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: 50 min 19 sec ago

Efficacy of curcumin for age-associated cognitive decline: a narrative review of preclinical and clinical studies.

Sun, 04/22/2018 - 07:33
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Efficacy of curcumin for age-associated cognitive decline: a narrative review of preclinical and clinical studies.

Geroscience. 2018 Apr 21;:

Authors: Sarker MR, Franks SF

Abstract
Processes such as aberrant redox signaling and chronic low-grade systemic inflammation have been reported to modulate age-associated pathologies such as cognitive impairment. Curcumin, the primary therapeutic component of the Indian spice, Turmeric (Curcuma longa), has long been known for its strong anti-inflammatory and antioxidant activity attributable to its unique molecular structure. Recently, an interest in this polyphenol as a cognitive therapeutic for the elderly has emerged. The purpose of this paper is to critically review preclinical and clinical studies that have evaluated the efficacy of curcumin in ameliorating and preventing age-associated cognitive decline and address the translational progress of preclinical to clinical efficacy. PubMed, semantic scholar, and Google scholar searches were used for preclinical studies; and clinicaltrials.gov , the Australian and New Zealand clinical trials registry, and PubMed search were used to select relevant completed clinical studies. Results from preclinical studies consistently demonstrate curcumin and its analogues to be efficacious for various aspects of cognitive impairment and processes that contribute to age-associated cognitive impairment. Results of published clinical studies, while mixed, continue to show promise for curcumin's use as a therapeutic for cognitive decline but overall remain inconclusive at this time. Both in vitro and in vivo studies have found that curcumin can significantly decrease oxidative stress, systemic inflammation, and obstruct pathways that activate transcription factors that augment these processes. Future clinical studies would benefit from including evaluation of peripheral and cerebrospinal fluid biomarkers of dementia and behavioral markers of cognitive decline, as well as targeting the appropriate population.

PMID: 29679204 [PubMed - as supplied by publisher]

Etiology of type 2 diabetes and Alzheimer's disease: Exploring the mitochondria.

Sun, 04/22/2018 - 07:33
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Etiology of type 2 diabetes and Alzheimer's disease: Exploring the mitochondria.

Mitochondrion. 2018 Apr 17;:

Authors: Silzer TK, Phillips NR

Abstract
Type 2 diabetes is a significant risk factor for developing Alzheimer's disease later in life, and particular populations have a disproportionate risk because of the high prevalence of type 2 diabetes. There are many overlapping pathologies, and teasing out the primary root cause, if one indeed exists, is very difficult. Here, we review (1) the key facets of mitochondrial biology that are relevant to the two conditions, and (2) the role that mitochondrial dysfunction plays in the shared pathophysiology. We posit that mitochondrial dysfunction lies at the root of the affected processes rather than alongside them as a co-pathology.

PMID: 29678670 [PubMed - as supplied by publisher]

Discriminative stimulus and locomotor effects of para-substituted and benzofuran analogs of amphetamine.

Sat, 04/21/2018 - 07:42
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Discriminative stimulus and locomotor effects of para-substituted and benzofuran analogs of amphetamine.

Drug Alcohol Depend. 2017 Nov 01;180:39-45

Authors: Dolan SB, Forster MJ, Gatch MB

Abstract
Novel psychoactive substances have maintained a prominent role in the global drug culture, despite increased regulation by governing bodies. Novel compounds continue to become available on the market, often in "Ecstasy" or "Molly" formulations in lieu of MDMA, at a much faster rate than they can be properly characterized. The current study aimed to investigate the discriminative stimulus and locomotor effects of three putatively entactogenic compounds that have become increasingly prevalent on the drug market: 5-(2-aminopropyl)-benzofuran (5-APB), 6-(2-aminopropryl)-2,3-dihydrobenzofuran (6-APDB), and 4-fluoroamphetamine (4-FA). Locomotor stimulant effects were assessed in an open-field assay for locomotor activity using Swiss-Webster mice. Discriminative stimulus effects were assessed in Sprague-Dawley rats trained to discriminate either cocaine, methamphetamine, DOM, or MDMA from vehicle. The benzofuran compounds produced locomotor stimulation whereas 4-FA depressed locomotor activity. The benzofurans substituted for the discriminative stimulus effects of MDMA, but only partially or not at all for methamphetamine, cocaine, and DOM, whereas 4-FA fully substituted for MDMA, methamphetamine and cocaine, but not DOM. These results indicate an MDMA-like pattern of abuse might be expected for the benzofurans, whereas 4-FA may be substituted for psychostimulants and MDMA.

PMID: 28865391 [PubMed - indexed for MEDLINE]

Mechanistic studies of DepR in regulating FK228 biosynthesis in Chromobacterium violaceum no. 968.

Fri, 04/20/2018 - 13:54
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Mechanistic studies of DepR in regulating FK228 biosynthesis in Chromobacterium violaceum no. 968.

PLoS One. 2018;13(4):e0196173

Authors: Qiao Y, Tong T, Xue J, Lin W, Deng Z, Cheng YQ, Zhu D

Abstract
DepR, a LysR-type transcriptional regulator encoded by the last gene of the putative min operon (orf21-20-19-depR) located at the downstream region of the anticancer agent FK228 biosynthetic gene cluster in Chromobacterium violaceum No. 968, positively regulates the biosynthesis of FK228. In this work, the mechanism underlining this positive regulation was probed by multiple approaches. Electrophoretic mobility shift assay (EMSA) and DNase I footprinting assay (DIFA) identified a conserved 35-nt DNA segment in the orf21-orf22 intergenic region where the purified recombinant DepR binds to. Quantitative reverse transcription PCR (RT-qPCR) and green fluorescent protein (GFP) promoter probe assays established that transcription of phasin gene orf22 increases in the depR deletion mutant of C. violaceum (CvΔdepR) compared to the wild-type strain. FK228 production in the orf22-overexpressed strain C. violaceum was reduced compared with the wild-type strain. DepR has two conserved cysteine residues C199 and C208 presumed to form a disulfide bridge upon sensing oxidative stress. C199X point mutations that locked DepR in a reduced conformation decreased the DNA-binding affinity of DepR; T232A or R278A mutation also had a negative impact on DNA binding of DepR. Complementation of CvΔdepR with any of those versions of depR carrying a single codon mutation was not able to restore FK228 production to the level of wild-type strain. All evidences collectively suggested that DepR positively regulates the biosynthesis of FK228 through indirect metabolic networking.

PMID: 29672625 [PubMed - in process]

High-alcohol-content flavored alcoholic beverages (supersized alcopops) should be reclassified to reduce public health hazard.

Fri, 04/20/2018 - 13:54
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High-alcohol-content flavored alcoholic beverages (supersized alcopops) should be reclassified to reduce public health hazard.

Am J Drug Alcohol Abuse. 2018 Apr 19;:1-5

Authors: Rossheim ME, Thombs DL, Treffers RD

Abstract
In the US, underage drinkers often consume supersized alcopop - a high-alcohol-content, ready-to-drink flavored alcoholic beverage that is currently regulated as beer. However, calculations in this paper illustrate how the high alcohol by volume and low price of supersized alcopops suggest that they rely on a larger proportion of additives for their alcohol content than permitted to meet the legal definition for beer. From a public safety perspective, it is urgently important that the Alcohol and Tobacco Tax and Trade Bureau assess the formulation of supersized alcopops - specifically, the percent of alcohol in the finished product that is derived from additives. Appropriate reclassification of supersized alcopops as distilled spirits would reduce youth access by resulting in increased price and reduced availability at the retail locations where youth most often obtain alcohol.

PMID: 29672179 [PubMed - as supplied by publisher]

Chromobacterium spp. mediate their anti-Plasmodium activity through secretion of the histone deacetylase inhibitor romidepsin.

Fri, 04/20/2018 - 13:54
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Chromobacterium spp. mediate their anti-Plasmodium activity through secretion of the histone deacetylase inhibitor romidepsin.

Sci Rep. 2018 Apr 18;8(1):6176

Authors: Saraiva RG, Huitt-Roehl CR, Tripathi A, Cheng YQ, Bosch J, Townsend CA, Dimopoulos G

Abstract
The Chromobacterium sp. Panama bacterium has in vivo and in vitro anti-Plasmodium properties. To assess the nature of the Chromobacterium-produced anti-Plasmodium factors, chemical partition was conducted by bioassay-guided fractionation where different fractions were assayed for activity against asexual stages of P. falciparum. The isolated compounds were further partitioned by reversed-phase FPLC followed by size-exclusion chromatography; high resolution UPLC and ESI/MS data were then collected and revealed that the most active fraction contained a cyclic depsipeptide, which was identified as romidepsin. A pure sample of this FDA-approved HDAC inhibitor allowed us to independently verify this finding, and establish that romidepsin also has potent effect against mosquito stages of the parasite's life cycle. Genomic comparisons between C. sp. Panama and multiple species within the Chromobacterium genus further demonstrated a correlation between presence of the gene cluster responsible for romidepsin production and effective antiplasmodial activity. A romidepsin-null Chromobacterium spp. mutant loses its anti-Plasmodium properties by losing the ability to inhibit P. falciparum HDAC activity, and romidepsin is active against resistant parasites to commonly deployed antimalarials. This independent mode of action substantiates exploring a chromobacteria-based approach for malaria transmission-blocking.

PMID: 29670144 [PubMed - in process]

Time Course of Compensatory Physiological Responses to Central Hypovolemia in High and Low Tolerant Human Subjects.

Thu, 04/19/2018 - 07:37
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Time Course of Compensatory Physiological Responses to Central Hypovolemia in High and Low Tolerant Human Subjects.

Am J Physiol Regul Integr Comp Physiol. 2018 Apr 18;:

Authors: Xiang L, Hinojosa-Laborde C, Ryan KL, Rickards CA, Convertino VA

Abstract
Lower body negative pressure (LBNP) simulates hemorrhage in humans. Most subjects (67%) exhibited high tolerance (HT) to hypovolemia, while the remainder (33%) has low tolerance (LT). To investigate the mechanisms for decompensation to hypovolemia in HT and LT subjects, we characterized the time course of total peripheral resistance (TPR), heart rate (HR) and muscle sympathetic nerve activity (MSNA) during LBNP to tolerance determined by the onset of decompensation (presyncope, PS). We hypothesized that 1) maximum (max) TPR, HR, and MSNA would coincide, and 2) PS results from simultaneous decreases in TPR, HR and MSNA in LT and HT, but occur earlier in LT versus HT subjects. Max TPR was lower and occurred earlier in LT (n=59) than HT (n=113) subjects (LT: 24{plus minus}1 mmHg*min/L at 756{plus minus}31s; HT: 28{plus minus}1 mmHg*min/L at 1265{plus minus}37s, p<0.01). Max TPR occurred several minutes before PS. During subsequent decrease in TPR, HR and MSNA continued to increase. Max HR (LT: 111{plus minus}2 bpm at 923{plus minus}27s; HT: 130{plus minus}2 bpm at 1489{plus minus}23s, p<0.01) occurred several seconds before PS. Higher MSNA (p<0.01) was attained in HT (n= 10; 51{plus minus}5 b/min at max TPR; 54{plus minus}5 b/min at max HR) than LT subjects (n= 4; 41{plus minus}8 b/min at max TPR; 39{plus minus}8 b/min at max HR). Onset of cardiovascular decompensation is a biphasic process in which vasodilation occurs prior to bradycardia and sympathetic withdrawal. This pattern was similar in LT and HT, but occurred earlier in LT subjects. We conclude that sudden bradycardia plays a critical role in the determination of tolerance to central hypovolemia.

PMID: 29668322 [PubMed - as supplied by publisher]

Contraceptive Use Effectiveness and Pregnancy Prevention Information Preferences Among Heterosexual and Sexual Minority College Women.

Thu, 04/19/2018 - 07:37
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Contraceptive Use Effectiveness and Pregnancy Prevention Information Preferences Among Heterosexual and Sexual Minority College Women.

Womens Health Issues. 2018 Apr 14;:

Authors: Blunt-Vinti HD, Thompson EL, Griner SB

Abstract
BACKGROUND: Previous research shows that sexual minority women have higher rates of unintended pregnancy than heterosexual women, but has not considered the wide range of contraceptive method effectiveness when exploring this disparity. We examine contraceptive use effectiveness and desire for pregnancy prevention information among college women across sexual orientation identity as a risk factor for unintended pregnancy.
METHODS: Using the National College Health Assessment Fall-2015 dataset, restricted to women who reported engaging in vaginal sex and not wanting to be pregnant (N = 6,486), logistic regression models estimated the odds of contraceptive method effectiveness and desire for pregnancy prevention information by sexual orientation.
RESULTS: Most women (57%) reported using a moderately effective contraceptive method (e.g., pill, patch, ring, shot) at last vaginal sex. Compared with heterosexual women, bisexual (adjusted odds ratio [aOR], 0.48; 95% confidence interval [CI], 0.37-0.62), lesbian (aOR, 0.03; 95% CI, 0.02-0.06), pansexual/queer (aOR, 0.38; 95% CI, 0.25-.56) and other (aOR, 0.50; 95% CI, 0.30-0.81) women were significantly less likely to have used a moderately effective method compared with no method. Only 9% of the sample used a highly effective method; asexual (aOR, 0.58; 95% CI, 0.37-0.92) and lesbian (aOR, 0.07; 95% CI, 0.03-0.20) women were significantly less likely than heterosexual women to have used these methods. Pansexual/queer and bisexual women were more likely than heterosexual women to desire pregnancy prevention information.
CONCLUSIONS: Several groups of sexual minority women were less likely than heterosexual women to use highly or moderately effective contraceptive methods, putting them at increased risk for unintended pregnancy, but desired pregnancy prevention information. These findings bring attention to the importance of patient-centered sexual and reproductive care to reduce unintended pregnancy.

PMID: 29666034 [PubMed - as supplied by publisher]

Probabilistic Modeling Approach to Reducing Healthcare Costs With Reflex Testing.

Thu, 04/19/2018 - 07:37
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Probabilistic Modeling Approach to Reducing Healthcare Costs With Reflex Testing.

Lab Med. 2017 Nov 08;48(4):384-387

Authors: Prakash S, Hamby T, Leung-Pineda V, Wilson DP

Abstract
Objective: Statistical methods can be utilized to optimize the order for reflex diagnostic testing to attenuate patient and hospital costs without affecting quality of care. Our objective is to demonstrate the method of developing an order for testing and to apply this method to an illustrative example.
Methods: An algorithm was developed for minimizing costs for any given number of diagnostic tests, and it was retrospectively applied to a sample.
Results: The actual scenario of using both tests on all patients was compared to 2 other hypothetical reflex testing approaches: all patients are given 1 test, and those patients who tested negative were then given the second test. The 2 scenarios would have saved 37.1% and 17.4% in testing costs, respectively.
Conclusion: These calculations could be applied to numerous situations to reduce costs for patients and hospitals. We propose that this methodology would be best used in conjunction with any existing quality improvement initiatives.

PMID: 29036315 [PubMed - indexed for MEDLINE]

The Impact of Race and Neighborhood Racial Composition on Preventable Readmissions for Diabetic Medicare Home Health Beneficiaries.

Thu, 04/19/2018 - 07:37
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The Impact of Race and Neighborhood Racial Composition on Preventable Readmissions for Diabetic Medicare Home Health Beneficiaries.

J Racial Ethn Health Disparities. 2017 Aug;4(4):648-658

Authors: Chen HF, Homan S, Carlson E, Popoola T, Radhakrishnan K

Abstract
BACKGROUND: The recommended home health financial penalty program for preventable readmission does not factor race/ethnicity and neighborhood racial compositions into the determination of preventable readmission rates. Home health agencies may avoid beneficiaries from certain racial/ethnic groups and neighborhoods if these two factors have an effect on preventable readmissions. We examined the association between preventable readmissions with race/ethnicity and neighborhood racial composition.
METHODS: Several 2009 national data were used, such as the Master Beneficiary Summary File, Medicare Provider Analysis and Review File, and Outcome Assessment Information Set. Our sample consisted of diabetic Medicare home health beneficiaries (African-Americans and Whites only). We analyzed predictors of time-to-first 30-day preventable readmission, including short/long-term diabetic complications, chronic obstructive pulmonary disease/asthma, bacterial pneumonia, dehydration, urinary tract infection, hypertension, heart failure, angina without procedure, uncontrolled diabetes, and lower-extremity amputation.
RESULTS: There were 86,567, 17,262, and 11,392 observations in neighborhoods with low (6 % African-Americans), moderate (35 % African-Americans), and high (76 % African-Americans) density of African-Americans, respectively. Using Cox regression models, we found that in neighborhoods with moderate and high density of African-Americans, African-Americans had 21 % (hazard ratio (HR) 1.21; 95 % confidence interval (CI) 1.04-1.39) and 24 % (HR 1.24; 95 % CI 1.01-1.52) significantly higher hazards of 30-day preventable readmissions than Whites, respectively.
CONCLUSION: Race and neighborhood racial compositions are beyond home health providers' control. These two factors should be considered as covariates for the preventable readmissions in the recommended home health financial penalty program.

PMID: 27514389 [PubMed - indexed for MEDLINE]

Factors Associated with Self-Estimated Breath Alcohol Concentration Among Bar Patrons.

Wed, 04/18/2018 - 07:39
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Factors Associated with Self-Estimated Breath Alcohol Concentration Among Bar Patrons.

Alcohol Clin Exp Res. 2017 Aug;41(8):1492-1501

Authors: Rossheim ME, Barry AE, Thombs DL, Weiler RM, Krall JR, Stephenson CJ, Walters ST, Reed MB, Clapp JD, Suzuki S, Barnett TE, Cannell MB

Abstract
BACKGROUND: Few studies have examined the context in which drinkers underestimate their breath alcohol concentration (BrAC) in natural drinking environments. This study examined factors associated with bar patrons' self-estimated BrAC in high-risk college town settings.
METHODS: Guided interview and BrAC data were collected from 510 participants recruited as they exited bars located close to large universities: 1 in Florida and 1 in Texas.
RESULTS: Participants with the highest measured BrACs underestimated their BrAC levels the most. Findings from multivariable linear regression analysis indicated that BrAC (std β = 0.014, p < 0.001), number of alcoholic drinks consumed (std β = 0.006, p < 0.01), and perceived drunkenness (std β = 0.024, p < 0.001) had significant positive associations with BrAC self-estimates, where the regression coefficients were scaled by values approximately equal to each variable's interquartile range. Among the 321 participants with BrAC levels ≥ 0.08 g/dl, 21.2% believed their BrAC was below the legal per se driving limit of 0.08 g/dl. Results from a logistic regression analysis indicated that higher levels of perceived drunkenness were associated with better self-recognition that one's BrAC level exceeded the legal driving threshold (OR = 3.312, p < 0.001). Further, participants under 26 years of age had reduced odds of recognizing that their BrAC was greater than 0.079 g/dl (OR = 0.245, p < 0.05).
CONCLUSIONS: These findings highlight the inaccuracy of self-estimated BrAC when drinking, particularly among younger drinkers. Adjusting for BrAC, situational factors were strongly associated with self-estimated BrAC. Future research is needed to better understand how altering drinking environments may improve accuracy of BrAC self-estimates and deter driving after drinking.

PMID: 28683518 [PubMed - indexed for MEDLINE]

Cardioprotection by Intermittent Hypoxia Conditioning: Evidence, Mechanisms and Therapeutic Potential.

Sat, 04/14/2018 - 07:34
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Cardioprotection by Intermittent Hypoxia Conditioning: Evidence, Mechanisms and Therapeutic Potential.

Am J Physiol Heart Circ Physiol. 2018 Apr 13;:

Authors: Mallet RT, Manukhina EB, Ruelas SS, Caffrey JL, Downey HF

Abstract
The calibrated application of limited duration, cyclic, moderately intense hypoxia-reoxygenation increases cardiac resistance to ischemia-reperfusion stress. These intermittent hypoxic conditioning (IHC) programs consistently produce striking reductions in myocardial infarction and ventricular tachyarrhythmias following coronary artery occlusion and reperfusion, and in many cases, improved contractile function and coronary blood flow. These IHC protocols are fundamentally different from those used to simulate sleep apnea, a recognized cardiovascular risk factor. In clinical studies, IHC improved exercise capacity and decreased arrhythmias in patients with coronary artery or pulmonary disease, and produced robust, persistent anti-hypertensive effects in patients with essential hypertension. The protection afforded by IHC develops gradually and depends on β-adrenergic, δ-opioidergic, and reactive oxygen-nitrogen signaling pathways that employ protein kinases and adaptive transcription factors. In summary, adaptation to intermittent hypoxia offers a practical, largely unrecognized means of protecting myocardium from impending ischemia. The myocardial and perhaps broader systemic protection provided by IHC, clearly merits further clinical evaluation as a discrete intervention and as a potential complement to conventional pharmaceutical and surgical interventions.

PMID: 29652543 [PubMed - as supplied by publisher]

Role and Possible Mechanisms of Sirt1 in Depression.

Fri, 04/13/2018 - 07:34

Role and Possible Mechanisms of Sirt1 in Depression.

Oxid Med Cell Longev. 2018;2018:8596903

Authors: Lu G, Li J, Zhang H, Zhao X, Yan LJ, Yang X

Abstract
Depression is a common, devastating illness. Due to complicated causes and limited treatments, depression is still a major problem that plagues the world. Silent information regulator 1 (Sirt1) is a deacetylase at the consumption of NAD+ and is involved in gene silencing, cell cycle, fat and glucose metabolism, cellular oxidative stress, and senescence. Sirt1 has now become a critical therapeutic target for a number of diseases. Recently, a genetic study has received considerable attention for depression and found that Sirt1 is a potential gene target. In this short review article, we attempt to present an up-to-date knowledge of depression and Sirt1 of the sirtuin family, describe the different effects of Sirt1 on depression, and further discuss possible mechanisms of Sirt1 including glial activation, neurogenesis, circadian control, and potential signaling molecules. Thus, it will open a new avenue for clinical treatment of depression.

PMID: 29643977 [PubMed - in process]

Evidence-based approaches to reduce cancer health disparities: Discover, develop, deliver, and disseminate.

Fri, 04/13/2018 - 07:34

Evidence-based approaches to reduce cancer health disparities: Discover, develop, deliver, and disseminate.

J Carcinog. 2018;17:1

Authors: Desai PP, Lampe JB, Bakre SA, Basha RM, Jones HP, Vishwanatha JK

Abstract
The Texas Center for Health Disparities (TCHD) at the University of North Texas Health Science Center is a National Institute on Minority Health and Health Disparities-funded, specialized center of excellence for health disparities. TCHD organized its 12th annual conference focusing on "Evidence-Based Approaches to Reduce Cancer Health Disparities: Discover, Develop, Deliver, and Disseminate." At this conference, experts in health care, biomedical sciences, and public health gathered to discuss the current status and strategies for reducing cancer health disparities. The meeting was conducted in three sessions on breast cancer, prostate cancer, and colorectal cancer disparities, in addition to roundtable discussions and a poster session. Each session highlighted differences in the effects of cancer, based on factors such as race/ethnicity, gender, socioeconomic status, and geographical location. In each session, expert speakers presented their findings, and this was followed by a discussion panel made up of experts in that field and cancer survivors, who responded to questions from the audience. This article summarizes the approaches to fundamental, translational, clinical, and public health issues in cancer health disparities discussed at the conference.

PMID: 29643743 [PubMed]

Effect of centrally acting angiotensin converting enzyme inhibitor on the exercise-induced increases in muscle sympathetic nerve activity.

Wed, 04/11/2018 - 16:53
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Effect of centrally acting angiotensin converting enzyme inhibitor on the exercise-induced increases in muscle sympathetic nerve activity.

J Physiol. 2018 Apr 10;:

Authors: Moralez G, Jouett NP, Tian J, Zimmerman MC, Bhella P, Raven PB

Abstract
We tested the hypothesis that the signalling mechanisms associated with the dynamic exercise intensity related increases in muscle sympathetic nerve activity (MSNA) and arterial baroreflex resetting during exercise are located within the central nervous system. Participants performed three randomly ordered trials of 70° upright back-supported dynamic leg cycling after ingestion of placebo and two different lipid soluble angiotensin converting enzyme inhibitors (ACEi): Perindopril ((high-lipid soluble Captopril (low-lipid soluble), and/or placebo. Repeated measurements of whole venous blood (N = 8), MSNA (N = 7) and arterial blood pressures (N = 14) were obtained at rest and during an acute (SS1) and prolonged (SS2) bout of steady-state dynamic exercise. Arterial baroreflex (ABR) function curves were modelled at rest and during exercise. Peripheral venous superoxide concentrations measured by electron spin resonance (ESR) spectroscopy were elevated during exercise and were not altered by ACEi at rest (P ≥ 0.4) or during exercise (P ≥ 0.3). Baseline MSNA and mean arterial pressure (MAP) were unchanged at rest (P ≥ 0.1; P ≥ 0.8, respectively). However, during both SS1 and SS2, the centrally acting ACEi perindopril attenuated MSNA compared to captopril and the placebo (P < 0.05). Arterial pressures at the operating point and threshold pressures were decreased with perindopril from baseline to SS1 with no further changes in the operating point pressure during SS2 under all three conditions. These data suggest that centrally acting ACEi is significantly more effective at attenuating the increase in the acute and prolonged exercise induced increases in MSNA. This article is protected by copyright. All rights reserved.

PMID: 29635787 [PubMed - as supplied by publisher]

Beyond Body Mass Index: Are Weight-loss Programs the Best Way to Improve the Health of African American Women?

Tue, 04/10/2018 - 07:36
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Beyond Body Mass Index: Are Weight-loss Programs the Best Way to Improve the Health of African American Women?

Prev Chronic Dis. 2017 Jun 15;14:E48

Authors: Dodgen L, Spence-Almaguer E

Abstract
African American women have higher prevalence (82%) of overweight (body mass index [BMI] 25-29) and obesity (BMI ≥30) than white women (63.2%) or Hispanic women (77.2%), and weight-loss programs yield minimal results in this population. We examine the concept of BMI as a measure of health for African American women and suggests a more holistic, multifaceted approach to preventing chronic disease.

PMID: 28617664 [PubMed - indexed for MEDLINE]

The Role of Wnt/β-Catenin Signaling and K-Cadherin in the Regulation of Intraocular Pressure.

Sat, 04/07/2018 - 07:34

The Role of Wnt/β-Catenin Signaling and K-Cadherin in the Regulation of Intraocular Pressure.

Invest Ophthalmol Vis Sci. 2018 Mar 01;59(3):1454-1466

Authors: Webber HC, Bermudez JY, Millar JC, Mao W, Clark AF

Abstract
Purpose: Wnt/β-catenin signaling in the trabecular meshwork (TM) is required for maintaining normal intraocular pressure (IOP), although the mechanism(s) behind this are unknown. We hypothesize that Wnt/β-catenin signaling regulates IOP via β-catenin's effects on cadherin junctions.
Methods: Nonglaucomatous primary human TM (NTM) cells were treated with or without 100 ng/ml Wnt3a, 1 μg/ml sFRP1, or both for 4 to 48 hours. Cells were immunostained for β-catenin, total cadherins, or cadherin isoforms. Membrane proteins or whole-cell lysates were isolated for Western immunoblotting and probed for cadherin isoforms. RNA was extracted for cDNA synthesis and qPCR analysis of cadherin expression. Some NTM cells were cultured on electric plates for cell impedance assays. Ad5.CMV recombinant adenoviruses encoding K-cadherin, and/or sFRP1 were injected into eyes of 4- to 6-month-old female BALB/cJ mice (n = 8-10). Conscious IOPs were assessed for 35 days.
Results: Upon Wnt3a treatment, total cadherin expression increased and β-catenin accumulated at the TM cell membrane and on processes formed between TM cells. qPCR showed that Wnt3a significantly increased K-cadherin expression in NTM cells (P < 0.01, n = 3), and Western immunoblotting showed that Wnt3a increased K-cadherin in NTM cells, which was inhibited by the addition of sFRP1. Cell impedance assays showed that Wnt3a treatment increased transcellular resistance and anti-K-cadherin siRNA decreased transcellular resistance (P < 0.001, n = 4-6). Our in vivo study showed that K-cadherin significantly decreased sFRP1-induced ocular hypertension (P < 0.05, n = 6). Western immunoblotting also showed that K-cadherin alleviated sFRP1-induced β-catenin decrease in mouse anterior segments.
Conclusions: Our results suggest that cadherins play important roles in the regulation of TM homeostasis and IOP via the Wnt/β-catenin pathway.

PMID: 29625468 [PubMed - in process]

Mass spectrometric analysis of carisoprodol and meprobamate in rat brain microdialysates.

Fri, 04/06/2018 - 11:12
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Mass spectrometric analysis of carisoprodol and meprobamate in rat brain microdialysates.

J Mass Spectrom. 2016 Oct;51(10):900-907

Authors: Prokai L, Fryčák P, Nguyen V, Forster MJ

Abstract
We report the evaluation of several mass spectrometry-based methods for the determination of carisoprodol and meprobamate in samples obtained from the rat brain by in vivo intracranial microdialyis. Among the techniques that aspire to perform analyses without chromatographic separation and thereby increase throughput, chip-based nanoelectrospray ionization and the use of an atmospheric pressure solids analysis probe fell short of requirements because of insufficient detection sensitivity and hard ionization, respectively. Although direct analysis in real time provided the required soft ionization, shortcomings of a tandem mass spectrometry-based assay also included inadequate detection sensitivity and, in addition, poor quantitative reproducibility. Therefore, liquid chromatography coupled with atmospheric pressure chemical ionization tandem mass spectrometry was developed to determine carisoprodol and meprobamate from artificial cerebrospinal fluid as the medium. No desalting and/or extraction of the samples was necessary. The assay, combined with in vivo sampling via intracranial microdialyis, afforded time-resolved concentration profiles for the drug and its major metabolite from the nucleus accumbens region of the brain in rats after systemic administration of carisoprodol. Copyright © 2016 John Wiley & Sons, Ltd.

PMID: 27747995 [PubMed - indexed for MEDLINE]

Oral bisphosphonate use and lung cancer incidence among postmenopausal women.

Thu, 04/05/2018 - 07:36
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Oral bisphosphonate use and lung cancer incidence among postmenopausal women.

Ann Oncol. 2018 Mar 29;:

Authors: Tao MH, Chen S, Freudenheim JL, Cauley JA, Johnson KC, Mai X, Sarto GE, Wakelee H, Boffetta P, Wactawski-Wende J

Abstract
Background: Bisphosphonates are common medications for the treatment of osteoporosis in older populations. Several studies, including the Women's Health Initiative (WHI), have found inverse associations of bisphosphonate use with risk of breast and endometrial cancer, but little is known about its association with other common malignancies. The objective of this study was to evaluate the association of bisphosphonate use on the incidence of lung cancer in the WHI.
Patients and methods: The association between oral bisphosphonate use and lung cancer risk was examined in 151,432 postmenopausal women enrolled into the WHI in 1993-1998. At baseline and during follow-up, participants completed an inventory of regularly used medications including bisphosphonates.
Results: After a mean follow-up of 13.3 years, 2,511 women were diagnosed with incident lung cancer. There was no evidence of a difference in lung cancer incidence between oral bisphosphonate users and never users (adjusted hazard ratio (HR), 0.91; 95% confidence intervals (CI), 0.80-1.04; P = 0.16). However, an inverse association was observed among those who were never smokers (HR = 0.57, 95% CI, 0.39-0.84; P < 0.01).
Conclusion: In this large prospective cohort of postmenopausal women, oral bisphosphonate use was associated with significantly lower lung cancer risk among never smokers, suggesting bisphosphonates may have a protective effect against lung cancer. Additional studies are needed to confirm our findings.

PMID: 29617712 [PubMed - as supplied by publisher]

Mutacin 1140 Lantibiotic Variants Are Efficacious Against Clostridium difficile Infection.

Thu, 04/05/2018 - 07:36
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Mutacin 1140 Lantibiotic Variants Are Efficacious Against Clostridium difficile Infection.

Front Microbiol. 2018;9:415

Authors: Kers JA, Sharp RE, Defusco AW, Park JH, Xu J, Pulse ME, Weiss WJ, Handfield M

Abstract
Lantibiotics offer an untapped pipeline for the development of novel antibiotics to treat serious Gram-positive (+) infections including Clostridium difficile. Mutacin 1140 (MU1140) is a lantibiotic produced by Streptococcus mutans and acts via a novel mechanism of action, which may limit the development of resistance. This study sought to identify a lead compound for the treatment of C. difficile associated diarrhea (CDAD). Compounds were selected from a saturation mutagenesis library of 418 single amino acid variants of MU1140. Compounds were produced by small scale fermentation, purified, characterized and then subjected to a panel of assays aimed at identifying the best performers. The screening assays included: in vitro susceptibility testing [MIC against Micrococcus luteus, Clostridium difficile, vancomycin-resistant enterococci (VRE), Staphylococcus aureus, Streptococcus pneumonia, Mycobacterium phlei, and Pseudomonas aeruginosa; cytotoxicity screening on HepG2 hepatocytes; in vitro pharmacological profiling with the Safety Screen 44TM, metabolic and chemical stability in biologically relevant fluids (FaSSGF, FaSSIF and serum); and efficacy in vivo]. Several lantibiotic compounds had better MIC against C. difficile, compared to vancomycin, but not against other bacterial species tested. The Safety Screen 44TMin vitro pharmacological profiling assay suggested that this class of compounds has relatively low overall toxicity and that compound OG253 (MU1140, Phe1Ile) is not likely to present inadvertent off-target effects, as evidenced by a low promiscuity score. The in vitro cytotoxicity assay also indicated that this class of compounds was characterized by low toxicity; the EC50 of OG253 was 636 mg/mL on HepG2 cells. The half-life in simulated gastric fluid was >240 min. for all compound tested. The stability in simulated intestinal fluid ranged between a half-life of 5 min to >240 min, and paralleled the half-life in serum. OG253 ultimately emerged as the lead compound based on superior in vivo efficacy along with an apparent lack of relapse in a hamster model of infection. The lessons learned from this report are applicable to therapeutic lanthipeptides in general and may assist in the design of novel molecules with improved pharmacological, therapeutic and physicochemical profiles. The data presented also support the continued clinical development of OG253 as a novel antibiotic against CDAD that could prevent recurrence of the infection.

PMID: 29615987 [PubMed]

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