Publications by authors named "Hea Jin Park"

34 Publications

Intracisternal administration of tanshinone IIA-loaded nanoparticles leads to reduced tissue injury and functional deficits in a porcine model of ischemic stroke.

IBRO Neurosci Rep 2021 Jun 5;10:18-30. Epub 2021 Jan 5.

Regenerative Bioscience Center, University of Georgia, Athens, GA 30602, United States.

Background: The absolute number of new stroke patients is annually increasing and there still remains only a few Food and Drug Administration (FDA) approved treatments with significant limitations available to patients. Tanshinone IIA (Tan IIA) is a promising potential therapeutic for ischemic stroke that has shown success in pre-clinical rodent studies but lead to inconsistent efficacy results in human patients. The physical properties of Tan-IIA, including short half-life and low solubility, suggests that Poly (lactic-co-glycolic acid) (PLGA) nanoparticle-assisted delivery may lead to improve bioavailability and therapeutic efficacy. The objective of this study was to develop Tan IIA-loaded nanoparticles (Tan IIA-NPs) and to evaluate their therapeutic effects on cerebral pathological changes and consequent motor function deficits in a pig ischemic stroke model.

Results: Tan IIA-NP treated neural stem cells showed a reduction in SOD activity in in vitro assays demonstrating antioxidative effects. Ischemic stroke pigs treated with Tan IIA-NPs showed reduced hemispheric swelling when compared to vehicle only treated pigs (7.85 ± 1.41 vs. 16.83 ± 0.62%), consequent midline shift (MLS) (1.72 ± 0.07 vs. 2.91 ± 0.36 mm), and ischemic lesion volumes (9.54 ± 5.06 vs. 12.01 ± 0.17 cm) when compared to vehicle-only treated pigs. Treatment also lead to lower reductions in diffusivity (-37.30 ± 3.67 vs. -46.33 ± 0.73%) and white matter integrity (-19.66 ± 5.58 vs. -30.11 ± 1.19%) as well as reduced hemorrhage (0.85 ± 0.15 vs 2.91 ± 0.84 cm) 24 h post-ischemic stroke. In addition, Tan IIA-NPs led to a reduced percentage of circulating band neutrophils at 12 (7.75 ± 1.93 vs. 14.00 ± 1.73%) and 24 (4.25 ± 0.48 vs 5.75 ± 0.85%) hours post-stroke suggesting a mitigated inflammatory response. Moreover, spatiotemporal gait deficits including cadence, cycle time, step time, swing percent of cycle, stride length, and changes in relative mean pressure were less severe post-stroke in Tan IIA-NP treated pigs relative to control pigs.

Conclusion: The findings of this proof of concept study strongly suggest that administration of Tan IIA-NPs in the acute phase post-stroke mitigates neural injury likely through limiting free radical formation, thus leading to less severe gait deficits in a translational pig ischemic stroke model. With stroke as one of the leading causes of functional disability in the United States, and gait deficits being a major component, these promising results suggest that acute Tan IIA-NP administration may improve functional outcomes and the quality of life of many future stroke patients.
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http://dx.doi.org/10.1016/j.ibneur.2020.11.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8019951PMC
June 2021

Dynamic Changes in the Gut Microbiome at the Acute Stage of Ischemic Stroke in a Pig Model.

Front Neurosci 2020 3;14:587986. Epub 2020 Dec 3.

Department of Foods and Nutrition, College of Family and Consumer Sciences, University of Georgia, Athens, GA, United States.

Stroke is a major cause of death and long-term disability affecting seven million adults in the United States each year. Recently, it has been demonstrated that neurological diseases, associated pathology, and susceptibility changes correlated with changes in the gut microbiota. However, changes in the microbial community in stroke has not been well characterized. The acute stage of stroke is a critical period for assessing injury severity, therapeutic intervention, and clinical prognosis. We investigated the changes in the gut microbiota composition and diversity using a middle cerebral artery (MCA) occlusion ischemic stroke pig model. Ischemic stroke was induced by cauterization of the MCA in pigs. Blood samples were collected prestroke and 4 h, 12 h, 1 day, and 5 days poststroke to evaluate circulating proinflammatory cytokines. Fecal samples were collected prestroke and 1, 3, and 5 days poststroke to assess gut microbiome changes. Results showed elevated systemic inflammation with increased plasma levels of tumor necrosis factor alpha at 4 h and interleukin-6 at 12 h poststroke, relative to prestroke. Microbial diversity and evenness were reduced at 1 day poststroke compared to prestroke. Microbial diversity at 3 days poststroke was negatively correlated with lesion volume. Moreover, beta-diversity analysis revealed trending overall differences over time, with the most significant changes in microbial patterns observed between prestroke and 3 days poststroke. Abundance of the Proteobacteria was significantly increased, while Firmicutes decreased at 3 days poststroke, compared to prestroke populations. Abundance of the lactic acid bacteria was reduced at 3 days poststroke. By day 5, the microbial pattern returned to similar values as prestroke, suggesting the plasticity of gut microbiome in an acute period of stroke in a pig model. These findings provide a basis for characterizing gut microbial changes during the acute stage of stroke, which can be used to assess stroke pathology and the potential development of therapeutic targets.
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http://dx.doi.org/10.3389/fnins.2020.587986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744295PMC
December 2020

Perinatal Docosahexaenoic Acid Supplementation Improves Cognition and Alters Brain Functional Organization in Piglets.

Nutrients 2020 Jul 15;12(7). Epub 2020 Jul 15.

Department of Foods and Nutrition, College of Family and Consumer Sciences, University of Georgia, Athens, GA 30602, USA.

Epidemiologic studies associate maternal docosahexaenoic acid (DHA)/DHA-containing seafood intake with enhanced cognitive development; although, it should be noted that interventional trials show inconsistent findings. We examined perinatal DHA supplementation on cognitive performance, brain anatomical and functional organization, and the brain monoamine neurotransmitter status of offspring using a piglet model. Sows were fed a control (CON) or a diet containing DHA (DHA) from late gestation throughout lactation. Piglets underwent an open field test (OFT), an object recognition test (ORT), and magnetic resonance imaging (MRI) to acquire anatomical, diffusion tensor imaging (DTI), and resting-state functional MRI (rs-fMRI) at weaning. Piglets from DHA-fed sows spent 95% more time sniffing the walls than CON in OFT and exhibited an elevated interest in the novel object in ORT, while CON piglets demonstrated no preference. Maternal DHA supplementation increased fiber length and tended to increase fractional anisotropy in the hippocampus of offspring than CON. DHA piglets exhibited increased functional connectivity in the cerebellar, visual, and default mode network and decreased activity in executive control and sensorimotor network compared to CON. The brain monoamine neurotransmitter levels did not differ in healthy offspring. Perinatal DHA supplementation may increase exploratory behaviors, improve recognition memory, enhance fiber tract integrity, and alter brain functional organization in offspring at weaning.
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http://dx.doi.org/10.3390/nu12072090DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400913PMC
July 2020

How normative multiculturalism relates to immigrant well-being.

Cultur Divers Ethnic Minor Psychol 2020 Oct 16;26(4):581-591. Epub 2020 Mar 16.

School of Languages and Cultures.

Objectives: In this study we examine the relationship between contextual factors, that is, perceived multicultural norms, and immigrant well-being. Specifically, we test a model whereby each of the three dimensions of normative multiculturalism, perceived Multicultural Ideology, Multicultural Policies and Practices, and Multicultural Contact, positively predicts immigrant well-being both directly and indirectly via belongingness.

Method: Korean immigrants in New Zealand ( = 306, 56% female) participated in the research. Their average age was 31.17 ( = 10.46), and the average length of residence was 10.04 years ( = 7.21). Participants completed a survey that included the Normative Multiculturalism Scale along with measures of belonging and well-being (flourishing, life satisfaction, and positive affect).

Results: Structural equation modeling showed that perceived normative Multicultural Policies and Practices exerted a direct positive effect on well-being and an indirect positive effect via belongingness; Multicultural Ideology exerted only an indirect effect; and Multicultural Contact did not significantly relate to belongingness or subjective well-being.

Implications: The results are discussed in terms of everyday experiences of intercultural encounters, social norms and the contextual influences of diversity climates, as well as the importance of distinguishing the defining features of multiculturalism in diversity science research. We also propose that multicultural norm setting and norms marketing may lead to positive social and psychological outcomes for immigrants. (PsycInfo Database Record (c) 2020 APA, all rights reserved).
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http://dx.doi.org/10.1037/cdp0000317DOI Listing
October 2020

Effect of Acute Ingestion of Green Tea Extract and Lemon Juice on Oxidative Stress and Lipid Profile in Pigs Fed a High-Fat Diet.

Antioxidants (Basel) 2019 Jun 23;8(6). Epub 2019 Jun 23.

Department of Foods and Nutrition, University of Georgia, Athens, GA 30602, USA.

Green tea and its catechins have been shown to ameliorate high fat diet-induced oxidative stress and hyperlipidemia. However, low bioavailability of catechins limits their therapeutic potential. Lemon juice (LJ) has been suggested to enhance the bioavailability of catechins in vitro. This study investigated the antioxidative and hypolipidemic efficacy of a single dose of green tea extract (GTE) or GTE plus LJ (GTE + LJ) in high-fat diet fed pigs. Sixteen pigs ingested a single dose of GTE (190 mg/kg/day) or GTE + LJ (0.75 mL/kg/day) mixed with low-fat (LF; 5% fat) or high-fat (HF; 22% fat) diets and blood samples were collected for 24 h. Plasma catechin level peaked at two hours, and gradually returned to baseline after six hours following the intake. The addition of LJ significantly increased plasma catechin level. The diet containing GTE did not lower plasma cholesterol and triacylglycerol (TG) concentrations, superoxide dismutase (SOD) and catalase activity, or malondialdehyde concentration in 24 h in HF-fed pigs. Addition of a single dose of LJ, however, significantly decreased plasma TG level in LF groups but did not cause further changes on any other markers compared to the GTE alone. Our findings indicate limited effect of a single meal containing GTE on plasma antioxidant enzymes, lipid profile, and lipid peroxidation in pigs and no significant synergistic/additive action of adding LJ to GTE within 24 h in pigs. A study with a longer treatment period is warranted to further understand the potential role of GTE in reducing HF diet-induced oxidative stress and the possible synergistic role of LJ.
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http://dx.doi.org/10.3390/antiox8060195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6617406PMC
June 2019

Pig Brains Have Homologous Resting-State Networks with Human Brains.

Brain Connect 2019 09 24;9(7):566-579. Epub 2019 Jun 24.

Bio-Imaging Research Center, University of Georgia, Athens, Georgia.

Many neurological and psychiatric diseases in humans are caused by disruptions to large-scale functional properties of the brain, including functional connectivity. There has been growing interest in discovering the functional organization of brain networks in larger animal models. As a result, the use of translational pig models in neuroscience has significantly increased in the past decades. The gyrencephalic pig brain resembles the human brain more in anatomy, growth, and development than the brains of commonly used small laboratory animals such as rodents. In this work, resting-state functional magnetic resonance imaging (rs-fMRI) and diffusion tensor imaging (DTI) data were acquired from a group of pigs ( = 12). rs-fMRI data were analyzed for resting-state networks (RSNs) by using independent component analysis and sparse dictionary learning. Six RSNs (executive control, cerebellar, sensorimotor, visual, auditory, and default mode) were detected that resemble their counterparts in human brains, as measured by Pearson spatial correlations and mean ratios. Supporting evidence of the validity of these RSNs was provided through the evaluation and quantification of structural connectivity measures (mean diffusivity, fractional anisotropy, fiber length, and fiber density) estimated from the DTI data. This study shows that as a translational, large animal model, pigs demonstrate great potential for mapping connectome-scale functional connectivity in experimental modeling of human brain disorders.
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http://dx.doi.org/10.1089/brain.2019.0673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6727477PMC
September 2019

DNA Methylation Changes in Whole Blood and CD16+ Neutrophils in Response to Chronic Folic Acid Supplementation in Women of Childbearing Age.

Int J Vitam Nutr Res 2017 Sep 30;87(5-6):271-278. Epub 2018 Nov 30.

1 Department of Foods and Nutrition, University of Georgia, Athens, GA, USA.

Folate, a water-soluble vitamin, is a key source of one-carbon groups for DNA methylation, but studies of the DNA methylation response to supplemental folic acid yield inconsistent results. These studies are commonly conducted using whole blood, which contains a mixed population of white blood cells that have been shown to confound results. The objective of this study was to determine if CD16+ neutrophils may provide more specific data than whole blood for identifying DNA methylation response to chronic folic acid supplementation. The study was performed in normal weight (BMI 18.5 - 24.9 kg/m2) women (18 - 35 y; n = 12), with blood samples taken before and after 8 weeks of folic acid supplementation at 800 μg/day. DNA methylation patterns from whole blood and isolated CD16+ neutrophils were measured across >485,000 CpG sites throughout the genome using the Infinium HumanMethylation450 BeadChip. Over the course of the 8-week supplementation, 6746 and 7513 CpG sites changed (p < 0.05) in whole blood and CD16+ neutrophils, respectively. DNA methylation decreased in 68.4% (whole blood) and 71.8% (CD16+ neutrophils) of these sites. There were only 182 CpG sites that changed in both the whole blood and CD16+ neutrophils, 139 of which changed in the same direction. These results suggest that the genome-wide DNA methylation response to chronic folic acid supplementation is different between whole blood and CD16+ neutrophils and that a single white blood cell type may function as a more specific epigenetic reporter of folate status than whole blood.
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http://dx.doi.org/10.1024/0300-9831/a000491DOI Listing
September 2017

Association between one-carbon metabolism indices and DNA methylation status in maternal and cord blood.

Sci Rep 2018 11 15;8(1):16873. Epub 2018 Nov 15.

Department of Foods and Nutrition, University of Georgia, Athens, GA, USA.

One-carbon metabolism is essential for multiple cellular processes and can be assessed by the concentration of folate metabolites in the blood. One-carbon metabolites serve as methyl donors that are required for epigenetic regulation. Deficiencies in these metabolites are associated with a variety of poor health outcomes, including adverse pregnancy complications. DNA methylation is known to vary with one-carbon metabolite concentration, and therefore may modulate the risk of adverse pregnancy outcomes. This study addresses changes in one-carbon indices over pregnancy and the relationship between maternal and child DNA methylation and metabolite concentrations by leveraging data from 24 mother-infant dyads. Five of the 13 metabolites measured from maternal blood and methylation levels of 993 CpG sites changed over the course of pregnancy. In dyads, maternal and fetal one-carbon concentrations were highly correlated, both early in pregnancy and at delivery. The 993 CpG sites whose methylation levels changed over pregnancy in maternal blood were also investigated for associations with metabolite concentrations in infant blood at delivery, where five CpG sites were associated with the concentration of at least one metabolite. Identification of CpG sites that change over pregnancy may result in better characterization of genes and pathways involved in maintaining a healthy, term pregnancy.
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http://dx.doi.org/10.1038/s41598-018-35111-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237996PMC
November 2018

Depletion of regulator-of-G-protein signaling-10 in mice exaggerates high-fat diet-induced insulin resistance and inflammation, and this effect is mitigated by dietary green tea extract.

Nutr Res 2019 10 28;70:50-59. Epub 2018 Jun 28.

Department of Physiology and Pharmacology, College of Veterinary Medicine, University of Georgia, Athens, GA 30602. Electronic address:

The interaction between insulin resistance and inflammation plays a central role in the development of chronic diseases, although the mechanism is not fully understood. We previously demonstrated that regulator of G-protein signaling-10 (RGS10) protein is a negative modulator of the inflammatory response in macrophages and microglia. Because inflammation is a critical component in the development of high fat diet-induced insulin resistance, in this study we investigated whether RGS10 is involved in the diet-dependent regulation of glucose tolerance and insulin sensitivity. We hypothesized that the absence of RGS10 would exaggerate high-fat diet (HFD)-induced insulin resistance and inflammation response. Our results showed that RGS10 knockout (KO) mice fed a HFD gained significantly more weight and developed severe insulin resistance compared to wild-type (WT) mice fed HFD. Furthermore, compared to WT HFD-fed mice, KO mice fed the HFD displayed inflammatory phenotypes such as decreased adipose tissue expression of the anti-inflammatory M2 markers YM1 and Fizz1 and increased expression of the proinflammatory M1 cytokine interleukin 6 in adipose and CD11b, CD68 and interleukin 1β in liver tissues. The impact of RGS10 deficiency on the exaggeration of HFD-induced insulin resistance and inflammation was ameliorated by oral consumption of green tea extract. Our results demonstrate that RGS10 is an important part of a protective mechanism involved in in regulating metabolic homeostasis by reducing inflammatory responses, which could potentially lead to an innovative new approach targeting inflammation and insulin resistance.
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http://dx.doi.org/10.1016/j.nutres.2018.06.004DOI Listing
October 2019

CD4 and CD8 T-Cell-Specific DNA Cytosine Methylation Differences Associated With Obesity.

Obesity (Silver Spring) 2018 08 28;26(8):1312-1321. Epub 2018 Jun 28.

Department of Genetics, University of Georgia, Athens, Georgia, USA.

Objective: Lifestyle factors associated with obesity may alter epigenome-regulated gene expression. Most studies examining epigenetic changes in obesity have analyzed DNA 5´-methylcytosine (5mC) in whole blood, representing a weighted average of several distantly related and regulated leukocyte classes. To examine leukocyte-specific differences associated with obesity, a pilot study examining 5mC in three distinct leukocyte types isolated from peripheral blood of women with normal weight and obesity was conducted.

Methods: CD4 T cells, CD8 T cells, and CD16 neutrophils were reiteratively isolated from blood, and 5mC levels were measured across >450,000 CG sites.

Results: Nineteen CG sites were differentially methylated between women with obesity and with normal weight in CD4 cells, 16 CG sites in CD8 cells, and 0 CG sites in CD16 neutrophils (q < 0.05). There were no common differentially methylated sites between the T-cell types. The amount of visceral adipose tissue was strongly associated with the methylation level of 79 CG sites in CD4 cells, including 4 CG sites in CLSTN1's promoter, which, this study shows, may regulate its expression.

Conclusions: The methylomes of various leukocytes respond differently to obesity and levels of visceral adipose tissue. Highly significant differentially methylated sites in CD4 and CD8 cells in women with obesity that have apparent biological relevance to obesity were identified.
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http://dx.doi.org/10.1002/oby.22225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6107382PMC
August 2018

Accuracy of an oscillometric blood pressure monitor in anesthetized pigs.

Lab Anim 2018 Oct 20;52(5):490-496. Epub 2018 Mar 20.

2 Department of Small Animal Medicine & Surgery, College of Veterinary Medicine, University of Georgia, USA.

The purpose of this study is to evaluate the accuracy of an oscillometric blood pressure monitor in anesthetized pigs. Invasive blood pressure (IBP) and noninvasive blood pressure (NIBP) measurements were taken using a DRE Waveline Pro multiparameter monitor at four different time points in 17 pigs undergoing injectable anesthesia. NIBP measurements were taken on both the thoracic and pelvic limbs. Bland Altman analysis was used to assess agreement between methods and a linear mixed-effects model was used to evaluate the effect of cuff position and blood pressure on bias. Invasive systolic arterial pressure (SAP) ranged between 112 and 161 mmHg (mean ± SD: 138.8 ± 13.3; median: 139.5). Invasive diastolic arterial pressure (DAP) ranged between 60 and 104 mmHg (mean ± SD: 86.0 ± 9.1; median: 87.0). Invasive mean arterial pressure (MAP) ranged between 79 and 121 mmHg (mean ± SD: 103.2 ± 9.3; median 103.0). Only the diastolic and mean measurements obtained from the pelvic limb met criteria outlined by the American College of Internal Medicine for required accuracy of NIBP monitors. Bias was significantly higher in the thoracic limb in comparison to the pelvic limb and was significantly higher at blood pressures above median. In general, NIBP measurements underestimated IBP measurements. In conclusion, the use of the DRE Waveline Pro to assess NIBP in anesthetized pigs may be useful in monitoring trends in mean and diastolic blood pressure and is most accurate when used on the pelvic limb.
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http://dx.doi.org/10.1177/0023677218763686DOI Listing
October 2018

Distinctions in gene-specific changes in DNA methylation in response to folic acid supplementation between women with normal weight and obesity.

Obes Res Clin Pract 2017 Nov - Dec;11(6):665-676. Epub 2017 Jul 18.

Psychiatry and Behavioral Sciences, Emory University, Atlanta, GA, USA.

Background/objectives: Obesity and maternal folate deficiency are associated with increased risk for neural tube defects (NTDs). Limited knowledge exists on the impact of folate status or obesity on DNA methylation of genes related to NTD risk and folate metabolism.

Subjects/methods: Women (18-35y) with normal weight (NW; BMI 18.5-24.9kg/m; n=12) and obesity (OB; BMI >30kg/m; n=6) were provided FA (800μg/d) for 8-weeks. Serum folate concentration and changes in DNA methylation across 2098 CpG sites in 91 genes related to NTD risk and folate metabolism were examined.

Results: Serum folate concentration increased in both groups following FA supplementation, but OB maintained a relative lower concentration (NW; 38.36±2.50-71.41±3.02nmol/L and OB; 27.12±3.09-56.85±3.90nmol/L). Methylation of 56 and 99 CpG sites changed in response to supplementation in NW and OB, respectively, and majority of these sites decreased in methylation in both groups. Only 4 CpG sites responded to supplementation in both groups. Gene ontology analysis revealed a response to supplementation in 61 biological processes (BPs) from the selected genes. Five of the 61 BPs were identified only in NW, including neural tube closure, while 13 of the 61 BPs were enriched only in OB, including folate metabolism, vitamin B12 metabolism and methylation related processes.

Conclusions: Changes in DNA methylation in genes related to NTD risk and folate metabolism in response to FA supplementation were different in NW and OB. Increased NTD risk and abnormal folate metabolism in obesity may be due to a distinctive epigenetic response to folate status in these genes.
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http://dx.doi.org/10.1016/j.orcp.2017.06.004DOI Listing
June 2018

An epigenetic clock for gestational age at birth based on blood methylation data.

Genome Biol 2016 10 7;17(1):206. Epub 2016 Oct 7.

Institute of Behavioral Sciences, University of Helsinki, 00014, Helsinki, Finland.

Background: Gestational age is often used as a proxy for developmental maturity by clinicians and researchers alike. DNA methylation has previously been shown to be associated with age and has been used to accurately estimate chronological age in children and adults. In the current study, we examine whether DNA methylation in cord blood can be used to estimate gestational age at birth.

Results: We find that gestational age can be accurately estimated from DNA methylation of neonatal cord blood and blood spot samples. We calculate a DNA methylation gestational age using 148 CpG sites selected through elastic net regression in six training datasets. We evaluate predictive accuracy in nine testing datasets and find that the accuracy of the DNA methylation gestational age is consistent with that of gestational age estimates based on established methods, such as ultrasound. We also find that an increased DNA methylation gestational age relative to clinical gestational age is associated with birthweight independent of gestational age, sex, and ancestry.

Conclusions: DNA methylation can be used to accurately estimate gestational age at or near birth and may provide additional information relevant to developmental stage. Further studies of this predictor are warranted to determine its utility in clinical settings and for research purposes. When clinical estimates are available this measure may increase accuracy in the testing of hypotheses related to developmental age and other early life circumstances.
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http://dx.doi.org/10.1186/s13059-016-1068-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5054584PMC
October 2016

Green Tea Lowers Hepatic COX-2 and Prostaglandin E2 in Rats with Dietary Fat-Induced Nonalcoholic Steatohepatitis.

J Med Food 2015 Jun 2;18(6):648-55. Epub 2014 Dec 2.

1Department of Nutritional Sciences, University of Connecticut, Storrs, Connecticut, USA.

Green tea extract (GTE) protects against nonalcoholic steatohepatitis (NASH) by decreasing hepatic steatosis and nuclear factor kappa B (NFκB) activation. We hypothesized that hypolipidemic and anti-inflammatory activities of GTE would protect against NASH by reducing cyclooxygenase-2 (COX-2), an NFκB-dependent enzyme, and prostaglandin E2 (PGE2) in a dietary fat-induced obese model. Male Wistar rats were fed a low-fat diet containing no GTE or a high-fat (HF) diet containing GTE at 0%, 1%, or 2% for 8 weeks. Insulin resistance and total hepatic fatty acids increased following HF feeding (P<.05) and these were normalized by GTE at 1-2%. GTE (1-2%) normalized hepatic malondialdehyde without affecting cytochrome P450 2E1 mRNA expression, which was otherwise increased by HF feeding. HF-mediated increases in hepatic COX-2 protein and activity as well as PGE2 concentrations were normalized by GTE (1-2%). COX-2 activity and PGE2 were correlated to each other, and to serum alanine aminotransferase (ALT) and hepatic NFκB-binding activity (P<.05; r=0.28-0.49). GTE attenuated HF-mediated increases in total hepatic n-6 and n-3, without affecting the n-6/n-3 ratio. GTE did not affect HF-mediated increases in n-6 in nonesterified fatty acid (NEFA) and phospholipid pools, whereas n-3 and n-6/n-3 in both pools were unaffected by GTE and HF feeding. GTE decreased total hepatic arachidonic acid without affecting HF-mediated increases in arachidonic acid in NEFA or phospholipid pools. Thus, GTE attenuates lipid peroxidation and PGE2 accumulation by decreasing COX-2 activity independent of arachidonic acid availability and supports an additional mechanism by which GTE protects against liver injury during NASH in an HF-feeding model.
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http://dx.doi.org/10.1089/jmf.2014.0048DOI Listing
June 2015

Supplementation of a γ-tocopherol-rich mixture of tocopherols in healthy men protects against vascular endothelial dysfunction induced by postprandial hyperglycemia.

J Nutr Biochem 2013 Jan 25;24(1):196-203. Epub 2012 Jul 25.

Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269-4010, USA.

Postprandial hyperglycemia induces oxidative stress responses, impairs vascular endothelial function (VEF) and increases the risk of cardiovascular disease. We hypothesized that the antioxidant and anti-inflammatory activities of a γ-tocopherol-rich mixture of tocopherols (γ-TmT) would protect against vascular dysfunction that is otherwise caused by postprandial hyperglycemia by decreasing oxidative stress and proinflammatory responses, and improving nitric oxide (NO•) homeostasis. In a randomized, crossover study, healthy men (n=15; 21.8 ± 0.8 years) completed a fasting oral glucose challenge (75 g) with or without prior supplementation of γ-TmT (5 days). Brachial artery flow-mediated dilation (FMD), plasma glucose, insulin, antioxidants, malondialdehyde (MDA), inflammatory proteins, arginine and asymmetric dimethylarginine (ADMA) were measured at regular intervals during a 3-h postprandial period. Supplementation of γ-TmT increased (P<.05) plasma γ-T by threefold and γ-carboxyethyl-hydroxychroman by more than ninefold without affecting α-T, glucose, arginine or ADMA. Baseline FMD, MDA, arginine and ADMA were unaffected by γ-TmT (P>.05). Postprandial FMD decreased 30%-44% (P<.05) following glucose ingestion, but was maintained with γ-TmT. Supplementation of γ-TmT also attenuated postprandial increases in MDA that occurred following glucose ingestion. Plasma arginine decreased (P<.05) in both trials to a similar extent regardless of γ-TmT supplementation. However, the ratio of ADMA/arginine increased time-dependently in both trials (P<.05), but to a lesser extent following γ-TmT supplementation (P<.05). Inflammatory proteins were unaffected by glucose ingestion or γ-TmT. Collectively, these findings support that short-term supplementation of γ-TmT maintains VEF during postprandial hyperglycemia possibly by attenuating lipid peroxidation and disruptions in NO• homeostasis, independent of inflammation.
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http://dx.doi.org/10.1016/j.jnutbio.2012.04.015DOI Listing
January 2013

Report of the 2nd Chagas Drug Discovery Consortium meeting, held on 3 November 2010; Atlanta GA, USA.

Expert Opin Drug Discov 2011 09 19;6(9):965-73. Epub 2011 Jul 19.

University of Georgia, Center for Tropical and Emerging Global Diseases , Department of Cellular Biology , Athens, 500 D.W Brooks Dr. S310 Coverdell Center, GA 30602 , USA +1 706 542 3378 ; +1 706 542 3582 ;

Chagas disease is an infectious disease with the highest impact in Latin America and a growing worldwide problem. Chagas disease is the result of long-term, persistent infection with the protozoan parasite Trypanosoma cruzi. The current therapies for treating T. cruzi infection and thus preventing Chagas disease often have adverse effects, unpredictable efficacy and require long courses of treatment. Development of new therapies has been very limited, in part due to lack of interest but also as a result of poor support and inappropriate models for discovering and evaluating candidate drugs. The Chagas Drug Discovery Consortium (CDDC) was created with funding from the US National Institutes of Health to help address some of these issues. The goals of the CDDC are to discover and evaluate new candidate drugs and develop rigorous assays of drug efficacy. This report summarizes the second meeting of the CDDC in November 2010.
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http://dx.doi.org/10.1517/17460441.2011.602063DOI Listing
September 2011

Green tea extract suppresses NFκB activation and inflammatory responses in diet-induced obese rats with nonalcoholic steatohepatitis.

J Nutr 2012 Jan 7;142(1):57-63. Epub 2011 Dec 7.

Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA.

Nonalcoholic steatohepatitis (NASH) is characterized by oxidative stress and inflammatory responses that exacerbate liver injury. The objective of this study was to determine whether the antioxidant and antiinflammatory activities of green tea extract (GTE) would protect against NASH in a model of diet-induced obesity. Adult Wistar rats were fed a low-fat (LF) diet or high-fat (HF) diet containing no GTE or GTE at 1% or 2% (HF+2GTE) for 8 wk. The HF group had greater (P ≤ 0.05) serum alanine (ALT) and aspartate aminotransferases and hepatic lipids than the LF group. Both GTE groups had lower ALT and hepatic lipid than the HF group. In liver and epididymal adipose, the HF group had lower glutathione as well as greater mRNA and protein expression of TNFα and monocyte chemoattractant protein-1 (MCP-1) and NFκB binding activity than the LF group. Compared to the HF group, the HF+2GTE group had greater glutathione and lower protein and mRNA levels of inflammatory cytokines in both tissues. NFκB binding activities at liver and adipose were also lower, likely by inhibiting the phosphorylation of inhibitor of NFκB. NFκB binding activities in liver and adipose (P ≤ 0.05; r = 0.62 and 0.46, respectively) were correlated with ALT, and hepatic NFκB binding activity was inversely related to liver glutathione (r = -0.35). These results suggest that GTE-mediated improvements in glutathione status are associated with the inhibition of hepatic and adipose inflammatory responses mediated by NFκB, thereby protecting against NASH.
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http://dx.doi.org/10.3945/jn.111.148544DOI Listing
January 2012

Astaxanthin-rich extract from the green alga Haematococcus pluvialis lowers plasma lipid concentrations and enhances antioxidant defense in apolipoprotein E knockout mice.

J Nutr 2011 Sep 6;141(9):1611-7. Epub 2011 Jul 6.

Department of Nutritional Sciences, University of Connecticut, Storrs, CT, USA.

Dyslipidemia and oxidative stress contribute to atherogenesis. Astaxanthin (ASTX) is a red-colored carotenoid well known for its high antioxidant capacity. However, its effects on lipid metabolism and antioxidant defense mechanisms have received only limited investigation. We fed male apoE knockout (apoE)(-/-) mice, a mouse model for atherosclerosis, a high-fat (15%)/high-cholesterol (0.2%) diet alone (control) or supplemented with ASTX-rich Hematococcus pluvialis extract (0.03% ASTX by weight) for 4 wk. ASTX-fed apoE(-/-) mice had significantly lower plasma total cholesterol and TG concentrations than controls, but body weight and plasma alanine aminotransferase and aspartate aminotransferase did not differ between the groups. qRT-PCR analysis demonstrated significantly greater mRNA levels of LDL receptor (LDLR), 3-hydroxy-3-methylglutaryl CoA reductase, and sterol regulatory element binding protein 2 (SREBP-2) and greater mature SREBP-2 protein in the livers of ASTX-fed mice, indicating that increased LDLR expression may be responsible for the hypocholesterolemic effect of ASTX. Hepatic lipogenic gene expression was not altered, but carnitine palmitoyl transferase 1, acetyl-CoA carboxylase β, and acyl-CoA oxidase mRNA abundance were significantly increased by ASTX supplementation, suggesting the TG-lowering effect of ASTX may be due to increased fatty acid β-oxidation in the liver. Expression of the nuclear factor E2 related factor 2-responsive endogenous antioxidant gene also was induced with concomitantly lower glutathione disulfide levels in the livers of ASTX-fed apoE(-/-) mice compared to controls. In conclusion, these results suggest that supplementation of ASTX-rich H. pluvialis extract improves cholesterol and lipid metabolism as well as antioxidant defense mechanisms, all of which could help mitigate the progression of atherosclerosis.
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http://dx.doi.org/10.3945/jn.111.142109DOI Listing
September 2011

Green tea extract protects against nonalcoholic steatohepatitis in ob/ob mice by decreasing oxidative and nitrative stress responses induced by proinflammatory enzymes.

J Nutr Biochem 2012 Apr 2;23(4):361-7. Epub 2011 May 2.

Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.

Oxidative and nitrative stress responses resulting from inflammation exacerbate liver injury associated with nonalcoholic steatohepatitis (NASH) by inducing lipid peroxidation and protein nitration. The objective of this study was to investigate whether the anti-inflammatory properties of green tea extract (GTE) would protect against NASH by suppressing oxidative and nitrative damage mediated by proinflammatory enzymes. Obese mice (ob/ob) and their 5-week-old C57BL6 lean littermates were fed 0%, 0.5% or 1% GTE for 6 weeks (n=12-13 mice/group). In obese mice, hepatic lipid accumulation, inflammatory infiltrates and serum alanine aminotransferase activity were markedly increased, whereas these markers of hepatic steatosis, inflammation and injury were significantly reduced among obese mice fed GTE. GTE also normalized hepatic 4-hydroxynonenal and 3-nitro-tyrosine (N-Tyr) concentrations to those observed in lean controls. These oxidative and nitrative damage markers were correlated with alanine aminotransferase (P<.05; r=0.410-0.471). Improvements in oxidative and nitrative damage by GTE were also associated with lower hepatic nicotinamide adenine dinucleotide phosphate oxidase activity. Likewise, GTE reduced protein expression levels of hepatic myeloperoxidase and inducible nitric oxide synthase and decreased the concentrations of nitric oxide metabolites. Correlative relationships between nicotinamide adenine dinucleotide phosphate oxidase and hepatic 4-hydroxynonenal (r=0.364) as well as nitric oxide metabolites and N-Tyr (r=0.598) suggest that GTE mitigates lipid peroxidation and protein nitration by suppressing the generation of reactive oxygen and nitrogen species. Further study is warranted to determine whether GTE can be recommended as an effective dietary strategy to reduce the risk of obesity-triggered NASH.
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http://dx.doi.org/10.1016/j.jnutbio.2011.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3704146PMC
April 2012

Anti-inflammatory effects of freeze-dried black raspberry powder in ulcerative colitis.

Carcinogenesis 2011 Mar 23;32(3):343-50. Epub 2010 Nov 23.

Center for Molecular Medicine and Colon Cancer Prevention Program, University of Connecticut Health Center, Farmington, CT 06030, USA.

Ulcerative colitis (UC) is a chronic inflammatory disease of the colonic mucosa that can dramatically increase the risk of colon cancers. In the present study, we evaluated the effects of a dietary intervention of freeze-dried black raspberries (BRB), a natural food product with antioxidant and anti-inflammatory bioactivities, on disease severity in an experimental mouse model of UC using 3% dextran sodium sulfate (DSS). C57BL/6J mice were fed either a control diet or a diet containing BRB (5 or 10%) for 7-14 days and then the extent of colonic injury was assessed. Dietary BRB markedly reduced DSS-induced acute injury to the colonic epithelium. This protection included better maintenance of body mass and reductions in colonic shortening and ulceration. BRB treatment, however, did not affect the levels of either plasma nitric oxide or colon malondialdehyde, biomarkers of oxidative stress that are otherwise increased by DSS-induced colonic injury. BRB treatment for up to 7 days suppressed tissue levels of several key pro-inflammatory cytokines, including tumor necrosis factor α and interleukin 1β. Further examination of the inflammatory response by western blot analysis revealed that 7 day BRB treatment reduced the levels of phospho-IκBα within the colonic tissue. Colonic cyclooxygenase 2 levels were also dramatically suppressed by BRB treatment, with a concomitant decrease in the plasma prostaglandin E₂ (276 versus 34 ng/ml). These findings demonstrate a potent anti-inflammatory effect of BRB during DSS-induced colonic injury, supporting its possible therapeutic or preventive role in the pathogenesis of UC and related neoplastic events.
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http://dx.doi.org/10.1093/carcin/bgq248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3047236PMC
March 2011

Validation of high-performance liquid chromatography-boron-doped diamond detection for assessing hepatic glutathione redox status.

Anal Biochem 2010 Dec 10;407(2):151-9. Epub 2010 Aug 10.

Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269, USA.

Glutathione redox status is a commonly used oxidative stress biomarker. High-performance liquid chromatography-ultraviolet (HPLC-UV) and HPLC-electrochemical detection (HPLC-ECD) have been used to assess glutathione status but have potential limitations due to challenging sample preparation procedures or electrochemical signal degradation. Thus, this study aimed to validate an HPLC-ECD approach using boron-doped diamond (BDD), a novel electrode material exhibiting excellent electrochemical stability. Liver homogenates from obese (ob/ob) mice and their lean littermates (n=4/genotype) as well as from rats fed high- or low-fat diets (n=8/treatment) were analyzed in parallel by HPLC-BDD and -UV. HPLC-BDD responses for reduced glutathione (GSH) and oxidized glutathione (GSSG) were linear over more than four orders of magnitude at 1475 mV, the optimal oxidation potential. Within- and between-day precision values of GSH, GSSG, and GSH/GSSG were 2.1% to 7.9%, and accuracy values of GSH and GSSG were 96% and 105%, respectively. Electrochemical responses were stable up to 48 h of continuous system use. Using HPLC-BDD and -UV, hepatic GSH, GSSG, and GSH/GSSG from mice (r=0.64-0.94) and rats (r=0.79-0.92) were well correlated (P<0.05), and no significant differences in thiol levels were observed between detection methods. Collectively, our findings support HPLC-BDD as a relatively simple, accurate, and validated approach for evaluating hepatic glutathione redox status.
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http://dx.doi.org/10.1016/j.ab.2010.08.012DOI Listing
December 2010

Green tea extract attenuates hepatic steatosis by decreasing adipose lipogenesis and enhancing hepatic antioxidant defenses in ob/ob mice.

J Nutr Biochem 2011 Apr 23;22(4):393-400. Epub 2010 Jul 23.

Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269-4017, USA.

Excess hepatic lipid accumulation and oxidative stress contribute to nonalcoholic fatty liver disease (NAFLD). Thus, we hypothesized that the hypolipidemic and antioxidant activities of green tea extract (GTE) would attenuate events leading to NAFLD. Obese mice (ob/ob; 5 weeks old, n=38) and their lean littermates (n=12) were fed 0%, 0.5% or 1% GTE for 6 weeks. Then, hepatic steatosis, oxidative stress and inflammatory markers were measured. Obese mice, compared to lean controls, had greater hepatic lipids and serum alanine aminotransferase (ALT). GTE at 1% lowered (P<.05) hepatic lipids and ALT in obese mice. The GTE-mediated attenuation in hepatic steatosis was accompanied by decreased mRNA expression of adipose sterol regulatory element-binding protein-1c, fatty acid synthase, stearoyl CoA desaturase-1, and hormone-sensitive lipase and decreased serum nonesterified fatty acid concentrations. Immunohistochemical data indicated that steatotic livers from obese mice had extensive accumulation of tumor necrosis factor-α (TNF-α), whereas GTE at 1% decreased hepatic TNF-α protein and inhibited adipose TNF-α mRNA expression. Hepatic total glutathione, malondialdehyde and Mn- and Cu/Zn-superoxide dismutase activities in obese mice fed GTE were normalized to the levels of lean littermates. Also, GTE increased hepatic catalase and glutathione peroxidase activities, and these activities were inversely correlated with ALT and liver lipids. Collectively, GTE mitigated NAFLD and hepatic injury in ob/ob mice by decreasing the release of fatty acids from adipose and inhibiting hepatic lipid peroxidation as well as restoring antioxidant defenses and decreasing inflammatory responses. These findings suggest that GTE may be used as an effective dietary strategy to mitigate obesity-triggered NAFLD.
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http://dx.doi.org/10.1016/j.jnutbio.2010.03.009DOI Listing
April 2011

Chlorogenic acid differentially alters hepatic and small intestinal thiol redox status without protecting against azoxymethane-induced colon carcinogenesis in mice.

Nutr Cancer 2010 ;62(3):362-70

University of Connecticut, Storrs, Connecticut 06269-4017, USA.

Colorectal cancer (CRC) is a leading cause of cancer-related deaths in the United States. Epidemiological data have suggested that coffee consumption is inversely related to CRC risk, which may be attributed to chlorogenic acid (CGA), an ester of caffeic acid (CA) and quinic acid. This study was conducted to determine whether chronic dietary CGA supplementation would attenuate tumorigenesis and oxidative stress in a mouse model of azoxymethane (AOM)-induced colon cancer. Mice (4-wk old; n = 15/group) were fed CGA (0%, 0.01%, or 0.1%) for 20 wk and received 6 weekly intraperitoneal AOM injections (10 mg/kg). CGA and CA dose-dependently accumulated in the small intestinal mucosa. AOM induced (P < 0.05) colonic aberrant crypt foci (14.2 +/- 1.9/field) and tumors (14.6 +/- 1.1/colon), which were correlated (r = .677; P < 0.05), and CGA at either dose did not reduce tumorigenesis. Hepatic GSH/GSSG and Cys/CySS ratios were unaffected by AOM, but CGA at 0.1% increased these ratios by decreasing GSSG and CySS. CGA did not affect the ratios of small intestinal GSH/GSSG or Cys/CySS, which were decreased in response to AOM treatment. Collectively, these data indicated that CGA did not protect against AOM-induced tumorigenesis but affected hepatic thiol redox status in this colon cancer model.
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http://dx.doi.org/10.1080/01635580903407239DOI Listing
June 2010

Dietary α- and γ-tocopherol supplementation attenuates lipopolysaccharide-induced oxidative stress and inflammatory-related responses in an obese mouse model of nonalcoholic steatohepatitis.

J Nutr Biochem 2010 Dec;21(12):1200-6

Department of Nutritional Sciences, University of Connecticut, Storrs, CT 06269-4017, USA.

Oxidative stress contributes towards the development of nonalcoholic steatohepatitis (NASH). Thus, antioxidants may decrease oxidative stress and ameliorate the events contributing to NASH. We hypothesized that α- or γ-tocopherol would protect against lipopolysaccharide (LPS)-triggered NASH in an obese (ob/ob) mouse model. Five-week-old obese mice (n=18/dietary treatment) were provided 15 mg/kg each of α- and γ-tocopherol or 500 mg/kg of α- or γ-tocopherol for 5-weeks. Then, all mice were injected ip once with LPS (250 μg/kg) before being sacrificed at 0, 1.5 or 6 h. Body weight and hepatic steatosis were unaffected by tocopherols and LPS. Hepatic α- and γ-tocopherol increased (P<.05) ~9.8- and 10-fold in respective tocopherol supplemented mice and decreased in response to LPS. LPS increased serum alanine aminotransferase (ALT) by 86% at 6 h and each tocopherol decreased this response by 29-31%. By 6 h, LPS increased hepatic malondialdehyde (MDA) and tumor necrosis factor-α by 81% and 44%, respectively, which were decreased by α- or γ-tocopherol. Serum ALT was correlated (P<.05) to hepatic tumor necrosis factor-α (r=0.585) and MDA (r=0.592), suggesting that inflammation and lipid peroxidation contributed to LPS-triggered hepatic injury. α- and γ-Tocopherol similarly attenuated LPS-triggered increases in serum free fatty acid, and α-tocopherol only maintained the LPS-triggered serum triacylglycerol responses at 6 h. These findings indicate that increasing hepatic α- or γ-tocopherol protected against LPS-induced NASH by decreasing liver damage, lipid peroxidation, and inflammation without affecting body mass or hepatic steatosis. Further study is needed to define the mechanisms by which these tocopherols protected against LPS-triggered NASH.
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http://dx.doi.org/10.1016/j.jnutbio.2009.10.006DOI Listing
December 2010

Anti-obesity effects of xanthohumol plus guggulsterone in 3T3-L1 adipocytes.

J Med Food 2009 Aug;12(4):846-53

Department of Animal & Dairy Science, University of Georgia, Athens, Georgia 30602-2771, USA.

Xanthohumol (XN) and guggulsterone (GS) have each been shown to inhibit adipogenesis and induce apoptosis in adipocytes. In the present study effects of the combination of XN + GS on 3T3-L1 adipocyte apoptosis and adipogenesis were investigated. Mature adipocytes were treated with XN and GS individually and in combination. XN and GS individually decreased cell viability, but XN + GS caused an enhanced decrease in viability and potentiated induction of apoptosis. Likewise, XN + GS caused a potentiated increase in caspase-3/7 activation, whereas neither of the compounds showed any effect individually. In addition, western blot analysis revealed that XN + GS increased Bax expression and decreased Bcl-2 expression, whereas individual compounds did not show any significant effect. XN and GS both decreased lipid accumulation. Individually, XN at 1.5 microM and GS at 3.12 microM decreased lipid accumulation by 26 +/- 4.5% (P < .001) each, whereas XN1.5 + GS3.12 decreased lipid accumulation by 78.2 +/- 1.8% (P < .001). Moreover, expression of the adipocyte-specific proteins was down-regulated with XN1.5 + GS3.12, but no effect was observed with the individual compounds. Finally, XN + GS caused an enhanced stimulation of lipolysis. Thus, combination of XN and GS is more potent in exerting anti-obesity effects than additive effects of the individual compounds.
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http://dx.doi.org/10.1089/jmf.2008.0158DOI Listing
August 2009

Combined effects of genistein, quercetin, and resveratrol in human and 3T3-L1 adipocytes.

J Med Food 2008 Dec;11(4):773-83

Department of Animal & Dairy Science, University of Georgia, Athens, Georgia 30602-2771, USA.

The natural compounds genistein (G), quercetin (Q), and resveratrol (R) have been reported to each exhibit anti-adipogenic activities in adipocytes and antiproliferative and pro-apoptotic activities in several cell types. We studied the combined effects of G, Q, and R on adipogenesis and apoptosis in primary human adipocytes (HAs) and 3T3-L1 murine adipocyte (MAs). Combined treatment with 6.25 microM G, 12.5 microM Q, and 12.5 microM R during the 14-day differentiation period caused an enhanced inhibition of lipid accumulation in maturing HAs that was greater than the responses to individual compounds and to the calculated additive response. Glycerol 3-phosphate dehydrogenase activity, a marker of late adipocyte differentiation, was decreased markedly in HAs treated with the combination of G+Q+R. In addition, combined treatment with 50 microM G, 100 microM Q, and 100 microM R for 3 days decreased cell viability and induced apoptosis in early- and mid- phase maturing and lipid-filled mature HAs. In contrast, no compound alone induced apoptosis. Oil Red O stain and Hoechst 33342 stain were performed to confirm the effects on lipid accumulation and apoptosis, respectively. We also determined whether MAs responded to the combination treatment similarly to HAs. As in HAs, G+Q+R treatment decreased lipid accumulation in maturing MAs and increased apoptosis in pre- and lipid-filled mature MAs more than the responses to G, Q, and R when used separately. These results show that lower concentrations of combined treatments with several natural compounds may be useful for treatments for obesity through the suppression of adipogenesis and enhanced adipocyte apoptosis.
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http://dx.doi.org/10.1089/jmf.2008.0077DOI Listing
December 2008

Ajoene exerts potent effects in 3T3-L1 adipocytes by inhibiting adipogenesis and inducing apoptosis.

Phytother Res 2009 Apr;23(4):513-8

Department of Animal and Dairy Science, University of Georgia, Athens, GA 30602-2771, USA.

This paper describes effects of several sulfur-containing compounds from garlic on the cell viability, apoptosis and adipogenesis in 3T3-L1 adipocytes. In both preadipocytes and mature adipocytes, 100 and 200 microM ajoene significantly decreased cell viability and increased apoptosis. The effect on apoptosis was further confirmed with Hoechst staining. In contrast, diallyl sulfide, diallyl disulfide, diallyl trisulfide, deoxyalliin, and allyl methyl sulfide had no significant effect on cell viability or apoptosis in either preadipocytes or mature adipocytes. In maturing preadipocytes ajoene significantly decreased lipid accumulation in a dose-dependent manner and these results were further confirmed by a decrease in lipid droplet number and lipid content through Oil Red O staining. There was no significant change in lipid accumulation in maturing preadipocytes treated with other garlic derivatives. Thus, despite the same source of origin, garlic, ajoene was the only one with potent effects on cell viability, apoptosis and adipogenesis in 3T3-L1 adipocytes.
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http://dx.doi.org/10.1002/ptr.2663DOI Listing
April 2009

Regulation of adipogenesis by medium-chain fatty acids in the absence of hormonal cocktail.

J Nutr Biochem 2009 Jul 11;20(7):537-43. Epub 2008 Sep 11.

Department of Animal and Dairy Science, University of Georgia, Athens, GA 30602-2771, USA.

We report here that octanoate and decanoate, 8-carbon and 10-carbon medium-chain fatty acids (MCFA), decreased adipogenesis in 3T3-L1 preadipocytes when treated with standard hormonal cocktail, but increased adipogenesis in a dose-dependent manner (with decanoate being more effective) when treated with basal media. Addition of dexamethasone to basal medium with either octanoate or decanoate further increased adipogenesis. In order to understand the adipogenic effects of MCFA in the absence of standard hormonal cocktail, postconfluent 3T3-L1 preadipocytes were treated with octanoate or decanoate, and the change in the expression of several adipogenic transcription factors and enzymes was investigated using real-time RT-PCR. Octanoate and decanoate up-regulated the mRNA expression of peroxisome-proliferator-activated receptor (PPAR) gamma, CCAAT/enhancer-binding protein (C/EBP) alpha, fatty-acid-binding protein, sterol-regulatory element binding protein 1c, lipoprotein lipase and hormone-sensitive lipase, and the protein expression of PPARgamma and C/EBPalpha, with decanoate being more effective. Moreover, the PPARgamma antagonist GW9662 inhibited MCFA-induced lipid accumulation by about 50%. Decanoate and octanoate, to a lesser degree, increased lipid accumulation, which was associated with an increase in glycerol-3-phosphate dehydrogenase activity. These results show that octanoate and decanoate may stimulate differentiation of preadipocytes, at least in part, by their influence on the expression of PPARgamma and other adipocyte-specific factors.
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http://dx.doi.org/10.1016/j.jnutbio.2008.05.013DOI Listing
July 2009

Genistein inhibits differentiation of primary human adipocytes.

J Nutr Biochem 2009 Feb 10;20(2):140-8. Epub 2008 Jun 10.

Department of Animal & Dairy Science, University of Georgia, Athens, GA 30602-2771, USA.

Genistein, a major soy isoflavone, has been reported to exhibit antiadipogenic and proapoptotic potential in vivo and in vitro. It is also a phytoestrogen which has high affinity to estrogen receptor beta. In this study, we determined the effect of genistein on adipogenesis and estrogen receptor (ER) alpha and beta expression during differentiation in primary human preadipocytes. Genistein inhibited lipid accumulation in a dose-dependent manner at concentrations of 6.25 microM and higher, with 50 microM genistein inhibiting lipid accumulation almost completely. Low concentrations of genistein (3.25 microM) increased cell viability and higher concentrations (25 and 50 microM) decreased it by 16.48+/-1.35% (P<.0001) and 50.68+/-1.34% (P<.0001). Oil Red O staining was used to confirm the effects on lipid accumulation. The inhibition of lipid accumulation was associated with inhibition of glycerol-3-phosphate dehydrogenase activity and down-regulation of expression of adipocyte-specific genes, including peroxisome proliferator-activated receptor gamma, CCAAT/enhancer binding protein alpha, glycerol-3-phosphate dehydrogenase, adipocyte fatty acid binding protein, fatty acid synthase, sterol regulatory element-binding protein 1, perilipin, leptin, lipoprotein lipase and hormone-sensitive lipase. These effects of genistein during the differentiation period were associated with down-regulation of ERalpha and ERbeta expression. This study adds to the elucidation of the molecular pathways involved in the inhibition of adipogenesis by phytoestrogens.
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http://dx.doi.org/10.1016/j.jnutbio.2008.01.006DOI Listing
February 2009

Isolation and culture of preadipocytes from rodent white adipose tissue.

Methods Mol Biol 2008 ;456:201-19

Department of Foods and Nutrition, University of Georgia, Athens, GA, USA.

Much of the research devoted to understanding adipose tissue development is currently performed in vitro. Several cell culture models, including preadipocyte cell lines and primary culture of adipose-derived stromal vascular precursor cells, are commonly used to study molecular and cellular events and regulatory influences on preadipocyte proliferation and differentiation. Primary preadipocyte culture systems have several distinct advantages over preadipose cell lines. Because they have not been passaged continuously in culture, primary cultures of adipose derived stromal-vascular (SV) cells more closely reflect the in vivo characteristics of the tissue from which they are derived. In addition, primary cells can be obtained from various adipose tissue depots and from animals at different stages of development, from early postnatal life through advanced age. Cells can also be obtained from genetic rodent models of obesity or from rats and/or mice subjected to nutritional or hormonal manipulation. In each case, specific adipose tissue depots are dissected and the SV cells obtained after collagenase digestion. To examine the effect of tissue source or in vivo or in vitro treatment on preadipocyte proliferation, SV cells are labeled by thymidine incorporation during the exponential growth phase and maintained in culture until sufficiently lipid-filled to allow separation by density. Regulatory influences on various stages of preadipocyte differentiation can be examined in rat SV cultures in a controlled environment featuring chemically defined serum-free medium; whereas, more temperamental mouse SV cultures require the presence of serum for optimal differentiation. Alternatively, preadipocytes differentiated in vitro may be used for examining adipocyte metabolic or secretory responses.
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http://dx.doi.org/10.1007/978-1-59745-245-8_15DOI Listing
July 2008