Recent Research Articles from UNTHSC

Recent research articles indexed in PubMed from authors affiliated with the UNT Health Science Center.

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Do physical activity levels differ by number of children at home in women aged 25-44 in the general population?

Tue, 06/23/2020 - 07:03
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Do physical activity levels differ by number of children at home in women aged 25-44 in the general population?

Womens Health (Lond). 2019 Jan-Dec;15:1745506519871186

Authors: Abell LP, Tanase KA, Gilmore ML, Winnicki AE, Holmes VL, Hartos JL

Abstract
OBJECTIVES: While physical activity is important for health, many women do not meet recommended levels, particularly mothers. The purpose of this study was to assess whether physical activity levels differ by number of children at home in women aged 25-44 in the general US population.
METHODS: This cross-sectional analysis used 2017 Behavioral Risk Factor Surveillance System data for females aged 25-44 (N = 6266) from California, Colorado, New York, Texas, and Utah. Ordered logistic regression analysis assessed the relationship between physical activity levels and number of children at home while controlling for state and demographic, socioeconomic, and health-related factors.
RESULTS: About half of participants reported "inactive" or "insufficiently active" physical activity levels and about two-thirds reported having one or more children at home. The results of adjusted analysis indicated that physical activity level was significantly related to having one child (adjusted odds ratio = 0.75, 95% confidence interval = 0.63, 0.89), two children (adjusted odds ratio = 0.79; 95% confidence interval = 0.67, 0.93), and three or more children (adjusted odds ratio = 0.80, 95% confidence interval = 0.67, 0.94) at home.
CONCLUSION: Overall, physical activity levels were significantly related to presence of children at home for women aged 25-44, but increasing number of children at home did not impact effect size. For women aged 25-44 in a primary care setting, a moderate prevalence of inactive or insufficiently active physical activity may be expected. Providers should address physical activity with all patients in this target population during well-visits, but particularly for women with children at home; educate patients about the health benefits of regular physical activity; and provide resources that will help them integrate physical activity into their daily lifestyles.

PMID: 31495288 [PubMed - indexed for MEDLINE]

Examining the association between prescription opioid misuse and suicidal behaviors among adolescent high school students in the United States.

Tue, 06/23/2020 - 07:03
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Examining the association between prescription opioid misuse and suicidal behaviors among adolescent high school students in the United States.

J Psychiatr Res. 2019 05;112:44-51

Authors: Baiden P, Graaf G, Zaami M, Acolatse CK, Adeku Y

Abstract
Although some studies have examined the association between prescription opioid misuse and mental health outcomes, few studies have examined the effects of prescription opioid misuse on suicidal behaviors among adolescents. The objective of this study was to examine the association between prescription opioid misuse and suicidal ideation, suicide plan, and suicide attempt among adolescents. Data for this study came from the 2017 Youth Risk Behavior Surveillance System. A sample of 8830 adolescents aged 14-18 years (50.9% female) were analyzed using logistic regression with suicidal ideation, suicide plan, and suicide attempt as outcome variables and prescription opioid misuse as the main explanatory variable. Of the 8830 adolescents, 13.3% ever misused prescription opioids; 17.7% experienced suicidal ideation, 13.3% made a suicide plan, and 6.5% attempted suicide during the past 12 months. In the multivariate logistic regression models, adolescent students who misused prescription opioids were 1.50 times more likely to have experienced suicidal ideation, 1.44 times more likely to have made a suicide plan, and 1.58 times more likely to have attempted suicide during the past 12 months when compared to their counterparts who did not misuse prescription opioids. Other significant predictors of suicidal behaviors include sexual minority, history of sexual assault, traditional bullying and cyberbullying victimization, feeling sad or hopeless, cigarette smoking, and illicit drug use. The findings of the present study demonstrate the harmful effects of prescription opioid misuse and its association with suicidal behaviors among adolescents.

PMID: 30852426 [PubMed - indexed for MEDLINE]

The Connection Between Social Determinants of Health and Human Papillomavirus Testing Knowledge Among Women in the USA.

Mon, 06/22/2020 - 06:49
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The Connection Between Social Determinants of Health and Human Papillomavirus Testing Knowledge Among Women in the USA.

J Cancer Educ. 2020 Jun 20;:

Authors: Garg A, Galvin AM, Matthes S, Maness SB, Thompson EL

Abstract
Human papillomavirus (HPV) causes 99% of cervical cancers. In the USA, HPV testing has recently been recommended as a stand-alone option for cervical cancer screening in women over 30 years of age. Yet, studies have shown low awareness of HPV testing. This study examines awareness and knowledge that US women possess regarding HPV testing using the social determinants of health (SDOH) framework. Women aged 30 to 65 years, without hysterectomy, completed an online survey (N = 812). The outcome variables included HPV testing awareness and HPV testing knowledge, a six-item validated scale. Predictor variables included three domains of the Healthy People 2020 SDOH framework: economic stability, education, and health and healthcare. Other important sociodemographic predictors were also included. Multiple logistic and linear regression identified variables associated with HPV testing awareness and knowledge, respectively. 62.4% of the women were aware of HPV testing, and the mean knowledge score was 2.8 (out of 6). Lower awareness and knowledge were observed in older women compared with younger women and among women who had either not received HPV vaccination or were unsure of their vaccination status. Higher education attainment was associated with greater awareness and knowledge. Also, women who had a well-woman visit in the last year had better knowledge. Findings from the study can be used to develop targeted prevention strategies and initiatives to improve HPV testing awareness and knowledge to help women make more informed health decisions and promote uptake of this screening tool.

PMID: 32564250 [PubMed - as supplied by publisher]

Patient genetics is linked to chronic wound microbiome composition and healing.

Sat, 06/20/2020 - 06:08

Patient genetics is linked to chronic wound microbiome composition and healing.

PLoS Pathog. 2020 Jun;16(6):e1008511

Authors: Tipton CD, Wolcott RD, Sanford NE, Miller C, Pathak G, Silzer TK, Sun J, Fleming D, Rumbaugh KP, Little TD, Phillips N, Phillips CD

Abstract
The clinical importance of microbiomes to the chronicity of wounds is widely appreciated, yet little is understood about patient-specific processes shaping wound microbiome composition. Here, a two-cohort microbiome-genome wide association study is presented through which patient genomic loci associated with chronic wound microbiome diversity were identified. Further investigation revealed that alternative TLN2 and ZNF521 genotypes explained significant inter-patient variation in relative abundance of two key pathogens, Pseudomonas aeruginosa and Staphylococcus epidermidis. Wound diversity was lowest in Pseudomonas aeruginosa infected wounds, and decreasing wound diversity had a significant negative linear relationship with healing rate. In addition to microbiome characteristics, age, diabetic status, and genetic ancestry all significantly influenced healing. Using structural equation modeling to identify common variance among SNPs, six loci were sufficient to explain 53% of variation in wound microbiome diversity, which was a 10% increase over traditional multiple regression. Focusing on TLN2, genotype at rs8031916 explained expression differences of alternative transcripts that differ in inclusion of important focal adhesion binding domains. Such differences are hypothesized to relate to wound microbiomes and healing through effects on bacterial exploitation of focal adhesions and/or cellular migration. Related, other associated loci were functionally enriched, often with roles in cytoskeletal dynamics. This study, being the first to identify patient genetic determinants for wound microbiomes and healing, implicates genetic variation determining cellular adhesion phenotypes as important drivers of infection type. The identification of predictive biomarkers for chronic wound microbiomes may serve as risk factors and guide treatment by informing patient-specific tendencies of infection.

PMID: 32555671 [PubMed - in process]

Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through Toll-like receptor 4 signaling.

Sat, 06/20/2020 - 06:08

Fibronectin extra domain A (FN-EDA) elevates intraocular pressure through Toll-like receptor 4 signaling.

Sci Rep. 2020 Jun 17;10(1):9815

Authors: Roberts AL, Mavlyutov TA, Perlmutter TE, Curry SM, Harris SL, Chauhan AK, McDowell CM

Abstract
Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of primary open angle glaucoma and is due to trabecular meshwork (TM) damage, which leads to impaired aqueous humor outflow. Here, we explore a novel molecular mechanism involved in glaucomatous TM damage. We investigated the role of an endogenous Toll-like receptor 4 (TLR4) ligand, fibronectin-EDA (FN-EDA), in TGFβ2-induced ocular hypertension in mice. We utilized transgenic mouse strains that either constitutively express only FN containing the EDA isoform or contain an EDA-null allele and express only FN lacking EDA, with or without a mutation in Tlr4, in our inducible mouse model of ocular hypertension by injection of Ad5.TGFβ2. IOP was measured over time and eyes accessed by immunohistochemistry for total FN and FN-EDA expression. Constitutively active EDA caused elevated IOP starting at 14 weeks of age. Ad5.TGFβ2 induced ocular hypertension in wildtype C57BL/6J mice and further amplified the IOP in constitutively active EDA mice. TLR4 null and EDA null mice blocked Ad5.TGFβ-induced ocular hypertension. Total FN and FN-EDA isoform expression increased in response to Ad5.TGFβ2. These data suggest that both TLR4 and FN-EDA contribute to TGFβ2 induced ocular hypertension.

PMID: 32555351 [PubMed - in process]

5-Methoxyindole-2-Carboylic Acid (MICA) Fails to Retard Development and Progression of Type II Diabetes in ZSF1 Diabetic Rats.

Sat, 06/20/2020 - 06:08
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5-Methoxyindole-2-Carboylic Acid (MICA) Fails to Retard Development and Progression of Type II Diabetes in ZSF1 Diabetic Rats.

React Oxyg Species (Apex). 2020 May 01;9(27):144-147

Authors: Li CY, Ma WX, Yan LJ

Abstract
5-Methoxyindole-2-carboxylic acid (MICA) is a well-established reversible inhibitor of mitochondrial dihydrolipoamide dehydrogenase (DLDH). This chemical, as an indole derivative, has been shown to be neuroprotective against ischemic stroke injury when administered either before or after ischemic stroke in animal models. MICA has also been studied as a potential antidiabetic agent by numerous investigators, though the underlying mechanisms remain sketchy. To attempt to elucidate the mechanisms of its antidiabetic action, we tested the effect of MICA on ZSF1 rat, a widely used rodent model of type 2 diabetes. ZSF1 rats as well as its healthy controls were fed with control diet or MICA-containing diet (200 mg/kg/day) for 9 weeks. Unexpectedly, comparison of body weight changes and blood glucose levels at the end of the 9-week's feeding period indicated that MICA failed to show any anti-diabetic effect in the ZSF1 diabetic rats. The reasons for this failure were discussed.

PMID: 32551363 [PubMed]

Regulation of Autophagy by Protein Kinase C-ε in Breast Cancer Cells.

Fri, 06/19/2020 - 05:38
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Regulation of Autophagy by Protein Kinase C-ε in Breast Cancer Cells.

Int J Mol Sci. 2020 Jun 15;21(12):

Authors: Basu A

Abstract
Protein kinase C-ε (PKCε), an anti-apoptotic protein, plays critical roles in breast cancer development and progression. Although autophagy is an important survival mechanism, it is not known if PKCε regulates autophagy in breast cancer cells. We have shown that silencing of PKCε by siRNA inhibited basal and starvation-induced autophagy in T47D breast cancer cells as determined by the decrease in LC3-II, increase in p62, and decrease in autophagy puncta both in the presence and absence of bafilomycin A1. The mechanistic target of rapamycin (mTOR) associates with Raptor or Rictor to form complex-1 (mTORC1) or complex-2 (mTORC2), respectively. Knockdown of PKCε attenuated an increase in autophagy caused by the depletion of Raptor and Rictor. Overexpression of PKCε in MCF-7 cells caused activation of mTORC1 and an increase in LC3-I, LC3-II, and p62. The mTORC1 inhibitor rapamycin abolished the increase in LC3-I and p62. Knockdown of mTOR and Rictor or starvation enhanced autophagy in PKCε overexpressing cells. While overexpression of PKCε in MCF-7 cells inhibited apoptosis, it induced autophagy in response to tumor necrosis factor-α. However, inhibition of autophagy by Atg5 knockdown restored apoptosis in PKCε-overexpressing cells. Thus, PKCε promotes breast cancer cell survival not only by inhibiting apoptosis but also by inducing autophagy.

PMID: 32549199 [PubMed - in process]

Longitudinal Changes in Allostatic Load during a Randomized Church-based, Lifestyle Intervention in African American Women.

Fri, 06/19/2020 - 05:38
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Longitudinal Changes in Allostatic Load during a Randomized Church-based, Lifestyle Intervention in African American Women.

Ethn Dis. 2019;29(2):297-308

Authors: Tan M, Mamun A, Kitzman H, Dodgen L

Abstract
Introduction: African American (AA) women have disproportionately higher risk of cardiovascular disease than White women, which may be explained by the uniquely higher allostatic load (AL) found in AA women. No studies have tested the effect of lifestyle interventions on AL in AA women. Our objectives were to assess the change in allostatic load following a lifestyle intervention and explore the roles of lifestyle behaviors and socioeconomic factors on allostatic load change.
Methods: Participants were non-diabetic (mean age and SD: 48.8±11.2 y) AA women (n=221) enrolled in a church-based, cluster randomized trial testing a standard diabetes prevention program (DPP) and a faith-enhanced DPP with 4-months of follow-up. We assessed the relationships of changes in diet, physical activity, neighborhood disadvantage, individual socioeconomic factors, and other lifestyle variables to changes in AL at 4-months using a multilevel multinomial logistic regression model.
Results: Average AL decreased (-.13±.99, P=.02) from baseline to 4-months. After adjusting for other variables, a high school education or less (OR:.1, CI:.02-.49) and alcohol use (OR: .31, CI: .09-.99) contributed to increased AL. Living in a disadvantaged neighborhood was responsible for increased AL, though it was not statistically significant. There were no statistically significant associations between AL and other health behavior changes.
Conclusions: Lower education levels may dampen the benefits of lifestyle interventions in reducing AL. Although a significant reduction in AL was found after participation in a lifestyle intervention, more research is needed to determine how lifestyle behaviors and socioeconomic factors influence AL in AA women.

PMID: 31057315 [PubMed - indexed for MEDLINE]

Arginine-Modified Polymers Facilitate Poly (Lactide-Co-Glycolide)-Based Nanoparticle Gene Delivery to Primary Human Astrocytes.

Thu, 06/18/2020 - 05:21
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Arginine-Modified Polymers Facilitate Poly (Lactide-Co-Glycolide)-Based Nanoparticle Gene Delivery to Primary Human Astrocytes.

Int J Nanomedicine. 2020;15:3639-3647

Authors: Proulx J, Joshi C, Vijayaraghavalu S, Saraswathy M, Labhasetwar V, Ghorpade A, Borgmann K

Abstract
Purpose: Astrocyte dysfunction is a hallmark of central nervous system injury or infection. As a primary contributor to neurodegeneration, astrocytes are an ideal therapeutic target to combat neurodegenerative conditions. Gene therapy has arisen as an innovative technique that provides excellent prospect for disease intervention. Poly (lactide-co-glycolide) (PLGA) and polyethylenimine (PEI) are polymeric nanoparticles commonly used in gene delivery, each manifesting their own set of advantages and disadvantages. As a clinically approved polymer by the Federal Drug Administration, well characterized for its biodegradability and biocompatibility, PLGA-based nanoparticles (PLGA-NPs) are appealing for translational gene delivery systems. However, our investigations revealed PLGA-NPs were ineffective at facilitating exogenous gene expression in primary human astrocytes, despite their success in other cell lines. Furthermore, PEI polymers illustrate high delivery efficiency but induce cytotoxicity. The purpose of this study is to develop viable and biocompatible NPsystem for astrocyte-targeted gene therapy.
Materials and Methods: Successful gene expression by PLGA-NPs alone or in combination with arginine-modified PEI polymers (AnPn) was assessed by a luciferase reporter gene encapsulated in PLGA-NPs. Cytoplasmic release and nuclear localization of DNA were investigated using fluorescent confocal imaging with YOYO-labeled plasmid DNA (pDNA). NP-mediated cytotoxicity was assessed via lactate dehydrogenase in primary human astrocytes and neurons.
Results: Confocal imaging of YOYO-labeled pDNA confirmed PLGA-NPs delivered pDNA to the cytoplasm in a dose and time-dependent manner. However, co-staining revealed pDNA delivered by PLGA-NPs did not localize to the nucleus. The addition of AnPn significantly improved nuclear localization of pDNA and successfully achieved gene expression in primary human astrocytes. Moreover, these formulations were biocompatible with both astrocytes and neurons.
Conclusion: By co-transfecting two polymeric NPs, we developed an improved system for gene delivery and expression in primary human astrocytes. These findings provide a basis for a biocompatible and clinically translatable method to regulate astrocyte function during neurodegenerative diseases and disorders.

PMID: 32547019 [PubMed - in process]

Chronic unilateral cervical vagotomy reduces renal inflammation, blood pressure, and renal injury in a mouse model of lupus.

Wed, 06/17/2020 - 05:01
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Chronic unilateral cervical vagotomy reduces renal inflammation, blood pressure, and renal injury in a mouse model of lupus.

Am J Physiol Renal Physiol. 2020 Jun 15;:

Authors: Pham GS, Gusson Shimoura C, Chaudhari S, Kulp DV, Mathis KW

Abstract
BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by hypertension that results from chronic renal inflammation and dysautonomia in the form of dampened vagal tone. In health, the vagus nerve regulates inflammatory processes through mechanisms like the cholinergic anti-inflammatory pathway; so in the case of SLE, reduced efferent vagus nerve activity may indirectly affect renal inflammation, and therefore hypertension. In this study, we sought to investigate the impact of disrupting vagal neurotransmission on renal inflammation and hypertension in the setting of chronic inflammatory disease.
METHODS: Female SLE (NZBWF1) and control (NZW) mice were subjected to a right unilateral cervical vagotomy or sham surgery and 3 weeks later were implanted with indwelling catheters to measure blood pressure. Indices of splenic and renal inflammation, as well as renal injury, were assessed.
RESULTS: Unilateral vagotomy blunted SLE-induced increases in mean arterial pressure, albumin excretion rate, and glomerulosclerosis. This protection was associated with reduced splenic T cells and attenuated SLE-induced increases in renal pro-inflammatory mediators.
CONCLUSION: In summary, these data indicate that unilateral vagotomy reduces renal inflammation and reduces blood pressure in SLE mice. The vagus nerves have myriad functions and perhaps other neuroimmune interactions compensate for the ligation of one nerve.

PMID: 32538149 [PubMed - as supplied by publisher]

Human plasma biomarker responses to inhalational general anaesthesia without surgery.

Wed, 06/17/2020 - 05:01
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Human plasma biomarker responses to inhalational general anaesthesia without surgery.

Br J Anaesth. 2020 Jun 11;:

Authors: Deiner S, Baxter MG, Mincer JS, Sano M, Hall J, Mohammed I, O'Bryant S, Zetterberg H, Blennow K, Eckenhoff R

Abstract
BACKGROUND: Postoperative neurocognitive disorders may arise in part from adverse effects of general anaesthetics on the CNS, especially in older patients or individuals otherwise vulnerable to neurotoxicity because of systemic disease or the presence of pre-existing neuropathology. Previous studies have documented cytokine and injury biomarker responses to surgical procedures that included general anaesthesia, but it is not clear to what degree anaesthetics contribute to these responses.
METHODS: We performed a prospective cohort study of 59 healthy volunteers aged 40-80 yr who did not undergo surgery. Plasma markers of neurological injury and inflammation were measured immediately before and 5 h after induction of general anaesthesia with 1 minimum alveolar concentration of sevoflurane. Biomarkers included interleukin-6 (IL-6), tumour necrosis factor alpha (TNF-α), C-reactive protein (CRP), and neural injury (tau, neurofilament light [NF-L], and glial fibrillary acidic protein [GFAP]).
RESULTS: Baseline biomarkers were in the normal range, although NF-L and GFAP were elevated as a function of age. At 5 h after induction of anaesthesia, plasma tau, NF-L, and GFAP were significantly decreased relative to baseline. Plasma IL-6 was significantly increased after anaesthesia, but by a biologically insignificant degree (<1 pg ml-1); plasma TNF-α and CRP were unchanged.
CONCLUSIONS: Sevoflurane general anaesthesia without surgery, even in older adults, did not provoke an inflammatory state or neuronal injury at a concentration that is detectable by an acute elevation of measured plasma biomarkers in the early hours after exposure.
CLINICAL TRIAL REGISTRATION: NCT02275026.

PMID: 32536445 [PubMed - as supplied by publisher]

Methylenedioxymethamphetamine-like discriminative stimulus effects of pyrrolidinyl cathinones in rats.

Wed, 06/17/2020 - 05:01
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Methylenedioxymethamphetamine-like discriminative stimulus effects of pyrrolidinyl cathinones in rats.

J Psychopharmacol. 2020 Jun 13;:269881120914213

Authors: Gatch MB, Forster MJ

Abstract
BACKGROUND: Synthetic cathinone derivatives are used as alternatives both for stimulant drugs such as cocaine and methamphetamine and for club drugs such as 3,4-methylenedioxymethamphetamine (MDMA), but little is known about their MDMA-like subjective effects.
METHODS: In order to determine their similarity to MDMA, the discriminative stimulus effects of 10 pyrrolidinyl cathinones (α-pyrrolidinopropiophenone, 4'-methyl-α-pyrrolidinopropiophenone (4'-MePPP), α-pyrrolidinobutiophenone, 3',4'-methylenedioxy-α-pyrrolidinobutyrophenone (MD-PBP), α-pyrrolidinovalerophenone, 3,4-methylenedioxy-pyrovalerone (MDPV), α-pyrrolidinopentiothiophenone, napthylpyrovalerone (naphyrone), α-pyrrolidinohexiophenone, and 4'-methyl-α-pyrrolidinohexiophenone (4'-MePHP)) were assessed in Sprague-Dawley rats trained to discriminate 1.5 mg/kg racemic ±-MDMA from vehicle.
RESULTS: Compounds with no substitutions on the phenyl ring and the thiophene produced 44-67% MDMA-appropriate responding. In contrast, the substituted pyrrolidinyl cathinones produced a range of MDMA-appropriate responding dependent upon the length of the alpha side chain. 4'-MePPP, with a single carbon on the alpha position, produced 99.8% MDMA-appropriate responding, MD-PBP (two carbons) produced 83%, naphyrone (three carbons) produced 71%, MDPV (three carbons) produced, 66%, and 4'-MePHP (four carbons) produced 47%.
CONCLUSIONS: Many cathinone compounds have discriminative stimulus effects similar to those of MDMA. However, the pyrrolidine substitution appears to reduce serotonergic effects, with a commensurate decrease in MDMA-like effects. Substitutions on the phenyl ring appear to be able to restore MDMA-like responding, but only in compounds with short alpha side chains. These findings agree with earlier findings of increasing dopaminergic effects and stronger reinforcing effects with increasing side chain. Assessment of more compounds is necessary to establish the replicability/robustness of this phenomenon. These findings may be of use in predicting which compounds will have MDMA/club drug-like effects versus psychostimulant-like effects.

PMID: 32536334 [PubMed - as supplied by publisher]

Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D3 Receptor (D3R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs).

Wed, 06/17/2020 - 05:01
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Leveraging a Low-Affinity Diazaspiro Orthosteric Fragment to Reduce Dopamine D3 Receptor (D3R) Ligand Promiscuity across Highly Conserved Aminergic G-Protein-Coupled Receptors (GPCRs).

J Med Chem. 2019 05 23;62(10):5132-5147

Authors: Reilly SW, Riad AA, Hsieh CJ, Sahlholm K, Jacome DA, Griffin S, Taylor M, Weng CC, Xu K, Kirschner N, Luedtke RR, Parry C, Malhotra S, Karanicolas J, Mach RH

Abstract
Previously, we reported a 3-(2-methoxyphenyl)-9-(3-((4-methyl-5-phenyl-4 H-1,2,4-triazol-3-yl)thio)propyl)-3,9-diazaspiro[5.5]undecane (1) compound with excellent dopamine D3 receptor (D3R) affinity (D3R Ki = 12.0 nM) and selectivity (D2R/D3R ratio = 905). Herein, we present derivatives of 1 with comparable D3R affinity (32, D3R Ki = 3.2 nM, D2R/D3R ratio = 60) and selectivity (30, D3R Ki = 21.0 nM, D2R/D3R ratio = 934). Fragmentation of 1 revealed orthosteric fragment 5a to express an unusually low D3R affinity ( Ki = 2.7 μM). Compared to piperazine congener 31, which retains a high-affinity orthosteric fragment (5d, D3R Ki = 23.9 nM), 1 was found to be more selective for the D3R among D1- and D2-like receptors and exhibited negligible off-target interactions at serotoninergic and adrenergic G-protein-coupled receptors (GPCRs), common off-target sites for piperazine-containing D3R scaffolds. This study provides a unique rationale for implementing weakly potent orthosteric fragments into D3R ligand systems to minimize drug promiscuity at other aminergic GPCR sites.

PMID: 31021617 [PubMed - indexed for MEDLINE]

Experimental ischemic stroke induces long-term T cell activation in the brain.

Wed, 06/17/2020 - 05:01
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Experimental ischemic stroke induces long-term T cell activation in the brain.

J Cereb Blood Flow Metab. 2019 11;39(11):2268-2276

Authors: Xie L, Li W, Hersh J, Liu R, Yang SH

Abstract
Mounting evidence has demonstrated that both innate and adaptive immune cells infiltrate into the brain after ischemic stroke. T cell invasion has been found in the ischemic region up to one month post experimental ischemic stroke and has been shown to persist for years in stroke patients. However, the function and phenotypic characteristics of the brain invading T cells after ischemic stroke have not been investigated. In the current study, we determined the function of brain invading T cells in the acute and chronic phase following experimental ischemic stroke induced by transient middle cerebral artery occlusion. We observed a significant increase of CD4+ and CD8+ T cells presented in the peri-infarct area at up to one month after experimental ischemic stroke. The brain invading T cells after ischemic stroke demonstrated close interaction with active astrocytes and a progressive proinflammatory phenotype as evidenced by the increased expression of T cell activation markers CD44 and CD25, proinflammatory cytokines INF-γ, IL-17, IL-10, TNF-α, and perforin, with corresponding transcriptional factors T-bet and RORc. Our results indicated a prolonged activation of brain invading CD4+ and CD8+ T cells after ischemic stroke which may play a role in the neural repair process after stroke.

PMID: 30092705 [PubMed - indexed for MEDLINE]

Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model.

Sun, 06/14/2020 - 06:19
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Brain-Selective Estrogen Therapy Prevents Androgen Deprivation-Associated Hot Flushes in a Rat Model.

Pharmaceuticals (Basel). 2020 Jun 10;13(6):

Authors: Merchenthaler I, Lane M, Stennett C, Zhan M, Nguyen V, Prokai-Tatrai K, Prokai L

Abstract
Hot flushes are best-known for affecting menopausal women, but men who undergo life-saving castration due to androgen-sensitive prostate cancer also suffer from these vasomotor symptoms. Estrogen deficiency in these patients is a direct consequence of androgen deprivation, because estrogens (notably 17β-estradiol, E2) are produced from testosterone. Although estrogens alleviate hot flushes in these patients, they also cause adverse systemic side effects. Because only estrogens can provide mitigation of hot flushes on the basis of current clinical practices, there is an unmet need for an effective and safe pharmacotherapeutic intervention that would also greatly enhance patient adherence. To this end, we evaluated treatment of orchidectomized (ORDX) rats with 10β, 17β-dihydroxyestra-1,4-dien-3-one (DHED), a brain-selective bioprecursor prodrug of E2. A pilot pharmacokinetic study using oral administration of DHED to these animals revealed the formation of E2 in the brain without the appearance of the hormone in the circulation. Therefore, DHED treatment alleviated androgen deprivation-associated hot flushes without peripheral impact in the ORDX rat model. Concomitantly, we showed that DHED-derived E2 induced progesterone receptor gene expression in the hypothalamus without stimulating galanin expression in the anterior pituitary, further indicating the lack of systemic estrogen exposure upon oral treatment with DHED.

PMID: 32531919 [PubMed - as supplied by publisher]

Urine Sample-Derived Cerebral Organoids Suitable for Studying Neurodevelopment and Pharmacological Responses.

Sat, 06/13/2020 - 05:47
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Urine Sample-Derived Cerebral Organoids Suitable for Studying Neurodevelopment and Pharmacological Responses.

Front Cell Dev Biol. 2020;8:304

Authors: Lin VJT, Hu J, Zolekar A, Yan LJ, Wang YC

Abstract
Cerebral organoids (COs) developed from human induced pluripotent stem cells (hiPSCs) have been noticed for their potential in research and clinical applications. While skin fibroblast-derived hiPSCs are proficient at forming COs, the cellular and molecular features of COs developed using hiPSCs generated from other somatic cells have not been systematically examined. Urinary epithelial cells (UECs) isolated from human urine samples are somatic cells that can be non-invasively collected from most individuals. In this work, we streamlined the production of COs using hiPSCs reprogrammed from urine sample-derived UECs. UEC-derived hiPSC-developed COs presented a robust capacity for neurogenesis and astrogliogenesis. Although UEC-derived hiPSCs required specific protocol optimization to properly form COs, the cellular and transcriptomic features of COs developed from UEC-derived hiPSCs were comparable to those of COs developed from embryonic stem cells. UEC-derived hiPSC-developed COs that were initially committed to forebrain development showed cellular plasticity to transition between prosencephalic and rhombencephalic fates in vitro and in vivo, indicating their potential to develop into the cell components of various brain regions. The opposite regulation of AKT activity and neural differentiation was found in these COs treated with AKT and PTEN inhibitors. Overall, our data reveal the suitability, advantage, and possible limitations of human urine sample-derived COs for studying neurodevelopment and pharmacological responses.

PMID: 32528947 [PubMed]

A tutorial on individual participant data meta-analysis using Bayesian multilevel modeling to estimate alcohol intervention effects across heterogeneous studies.

Sat, 06/13/2020 - 05:47
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A tutorial on individual participant data meta-analysis using Bayesian multilevel modeling to estimate alcohol intervention effects across heterogeneous studies.

Addict Behav. 2019 07;94:162-170

Authors: Huh D, Mun EY, Walters ST, Zhou Z, Atkins DC

Abstract
This paper provides a tutorial companion for the methodological approach implemented in Huh et al. (2015) that overcame two major challenges for individual participant data (IPD) meta-analysis. Specifically, we show how to validly combine data from heterogeneous studies with varying numbers of treatment arms, and how to analyze highly-skewed count outcomes with many zeroes (e.g., alcohol and substance use outcomes) to estimate overall effect sizes. These issues have important implications for the feasibility, applicability, and interpretation of IPD meta-analysis but have received little attention thus far in the applied research literature. We present a Bayesian multilevel modeling approach for combining multi-arm trials (i.e., those with two or more treatment groups) in a distribution-appropriate IPD analysis. Illustrative data come from Project INTEGRATE, an IPD meta-analysis study of brief motivational interventions to reduce excessive alcohol use and related harm among college students. Our approach preserves the original random allocation within studies, combines within-study estimates across all studies, overcomes between-study heterogeneity in trial design (i.e., number of treatment arms) and/or study-level missing data, and derives two related treatment outcomes in a multivariate IPD meta-analysis. This methodological approach is a favorable alternative to collapsing or excluding intervention groups within multi-arm trials, making it possible to directly compare multiple treatment arms in a one-step IPD meta-analysis. To facilitate application of the method, we provide annotated computer code in R along with the example data used in this tutorial.

PMID: 30791977 [PubMed - indexed for MEDLINE]

Cardiac Structure and Function in Well-Healed Burn Survivors.

Sat, 06/13/2020 - 05:47
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Cardiac Structure and Function in Well-Healed Burn Survivors.

J Burn Care Res. 2019 02 20;40(2):235-241

Authors: Samuel TJ, Nelson MD, Nasirian A, Jaffery M, Moralez G, Romero SA, Cramer MN, Huang M, Kouda K, Hieda M, Sarma S, Crandall CG

Abstract
Long-term burn survivors have reduced aerobic capacity, placing them at increased risk for cardiovascular disease, morbidity, and mortality. However, the exact mechanism contributing to a reduced aerobic capacity remains incompletely understood, but may be related to adverse cardiovascular remodeling. Therefore, it was hypothesized that well-healed burn survivors would exhibit adverse left ventricular (LV) remodeling and impaired LV function. To test this hypothesis, 22 well-healed moderately burned individuals (age: 41 ± 14 years; BMI: 27.7 ± 5.4 kg/m2; male/female: 12/10; extent of burn: 37 ± 12 %BSA), 11 well-healed severely burned individuals (age: 43 ± 12 years; BMI: 29.5 ± 5.8 kg/m2; male/female: 8/3; extent of burn: 73 ± 11 %BSA), and 12 healthy, age-matched controls (age: 34 ± 9 years; BMI: 28.6 ± 5.2 kg/m2; male/female: 5/7) were enrolled in the study. All subjects were sedentary, performing less than 30 minutes of aerobic exercise per day, 3 days per week. LV morphology and function were assessed via cardiac magnetic resonance imaging. In contrast to the hypothesis, neither the presence nor severity of burn injury adversely affected LV morphology or function, when compared with equally sedentary nonburned controls. However, of note, LV mass of all three groups was in the lowest 5th percentile compared with normative values. Finally, group differences in LV morphology were largely explained by differences in aerobic capacity. Taken together, these data suggest a prior burn injury itself does not result in pathological remodeling of the LV and support a role for aerobic exercise training to improve cardiac function.

PMID: 30649454 [PubMed - indexed for MEDLINE]

Determination of metformin bio-distribution by LC-MS/MS in mice treated with a clinically relevant paradigm.

Fri, 06/12/2020 - 05:30

Determination of metformin bio-distribution by LC-MS/MS in mice treated with a clinically relevant paradigm.

PLoS One. 2020;15(6):e0234571

Authors: Chaudhari K, Wang J, Xu Y, Winters A, Wang L, Dong X, Cheng EY, Liu R, Yang SH

Abstract
Metformin, an anti-diabetes drug, has been recently emerging as a potential "anti-aging" intervention based on its reported beneficial actions against aging in preclinical studies. Nonetheless, very few metformin studies using mice have determined metformin concentrations and many effects of metformin have been observed in preclinical studies using doses/concentrations that were not relevant to therapeutic levels in human. We developed a liquid chromatography-tandem mass spectrometry protocol for metformin measurement in plasma, liver, brain, kidney, and muscle of mice. Young adult male and female C57BL/6 mice were voluntarily treated with metformin of 4 mg/ml in drinking water which translated to the maximum dose of 2.5 g/day in humans. A clinically relevant steady-state plasma metformin concentrations were achieved at 7 and 30 days after treatment in male and female mice. Metformin concentrations were slightly higher in muscle than in plasma, while, ~3 and 6-fold higher in the liver and kidney than in plasma, respectively. Low metformin concentration was found in the brain at ~20% of the plasma level. Furthermore, gender difference in steady-state metformin bio-distribution was observed. Our study established steady-state metformin levels in plasma, liver, muscle, kidney, and brain of normoglycemic mice treated with a clinically relevant dose, providing insight into future metformin preclinical studies for potential clinical translation.

PMID: 32525922 [PubMed - as supplied by publisher]

Characterization of Tear Immunoglobulins in a Small-Cohort of Keratoconus Patients.

Fri, 06/12/2020 - 05:30
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Characterization of Tear Immunoglobulins in a Small-Cohort of Keratoconus Patients.

Sci Rep. 2020 Jun 10;10(1):9426

Authors: McKay TB, Serjersen H, Hjortdal J, Zieske JD, Karamichos D

Abstract
Keratoconus (KC) is classically considered a non-inflammatory condition caused by central corneal thinning that leads to astigmatism and reduced visual acuity. Previous studies have identified increased systemic levels of pro-inflammatory factors, including interleukin-6, tumor necrosis factor-α, and matrix metalloproteinase-9, suggesting that KC may have an inflammatory component in at least a subset of patients. In this study, we evaluated the levels of different immunoglobulins (light and heavy chains) based on Ig α, Ig λ, Ig κ, Ig µ, and Ig heavy chain subunits in non-KC tears (n = 7 control individuals) and KC tears (n = 7 KC patients) using tandem-liquid chromatography mass spectrometry. The most abundant Ig heavy chains detected in both control individuals and KC patients were Ig α-1 and Ig α-2 likely correlating to the higher IgA levels reported in human tears. We identified significant differences in immunoglobulin κ-chain V-II levels in KC patients compared to control individuals with no significant difference in Ig κ/Ig λ ratios or heavy chain levels. Our study supports previous findings suggesting that KC possesses a systemic component that may contribute to the KC pathology. Further studies are required to define causality and establish a role for systemic immune system-dependent factors and pro-inflammatory processes in KC development or progression.

PMID: 32523038 [PubMed - in process]

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