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Recent Research Articles from UNTHSC

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HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders.

Fri, 04/17/2015 - 3:30am
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HIV-1 Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome: implications for HIV-associated neurocognitive disorders.

J Neurosci. 2015 Feb 4;35(5):1921-38

Authors: Fields J, Dumaop W, Elueteri S, Campos S, Serger E, Trejo M, Kosberg K, Adame A, Spencer B, Rockenstein E, He JJ, Masliah E

Abstract
Antiretroviral therapy has increased the life span of HIV+ individuals; however, HIV-associated neurocognitive disorder (HAND) occurrence is increasing in aging HIV patients. Previous studies suggest HIV infection alters autophagy function in the aging CNS and HIV-1 proteins affect autophagy in monocyte-derived cells. Despite these findings, the mechanisms leading to dysregulated autophagy in the CNS remain unclear. Here we sought to determine how HIV Tat dysregulates autophagy in neurons. Tat caused a dose-dependent decrease in autophagosome markers, microtubule-associated protein-1 light chain β II (LC3II), and sequestosome 1(SQSTM1), in a membrane-enriched fraction, suggesting Tat increases autophagic degradation. Bafilomycin A1 increased autophagosome number, LC3II, and SQSTM1 accumulation; Tat cotreatment diminished this effect. Tat had no effect when 3-methyladenine or knockdown of beclin 1 blocked early stages of autophagy. Tat increased numbers of LC3 puncta and resulted in the formation of abnormal autophagosomes in vitro. Likewise, in vivo studies in GFAP-Tat tg mice showed increased autophagosome accumulation in neurons, altered LC3II levels, and neurodegeneration. These effects were reversed by rapamycin treatment. Tat colocalized with autophagosome and lysosomal markers and enhanced the colocalization of autophagosome with lysosome markers. Furthermore, co-IP studies showed that Tat interacts with lysosomal-associated membrane protein 2A (LAMP2A) in vitro and in vivo, and LAMP2A overexpression reduces Tat-induced neurotoxicity. Hence, Tat protein may induce autophagosome and lysosome fusion through interaction with LAMP2A leading to abnormal neuronal autophagy function and dysregulated degradation of critical intracellular components. Therapies targeting Tat-mediated autophagy alterations may decrease neurodegeneration in aging patients with HAND.

PMID: 25653352 [PubMed - indexed for MEDLINE]

Clinical Outcomes Associated With Serial Sharp Debridement of Diabetic Foot Ulcers With and Without Clostridial Collagenase Ointment.

Tue, 04/14/2015 - 3:29am

Clinical Outcomes Associated With Serial Sharp Debridement of Diabetic Foot Ulcers With and Without Clostridial Collagenase Ointment.

Wounds. 2014 Mar;26(3):57-64

Authors: Motley TA, Lange DL, Dickerson JE, Slade HB

Abstract
OBJECTIVE: Fifty-five subjects with diabetes mellitus type 1 or 2 and a neuropathic, nonischemic foot ulcer were enrolled into this randomized, controlled, multicenter trial designed to examine the effects of debridement with clostridial collagenase ointment (CCO) used in conjunction with serial sharp debridement for a period of 6 weeks.
METHODS: Serial sharp debridement without adjunctive CCO was used in the control group. Various standard care therapies thought to support debridement by endogenous proteases were selected at the discretion of the investigators for use in the control group. The primary outcome measure of this trial was the percent change in ulcer area from baseline at the end of the debridement/treatment period (EOT) and at the end of an additional 6 weeks of follow-up (EOS). Secondary objectives were to assess wound status at EOT and EOS using a standardized wound assessment tool, and to compare the average time to closure for ulcers debrided with serial sharp debridement with and without adjunctive CCO.
RESULTS: Wound area decreased relative to baseline for both the CCO group (-68%, -61%) and the control group (-36%, -46%) at EOT and EOS, respectively. While the inter-group differences did not reach statistical significance, wound area was significantly decreased from baseline at both EOT and EOS for the CCO (P < 0.001) but not for the control group. Wound status scores (scale range 8 to 40) improved for both groups during treatment (CCO: -3.5, control: -3.2) and follow-up (CCO: -5.3, control: -6.4). No differences were observed in the number of sharp debridements (CCO: 3.7, control: 4.0). Median time to closure for wounds that healed was 6 weeks for CCO and 8 weeks for control. On average, ulcers treated with serial sharp debridement plus adjunctive CCO decreased in size more rapidly than ulcers treated without adjunctive CCO debridement. No safety issues were identified based on a review of reported adverse events.
CONCLUSION: These results suggest there is more to wound debridement than meets the eye, and establish a foundation for larger, confirmatory studies.

PMID: 25860329 [PubMed - as supplied by publisher]

Two dimensional blue native/SDS-PAGE to identify mitochondrial complex I subunits modified by 4-hydroxynonenal (HNE).

Tue, 04/14/2015 - 3:29am

Two dimensional blue native/SDS-PAGE to identify mitochondrial complex I subunits modified by 4-hydroxynonenal (HNE).

Front Physiol. 2015;6:98

Authors: Wu J, Luo X, Yan LJ

Abstract
The lipid peroxidation product 4-hydroxynonenal (HNE) can form protein-linked HNE adducts, thereby impacting protein structure and function. Mitochondrial complex I (NADH-ubiquinone oxidoreductase), containing at least 45 subunits in mammalian cells, sits in a lipid-rich environment and is thus very susceptible to HNE modifications. In this paper, a procedure for the identification of HNE-modified complex I subunits is described. Complex I was isolated by first dimensional non-gradient blue native polyacrylamide gel electrophoresis (BN-PAGE). The isolated complex I band, visualized by either Coomassie blue staining or silver staining, was further analyzed by second dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). HNE-modified proteins were visualized by Western blotting probed with anti-HNE antibodies. HNE-positive bands were then excised and the proteins contained in them were identified by mass spectrometric peptide sequencing. The method was successfully applied for the identification of two complex I subunits that showed enhanced HNE-modifications in diabetic kidney mitochondria.

PMID: 25859224 [PubMed]

Risk of Intracranial Hemorrhage from Statin Use in Asians: A Nationwide Cohort Study.

Tue, 04/14/2015 - 3:29am

Risk of Intracranial Hemorrhage from Statin Use in Asians: A Nationwide Cohort Study.

Circulation. 2015 Apr 9;

Authors: Chang CH, Lin CH, Caffrey JL, Lee YC, Liu YC, Lin JW, Lai MS

Abstract
BACKGROUND: -Reports of statin usage and increased risk of intracranial hemorrhage (ICH) have been inconsistent. This study examined potential associations between statin usage and the risk of ICH in subjects without a prior history of stroke.
METHODS AND RESULTS: -Patients initiating statin therapy between 2005 and 2009 without a prior history of ischemic or hemorrhagic stroke were identified from Taiwan's National Health Insurance database. Participants were stratified by advanced age (≥ 70 years), sex, and diagnosed hypertension. The outcome of interest was hospital admission for ICH (ICD-9-CM codes 430, 431, 432). Cox regression models were applied to estimate the hazard ratio (HR) of ICH. The cumulative statin dosage stratified by quartile and adjusted for baseline disease risk score served as the primary variable using the lowest quartile of cumulative dosage as a reference. There were 1,096,547 statin initiators with an average follow-up of 3.3 years. The adjusted HR for ICH between the highest the lowest quartile was non-significant at 1.06 with a 95% confidence interval [CI] spanning 1.00 (0.94-1.19). Similar non-significant results were found in sensitivity analyses using different outcome definitions or model adjustments, reinforcing the robustness of the study findings. Subgroup analysis identified an excess of ICH frequency in patients without diagnosed hypertension (adjusted HR 1.36 [1.11-1.67]).
CONCLUSIONS: -Generally, no association was observed between cumulative statin use and risk of ICH among subjects without a prior history of stroke. An increased risk was identified among the non-hypertensive cohort, but this finding should be interpreted with caution.

PMID: 25858194 [PubMed - as supplied by publisher]

Personalized feedback interventions for college alcohol misuse: an update of Walters & Neighbors (2005).

Tue, 04/14/2015 - 3:29am
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Personalized feedback interventions for college alcohol misuse: an update of Walters & Neighbors (2005).

Psychol Addict Behav. 2013 Dec;27(4):909-20

Authors: Miller MB, Leffingwell T, Claborn K, Meier E, Walters S, Neighbors C

Abstract
Personalized drinking feedback is an evidence-based and increasingly common way of intervening with high-risk college drinking. This article extends an earlier review by Walters and Neighbors (S. T. Walters & C. Neighbors, 2005, Feedback interventions for college alcohol misuse: What, why, and for whom? Addictive Behaviors, 30, 1168-1182) by reviewing the literature of published studies using personalized feedback as an intervention for heavy drinking among college students. This article updates and extends the original review with a more comprehensive and recent set of 41 studies, most of which were not included in the original article. This article also examines within-subject effect sizes for personalized feedback interventions (PFIs) for high-risk alcohol use and examines the content of PFIs more closely to provide insight on the most essential components that will guide the future development of feedback-based interventions. In general, PFIs appear to be reliably effective at reducing harmful alcohol misuse among college students. Some components are almost universally included (i.e., drinking profile and normative comparison), precluding inferences regarding their unique contribution. Significantly larger effect sizes were observed for interventions that included decisional balance, practical costs, and strategies to limit risks. The present research provides an important empirical foundation for determining the relative contribution of individual components and facets in the efficacy of PFIs.

PMID: 23276309 [PubMed - indexed for MEDLINE]

Acute intermittent optogenetic stimulation of nucleus tractus solitarius neurons induces sympathetic long-term facilitation.

Sat, 04/11/2015 - 3:30am
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Acute intermittent optogenetic stimulation of nucleus tractus solitarius neurons induces sympathetic long-term facilitation.

Am J Physiol Regul Integr Comp Physiol. 2015 Feb 15;308(4):R266-75

Authors: Yamamoto K, Lalley P, Mifflin S

Abstract
Acute intermittent hypoxia (AIH) induces sympathetic and phrenic long-term facilitation (LTF), defined as a sustained increase in nerve discharge. We investigated the effects of AIH and acute intermittent optogenetic (AIO) stimulation of neurons labeled with AAV-CaMKIIa, hChR2(H134R), and mCherry in the nucleus of the solitary tract (NTS) of anesthetized, vagotomized, and mechanically ventilated rats. We measured renal sympathetic nerve activity (RSNA), phrenic nerve activity (PNA), power spectral density, and coherence, and we made cross-correlation measurements to determine how AIO stimulation and AIH affected synchronization between PNA and RSNA. Sixty minutes after AIH produced by ventilation with 10% oxygen in balanced nitrogen, RSNA and PNA amplitude increased by 80% and by 130%, respectively (P < 0.01). Sixty minutes after AIO stimulation, RSNA and PNA amplitude increased by 60% and 100%, respectively, (P < 0.01). These results suggest that acute intermittent stimulation of NTS neurons can induce renal sympathetic and phrenic LTF in the absence of hypoxia or chemoreceptor afferent activation. We also found that while acute intermittent optogenetic and hypoxic stimulations increased respiration-related RSNA modulation (P < 0.01), they did not increase synchronization between central respiratory drive and RSNA. We conclude that mechanisms that induce LTF originate within the caudal NTS and extend to other interconnecting neuronal elements of the central nervous cardiorespiratory network.

PMID: 25519734 [PubMed - indexed for MEDLINE]

Rhodopseudomonas palustris CGA010 Proteome Implicates Extracytoplasmic Function Sigma Factor in Stress Response.

Fri, 04/10/2015 - 3:29am

Rhodopseudomonas palustris CGA010 Proteome Implicates Extracytoplasmic Function Sigma Factor in Stress Response.

J Proteome Res. 2015 Apr 8;

Authors: Allen MS, Hurst GB, Lu TY, Perry LM, Pan C, Lankford PK, Pelletier DA

Abstract
Rhodopseudomonas palustris encodes 16 extracytoplasmic function (ECF) σ factors. To begin to investigate the regulatory network of one of these ECF σ factors, the whole proteome of R. palustris CGA010 was quantitatively analyzed by tandem mass spectrometry from cultures episomally expressing the ECF σ(RPA4225) (ecfT) versus a WT control. Among the proteins with the greatest increase in abundance were catalase KatE, trehalose synthase, a DPS-like protein, and several regulatory proteins. Alignment of the cognate promoter regions driving expression of several upregulated proteins suggested a conserved binding motif in the -35 and -10 regions with the consensus sequence GGAAC-18N-TT. Additionally, the putative anti-σ factor RPA4224, whose gene is contained in the same predicted operon as RPA4225, was identified as interacting directly with the predicted response regulator RPA4223 by mass spectrometry of affinity-isolated protein complexes. Furthermore, another gene (RPA4226) coding for a protein that contains a cytoplasmic histidine kinase domain is located immediately upstream of RPA4225. The genomic organization of orthologs for these four genes is conserved in several other strains of R. palustris as well as in closely related α-Proteobacteria. Taken together, these data suggest that ECF σ(RPA4225) and the three additional genes make up a sigma factor mimicry system in R. palustris.

PMID: 25853567 [PubMed - as supplied by publisher]

Methylene Blue Protects Astrocytes against Glucose Oxygen Deprivation by Improving Cellular Respiration.

Thu, 04/09/2015 - 3:30am

Methylene Blue Protects Astrocytes against Glucose Oxygen Deprivation by Improving Cellular Respiration.

PLoS One. 2015;10(4):e0123096

Authors: Roy Choudhury G, Winters A, Rich RM, Ryou MG, Gryczynski Z, Yuan F, Yang SH, Liu R

Abstract
Astrocytes outnumber neurons and serve many metabolic and trophic functions in the mammalian brain. Preserving astrocytes is critical for normal brain function as well as for protecting the brain against various insults. Our previous studies have indicated that methylene blue (MB) functions as an alternative electron carrier and enhances brain metabolism. In addition, MB has been shown to be protective against neurodegeneration and brain injury. In the current study, we investigated the protective role of MB in astrocytes. Cell viability assays showed that MB treatment significantly protected primary astrocytes from oxygen-glucose deprivation (OGD) & reoxygenation induced cell death. We also studied the effect of MB on cellular oxygen and glucose metabolism in primary astrocytes following OGD-reoxygenation injury. MB treatment significantly increased cellular oxygen consumption, glucose uptake and ATP production in primary astrocytes. In conclusion our study demonstrated that MB protects astrocytes against OGD-reoxygenation injury by improving astrocyte cellular respiration.

PMID: 25848957 [PubMed - as supplied by publisher]

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