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Methylene blue inhibits GABAA receptors by interaction with GABA binding site.

Recent Research Articles from UNTHSC - Fri, 09/01/2017 - 07:38
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Methylene blue inhibits GABAA receptors by interaction with GABA binding site.

Neuropharmacology. 2017 Jun;119:100-110

Authors: Chen Z, Liu R, Yang SH, Dillon GH, Huang R

Abstract
Methylene blue (MB) is commonly used in diagnostic procedures and is also used to treat various medical conditions. Neurological effects of MB have been reported in clinical observations and experimental studies. Thus the modulation of GABAA receptor function by MB was investigated. Whole-cell GABA-activated currents were recorded from HEK293 cells expressing various GABAA receptor subunit configurations. MB inhibition of GABA currents was apparent at 3 μM, and it had an IC50 of 31 μM in human α1β2γ2 receptors. The MB action was rapid and reversible. MB inhibition was not mediated via the picrotoxin site, as a mutation (T6'F of the β2 subunit) known to confer resistance to picrotoxin had no effect on MB-induced inhibition. Blockade of GABAA receptors by MB was demonstrated across a range of receptors expressing varying subunits, including those expressed at extrasynaptic sites. The sensitivity of α1β2 receptors to MB was similar to that observed in α1β2γ2 receptors, indicating that MB's action via the benzodiazepine or Zn(2+) site is unlikely. MB-induced inhibition of GABA response was competitive with respect to GABA. Furthermore, mutation of α1 F64 to A and β2 Y205 to F in the extracellular N-terminus, both residues which are known to comprise GABA binding pocket, remarkably diminished MB inhibition of GABA currents. These data suggest that MB inhibits GABAA receptor function by direct or allosteric interaction with the GABA binding site. Finally, in mouse hippocampal CA1 pyramidal neurons, MB inhibited GABA-activated currents as well as GABAergic IPSCs. We demonstrate that MB directly inhibits GABAA receptor function, which may underlie some of the effects of MB on the CNS.

PMID: 28390894 [PubMed - indexed for MEDLINE]

Precision Medicine for Ischemic Stroke, Let Us Move Beyond Time Is Brain.

Recent Research Articles from UNTHSC - Wed, 08/30/2017 - 07:32
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Precision Medicine for Ischemic Stroke, Let Us Move Beyond Time Is Brain.

Transl Stroke Res. 2017 Aug 29;:

Authors: Yang SH, Lou M, Luo B, Jiang WJ, Liu R

PMID: 28849548 [PubMed - as supplied by publisher]

Markov Mixed Effects Modeling Using Electronic Adherence Monitoring Records Identifies Influential Covariates to HIV Preexposure Prophylaxis.

Recent Research Articles from UNTHSC - Wed, 08/30/2017 - 07:32
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Markov Mixed Effects Modeling Using Electronic Adherence Monitoring Records Identifies Influential Covariates to HIV Preexposure Prophylaxis.

J Clin Pharmacol. 2017 May;57(5):606-615

Authors: Madrasi K, Chaturvedula A, Haberer JE, Sale M, Fossler MJ, Bangsberg D, Baeten JM, Celum C, Hendrix CW

Abstract
Adherence is a major factor in the effectiveness of preexposure prophylaxis (PrEP) for HIV prevention. Modeling patterns of adherence helps to identify influential covariates of different types of adherence as well as to enable clinical trial simulation so that appropriate interventions can be developed. We developed a Markov mixed-effects model to understand the covariates influencing adherence patterns to daily oral PrEP. Electronic adherence records (date and time of medication bottle cap opening) from the Partners PrEP ancillary adherence study with a total of 1147 subjects were used. This study included once-daily dosing regimens of placebo, oral tenofovir disoproxil fumarate (TDF), and TDF in combination with emtricitabine (FTC), administered to HIV-uninfected members of serodiscordant couples. One-coin and first- to third-order Markov models were fit to the data using NONMEM(®) 7.2. Model selection criteria included objective function value (OFV), Akaike information criterion (AIC), visual predictive checks, and posterior predictive checks. Covariates were included based on forward addition (α = 0.05) and backward elimination (α = 0.001). Markov models better described the data than 1-coin models. A third-order Markov model gave the lowest OFV and AIC, but the simpler first-order model was used for covariate model building because no additional benefit on prediction of target measures was observed for higher-order models. Female sex and older age had a positive impact on adherence, whereas Sundays, sexual abstinence, and sex with a partner other than the study partner had a negative impact on adherence. Our findings suggest adherence interventions should consider the role of these factors.

PMID: 27922719 [PubMed - indexed for MEDLINE]

No increased risk of hospitalization for heart failure for patients treated with dipeptidyl peptidase-4 inhibitors in Taiwan.

Recent Research Articles from UNTHSC - Wed, 08/30/2017 - 07:32
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No increased risk of hospitalization for heart failure for patients treated with dipeptidyl peptidase-4 inhibitors in Taiwan.

Int J Cardiol. 2016 Oct 01;220:14-20

Authors: Chang CH, Chang YC, Lin JW, Caffrey JL, Wu LC, Lai MS, Chuang LM

Abstract
BACKGROUND: Saxagliptin has been reported to be associated with an increased risk of hospitalization for heart failure (HF). The objective of this study was to test whether the increased risk is drug specific or a class effect for dipeptidyl peptidase-4 (DPP-4) inhibitors.
METHODS: Diabetic patients prescribed sitagliptin, saxagliptin, and vildagliptin between 2011 and 2013 were identified from Taiwan's National Health Insurance (NHI) claims database. The outcome of interest was the first hospitalization for HF. The patients were followed for one year from drug initiation to outcome occurrence, death, or study termination (December 31, 2013). A Cox proportional hazards regression model was used to calculate the hazard ratios (HR) and their 95% confidence intervals, using sitagliptin as the reference group.
RESULTS: A total of 239,669 patients, including 159,330 sitagliptin, 38,561 saxagliptin, and 41,778 vildagliptin initiators, were included in the analysis. With a follow-up period ranging from 269days (vildagliptin) to 313days (sitagliptin), the crude incidence rate of HF was 2.77, 2.63, and 1.91 per 100 person-years for sitagliptin, saxagliptin, and vildagliptin, respectively. Saxagliptin had a similar risk (HR: 0.98, 95% CI: 0.91-1.06) to sitagliptin, while vildagliptin was associated with a lower risk of HF (HR: 0.85, 95% CI: 0.78-0.93). Auxiliary analyses using acarbose (n=130,800) as a reference group consistently showed no increased risk of HF associated with DDP-4 inhibitors.
CONCLUSION: Three DPP-4 inhibitors studied seem to be safe regarding the risk of HF, while the reduced risk of vildagliptin might be a spurious association or a chance finding.

PMID: 27389437 [PubMed - indexed for MEDLINE]

Opioids' Effect on Healing of Venous Leg Ulcers.

Recent Research Articles from UNTHSC - Sun, 08/27/2017 - 07:34
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Opioids' Effect on Healing of Venous Leg Ulcers.

J Invest Dermatol. 2017 Aug 22;:

Authors: Herskovitz I, MacQuhae FE, Dickerson JE, Cargill DI, Slade HB, Margolis DJ, Kirsner RS

PMID: 28842329 [PubMed - as supplied by publisher]

Ten-Year Follow-Up of Metatarsal Head Resurfacing Implants for Treatment of Hallux Rigidus.

Recent Research Articles from UNTHSC - Sun, 08/27/2017 - 07:34
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Ten-Year Follow-Up of Metatarsal Head Resurfacing Implants for Treatment of Hallux Rigidus.

J Foot Ankle Surg. 2017 Sep - Oct;56(5):1052-1057

Authors: Hilario H, Garrett A, Motley T, Suzuki S, Carpenter B

Abstract
Controversy remains regarding the use of arthroplasty versus arthrodesis in the surgical treatment of late-stage hallux rigidus. The purpose of our retrospective study was to report the long-term follow-up results of the metatarsal head resurfacing implant used for hemiarthroplasty. The patient assessments were conducted using the American Orthopaedic Foot and Ankle Society (AOFAS) metatarsophalangeal clinical rating system and a satisfaction questionnaire. A total of 59 consecutive implantations were performed from January 2005 to December 2009 at our institution. Of the 59 patients, 2 had died and 12 were lost to follow-up, for a 76.3% follow-up rate (45 of 59 procedures) at a mean of 117.67 (range 96 to 143) months. The mean overall AOFAS scale score was 90.6 ± 7.6. The AOFAS pain scale score was 37.78 ± 4.71. One implant was removed, and all remaining patients were happy with their outcome and would repeat the procedure on their other foot, if needed. A subset of patients from a previous mid-term study at our institution showed no significant change in the AOFAS scale scores. Of these 32 patients, 30 (93.75%) were available for follow-up examination at a mean of 122.62 (range 96 to 143) months. We were able to obtain long-term results for 32 implants (30 patients), resulting in a 10-year follow-up rate of 93.7%. With the minimal resection required for this implant, salvage arthrodesis remains a viable option if revision is needed. The surgical treatment of late-stage hallux rigidus with metatarsal head resurfacing allows for low-risk and excellent outcomes at long-term follow-up point.

PMID: 28842091 [PubMed - in process]

Recent Progress in Vascular Aging: Mechanisms and Its Role in Age-related Diseases.

Recent Research Articles from UNTHSC - Sat, 08/26/2017 - 07:34
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Recent Progress in Vascular Aging: Mechanisms and Its Role in Age-related Diseases.

Aging Dis. 2017 Jul;8(4):486-505

Authors: Xu X, Wang B, Ren C, Hu J, Greenberg DA, Chen T, Xie L, Jin K

Abstract
As with many age-related diseases including vascular dysfunction, age is considered an independent and crucial risk factor. Complicated alterations of structure and function in the vasculature are linked with aging hence, understanding the underlying mechanisms of age-induced vascular pathophysiological changes holds possibilities for developing clinical diagnostic methods and new therapeutic strategies. Here, we discuss the underlying molecular mediators that could be involved in vascular aging, e.g., the renin-angiotensin system and pro-inflammatory factors, metalloproteinases, calpain-1, monocyte chemoattractant protein-1 (MCP-1) and TGFβ-1 as well as the potential roles of testosterone and estrogen. We then relate all of these to clinical manifestations such as vascular dementia and stroke in addition to reviewing the existing clinical measurements and potential interventions for age-related vascular dysfunction.

PMID: 28840062 [PubMed]

Dopamine Burden Induced the Inactivation of Sonic Hedgehog Signaling to Cognitive Decline in Minimal Hepatic Encephalopathy.

Recent Research Articles from UNTHSC - Sat, 08/26/2017 - 07:34
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Dopamine Burden Induced the Inactivation of Sonic Hedgehog Signaling to Cognitive Decline in Minimal Hepatic Encephalopathy.

Aging Dis. 2017 Jul;8(4):442-457

Authors: Ding S, Yang J, Huang X, Liu L, Hu J, Xu Z, Zhuge Q

Abstract
Minimal hepatic encephalopathy (MHE) is induced by elevated intracranial dopamine (DA). The relationship of the Shh pathway with memory loss in MHE, however, is elusive. In the current study, rats with MHE induced with DA displayed downregulation of the Shh pathway. Additionally, injection of Shh into MHE/DA-treated rats reversed downregulation of BDNF/NT3, whereas administration of cyclopamine (Cyc) enhanced the inhibition of expression of BDNF/NT3. Furthermore, naringin (Nrg) substantially prevented cognitive impairment in MHE/DA-treated rats and upregulated the Shh pathway, paralleling the elevated expression of BDNF/NT3. Overall, our results indicate that the Shh pathway can induce the expression of BDNF/NT3, and DA causes memory loss by inactivation of Shh pathway signaling to BDNF/NT3 in MHE rats, which is reversed by Nrg. Our study may provide new theory basis of pathogenesis and therapeutic target of MHE.

PMID: 28840059 [PubMed]

Limb Remote Ischemic Conditioning Promotes Myelination by Upregulating PTEN/Akt/mTOR Signaling Activities after Chronic Cerebral Hypoperfusion.

Recent Research Articles from UNTHSC - Sat, 08/26/2017 - 07:34
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Limb Remote Ischemic Conditioning Promotes Myelination by Upregulating PTEN/Akt/mTOR Signaling Activities after Chronic Cerebral Hypoperfusion.

Aging Dis. 2017 Jul;8(4):392-401

Authors: Li X, Ren C, Li S, Han R, Gao J, Huang Q, Jin K, Luo Y, Ji X

Abstract
Limb Remote ischemic conditioning (LRIC) has been proved to be a promising neuroprotective method in white matter lesions after ischemia; however, its mechanism underlying protection after chronic cerebral hypoperfusion remains largely unknown. Here, we investigated whether LRIC promoted myelin growth by activating PI3K/Akt/mTOR signal pathway in a rat chronic hypoperfusion model. Thirty adult male Sprague Dawley underwent permanent double carotid artery (2VO), and limb remote ischemic conditioning was applied for 3 days after the 2VO surgery. Cognitive function, oligodendrocyte counts, myelin density, apoptosis and proliferation activity, as well as PTEN/Akt/mTOR signaling activity were determined 4 weeks after treatment. We found that LRIC significantly inhibited oligodendrocytes apoptosis (p<0.05), promoted myelination (p<0.01) in the corpus callosum and improved spatial learning impairment (p<0.05) at 4 weeks after chronic cerebral hypoperfusion. Oligodendrocytes proliferation, along with demyelination, in corpus callosum were not obviously affected by LRIC (p>0.05). Western blot analysis indicated that LRIC upregulated PTEN/Akt/mTOR signaling activities in corpus callosum (p<0.05). Our results suggest that LRIC exerts neuroprotective effect on white matter injuries through activating PTEN/Akt/mTOR signaling pathway after chronic cerebral hypoperfusion.

PMID: 28840054 [PubMed]

Cyclical Blood Flow Restriction Resistance Exercise: A Potential Parallel to Remote Ischemic Preconditioning?

Recent Research Articles from UNTHSC - Fri, 08/25/2017 - 07:36
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Cyclical Blood Flow Restriction Resistance Exercise: A Potential Parallel to Remote Ischemic Preconditioning?

Am J Physiol Regul Integr Comp Physiol. 2017 Aug 23;:ajpregu.00112.2017

Authors: Sprick JD, Rickards CA

Abstract
Remote ischemic preconditioning (RIPC) is characterized by the cyclical application of limb blood flow restriction and reperfusion, and has been shown to protect vital organs during a subsequent ischemic insult. Blood flow restriction exercise (BFRE) similarly combines bouts of blood flow restriction with low-intensity exercise and thus could potentially emulate the protection demonstrated by RIPC. One concern with BFRE, however, is the potential for an augmented rise in sympathetic outflow, due to greater activation of the exercise pressor reflex. Due to the use of lower workloads, however, we hypothesized that BFRE would elicit an attenuated increase in sympathetic outflow (assessed via plasma norepinephrine (NE) and mean arterial pressure (MAP)), and middle cerebral artery velocity (MCAv) when compared with conventional exercise (CE). Fifteen subjects underwent two leg-press exercise interventions: 1.BFRE-220 mmHg bilateral thigh occlusion at 20% 1 rep-max (1RM), and; 2.CE-65% 1RM without occlusion. Each condition consisted of 4 x 5-min cycles of exercise, with 3 x 10-reps in each cycle. 5-min of rest and reperfusion (for BFRE) followed each cycle. MAP increased with exercise (P<0.001), and was 4-5 mmHg higher with CE vs. BFRE (P≤0.09). Mean MCAv also increased with exercise (P<0.001) and was higher with CE compared to BFRE during the first bout of exercise only (P=0.07). Plasma [NE] increased with CE only (P<0.001), and was higher than BFRE throughout exercise (P≤0.02). The attenuated sympathetic response combined with similar cerebrovascular responses suggest that cyclical BFRE could be explored as an alternative to CE in the clinical setting.

PMID: 28835448 [PubMed - as supplied by publisher]

Combining Remote Ischemic Preconditioning and Aerobic Exercise: A Novel Adaptation of Blood Flow Restriction Exercise.

Recent Research Articles from UNTHSC - Fri, 08/25/2017 - 07:36
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Combining Remote Ischemic Preconditioning and Aerobic Exercise: A Novel Adaptation of Blood Flow Restriction Exercise.

Am J Physiol Regul Integr Comp Physiol. 2017 Aug 23;:ajpregu.00111.2017

Authors: Sprick JD, Rickards CA

Abstract
Remote ischemic preconditioning (RIPC) can attenuate tissue damage sustained by ischemia-reperfusion injury. Blood flow restriction exercise (BFRE) restricts blood flow to exercising muscles. We implemented a novel approach to BFRE with cyclical bouts of blood flow restriction-reperfusion, reflecting the RIPC model. A concern about BFRE, however, is potential amplification of the exercise pressor reflex, which could be unsafe in at-risk populations. We hypothesized that cyclical BFRE would elicit greater increases in sympathetic outflow and arterial pressure than conventional exercise (CE), performed at the same relative intensity. We also assessed the cerebrovascular responses, due to potential implementation of BFRE in stroke rehabilitation. Fourteen subjects performed treadmill exercise at 65-70% HRmax with and without intermittent BFR (4x5-min intervals of bilateral thigh-cuff pressure followed by 5-min reperfusion periods). Mean arterial pressure (MAP), plasma norepinephrine (NE), and middle and posterior cerebral artery velocities (MCAv and PCAv) were compared between trials. As expected, BFRE elicited higher [NE] compared to CE (1249±170 vs 962±114 pg/ml; P=0.06). Unexpectedly, however, there were no differences in MAP between conditions (overall P=0.33), and MAP was 4-5 mmHg lower with BFRE vs. CE during the reperfusion periods (P≤0.05 for reperfusion periods 3 and 4). There were no differences in MCAv or PCAv between trials (P≥0.22), suggesting equivalent cerebro-metabolic demand. The exaggerated sympatho-excitatory response with BFRE was not accompanied by higher MAP, likely due to the cyclical reperfusions. This cyclical BFRE paradigm could be adapted to cardiac- or stroke-rehabilitation, where exercising patients could benefit from the cardio- and cerebro-protection associated with RIPC.

PMID: 28835447 [PubMed - as supplied by publisher]

Anterior chamber perfusion versus posterior chamber perfusion does not influence measurement of aqueous outflow facility in living mice by constant flow infusion.

Recent Research Articles from UNTHSC - Tue, 08/22/2017 - 07:40

Anterior chamber perfusion versus posterior chamber perfusion does not influence measurement of aqueous outflow facility in living mice by constant flow infusion.

Exp Eye Res. 2017 Aug 16;:

Authors: Lopez NN, Patel GC, Raychaudhuri U, Aryal S, Phan TN, Clark AF, Millar JC

Abstract
Mice are now routinely utilized in studies of aqueous humor outflow dynamics. In particular, conventional aqueous outflow facility (C) is routinely measured via perfusion of the aqueous chamber by a number of laboratories. However, in mouse eyes perfused ex-vivo, values for C are variable depending upon whether the perfusate is introduced into the posterior chamber (PC) versus the anterior chamber (AC). Perfusion via the AC leads to posterior bowing of the iris, and traction on the iris root/scleral spur, which may increase C. Perfusion via the PC does not yield this effect. But the equivalent situation in living mice has not been investigated. We sought to determine whether AC versus PC perfusion of the living mouse eye may lead to different values for C. All experiments were conducted in C57BL/6J mice (all ♀) between the ages of 20 and 30 weeks. Mice were divided into groups of 3-4 animals each. In all groups, both eyes were perfused. C was measured in groups 1 and 2 by constant flow infusion (from a 50 μL microsyringe) via needle placement in the AC, and in the PC, respectively. To investigate the effect of ciliary muscle (CM) tone on C, groups 3 and 4 were perfused live via the AC or PC with tropicamide (muscarinic receptor antagonist) added to the perfusate at a concentration of 100 μM. To investigate immediate effect of euthanasia, groups 5 and 6 were perfused 15-30 min after death via the AC or PC. To investigate the effect of CM tone on C immediately following euthanasia, groups 7 and 8 were perfused 15-30 min after death via the AC or PC with tropicamide added to the perfusate at a concentration of 100 μM. C in Groups 1 (AC perfusion) and 2 (PC perfusion) was computed to be 19.5 ± 0.8 versus 21.0 ± 2.1 nL/min/mmHg, respectively (mean ± SEM, p > 0.4, not significantly different). In live animals in which tropicamide was present in the perfusate, C in Group 3 (AC perfusion) was significantly greater than C in Group 4 (PC perfusion) (22.0 ± 4.0 versus 14.0 ± 2.0 nL/min/mmHg, respectively, p = 0.0021). In animals immediately following death, C in groups 5 (AC perfusion) and 6 (PC perfusion) was computed to be 21.2 ± 2.0 versus 22.8 ± 1.4 nL/min/mmHg, respectively (mean ± SEM, p = 0.1196, not significantly different). In dead animals in which tropicamide was present in the perfusate, C in group 7 (AC perfusion) was greater than C in group 8 (PC perfusion) (20.6 ± 1.4 versus 14.2 ± 2.6 nL/min/mmHg, respectively, p < 0.0001). C in eyes in situ in living mice or euthanized animals within 15-30 min post mortem is not significantly different when measured via AC perfusion or PC perfusion. In eyes of live or freshly euthanized mice, C is greater when measured via AC versus PC perfusion when tropicamide (a mydriatic and cycloplegic agent) is present in the perfusate.

PMID: 28822760 [PubMed - as supplied by publisher]

Hybrid Nitric Oxide Donor and its Carrier for the Treatment of Peripheral Arterial Diseases.

Recent Research Articles from UNTHSC - Sun, 08/20/2017 - 07:35

Hybrid Nitric Oxide Donor and its Carrier for the Treatment of Peripheral Arterial Diseases.

Sci Rep. 2017 Aug 18;7(1):8692

Authors: Le DQ, Kuriakose AE, Nguyen DX, Nguyen KT, Acharya S

Abstract
Nitric oxide (NO) has been known to promote physiological angiogenesis to treat peripheral arterial diseases (PAD) by increasing the vascular endothelial growth factor (VEGF) level in endothelial cells (ECs) and preventing platelet adherence and leukocyte chemotaxis. However, the ongoing ischemic event during peripheral ischemia produces superoxide and diminishes the NO bioavailability by forming toxic peroxynitrite anion. Here we disclose an efficacious hybrid molecule 4-(5-Amino-1,2,3-oxadiazol-3-yl)-2,2,6,6-tetramethyl-1-piperidinol (SA-2) containing both antioxidant and NO donor functionalities that provide a therapeutic level of NO necessary to promote angiogenesis and to protect ECs against hydrogen peroxide-induced oxidative stress. Compound SA-2 scavenged reactive oxygen species, inhibited proliferation and migration of smooth muscle cells (SMCs) and promoted the tube formation from ECs. Copolymer poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with SA-2 provided a sustained release of NO over days, improved aqueous stability in serum, protected ECs against oxidative stress, and enhanced angiogenesis under stress conditions as compared to that of the control in the in vitro matrigel tube formation assay. These results indicated the potential use of SA-2 nanoparticles as an alternative therapy to treat PAD.

PMID: 28821752 [PubMed - in process]

Targets of Neuroprotection in Glaucoma.

Recent Research Articles from UNTHSC - Sat, 08/19/2017 - 07:43

Targets of Neuroprotection in Glaucoma.

J Ocul Pharmacol Ther. 2017 Aug 18;:

Authors: He S, Stankowska DL, Ellis DZ, Krishnamoorthy RR, Yorio T

Abstract
Progressive neurodegeneration of the optic nerve and the loss of retinal ganglion cells is a hallmark of glaucoma, the leading cause of irreversible blindness worldwide, with primary open-angle glaucoma (POAG) being the most frequent form of glaucoma in the Western world. While some genetic mutations have been identified for some glaucomas, those associated with POAG are limited and for most POAG patients, the etiology is still unclear. Unfortunately, treatment of this neurodegenerative disease and other retinal degenerative diseases is lacking. For POAG, most of the treatments focus on reducing aqueous humor formation, enhancing uveoscleral or conventional outflow, or lowering intraocular pressure through surgical means. These efforts, in some cases, do not always lead to a prevention of vision loss and therefore other strategies are needed to reduce or reverse the progressive neurodegeneration. In this review, we will highlight some of the ocular pharmacological approaches that are being tested to reduce neurodegeneration and provide some form of neuroprotection.

PMID: 28820649 [PubMed - as supplied by publisher]

Oscillation patterns are enhanced and firing threshold is lowered in medullary respiratory neuron discharges by threshold doses of a μ-opioid receptor agonist.

Recent Research Articles from UNTHSC - Sat, 08/19/2017 - 07:43
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Oscillation patterns are enhanced and firing threshold is lowered in medullary respiratory neuron discharges by threshold doses of a μ-opioid receptor agonist.

Am J Physiol Regul Integr Comp Physiol. 2017 May 01;312(5):R727-R738

Authors: Lalley PM, Mifflin SW

Abstract
μ-Opioid receptors are distributed widely in the brain stem respiratory network, and opioids with selectivity for μ-type receptors slow in vivo respiratory rhythm in lowest effective doses. Several studies have reported μ-opioid receptor effects on the three-phase rhythm of respiratory neurons, but there are until now no reports of opioid effects on oscillatory activity within respiratory discharges. In this study, effects of the μ-opioid receptor agonist fentanyl on spike train discharge properties of several different types of rhythm-modulating medullary respiratory neuron discharges were analyzed. Doses of fentanyl that were just sufficient for prolongation of discharges and slowing of the three-phase respiratory rhythm also produced pronounced enhancement of spike train properties. Oscillation and burst patterns detected by autocorrelation measurements were greatly enhanced, and interspike intervals were prolonged. Spike train properties under control conditions and after fentanyl were uniform within each experiment, but varied considerably between experiments, which might be related to variability in acid-base balance in the brain stem extracellular fluid. Discharge threshold was shifted to more negative levels of membrane potential. The effects on threshold are postulated to result from opioid-mediated disinhibition and postsynaptic enhancement of N-methyl-d- aspartate receptor current. Lowering of firing threshold, enhancement of spike train oscillations and bursts and prolongation of discharges by lowest effective doses of fentanyl could represent compensatory adjustments in the brain stem respiratory network to override opioid blunting of CO2/pH chemosensitivity.

PMID: 28202437 [PubMed - indexed for MEDLINE]

Tolfenamic acid-induced alterations in genes and pathways in pancreatic cancer cells.

Recent Research Articles from UNTHSC - Sat, 08/19/2017 - 07:43
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Tolfenamic acid-induced alterations in genes and pathways in pancreatic cancer cells.

Oncotarget. 2017 Feb 28;8(9):14593-14603

Authors: Sankpal UT, Goodison S, Jones-Pauley M, Hurtado M, Zhang F, Basha R

Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are being tested extensively for their role in the treatment and prevention of several cancers. Typically NSAIDs exhibit anti-tumor activities via modulation of cyclooxygenase (COX)-dependent mechanisms, however, an anti-cancer NSAID tolfenamic acid (TA) is believed to work through COX-independent pathways. Results from our laboratory and others have demonstrated the anti-cancer activity of TA in various cancer models including pancreatic cancer. TA has been shown to modulate certain cellular processes including, apoptosis, reactive oxygen species and signaling. In this study, molecular profiling was performed to precisely understand the mode of action of TA. Three pancreatic cancer cell lines, L3.6pl, MIA PaCa-2, and Panc1 were treated with TA (50 μM for 48 h) and the changes in gene expression was evaluated using the Affymetrix GeneChip Human Gene ST Array platform. Microarray results were further validated using quantitative PCR for seven genes altered by TA treatment in all three cell lines. Functional analysis of differentially expressed genes (2 fold increase or decrease, p < 0.05) using Ingenuity Pathway Analysis software, revealed that TA treatment predominantly affected the genes involved in cell cycle, cell growth and proliferation, and cell death and survival. Promoter analysis of the differentially expressed genes revealed that they are enriched for Sp1 binding sites, suggesting that Sp1 could be a major contributor in mediating the effect of TA. The gene expression studies identified new targets involved in TA's mode of action, while supporting the hypothesis about the association of Sp1 in TA mediated effects in pancreatic cancer.

PMID: 28099934 [PubMed - indexed for MEDLINE]

The effect of the sigma-1 receptor selective compound LS-1-137 on the DOI-induced head twitch response in mice.

Recent Research Articles from UNTHSC - Fri, 08/18/2017 - 07:39
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The effect of the sigma-1 receptor selective compound LS-1-137 on the DOI-induced head twitch response in mice.

Pharmacol Biochem Behav. 2016 Sep;148:136-44

Authors: Malik M, Rangel-Barajas C, Mach RH, Luedtke RR

Abstract
Several receptor mediated pathways have been shown to modulate the murine head twitch response (HTR). However, the role of sigma receptors in the murine (±)-2,5-dimethoxy-4-iodoamphetamine (DOI)-induced HTR has not been previously investigated. We examined the ability of LS-1-137, a novel sigma-1 vs. sigma-2 receptor selective phenylacetamide, to modulate the DOI-induced HTR in DBA/2J mice. We also assessed the in vivo efficacy of reference sigma-1 receptor antagonists and agonists PRE-084 and PPCC. The effect of the sigma-2 receptor selective antagonist RHM-1-86 was also examined. Rotarod analysis was performed to monitor motor coordination after LS-1-137 administration. Radioligand binding techniques were used to determine the affinity of LS-1-137 at 5-HT2A and 5-HT2C receptors. LS-1-137 and the sigma-1 receptor antagonists haloperidol and BD 1047 were able to attenuate a DOI-induced HTR, indicating that LS-1-137 was acting in vivo as a sigma-1 receptor antagonist. LS-1-137 did not compromise rotarod performance within a dose range capable of attenuating the effects of DOI. Radioligand binding studies indicate that LS-1-137 exhibits low affinity binding at both 5-HT2A and 5-HT2C receptors. Based upon the results from these and our previous studies, LS-1-137 is a neuroprotective agent that attenuates the murine DOI-induced HTR independent of activity at 5-HT2 receptor subtypes, D2-like dopamine receptors, sigma-2 receptors and NMDA receptors. LS-1-137 appears to act as a sigma-1 receptor antagonist to inhibit the DOI-induced HTR. Therefore, the DOI-induced HTR can be used to assess the in vivo efficacy of sigma-1 receptor selective compounds.

PMID: 27397487 [PubMed - indexed for MEDLINE]

Intermittent Hypoxia Training: Powerful, Non-Invasive Cerebroprotection Against Ethanol Withdrawal Excitotoxicity.

Recent Research Articles from UNTHSC - Thu, 08/17/2017 - 10:43
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Intermittent Hypoxia Training: Powerful, Non-Invasive Cerebroprotection Against Ethanol Withdrawal Excitotoxicity.

Respir Physiol Neurobiol. 2017 Aug 12;:

Authors: Jung ME, Mallet RT

Abstract
Ethanol intoxication and withdrawal exact a devastating toll on the central nervous system. Abrupt ethanol withdrawal provokes massive release of the excitatory neurotransmitter glutamate, which over-activates its postsynaptic receptors, causing intense Ca(2+) loading, p38 mitogen activated protein kinase activation and oxidative stress, culminating in ATP depletion, mitochondrial injury, amyloid β deposition and neuronal death. Collectively, these mechanisms produce neurocognitive and sensorimotor dysfunction that discourages continued abstinence. Although the brain is heavily dependent on blood-borne O2 to sustain its aerobic ATP production, brief, cyclic episodes of moderate hypoxia and reoxygenation, when judiciously applied over the course of days or weeks, evoke adaptations that protect the brain from ethanol withdrawal-induced glutamate excitotoxicity, mitochondrial damage, oxidative stress and amyloid β accumulation. This review summarizes evidence from ongoing preclinical research that demonstrates intermittent hypoxia training to be a potentially powerful yet non-invasive intervention capable of affording robust, sustained neuroprotection during ethanol withdrawal.

PMID: 28811138 [PubMed - as supplied by publisher]

Community-based participatory research to design a faith-enhanced diabetes prevention program: The Better Me Within randomized trial.

Recent Research Articles from UNTHSC - Thu, 08/17/2017 - 10:43
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Community-based participatory research to design a faith-enhanced diabetes prevention program: The Better Me Within randomized trial.

Contemp Clin Trials. 2017 Aug 11;:

Authors: Kitzman H, Dodgen L, Mamun A, Lee Slater J, King G, Slater D, King A, Mandapati S, DeHaven M

Abstract
Reducing obesity positively impacts diabetes and cardiovascular risk; however, evidence-based lifestyle programs, such as the diabetes prevention program (DPP), show reduced effectiveness in African American (AA) women. In addition to an attenuated response to lifestyle programs, AA women also demonstrate high rates of obesity, diabetes, and cardiovascular disease. To address these disparities, enhancements to evidence-based lifestyle programs for AA women need to be developed and evaluated with culturally relevant and rigorous study designs. This study describes a community-based participatory research (CBPR) approach to design a novel faith-enhancement to the DPP for AA women. A long-standing CBPR partnership designed the faith-enhancement from focus group data (N=64 AA adults) integrating five components: a brief pastor led sermon, memory verse, in class or take-home faith activity, promises to remember, and scripture and prayer integrated into participant curriculum and facilitator materials. The faith components were specifically linked to weekly DPP learning objectives to strategically emphasize behavioral skills with religious principles. Using a CBPR approach, the Better Me Within trial was able to enroll 12 churches, screen 333 AA women, and randomize 221 (Mage=48.8±11.2; MBMI=36.7±8.4; 52% technical or high school) after collection of objective eligibility measures. A prospective, randomized, nested by church, design will be used to evaluate the faith-enhanced DPP as compared to a standard DPP on weight, diabetes and cardiovascular risk, over a 16-week intervention and 10-month follow up. This study will provide essential data to guide enhancements to evidence-based lifestyle programs for AA women who are at high risk for chronic disease.

PMID: 28807739 [PubMed - as supplied by publisher]

A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing.

Recent Research Articles from UNTHSC - Thu, 08/17/2017 - 10:43
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A Comparison of Gene Expression Profiles between Glucocorticoid Responder and Non-Responder Bovine Trabecular Meshwork Cells Using RNA Sequencing.

PLoS One. 2017;12(1):e0169671

Authors: Bermudez JY, Webber HC, Brown B, Braun TA, Clark AF, Mao W

Abstract
The most common ocular side effect of glucocorticoid (GC) therapy is GC-induced ocular hypertension (OHT) and GC-induced glaucoma (GIG). GC-induced OHT occurs in about 40% of the general population, while the other 60% are resistant. This study aims to determine the genes and pathways involved in differential GC responsiveness in the trabecular meshwork (TM). Using paired bovine eyes, one eye was perfusion-cultured with 100nM dexamethasone (DEX), while the fellow eye was used to establish a bovine TM (BTM) cell strain. Based on maximum IOP change in the perfused eye, the BTM cell strain was identified as a DEX-responder or non-responder strain. Three responder and three non-responder BTM cell strains were cultured, treated with 0.1% ethanol or 100nM DEX for 7 days. RNA and proteins were extracted for RNA sequencing (RNAseq), qPCR, and Western immunoblotting (WB), respectively. Data were analyzed using the human and bovine genome databases as well as Tophat2 software. Genes were grouped and compared using Student's t-test. We found that DEX induced fibronectin expression in responder BTM cells but not in non-responder cells using WB. RNAseq showed between 93 and 606 differentially expressed genes in different expression groups between responder and non-responder BTM cells. The data generated by RNAseq were validated using qPCR. Pathway analyses showed 35 pathways associated with differentially expressed genes. These genes and pathways may play important roles in GC-induced OHT and will help us to better understand differential ocular responsiveness to GCs.

PMID: 28068412 [PubMed - indexed for MEDLINE]

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