Recent Research Articles from UNTHSC

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

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NCBI: db=pubmed; Term="University of North Texas Health Science Center"[All Fields] OR "Univ. of North Texas Health Science Center"[All Fields] OR "UNT Health Science Center"[All Fields] OR "Osteopathic Research Center"[All Fields] OR "University of North Texas System College of Pharmacy"[All Fields] OR "UNT System College of Pharmacy"[All Fields] OR "College of Pharmacy, University of North Texas System"[All Fields]
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The Effects of Traditional Chinese Exercise in Patients with Chronic Obstructive Pulmonary Disease: A Meta-Analysis.

Wed, 08/02/2017 - 07:37
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The Effects of Traditional Chinese Exercise in Patients with Chronic Obstructive Pulmonary Disease: A Meta-Analysis.

PLoS One. 2016;11(9):e0161564

Authors: Luo X, Zhang J, Castelberg R, Wu T, Yu P, He C, Wang P

Abstract
BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major public health problem worldwide. However, several studies that have assessed the role of traditional Chinese exercise in the management of this disease include broad variations in sample sizes and results. Therefore, this meta-analysis was conducted to assess the effects of traditional Chinese exercise on patients with COPD.
METHODS: Two investigators independently identified and extracted data from selected articles. A computerized search of electronic databases through August 2015 was conducted. Mean differences (MDs) and 95% confidence intervals (CIs) were calculated to analyze the combined data. The methodological quality was evaluated using the Cochrane risk-of-bias tool. Heterogeneity was assessed with the I2 test.
RESULTS: Ten randomized, controlled trials (RCTs) involving 622 patients met the inclusion criteria. There were significant improvements in the 6-minute walking distance test (6 MWD;MWD = 12.10 m; 95% CI, 7.56-16.65 m; p<0.001); forced expiratory volume in one second (FEV1% predicted; WMD = 9.02; 95% CI, 6.80-11.23; p<0.00001); forced expiratory volume in 1 second/forced vital capacity (FEV(1)/FVC) ratio (Tiffenau Index; WMD = 6.67; 95% CI, 5.09-8.24; p<0.00001); and quality of life, as evaluated by the Chronic Respiratory Disease Questionnaire (CRDQ; WMD = 0.85 score; 95% CI, 0.52-1.18; p<0.00001).
CONCLUSIONS: Traditional Chinese exercise could provide an effective alternative method for managing COPD. Larger and higher-quality trials are required.

PMID: 27589054 [PubMed - indexed for MEDLINE]

Mechanisms by Which 17β-Estradiol (E2) Suppress Neuronal cox-2 Gene Expression.

Wed, 08/02/2017 - 07:37
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Mechanisms by Which 17β-Estradiol (E2) Suppress Neuronal cox-2 Gene Expression.

PLoS One. 2016;11(9):e0161430

Authors: Stacey W, Bhave S, Uht RM

Abstract
E2 attenuates inflammatory responses by suppressing expression of pro-inflammatory genes. Given that inflammation is increasingly being associated with neurodegenerative and psychiatric processes, we sought to elucidate mechanisms by which E2 down-regulates a component of an inflammatory response, cyclooxygenase- 2 (COX-2) expression. Although inflammatory processes in the brain are usually associated with microglia and astrocytes, we found that the COX-2 gene (cox-2) was expressed in a neuronal context, specifically in an amygdalar cell line (AR-5). Given that COX-2 has been reported to be in neurons in the brain, and that the amygdala is a site involved in neurodegenerative and neuropsychiatric processes, we investigated mechanisms by which E2 could down-regulate cox-2 expression in the AR-5 line. These cells express estrogen receptors alpha (ERα) and beta (ERβ), and as shown here cox-2. At the level of RNA, E2 and the ERβ selective ligand diarylpropionitrile (DPN) both attenuated gene expression, whereas the ERα selective ligand propyl pyrazole triol (PPT) had no effect. Neither ligand increased ERβ at the cox-2 promoter. Rather, DPN decreased promoter occupancy of NF-κB p65 and histone 4 (H4) acetylation. Treatment with the non-specific HDAC inhibitor Trichostatin A (TSA) counteracted DPN's repressive effects on cox-2 expression. In keeping with the TSA effect, E2 and DPN increased histone deacetylase one (HDAC1) and switch-independent 3A (Sin3A) promoter occupancy. Lastly, even though E2 increased CpG methylation, DPN did not. Taken together, the pharmacological data indicate that ERβ contributes to neuronal cox-2 expression, as measured by RNA levels. Furthermore, ER ligands lead to increased recruitment of HDAC1, Sin3A and a concomitant reduction of p65 occupancy and Ac-H4 levels. None of the events, however, are associated with a significant recruitment of ERβ at the promoter. Thus, ERβ directs recruitment to the cox-2 promoter, but does so in the absence of being recruited itself.

PMID: 27588681 [PubMed - indexed for MEDLINE]

Empirical testing of a 23-AIMs panel of SNPs for ancestry evaluations in four major US populations.

Wed, 08/02/2017 - 07:37
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Empirical testing of a 23-AIMs panel of SNPs for ancestry evaluations in four major US populations.

Int J Legal Med. 2016 Jul;130(4):891-6

Authors: Zeng X, Warshauer DH, King JL, Churchill JD, Chakraborty R, Budowle B

Abstract
Ancestry informative markers (AIMs) can be used to determine population affiliation of the donors of forensic samples. In order to examine ancestry evaluations of the four major populations in the USA, 23 highly informative AIMs were identified from the International HapMap project. However, the efficacy of these 23 AIMs could not be fully evaluated in silico. In this study, these 23 SNPs were multiplexed to test their actual performance in ancestry evaluations. Genotype data were obtained from 189 individuals collected from four American populations. One SNP (rs12149261) on chromosome 16 was removed from this panel because it was duplicated on chromosome 1. The resultant 22-AIMs panel was able to empirically resolve the four major populations as in the in silico study. Eight individuals were assigned to a different group than indicated on their samples. The assignments of the 22 AIMs for these samples were consistent with AIMs results from the ForenSeq(TM) panel. No departures from Hardy-Weinberg equilibrium (HWE) and linkage disequilibrium (LD) were detected for all 22 SNPs in four US populations (after removing the eight problematic samples). The principal component analysis (PCA) results indicated that 181 individuals from these populations were assigned to the expected groups. These 22 SNPs can contribute to the candidate AIMs pool for potential forensic identification purposes in major US populations.

PMID: 26914801 [PubMed - indexed for MEDLINE]

Effects of Popular Diets without Specific Calorie Targets on Weight Loss Outcomes: Systematic Review of Findings from Clinical Trials.

Tue, 08/01/2017 - 17:06
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Effects of Popular Diets without Specific Calorie Targets on Weight Loss Outcomes: Systematic Review of Findings from Clinical Trials.

Nutrients. 2017 Jul 31;9(8):

Authors: Anton SD, Hida A, Heekin K, Sowalsky K, Karabetian C, Mutchie H, Leeuwenburgh C, Manini TM, Barnett TE

Abstract
The present review examined the evidence base for current popular diets, as listed in the 2016 U.S. News &amp; World Report, on short-term (≤six months) and long-term (≥one year) weight loss outcomes in overweight and obese adults. For the present review, all diets in the 2016 U.S. News &amp; World Report Rankings for "Best Weight-Loss Diets", which did not involve specific calorie targets, meal replacements, supplementation with commercial products, and/or were not categorized as "low-calorie" diets were examined. Of the 38 popular diets listed in the U.S. News &amp; World Report, 20 met our pre-defined criteria. Literature searches were conducted through PubMed, Cochrane Library, and Web of Science using preset key terms to identify all relevant clinical trials for these 20 diets. A total of 16 articles were identified which reported findings of clinical trials for seven of these 20 diets: (1) Atkins; (2) Dietary Approaches to Stop Hypertension (DASH); (3) Glycemic-Index; (4) Mediterranean; (5) Ornish; (6) Paleolithic; and (7) Zone. Of the diets evaluated, the Atkins Diet showed the most evidence in producing clinically meaningful short-term (≤six months) and long-term (≥one-year) weight loss. Other popular diets may be equally or even more effective at producing weight loss, but this is unknown at the present time since there is a paucity of studies on these diets.

PMID: 28758964 [PubMed - in process]

Duration of isoflurane-based surgical anesthesia determines severity of brain injury and neurological deficits after a transient focal ischemia in young adult rats.

Tue, 08/01/2017 - 17:06
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Duration of isoflurane-based surgical anesthesia determines severity of brain injury and neurological deficits after a transient focal ischemia in young adult rats.

Brain Res Bull. 2017 Jul 26;:

Authors: Gaidhani N, Sun F, Schreihofer D, Uteshev VV

Abstract
Tremendous efforts and funds invested in discovery of novel drug treatments for ischemic stroke have so far failed to deliver clinically efficacious therapies. The reasons for these failures are not fully understood. An indiscriminate use of isoflurane-based surgical anesthesia with or without nitrous oxide may act as an unconstrained, untraceable source of data variability, potentially causing false-positive or false-negative results. To test this hypothesis, a common transient suture middle cerebral artery occlusion (tMCAO) model of ischemic stroke in young adult male rats was used to determine the impact of a typical range of anesthesia durations required for this model on data variability (i.e., infarct volume and neurological deficits). The animals were maintained on spontaneous ventilation. The study results indicated that: (1) Variable duration of isoflurane anesthesia prior, during and after tMCAO is a significant source of data variability as evidenced by measurements of infarct volume and neurological deficits; and (2) Severity of brain injury and neurological deficits after tMCAO is inversely related to the duration of isoflurane anesthesia: e.g., in our study, a 90min isoflurane anesthesia nearly completely protected brain tissues from tMCAO-induced injury and thus, would be expected to obscure the effects of stroke treatments in pre-clinical trials. To elevate transparency, rigor and reproducibility of stroke research and minimize undesirable effects of isoflurane on the outcome of novel drug testing, we propose to monitor, minimize and standardize isoflurane anesthesia in experimental surgeries and make anesthesia duration a required reportable parameter in pre-clinical studies. Specifically, we propose to adopt 20-30min as an optimal anesthesia duration that both minimizes neuroprotective effects of isoflurane and permits a successful completion of surgical procedures in a suture tMCAO model of ischemic stroke in rodents. As the mechanisms and neuroprotective, metabolic and immune effects of general anesthesia are not fully understood, the results of this study cannot be blindly generalized to other anesthetics, animal species and experimental models.

PMID: 28755978 [PubMed - as supplied by publisher]

Effectiveness of a computerized motivational intervention on treatment initiation and substance use: Results from a randomized trial.

Tue, 08/01/2017 - 17:06
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Effectiveness of a computerized motivational intervention on treatment initiation and substance use: Results from a randomized trial.

J Subst Abuse Treat. 2017 Sep;80:59-66

Authors: Lerch J, Walters ST, Tang L, Taxman FS

Abstract
As many as 80% of the nearly five million adults under community supervision (i.e., probation, parole) are substance involved; however, treatment utilization is low. Using a multi-site randomized controlled trial, we tested the efficacy of in-person motivational interviewing (MI), a motivational computer intervention (MAPIT), or standard probation intake (SAU) to encourage treatment initiation among 316 substance-involved probationers in Dallas, Texas and Baltimore City, Maryland. Ninety-three percent (n=295) of participants completed the 2-month follow-up and 90% (n=285) completed the 6-month follow-up. At 2-months, individuals in the MAPIT condition were more likely to report treatment initiation compared to the SAU condition (OR=2.40, 95% CI=1.06, 5.47) via intent-to-treat analysis, especially among those completing both sessions (RE=0.50, 95% CI=0.05, 0.95) via instrumental variable analysis. At 6-months, MAPIT approached significance for treatment initiation in both analyses. MI did not achieve significance in any model. We did not find any differential impact on substance use. The success of MAPIT suggests that an integrated health-justice computerized intervention as part of a Screening, Brief Intervention, and Referral to Treatment (SBIRT) can be used to address public safety and health issues.

PMID: 28755774 [PubMed - in process]

The Essential Role of Neutrophils during Infection with the Intracellular Bacterial Pathogen Listeria monocytogenes.

Tue, 08/01/2017 - 17:06
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The Essential Role of Neutrophils during Infection with the Intracellular Bacterial Pathogen Listeria monocytogenes.

J Immunol. 2016 Sep 01;197(5):1557-65

Authors: Witter AR, Okunnu BM, Berg RE

Abstract
Neutrophils have historically been characterized as first responder cells vital to host survival because of their ability to contain and eliminate bacterial and fungal pathogens. However, recent studies have shown that neutrophils participate in both protective and detrimental responses to a diverse array of inflammatory and infectious diseases. Although the contribution of neutrophils to extracellular infections has been investigated for decades, their specific role during intracellular bacterial infections has only recently been appreciated. During infection with the Gram-positive intracellular pathogen Listeria monocytogenes, neutrophils are recruited from the bone marrow to sites of infection where they use novel bacterial-sensing pathways leading to phagocytosis and production of bactericidal factors. This review summarizes the requirement of neutrophils during L. monocytogenes infection by examining both neutrophil trafficking and function during primary and secondary infection.

PMID: 27543669 [PubMed - indexed for MEDLINE]

Metabolic syndrome is associated with an increased incidence of subclinical hypothyroidism - A Cohort Study.

Sun, 07/30/2017 - 07:33
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Metabolic syndrome is associated with an increased incidence of subclinical hypothyroidism - A Cohort Study.

Sci Rep. 2017 Jul 28;7(1):6754

Authors: Chang CH, Yeh YC, Caffrey JL, Shih SR, Chuang LM, Tu YK

Abstract
Prior cross-sectional analyses have demonstrated an association between subclinical hypothyroidism and metabolic syndrome and selected components. However, the temporal relation between metabolic syndrome and declining thyroid function remains unclear. In a prospective study, an unselected cohort of 66,822 participants with and without metabolic syndrome were followed. A proportional hazards regression model was used to estimate hazard ratios (HRs) and 95% CIs for hypothyroidism. Exploratory analyses for the relation between components of metabolic syndrome and declining thyroid function were also undertaken. During an average follow-up of 4.2 years, the incident rates for subclinical hypothyroidism were substantially higher in participants who began the study with metabolic syndrome compared with metabolically normal controls. After controlling for risk factors, patients with metabolic syndrome were at a 21% excess risk of developing subclinical hypothyroidism (adjusted HR 1.21; 95% CI 1.03-1.42). When individual components were analyzed, an increased risk of subclinical hypothyroidism was associated with high blood pressure (1.24; 1.04-1.48) and high serum triglycerides (1.18; 1.00-1.39), with a trend of increasing risk as participants had additional more components. Individuals with metabolic syndrome are at a greater risk for developing subclinical hypothyroidism, while its mechanisms and temporal consequences of this observation remain to be determined.

PMID: 28754977 [PubMed - in process]

Mannich Ketones as Possible Antimycobacterial Agents.

Sat, 07/29/2017 - 07:42
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Mannich Ketones as Possible Antimycobacterial Agents.

Arch Pharm (Weinheim). 2017 Jul 28;:

Authors: Lutz Z, Orbán K, Bóna Á, Márk L, Maász G, Prókai L, Seress L, Lóránd T

Abstract
Twenty-three known unsaturated and fused Mannich ketones and their reduced derivatives (amino alcohols) were selected for an antituberculotic study. They were screened against several mycobacterial strains including Mycobacterium tuberculosis, M. xenopi, and M. gordonae, and minimum inhibitory concentration values were also determined using the standard antituberculotic drug isoniazid (INH) as a reference. Structure-activity relationships were also studied. The mode of action of the test compounds was investigated using transmission electron microscopy, high-performance liquid chromatography, and matrix-assisted desorption/ionization mass spectrometry. Several test substances proved to be as potent as INH, but their antimycobacterial spectra were broader than that of INH. Our findings suggest that their mode of action is probably through the inhibition of mycobacterial cell wall biosynthesis.

PMID: 28752666 [PubMed - as supplied by publisher]

Evaluation of InnoTyper® 21 in a sample of Rio de Janeiro population as an alternative forensic panel.

Fri, 07/28/2017 - 07:38
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Evaluation of InnoTyper® 21 in a sample of Rio de Janeiro population as an alternative forensic panel.

Int J Legal Med. 2017 Jul 26;:

Authors: Moura-Neto RS, Mello ICT, Silva R, Maette APC, Bottino CG, Woerner A, King J, Wendt F, Budowle B

Abstract
The use of bi-allelic markers such as retrotransposable element insertion polymorphisms or Innuls (for insertion/null) can overcome some limitations of short tandem repeat (STR) loci in typing forensic biological evidence. This study investigated the efficiency of the InnoTyper® 21 Innul markers in an urban admixed population sample in Rio de Janeiro (n = 40) and one highly compromised sample collected as evidence by the Rio de Janeiro police. No significant departures from Hardy-Weinberg equilibrium were detected after the Bonferroni correction (α' ≈ 0.05/20, p < 0.0025), and no significant linkage disequilibrium was observed between markers. Assuming loci independence, the cumulative random match probability (RMP) was 2.3 × 10(-8). A lower mean Fis value was obtained for this sample population compared with those of three North American populations (African-American, Southwest Hispanic, US Caucasian). Principal component analysis with the three North American populations and one from 21 East Asian population showed that African Americans segregated as an independent group while US Caucasian, Southwest Hispanic, East Asian, and Rio de Janeiro populations are in a single large heterogeneous group. Also, a full Innuls profile was produced from an evidence sample, despite the DNA being highly degraded. In conclusion, this system is a useful complement to standard STR kits.

PMID: 28748403 [PubMed - as supplied by publisher]

Sleep and Mental Health in the General Population of Elderly Women.

Fri, 07/28/2017 - 07:38
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Sleep and Mental Health in the General Population of Elderly Women.

J Prim Prev. 2017 Jul 26;:

Authors: Thomas KM, Redd LA, Wright JD, Hartos JL

Abstract
Sleep and mental health complaints are prevalent in the elderly and share common risk factors. We assessed the relationship between sleep and mental health in three representative samples of elderly women while controlling for multiple risk factors common to both. We performed this cross sectional secondary data analysis in 2015 using 2013 data from the Behavioral Risk Factor Surveillance System (BRFSS) for females ages 65 years and older from California (N = 1912), Florida (N = 9120), and Pennsylvania (N = 2429). We conducted multiple logistic regression analysis to assess the relationship between sleep duration group (short, moderate/reference, or long) and mental health issues in the past 30 days (yes or no) in elderly females, while controlling for multiple covariates. About 25% of the elderly females reported mental health issues and 20% reported short or long sleep durations. In adjusted analysis, compared to the elderly females in the moderate sleep duration group (averaging 6-8 h of sleep per day), those in the short and long sleep duration groups had increased prevalence of mental health issues by 66% and 26%, respectively. Mental health was also related to physical health issues including general health status, activity limitations, and chronic health conditions. Overall, sleep was related to mental health in representative samples of elderly females even after controlling for risk factors common to both. Even though we could not determine the direction of influence, the findings indicate a need for clinicians to screen their elderly female patients for both sleep and mental health issues, especially in those with physical health comorbidities.

PMID: 28748316 [PubMed - as supplied by publisher]

Nanomaterial Applications for Neurological Diseases and Central Nervous System Injury.

Thu, 07/27/2017 - 07:35
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Nanomaterial Applications for Neurological Diseases and Central Nervous System Injury.

Prog Neurobiol. 2017 Jul 22;:

Authors: Huang L, Hu J, Huang S, Wang B, Siaw-Debrah F, Nyanzu M, Zhang Y, Zhuge Q

Abstract
The effectiveness of noninvasive treatment for neurological disease is generally limited by the poor entry of therapeutic agents into the central nervous system (CNS). Most CNS drugs cannot permeate into the brain parenchyma because of the blood-brain barrier thus, overcoming this problem has become one of the most significant challenges in the development of neurological therapeutics. Nanotechnology has emerged as an innovative alternative for treating neurological diseases. In fact, rapid advances in nanotechnology have provided promising solutions to this challenge. This review highlights the applications of nanomaterials in the developing neurological field and discusses the evidence for their efficacies.

PMID: 28743465 [PubMed - as supplied by publisher]

Protection of hamsters from mortality by reducing fecal moxifloxacin concentration with DAV131A in a model of moxifloxacin-induced Clostridium difficile colitis.

Wed, 07/26/2017 - 07:46
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Protection of hamsters from mortality by reducing fecal moxifloxacin concentration with DAV131A in a model of moxifloxacin-induced Clostridium difficile colitis.

Antimicrob Agents Chemother. 2017 Jul 24;:

Authors: Burdet C, Sayah-Jeanne S, Nguyen TT, Miossec C, Saint-Lu N, Pulse M, Weiss W, Andremont A, Mentré F, de Gunzburg J

Abstract
BACKGROUND: Lowering the gut exposure to antibiotics during treatments can prevent microbiota disruption. We evaluated the effect of an activated charcoal-based adsorbent, DAV131A, on fecal free moxifloxacin concentration and mortality in a hamster model of moxifloxacin-induced C. difficile infection.
METHODS: 215 hamsters receiving moxifloxacin subcutaneously (D1-D5) were orally infected at D3 with C. difficile spores. They received various doses (0-1800mg/kg/day) and schedules (BID, TID) of DAV131A (D1-D8). Moxifloxacin concentration and C. difficile counts were determined at D3, and mortality at D12. We compared mortality, moxifloxacin concentration and C. difficile counts according to DAV131A regimens, and modelled the link between DAV131A regimen, moxifloxacin concentration and mortality.
RESULTS: All hamsters that received no DAV131A died, but none of those that received 1800mg/kg/day. A significant dose-dependent relationship between DAV131A dose and (i) mortality rates, (ii) moxifloxacin concentration and (iii) C. difficile counts was evidenced. Mathematical modeling suggested that (i) lowering moxifloxacin concentration at D3, which was 58μg/g (95%CI=50-66) without DAV131A, to 17μg/g (14-21) would reduce mortality by 90% and (ii) this would be achieved with a daily DAV131A dose of 703mg/kg (596-809).
CONCLUSIONS: In this model of C. difficile infection, DAV131A reduced mortality in a dose-dependent manner by decreasing fecal free moxifloxacin concentration.

PMID: 28739791 [PubMed - as supplied by publisher]

Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology.

Tue, 07/25/2017 - 07:34
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Canonical Transient Receptor Potential 6 Channel: A New Target of Reactive Oxygen Species in Renal Physiology and Pathology.

Antioxid Redox Signal. 2016 Nov 01;25(13):732-748

Authors: Ma R, Chaudhari S, Li W

Abstract
SIGNIFICANCE: Regulation of Ca(2+) signaling cascade by reactive oxygen species (ROS) is becoming increasingly evident and this regulation represents a key mechanism for control of many fundamental cellular functions. Canonical transient receptor potential (TRPC) 6, a member of Ca(2+)-conductive channel in the TRPC family, is widely expressed in kidney cells, including glomerular mesangial cells, podocytes, tubular epithelial cells, and vascular myocytes in renal microvasculature. Both overproduction of ROS and dysfunction of TRPC6 channel are involved in renal injury in animal models and human subjects. Although regulation of TRPC channel function by ROS has been well described in other tissues and cell types, such as vascular smooth muscle, this important cell regulatory mechanism has not been fully reviewed in kidney cells. Recent Advances: Accumulating evidence has shown that TRPC6 is a redox-sensitive channel, and modulation of TRPC6 Ca(2+) signaling by altering TRPC6 protein expression or TRPC6 channel activity in kidney cells is a downstream mechanism by which ROS induce renal damage.
CRITICAL ISSUES: This review highlights how recent studies analyzing function and expression of TRPC6 channels in the kidney and their response to ROS improve our mechanistic understanding of oxidative stress-related kidney diseases.
FUTURE DIRECTIONS: Although it is evident that ROS regulate TRPC6-mediated Ca(2+) signaling in several types of kidney cells, further study is needed to identify the underlying molecular mechanism. We hope that the newly identified ROS/TRPC6 pathway will pave the way to new, promising therapeutic strategies to target kidney diseases such as diabetic nephropathy. Antioxid. Redox Signal. 25, 732-748.

PMID: 26937558 [PubMed - indexed for MEDLINE]

Identification and Characterization of Novel Matrix-Derived Bioactive Peptides: A Role for Collagenase from Santyl® Ointment in Post-Debridement Wound Healing?

Tue, 07/25/2017 - 07:34
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Identification and Characterization of Novel Matrix-Derived Bioactive Peptides: A Role for Collagenase from Santyl® Ointment in Post-Debridement Wound Healing?

PLoS One. 2016;11(7):e0159598

Authors: Sheets AR, Demidova-Rice TN, Shi L, Ronfard V, Grover KV, Herman IM

Abstract
Debridement, the removal of diseased, nonviable tissue, is critical for clinicians to readily assess wound status and prepare the wound bed for advanced therapeutics or downstream active healing. Removing necrotic slough and eschar through surgical or mechanical methods is less specific and may be painful for patients. Enzymatic debridement agents, such as Clostridial collagenase, selectively and painlessly degrade devitalized tissue. In addition to its debriding activities, highly-purified Clostridial collagenase actively promotes healing, and our past studies reveal that extracellular matrices digested with this enzyme yield peptides that activate cellular migratory, proliferative and angiogenic responses to injury in vitro, and promote wound closure in vivo. Intriguingly, while collagenase Santyl® ointment, a sterile preparation containing Clostridial collagenases and other non-specific proteases, is a well-accepted enzymatic debridement agent, its role as an active healing entity has never been established. Based on our previous studies of pure Clostridial collagenase, we now ask whether the mixture of enzymes contained within Santyl® produces matrix-derived peptides that promote cellular injury responses in vitro and stimulate wound closure in vivo. Here, we identify novel collagen fragments, along with collagen-associated peptides derived from thrombospondin-1, multimerin-1, fibronectin, TGFβ-induced protein ig-h3 and tenascin-C, generated from Santyl® collagenase-digested human dermal capillary endothelial and fibroblastic matrices, which increase cell proliferation and angiogenic remodeling in vitro by 50-100% over controls. Using an established model of impaired healing, we further demonstrate a specific dose of collagenase from Santyl® ointment, as well as the newly-identified and chemically-synthesized ECM-derived peptides significantly increase wound re-epithelialization by 60-100% over saline-treated controls. These results not only confirm and extend our earlier studies using purified collagenase- and matrix-derived peptides to stimulate healing in vitro and in vivo, but these Santyl®-generated, matrix-derived peptides may also represent exciting new opportunities for creating advanced wound healing therapies that are enabled by enzymatic debridement and potentially go beyond debridement.

PMID: 27459729 [PubMed - indexed for MEDLINE]

Comparison of Outcomes between Individuals with Pure and Mixed Lupus Nephritis: A Retrospective Study.

Tue, 07/25/2017 - 07:34
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Comparison of Outcomes between Individuals with Pure and Mixed Lupus Nephritis: A Retrospective Study.

PLoS One. 2016;11(6):e0157485

Authors: Ilori TO, Enofe N, Oommen A, Cobb J, Navarrete J, Adedinsewo DA, Oshikoya O, Fevrier H, Farris AB, Plantinga L, Ojo AO

Abstract
INTRODUCTION: Lupus nephritis (LN) is a serious organ manifestation of systemic lupus erythematosus. Histologic overlap is relatively common in the six pathologic classes (I to VI) of LN. For example, mixed proliferative LN (MPLN) often includes features of classes III & V or classes IV & V combined. We performed a comparative evaluation of renal outcomes in patients with MPLN to patients with pure proliferative LN (PPLN) against pre-specified renal outcomes, and we also identified predictor of clinical outcomes among those with PPLN and MPLN.
HYPOTHESIS: Individuals with MPLN will have worse short-term renal outcomes compared to those with PPLN.
METHODS: We retrospectively reviewed 278 adult LN patients (≥18 years old) identified from an Emory University Hospital registry of native renal biopsies performed between January 2000 and December 2011. The final analytic sample consisted of individuals with a diagnosis of PPLN (n = 60) and MPLN (n = 96). We analyzed differences in clinical and laboratory characteristics at baseline. We also assessed associations between LN category and renal outcomes (complete remission and time to ESRD) with logistic and Cox proportional hazards models within two years of baseline.
RESULTS: The study population was predominantly female (83.97%) and African American (71.8%) with a mean age of 33.4 years at baseline. Over a median follow up of 1.02 years, we did not find any statistically significant associations between MPLN and the development of ESRD or remission when compared to patients with PPLN (adjusted HR = 0.30, 95% CI = 0.07, 1.26).
CONCLUSION: There was no association between mixed or pure histopathologic features of LN at presentation and rate of complete or partial remission but higher baseline eGFR was associated with a lower probability of complete remission among patients with lupus nephritis.

PMID: 27304068 [PubMed - indexed for MEDLINE]

Identification and analysis of mtDNA genomes attributed to Finns reveal long-stagnant demographic trends obscured in the total diversity.

Mon, 07/24/2017 - 01:35
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Identification and analysis of mtDNA genomes attributed to Finns reveal long-stagnant demographic trends obscured in the total diversity.

Sci Rep. 2017 Jul 21;7(1):6193

Authors: Översti S, Onkamo P, Stoljarova M, Budowle B, Sajantila A, Palo JU

Abstract
In Europe, modern mitochondrial diversity is relatively homogeneous and suggests an ubiquitous rapid population growth since the Neolithic revolution. Similar patterns also have been observed in mitochondrial control region data in Finland, which contrasts with the distinctive autosomal and Y-chromosomal diversity among Finns. A different picture emerges from the 843 whole mitochondrial genomes from modern Finns analyzed here. Up to one third of the subhaplogroups can be considered as Finn-characteristic, i.e. rather common in Finland but virtually absent or rare elsewhere in Europe. Bayesian phylogenetic analyses suggest that most of these attributed Finnish lineages date back to around 3,000-5,000 years, coinciding with the arrival of Corded Ware culture and agriculture into Finland. Bayesian estimation of past effective population sizes reveals two differing demographic histories: 1) the 'local' Finnish mtDNA haplotypes yielding small and dwindling size estimates for most of the past; and 2) the 'immigrant' haplotypes showing growth typical of most European populations. The results based on the local diversity are more in line with that known about Finns from other studies, e.g., Y-chromosome analyses and archaeology findings. The mitochondrial gene pool thus may contain signals of local population history that cannot be readily deduced from the total diversity.

PMID: 28733587 [PubMed - in process]

The many faces of the trabecular meshwork cell.

Sat, 07/22/2017 - 07:34
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The many faces of the trabecular meshwork cell.

Exp Eye Res. 2017 May;158:112-123

Authors: Stamer WD, Clark AF

Abstract
With the combined purpose of facilitating useful vision over a lifetime, a number of ocular cells have evolved specialized features not found elsewhere in the body. The trabecular meshwork (TM) cell at the irido-corneal angle, which is a key regulator of intraocular pressure, is no exception. Examination of cells in culture isolated from the human TM has shown that they are unique in many ways, displaying characteristic features of several different cell types. Thus, these neural crest derived cells display expression patterns and behaviors typical of endothelia, fibroblasts, smooth muscle and macrophages, owing to the multiple roles and two distinct environments where they operate to maintain intraocular pressure homeostasis. In most individuals, TM cells function normally over a lifetime in the face of persistent stressors, including phagocytic, oxidative, mechanical and metabolic stress. Study of TM cells isolated from ocular hypertensive eyes has shown a compromised ability to perform their daily duties. This review highlights the many responsibilities of the TM cell and its challenges, progress in our understanding of TM biology over the past 30 years, as well as discusses unanswered questions about TM dysfunction that results in IOP dysregulation and glaucoma.

PMID: 27443500 [PubMed - indexed for MEDLINE]

Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer.

Thu, 07/20/2017 - 07:37

Developing new targeting strategy for androgen receptor variants in castration resistant prostate cancer.

Int J Cancer. 2017 Jul 19;:

Authors: Wang B, Lo UG, Wu K, Kapur P, Liu X, Huang J, Chen W, Hernandez E, Santoyo J, Ma SH, Pong RC, He D, Cheng YQ, Hsieh JT

Abstract
The presence of androgen receptor variant 7 (AR-V7) variants becomes a significant hallmark of castration resistant prostate cancer (CRPC) relapsed from hormonal therapy and is associated with poor survival of CRPC patients because of lacking a ligand-binding domain. Currently, it still lacks an effective agent to target AR-V7 or AR-Vs in general. Here, we showed a novel class of agents (thailanstatins, TSTs, spliceostatin A analogs) can significantly suppress the expression of AR-V7 mRNA and protein but in a less extent on the full-length AR expression. Mechanistically, TST-D is able to inhibit AR-V7 gene splicing by interfering the interaction between U2AF65 and SAP155 and preventing them from binding to polypyrimidine tract located between the branch point and the 3' splice site. In vivo, TST-D exhibits a potent tumor inhibitory effect on human CRPC xenografts leading to cell apoptosis. The machinery associated with AR gene splicing in CRPC is a potential target for drugs. Based on their potency in the suppression of AR-V7 responsible for the growth/survival of CRPC, TSTs representing a new class of anti-AR-V agents warrant further development into clinical application. This article is protected by copyright. All rights reserved.

PMID: 28722220 [PubMed - as supplied by publisher]

HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway.

Thu, 07/20/2017 - 07:37
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HIV Tat Impairs Neurogenesis through Functioning As a Notch Ligand and Activation of Notch Signaling Pathway.

J Neurosci. 2016 Nov 02;36(44):11362-11373

Authors: Fan Y, Gao X, Chen J, Liu Y, He JJ

Abstract
Alterations in adult neurogenesis have been noted in the brain of HIV-infected individuals and are likely linked to HIV-associated neurocognitive deficits, including those in learning and memory. But the underlying molecular mechanisms are not fully understood. In the study, we took advantage of doxycycline-inducible and astrocyte-specific HIV-1 Tat transgenic mice (iTat) and determined the relationship between Tat expression and neurogenesis. Tat expression in astrocytes was associated with fewer neuron progenitor cells (NPCs), fewer immature neurons, and fewer mature neurons in the dentate gyrus of the hippocampus of the mouse brain. In vitro NPC-derived neurosphere assays showed that Tat-containing conditioned media from astrocytes or recombinant Tat protein inhibited NPC proliferation and migration and altered NPC differentiation, while immunodepletion of Tat from Tat-containing conditioned media or heat inactivation of recombinant Tat abrogated those effects. Notch signaling downstream gene Hes1 promoter-driven luciferase reporter gene assay and Western blotting showed that recombinant Tat or Tat-containing conditioned media activated Hes1 transcription and protein expression, which were abrogated by Tat heat inactivation, immunodepletion, and cysteine mutation at position 30. Last, Notch signaling inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT) significantly rescued Tat-impaired NPC differentiation in vitro and neurogenesis in vivo Together, these results show that Tat adversely affects NPCs and neurogenesis through Notch signaling and point to the potential of developing Notch signaling inhibitors as HIV/neuroAIDS therapeutics.
SIGNIFICANCE STATEMENT: HIV infection of the CNS causes cognitive and memory deficits, which have become more prevalent in the era of combination antiretroviral therapy (cART). Neurogenesis is impaired in HIV-infected individuals. But the underlying molecular mechanisms remain largely unknown. In this study, we have discovered that HIV Tat impairs neurogenesis through the Notch signaling pathway. These findings are particularly important because Tat protein has recently been detected in the brain of HIV-infected individuals with HIV replication in the periphery being effectively controlled by cART. The current study not only further highlights the importance of HIV Tat protein in HIV/neuroAIDS, but also presents a new strategy to develop novel HIV/neuroAIDS therapeutics, particularly in the era of cART.

PMID: 27807176 [PubMed - indexed for MEDLINE]

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