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: 28 min 45 sec ago

Aerobic Exercise Training Improves Orthostatic Tolerance in Aging Humans.

Wed, 11/09/2016 - 16:45
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Aerobic Exercise Training Improves Orthostatic Tolerance in Aging Humans.

Med Sci Sports Exerc. 2016 Nov 7;

Authors: Xu D, Wang H, Chen S, Ross S, Liu H, Olivencia-Yurvati A, Raven PB, Shi X

Abstract
PURPOSE: This study was designed to test the hypothesis that aerobic exercise training of the elderly will increase aerobic fitness without compromising orthostatic tolerance (OT).
METHODS: Eight healthy sedentary volunteers (67.0±1.7 years old, 4 women) participated in 1-year of endurance exercise training (stationary bicycle and/or treadmill) program at the individuals' 65%-75% of peak heart rate (HRpeak). Peak O2 uptake (VO2peak) and HRpeak were determined by a maximal exercise stress test using a bicycle ergometer. Carotid baroreceptor reflex (CBR) control of HR and mean arterial pressure (MAP) were assessed by a neck pressure-neck suction (NP/NS) protocol. Each subject's maximal gain (Gmax), or sensitivity, of the CBR function curves were derived from fitting their reflex HR and MAP responses to the corresponding NP/NS stimuli using a logistic function curve. The subjects' OT was assessed using lower-body negative pressure (LBNP) graded to -50 mmHg; the sum of the product of LBNP intensity and time (mmHg•min) was calculated as the cumulative stress index (CSI).
RESULTS: Training increased VO2peak (before vs after: 22.8±0.92 vs 27.9±1.33 ml/min/kg, P < 0.01) and HRpeak (154±4 vs 159±3 beats/min, P < 0.02); and decreased resting HR (65±5 vs 59±5 beats/min, P < 0.02) and MAP (99±2 vs 87±2 mmHg, P < 0.05). CBR stimulus-response curves identified a leftward shift with an increase in CBR-HR Gmax (from -0.13±0.02 to -0.27±0.04 bpm/mmHg, P = 0.01). CSI was increased from 767±68 mmHg•min pre-training to 946±44 mmHg•min post-training (P < 0.05).
CONCLUSION: Aerobic exercise training improved the aerobic fitness and OT in elderly subjects. An improved OT is likely associated with an enhanced CBR function that has been reset to better maintain cerebral perfusion and cerebral tissue oxygenation during LBNP.

PMID: 27824693 [PubMed - as supplied by publisher]

In vitro and in vivo neuroprotective effects of cJun N-terminal kinase inhibitors on retinal ganglion cells.

Wed, 11/09/2016 - 16:45
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In vitro and in vivo neuroprotective effects of cJun N-terminal kinase inhibitors on retinal ganglion cells.

Mol Neurodegener. 2016 Apr 21;11:30

Authors: Kim BJ, Silverman SM, Liu Y, Wordinger RJ, Pang IH, Clark AF

Abstract
BACKGROUND: The c-Jun N-terminal kinase (JNK) signaling pathway plays an important role in neuronal pathophysiology. Using JNK inhibitors, we examined involvement of the JNK pathway in cultured rat retinal ganglion cell (RGC) death and in mouse retinal ischemia/reperfusion (I/R) injury of the visual axis. The in vitro effects of JNK inhibitors were evaluated in cultured adult rat retinal cells enriched in RGCs. Retinal I/R was induced in C57BL/6J mice through elevation of intraocular pressure to 120 mmHg for 60 min followed by reperfusion. SP600125 was administered intraperitoneally once daily for 28 days. Phosphorylation of JNK and c-Jun in the retina was examined by immunoblotting and immunohistochemistry. The thickness of retinal layers and cell numbers in the ganglion cell layer (GCL) were examined using H&E stained retinal cross sections and spectral domain optical coherence tomography (SD-OCT). Retinal function was measured by scotopic flash electroretinography (ERG). Volumetric measurement of the superior colliculus (SC) as well as VGLUT2 and PSD95 expression were studied.
RESULTS: JNK inhibitors SP600125 and TAT-JNK-III, dose-dependently and significantly (p < 0.05) protected against glutamate excitotoxicity and trophic factor withdrawal induced RGC death in culture. In the I/R model, phosphorylation of JNK (pJNK) in the retina was significantly (p < 0.05) increased after injury. I/R injury significantly (p < 0.05) decreased the thickness of retinal layers, including the whole retina, inner plexiform layer, and inner nuclear layer and cell numbers in the GCL. Administration of SP600125 for 28 days protected against all these degenerative morphological changes (p < 0.05). In addition, SP600125 significantly (p < 0.05) protected against I/R-induced reduction in scotopic ERG b-wave amplitude at 3, 7, 14, 21 and 28 days after injury. SP600125 also protected against the I/R-induced losses in volume and levels of synaptic markers in the SC. Moreover, the protective effects of SP600125 in the retina and SC were also detected even with only 7 days (Days 1-7 after I/R) of SP600125 treatment.
CONCLUSIONS: Our results demonstrate the important role the JNK pathway plays in retinal degeneration in both in vitro and in vivo models and suggest that JNK inhibitors may be a useful therapeutic strategy for neuroprotection of RGCs in the retina.

PMID: 27098079 [PubMed - indexed for MEDLINE]

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

Wed, 11/09/2016 - 16:45
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C1q propagates microglial activation and neurodegeneration in the visual axis following retinal ischemia/reperfusion injury.

Mol Neurodegener. 2016 Mar 24;11:24

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 - indexed for MEDLINE]

Expression of Mutant Myocilin Induces Abnormal Intracellular Accumulation of Selected Extracellular Matrix Proteins in the Trabecular Meshwork.

Tue, 11/08/2016 - 07:33

Expression of Mutant Myocilin Induces Abnormal Intracellular Accumulation of Selected Extracellular Matrix Proteins in the Trabecular Meshwork.

Invest Ophthalmol Vis Sci. 2016 Nov 1;57(14):6058-6069

Authors: Kasetti RB, Phan TN, Millar JC, Zode GS

Abstract
Purpose: Abnormal accumulation of extracellular matrix (ECM) in the trabecular meshwork (TM) is associated with decreased aqueous humor outflow facility and IOP elevation in POAG. Previously, we have developed a transgenic mouse model of POAG (Tg-MYOCY437H) by expressing human mutant myocilin (MYOC), a known genetic cause of POAG. The purpose of this study is to examine whether expression of mutant myocilin leads to reduced outflow facility and abnormal ECM accumulation in Tg-MYOCY437H mice and in cultured human TM cells.
Methods: Conscious IOP was measured at various ages of Tg-MYOCY437H mice using a rebound tonometer. Outflow facility was measured in 10-month-old Tg-MYOCY437H mice. Selected ECM proteins were examined in human TM-3 cells stably expressing mutant myocilin and primary human TM cells (n = 4) as well as in the TM of Tg-MYOCY437H mice by real-time PCR, Western blotting, and immunostaining. Furthermore, TM cells expressing WT or mutant myocilin were treated with 5 mM sodium 4-phenylbutyrate (PBA), and ECM proteins were examined by Western blot and immunostaining.
Results: Starting from 3 months of age, Tg-MYOCY437H mice exhibited significant IOP elevation compared with wild-type (WT) littermates. Outflow facility was significantly reduced in Tg-MYOCY437H mice (0.0195 μl/min/mm Hg in Tg-MYOCY437H vs. 0.0332 μl/min/mm Hg in WT littermates). Increased accumulation of fibronectin, elastin, and collagen type IV and I was observed in the TM of Tg-MYOCY437H mice compared with WT littermates. Furthermore, increased ECM proteins were also associated with induction of endoplasmic reticulum (ER) stress markers, GRP78 and CHOP in the TM of Tg-MYOCY437H mice. Human TM-3 cells stably expressing DsRed-tagged Y437H mutant MYOC exhibited inhibition of myocilin secretion and its intracellular accumulation compared with TM cells expressing WT MYOC. Expression of mutant MYOC in TM-3 cells or human primary TM cells induced ER stress and also increased intracellular protein levels of fibronectin, elastin, laminin, and collagen IV and I. In addition, TM-3 cells expressing mutant myocilin exhibited reduced active forms of matrix metalloproteinase (MMP)-2 and MMP-9 in conditioned medium compared with TM-3 cells expressing WT myocilin. Interestingly, both intracellularly accumulated fibronectin and collagen I colocalized with mutant myocilin and also with ER marker KDEL further suggesting intracellular accumulation of these proteins in the ER of TM cells. Furthermore, reduction of ER stress via PBA decreased selected ECM proteins in primary TM cells.
Conclusions: These studies demonstrate that mutant myocilin induces abnormal ECM accumulation in the ER of TM cells, which may be responsible for reduced outflow facility and IOP elevation in myocilin-associated glaucoma.

PMID: 27820874 [PubMed - in process]

Clear cell "sugar" tumor of the lung: benign or malignant?

Tue, 11/08/2016 - 07:33
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Clear cell "sugar" tumor of the lung: benign or malignant?

Int Surg. 2015 May;100(5):924-6

Authors: Olivencia-Yurvati AH, Rodriguez AE

Abstract
Clear cell "sugar" tumors of the lung are rare pulmonary tumors. This case study illustrates a patient who was found to have a persistent nodule in the left-upper lobe of the lung. Positron emission tomographic scanning showed mild-moderate 18-fluorodeoxyglucose uptake. Based on these findings, a video-assisted resection of the tumor was undertaken. The mass was identified histologically, as a clear cell "sugar" tumor of the lung. This case report discusses the benign versus malignant nature of this rare tumor.

PMID: 26011217 [PubMed - indexed for MEDLINE]

Dysregulated corticostriatal activity in open-field behavior and the head-twitch response induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine.

Mon, 11/07/2016 - 10:32
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Dysregulated corticostriatal activity in open-field behavior and the head-twitch response induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine.

Neuropharmacology. 2016 Nov 2;:

Authors: Rangel-Barajas C, Estrada-Sánchez AM, Barton SJ, Luedtke RR, Rebec GV

Abstract
The substituted amphetamine, 2,5-dimethoxy-4-iodoamphetamine (DOI), is a hallucinogen that has been used to model a variety of psychiatric conditions. Here, we studied the effect of DOI on neural activity recorded simultaneously in the primary motor cortex (M1) and dorsal striatum of freely behaving FvB/N mice. DOI significantly decreased the firing rate of individually isolated neurons in M1 and dorsal striatum relative to pre-drug baseline. It also induced a bursting pattern of activity by increasing both the number of spikes within a burst and burst duration. In addition, DOI increased coincident firing between simultaneously recorded neuron pairs within the striatum and between M1 and dorsal striatum. Local field potential (LFP) activity also increased in coherence between M1 and dorsal striatum after DOI in the low frequency gamma band (30-50 Hz), while corticostriatal coherence in delta, theta, alpha, and beta activity decreased. We also assessed corticostriatal LFP activity in relation to the DOI-induced head-twitch response (HTR), a readily identifiable behavior used to assess potential treatments for the conditions it models. The HTR was associated with increased delta and decreased theta power in both M1 and dorsal striatum. Together, our results suggest that DOI dysregulates corticostriatal communication and that the HTR is associated with this dysregulation.

PMID: 27816502 [PubMed - as supplied by publisher]

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