2016 Mar 29;

Authors: Gatch MB, Dolan SB, Forster MJ

Abstract
5,6-Methylenedioxy-2-aminoindane (MDAI) has become a common substitute for (±)-3,4-methylenedioxymethamphetamine (MDMA) in Ecstasy. MDAI is known to produce MDMA-like discriminative stimulus effects, but it is not known whether MDAI has psychostimulant or hallucinogen-like effects. MDAI was tested for locomotor stimulant effects in mice and subsequently for discriminative stimulus effects in rats trained to discriminate cocaine (10 mg/kg, intraperitoneally), methamphetamine (1 mg/kg, intraperitoneally), ±MDMA (1.5 mg/kg, intraperitoneally), or (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (0.5 mg/kg, intraperitoneally) from saline. The ability of MDAI to produce conditioned place preference was also tested in mice. MDAI (3 to 30 mg/kg) depressed locomotor activity from 10 to 60 min. A rebound stimulant effect was observed at 1 to 3.5 h following 30 mg/kg. Lethality occurred in 8/8 mice following 100 mg/kg MDAI. Similarly, MDMA depressed locomotor activity immediately following the administration of 0.25 mg/kg and stimulant effects were observed 50-70 min following the administration of 0.5 and 1 mg/kg. MDAI fully substituted for the discriminative stimulus effects of MDMA (2.5 mg/kg), (-)-2,5-dimethoxy-4-methylamphetamine hydrochloride (5 mg/kg), and cocaine (7.5 mg/kg), but produced only 73% methamphetamine-appropriate responding at a dose that suppressed responding (7.5 mg/kg). MDAI produced tremors at 10 mg/kg in one methamphetamine-trained rat. MDAI produced conditioned place preference from 0.3 to 10 mg/kg. The effects of MDAI on locomotor activity and drug discrimination were similar to those produced by MDMA, having both psychostimulant-like and hallucinogen-like effects; thus, MDAI may have similar abuse potential as MDMA.

PMID: 27028902 [PubMed - as supplied by publisher]

N-Acetylcysteine reduces hyperacute intermittent hypoxia-induced sympathoexcitation in human subjects.

Thu, 03/31/2016 - 06:31

N-Acetylcysteine reduces hyperacute intermittent hypoxia-induced sympathoexcitation in human subjects.

Exp Physiol. 2016 Mar 1;101(3):387-396

Authors: Jouett NP, Moralez G, White DW, Eubank WL, Chen S, Tian J, Smith ML, Zimmerman MC, Raven PB

Abstract
NEW FINDINGS: What is the central question of this study? This study evaluated the following central question: does N-acetylcysteine (N-AC), an antioxidant that readily penetrates the blood-brain barrier, have the capability to reduce the increase in sympathetic nerve activity observed during hyperacute intermittent hypoxia? What is the main finding and its importance? We demonstrate that N-AC decreases muscle sympathetic nerve activity in response to hyperacute intermittent hypoxia versus placebo control. This finding suggests that antioxidants, such as N-AC, have therapeutic potential in obstructive sleep apnoea. This investigation tested the following hypotheses: that (i) N-acetylcysteine (N-AC) attenuates hyperacute intermittent hypoxia-induced sympathoexcitation, (ii) without elevating superoxide measured in peripheral venous blood. Twenty-eight healthy human subjects were recruited to the study. One hour before experimentation, each subject randomly ingested either 70 mg kg(-1) of N-AC (n = 16) or vehicle placebo (n = 12). Three-lead ECG and arterial blood pressure, muscle sympathetic nerve activity (n = 17) and whole-blood superoxide concentration (using electron paramagnetic resonance spectroscopy; n = 12) were measured. Subjects underwent a 20 min hyperacute intermittent hypoxia training (hAIHT) protocol that consisted of cyclical end-expiratory apnoeas with 100% nitrogen. N-AC decreased muscle sympathetic nerve activity after hAIHT compared with placebo (P < 0.02). However, N-AC did not alter superoxide concentrations in venous blood compared with placebo (P > 0.05). Moreover, hAIHT did not increase superoxide concentrations in the peripheral circulation as measured by electron paramagnetic resonance (P > 0.05). Based on these findings, we contend that (i) hAIHT and (ii) the actions of N-AC in hAIHT are primarily mediated centrally rather than peripherally, although central measurements of reactive oxygen species are difficult to obtain in human subjects, thus making this assertion difficult to verify. This investigation suggests the possibility of developing a pharmaceutical therapy to inhibit the sympathoexcitation associated with obstructive sleep apnoea.

PMID: 27027616 [PubMed - as supplied by publisher]

Effects of the Ion PGM™ Hi-Q™ sequencing chemistry on sequence data quality.

Thu, 03/31/2016 - 06:31

Effects of the Ion PGM™ Hi-Q™ sequencing chemistry on sequence data quality.

Int J Legal Med. 2016 Mar 30;

Authors: Churchill JD, King JL, Chakraborty R, Budowle B

Abstract
Massively parallel sequencing (MPS) offers substantial improvements over current forensic DNA typing methodologies such as increased resolution, scalability, and throughput. The Ion PGM™ is a promising MPS platform for analysis of forensic biological evidence. The system employs a sequencing-by-synthesis chemistry on a semiconductor chip that measures a pH change due to the release of hydrogen ions as nucleotides are incorporated into the growing DNA strands. However, implementation of MPS into forensic laboratories requires a robust chemistry. Ion Torrent's Hi-Q™ Sequencing Chemistry was evaluated to determine if it could improve on the quality of the generated sequence data in association with selected genetic marker targets. The whole mitochondrial genome and the HID-Ion STR 10-plex panel were sequenced on the Ion PGM™ system with the Ion PGM™ Sequencing 400 Kit and the Ion PGM™ Hi-Q™ Sequencing Kit. Concordance, coverage, strand balance, noise, and deletion ratios were assessed in evaluating the performance of the Ion PGM™ Hi-Q™ Sequencing Kit. The results indicate that reliable, accurate data are generated and that sequencing through homopolymeric regions can be improved with the use of Ion Torrent's Hi-Q™ Sequencing Chemistry. Overall, the quality of the generated sequencing data supports the potential for use of the Ion PGM™ in forensic genetic laboratories.

PMID: 27025714 [PubMed - as supplied by publisher]

Δ9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids found on the gray market.

Wed, 03/30/2016 - 06:40
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Δ9-Tetrahydrocannabinol-like effects of novel synthetic cannabinoids found on the gray market.

Behav Pharmacol. 2015 Aug;26(5):460-8

Authors: Gatch MB, Forster MJ

Abstract
When synthetic cannabinoid compounds became controlled by state and federal governments, different, noncontrolled compounds began to appear as marijuana substitutes. Unlike the scheduled cannabinoids, the newer compounds have not been characterized for potency and efficacy in preclinical studies. The purpose of these experiments was to determine whether some of the more recent synthetic compounds sold as marijuana substitutes have behavioral effects similar to those of Δ-tetrahydrocannabinol (Δ-THC), the pharmacologically active compound in marijuana. The compounds UR-144, XLR-11, AKB-48 (APINACA), PB-22 (QUPIC), 5F-PB-22, and AB-FUBINACA were tested for locomotor depressant effects in male Swiss-Webster mice and subsequently for their ability to substitute for Δ-THC (3 mg/kg, intraperitoneally) in drug discrimination experiments with male Sprague-Dawley rats. UR-144, XLR-11, AKB-48, and AB-FUBINACA each decreased locomotor activity for up to 90 min, whereas PB-22 and 5F-PB-22 produced depressant effects lasting 120-150 min. Each of the compounds fully substituted for the discriminative stimulus effects of Δ-THC. These findings confirm the suggestion that these compounds have marijuana-like psychoactive effects and abuse liability.

PMID: 26061356 [PubMed - indexed for MEDLINE]

ERG oncoprotein inhibits ANXA2 expression and function in prostate cancer.

Wed, 03/30/2016 - 06:40
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ERG oncoprotein inhibits ANXA2 expression and function in prostate cancer.

Mol Cancer Res. 2015 Feb;13(2):368-79

Authors: Griner NB, Young D, Chaudhary P, Mohamed AA, Huang W, Chen Y, Sreenath T, Dobi A, Petrovics G, Vishwanatha JK, Sesterhenn IA, Srivastava S, Tan SH

Abstract
UNLABELLED: Overexpression of ERG in the prostate epithelium, due to chromosomal translocations, contributes to prostate tumorigenesis. Here, genomic analysis of ERG siRNA-treated prostate cells harboring the endogenous TMPRSS2-ERG fusion revealed an inverse relationship between ERG and Annexin A2 (ANXA2) expression at both the RNA and protein level. ANXA2, a Ca(2+)-dependent and phospholipid-binding protein, is involved in various cellular functions, including maintenance of epithelial cell polarity. Mechanistic studies defined the prostate-specific transcription start site of ANXA2 and showed that the recruitment of ERG to the ANXA2 promoter is required for transcriptional repression by ERG. Knockdown of ERG enhanced the apical localization of ANXA2, the bundling of actin filaments at cell-cell junctions and formation of a polarized epithelial phenotype. ERG overexpression disrupted ANXA2-mediated cell polarity and promoted epithelial-mesenchymal transition (EMT) by inhibiting CDC42 and RHOA, and by activating cofilin. Immunohistochemistry demonstrated a reciprocal relationship of ANXA2 and ERG expression in a large fraction of primary prostate cancer clinical specimens. ANXA2 was absent or markedly reduced in ERG(+) tumors, which were mostly well differentiated. ERG(-) tumors, meanwhile, expressed moderate to high levels of ANXA2, and were either poorly differentiated or displayed subsets of poorly differentiated cells. Taken together, the transcriptional repression of ANXA2 by ERG in prostate epithelial cells plays a critical role in abrogating differentiation, promoting EMT, and in the reciprocal correlation of ERG and ANXA2 expression observed in human prostate cancer.
IMPLICATIONS: ANXA2 is a new component of the ERG network with potential to enhance biologic stratification and therapeutic targeting of ERG-stratified prostate cancers.

PMID: 25344575 [PubMed - indexed for MEDLINE]

Comparing biological markers of Alzheimer's disease across blood fraction and platforms: Comparing apples to oranges.

Tue, 03/29/2016 - 06:29

Comparing biological markers of Alzheimer's disease across blood fraction and platforms: Comparing apples to oranges.

Alzheimers Dement (Amst). 2016;3:27-34

Authors: O'Bryant SE, Lista S, Rissman RA, Edwards M, Zhang F, Hall J, Zetterberg H, Lovestone S, Gupta V, Graff-Radford N, Martins R, Jeromin A, Waring S, Oh E, King M, Baker L, Hampel H

Abstract
INTRODUCTION: This study investigated the comparability of potential AD biomarkers across blood fractions and assay platforms.
METHODS: Non-fasting serum and plasma samples from 300 participants (150 AD patients, 150 controls) were analyzed. Proteomic markers were obtained via electrochemiluminescence or Luminex technology. Comparisons were conducted via Pearson correlations. The relative importance of proteins within an AD diagnostic profile was examined using random forest importance plots.
RESULTS: On the MSD multi-plex platform, 10 out of the 21 markers shared >50% of the variance across blood fractions (SAA R(2)=0.99, IL10 R(2)=0.95, FABP R(2)=0.94, I309 R(2)=0.94, IL5 R(2)=0.94, IL6 R(2)=0.94, Eotaxin3 R(2)=0.91, IL18 R(2)=0.87, sTNFR1 R(2)=0.85, PPY R(2)=0.81). When examining protein concentrations across platforms, only five markers shared >50% of the variance (β2M R(2)=0.92, IL18 R(2)=0.80, FVII R(2)=0.78, CRP R(2)=0.74, FABP R(2)=0.70).
DISCUSSION: The current findings highlight the importance of considering blood fractions and assay platforms when searching for AD relevant biomarkers.

PMID: 27019866 [PubMed - as supplied by publisher]

Antiangiogenic mechanisms and factors in breast cancer treatment.

Sat, 03/26/2016 - 06:37

Antiangiogenic mechanisms and factors in breast cancer treatment.

J Carcinog. 2016;15:1

Authors: Castañeda-Gill JM, Vishwanatha JK

Abstract
Breast cancer is known to metastasize in its latter stages of existence. The different angiogenic mechanisms and factors that allow for its progression are reviewed in this article. Understanding these mechanisms and factors will allow researchers to design drugs to inhibit angiogenic behaviors and control the rate of tumor growth.

PMID: 27013929 [PubMed]

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

Sat, 03/26/2016 - 06:37

Preclinical Alzheimer's disease: Definition, natural history, and diagnostic criteria.

Alzheimers Dement. 2016 Mar;12(3):292-323

Authors: Dubois B, Hampel H, Feldman HH, Scheltens P, Aisen P, Andrieu S, Bakardjian H, Benali H, Bertram L, Blennow K, Broich K, Cavedo E, Crutch S, Dartigues JF, Duyckaerts C, Epelbaum S, Frisoni GB, Gauthier S, Genthon R, Gouw AA, Habert MO, Holtzman DM, Kivipelto M, Lista S, Molinuevo JL, O'Bryant SE, Rabinovici GD, Rowe C, Salloway S, Schneider LS, Sperling R, Teichmann M, Carrillo MC, Cummings J, Jack CR, Proceedings of the Meeting of the International Working Group (IWG) and the American Alzheimer's Association on “The Preclinical State of AD”; July 23, 2015; Washington DC, USA

Abstract
During the past decade, a conceptual shift occurred in the field of Alzheimer's disease (AD) considering the disease as a continuum. Thanks to evolving biomarker research and substantial discoveries, it is now possible to identify the disease even at the preclinical stage before the occurrence of the first clinical symptoms. This preclinical stage of AD has become a major research focus as the field postulates that early intervention may offer the best chance of therapeutic success. To date, very little evidence is established on this "silent" stage of the disease. A clarification is needed about the definitions and lexicon, the limits, the natural history, the markers of progression, and the ethical consequence of detecting the disease at this asymptomatic stage. This article is aimed at addressing all the different issues by providing for each of them an updated review of the literature and evidence, with practical recommendations.

PMID: 27012484 [PubMed - in process]

Large-scale recent expansion of European patrilineages shown by population resequencing.

Sat, 03/26/2016 - 06:37
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Large-scale recent expansion of European patrilineages shown by population resequencing.

Nat Commun. 2015;6:7152

Authors: Batini C, Hallast P, Zadik D, Delser PM, Benazzo A, Ghirotto S, Arroyo-Pardo E, Cavalleri GL, de Knijff P, Dupuy BM, Eriksen HA, King TE, López de Munain A, López-Parra AM, Loutradis A, Milasin J, Novelletto A, Pamjav H, Sajantila A, Tolun A, Winney B, Jobling MA

Abstract
The proportion of Europeans descending from Neolithic farmers ∼ 10 thousand years ago (KYA) or Palaeolithic hunter-gatherers has been much debated. The male-specific region of the Y chromosome (MSY) has been widely applied to this question, but unbiased estimates of diversity and time depth have been lacking. Here we show that European patrilineages underwent a recent continent-wide expansion. Resequencing of 3.7 Mb of MSY DNA in 334 males, comprising 17 European and Middle Eastern populations, defines a phylogeny containing 5,996 single-nucleotide polymorphisms. Dating indicates that three major lineages (I1, R1a and R1b), accounting for 64% of our sample, have very recent coalescent times, ranging between 3.5 and 7.3 KYA. A continuous swathe of 13/17 populations share similar histories featuring a demographic expansion starting ∼ 2.1-4.2 KYA. Our results are compatible with ancient MSY DNA data, and contrast with data on mitochondrial DNA, indicating a widespread male-specific phenomenon that focuses interest on the social structure of Bronze Age Europe.

PMID: 25988751 [PubMed - indexed for MEDLINE]

Wikipedia vs peer-reviewed medical literature for information about the 10 most costly medical conditions-III.

Sat, 03/26/2016 - 06:37
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Wikipedia vs peer-reviewed medical literature for information about the 10 most costly medical conditions-III.

J Am Osteopath Assoc. 2014 Oct;114(10):764-5

Authors: Chen GS, Xiong Y

PMID: 25288709 [PubMed - indexed for MEDLINE]

C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury.

Fri, 03/25/2016 - 06:29

C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury.

Mol Neurodegener. 2016;11(1):24

Authors: Silverman SM, Kim BJ, Howell GR, Miller J, John SW, Wordinger RJ, Clark AF

Abstract
BACKGROUND: C1q represents the initiating protein of the classical complement cascade, however recent findings indicate pathway independent roles such as developmental pruning of retinal ganglion cell (RGC) axons. Furthermore, chronic neuroinflammation, including increased expression of C1q and activation of microglia and astrocytes, appears to be a common finding among many neurodegenerative disease models. Here we compare the effects of a retinal ischemia/reperfusion (I/R) injury on glial activation and neurodegeneration in wild type (WT) and C1qa-deficient mice in the retina and superior colliculus (SC). Retinal I/R was induced in mice through elevation of intraocular pressure to 120 mmHg for 60 min followed by reperfusion. Glial cell activation and population changes were assessed using immunofluorescence. Neuroprotection was determined using histological measurements of retinal layer thickness, RGC counts, and visual function by flash electroretinography (ERG).
RESULTS: Retinal I/R injury significantly upregulated C1q expression in the retina as early as 72 h and within 7 days in the superficial SC, and was sustained as long as 28 days. Accompanying increased C1q expression was activation of microglia and astrocytes as well as a significantly increased glial population density observed in the retina and SC. Microglial activation and changes in density were completely ablated in C1qa-deficient mice, interestingly however there was no effect on astrocytes. Furthermore, loss of C1qa significantly rescued I/R-induced loss of RGCs and protected against retinal layer thinning in comparison to WT mice. ERG assessment revealed early preservation of b-wave amplitude deficits from retinal I/R injury due to C1qa-deficiency that was lost by day 28.
CONCLUSIONS: Our results for the first time demonstrate the spatiotemporal changes in the neuroinflammatory response following retinal I/R injury at both local and distal sites of injury. In addition, we have shown a role for C1q as a primary mediator of microglial activation and pathological damage. This suggests developmental mechanisms of C1q may be re-engaged during injury response, modulation of which may be beneficial for neuroprotection.

PMID: 27008854 [PubMed - in process]

MIEN1, a novel interactor of Annexin A2, promotes tumor cell migration by enhancing AnxA2 cell surface expression.

Fri, 03/25/2016 - 06:29
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MIEN1, a novel interactor of Annexin A2, promotes tumor cell migration by enhancing AnxA2 cell surface expression.

Mol Cancer. 2015;14:156

Authors: Kpetemey M, Dasgupta S, Rajendiran S, Das S, Gibbs LD, Shetty P, Gryczynski Z, Vishwanatha JK

Abstract
BACKGROUND: Migration and invasion enhancer 1 (MIEN1) is a novel gene found to be abundantly expressed in breast tumor tissues and functions as a critical regulator of tumor cell migration and invasion to promote systemic metastases. Previous studies have identified post-translational modifications by isoprenylation at the C-terminal tail of MIEN1 to favor its translocation to the inner leaflet of plasma membrane and its function as a membrane-bound adapter molecule. However, the exact molecular events at the membrane interface activating the MIEN1-driven tumor cell motility are vaguely understood.
METHODS: MIEN1 was first studied using in-silico analysis on available RNA sequencing data of human breast tissues and its expression was ascertained in breast cells. We performed several assays including co-immunoprecipitation, wound healing, western blotting and immunofluorescence to decipher the molecular events involved in MIEN1-mediated tumor cell migration.
RESULTS: Clinically, MIEN1 is predominantly overexpressed in Her-2 and luminal B subtypes of breast tumors, and its increased expression correlates with poor disease free survival. Molecular studies identified a phosphorylation-dependent activation signal in the immunoreceptor tyrosine based activation motif (ITAM) of MIEN1 and the phosphorylation-deficient MIEN1-mutants (Y39F/50 F) to regulate filopodia generation, migration and invasion. We found that ITAM-phosphorylation of MIEN1 is significantly impaired in isoprenylation-deficient MIEN1 mutants indicating that prenylation of MIEN1 and membrane association is required for cross-phosphorylation of tyrosine residues. Furthermore, we identified MIEN1 as a novel interactor of Annexin A2 (AnxA2), a Ca(2+) -dependent phospholipid binding protein, which serves as an extracellular proteolytic center regulating plasmin generation. Fluorescence resonance energy transfer (FRET) confirmed that MIEN1 physically interacts with AnxA2 and functional studies revealed that they mutually cooperate to accentuate tumor cell motility. Interestingly, our study identified that ectopic overexpression of MIEN1 significantly enhances Tyr23-phosphorylation on AnxA2, thereby stimulating cell surface translocation of AnxA2 and catalyzing the activation of its proteolytic activity.
CONCLUSION: Our data show that the presence and interaction of both MIEN1 and AnxA2 in breast tumors are crucial drivers of cell motility. Our study has now deciphered a novel regulatory network governing the vicious process of breast tumor cell invasion-metastasis, and findings suggest MIEN1-AnxA2 as prospective targets to counter the deadly disease.

PMID: 26272794 [PubMed - indexed for MEDLINE]

Alcohol Withdrawal and Cerebellar Mitochondria.

Fri, 03/25/2016 - 06:29
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Alcohol Withdrawal and Cerebellar Mitochondria.

Cerebellum. 2015 Aug;14(4):421-37

Authors: Jung ME

Abstract
Cerebellar disorders trigger the symptoms of movement problems, imbalance, incoordination, and frequent fall. Cerebellar disorders are shown in various CNS illnesses including a drinking disorder called alcoholism. Alcoholism is manifested as an inability to control drinking in spite of adverse consequences. Human and animal studies have shown that cerebellar symptoms persist even after complete abstinence from drinking. In particular, the abrupt termination (ethanol withdrawal) of long-term excessive ethanol consumption has shown to provoke a variety of neuronal and mitochondrial damage to the cerebellum. Upon ethanol withdrawal, excitatory neurotransmitter molecules such as glutamate are overly released in brain areas including cerebellum. This is particularly relevant to the cerebellar neuronal network as glutamate signals are projected to Purkinje neurons through granular cells that are the most populated neuronal type in CNS. This excitatory neuronal signal may be elevated by ethanol withdrawal stress, which promotes an increase in intracellular Ca(2+) level and a decrease in a Ca(2+)-binding protein, both of which result in the excessive entry of Ca(2+) to the mitochondria. Subsequently, mitochondria undergo a prolonged opening of mitochondrial permeability transition pore and the overproduction of harmful free radicals, impeding adenosine triphosphate (ATP)-generating function. This in turn provokes the leakage of mitochondrial molecule cytochrome c to the cytosol, which triggers a cascade of adverse cytosol reactions. Upstream to this pathway, cerebellum under the condition of ethanol withdrawal has shown aberrant gene modifications through altered DNA methylation, histone acetylation, or microRNA expression. Interplay between these events and molecules may result in functional damage to cerebellar mitochondria and consequent neuronal degeneration, thereby contributing to motoric deficit. Mitochondria-targeting research may help develop a powerful new therapy to manage cerebellar disorders associated with hyperexcitatory CNS disorders like ethanol withdrawal.

PMID: 25195804 [PubMed - indexed for MEDLINE]

Chemical Conditioning as an Approach to Ischemic Stroke Tolerance: Mitochondria as the Target.

Thu, 03/24/2016 - 06:33

Chemical Conditioning as an Approach to Ischemic Stroke Tolerance: Mitochondria as the Target.

Int J Mol Sci. 2016;17(3)

Authors: Jin Z, Wu J, Yan LJ

Abstract
It is well established that the brain can be prepared to resist or tolerate ischemic stroke injury, and mitochondrion is a major target for this tolerance. The preparation of ischemic stroke tolerance can be achieved by three major approaches: ischemic conditioning, hypoxic conditioning and chemical conditioning. In each conditioning approach, there are often two strategies that can be used to achieve the conditioning effects, namely preconditioning (Pre-C) and postconditioning (Post-C). In this review, we focus on chemical conditioning of mitochondrial proteins as targets for neuroprotection against ischemic stroke injury. Mitochondrial targets covered include complexes I, II, IV, the ATP-sensitive potassium channel (mitoKATP), adenine dinucleotide translocase (ANT) and the mitochondrial permeability transition pore (mPTP). While numerous mitochondrial proteins have not been evaluated in the context of chemical conditioning and ischemic stroke tolerance, the paradigms and approaches reviewed in this article should provide general guidelines on testing those mitochondrial components that have not been investigated. A deep understanding of mitochondria as the target of chemical conditioning for ischemic stroke tolerance should provide valuable insights into strategies for fighting ischemic stroke, a leading cause of death in the world.

PMID: 27005615 [PubMed - in process]

B7-H4(B7x)-Mediated Cross-talk between Glioma-Initiating Cells and Macrophages via the IL6/JAK/STAT3 Pathway Lead to Poor Prognosis in Glioma Patients.

Thu, 03/24/2016 - 06:33

B7-H4(B7x)-Mediated Cross-talk between Glioma-Initiating Cells and Macrophages via the IL6/JAK/STAT3 Pathway Lead to Poor Prognosis in Glioma Patients.

Clin Cancer Res. 2016 Mar 21;

Authors: Yao Y, Ye H, Qi Z, Mo L, Yue Q, Baral A, Hoon DS, Vera JC, Heiss JD, Chen CC, Hua W, Zhang J, Jin K, Wang Y, Zang X, Mao Y, Zhou L

Abstract
PURPOSE: The objective of this study was to evaluate clinical significance and immunosuppressive mechanisms of B7-H4 (B7x/B7S1), a B7 family member, in glioma.
EXPERIMENTAL DESIGN: B7-H4 levels in glioma tissue/cerebral spinal fluid (CSF) were compared between different grades of glioma patients. Survival data were analyzed with Kaplan-Meier to determine the prognostic value of B7-H4. Cytokines from CD133(+) cells to stimulate the expression of B7-H4 on human macrophages (Mφs) were investigated by FACS, neutralizing antibodies, and Transwell chemotaxis assay. shRNA, reporter vector, and chromatin immunoprecipitation were used to determine the binding of STAT3 to the B7-H4 promoter. The function of B7-H4(+) Mφs in vitro was evaluated through phagocytosis, T-cell proliferation/apoptosis, and cytokine production as well as in the xenografted model for in vivo analysis.
RESULTS: We found that B7-H4 expression in tumors was associated with prognosis of human glioblastoma and correlated directly with malignant grades. Mechanistically, glioma initiating CD133(+) cells and Mφs/microglia cointeraction activated expression of B7-H4 via IL6 and IL10 in both tumor cells and microenvironment supporting cells. IL6-activated STAT3 bound to the promoter of B7-H4 gene and enhanced B7-H4 expression. Furthermore, CD133(+) cells mediated immunosuppression through B7-H4 expression on Mφs/microglia by silencing of B7-H4 expression on these cells, which led to increased microenvironment T-cell function and tumor regression in the xenograft glioma mouse model.
CONCLUSION: We have identified B7-H4 activation on Mφs/microglia in the microenvironment of gliomas as an important immunosuppressive event blocking effective T-cell immune responses. Clin Cancer Res; 1-13. ©2016 AACR.

PMID: 27001312 [PubMed - as supplied by publisher]

Caspase-7: a critical mediator of optic nerve injury-induced retinal ganglion cell death.

Tue, 03/22/2016 - 06:37
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Caspase-7: a critical mediator of optic nerve injury-induced retinal ganglion cell death.

Mol Neurodegener. 2015;10:40

Authors: Choudhury S, Liu Y, Clark AF, Pang IH

Abstract
BACKGROUND: Axonal injury of the optic nerve (ON) is involved in various ocular diseases, such as glaucoma and traumatic optic neuropathy, which leads to apoptotic death of retinal ganglion cells (RGCs) and loss of vision. Caspases have been implicated in RGC pathogenesis. However, the role of caspase-7, a functionally unique caspase, in ON injury and RGC apoptosis has not been reported previously. The purpose of this study is to evaluate the role of caspase-7 in ON injury-induced RGC apoptosis.
RESULTS: C57BL/6 (wildtype, WT) and caspase-7 knockout (Casp7(-/-)) mice were used. We show that ON crush activated caspase-7 and calpain-1, an upstream activator of caspase-7, in mouse RGCs, as well as hydrolysis of kinectin and co-chaperone P23, specific substrates of caspase-7. ON crush caused a progressive loss of RGCs to 28 days after injury. Knockout of caspase-7 partially and significantly protected against the ON injury-induced RGC loss; RGC density at 28 days post ON crush in Casp7(-/-) mice was approximately twice of that in WT ON injured retinas. Consistent with changes in RGC counts, spectral-domain optical coherence tomography analysis revealed that ON crush significantly reduced the in vivo thickness of the ganglion cell complex layer (including ganglion cell layer, nerve fiber layer, and inner plexiform layer) in the retina. The ON crush-induced thinning of retinal layer was significantly ameliorated in Casp7(-/-) mice when compared to WT mice. Moreover, electroretinography analysis demonstrated a decline in the positive component of scotopic threshold response amplitude in ON crushed eyes of the WT mice, whereas this RGC functional response was significantly higher in Casp7(-/-) mice at 28 days post injury.
CONCLUSION: Altogether, our findings indicate that caspase-7 plays a critical role in ON injury-induced RGC death, and inhibition of caspase-7 activity may be a novel therapeutic strategy for glaucoma and other neurodegenerative diseases of the retina.

PMID: 26306916 [PubMed - indexed for MEDLINE]

Fluorescent biosensor for the detection of hyaluronidase: intensity-based ratiometric sensing and fluorescence lifetime-based sensing using a long lifetime azadioxatriangulenium (ADOTA) fluorophore.

Sun, 03/20/2016 - 06:36

Fluorescent biosensor for the detection of hyaluronidase: intensity-based ratiometric sensing and fluorescence lifetime-based sensing using a long lifetime azadioxatriangulenium (ADOTA) fluorophore.

Anal Bioanal Chem. 2016 Mar 18;

Authors: Chib R, Mummert M, Bora I, Laursen BW, Shah S, Pendry R, Gryczynski I, Borejdo J, Gryczynski Z, Fudala R

Abstract
In this report, we have designed a rapid and sensitive, intensity-based ratiometric sensing as well as lifetime-based sensing probe for the detection of hyaluronidase activity. Hyaluronidase expression is known to be upregulated in various pathological conditions. We have developed a fluorescent probe by heavy labeling of hyaluronic acid with a new orange/red-emitting organic azadioxatriangulenium (ADOTA) fluorophore, which exhibits a long fluorescence lifetime (∼20 ns). The ADOTA fluorophore in water has a peak fluorescence lifetime of ∼20 ns and emission spectra centered at 560 nm. The heavily ADOTA-labeled hyaluronic acid (HA-ADOTA) shows a red shift in the peak emission wavelength (605 nm), a weak fluorescence signal, and a shorter fluorescence lifetime (∼4 ns) due to efficient self-quenching and formation of aggregates. In the presence of hyaluronidase, the brightness and fluorescence lifetime of the sample increase with a blue shift in the peak emission to its original wavelength at 560 nm. The ratio of the fluorescence intensity of the HA-ADOTA probe at 560 and 605 nm can be used as the sensing method for the detection of hyaluronidase. The cleavage of the hyaluronic acid macromolecule reduces the energy migration between ADOTA molecules, as well as the degree of self-quenching and aggregation. This probe can be efficiently used for both intensity-based ratiometric sensing as well as fluorescence lifetime-based sensing of hyaluronidase. The proposed method makes it a rapid and sensitive assay, useful for analyzing levels of hyaluronidase in relevant clinical samples like urine or plasma. Graphical Abstract Scheme showing cleavage of HA-ADOTA probe by hyaluronidase and the change in the emission spectrum of HA-ADOTA probe before and after cleavage by hyaluronidase.

PMID: 26993308 [PubMed - as supplied by publisher]

Statin Effects on Exacerbation Rates, Mortality, and Inflammatory Markers in Patients with Chronic Obstructive Pulmonary Disease: A Review of Prospective Studies.

Sat, 03/19/2016 - 06:36

Statin Effects on Exacerbation Rates, Mortality, and Inflammatory Markers in Patients with Chronic Obstructive Pulmonary Disease: A Review of Prospective Studies.

Pharmacotherapy. 2016 Mar 16;

Authors: Howard ML, Vincent AH

Abstract
Chronic obstructive pulmonary disease (COPD) is a debilitating, irreversible disease with currently available therapies targeting symptom control and exacerbation reduction. A need for alternative disease-modifying therapies remains, specifically those that may have antiinflammatory and immunomodulatory properties that impact the pathophysiologic components of COPD. Statin drugs, the current gold standard for treatment of dyslipidemia and prevention of cardiovascular disease (CVD), contain properties that affect the inflammatory disease processes seen in COPD. Several retrospective studies have demonstrated that statins may have a benefit in the reduction of morbidity and mortality in patients with COPD. This has led to prospective trials evaluating the impact of statins on various COPD-related outcomes. The purpose of this article is to review the current body of prospective evidence for use of statins in patients with COPD. A search of the PubMed/Medline database of English-language articles was conducted from 1964 through November 2015; references of relevant articles were also reviewed for qualifying studies. Prospective studies of all types relating to statin use in patients with COPD were included if they had COPD- or respiratory-related outcomes; ultimately, eight studies were identified for this review. Statin effects on exacerbation rates, mortality, and inflammatory markers in patients with COPD are discussed. Strong prospective evidence does not currently exist to suggest that statins provide a clinical benefit in patients with COPD who do not have other CVD risk factors. Benefits from statins that have been illustrated are likely explained by their impact on underling CVD risk factors rather than the COPD disease process. An opportunity exists for unanswered questions to be addressed in future studies. This article is protected by copyright. All rights reserved.

PMID: 26990316 [PubMed - as supplied by publisher]

M2b Monocytes Provoke Bacterial Pneumonia and Gut Bacteria-Associated Sepsis in Alcoholics.

Wed, 03/16/2016 - 06:31
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M2b Monocytes Provoke Bacterial Pneumonia and Gut Bacteria-Associated Sepsis in Alcoholics.

J Immunol. 2015 Dec 1;195(11):5169-77

Authors: Tsuchimoto Y, Asai A, Tsuda Y, Ito I, Nishiguchi T, Garcia MC, Suzuki S, Kobayashi M, Higuchi K, Suzuki F

Abstract
Chronic alcohol consumption markedly impairs host antibacterial defense against opportunistic infections. γ-irradiated NOD-SCID IL-2Rγ(null) mice inoculated with nonalcoholic PBMCs (control PBMC chimeras) resisted Klebsiella pneumonia and gut bacteria-associated sepsis, whereas the chimeras created with alcoholic PBMCs (alcoholic PBMC chimeras) were very susceptible to these infections. M1 monocytes (IL-12(+)IL-10(-)CD163(-)CD14(+) cells), major effector cells in antibacterial innate immunity, were not induced by a bacterial Ag in alcoholic PBMC cultures, and M2b monocytes (CCL1(+)CD163(+)CD14(+) cells), which predominated in alcoholic PBMCs, were shown to be inhibitor cells on the Ag-stimulated monocyte conversion from quiescent monocytes to M1 monocytes. CCL1, which functions to maintain M2b macrophage properties, was produced by M2b monocytes isolated from alcoholic PBMCs. These M2b monocytes reverted to quiescent monocytes (IL-12(-)IL-10(-)CCL1(-)CD163(-)CD14(+) cells) in cultures supplemented with CCL1 antisense oligodeoxynucleotide, and the subsequent quiescent monocytes easily converted to M1 monocytes under bacterial Ag stimulation. Alcoholic PBMC chimeras treated with CCL1 antisense oligodeoxynucleotide were resistant against pulmonary infection by K. pneumoniae and sepsis stemming from enterococcal translocation. These results indicate that a majority of monocytes polarize to an M2b phenotype in association with alcohol abuse, and this polarization contributes to the increased susceptibility of alcoholics to gut and lung infections. Bacterial pneumonia and gut bacteria-associated sepsis, frequently seen in alcoholics, can be controlled through the polarization of macrophage phenotypes.

PMID: 26525287 [PubMed - indexed for MEDLINE]

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