¡Miranos! An 8-Month Comprehensive Preschool Obesity Prevention Program in Low-Income Latino Children: Effects on Children's Gross Motor Development.

Organized childcare is an ideal setting to promote gross motor development in young children from low-income minority families. A three-group clustered randomized controlled trial was conducted in Head Start centers serving low-income Latino children to evaluate the impact of an 8-month comprehensive obesity-prevention intervention on children's percentile scores for locomotive skills (LS pctl) and ball skills (BS pctl), and general motor quotient (GMQ). Trained Head Start staff delivered the center-based intervention (CBI) to modify center physical activity and nutrition policies, staff practices, and child behaviors, while the home-based intervention (HBI) offered training and support to parents for obesity prevention at home. Participants were 3-year-old children (n = 310; 87% Latino; 58% female) enrolled in Head Start centers in South Texas. Twelve centers were randomized (1:1:1 ratio) to receive CBI, CBI and HBI (CBI + HBI), or control treatment. Posttest data were collected from 79.1% of participants. All gross motor development measures improved significantly for children in CBI compared to the control, while children in CBI + HBI only showed improvement for GMQ (p = 0.09) and LS pctl (p < 0.001) compared to the control. A comprehensive and culturally competent intervention targeting childcare centers and children's homes was effective at improving children's gross motor development and reducing disparities in child development.

Food insecurity and academic function among college students during the COVID-19 pandemic: A moderating role of the first-generation college student status.

OBJECTIVE: To examine food insecurity (FI) prevalence among college students during the COVID-19 pandemic (April 2021) using cross-sectional design, and the moderating role of the first-generation student status in the relationship between FI and grade point average (GPA). PARTICIPANTS: Three-hundred sixty students recruited mostly from upper-level kinesiology courses. METHODS: General linear model was used to predict GPA based on food security status, psychological health, and bodily pain, with subgroup analysis performed by first-generation student status. RESULTS: Approximately 19% were classified as having FI. Those with FI showed lower GPA and poor health compared to those without FI. The link between FI and GPA was moderated by first-generation student status, with the negative impact of FI on GPA more clearly observed among non-first-generation students. CONCLUSION: First-generation student status could play a role in determining the impact of FI on academic performance.

Impact of ¡Míranos! on parent-reported home-based healthy energy balance-related behaviors in low-income Latino preschool children: a clustered randomized controlled trial.

BACKGROUND: Widespread establishment of home-based healthy energy balance-related behaviors (EBRBs), like diet, physical activity, sedentary behavior, screen time, and sleep, among low-income preschool-aged children could curb the childhood obesity epidemic. We examined the effect of an 8-month multicomponent intervention on changes in EBRBs among preschool children enrolled in 12 Head Start centers. METHODS: The Head Start (HS) centers were randomly assigned to one of three treatment arms: center-based intervention group (CBI), center-based plus home-based intervention group (CBI + HBI), or control. Before and following the intervention, parents of 3-year-olds enrolled in participating HS centers completed questionnaires about their child's at-home EBRBs. Adult-facilitated physical activity (PA) was measured by an index based on questions assessing the child's level of PA participation at home, with or facilitated by an adult. Fruit, vegetable, and added sugar intake were measured via a short food frequency questionnaire, and sleep time and screen time were measured using 7-day logs. A linear mixed effects model examined the intervention's effect on post-intervention changes in PA, intake of fruit, vegetable, and added sugar, sleep time, and screen time from baseline to post-intervention. RESULTS: A total of 325 parents participated in the study (CBI n = 101; CBI + HBI n = 101; and control n = 123). Compared to control children, CBI and CBI + HBI parents reported decreases in children's intake of added sugar from sugar-sweetened beverages. Both CBI and CBI + HBI parents also reported smaller increases in children's average weekday screen time relative to controls. In addition, CBI + HBI parents reported CBI + HBI parents reported increases in children's adult-facilitated PA, fruit and vegetable intake, and daily sleep time during weekdays (excluding weekends) and the total week from baseline to post-intervention, while children in the CBI increased sleep time over the total week compared to the children in the control group. CONCLUSIONS: Parent engagement strengthened the improvement in parent-reported EBRBs at home in young children participating in an evidence-based obesity prevention program in a childcare setting. Future studies should investigate equity-related contextual factors that influence the impact of obesity prevention in health-disparity populations. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03590834. Registered July 18, 2018, https://clinicaltrials.gov/ct2/show/NCT03590834.

Switching to a Standard Chow Diet at Weaning Improves the Effects of Maternal and Postnatal High-Fat and High-Sucrose Diet on Cardiometabolic Health in Adult Male Mouse Offspring.

Cardiac mitochondrial dysfunction contributes to obesity-associated heart disease. Maternal and postnatal diet plays an important role in cardiac function, yet the impacts of a mismatch between prenatal and postweaning diet on cardiometabolic function are not well understood. We tested the hypothesis that switching to a standard chow diet after weaning would attenuate systemic metabolic disorders and cardiac and mitochondrial dysfunction associated with maternal and postnatal high-fat/high-sucrose (HFHS) diet in mice. Six-month-old male CD1 offspring from dams fed a HFHS diet and weaned to the same HFHS diet (HH) or switched to a standard chow diet (HC) were compared to offspring from dams fed a low-fat/low-sucrose diet and maintained on the same diet (LL). HC did not decrease body weight (BW) but normalized glucose tolerance, plasma cholesterol, LDL, and insulin levels compared to the HH. Systolic function indicated by the percent fractional shortening was not altered by diet. In freshly isolated cardiac mitochondria, maximal oxidative phosphorylation-linked respiratory capacity and coupling efficiency were significantly higher in the HC in the presence of fatty acid substrate compared to LL and HH, with modification of genes associated with metabolism and mitochondrial function. Switching to a standard chow diet at weaning can attenuate the deleterious effects of long-term HFHS in adult male mouse offspring.

Egg protein supplementation improved upper body muscle strength and protein intake in community-dwelling older adult females who attended congregate meal sites or adult learning centers: A pilot randomized controlled trial.

Background: Older adults that utilize community-based nutrition services are at higher nutritional risk than the general aging population, yet studies on the efficacy of protein interventions in this population are lacking. Aim: A double-blinded randomized controlled pilot study trial evaluated the impact of egg white protein supplementation on muscle mass, strength, and physical function in predominantly low-income Latina community-dwelling adult females aged 60 or older with reduced muscle strength or function. Methods: Participants (mean age = 73.6 ± 8.3 years) were randomly assigned to receive a daily dried egg white (20 g protein) or isocaloric maltodextrin supplement for 6 months (n = 16 intervention; n = 13 control). The primary outcome measure was appendicular skeletal muscle mass. Secondary outcomes were measures of muscle strength and function and dietary protein intake. Comparisons of baseline demographics were conducted using t-tests and χ2 or Fisher's exact tests. Differences between groups were assessed using general linear models, adjusted for baseline values, and differences within groups were assessed using paired t-tests or Kruskal-Wallis. Results: No significant between-group differences were found for all measures, but protein intake, handgrip strength, and the number of arm curls significantly improved in the intervention group. Under-recruitment of study participants and a high dropout rate impacted the ability of this study to detect significant differences between groups. Conclusion: Daily egg white protein supplementation increases protein intake and supports upper body physical function in older adults, but additional studies are needed to investigate its role in the prevention of age-related muscle mass decline in older adults. Trial #NCT03530774 (https://clinicaltrials.gov/ct2/show/NCT03530774).

Strategic Sodium Reduction Initiative Reduces Sodium in Meals Served at Older Adult Congregate Meal Program Sites.

Excessive sodium consumption is a public health issue and congregate meal programs provide a unique opportunity to reduce sodium served to a large, at-risk population. A Sodium Reduction Initiative (SRI) was implemented in a congregate meal program that serves over 3,000 older adults. Nutrient analyses conducted at baseline and post-intervention were used to calculate average sodium reduction and the number of low sodium foods; targeted foods were categorized by strategy. Customer satisfaction surveys were collected at baseline and 3- and 6-months post-intervention. Kruskal Wallis and analysis of variance were used to compare sodium reduction differences. Chi-square analysis determined associations among strategies. The SRI impacted 55 foods, low sodium foods increased by 22%, and the average sodium per menu cycle was reduced by 21%. Replacement with a lower sodium food was the most frequently used strategy and had the largest sodium reduction. Sauces and main entrees were most frequently impacted, and thirteen ingredients accounted for 75% of all reduced-sodium foods. Over 50% of the 1,424 survey respondents consumed the reduced-sodium foods and food satisfaction remained stable from baseline to post-intervention. Congregate meals programs that target commonly used foods and key ingredients can significantly reduce sodium served to older adults.

Adapting Chinese Qigong Mind-Body Exercise for Healthy Aging in Older Community-Dwelling Low-income Latino Adults: Pilot Feasibility Study.

BACKGROUND: Research translating the evidence for the benefit of mind-body exercise in older Latinos with limited access to community-based healthy aging programs is sparse. OBJECTIVE: This study aimed to evaluate the feasibility of Function Improvement Exercises for Older Sedentary Community-Dwelling Latino Residents (FITxOlder), a Community Health Worker (CHW)-led, mobile technology-facilitated Chinese Qigong mind-body exercise program for healthy aging and to explore its impact on physical and cognitive function and quality of life (QoL) in older community-dwelling low-income Latino adults. METHODS: This study was designed as a Stage 1 feasibility study to develop and pilot-test FITxOlder. In Phase 1 (Stage 1A), a working group of seniors, CHWs, and senior center staff guided the adaptation of Chinese Qigong into a healthy aging program. In Phase 2 (Stage 1B), 49 older Latino adults participated in a 3-arm controlled study to test the feasibility and preliminary effect of CHW-led FITxOlder on physical and cognitive function and QoL measures over 16 weeks. RESULTS: Although the COVID-19 pandemic disrupted the implementation of the study protocol, we found favorable results regarding participant recruitment, retention, and fidelity of implementation. Notable findings included an 89.3% participant retention, 79.4% of the participants completed at least 70% of the weekly exercise goal, and no report of adverse events. The effects on intervention outcome measures were modest. CONCLUSIONS: FITxOlder is feasible for promoting healthy aging in older Latino adults; future research needs to compare its feasibility with other low-impact exercise programs for healthy aging using a randomized controlled trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT04284137; https://clinicaltrials.gov/ct2/show/NCT04284137.

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

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.

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

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.

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

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.

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

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 B12. 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.

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

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.

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

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. Participants: Students, staff, and faculty established a campus garden (February 2016) and food pantry (March 2017). Methods: University administration approved funds to establish both a campus garden and food pantry after adequate student and academic support was provided. Results: 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. Conclusions: 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.

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

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.

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

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 ß-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.

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

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.

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

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.

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

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-1ß, IFN γ, IL-6, CCL3, CCL4, CCL-7, CCL9,) or M2-like (TGF-ß, 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-1ß, 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-1ß, 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-ß, 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.

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

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 (H2O2)-treated cells, suggesting that H2O2 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.

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

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.