bluuebunny/crossref_metadata_2025 huggingface dataset:
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 Information

Funded 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 Information

This 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 Information

Supported 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 Information

Supported 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 Information

Funding is provided by ACS grant RSG‐11‐179‐01‐TBE to CDA.
Drug treatment of prostate cancer cells using a combination of naturally occurring compounds leads to activation of apoptosis
Authors: Oblad Richard Vernon , Dixon Andrew , Bernhisel Drew , Eggett Dennis , Kenealey Jason
Published: November 2023

Chemotherapy often uses a combination of drugs in order to activate apoptosis in cancer cells. Combination drug therapy allows for higher sustained rates of apoptosis due to activation of complimentary mechanisms and a lower likelihood of developing resistance. Chemotherapeutics are often toxic, and lead to organ damage and apoptosis in non‐cancerous cells. Naturally occurring compounds, such as resveratrol (RES), epigallocatechin gallate (EGCG), quercetin and avenanthramides have been identified as activators of apoptosis in cancer cells, but are non‐toxic to non‐tumorigenic cells. Since these compounds activate apoptosis through extrinsic and intrinsic pathways as well as the perforin/granzyme pathway, we have used them in combination to activate apoptosis in prostate cancer cells, and have identified an ideal concentration of these compounds using Response Surface Methodology (RSM) of data collected from cell viability assays (MTT assays). Cells were treated with the optimal combination and immunoblotting techniques were used to identify the pathways activated, and to show biomarkers of apoptosis. Time resolved activation of apoptosis was measured by the use of high resolution respirometry which allowed us to measure decreases in mitochondrial function. These techniques were used to demonstrate that combination drug therapy with these naturally occurring compounds is an effective activator of apoptosis in cancer cell models.
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 Information

In‐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 Information

VRDÜR Foundation
Improved Osteoporotic Condition of Soybean and Yak‐kong (Blackbean: Rhynchosia Molubilis) in Korean Postmenopausal Women
Authors: KANG SOON AH , Jung Kwang‐Gyun , Kim Seong‐Hee , Park Jong‐Guk , Seo Myung‐Hee , Cha Jae‐Hak , Oh Hyun‐Ji , Lee Ji‐Yeon
Published: November 2023

Osteoporosis is a major public health problem in elderly population around the world, in particular in women. The most common form of osteoporosis in postmenopausal women is associated with deficiency of estrogen. Phytoestrogens, especially soy‐derived isoflavones, are receiving great scrutiny as a food supplement for preventing hormone dependent disease such as postmenopausal osteoporosis. To investigate the effects of supplementation of soybean and blackbean on bone mineral density and parameters of biochemical bone formation of Korean postmenopausal women were observed. Forty eight healthy postmenopausal women were randomly divided into three groups in a double‐blind parallel design and consumed one of the supplements for 3 months; placebo of maltodextrins /sucrose mixture, soybean, and blackbean. During the 3 months of experiment no differences were found in bone mineral density (BMD) among the groups. The level of serum Ca and P showed a trend to be slightly increased after 3 months supplementation of blackbean. Apparent calcium absorption increased blackbean group, while in control group showed decreasing as compared with the baseline. The levels of serum osteocalcin and activity of ALP in soybean groups were lower than those of control groups. Supplementation of blackbean and soybean might increase calcium absorption and improved osteoporotic condition in the Korean postmenopausal women
The effect of guava leaf extracts on antioxidant properties and lipid profile in ovariectomized rats
Authors: Liu Yanan , Ko Eun‐Jeong , Yoo Jeong‐Hyun , Song Eun‐Kyung , Kim Hyun‐Sook
Published: November 2023

Postmenopause have been reported to be associated with increased oxidative stress and cardiovascular risk. Previous studies investigated the effects of Guava leaves on antioxidant activity, lipid profiles, and cardiovascular diseases, but none of them were tested using ovariectomized model. In this study, we evaluated the effects of guava leaf extracts on lipid profile and antioxidant activity in an ovariectomized rat model. Female Sprague‐Dawley rats were randomly assigned to four groups(n=7 for each group): sham‐operated rats(SHAM), ovariectomized rats(OVX‐CON), and ovariectomized rats that were treated with guava leaf extracts(OVX‐GL 150mg/kg and OVX‐GH 300mg/kg). Treatment groups were administered with guava leaf extracts(GLE) every day for 8 weeks. The body weight was significantly decreased in GLE groups compared with the OVX‐CON group(p<0.05). Serum 17β‐estradiol(E2) was significantly lower for the OVX groups than the sham group(p<0.05). Serum triglyceride(TG) level showed no significant difference in all groups. However, serum free fatty acid (FFA) level and liver triglyceride(TG) level were significantly decreased in both GL and GH group compared with OVX‐CON group(p<0.05). Serum total cholesterol(TC) level was significantly decreased in OVX‐GH group compared with OVX‐CON group(p<0.05). Furthermore, serum glutathione peroxidase(GPx) activity was significantly increased in GLE group(p<0.05). No significant changes were observed in serum superoxide dismutase(SOD) activity among all groups. These results suggest that GLE could have protective effect on OVX model by lowering cholesterol level and increasing antioxidant enzyme activity. These results indicate that administration of GLE have improving effects toward lipid profiles and hypercholesterolemia in ovariectomized rats.
Evaluating the effect of plant origin prebiotics (Raffinose and Stachyose) on iron status, intestinal functionality and intestinal bacterial populations in vivo
Authors: Pacifici Sarina , Song Jaehong , Zhang Cathy Kexin , Tako Elad
Published: November 2023

Iron (Fe) deficiency is the most common nutritional deficiency worldwide. Certain prebiotics (e.g. inulin) have been shown to improve Fe absorption. This study investigates the effectiveness of various prebiotics that are present in staple food crops that are widely consumed in regions where dietary Fe deficiency is a health concern to improve Fe status, intestinal functionality and cecal microbiome in vivo (Gallus gallus), and by using the intra‐amniotic administration procedure. On day 17th of embryonic incubation 120 fertile eggs were divided into 6 groups (n=20) and the respective prebiotic treatment solutions (1 mL) were then injected into the amniotic fluid of the eggs. Treatment group were as follows: 1. 5% Raffinose (in saline); 2. 10% Raffinose (in saline); 3. 5% Stachyose (in saline); 4. 10% Stachyose (in saline); 5. Saline; 6. Non injected. At hatch, cecum and small intestine were collected for assessment of relative abundance of the various gut micro flora analysis and gene expression analysis respectively. The prebiotic treatment groups showed to significantly (p<0.05) increase the relative expression (AU) in aminopeptidase, sucrase isomaltase, ATPase, and sodium glucose co‐transporter 1 (SGLT1), these are proteins reflect the functionality of the intestinal enterocyte brush border membrane (BBM). The relative expression of Fe related proteins; ferroportin and Divalent Metal Transporter 1 (DMT 1) resulted in an overall down regulation (p<0.05) in most of the prebiotic treatment groups. The prebiotic treatment groups promoted an increase in the relative abundance of Bifidobacteria, Lactobacillus and E. coli yet not in Clostridium (p<0.05). Taken together, these results suggest the prebiotics affected probiotic increase, Fe bioavailability, and BBM functionality. Our investigations have led to a greater understanding of these various prebiotics’ effects on intestinal health.
RESVERATROL ATTENUATES OBESITY RELATED RENAL AND SYSTEMIC ALTERATIONS DURING ACUTE AND CHRONIC ENDOPLASMIC RETICULUM STRESS
Authors: Tovar‐Palacio Claudia , Terán‐García Margarita , Figueroa‐Juarez Elizabeth , Torre‐Villalvazo Ivan , Noriega Lilia G , Tovar Armando R , Correa‐Rotter Ricardo
Published: November 2023

Renal lipid accumulation has been associated with chronic renal failure in obese patients. Molecular mechanisms seem to implicate lipotoxicity and induction of endoplasmic reticulum (ER) stress. Resveratrol (R) is a natural bioactive compound that elicits benefits over some obesity–related metabolic disorders. The objective of this study was to evaluate the effect of R supplementation on a high fat (HF) diet over a chronic and acute induction of ER stress in C57BL/6 mice. Male mice were fed for 28 weeks with four different dietary treatments: Control (C), C+R (CR), HF, and HF+R (HFR). At the end of the study, half of the animals on each group were treated with tunicamycin (T) to induce acute ER stress. Weight gain, glucose tolerance test (GTT), indirect calorimetry and serum biomarkers were analyzed. Weight gain of the HFR group was lower than HF accompanied with a significant increase in O2 consumption and CO2 production during fasting and fed state. Mice in the HF and HFR groups had lower glucose tolerance compared to C and CR. Total‐ and LDL‐cholesterol were lower in HFR group compared to HF group. Mice treated with T had lower glucose, total‐ and LDL‐cholesterol compared to C and HF groups. No differences were observed in other biomarkers (albumin, creatinine, AST, ALT and triglycerides) in CR+T and HFR+T groups despite the acute ER stress induction. In conclusion, resveratrol supplementation showed beneficial effects on body weight gain, energy expenditure and biochemical variables with and without pharmacological induction of ER stress.
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 Information

Supported by the University of Connecticut.
The Acute Effects of White Button and Shiitake Mushroom Powder Supplementation on Postprandial Lipemia Following a High Fat Meal
Authors: Morris Matthew J , Robak Theodore J , Talal Lillian A , Williams Brian T , Browne Richard W , Horvath Peter J
Published: November 2023

Background

The current trend of rising obesity levels and poor dietary choices have led to an increased incidence of chronic diseases in the United States, including cardiovascular disease (CVD) and dyslipidemia. Fortifying popular meals in a typical Western diet with bioactive compounds that may negate some consequences of consumption is a novel approach to reducing a high fat meal's impact on post prandial lipemia. Bioactive compounds (ergosterol and beta‐glucan), found in high levels in mushrooms, has been shown to reduce cholesterol absorption. Fortifying food with ergosterol and Beta‐glucans may be an effective way to reduce post prandial lipemia from a high fat meal.

Purpose

To determine the acute effect on postprandial Lipemia by fortifying a high fat meal with either White Button (WB) or Shiitake (SH) mushroom powder.

Methods

9 Healthy Subjects (5 females and 4 males, 23.3±1.2yr, 17.8±6% body fat, 56.2±11.4kg fat free mass) were randomized to receive three different meals. One meal consisted of an 8oz cooked beef patty and a bun (883kcal, 47g fat, 37.5g carbohydrate, 73.2g protein) with no mushrooms (control). The other two meals had 14g of either white button (WB), or shiitake (SH) dried mushroom powder incorporated into the beef patty. Subjects were fasted for 12h and avoided vigorous exercise on the day prior to testing. Prior to the consumption of each meal an indwelling venous catheter was placed. Blood was drawn directly before burger consumption and every two hours after for a total of six hours. A Lipid Panel was performed on all blood samples to determine lipemia following the test meal.

Results

Postprandial serum triglycerides were generally lower in the WB group 38.9±4.4 vs SH group 19.1±4.4 (P=0.01). At hour two, the triglycerides in the SH group 32.0±5.9 was lower than the WB group 57.6±5.9( P=0.02), and also lower than the control group 51.7±5.9 (P=0.04). At hours four and six the triglycerides in the SH group 40.1±5.9, 4.2±5.9 was lower than the WB group 69.6±5.9, 28.3±5.9 (P=0.009, P= 0.03) respectively. The overall incremental area under the curve for serum triglycerides in the SH group 148.0±45.4 was lower than the WB group 283.1±50.1 (P=0.028). Specifically, Serum triglycerides were lower in the SH vs WB group at hours 2–4 71.9±20.1and 127.3±22.6 (P=0.05), and from hours 4–6, 44.1±19.9 vs 98.2±20.3 (P=0.02) respectively.

Conclusion

Consumption of shiitake mushroom powder in conjunction with a high fat meal was effective in lowering serum triglycerides when compared to supplementation with white button mushroom powder, or a high fat meal with no mushroom powder. Fortifying a high fat meal with shiitake mushrooms may be protective against the dyslipidemic impact of a typical high fat meal.

Support or Funding Information

Supported by a grant through the University of Buffalo's Honors College
Blueberries Improve Whole‐Body Insulin Action and Alter the Development of Obesity in High‐Fat Fed Mice
Authors: Stull April J. , Beyl Robbie A.
Published: November 2023

Consumption of blueberries (BB) has been shown to modulate glucose metabolism and the development of obesity in vivo. This study investigated the therapeutic efficacy of BB on whole‐body and tissue‐specific insulin action during the hyperinsulinemic‐euglycemic clamps in diet‐induced obese mice. The C57BL/6J male mice (n=12/group) were fed one of three diets for 12 weeks: low‐fat diet (LFD; 10% fat), high‐fat diet (HFD; 45% fat), and high‐fat diet plus BB (HFD+BB; 4% freeze‐dried BB powder, wt:wt). The diets were pelleted and also matched for sucrose and fiber. Energy intake, body weight, and fat mass (determined by nuclear magnetic resonance) were assessed pre‐and post‐intervention. Also, whole‐body insulin action (i.e., insulin sensitivity), tissue‐specific glucose uptake, and hepatic glucose production were assessed post‐intervention by using the hyperinsulinemic‐euglycemic clamp. Both HFD groups had a significantly higher average energy intake than the LFD group during the duration of the study (P<0.05). However, the addition of BB to the HFD did not affect the energy intake with no significant differences existing between the HFD and HFD+BB groups. Although the mice exhibited similar energy intakes, they still differed in their body weight and composition. At the end of the study, the HFD mice gained significantly more body weight, fat mass, and %body fat than the HFD+BB and LFD mice (P<0.05). Consuming BB helped to reduce the body weight gain, fat mass, and %body fat of the mice on the HFD+BB (P<0.05). In addition, the steady‐state glucose infusion rate (GIR) required to maintain euglycemia was 62% higher in the HFD+BB mice when compared to the HFD mice (P<0.05), but the HFD+BB mice had a similar GIR to the LFD mice. Thus, this is indicative of an improvement in whole‐body insulin action after BB consumption when compared to consuming a HFD without BB. The suppression of hepatic glucose production by insulin was comparable between the three groups. Also, insulin‐stimulated glucose uptake into the peripheral tissues (i.e., skeletal muscle, adipose tissue, heart, and brain) was not affected by BB intake. In conclusion, consuming blueberries reduced body weight gain and fat mass, and enhanced whole‐body insulin action in diet‐induced obese mice.

Support or Funding Information

Supported by the National Center For Complementary & Integrative Health, National Institutes of Health (Award Numbers K01AT006975 and P50AT002776).
Improved Peripheral Insulin Sensitivity and Pancreatic Islet Function in Obese Rats Treated with Polyphenol‐Rich Extract of Syzygium cumini Leaves
Authors: França Lucas Martins , Sanches Jonas Rodrigues , Chagas Vinicyus Teles , Gaspar Renato Simões , Santos Kayque Almeida , Maranhão Marina Cristine Silva , Carneiro Everardo Magalhaes , Cappelli Ana Paula Gameiro , de Andrade Paes Antonio Marcus
Published: November 2023

Syzygium cumini (L.) Skeels (Myrtaceae) has been traditionally used to treat of metabolic disorders, especially diabetes mellitus. Although there are many studies used extracts from seed and fruit pulp, the works with the leaves are scarce. As there is considerable interest in bioactive compounds to treat metabolic syndrome and its clustered risk factors, we sought to characterize the metabolic effects of hydroethanolic extract of S. cumini leaves (HESc) on lean and monosodium L‐glutamate(MSG)‐induced obese rats. At 60 days of age, both groups were randomly assigned to receive HESc (500 mg/kg; v.o) or vehicle for 30 days. At the end of treatment, obese+HESc exhibited significantly lower body weight gain (199.4 ± 8.6 g), body mass index (328.0 ± 3.8 g1/3.cm−1), and white adipose tissue mass (2.58 ± 0.19 g/100 g bw), compared to obese rats receiving vehicle (245.1 ± 14.9 g; 3.47 ± 3.09 g1/3.cm−1; 3.65 ± 0.55 g/100 g bw, respectively). No difference was observed between lean groups. Obese rats treated with HESc showed a 2‐fold increase in lipolytic activity in the periepididymal fat pad compared to obese rats without treatment (4.81 ± 0.44 vs. 2.75 ± 0.36 mg/mg/h), as well as, reduced triglyceride levels in serum (129.3 ± 13.2 vs. 237.4 ± 36.3 mg/dL), liver (8.71 ± 1.04 vs. 18.38 ± 2.39 mg/g tissue) and skeletal muscle (8.03 ± 1.03 vs. 13.2 ± 1.44 mg/g tissue). Furthermore, HESc also improved hyperinsulinemia (1.125 ± 0.23 vs. 1.93 ± 0.24 ng/mL) and insulin resistance in obese+HESc rats (HOMA‐IR index: 6.02 ± 1.3 vs. 10.8 ± 1.9), as compared to obese rats. HESc had no effect in lean rats. Assessment of ex vivo glucose‐stimulated insulin secretion showed HESc potentiated pancreatic function in islets isolated from both lean (1.84 ± 0.24 vs. 0.96 ± 0.14 ng/mL/h) and obese rats (3.20 ± 0.39 vs. 2.32 ± 0.22 ng/mL/h) treated with HESc. In addition, HESc (100 μg/mL) increased glucose stimulated insulin secretion from both isolated rat islets (4.2 ± 1.09 vs. 1.83 ± 0.29 ng/mL/4 islets/h) and INS‐1E β cells (23.9 ± 2.5 vs. 12.3 ± 1.11 ng/mL/4h), as compared to basal insulin release. HPLC‐MS/MS characterization of the HESc polyphenolic profile, at 254 nm, identified 15 compounds pertaining to hydrolysable tannins and flavanol subclasses. These data demonstrate that S. cumini leaves improved peripheral insulin sensitivity via stimulating/modulating beta cell insulin release, which was associated with improvements in metabolic outcomes in MSG‐induced obese rats.

Support or Funding Information

FAPEMA, CAPES, CNPQ and UFMA
HPV Related Squamous Cell Carcinomas of the Head and Neck Metastatic to the Small Bowel: First Case Report and Review of the Literature
Authors: Patel Amit P , Neill Kevin G , Leon Marino , Coppola Domenico
Published: November 2023

BACKGROUND

Human papillomavirus (HPV) related squamous cell carcinomas of the oropharynx (OHPV‐SCC) have become increasingly prevalent in recent years. We report the first case of metastatic OHPV‐SCC to the small bowel and its clinical pathological features, illustrating the nature of this lesion. A review of the literature is included to discuss the current understanding of oropharyngeal HPV‐SCC (OHPV‐SCC), the role of p16 immunostain and HPV detection in these clinical settings.

CASE PRESENTATION

We report the first proven case of OHPV‐SCC metastatic to the small bowel. The patient is a 68 year‐old male that was originally diagnosed with OHPV‐SCC. He was treated with chemoradiation that resulted in tumor regression. Two years later, he presented with acute neurological symptoms suggestive of a cerebrovascular accident. Computed tomography scan and magnetic resonance imaging showed numerous metastatic lesions that involved multiple organs including the brain, lungs and liver. Imaging also showed an area of small bowel thickening with mesenteric stranding and pneumatosis that was suggestive of perforation. During exploratory surgery, a small bowel perforation was identified and a partial bowel resection was performed. Histopathological examination of the small bowel specimen showed transmural infiltration of a squamous cell carcinoma (Figure 1A,B). The tumor cells were strongly positive for p16 (Figure 2), cytokeratin 5/6 and high‐risk HPV chromogenic in situ hybridization, conclusive of a metastatic OHPV‐SCCA. A review of the literature showed prior cases of head and neck SCC metastatic to the small bowel, but none of the cases were identified as HPV related.

CONCLUSION

We present here the first reported case of OHPV‐SCC metastatic to the small bowel. A review of the literature showed that previous cases of head and neck cancers metastatic to the small bowel have been reported. However, none of these reports was proven to be HPV related. Our case presents immunohistochemical and in situ hybridization features supporting the final diagnosis.
Exploring the Proteomic and Genomic Relationships between CtBP Expression and Metabolic Imbalance in Breast Cancer
Authors: Crawford Lindsey , Hernandez‐Mora Roberto , Park Sam , Byun Jung S. , Gardner Kevin
Published: November 2023

Over 200,000 American women are diagnosed with breast cancer annually. Although the mortality rate of diagnosed patients has decreased over the years, there are still breast cancer health disparities that exist in the United States. Research studies have shown that although European American women have the highest breast cancer incidence rate, the highest breast cancer death rate is observed in African American women. Additionally, obesity has also been associated with an increased risk of breast cancer in postmenopausal women, having a three times higher risk of death from disease, with a body mass index (BMI) greater than 40 kg/m2, compared to their healthier counterparts. Our lab is currently focused on analyzing the role of C‐Terminal Binding Proteins (CtBP), a family of NADH‐dependent nuclear regulators that respond to metabolic imbalance and function as transcriptional corepressors when targeted to gene promotors. As cancer cells exhibit higher levels of lactic acid production and glucose consumption in the presence of a significant amount of oxygen, the steady state levels of NADH rises creating aNAD+/NADH redox imbalance. This metabolic imbalance, called the Warburg Effect, can be linked to CtBP's possible role in breast cancer.

Using Immunohistochemistry and RNA‐seq to profile both the protein levels and RNA expression, we are exploring the trends across the breast cancer subtypes and determining how they correlate with certain patient parameters, such as ethnicity, menopausal status, ERstatus, and BMI. From the numerous fixed parameters, multiple correlations within the patient data set were found revealing an intriguing set of trends that form the basis for future analysis. For example, we have discovered a correlation between high protein levels of CtBP with the Luminal B subtype, a more aggressive subtype of estrogen receptor positive breast cancer. Although a high gene expression of ESPL1, a newly discovered Luminal B breast cancer subtype oncogene, has also been correlated with Luminal B, ESPL1 was anti‐correlated with CtBP. This finding suggests that there may be two different molecular/phenotypic subtypes of Luminal B. The significant anti‐correlation between ESPL1 and CtBP was not seen in the other breast cancer subtypes. Notably this relationship is significantly modified by Race, menopausal status and BMI. The trends found exploring the proteomic and genomic relationships allows us to begin to explore how CtBP may link race and metabolic status with gene expression and outcome in breast cancer.
Apigenin attenuates CCL2 release from TNFα and IL‐1a stimulated MDA‐MB‐231 triple negative breast cancer cells
Authors: Bauer David F. , Mazzio Elizabeth A , Soliman Karam F.
Published: November 2023

Apigenin is a natural chemo‐preventative bioflavonoid found in parsley, which exerts anti‐tumor and anti‐inflammatory properties. The role of the immune system in tumor initiation, promotion and progression is highly a function of tumor associated macrophage (TAM) infiltrates to the tumor tissue, which are drawn in by chemokines such as CCL2 and IL‐1a released from malignant tissue itself. High concentrations of both CCL2 and IL‐1a are implicated in aggressive metastatic tumors with poor prognosis. In this study we explore the tumorigenic effects of TNFα on MDA‐MB‐231 triple negative cells (ATCC® HTB‐26™) on CCL2 and IL‐1a and evaluate if apigenin can attenuate both TAM recruitment chemokines. RT‐PCR microarray results show that TNFα (40ng/mL) induced a major shift in cell release of 1/88 cytokines tested; found to be IL‐1 and co‐expressed with CCL2. IL‐1a alone evoked a rise in CCL2, suggesting that either TNFα mediates its effects through IL‐1a or they are likely to trigger similar downstream pathway signaling. Both cytokines were attenuated by sub‐lethal concentration of apigenin (40μM) which corresponded to significant down regulation of mRNA transcription and protein synthesis. These findings provide evidence to suggest apigenin has the capacity to modulate immunological signaling of cancer cells, which prevent cascades that further direct infiltration of TAMS, a pivotal role in tumor cell immunological evasion, initiation and growth.

Support or Funding Information

NIMHD Grants G12MD007582 and Grant Number P20 MD006738.
Anti‐angiogenic activity of nicotinic receptor antagonists in lung cancer
Authors: Robateau Zachary , Brown Kathleen C , Creel Rebecca G , Chen Yi C , Grover Lawrence M , Mangiarua Elsa I , Egleton Richard D , Dasgupta Piyali
Published: November 2023

Small cell lung cancer (SCLC) is a highly angiogenic tumor with a dismal survival rate. Cisplatin‐based therapies are initially effective in SCLC. However, the tumor relapses and subsequently becomes resistant to cisplatin‐based therapies. Pilot clinical trials have shown that the combination of cisplatin with an anti‐angiogenic agent can improve therapeutic response of small cell lung cancer patients. A unique feature of SCLC is that it occurs almost exclusively in smokers. Nicotine, the addictive component of cigarettes, can promote angiogenesis in lung cancer. We show that nicotine stimulates angiogenesis in human retinal microvascular endothelial cells (HRMECs) and human lung microvascular endothelial cells (HMECLs). The proangiogenic effects of nicotine were mediated via the α7‐nAChR subunit. We conjectured that α7‐nAChR antagonists should attenuate nicotine‐induced angiogenesis and be useful for the therapy of angiogenesis‐related diseases. Our results show that the α7‐nAChR antagonist memantine displays potent anti‐angiogenic activity in the Matrigel model and chicken chorioallantoic membrane (CAM) model. Another α7‐nAChR antagonist MG624 also inhibited nicotine‐induced angiogenesis in lung endothelial cells. Our studies show that α7‐nAChR antagonists may be useful for novel combination therapies in human SCLC.

Support or Funding Information

Funding for our study was supported by ACTSI Grant from Marshall University
Combinatorial apoptotic activity of capsaicin and camptothecin in small cell lung cancer
Authors: Stover Cody A , Perry Haley E , Brown Kathleen C , Rollyson William D , Dasgupta Piyali
Published: November 2023

Cisplatin‐based chemotherapy is the standard of care for small cell lung cancer. However, one of the challenges with SCLC therapy is that patients quickly become resistant to cisplatin. Patients with platinum resistant or refractory disease have very limited options, as the only standard chemotherapy with an FDA‐approved drug, camptothecin, has an objective response rate of approximately 3% and little or no survival benefit. Such sobering statistics define the arena where there is an urgent need for drugs which may increase the efficacy of camptothecin in platinum resistant disease. The present study tests the hypothesis that capsaicin can sensitize human SCLC cells to the apoptotic effects of cisplatin or camptothecin. Caspase‐3 activity assays reveal that the combination of camptothecin and capsaicin displayed greater apoptotic activity than any of the compounds used alone. We verified these results using a second apoptosis assay and obtained similar results. Chicken chorioallantoic membrane assays confirmed the combinatorial effects of capsaicin and camptothecin. Capsaicin also sensitized cisplatin‐resistant SCLC cells to camptothecin‐induced apoptosis. The synergistic effects of capsaicin and camptothecin are mediated by intracellular calcium and the calpain pathway. Our data foster the hope of novel combination therapies for platinum‐resistant SCLCs.

Support or Funding Information

Funding for our study was supported by the an NIH R15‐AREA Grant (1R15HL113681‐01A1) and an AICR Investigator Grant.