bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Pomegranate Extract on High Fat/High Sucrose Diet induced Obesity are Dependent on the Intestinal Formation of Urolithin A
Authors: Yang Jieping , Henning Susanne M , Lee Rupo , Hsu Mark , Grojean Emma M , Ly Austin , Heber David , Li Zhaoping 
Published: November 2023

Recent studies strongly suggest the association of gut microbiota and obesity related diseases. Published data from a mouse study demonstrated that pomegranate extract (PomX) administration increased cecum Bifidobacteria, decreased inflammation and counteracted the HF‐induced expression of inflammatory markers both in colon and visceral adipose tissue. The major phytochemicals in PomX are ellagitannins (ETs), which are not absorbed in the small intestine. ETs are hydrolyzed to ellagic acid (EA) in the stomach and further metabolized to urolithin A (UA) by bacteria in the gastrointestinal tract. Inter‐individual differences in the production of UA from PomX were previously reported in humans. About 30% of individuals cannot produce UA when consuming POM.The aim of the present study was to investigateand link the potential effects of PomX on metabolic abnormalities of mice fed with HF/HS diet to intestinal UA formation.C57BL/6 male mice were randomly assigned to two treatment groups: control high fat /high sucrose [HF/HS (32% kcal from butter fat and corn oil, 25% kcal from sucrose)], or a HF/HS diet supplemented with 0.25% PomX for 4 weeks. In the mice receiving 0.25% PomX diet, stool samples were collected and analyzed by high performance liquid chromatography for UA production. We observed two distinct groups: UA producer (Producer) and UA non‐producer (Non‐P). All observations are in comparison to the HF/HS fed control mice. About 40% of mice fed the 0.25% PomX diet did not produce UA during the 4 week feeding period. The Non‐Ps showed significantly higher concentration of EA in blood and feces compared to producers. PomX administration significantly decreased liver lipid content and serum endotoxin in both producers and Non‐Ps associated with increase of hepatic AMPK phosporylation. However epididymal and mesenteric fat depots were only significantly increased by PomX consumption in producers meanwhile the cecum Bifidobacterium and Lactobacillus abundance only increased in Non‐Ps. In both Non‐Ps and producers PomX consumption did not significantly modify body weight gain, subcutaneous fat, Bacteroidetes/Firmicutes ratio and Akkermansia abundance.In summary, mice lacking UA production show higher EA concentrations in blood and feces while UA producers showed higher UA in blood and feces. Depending on their capacity to form UA we observed different effects of PomX diet on Bifidobacterium and Lactobacillus abundance and fat disposition using this HF/HS diet induced obesity mouse model.Support or Funding InformationSupported by departmental funds from the Center for Human Nutrition, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles.
Obesity‐Breast Cancer Interactions: Effects of Adipocytes on Breast Cancer Cells and Preventive Effects of Omega 3 Fatty Acids
Authors: Alhaj Sara Achraf , Aljawadi Arwa , Ramalingam Latha , Moustaid‐Moussa Naima 
Published: November 2023

Obesity is a prominent health problem in the United States with one in every three adults in the United States suffering from obesity. Furthermore, Breast cancer is a chronic disease, being the leading cause of death among cancer types in women in the United States, according to the American Cancer Society. There is a strong positive association between postmenopausal obesity in women and the development of breast cancer but the relationship between the two is not completely understood. Our research aim is to understand the mechanism(s) by which obesity promotes the occurrence of breast cancer and to further identify dietary interventions such as eicosapentaenoic acid (EPA), an omega‐3 fatty acid that may reduce obesity‐associated breast cancer. We hypothesized that obesity increases the risk of breast cancer through secretion of pro‐inflammatory adipokines from fat cells and/or through secretion of small microvesicles (exosomes or adiposomes), known to mediate cell‐cell interactions. To test this hypothesis, we used cultured murine 3T3‐L1 cells and human mesenchymal stem cells, either as non‐differentiated preadipocytes or differentiated into adipocytes, and human breast cancer cell lines (MCF‐7 or MDA‐MB‐231). We first conducted media transfer experiments where we transferred conditioned media from the preadipocytes or adipocytes into the cancer cells and collected media and cells at various times post exposure to conditioned media. We then measured the media levels of the pro‐inflammatory cytokines Interleukin‐6 (IL‐6) and/or IL‐8 and monocyte chemoattractant protein‐1 (MCP‐1) as well as gene expression in breast cancer cells exposed to their own media or conditioned media from preadipocytes or adipocytes. Our data shows that conditioned media from preadipocytes/adipocyte significantly increased breast cancer cell inflammatory markers. Furthermore, using the Seahorse extracellular flux analyzer, we also observed that MCF‐7 cells exposed to preadipocytes conditioned medium treated with 100 μM EPA exhibited lower glycolytic activity compared to those treated without EPA. Moreover, gene expression of IL‐6 and IL‐8 were significantly increased in MDA‐MB‐ 231 breast cancer cells exposed to adipocyte conditioned media and were significantly reduced by EPA. In summary, our study suggests that adipocytes secreted factors influence breast cancer cell inflammation and metabolism, these factors may include adipocyte‐secreted inflammatory cytokines and exosomes. Furthermore, our studies indicate that anti‐inflammatory dietary factors such as omega 3 fatty acids may help reduce the effects of adipocytes on breast cancer cells and possibly lessen the effects of obesity on breast cancer.Support or Funding InformationFunded by a pilot and feasibility grant from The President's Cluster Hire (Tier 2) and the Obesity Research Cluster and startup funds from Texas Tech University
a‐Tocopheryl phosphate induces VEGF expression via CD36/PI3Kg/Akt in THP‐1 monocytes
Authors: Zingg Jean‐Marc , Azzi Angelo , Meydani Mohsen 
Published: November 2023

The CD36 scavenger receptor binds several ligands and mediates ligand uptake and ligand‐dependent signal transduction and gene expression, events that may involve CD36 internalization. Here we show that CD36 internalization in THP‐1 monocytes is triggered by α‐tocopherol (αT) and more strongly by α‐tocopheryl phosphate (αTP) and EPC‐K1, a phosphate diester of αTP and L‐ascorbic acid. αTP‐triggered CD36 internalization is prevented by the specific covalent inhibitor of selective lipid transport by CD36, sulfo‐N‐succinimidyl oleate (SSO). Moreover, SSO inhibited the CD36‐mediated uptake of 14C‐labelled αTP suggesting that αTP binding and internalization of CD36 is involved in cellular αTP uptake, whereas the uptake of αT was less affected. Similar to that, inhibition of selective lipid transport by the SR‐BI scavenger receptor with BLT‐1 (Block Lipid Transport‐1, 2‐Hexyl‐1‐cyclopentanone thiosemicarbazone) mainly resulted in a reduction of αTP and not of αT uptake. In contrast, the uptake of αT was mainly inhibited by Dynasore, an inhibitor of clathrin‐mediated endocytosis, suggesting that the differential regulatory effects of αTP and αT on signalling may be influenced by their different routes of uptake. Interestingly, αTP and EPC‐K1 also reduced the neutral lipid content of THP‐1 cells and the phagocytosis of fluorescent Staphylococcus aureus bioparticles, most likely as a consequence of decreased surface CD36 expression and/or signal transduction and gene expression. Moreover, induction of the vascular endothelial growth factor (VEGF) promoter activity by αTP occurred via CD36/PI3Kγ/Akt, as it could be inhibited by specific inhibitors of this pathway (SSO, Wortmannin, AS‐605240). Amongst the tested transcription factor elements regulating the human VEGF promoter, the cAMP and hypoxia response elements (CRE and HRE, respectively) were induced by αTP treatment. These results suggest that αTP activates PI3Kγ/Akt signalling leading to VEGF expression in monocytes after binding to and/or transport by CD36, a receptor known to modulate angiogenesis in response to amyloid beta, oxLDL and thrombospondin.Support or Funding InformationThis material is based upon work supported by the U.S. Department of Agriculture – Agricultural Research Service (ARS), under Agreement No. #58‐1950‐4‐003.
Modulation of Serotonergic Stress Neurocircuitry by Dietary Prebiotics and Lactoferrin
Authors: Chichlowski Maciej , Mika Agnieszka , Berg Brian , Fleshner Monika 
Published: November 2023

Early life nutrition impacts many aspects of physiology and behavior. In our previous studies, rats fed prebiotic diets exhibited reduced anxiety and depressive‐like behavior produced by uncontrollable stress. The current study tested if 4 weeks of early life diets that vary in prebiotics (galactooligosaccharide, GOS + polydextrose, PDX) and globular glycoprotein (lactoferrin, LAC) would change the activation (cfos mRNA expression) of brain regions associated with the central stress response. The brain regions examined were the dorsal raphe nucleus (DRN), the locus coeruleus (LC), and nucleus of the solitary tract (NTS). Male F344 rats (p24) were pair‐housed in a barrier facility and fed experimental or control diet. The diet formulations were as follows: Control diet; LAC; GOS + PDX; and GOS + PDX+ LAC. After 4 weeks, rats were exposed to 100, 1.6mA, 5‐s, unpredictable, inescapable tail shocks (100 IS) or remained in their home cages. Immediately after stressor termination, rats were rapidly decapitated and blood, brain and peripheral tissues were collected. Brains were processed for assessment of mRNA expression using in situ hybridization. Expected increases in food intake and body weight were observed over time but not affected by diets. Stressor exposure reduced spleen wt (a proxy for sympathetic nervous system activation), corticosterone and glucose; and diet did not impact these responses. Stress increased cfos mRNA expression in all regions of the DRN. Mice fed diets including GOS+PDX exhibited reduced stress‐evoked cfos mRNA expression in the rostral DRN (dorsal, ventral and lateral regions); whereas GOS+PDX, LAC and LAC+GOS+PDX diets attenuated stress‐evoked cfos mRNA expression in the ventral mid and lateral mid regions of the DRN. In contrast, stress robustly increased cfos mRNA expression in the LC and NTS and diet did not modulate this effect. We further tested if diet would impact the effect of stress on 5‐HT1a receptor mRNA. The 5‐HT1a receptor is a serotonergic inhibitory autoreceptor that regulates DRN activation; prior work has demonstrated that enhanced stress resistance is associated with increased gene expression for the 5‐HT1a receptor. Stress decreased 5‐HT1a receptor mRNA in the rostral and mid DRN and this decrease was attenuated in all experimental diets (GOS+PDX, LAC and LAC+GOS+PDX) within the rostral DRN, whereas within the mid DRN, this decrease was only attenuated by diets containing GOS+PDX. These data suggest early life diets that contain prebiotics and/or lactoferrin may selectively modulate the serotonergic stress neurocircuitry in a manner that supports behavioral stress resistance.Support or Funding InformationSupported by Mead Johnson Nutrition.
In Vitro Effects of Grape Phenolics, Myricetin and Piceatannol, on Bovine Granulosa Cell Proliferation and Steroid Production
Authors: Spicer Leon J , Schutz Luis F , Zhang Lingna 
Published: November 2023

Myricetin (MYRI) and piceatannol (PICE) are naturally occurring phenolic compounds in red wine with cardio‐protective, anti‐carcinogenic, and anti‐osteoporosis effects. However, potential reproductive effects of MYRI (a flavonol) or PICE (a stilbenoid) have not been investigated in any animal species. The objective of the present study was to determine if MYRI and PICE can directly affect ovarian function using bovine granulosa cells (GC) as an in vitro model system to evaluate effects on GC proliferation and steroid production. Ovaries from non‐pregnant cattle were collected from a local slaughterhouse and follicular fluid was aspirated from small follicles (1–5 mm) to isolate GC. GC were cultured for 2 days in 10% fetal bovine serum followed by 2 days in serum‐free medium containing 500 ng/ml of testosterone (as an estradiol precursor), 30 ng/ml of follicle stimulating hormone and insulin‐like growth factor 1 (IGF1; 0 or 30 ng/ml) with MYRI (0, 1 or 30 μM) or PICE (0, 1 or 30 μM). These experiments were replicated with three independent pools of GC and treatments applied in triplicate for each pool. Data were analysed as a 2 (with/without IGF1) × 3 (3 doses of MYRI or PICE) factorial ANOVA. Statistical analyses revealed that both IGF1 and dose of MYRI and PICE significantly affected estradiol and progesterone production. IGF1 increased (P < 0.05) GC numbers (2‐fold) and estradiol (4‐fold) and progesterone (1.3‐fold) production. MYRI and PICE at 30 μM (but not at 1 μM) completely blocked IGF1‐induced progesterone production. In contrast, MYRI significantly stimulated IGF1‐induced estradiol production by 1.8‐fold, whereas PICE at 30 μM (but not at 1 μM) inhibited IGF1‐induced estradiol production by 90% (P < 0.05). Neither MYRI nor PICE significantly affected GC numbers. In conclusion, the red wine phenols, MYRI and PICE, affected GC steroidogenesis, and suggests that they may have the ability to impact reproductive function.Support or Funding InformationSupported in part by the Oklahoma State University Agricultural Experiment Station.
The Chemoprotective Effects of Mammalian Lignans Enterodiol and Enterolactone in Non‐Transformed Colonocytes
Authors: Curry Christina , Garcia‐Villatoro Erika , Hales Dale B. , Allred Clinton D. 
Published: November 2023

Previous epidemiological studies have shown that colon cancer incidence is correlated to diet and estrogen status. Phytoestrogens are molecules with similar structures to estrogen that occur naturally in plants. There is in vitro and in vivo evidence that phytoestrogens in the diet can inhibit carcinogenesis. The phytoestrogenic mammalian lignans enterolactone (EL) and enterodiol (ED) in flaxseed have been shown to be effective in decreasing tumor incidence in carcinogenic models, but there is little data regarding their effects in non‐malignant cells. The following studies used a non‐transformed cell line of young adult mouse colonocytes (YAMC) to determine the physiological effects of ED and EL in these cells. Our results demonstrate that low levels of EL (1μM) and ED (5μM) are effective at significantly reducing cell growth 20%, similar to physiological levels of estradiol. Apoptosis was also significantly increased with this treatment. Cell cycle distribution was not changed significantly by the compounds after 96 hours of treatment, but both EL and ED significantly down regulated expression of the cell cycle regulatory gene Cyclin D1 after 24 hours. Additionally, B‐cell lymphoma 2, a gene known to suppress apoptosis, was also down regulated at 24 hours by EL treatment. Ongoing experiments are investigating the effects of EL and ED on isogenic YAMC cell lines that either have a mutated p53 gene, over express Ras, or both. This is significant, because while they are derived from the YAMC cell line, these cells are fully transformed malignant colonocytes. Evaluating the role of ED and EL in these various cell lines will help determine at which stage of carcinogenesis these phytoestrogens may be acting and whether these effects are mediated via p53 and/or Ras pathways. Collectively, these data are the first to demonstrate that ED and EL can alter the physiology of non‐malignant colonocytes and suggest that consumption of these compounds in flaxseed may impact colon carcinogenesis.Support or Funding InformationFunding is provided by ACS grant RSG‐11‐179‐01‐TBE to CDA.
The regulation in key protein expression related to circadian rhythms with a natural compound containing rosemary and hemerocallis fulva extract in vitro
Authors: Qin Bolin , Shea‐Donohue Terez , Liu Chao , Timmcke Judi Quilici , Anderson Richard A 
Published: November 2023

Increasing evidence suggests that the core clock proteins of the circadian system play important roles in prevention, development, and/or progression of various pathologies, such as obesity, diabetes and sleep disorders. In this study, we investigated if the natural compound, CLOCK ® (mixture of rosemary and hemerocallis fulva extract) regulates the key protein expression related circadian rhythms in rat C6 glioma cells, using immunefluorescence and Western blotting analysis. The CLOCK complex incubation significantly enhanced Clock (circadian locomotor output cycles kaput), Bmal1 (brain and muscle Arnt‐like protein 1), Sirt (Sirtuin 1), F‐box and leucine‐rich repeat protein 21 (Fbxl21) and Fbxl3 expression in a dose‐dependent manner, compared to the control cells. CLOCK also stimulates the protein levels of brain‐derived neurotrophic factor (BDNF), which is a member of the neurotrophin family of growth factors. Oxidative stress can induce the dysregulated circadian rhythms. We also tested if CLOCK attenuates the damage of these core proteins expression in oxygen‐glucose deprivation (OGD) treated L6 muscle cells. OGD treatment significantly reduced 2‐NBDG uptake as measured by fluorescent microcopy and down‐regulated Clock, Bmal1 and Sirt1 protein levels in L6 muscle cells. CLOCK complex attenuated the damages‐induced by OGD on glucose uptake and the expression of these core proteins. These results indicate that the natural compound, CLOCK® may be beneficial on improving the dysfunction of circadian rhythms and likely circadian related diseases.Support or Funding InformationIn‐ingredients.com Funding
Molecular Effects of Cinnamon Bioactive Compounds for Neuroprotection in D. Melanogaster
Authors: Crews Rebecca , Gomada Yuki , Jamison Brandon , Vattem Dhiraj 
Published: November 2023

We previously reported that treatment with cinnamon bioactive compounds delay paralysis and extend lifespan in C. elegans and D. melanogaster. Here, we investigated the molecular effects of the bioactive compounds (10–25 mg/ml of sodium benzoate, cinnamic acid, cinnamaldehyde, ethyl cinnamate, and cinnamyl acetate) in D. melanogaster models of neurodegeneration. Alzheimer's and Parkinson's disease‐like neurodegeneration was induced in the flies by the UAS/GAL4 tissue specific expression system. Neurotoxicity was modeled by exposure to the neurotoxin rotenone (0.5 M). Samples of flies were frozen on days 0, 10, 15, and 30. We evaluated the catalytic activity of two important antioxidants, SOD and catalase. Additionally, we assessed the extent of lipid peroxidation in the flies by quantifying lipid hydroperoxides. For amyloid‐ beta induced neurodegeneration, we observed that treatment with the compounds modulated the activity of both SOD (FC=.89–1.66) and catalase (FC=0.89–2.44). The levels of lipid hydroperoxides were also variable when compared to control (FC=0.84–2.56). We also measured the level of SOD mRNA in the flies and found fold changes between 0.45–4.60. For flies with a‐synuclein‐induced neurodegeneration, SOD activity was higher in all treatment groups compared to control (FC=1.11–1.98); mRNA levels ranged from 1.0–4.0 relative to control. We also observed the catalytic activity of catalase in the flies was also modulated between treatment groups (FC=0.81–2.48). In flies that were treated with rotenone, the catalytic activity of SOD (FC=0.32‐.67) and catalase (.50–1.01) was reduced for all treatment samples. The mRNA levels of SOD ranged from 0.002–1.059 relative to control. Lipid hydroperoxides were reduced after treatment with cinnamyl acetate (FC=0.80) and cinnamic acid (FC=0.81), while elevated levels were observed in cinnamaldehyde (FC=1.24) and ethyl cinnamate (FC=1.19) treatment groups. These results suggest that cinnamon bioactive compounds may be neuroprotective and extend lifespan through the modulation of critical antioxidant pathways.Support or Funding InformationVRDÜR Foundation
Effects of Sphingomyelin‐rich Beta Serum on Lipid Metabolism in High Fat Diet‐fed Mice
Authors: Norris Gregory H , Blesso Christopher N 
Published: November 2023

Dietary phospholipids are a potential source of bioactive lipids that may impact inflammation and lipid metabolism. One such dietary phospholipid, sphingomyelin (SM), has been shown to dose‐dependently reduce the absorption of dietary lipids in rodents. These effects of dietary SM may influence dyslipidemia and the development of non‐alcoholic fatty liver disease. Consumption of dietary SM in Western diets is relatively common and comes mainly from dairy products. Beta serum is a byproduct of anhydrous milk fat production and contains high amounts of phospholipids, such as SM. In this preliminary study, C57BL/6J mice were fed either a control high fat diet (21% w/w as anhydrous milk fat) (n = 8) or a high fat diet with added beta serum (5% w/w, macronutrient‐ and micronutrient‐matched) (n = 8). The amount of dietary SM that the beta serum diet provided was approximately 64 mg per kg of body weight to the mice, with the human equivalent dose being approximately 350 mg per day (70 kg human). After 10 weeks, there were no significant differences in body weight or blood lipids between groups. However, H&E staining of liver showed an attenuation of hepatic steatosis in the beta serum group. More research is warranted to explore the potential effects of beta serum on lipid metabolism and liver health.Support or Funding InformationSupported by the University of Connecticut.