Publications by authors named "Sarah L Ullevig"

17 Publications

  • Page 1 of 1

Obesity, not a high fat, high sucrose diet alone, induced glucose intolerance and cardiac dysfunction during pregnancy and postpartum.

Sci Rep 2021 Sep 10;11(1):18057. Epub 2021 Sep 10.

Department of Kinesiology, University of Texas at San Antonio, One UTSA Circle, San Antonio, TX, 78249, USA.

Cardiovascular disease is the leading cause of death in women during pregnancy and the postpartum period. Obesity is an independent risk factor for cardiovascular diseases. Nearly 60% of women of reproductive age are considered overweight or obese, cardiovascular disease morbidity and mortality continue to be pervasive. The objective of this study was to determine the effects of an obesogenic diet on the cardiometabolic health of dams during pregnancy and postpartum. Female mice were fed either a high-fat, high-sucrose diet (HFHS) or a refined control diet (CON) for 8 weeks before initiation of pregnancy and throughout the study period. Mice in the HFHS showed two distinct phenotypes, obesity-prone (HFHS/OP) and obesity resistance (HFHS/OR). Pre-pregnancy obesity (HFHS/OP) induced glucose intolerance before pregnancy and during postpartum. Systolic function indicated by the percent fractional shortening (%FS) was significantly decreased in the HFHS/OP at late pregnancy (vs. HFHS/OR) and weaning (vs. CON), but no differences were found at 6 weeks of postpartum among groups. No induction of pathological cardiac hypertrophy markers was found during postpartum. Plasma adiponectin was decreased while total cholesterol was increased in the HFHS/OP. Our results suggested that obesity, not the diet alone, negatively affected cardiac adaptation during pregnancy and postpartum.
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http://dx.doi.org/10.1038/s41598-021-97336-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8433413PMC
September 2021

Ursolic Acid and Related Analogues: Triterpenoids with Broad Health Benefits.

Antioxidants (Basel) 2021 Jul 21;10(8). Epub 2021 Jul 21.

Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA.

Ursolic acid (UA) is a well-studied natural pentacyclic triterpenoid found in herbs, fruit and a number of traditional Chinese medicinal plants. UA has a broad range of biological activities and numerous potential health benefits. In this review, we summarize the current data on the bioavailability and pharmacokinetics of UA and review the literature on the biological activities of UA and its closest analogues in the context of inflammation, metabolic diseases, including liver and kidney diseases, obesity and diabetes, cardiovascular diseases, cancer, and neurological disorders. We end with a brief overview of UA's main analogues with a special focus on a newly discovered naturally occurring analogue with intriguing biological properties and potential health benefits, 23-hydroxy ursolic acid.
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http://dx.doi.org/10.3390/antiox10081161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8388988PMC
July 2021

Feasibility of dietary folic acid reduction intervention for men on active surveillance for prostate cancer.

Clin Nutr ESPEN 2021 08 3;44:270-275. Epub 2021 Jul 3.

Department of Urology, University of Texas Health Science Center San Antonio, 7703 Floyd Curl Dr, San Antonio, TX 78249, United States; College of Pharmacy, University of Texas at Austin, 110 Inner Campus Drive, Austin, TX 78705, United States. Electronic address:

Background & Aims: Fortification of the US food supply has increased folic acid intake and resulted in a concomitant decrease in neural tube defects in women. However, a body evidence supports the hypothesis that increased circulating folate levels due to excessive dietary or supplemental folic acid may be harmful for men with prostate cancer. Therefore, this pilot study aimed to investigate the feasibility of a reduced folic acid dietary intervention in men on an active surveillance monitoring program for prostate cancer.

Methods: Men with low-grade prostate cancer enrolled into a 12-week dietary folic acid reduction diet. Primary outcome was red blood cell (RBC) folate reduction at 12 weeks. Other outcomes include serum folate, homocysteine, and vitamin B12 levels. The number of patients who complete the trial and reasons for disenrollment or dropout were also assessed.

Results: Twenty-eight participants were enrolled into the dietary intervention study. Six participants withdrew from the study and a total of 21 participants completed all baseline and week 12 biochemical assessments. Only 18 participants completed all dietary questionnaires. Participants withdrew from the study due to difficulty with the diet or personal reasons. A substantial reduction was noted in serum folate (p < 0.007), RBC folate (p < 0.001) and dietary consumption of folic acid from foods (p = 0.003) and supplements (p = 0.003) without reduction in serum homocysteine or vitamin B. Although an overall decrease in PSA from baseline to twelve weeks was found, the reduction was not significant (-3.55 ng/mL, p = 0.197).

Conclusions: This phase 1 feasibility study reduced dietary folic acid intake from food and supplements and successfully lowered serum and RBC folate without resulting harmful effects. Data from this study supports future intervention trials with a larger prostate cancer active surveillance population and has the potential to reduce prostate cancer progression. There are no interventions to reduce progression of prostate cancer in man on active surveillance.
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http://dx.doi.org/10.1016/j.clnesp.2021.06.004DOI Listing
August 2021

Dietary quality modifies the association between multimorbidity and change in mobility limitations among older Americans.

Prev Med 2021 Jul 19;153:106721. Epub 2021 Jul 19.

Department of Oncology, Dell Medical School, University of Texas at Austin, Austin, TX, USA.

To identify potentially modifiable risk-factors in the age-related disablement process, we examined the association between change in mobility limitations and multimorbidity and how dietary quality moderates this association. Information from 3320 adults aged 65 and older in 2012 was drawn from the Health and Retirement Study and the Health Care and Nutrition Study. Mobility limitations reported in 2012 and change in mobility limitations from 2012 to 2014 were regressed on multimorbidity measured as number of chronic conditions in 2012, dietary quality measured in 2013 using the Alternative Healthy Eating Index-2010 (AHEI-2010), and their interaction term using Poisson regression. Respondents reported an average of 2.9 (SD, 2.9) mobility limitations in 2012 and 3.1 (SD, 3.0) mobility limitations in 2014, an average of 2.64 (SD, 1.4) chronic conditions in 2012, and mean AHEI-2010 score in 2013 of 57.1 (SD, 10.9). Greater AHEI-2010 scores were associated with fewer mobility limitations at baseline (p < .001) and slower progression of mobility limitations over the two-year observational window (p < .001). For those with AHEI-2010 scores ≥48.4, dietary quality appeared to moderate the association between multimorbidity and change in mobility limitations. These results suggest that improving dietary quality may be an effective means of reducing the progression of mobility limitations among older adults and that dietary quality may modify the effect of multimorbidity on progressive disablement. Our work adds to research supporting dietary quality as a potentially intervenable factor in the reduction of disablement in aging populations.
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http://dx.doi.org/10.1016/j.ypmed.2021.106721DOI Listing
July 2021

Higher levels of physical activity buffered the negative effect of pain severity on physical frailty in older Latinx adults.

Geriatr Nurs 2021 Mar-Apr;42(2):460-466. Epub 2021 Mar 11.

Department of Public Health, The University of Texas at San Antonio, United States.

This cross-sectional study examined whether and to what extent physical activity (PA) mediated the effect of chronic pain on physical frailty in a sample of predominantly older Latinx adults. Study participants were 118 community-dwelling older adults in southwest United States. Physical frailty was measured by a summary score of physical function tests. Pain severity and pain interference were measured by the Brief Pain Inventory. PA levels were defined as meeting the PA recommendation by 7-day accelerometry. Pain outcomes and PA were associated with physical frailty, respectively. Hierarchical regression analysis revealed that PA mediated the relationship between pain severity and physical frailty. However, no mediation effect of PA was found in the relationship between pain interference and physical frailty scores. Higher levels of PA buffered the negative effect of pain severity on physical frailty. Future studies should pay attention to PA promotion to prevent the negative consequences of frailty in older minority adults.
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http://dx.doi.org/10.1016/j.gerinurse.2021.02.004DOI Listing
September 2021

Depression Mediates the Relationship between Food Insecurity and Pain Interference in College Students.

Int J Environ Res Public Health 2020 12 24;18(1). Epub 2020 Dec 24.

Department of Psychology, University of Texas at San Antonio, San Antonio, TX 78249, USA.

Food insecurity (FI) typically produces unfavorable health conditions. Research shows the high prevalence of FI among college students, and depression is one of the adverse effects of FIamong them. It is possible that FI may increase the risk of pain via depression; however, it is currently unclear whether FI is linked to pain among college students. Therefore, this study compared pain experiences between students with and without FI, and examined the relationship between FI, depression, and pain. One hundred seventy-six college students at a Hispanic-serving institution in the southwestern region of US completed self-report measures to assess FI, depression, pain severity, and pain interference. Results indicated that approximately 24% of the students were categorized as food insecure, and those students scored higher on pain interference compared to food-secure students. FI was positively associated with depression and pain interference scores, and depression scores were positively associated with pain interference scores. The mediation analyses based on the counterfactual framework demonstrated a significant mediation effect of depression, where 50.59% of the total effect of FI on pain interference was attributable to the depression. These results suggest that FI extends its negative effects into pain interference among college students, but better management of depression may help alleviate the effects of FI on pain interference.
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http://dx.doi.org/10.3390/ijerph18010078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7796147PMC
December 2020

Establishing a campus garden and food pantry to address food insecurity: lessons learned.

J Am Coll Health 2021 Aug-Sep;69(6):684-688. Epub 2020 Jan 9.

Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio, San Antonio, USA.

Objective: This case study describes the simultaneous establishment of a campus garden and food pantry at an urban, Hispanic-serving institution. Lessons learned and implications for practice are discussed. : Students, staff, and faculty established a campus garden (February 2016) and food pantry (March 2017). University administration approved funds to establish both a campus garden and food pantry after adequate student and academic support was provided. : Both the campus garden and food pantry aligned with campus initiatives for student success and sustainability. The food pantry had adequate staffing and local partnerships that aided in its success, while the student-led garden struggled with student-turn over, limited financial support, and lack of regulatory guidance that has slowed progress to address food security. : Institutions considering these strategies to address food insecurity would benefit from university financial support based on student-relevant data, dedicated staff, students, and faculty, and collaboration with local organizations.
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http://dx.doi.org/10.1080/07448481.2019.1705830DOI Listing
January 2020

Maternal exercise before and during pregnancy alleviates metabolic dysfunction associated with high-fat diet in pregnant mice, without significant changes in gut microbiota.

Nutr Res 2019 09 8;69:42-57. Epub 2019 Aug 8.

Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio, San Antonio, TX.

Although maternal exercise before and during pregnancy is beneficial, the effects of exercise on microbiota changes during pregnancy are unknown. Here we tested the hypothesis that maternal exercise before and during pregnancy would positively affect glucose homeostasis, pancreatic cell function, and gut microbiota dysbiosis in high-fat diet (HFD) fed dams. Female C57BL/6 mice were fed either a HFD or a low-fat diet (LFD) for 12 weeks. The HFD mice were split into two groups for 4 weeks prior to pregnancy initiation and throughout the pregnancy: sedentary (HFD) or exercised (HFD + Ex). Food intake, body weight, body composition, and glucose and insulin tolerance were measured. At gestation day 19, blood, pancreas, gonadal visceral and subcutaneous fat, plantaris muscle, and cecum were collected for analysis. Both HFD and HFD + Ex mice had impaired glucose clearance compared to LFD mice at 15 days of gestation. No changes were found in pancreatic α- or β-cell health. HFD + Ex mice had significantly reduced visceral fat mass, serum insulin, and leptin levels and increased high-density lipoprotein levels, compared to HFD-fed mice. In contrast to our hypothesis, microbiota diversity and composition were not different among groups. The relative abundance of five bacterial phyla, such as Firmicutes, Bacteroidetes, Verrucomicrobia, Deferribacteres, and Actinobacteria, were not significantly altered with diet or exercise during pregnancy. Our findings suggest that maternal exercise prevents excess visceral fat accumulation, hyperinsulinemia, and hyperleptinemia associated with a HFD, but not through the alterations of gut microbiota composition or diversity during pregnancy.
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http://dx.doi.org/10.1016/j.nutres.2019.08.002DOI Listing
September 2019

Study protocol for a cluster randomized controlled trial to test "¡Míranos! Look at Us, We Are Healthy!" - an early childhood obesity prevention program.

BMC Pediatr 2019 06 10;19(1):190. Epub 2019 Jun 10.

Department of Mexican American and Latina/o Studies Austin, The University of Texas at Austin, Austin, TX, USA.

Background: One in three Head Start children is either overweight or obese. We will test the efficacy of an early childhood obesity prevention program, "¡Míranos! Look at Us, We Are Healthy!" (¡Míranos!), which promotes healthy growth and targets multiple energy balance-related behaviors in predominantly Latino children in Head Start. The ¡Míranos! intervention includes center-based (policy changes, staff development, gross motor program, and nutrition education) and home-based (parent engagement/education and home visits) interventions to address key enablers and barriers in obesity prevention in childcare. In partnership with Head Start, we have demonstrated the feasibility and acceptability of the proposed interventions to influence energy balance-related behaviors favorably in Head Start children.

Methods: Using a three-arm cluster randomized controlled design, 12 Head Start centers will be randomly assigned in equal number to one of three conditions: 1) a combined center- and home-based intervention, 2) center-based intervention only, or 3) comparison. The interventions will be delivered by trained Head Start staff during the academic year. A total of 444 3-year-old children (52% females; n = 37 per center at baseline) in two cohorts will be enrolled in the study and followed prospectively 1 year post-intervention. Data collection will be conducted at baseline, immediately post-intervention, and at the one-year follow-up and will include height, weight, physical activity (PA) and sedentary behaviors, sleep duration and screen time, gross motor development, dietary intake and food and activity preferences. Information on family background, parental weight, PA- and nutrition-related practices and behaviors, PA and nutrition policy and environment at center and home, intervention program costs, and treatment fidelity will also be collected.

Discussion: With endorsement and collaboration of two local Head Start administrators, ¡Míranos!, as a culturally tailored obesity prevention program, is poised to provide evidence of efficacy and cost-effectiveness of a policy and environmental approach to prevent early onset of obesity in low-income Latino preschool children. ¡Míranos! can be disseminated to various organized childcare settings, as it is built on the Head Start program and its infrastructure, which set a gold standard for early childhood education, as well as current PA and nutrition recommendations for preschool children.

Trial Registration: ClinicalTrials.Gov ( NCT03590834 ) July 18, 2018.
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http://dx.doi.org/10.1186/s12887-019-1541-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556954PMC
June 2019

Potential Dietary Supplement and Medication Interactions in a Subset of the Older Adult Population Attending Congregate Sites.

J Nutr Gerontol Geriatr 2018 Jul-Dec;37(3-4):218-230. Epub 2018 Nov 6.

a Department of Kinesiology, Health, and Nutrition , University of Texas at San Antonio , San Antonio , TX , USA.

This study assessed possible dietary supplement-medication interactions of 62 older adults recruited from 8 senior congregate sites in Bexar County, Texas. Dietary supplement and medication use were collected by paper questionnaire and potential supplement-medication interactions were assessed using online databases. The majority of participants reported dietary supplements (77%), non-prescription medication (50%), and prescription medication (73%) use. Fifty percent of participants who reported dietary supplement and medication use were at-risk for a potential supplement-medication interaction, ranging from one to eight potential interactions. Calcium and multivitamin-mineral supplements were the most common dietary supplements with potential medication interactions. Surveyed older adults reported dietary supplements should be reported to a physician (97%), but over 20% believe herbal products are pure (38%) and dietary supplements are risk free (34%) and will not cause harm (22%). In conclusion, regular education and screening of dietary supplement and medication use among older adults is recommended.
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http://dx.doi.org/10.1080/21551197.2018.1519481DOI Listing
October 2019

Acute maternal oxidant exposure causes susceptibility of the fetal brain to inflammation and oxidative stress.

J Neuroinflammation 2017 Sep 30;14(1):195. Epub 2017 Sep 30.

School of Medicine, Department of Biomedical Sciences, Regional Academic Health Center, University of Texas Rio Grande Valley, 1204 W. Schunior, Edinburg, 78241, TX, USA.

Background: Maternal exposure to environmental stressors poses a risk to fetal development. Oxidative stress (OS), microglia activation, and inflammation are three tightly linked mechanisms that emerge as a causal factor of neurodevelopmental anomalies associated with prenatal ethanol exposure. Antioxidants such as glutathione (GSH) and CuZnSOD are perturbed, and their manipulation provides evidence for neuroprotection. However, the cellular and molecular effects of GSH alteration in utero on fetal microglia activation and inflammation remain elusive.

Methods: Ethanol (EtOH) (2.5 g/kg) was administered to pregnant mice at gestational days 16-17. One hour prior to ethanol treatment, N-acetylcysteine (NAC) and L-buthionine sulfoximine (BSO) were administered to modulate glutathione (GSH) content in fetal and maternal brain. Twenty-four hours following ethanol exposure, GSH content and OS in brain tissues were analyzed. Cytokines and chemokines were selected based on their association with distinctive microglia phenotype M1-like (IL-1β, IFN γ, IL-6, CCL3, CCL4, CCL-7, CCL9,) or M2-like (TGF-β, IL-4, IL-10, CCL2, CCL22, CXCL10, Arg1, Chi1, CCR2 and CXCR2) and measured in the brain by qRT-PCR and ELISA. In addition, Western blot and confocal microscopy techniques in conjunction with EOC13.31 cells exposed to similar ethanol-induced oxidative stress and redox conditions were used to determine the underlying mechanism of microglia activation associated with the observed phenotypic changes.

Results: We show that a single episode of mild to moderate OS in the last trimester of gestation causes GSH depletion, increased protein and lipid peroxidation and inflammatory responses inclined towards a M1-like microglial phenotype (IL-1β, IFN-γ) in fetal brain tissue observed at 6-24 h post exposure. Maternal brain is resistant to many of these marked changes. Using EOC 13.31 cells, we show that GSH homeostasis in microglia is crucial to restore its anti-inflammatory state and modulate inflammation. Microglia under oxidative stress maintain a predominantly M1 activation state. Additionally, GSH depletion prevents the appearance of the M2-like phenotype, while enhancing morphological changes associated with a M1-like phenotype. This observation is also validated by an increased expression of inflammatory signatures (IL-1β, IFN-γ, IL-6, CCL9, CXCR2). In contrast, conserving intracellular GSH concentrations eliminates OS which precludes the nuclear translocation and more importantly the phosphorylation of the NFkB p105 subunit. These cells show significantly more pronounced elongations, ramifications, and the enhanced expression of M2-like microglial phenotype markers (IL-10, IL-4, TGF-β, CXCL10, CCL22, Chi, Arg, and CCR2).

Conclusions: Taken together, our data show that maintaining GSH homeostasis is not only important for quenching OS in the developing fetal brain, but equally critical to enhance M2 like microglia phenotype, thus suppressing inflammatory responses elicited by environmental stressors.
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http://dx.doi.org/10.1186/s12974-017-0965-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5622443PMC
September 2017

Protein S-Glutathionylation Mediates Macrophage Responses to Metabolic Cues from the Extracellular Environment.

Antioxid Redox Signal 2016 11 17;25(15):836-851. Epub 2016 May 17.

4 Department of Radiology, University of Texas Health Science Center at San Antonio , San Antonio, Texas.

Aims: Protein S-glutathionylation, the formation of a mixed disulfide between glutathione and protein thiols, is an oxidative modification that has emerged as a new signaling paradigm, potentially linking oxidative stress to chronic inflammation associated with heart disease, diabetes, cancer, lung disease, and aging. Using a novel, highly sensitive, and selective proteomic approach to identify S-glutathionylated proteins, we tested the hypothesis that monocytes and macrophages sense changes in their microenvironment and respond to metabolic stress by altering their protein thiol S-glutathionylation status.

Results: We identified over 130 S-glutathionylated proteins, which were associated with a variety of cellular functions, including metabolism, transcription and translation, protein folding, free radical scavenging, cell motility, and cell death. Over 90% of S-glutathionylated proteins identified in metabolically stressed THP-1 monocytes were also found in hydrogen peroxide (HO)-treated cells, suggesting that HO mediates metabolic stress-induced protein S-glutathionylation in monocytes and macrophages. We validated our findings in mouse peritoneal macrophages isolated from both healthy and dyslipidemic atherosclerotic mice and found that 52% of the S-glutathionylated proteins found in THP-1 monocytes were also identified in vivo. Changes in macrophage protein S-glutathionylation induced by dyslipidemia were sexually dimorphic.

Innovation: We provide a novel mechanistic link between metabolic (and thiol oxidative) stress, macrophage dysfunction, and chronic inflammatory diseases associated with metabolic disorders.

Conclusion: Our data support the concept that changes in the extracellular metabolic microenvironment induce S-glutathionylation of proteins central to macrophage metabolism and a wide array of cellular signaling pathways and functions, which in turn initiate and promote functional and phenotypic changes in macrophages. Antioxid. Redox Signal. 25, 836-851.
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http://dx.doi.org/10.1089/ars.2015.6531DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107721PMC
November 2016

Redox regulation of 14-3-3ζ controls monocyte migration.

Arterioscler Thromb Vasc Biol 2014 Jul 8;34(7):1514-21. Epub 2014 May 8.

From the Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio (H.S.K., D.V., R.A.); Department of Kinesiology, Health, and Nutrition, University of Texas at San Antonio (S.L.U.); and Department of Biochemistry, University of Texas Health Science Center at San Antonio (H.N.N., R.A.).

Objective: Metabolic stress primes monocytes for accelerated chemokine-mediated adhesion, migration, and recruitment into vascular lesions by increasing actin remodeling. The mechanism linking metabolic stress to accelerated actin turnover and enhanced monocyte migration was not known. We tested the hypothesis that in metabolically primed monocytes, the acceleration of monocyte chemoattractant protein-1-induced chemotaxis is mediated by the hyperactivation of cofilin.

Approach And Results: Metabolic priming was induced by exposing human THP-1 monocytes to diabetic conditions, that is, human native low-density lipoprotein plus high glucose concentrations. In healthy monocytes, monocyte chemoattractant protein-1 induced the phosphorylation and inactivation of cofilin. This response was completely blocked in metabolically primed monocytes but restored by overexpression of the thiol transferase, glutaredoxin 1. Cofilin kinase, LIM kinase 1, and cofilin phosphatase, Slingshot-1L, were not affected by metabolic stress. However, metabolic priming increased 3.8-fold the S-glutathionylation of the Slingshot-1L-binding protein 14-3-3ζ (zeta), resulting in its caspase-dependent degradation. Glutaredoxin 1 overexpression inhibited low-density lipoprotein plus high glucose-induced S-glutathionylation and degradation of 14-3-3ζ. The C25S mutant of 14-3-3ζ was resistant to both S-glutathionylation and degradation induced by low-density lipoprotein plus high glucose. Overexpression of the C25S mutant restored monocyte chemoattractant protein-1-induced cofilin phosphorylation and prevented accelerated migration of metabolically stressed monocytes, suggesting that loss of 14-3-3ζ increases the pool of free Slingshot-1L phosphatase, thereby preventing the phosphorylation and deactivation of cofilin in response to chemokine activation.

Conclusions: By preventing the inactivation of cofilin, metabolic stress-induced degradation of 14-3-3ζ promotes the conversion of blood monocytes into a hypermigratory, proatherogenic phenotype.
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http://dx.doi.org/10.1161/ATVBAHA.114.303746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4065841PMC
July 2014

Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4.

Redox Biol 2014 11;2:259-66. Epub 2014 Jan 11.

Department of Clinical Laboratory Sciences, University of Texas Health Science Center, San Antonio, United States ; Department of Biochemistry, University of Texas Health Science Center, San Antonio, United States ; Department of Radiology, University of Texas Health Science Center, San Antonio, United States.

Aims: Dietary supplementation with ursolic acid (UA) prevents monocyte dysfunction in diabetic mice and protects mice against atherosclerosis and loss of renal function. The goal of this study was to determine the molecular mechanism by which UA prevents monocyte dysfunction induced by metabolic stress.

Methods And Results: Metabolic stress sensitizes or "primes" human THP-1 monocytes and murine peritoneal macrophages to the chemoattractant MCP-1, converting these cells into a hyper-chemotactic phenotype. UA protected THP-1 monocytes and peritoneal macrophages against metabolic priming and prevented their hyper-reactivity to MCP-1. UA blocked the metabolic stress-induced increase in global protein-S-glutathionylation, a measure of cellular thiol oxidative stress, and normalized actin-S-glutathionylation. UA also restored MAPK phosphatase-1 (MKP1) protein expression and phosphatase activity, decreased by metabolic priming, and normalized p38 MAPK activation. Neither metabolic stress nor UA supplementation altered mRNA or protein levels of glutaredoxin-1, the principal enzyme responsible for the reduction of mixed disulfides between glutathione and protein thiols in these cells. However, the induction of Nox4 by metabolic stress, required for metabolic priming, was inhibited by UA in both THP-1 monocytes and peritoneal macrophages.

Conclusion: UA protects THP-1 monocytes against dysfunction by suppressing metabolic stress-induced Nox4 expression, thereby preventing the Nox4-dependent dysregulation of redox-sensitive processes, including actin turnover and MAPK-signaling, two key processes that control monocyte migration and adhesion. This study provides a novel mechanism for the anti-inflammatory and athero- and renoprotective properties of UA and suggests that dysfunctional blood monocytes may be primary targets of UA and related compounds.
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http://dx.doi.org/10.1016/j.redox.2014.01.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3909821PMC
June 2015

Redox regulation of MAPK phosphatase 1 controls monocyte migration and macrophage recruitment.

Proc Natl Acad Sci U S A 2012 Oct 18;109(41):E2803-12. Epub 2012 Sep 18.

Department of Clinical Laboratory Sciences, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3904, USA.

Monocytic adhesion and chemotaxis are regulated by MAPK pathways, which in turn are controlled by redox-sensitive MAPK phosphatases (MKPs). We recently reported that metabolic disorders prime monocytes for enhanced recruitment into vascular lesions by increasing monocytes' responsiveness to chemoattractants. However, the molecular details of this proatherogenic mechanism were not known. Here we show that monocyte priming results in the S-glutathionylation and subsequent inactivation and degradation of MKP-1. Chronic exposure of human THP-1 monocytes to diabetic conditions resulted in the loss of MKP-1 protein levels, the hyperactivation of ERK and p38 in response to monocyte chemoattractant protein-1 (MCP-1), and increased monocyte adhesion and chemotaxis. Knockdown of MKP-1 mimicked the priming effects of metabolic stress, whereas MKP-1 overexpression blunted both MAPK activation and monocyte adhesion and migration induced by MCP-1. Metabolic stress promoted the S-glutathionylation of MKP-1, targeting MKP-1 for proteasomal degradation. Preventing MKP-1 S-glutathionylation in metabolically stressed monocytes by overexpressing glutaredoxin 1 protected MKP-1 from degradation and normalized monocyte adhesion and chemotaxis in response to MCP-1. Blood monocytes isolated from diabetic mice showed a 55% reduction in MKP-1 activity compared with nondiabetic mice. Hematopoietic MKP-1 deficiency in atherosclerosis-prone mice mimicked monocyte priming and dysfunction associated with metabolic disorders, increased monocyte chemotaxis in vivo, and accelerated atherosclerotic lesion formation. In conclusion, we identified MKP-1 as a central redox-sensitive regulator of monocyte adhesion and migration and showed that the loss of MKP-1 activity is a critical step in monocyte priming and the metabolic stress-induced conversion of blood monocytes into a proatherogenic phenotype.
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http://dx.doi.org/10.1073/pnas.1212596109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3478659PMC
October 2012

Resveratrol and quercetin interact to inhibit neointimal hyperplasia in mice with a carotid injury.

J Nutr 2012 Aug 20;142(8):1487-94. Epub 2012 Jun 20.

Department of Pharmacology, Toxicology and Neuroscience, Louisiana State University Health Sciences Center, Shreveport, LA, USA.

Restenosis is a critical complication of angioplasty and stenting. Restenosis is multifactorial, involving endothelial injury, inflammation, platelet activation, and vascular smooth muscle cell (VSMC) proliferation. Thus, dietary strategies to prevent restenosis likely require the use of more than one agent. Resveratrol (R) and quercetin (Q) are polyphenols that are known to exhibit vascular protective effects. We tested whether R and Q administered in the diet interact to inhibit vessel stenosis in mice with a carotid injury. B6.129 mice were administered a high-fat diet containing 21% fat and 0.2% cholesterol along with R (25 mg/kg), Q (10 mg/kg), or R + Q for 2 wk. A carotid injury was induced and the mice were again administered the enriched diet for 2 wk. Compared with the controls, R significantly decreased stenosis, assessed as an intima:media ratio, by 76%. Although Q treatment alone exhibited no effect, it potentiated the effect of R in that treatment with R + Q significantly decreased the intima:media ratio by 94%. Moreover, this effect was greater than that of R treatment alone (P < 0.05). Although treatments with R, Q, and R + Q significantly affected platelet activation and endothelial function, the responses observed for R + Q were less than additive. Specifically, the effects of R + Q were less than the sum of effects for treatments with R and Q alone. In contrast, treatment with R + Q exhibited more-than-additive effects on inflammatory markers and significant interactions between R and Q were observed. The presence of synergy between R and Q was thus tested in cultures of VSMC and macrophages. Isobolographic analysis revealed that 2:1 molar ratios of R:Q exhibited synergistic inhibition of VSMC proliferation and macrophage chemotaxis. In conclusion, in combination, R and Q can interact to reduce the extent of restenosis, perhaps due to their synergistic inhibition of VSMC proliferation and inflammation.
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http://dx.doi.org/10.3945/jn.112.162628DOI Listing
August 2012

Ursolic acid protects diabetic mice against monocyte dysfunction and accelerated atherosclerosis.

Atherosclerosis 2011 Dec 17;219(2):409-16. Epub 2011 Jun 17.

Department of Biochemistry, University of Texas Health Science Center at San Antonio, San Antonio, TX 78229-3900, United States.

Aims: Accelerated atherosclerosis is a major diabetic complication initiated by the enhanced recruitment of monocytes into the vasculature. In this study, we examined the therapeutic potential of the phytonutrients ursolic acid (UA) and resveratrol (RES) in preventing monocyte recruitment and accelerated atherosclerosis.

Methods And Results: Dietary supplementation with either RES or UA (0.2%) protected against accelerated atherosclerosis induced by streptozotocin in high-fat diet-fed LDL receptor-deficient mice. However, mice that received dietary UA for 11 weeks were significantly better protected and showed a 53% reduction in lesion formation while mice fed a RES-supplemented diet showed only a 31% reduction in lesion size. Importantly, UA was also significantly more effective in preventing the appearance of proinflammatory GR-1(high) monocytes induced by these diabetic conditions and reducing monocyte recruitment into MCP-1-loaded Matrigel plugs implanted into these diabetic mice. Oxidatively stressed THP-1 monocytes mimicked the behavior of blood monocytes in diabetic mice and showed enhanced responsiveness to monocyte chemoattractant protein-1 (MCP-1) without changing MCP-1 receptor (CCR2) surface expression. Pretreatment of THP-1 monocytes with RES or UA (0.3-10μM) for 15h resulted in the dose-dependent inhibition of H(2)O(2)-accelerated chemotaxis in response to MCP-1, but with an IC(50) of 0.4μM, UA was 2.7-fold more potent than RES.

Conclusion: Dietary UA is a potent inhibitor of monocyte dysfunction and accelerated atherosclerosis induced by diabetes. These studies identify ursolic acid as a potential therapeutic agent for the treatment of diabetic complications, including accelerated atherosclerosis, and provide a novel mechanism for the anti-atherogenic properties of ursolic acid.
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http://dx.doi.org/10.1016/j.atherosclerosis.2011.06.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3199329PMC
December 2011
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