Publications by authors named "Sanjay Srivastava"

243 Publications

Subclinical markers of cardiovascular toxicity of benzene inhalation in mice.

Toxicol Appl Pharmacol 2021 Oct 5;431:115742. Epub 2021 Oct 5.

University of Louisville Superfund Research Center, University of Louisville, Louisville, KY 40202, United States of America; American Heart Association-Tobacco Center of Regulatory Science, University of Louisville, Louisville, KY 40202, United States of America; Envirome Institute, University of Louisville, Louisville, KY 40202, United States of America; Department of Medicine, Division of Environmental Medicine, University of Louisville, Louisville, KY 40202, United States of America. Electronic address:

Benzene is a ubiquitous environmental pollutant. Recent population-based studies suggest that benzene exposure is associated with an increased risk for cardiovascular disease. However, it is unclear whether benzene exposure by itself is sufficient to induce cardiovascular toxicity. We examined the effects of benzene inhalation (50 ppm, 6 h/day, 5 days/week, 6 weeks) or HEPA-filtered air exposure on the biomarkers of cardiovascular toxicity in male C57BL/6J mice. Benzene inhalation significantly increased the biomarkers of endothelial activation and injury including endothelial microparticles, activated endothelial microparticles, endothelial progenitor cell microparticles, lung endothelial microparticles, and activated lung and endothelial microparticles while having no effect on circulating levels of endothelial adhesion molecules, endothelial selectins, and biomarkers of angiogenesis. To understand how benzene may induce endothelial injury, we exposed human aortic endothelial cells to benzene metabolites. Of the metabolites tested, trans,trans-mucondialdehyde (10 μM, 18h) was the most toxic. It induced caspases-3, -7 and -9 (intrinsic pathway) activation and enhanced microparticle formation by 2.4-fold. Levels of platelet-leukocyte aggregates, platelet macroparticles, and a proportion of CD4 and CD8 T-cells were also significantly elevated in the blood of the benzene-exposed mice. We also found that benzene exposure increased the transcription of genes associated with endothelial cell and platelet activation in the liver; and induced inflammatory genes and suppressed cytochrome P450s in the lungs and the liver. Together, these data suggest that benzene exposure induces endothelial injury, enhances platelet activation and inflammatory processes; and circulatory levels of endothelial cell and platelet-derived microparticles and platelet-leukocyte aggregates are excellent biomarkers of cardiovascular toxicity of benzene.
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http://dx.doi.org/10.1016/j.taap.2021.115742DOI Listing
October 2021

Time spent outdoors and sleep normality: A preliminary investigation.

Popul Med 2021 Mar 4;3. Epub 2021 Mar 4.

Department of Communication, University of Louisville, Louisville, United States.

Introduction: Sleep deficiency is associated with health risks, and time outdoors is related to health benefits. This study assessed time outdoors and its association with sleep normality.

Methods: As part of a health study in Louisville, Kentucky, 735 participants completed questionnaires on their health status, behaviors, neighborhoods, and demographics in 2018-2019. The measures included information on sleep, time outdoors, and mental and physical health. Participant characteristics were assessed by dichotomized sleep normality (N=728), and logistic regression (N=709) examined potential associations between time outdoors and sleep.

Results: As time spent outdoors increased from ≤4 hours to >4 - ≤8 hours (OR=1.04; 95% CI: 0.65-1.64) and >8 - ≤12 hours (OR=1.17; 95% CI: 0.63-2.17), odds of normal sleep increased; however, those who spent >12 - ≤16 hours (OR=0.63; 95% CI: 0.31-1.27) or >16 hours (OR=0.83; 95% CI: 0.45-1.53) outdoors had a lower likelihood of normal sleep. No associations between time outdoors and sleep were significant. There was a significant trend of less bodily pain associated with normal sleep (p<0.001) and in the association of depression and sleep, where odds of normal sleep decreased as depression severity increased (p<0.001).

Conclusions: Consistent with extant literature, findings indicate associations between less pain and increased odds of normal sleep and between higher severity of depression and lower odds of normal sleep. Findings for an overall association between time outdoors and sleep normality were not significant. Future work should seek to better explicate the predictor variables to assess how greenness and activity type shape associations with sleep.
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http://dx.doi.org/10.18332/popmed/132119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8411876PMC
March 2021

The importance of urban planning: Views of greenness and open space is reversely associated with self-reported views and depressive symptoms.

Popul Med 2021 Jul;3

Department of Communication, University of Louisville, Louisville, United States.

Introduction: Exposure to green spaces is beneficial to mental health in a variety of ways, ranging from stress reduction to increased attentiveness and elevated self-esteem. The impact of views of greenness, as opposed to direct exposure, has been examined, but the association between self-reported views and depressive symptoms is not known. The purpose of this study is to examine the relationship between views of greenness and Patient Health Questionnaire-9 (PHQ-9) score.

Methods: Questionnaire responses from 191 participants in the Health, Environment, and Action in Louisville (HEAL) study were examined. Univariate statistical analyses included Mann-Whitney U, Kruskal-Wallis, and Spearman rank tests. Inferential statistical analysis was linear regression.

Results: Participant satisfaction with residential greenness was significantly associated with reduced PHQ-9 score (partially adjusted: linear coefficient = -0.42; 95% CI: -0.70 - -0.14; fully adjusted: linear coefficient = -0.21; 95% CI: -0.44 - 0.02). Additionally, being satisfied with local greenness was significantly associated with having views of greenness from home (linear coefficient = 1.97; 95% CI: 1.23-2.68).

Conclusions: Though views of greenness were not directly associated with depression, satisfaction with local greenness was associated with reduced PHQ-9 score, and having views of greenness from home was crudely associated with increased greenness satisfaction. The findings suggest urban greening interventions that focus on greenness satisfaction may be a strategy to reduce depression. Further research is necessary to better understand these relationships.
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http://dx.doi.org/10.18332/popmed/139173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341459PMC
July 2021

Atovaquone Suppresses the Growth of Metastatic Triple-Negative Breast Tumors in Lungs and Brain by Inhibiting Integrin/FAK Signaling Axis.

Pharmaceuticals (Basel) 2021 May 28;14(6). Epub 2021 May 28.

Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.

Triple-negative breast cancer (TNBC) is considered to be the most aggressive and malignant neoplasm and is highly metastatic in nature. In the current study, we investigated the anti-metastatic potential of atovaquone, a protozoal drug prescribed for Pneumocystis pneumonia. We showed that atovaquone induced apoptosis and reduced the survival of several aggressive metastatic TNBC cell lines including metastatic patient-derived cells by reducing the expression of integrin α6, integrin β4, FAK, Src, and Vimentin. In order to study the efficacy of atovaquone in suppressing metastasized breast tumor cells in brain and lungs, we performed three in vivo experiments. We demonstrated that oral administration of 50 mg/kg of atovaquone suppressed MDA-MB-231 breast tumor growth by 90% in lungs in an intravenous metastatic tumor model. Anti-metastatic effect of atovaquone was further determined by intracardiac injection of 4T1-luc breast tumor cells into the left ventricle of mouse heart. Our results showed that atovaquone treatment suppressed the growth of metastatic tumors in lungs, liver and brain by 70%, 50% and 30% respectively. In an intracranial model, the growth of HCC1806-luc brain tumors in atovaquone treated mice was about 55% less than that of control. Taken together, our results indicate the anti-metastatic effects of atovaquone in vitro and in vivo in various breast tumor metastasis models.
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http://dx.doi.org/10.3390/ph14060521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8229709PMC
May 2021

Atovaquone Suppresses Triple-Negative Breast Tumor Growth by Reducing Immune-Suppressive Cells.

Int J Mol Sci 2021 May 13;22(10). Epub 2021 May 13.

Department of Biomedical Sciences, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.

A major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through ribosomal protein S19 (RPS19), which facilitates myeloid-derived suppressor cells (MDSCs) recruitment in tumors, which generate cytokines TGF-β and IL-10 and induce regulatory T cells (Tregs), all of which are immunosuppressive and enhance tumor progression. Hence, enhancing the immune system in breast tumors could be a strategy for anticancer therapeutics. The present study evaluated the immune response of atovaquone, an antiprotozoal drug, in three independent breast-tumor models. Our results demonstrated that oral administration of atovaquone reduced HCC1806, CI66 and 4T1 paclitaxel-resistant (4T1-PR) breast-tumor growth by 45%, 70% and 42%, respectively. MDSCs, TGF-β, IL-10 and Tregs of blood and tumors were analyzed from all of these in vivo models. Our results demonstrated that atovaquone treatment in mice bearing HCC1806 tumors reduced MDSCs from tumor and blood by 70% and 30%, respectively. We also observed a 25% reduction in tumor MDSCs in atovaquone-treated mice bearing CI66 and 4T1-PR tumors. In addition, a decrease in TGF-β and IL-10 in tumor lysates was observed in atovaquone-treated mice with a reduction in tumor Tregs. Moreover, a significant reduction in the expression of RPS19 was found in tumors treated with atovaquone.
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http://dx.doi.org/10.3390/ijms22105150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152242PMC
May 2021

Lipid profiles in users of combustible and electronic cigarettes.

Vasc Med 2021 Oct 20;26(5):483-488. Epub 2021 May 20.

Evans Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.

Electronic cigarette use has especially risen among adolescents and young adults. The aim of this study was to investigate fasting blood glucose and lipid profiles in chronic combustible cigarette and electronic cigarette users. We evaluated participants aged 21 to 45 ( = 525, mean age 31 ± 7 years, 45% women) without established cardiovascular disease or risk factors who were combustible cigarette users ( = 290), electronic cigarette users ( = 131; 65 sole users and 66 dual users), or never users ( = 104). In the first wave of enrollment (2014-2017), electronic cigarette users reported their products as first, second and third generation devices (e-cig users) and were all largely current (i.e., dual) or former (sole) combustible cigarette users, whereas in the second wave of enrollment (2019-2020), electronic cigarette users all reported pod-based device use (pod users) and included more sole users who were never smokers. In multivariable-adjusted analyses comparing to never users, both sole e-cig users and combustible cigarette users had higher glucose and triglycerides and lower high-density lipoprotein (HDL) cholesterol levels. Dual e-cig users showed higher triglycerides and very-low-density lipoprotein cholesterol, and lower HDL cholesterol compared to never users. In contrast, pod users (both sole and dual) had lipid profiles and glucose levels similar to never users. Overall, users of early generation electronic cigarettes display adverse metabolic profiles. In contrast, pod-based electronic cigarette users have similar lipid profiles to never users. Future studies are needed to understand the cumulative effects of electronic cigarette use on cardiometabolic health.
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http://dx.doi.org/10.1177/1358863X211009313DOI Listing
October 2021

Potential of cotton for remediation of Cd-contaminated soils.

Environ Monit Assess 2021 Mar 13;193(4):186. Epub 2021 Mar 13.

ICAR-Indian Institute of Soil Science, Nabi Bagh, Berasia Road, Bhopal, India.

The present research was conducted to study the potential of cotton for the remediation of soils contaminated with Cd, to understand the biochemical basis of its tolerance to, and to investigate the plant-microbe interaction in the rhizosphere for enhancement of phytoextraction of Cd. Cotton (Bt RCH-2) was exposed to four Cd levels (0, 50, 100, and 200 mg/kg soil) in a completely randomised design and found that the plant could tolerate up to 200 mg/kg soil. Cd stress increased the total phenol, proline, and free amino acid contents in the plant leaf tissue compared with control but inhibited basal soil respiration, fluorescein diacetate hydrolysis, and activities of several enzymes viz. dehydrogenase, phosphatases, and β-glucosidase in the soil over control. The concentration of Cd in the shoot was less than the critical concentration of 100 µg/g dry weight, and bioconcentration and translocation factors were < 1 to classify the plant as a hyperaccumulator of Cd. This was further confirmed by another experiment in which the cotton plant was exposed various higher levels of Cd (200, 400, 600, 800, and 1000 mg/kg soil). Though the concentration of Cd in the shoot was > 100 µg g dw beyond 600 mg Cd/kg soil, the bioconcentration and translocation factors were < 1. The study on plant-microbe (Aspergillus awamori) interaction revealed that the fungus did not affect the absorption of Cd by cotton. It was concluded that the cotton was classified as an excluder of Cd and therefore could be suitable for the phytostabilization of Cd-contaminated soils.
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http://dx.doi.org/10.1007/s10661-021-08976-5DOI Listing
March 2021

Exposure to volatile organic compounds - acrolein, 1,3-butadiene, and crotonaldehyde - is associated with vascular dysfunction.

Environ Res 2021 05 24;196:110903. Epub 2021 Feb 24.

Christina Lee Brown Envirome Institute, 302 E Muhammad Ali Blvd, Louisville, KY, 40202, USA; Superfund Research Center, 302 E Muhammad Ali Blvd, Louisville, KY 40202, USA. Electronic address:

Background: Cardiovascular disease (CVD) is the leading cause of mortality worldwide. Exposure to air pollution, specifically particulate matter of diameter ≤2.5 μm (PM), is a well-established risk factor for CVD. However, the contribution of gaseous pollutant exposure to CVD risk is less clear.

Objective: To examine the vascular effects of exposure to individual volatile organic compounds (VOCs) and mixtures of VOCs.

Methods: We measured urinary metabolites of acrolein (CEMA and 3HPMA), 1,3-butadiene (DHBMA and MHBMA3), and crotonaldehyde (HPMMA) in 346 nonsmokers with varying levels of CVD risk. On the day of enrollment, we measured blood pressure (BP), reactive hyperemia index (RHI - a measure of endothelial function), and urinary levels of catecholamines and their metabolites. We used generalized linear models for evaluating the association between individual VOC metabolites and BP, RHI, and catecholamines, and we used Bayesian Kernel Machine Regression (BKMR) to assess exposure to VOC metabolite mixtures and BP.

Results: We found that the levels of 3HPMA were positively associated with systolic BP (0.98 mmHg per interquartile range (IQR) of 3HPMA; CI: 0.06, 1.91; P = 0.04). Stratified analysis revealed an increased association with systolic BP in Black participants despite lower levels of urinary 3HPMA. This association was independent of PM exposure and BP medications. BKMR analysis confirmed that 3HPMA was the major metabolite associated with higher BP in the presence of other metabolites. We also found that 3HPMA and DHBMA were associated with decreased endothelial function. For each IQR of 3HPMA or DHBMA, there was a -4.4% (CI: -7.2, -0.0; P = 0.03) and a -3.9% (CI: -9.4, -0.0; P = 0.04) difference in RHI, respectively. Although in the entire cohort the levels of several urinary VOC metabolites were weakly associated with urinary catecholamines and their metabolites, in Black participants, DHBMA levels showed strong associations with urinary norepinephrine and normetanephrine levels.

Discussion: Exposure to acrolein and 1,3-butadiene is associated with endothelial dysfunction and may contribute to elevated risk of hypertension in participants with increased sympathetic tone, particularly in Black individuals.
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http://dx.doi.org/10.1016/j.envres.2021.110903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8119348PMC
May 2021

Electronic cigarette solvents, pulmonary irritation, and endothelial dysfunction: role of acetaldehyde and formaldehyde.

Am J Physiol Heart Circ Physiol 2021 04 5;320(4):H1510-H1525. Epub 2021 Feb 5.

American Heart Association-Tobacco Regulation and Addiction Center, University of Louisville, Louisville, Kentucky.

After more than a decade of electronic cigarette (E-cig) use in the United States, uncertainty persists regarding E-cig use and long-term cardiopulmonary disease risk. As all E-cigs use propylene glycol and vegetable glycerin (PG-VG) and generate abundant saturated aldehydes, mice were exposed by inhalation to PG-VG-derived aerosol, formaldehyde (FA), acetaldehyde (AA), or filtered air. Biomarkers of exposure and cardiopulmonary injury were monitored by mass spectrometry (urine metabolites), radiotelemetry (respiratory reflexes), isometric myography (aorta), and flow cytometry (blood markers). Acute PG-VG exposure significantly affected multiple biomarkers including pulmonary reflex (decreased respiratory rate, -50%), endothelium-dependent relaxation (-61.8 ± 4.2%), decreased WBC (-47 ± 7%), and, increased RBC (+6 ± 1%) and hemoglobin (+4 ± 1%) versus air control group. Notably, FA exposure recapitulated the prominent effects of PG-VG aerosol on pulmonary irritant reflex and endothelial dysfunction, whereas AA exposure did not. To attempt to link PG-VG exposure with FA or AA exposure, urinary formate and acetate levels were measured by GC-MS. Although neither FA nor AA exposure altered excretion of their primary metabolite, formate or acetate, respectively, compared with air-exposed controls, PG-VG aerosol exposure significantly increased post-exposure urinary acetate but not formate. These data suggest that E-cig use may increase cardiopulmonary disease risk independent of the presence of nicotine and/or flavorings. This study indicates that FA levels in tobacco product-derived aerosols should be regulated to levels that do not induce biomarkers of cardiopulmonary harm. There remains a need for reliable biomarkers of exposure to inhaled FA and AA. Use of electronic cigarettes (E-cig) induces endothelial dysfunction (ED) in healthy humans, yet the specific constituents in E-cig aerosols that contribute to ED are unknown. Our study implicates formaldehyde that is formed in heating of E-cig solvents (propylene glycol, PG; vegetable glycerin, VG). Exposure to formaldehyde or PG-VG-derived aerosol alone stimulated ED in female mice. As ED was independent of nicotine and flavorants, these data reflect a "universal flaw" of E-cigs that use PG-VG.Listen to this article's corresponding podcast at https://ajpheart.podbean.com/e/e-cigarettes-aldehydes-and-endothelial-dysfunction/.
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http://dx.doi.org/10.1152/ajpheart.00878.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260384PMC
April 2021

Aldose reductase regulates doxorubicin-induced immune and inflammatory responses by activating mitochondrial biogenesis.

Eur J Pharmacol 2021 Mar 20;895:173884. Epub 2021 Jan 20.

Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, 77555, USA. Electronic address:

We have recently demonstrated that aldose reductase (AR) inhibitor; fidarestat prevents doxorubicin (Dox)-induced cardiotoxic side effects and inflammation in vitro and in vivo. However, the effect of fidarestat and its combination with Dox on immune cell activation and the immunomodulatory effects are not known. In this study, we examined the immunomodulatory effects of fidarestat in combination with Dox in vivo and in vitro. We observed that fidarestat decreased Dox-induced upregulation of CD11b in THP-1 monocytes. Fidarestat further attenuated Dox-induced upregulation of IL-6, IL-1β, and Nos2 in murine BMDM. Fidarestat also attenuated Dox-induced activation and infiltration of multiple subsets of inflammatory immune cells identified by expression of markers CD11b, CD11bF4/80, Ly6CCCR2, and Ly6CCD11b in the mouse spleen and liver. Furthermore, significant upregulation of markers of mitochondrial biogenesis PGC-1α, COX IV, TFAM, and phosphorylation of AMPKα1 (Ser485) was observed in THP-1 cells and livers of mice treated with Dox in combination with fidarestat. Our results suggest that fidarestat by up-regulating mitochondrial biogenesis exerts protection against Dox-induced immune and inflammatory responses in vitro and in vivo, providing further evidence for developing fidarestat as a combination agent with anthracycline drugs to prevent chemotherapy-induced inflammation and toxicity.
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http://dx.doi.org/10.1016/j.ejphar.2021.173884DOI Listing
March 2021

Role of Phytochemicals in Perturbation of Redox Homeostasis in Cancer.

Antioxidants (Basel) 2021 Jan 9;10(1). Epub 2021 Jan 9.

Department of Immunotherapeutics and Biotechnology, Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA.

Over the past few decades, research on reactive oxygen species (ROS) has revealed their critical role in the initiation and progression of cancer by virtue of various transcription factors. At certain threshold values, ROS act as signaling molecules leading to activation of oncogenic pathways. However, if perturbated beyond the threshold values, ROS act in an anti-tumor manner leading to cellular death. ROS mediate cellular death through various programmed cell death (PCD) approaches such as apoptosis, autophagy, ferroptosis, etc. Thus, external stimulation of ROS beyond a threshold is considered a promising therapeutic strategy. Phytochemicals have been widely regarded as favorable therapeutic options in many diseased conditions. Over the past few decades, mechanistic studies on phytochemicals have revealed their effect on ROS homeostasis in cancer. Considering their favorable side effect profile, phytochemicals remain attractive treatment options in cancer. Herein, we review some of the most recent studies performed using phytochemicals and, we further delve into the mechanism of action enacted by individual phytochemicals for PCD in cancer.
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http://dx.doi.org/10.3390/antiox10010083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827008PMC
January 2021

Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity.

ACS Med Chem Lett 2020 Dec 16;11(12):2389-2396. Epub 2020 Oct 16.

Genentech Inc., 1 DNA Way, South San Francisco, California 94080-4990, United States.

Amino-quinazoline BRaf kinase inhibitor was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1α was then targeted to build in selectivity over BRaf which instead possesses a histidine in this position (His539). Torsional angle analysis revealed that the quinazoline hinge binder core was ill-suited to accommodate the required conformation to effectively reach Glu651, prompting a change to the thienopyrimidine hinge binder. Resulting analogues such as demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.
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http://dx.doi.org/10.1021/acsmedchemlett.0c00344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7734639PMC
December 2020

Macrophages Mediate the Antitumor Effects of the Oncolytic Virus HSV1716 in Mammary Tumors.

Mol Cancer Ther 2021 03 9;20(3):589-601. Epub 2020 Dec 9.

Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, United Kingdom.

Oncolytic viruses (OV) have been shown to activate the antitumor functions of specific immune cells like T cells. Here, we show OV can also reprogram tumor-associated macrophage (TAM) to a less immunosuppressive phenotype. Syngeneic, immunocompetent mouse models of primary breast cancer were established using PyMT-TS1, 4T1, and E0771 cell lines, and a metastatic model of breast cancer was established using the 4T1 cell line. Tumor growth and overall survival was assessed following intravenous administration of the OV, HSV1716 (a modified herpes simplex virus). Infiltration and function of various immune effector cells was assessed by NanoString, flow cytometry of dispersed tumors, and immunofluorescence analysis of tumor sections. HSV1716 administration led to marked tumor shrinkage in primary mammary tumors and a decrease in metastases. This was associated with a significant increase in the recruitment/activation of cytotoxic T cells, a reduction in the presence of regulatory T cells and the reprograming of TAMs towards a pro-inflammatory, less immunosuppressive phenotype. These findings were supported by data demonstrating that human monocyte-derived macrophages host HSV1716 replication, and that this led to immunogenic macrophage lysis. These events were dependent on macrophage expression of proliferating cell nuclear antigen (PCNA). Finally, the antitumor effect of OV was markedly diminished when TAMs were depleted using clodronate liposomes. Together, our results show that TAMs play an essential role in support of the tumoricidal effect of the OV, HSV1716-they both host viral replication via a novel, PCNA-dependent mechanism and are reprogramed to express a less immunosuppressive phenotype.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0748DOI Listing
March 2021

Is perceived similarity more than assumed similarity? An interpersonal path to seeing similarity between self and others.

J Pers Soc Psychol 2021 Jul 22;121(1):184-200. Epub 2020 Oct 22.

University of Oregon.

People perceive similarity between their own personality characteristics and the personality characteristics of others. This association has sometimes been labeled "assumed similarity," reflecting the interpretation that it is a cognitive bias. Another possibility, however, is an interpersonal path to perceived similarity: personality traits that are manifested in behavior may elicit similar or dissimilar behavior from others, and people form perceptions based on what they have elicited. Drawing on theories of interpersonal perception and interpersonal theory, we proposed and tested for evidence of such effects, as well as trait and state assumed similarity. Previously unacquainted participants ( = 322) completed personality assessments, interacted in dyads the next day, and then reported perceptions of each other's personalities. The results showed broad support for the expression and accurate perceptions of most Big Five domains and facets. The preregistered directional hypotheses for behavior elicitation and perceiver-elicited similarity were supported for 3 of 5 traits. Participants interpersonally elicited and then accurately perceived similarity in sociability and openness, and dissimilarity in assertiveness. We also found evidence for assumed similarity for agreeableness and energy level, but participants did not elicit similar behavior from their partners for those traits. We discuss implications for treating perceived similarity as a dynamic, multicomponent phenomenon, and the possibility that assumed similarity emerges from the repeated experience of interpersonally elicited and perceived similarity. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pspp0000369DOI Listing
July 2021

Repurposing Pimavanserin, an Anti-Parkinson Drug for Pancreatic Cancer Therapy.

Mol Ther Oncolytics 2020 Dec 2;19:19-32. Epub 2020 Sep 2.

Department of Immunotherapeutics and Biotechnology, Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA.

Despite major advances in cancer treatment, pancreatic cancer is still incurable and the treatment outcomes are limited. The aggressive and therapy-resistant nature of pancreatic cancer warrants the need for novel treatment options for pancreatic cancer management. Drug repurposing is emerging as an effectual strategy in the treatment of various diseases, including cancer. In the present study, we evaluated the anticancer effects of pimavanserin tartrate (PVT), an antipsychotic drug used for the treatment of Parkinson disease psychosis. PVT significantly suppressed the proliferation and induced apoptosis in various pancreatic cancer cells and gemcitabine-resistant cells with minimal effects on normal pancreatic epithelial cells and lung fibroblasts. Growth-suppressive and apoptotic effects of PVT were mediated by the inhibition of the Akt/Gli1 signaling axis. The oral administration of PVT suppressed subcutaneous and orthotopic pancreatic tumor xenografts by 51%-77%. The chronic administration of PVT did not demonstrate any general signs of toxicity or change in behavioral activity of mice. Our results indicate that pancreatic tumor growth suppression by PVT was orchestrated by the inhibition of Akt/Gli1 signaling. Since PVT is already available in the clinic with an established safety profile, our results will accelerate its clinical development for the treatment of patients with pancreatic cancer.
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http://dx.doi.org/10.1016/j.omto.2020.08.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527685PMC
December 2020

Pimozide Suppresses the Growth of Brain Tumors by Targeting STAT3-Mediated Autophagy.

Cells 2020 09 22;9(9). Epub 2020 Sep 22.

Department of Biomedical Science, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.

Brain tumors are considered as one of the most aggressive and incurable forms of cancer. The majority of the patients with brain tumors have a median survival rate of 12%. Brain tumors are lethal despite the availability of advanced treatment options such as surgical removal, chemotherapy, and radiotherapy. In this study, we have evaluated the anti-cancer effects of pimozide, which is a neuroleptic drug used for the treatment of schizophrenia and chronic psychosis. Pimozide significantly reduced the proliferation of U-87MG, Daoy, GBM 28, and U-251MG brain cancer cell lines by inducing apoptosis with IC (Inhibitory concentration 50) ranging from 12 to 16 μM after 48 h of treatment. Our Western blotting analysis indicated that pimozide suppressed the phosphorylation of STAT3 at Tyr705 and Src at Tyr416, and it inhibited the expression of anti-apoptotic markers c-Myc, Mcl-1, and Bcl-2. Significant autophagy induction was observed with pimozide treatment. LC3B, Beclin-1, and ATG5 up-regulation along with autolysosome formation confirmed the induction of autophagy with pimozide treatment. Inhibiting autophagy using 3-methyladenine or LC3B siRNA significantly blocked the apoptosis-inducing effects of pimozide, suggesting that pimozide mediated its apoptotic effects by inducing autophagy. Oral administration of 25 mg/kg pimozide suppressed the intracranially implanted U-87MG tumor growth by 45% in athymic nude mice. The chronic administration of pimozide showed no general signs of toxicity, and the behavioral activity of the mice remained unchanged. Taken together, these results indicate that pimozide inhibits the growth of brain cancer by autophagy-mediated apoptosis.
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http://dx.doi.org/10.3390/cells9092141DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563195PMC
September 2020

Epsin-mediated degradation of IP3R1 fuels atherosclerosis.

Nat Commun 2020 08 7;11(1):3984. Epub 2020 Aug 7.

Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.

The epsin family of endocytic adapter proteins are widely expressed, and interact with both proteins and lipids to regulate a variety of cell functions. However, the role of epsins in atherosclerosis is poorly understood. Here, we show that deletion of endothelial epsin proteins reduces inflammation and attenuates atherosclerosis using both cell culture and mouse models of this disease. In atherogenic cholesterol-treated murine aortic endothelial cells, epsins interact with the ubiquitinated endoplasmic reticulum protein inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), which triggers proteasomal degradation of this calcium release channel. Epsins potentiate its degradation via this interaction. Genetic reduction of endothelial IP3R1 accelerates atherosclerosis, whereas deletion of endothelial epsins stabilizes IP3R1 and mitigates inflammation. Reduction of IP3R1 in epsin-deficient mice restores atherosclerotic progression. Taken together, epsin-mediated degradation of IP3R1 represents a previously undiscovered biological role for epsin proteins and may provide new therapeutic targets for the treatment of atherosclerosis and other diseases.
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http://dx.doi.org/10.1038/s41467-020-17848-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414107PMC
August 2020

Perceiving personality through the grapevine: A network approach to reputations.

J Pers Soc Psychol 2021 Jul 27;121(1):151-167. Epub 2020 Jul 27.

Department of Psychology.

Reputations are critical in human social life: they allow people to share and act on information about one another, even when they have never met. Reputations can be conceptualized as information about a target person that is stored in networks of perceivers and transmitted through either direct interaction or hearsay. We present a novel paradigm that integrates the network approach with interpersonal perception research. We apply that paradigm to study the consensus, accuracy, positivity bias, and consequences of personality trait information in hearsay-based reputations. In 2 preregistered studies ( = 260 and 369), we created naturalistic micronetworks in the lab in which participants interacted and got to know one another, then later described each other to naïve third parties. Across studies, we use the extended Social Accuracy Model (Wessels, Zimmermann, Biesanz, & Leising, 2020) and an extension of the domain-wise correlational approach (Kenny, 1994). Hearsay-based reputations are about as positively biased as direct reputations. They showed strong consensus (agreement) with direct reputations and modest accuracy, suggesting that they can consolidate around an inaccurate representation. Perceivers' extraversion was associated with more biased hearsay reputations. Experimentally manipulating the context of the hearsay exchange had no detectable impact on hearsay consensus or accuracy. Hearsay reputations were consequential, affecting the extent to which perceivers thought targets would be good leaders or friends. These results provide initial insights into reputation networks and suggest several important future directions for the network approach to reputations. We also present open materials and data analysis software for others to extend the reputations-as-networks approach. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
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http://dx.doi.org/10.1037/pspp0000362DOI Listing
July 2021

Special issue: Drug repurposing for cancer therapy.

Semin Cancer Biol 2021 Jan 15;68:1-2. Epub 2020 Jul 15.

Department of Immunotherapeutics and Biotechnology, Texas Tech University Health Sciences Center, 1718Pin. Street, Abilene, TX 79601, USA. Electronic address:

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http://dx.doi.org/10.1016/j.semcancer.2020.07.008DOI Listing
January 2021

Acute and chronic vascular effects of inhaled crotonaldehyde in mice: Role of TRPA1.

Toxicol Appl Pharmacol 2020 09 4;402:115120. Epub 2020 Jul 4.

Department of Pharmacology and Toxicology, School of Medicine, University of Louisville, United States of America; Christina Lee Brown Envirome Institute, University of Louisville, United States of America; Diabetes & Obesity Center, University of Louisville, United States of America; Superfund Research Center, University of Louisville, United States of America; Division of Environmental Medicine, Department of Medicine, University of Louisville, Louisville, KY 40202, United States of America. Electronic address:

Although crotonaldehyde (CR) is an abundant α,β-unsaturated aldehyde in mainstream cigarette smoke (MCS), the cardiovascular toxicity of inhaled CR is largely unexplored. Thus, male C57BL/6 J mice were exposed acutely (1 h, 6 h, and 4d) and chronically (12 weeks) to CR (at levels relevant to MCS; 1 and 3 ppm), and cardiovascular and systemic outcomes were measured in vivo and in vitro. Diastolic blood pressure was decreased (hypotension) by both acute and chronic CR exposure. Vascular toxicity of inhaled CR was quantified in isolated aorta in response to agonists of contraction (phenylephrine, PE) and relaxation (acetylcholine, ACh; sodium nitroprusside, SNP). Although no change in contractility was observed, ACh-induced relaxations were augmented after both acute and chronic CR exposures whereas SNP-induced relaxation was enhanced only following 3 ppm CR exposure. Because CR is a known agonist of the transient receptor potential ankyrin 1 (TRPA1) channel, male TRPA1-null mice were exposed to air or CR (4d, 1 ppm) and aortic function assessed in vitro. CR exposure had no effect on TRPA1-null aortic function indicating a role of TRPA1 in CR effects in C57BL/6 J mice. Notably, CR exposure (4d, 1 ppm) had no effect on aortic function in female C57BL/6 J mice. This study shows that CR inhalation exposure induces real-time and persistent vascular changes that promote hypotension-a known risk factor for stroke. Because of continued widespread exposures of humans to combustion-derived CR (environmental and tobacco products), CR may be an important cardiovascular disease risk factor.
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http://dx.doi.org/10.1016/j.taap.2020.115120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7485374PMC
September 2020

Drug rechanneling: A novel paradigm for cancer treatment.

Semin Cancer Biol 2021 Jan 11;68:279-290. Epub 2020 May 11.

Department of Immunotherapeutics and Biotechnology, and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA. Electronic address:

Cancer continues to be one of the leading contributors towards global disease burden. According to NIH, cancer incidence rate per year will increase to 23.6 million by 2030. Even though cancer continues to be a major proportion of the disease burden worldwide, it has the lowest clinical trial success rate amongst other diseases. Hence, there is an unmet need for novel, affordable and effective anti-neoplastic medications. As a result, a growing interest has sparkled amongst researchers towards drug repurposing. Drug repurposing follows the principle of polypharmacology, which states, "any drug with multiple targets or off targets can present several modes of action". Drug repurposing also known as drug rechanneling, or drug repositioning is an economic and reliable approach that identifies new disease treatment of already approved drugs. Repurposing guarantees expedited access of drugs to the patients as these drugs are already FDA approved and their safety and toxicity profile is completely established. Epidemiological studies have identified the decreased occurrence of oncological or non-oncological conditions in patients undergoing treatment with FDA approved drugs. Data from multiple experimental studies and clinical observations have depicted that several non-neoplastic drugs have potential anticancer activity. In this review, we have summarized the potential anti-cancer effects of anti-psychotic, anti-malarial, anti-viral and anti-emetic drugs with a brief overview on their mechanism and pathways in different cancer types. This review highlights promising evidences for the repurposing of drugs in oncology.
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http://dx.doi.org/10.1016/j.semcancer.2020.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7786449PMC
January 2021

Low Dose of Penfluridol Inhibits VEGF-Induced Angiogenesis.

Int J Mol Sci 2020 Jan 23;21(3). Epub 2020 Jan 23.

Department of Biomedical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, Amarillo, TX 79106, USA.

Metastasis is considered a major burden in cancer, being responsible for more than 90% of cancer-related deaths. Tumor angiogenesis is one of the main processes that lead to tumor metastasis. Penfluridol is a classic and commonly used antipsychotic drug, which has a great ability to cross the blood-brain barrier. Recent studies have revealed that penfluridol has significant anti-cancer activity in diverse tumors, such as metastatic breast cancer and glioblastoma. Here, we aim to identify the effect of low doses of penfluridol on tumor microenvironment and compare it with its effect on tumor cells. Although low concentration of penfluridol was not toxic for endothelial cells, it blocked angiogenesis in vitro and in vivo. In vitro, penfluridol inhibited VEGF-induced primary endothelial cell migration and tube formation, and in vivo, it blocked VEGF- and FGF-induced angiogenesis in the matrigel plug assay. VEGF-induced VEGFR2 phosphorylation and the downstream p38 and ERK signaling pathways were not affected in endothelial cells, although VEGF-induced Src and Akt activation were abrogated by penfluridol treatment. When cancer cells were treated with the same low concentration of penfluridol, basal Src activation levels were mildly impaired, thus impacting their cell migration and wound healing efficiency. The potential of cancer-induced paracrine effect on endothelial cells was explored, although that did not seem to be a player for angiogenesis. Overall, our data demonstrates that low penfluridol levels, similar to the ones clinically used for anti-psychotic conditions, suppress angiogenic efficiency in the tumor microenvironment.
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http://dx.doi.org/10.3390/ijms21030755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036977PMC
January 2020

Oxidative Stress and Cancer: Chemopreventive and Therapeutic Role of Triphala.

Antioxidants (Basel) 2020 Jan 13;9(1). Epub 2020 Jan 13.

Department of Immunotherapeutics and Biotechnology, and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX 79601, USA.

Oxidative stress, caused by the overproduction of free radicals, leads to the development of many chronic diseases including cancer. Free radicals are known to damage cellular biomolecules like lipids, proteins, and DNA that results in activation of multiple signaling pathways, growth factors, transcription factors, kinases, inflammatory and cell cycle regulatory molecules. Antioxidants, which are classified as exogenous and endogenous, are responsible for the removal of free radicals and consequently the reduction in oxidative stress-mediated diseases. Diet and medicinal herbs are the major source of antioxidants. Triphala, which is a traditional Ayurvedic formulation that has been used for centuries, has been shown to have immense potential to boost antioxidant activity. It scavenges free radicals, restores antioxidant enzymes and non-enzyme levels, and decreases lipid peroxidation. In addition, Triphala is revered as a chemopreventive, chemotherapeutic, immunomodulatory, and radioprotective agent. Accumulated evidence has revealed that Triphala modulates multiple cell signaling pathways including, ERK, MAPK, NF-κB, Akt, c-Myc, VEGFR, mTOR, tubulin, p53, cyclin D1, anti-apoptotic and pro-apoptotic proteins. The present review focuses on the comprehensive appraisal of Triphala in oxidative stress and cancer.
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http://dx.doi.org/10.3390/antiox9010072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022920PMC
January 2020

Therapeutic Targeting of Vasculature in the Premetastatic and Metastatic Niches Reduces Lung Metastasis.

J Immunol 2020 02 3;204(4):990-1000. Epub 2020 Jan 3.

Department of Immunotherapeutics and Biotechnology, School of Pharmacy, Texas Tech University Health Sciences Center, Abilene, TX 79601;

In the metastasis-targeted organs, angiogenesis is essential for the progression of dormant micrometastases to rapidly growing and clinically overt lesions. However, we observed changes suggesting angiogenic switching in the mouse lungs prior to arrival of tumor cells (i.e., in the premetastatic niche) in the models of breast carcinoma. This angiogenic switching appears to be caused by myeloid-derived suppressor cells recruited to the premetastatic lungs through complement C5a receptor 1 signaling. These myeloid cells are known to secrete several proangiogenic factors in tumors, including IL-1β and matrix metalloproteinase-9, and we found upregulation of these genes in the premetastatic lungs. Blockade of C5a receptor 1 synergized with antiangiogenic -based vaccines to decrease the lung metastatic burden by reducing vascular density and improving antitumor immunity in the lungs. This was mediated even when growth of primary breast tumors was not affected by these treatments. This work provides initial evidence that angiogenesis contributes to the premetastatic niche in rapidly progressing cancers and that inhibiting this process through immunotherapy is beneficial for reducing or even preventing metastasis.
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http://dx.doi.org/10.4049/jimmunol.1901208DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012400PMC
February 2020

Electronic cigarettes and insulin resistance in animals and humans: Results of a controlled animal study and the National Health and Nutrition Examination Survey (NHANES 2013-2016).

PLoS One 2019 31;14(12):e0226744. Epub 2019 Dec 31.

Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.

Background: The popularity of electronic cigarettes (E-cigarettes) has risen considerably. Several studies have suggested that nicotine may affect insulin resistance, however, the impact of E-cigarette exposure on insulin resistance, an early measure of cardiometabolic risk, is not known.

Methods And Results: Using experimental animals and human data obtained from 3,989 participants of the United States National Health and Nutrition Examination Survey (NHANES), respectively, we assessed the association between E-cigarette and conventional cigarette exposures and insulin resistance, as modelled using the homeostatic model assessment of insulin resistance (HOMA-IR) and glucose tolerance tests (GTT). C57BL6/J mice (on standard chow diet) exposed to E-cigarette aerosol or mainstream cigarette smoke (MCS) for 12 weeks showed HOMA-IR and GTT levels comparable with filtered air-exposed controls. In the NHANES cohort, there was no significant association between defined tobacco product use categories (non-users; sole E-cigarette users; cigarette smokers and dual users) and insulin resistance. Compared with non-users of e-cigarettes/conventional cigarettes, sole E-cigarette users showed no significant difference in HOMA-IR or GTT levels following adjustment for age, sex, race, physical activity, alcohol use and BMI.

Conclusion: E-cigarettes do not appear to be linked with insulin resistance. Our findings may inform future studies assessing potential cardiometabolic harms associated with E-cigarette use.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226744PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938328PMC
April 2020

Targeting Glioblastoma Tumor Microenvironment.

Adv Exp Med Biol 2020 ;1296:1-9

Department of Immunotherapeutics and Biotechnology and Center for Tumor Immunology and Targeted Cancer Therapy, Texas Tech University Health Sciences Center, Abilene, TX, USA.

Glioblastoma, also referred to as glioblastoma multiforme (GBM), is an aggressive type of brain cancer. The prognosis for GBM is poor with an average medium survival rate of 12-15 months. GBM is highly challenging to treat due to neural stem cells phenotypic variations. These variations are determined by the tumor microenvironment (TME), which refers to all the molecules, cells, and structures that encompass and support other cells and tissues. Along with these, other vital components of the TME are fibroblasts, immune and inflammatory cells, blood and lymphatic vascular networks, extracellular matrix, and signaling molecules. This chapter provides an in-depth review of the vital components that form the TME and methods currently under development attempting to target each key area.
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http://dx.doi.org/10.1007/978-3-030-59038-3_1DOI Listing
July 2021

Lipid Peroxidation Products in Human Health and Disease 2019.

Oxid Med Cell Longev 2019 27;2019:7147235. Epub 2019 Nov 27.

Medical Oncology and Therapeutics Research, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA.

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http://dx.doi.org/10.1155/2019/7147235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6900947PMC
June 2020

Electromyographic analysis of VMO and VL across straight leg raise, short arc quad, medial tibial rotation and hip adduction in normal individuals.

Work 2020 ;65(1):153-159

Department of Mechanical Engineering, Industrial Kinesiology Laboratory, Faculty of Engineering, Dayalbagh Educational Institute (Deemed University), Dayalbagh, Agra, India.

Background: The lateral malalignment of patella is considered to be the main cause of patellofemoral pain syndrome (PFPS). PFPS, in an occupational setup, is aggravated by prolonged sitting, climbing stairs, squatting, and kneeling. Strengthening of vastus medialis oblique (VMO) opposes the lateral force produced by vastus lateralis (VL) and helps in stabilizing patella.

Objective: The main objective was to compare six common rehabilitation exercises (REs) and to identify those which could possibly activate VMO selectively to alleviate PFPS of occupational workers.

Methods: Ten subjects, having no history of PFPS, performed six REs, namely, straight leg raise with neutral hip position (SLRN), straight leg raise with externally rotated hip position (SLRER), short arc quad with neutral hip position (SAQN), short arc quad with externally rotated hip position (SAQER), medial tibial rotation and hip adduction (HA). REs were compared on the basis of integrated electromyographic activity of VMO and VL.

Results: Results demonstrated that VMO activity was more than that of VL during all REs. However, this difference was not statistically significant in any of the six REs. HA produced significantly higher VMO activity than SLRN, SLRER and SAQN.

Conclusions: The results provided a wider range of options for selecting apposite REs for treating patients diagnosed with PFPS.
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http://dx.doi.org/10.3233/WOR-193068DOI Listing
August 2020

Association between residential greenness and exposure to volatile organic compounds.

Sci Total Environ 2020 Mar 23;707:135435. Epub 2019 Nov 23.

Christina Lee Brown Envirome Institute, University of Louisville, 302 E Muhammad Ali Blvd., Louisville, KY 40202, United States; Superfund Research Center, University of Louisville, 302 E Muhammad Ali Blvd., Louisville, KY 40202, United States; Diabetes and Obesity Center, University of Louisville, 580 S. Preston St., Louisville, KY 40202, United States. Electronic address:

Residential proximity to vegetation and plants is associated with many health benefits, including reduced risk of cardiovascular disease, diabetes and mental stress. Although the mechanisms by which proximity to greenness affects health remain unclear, plants have been shown to remove particulate air pollution. However, the association between residential-area vegetation and exposure to volatile organic chemicals (VOCs) has not been investigated. We recruited a cohort of 213 non-smoking individuals and estimated peak, cumulative, and contemporaneous greenery using satellite-derived normalized difference vegetation index (NDVI) near their residence. We found that the urinary metabolites of exposure to VOCs - acrolein, acrylamide, acrylonitrile, benzene, 1-bromopropane, propylene oxide were inversely associated (7-31% lower) with 0.1 higher peak NDVI values within 100 m radius of the participants' home. These associations were significant at radii ranging from 25 to 300 m. Strongest associations were observed within a 200 m radius, where VOC metabolites were 22% lower per 0.1 unit higher NDVI. Of the 18 measured urinary metabolites, 7 were positively associated with variation of greenness within a 200 m radius of homes. The percent of tree canopy and street trees around participants' residence were less strongly associated with metabolite levels. The associations between urinary VOC metabolites and residential NDVI values were stronger in winter than in summer, and in participants who were more educated, White, and those who lived close to areas of high traffic. These findings suggest high levels of residential greenness are associated with lower VOC exposure, particularly in winter.
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http://dx.doi.org/10.1016/j.scitotenv.2019.135435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294698PMC
March 2020

Acetaldehyde Induces an Endothelium-Dependent Relaxation of Superior Mesenteric Artery: Potential Role in Postprandial Hyperemia.

Front Physiol 2019 22;10:1315. Epub 2019 Oct 22.

Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, United States.

Acetaldehyde (AA) is a small, ubiquitous compound present in foods, beverages, as a gas phase combustion product, and also endogenously generated from metabolism as from ethanol (EtOH). Acetate is a short chain fatty acid derived from AA oxidation, and acetate levels were significantly higher in urine collected overnight with food provided compared with urine collected after 9 h fasting. Feeding increases gastrointestinal blood flow, and thus, we explored the direct effects of AA (and acetate) in isolated murine superior mesenteric artery (SMA). Over the concentration range of 1-100 mM, AA strongly, and reversibly relaxed agonist-induced contractions of SMA including phenylephrine (PE), thromboxane A analog (U46,619) and high potassium (High K) without toxicity. The sensitivity (EC) but not the efficacy (>90% relaxation of PE-precontraction) of AA-induced relaxations was dependent on blood vessel (SMA was 3× more sensitive than aorta) and contractile agonist (PE EC = 3.3 ± 0.4 mM; U46,619 EC = 14.9 ± 1.5 mM; and High K EC = 17.7 ± 0.5 mM) yet independent of circadian cycle and sex. The most sensitive component of the AA-induced relaxation was inhibited significantly by: (1) a mechanically impaired endothelium; (2) nitric oxide synthase (NOS) inhibitor (L-NAME); and (3) a guanylyl cyclase (GC) inhibitor (ODQ). Both acetate and EtOH stimulated much weaker relaxations in SMA than did AA, yet these relaxations were significantly inhibited by L-NAME as well. Neither EtOH nor acetate relaxed pre-contracted aorta. Although neither cyanamide, a non-specific aldehyde dehydrogenase (ALDH) enzyme inhibitor, nor Alda-1, a specific activator of ALDH2 activity, had any effect on either sensitivity or efficacy of AA-induced relaxation in SMA, cyanamide significantly blocked both EtOH- and acetate-induced relaxations in SMA implicating a role of ALDH activity in vasorelaxation. These data show that AA relaxes SMA via an endothelium- and NO-dependent mechanism indicating that AA may be one component of the complex post-prandial hyperemia reflex via vasodilatation of mesenteric vasculature.
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http://dx.doi.org/10.3389/fphys.2019.01315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6817488PMC
October 2019
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