bluuebunny/crossref_metadata_2025 huggingface dataset:
Defining Infant Rapid Weight Gain to Best Predict Subsequent Obesity
Authors: Eckhardt Cara L , Leo Michael C , Karanja Njeri
Published: November 2023

Infant rapid weight gain (RWG) is a growth pattern defined as an increase in weight‐for‐age z‐score (WAZ) > 0.67, and has been identified as a potentially useful predictor of childhood obesity. However, the relevant literature is primarily based on the Centers for Disease Control and Prevention (CDC) growth references rather than the currently recommended 2010 World Health Organization (WHO) growth standards, and is inconsistent with respect to the age interval used to determine RWG. We used anthropometric data from n=38,515 singleton, live term births among Kaiser Permanente Northwest HMO members from 1996–2012 to address these concerns. We compared the prevalence of RWG using criteria varying by growth reference and three key age intervals. The prevalence of RWG was significantly different (Exact McNemar's significance probability <0.05) between growth references (CDC v. WHO) for all three age intervals tested: 0–6 months (31.8% v. 21.2%), 6–12 months (3.4% v. 17.1%) and 0–12 months (19.9% v. 27.0%). Significant Cochran's Q tests indicated that prevalence also differed significantly (p<0.05) by age interval within each growth reference. In a series of logistic regressions, RWG was modeled as a predictor of obesity (BMI ≥ 95th percentile using the CDC growth references recommended for this age group) at 36 months of age for the subset of children with follow‐up data (n=13,424) using each of the different sets of RWG criteria. While RWG, regardless of the criteria used, was a statistically significant independent variable within each model, the ROC curves associated with the models indicated that none of the RWG specifications performed as a strong screening tool for obesity at 36 months; the highest area under the ROC curve value using the CDC references was observed for the 6–12 month age interval (0.64), and was seen for the 0–12 month age interval using the WHO growth standards (also 0.64). Clearly the growth reference and age interval used to define RWG have implications for determining prevalence and for potential screening of subsequent obesity risk, highlighting the importance of using a consistent reliable definition of this measure in practice. Future work will explore differences by gender, and will determine whether the inclusion of potential confounders and interactions in predictive models would provide improvement in the validity of RWG as a screening tool for childhood obesity.

Support or Funding Information

Research Support: R03 HD075841
HERBS FG MATRIX FOR ADVANCE WOUND CARE THERAPY FOR DIABETIC, VENOUS, ARTELOUS ULCER
Authors: Izunobi Felicia Ukamaka , Einstein George P
Published: November 2023

Over 6 million people in the United States is affected with chronic ulcer. The incidence is expected to as the population ages and as the number of individual with diabetes increase and approximately 15 to 25 % of diabetic patient will develop ulcers. The treatment of uleritic wounds has become a very challenging, most leading to amputation or death. The four cardinal signs of inflammation are (1) Rubor (redness),(2) Swelling, (3) Lost of function leading to acute or chronic ulcer. Most diabetic ulcers and bed sores heal by secondary intention – Here the wounds are chronic and as such there has been loss of tissues of the affected site and enlargement sideways and depth created by the loss of those tissues –including skins subcutaneous tissues and muscles or other fleshly tissues. Beta cells in the islet of Langerhans in the pancreas produces insulin which is responsible for the conversion of glucose into its usable and storage forms. In absence of insulin glucose or sugar will be there by presence and not there by function. The glucose by its physical presence and by lack of the chemical role of energy provision cause these ulcers. Managing the diabetes effectively also contributes a lot in the healing of the diabetic wound and ulcers.

Conclusion

The Matrix by its presence soak away the glucose in the wounded tissues and the vessels around the wound, thereby enhancing wound healing. In other words it is like a cleanser to the wound which filters out the glucose that is hindering the healing of these wounds. There is a restoration of extracellular membrane which was damaged by nonenzymatic glycosylation, affecting both its structure and function. The inflammation which is response to the infection modified by changes in both chemotaxis and phagocytic function of the white blood cells is healed by application of the Matrix formula. Whether the cleansing or filtration process also extends to the bacteria's which complicates the wound healing is something to be looked into.

Support or Funding Information

Einstein Medical Institute Corp. USA
An oral iron compound that decreases colon cancer cell growth
Authors: Scheers Nathalie M , Pereira Dora A , Powell Jonathan J
Published: November 2023

In several murine studies, supplemental or fortificant iron, that is used for human consumption, has been shown to promote colon tumorigenesis in mice. How this translates to humans is not clear but deserves careful investigation. Here, we studied how different potential oral iron compounds affected the growth of human colon cancer cells. The growth rate of intestinal adeno‐carcinoma cells (Caco‐2 and HT29) was monitored until confluence. In addition, the expression of 87 different cancer‐related proteins were investigated by antibody arrays. Surprisingly, we identified an iron compound that actually limited the growth rate of human cancer cells and the array data indicate that changes in cell cycle control may be implicated. This compound could play a role in colorectal cancer prevention, perhaps even as a food fortificant, and merits further investigation.

Support or Funding Information

The Swedish Research Council Formas (grant no. 222‐2014‐417)
Oat Avenanthramides (AVA) Are Bioavailable in Humans after Acute Consumption of Oat Cookies
Authors: Zhang Tianou , Shao Jing , Gao Yike , Chen Chi , Yao Dan , Wise Mitchell , Kang Chounghun , Yeo Dongwook , Ji Li Li
Published: November 2023

Objectives

Avenanthramides (AVA) are a group of diphenolic acids that are found only in oats and have anti‐inflammatory and antioxidant effects. Although previous publications have reported AVA are bioavailable in humans, our study is the first to examine whether AVA are bioavailable in humans after acute consumption of oat cookies made with natural and non‐treated oat flour. We examined the metabolic fate of orally ingested oat AVA by measuring plasma AVA concentrations and their pharmacological characteristics.

Methods

Sixteen male and female non‐obese subjects were enrolled in a randomized, crossover trial. Subjects received three cookies made with oat flour containing high (229.6 mg/kg, H‐AVA) or low (32.7 mg/kg, L‐AVA) AVA on separate occasions. The H‐AVA cookie (7.2 mg/cookie; 21.6 mg total) contained 5.09 mg AVA‐A, 8.67 mg AVA‐B and 7.85 mg AVA‐C, whereas the L‐AVA (1.03 mg/cookie; 3.09 mg total) contained 0.57 mg AVA‐A, 0.95 mg AVA‐B and 1.55 mg AVA‐C. Subjects consumed the cookies in the morning after 10 h fast and blood samples were collected at 0 (baseline), 0.5, 1, 2, 3, 5 and 10h. Plasma total (conjugated and free) AVA were quantified with Ultra Performance Liquid Chromatography Quadrupole Time‐of‐Flight Mass Spectrometer (UPLC Q‐TOF‐MS), and pharmacokinetic (PK) parameters were calculated and presented as mean±SD. Half life time (T1/2) was calculated through logarithmic transformation and elimination constant (Kel) was calculated using equation Kel=0.693/T1/2. At least three time points in elimination phase were required to calculate T1/2. All plasma concentrations used for estimation of PK parameters were above assay limit of quantitation.

Results

AVA‐A, ‐B and ‐C were present at the peak concentration (Tmax) in plasma at 2.50±1.2 h, 2.04±0.9 h and 2.29±1.0 h in H‐AVA and at 1.80±1.3 h, 1.50±1.5 h and 1.32±1.0 h in L‐AVA, respectively. Maximal plasma concentrations (Cmax) for AVA‐A, ‐B and ‐C were 8.39±4.2 ng/ml, 8.44±2.3 ng/ml and 4.26±2.0 ng/ml in H‐AVA, and 1.98±1.3 ng/ml, 2.43±1.1 ng/ml and 1.33±0.7 ng/ml in L‐AVA, respectively (P<0.001). H‐AVA cookies led to significantly higher AVA‐A and ‐B than ‐C concentrations (P<0.05). Half‐life (T1/2), the time taken to fall to half initial value was 2.16±0.6 h, 4.23±0.8 h and 2.71±1.2 h in H‐AVA, and 2.44±0.8 h, 4.60±2.7 h and 2.87±1.4 h in L‐AVA, respectively (P<0.05, AVA‐B vs. AVA‐A or AVA‐C in H‐AVA).

Conclusions

AVA found naturally in oats are bioavailable in humans. AVA‐B has the slowest elimination rate and highest half‐life compared to AVA‐A and AVA‐C, while AVA‐C has the lowest absorption rate.

Support or Funding Information

This study is sponsored by PepsiCo Nutrition.
Effects of Resveratrol Derivatives on Plasma Membrane Ca2+‐ATPase and Ca2+ Homeostasis in MDA‐MB‐231 Human Breast Cancer Cells
Authors: Peterson Joshua Allen , Kenealey Jason Donald
Published: November 2023

Resveratrol (RES), a naturally occurring polyphenol found in grapes, peanuts, and berries, selectively facilitates apoptosis in cancer cells. The apoptotic activity of RES in tumor cells is, in part, due to a large, sustained increase in cytosolic calcium ion concentration. In properly functioning cells, plasma membrane Ca2+‐ATPase (PMCA) extrudes excess calcium from the cytosol to the extracellular space. PMCA prevents toxically high levels of calcium from accumulating in the cytosol and maintains cytosolic calcium homeostasis. Via a recently developed PMCA activity assay that utilizes live cell fluorescence imaging, we found that RES inhibits PMCA. Because we have seen in past experiments that altering the hydroxyl groups in RES modifies the cytosolic calcium response, we performed a structure‐function experiment to determine which RES hydroxyl groups are most important to PMCA inhibition. In order to identify the structurally important components of RES, we conducted PMCA activity experiments using RES derivatives p‐hydroxystilbene, pinosylvin, piceatannol, and oxyresveratrol. We have determined the role of RES hydroxyl groups in inhibiting PMCA activity in the human breast cancer cell line MDA‐MB‐231.

Support or Funding Information

Brigham Young University, College of Life Sciences Startup Grant
Inhibitory Effects of Red Raspberry Polyphenols on Osteoclastogenesis in RANKL‐Stimulated RAW264.7 Murine Macrophages
Authors: Thomas Amber , South Sanique , Imrhan Victorine , Prasad Chandan , Vijayagopal Parakat , Juma Shanil
Published: November 2023

Osteoclasts and osteoblasts regulate skeletal mass, structure, and strength via their respective roles in resorbing and forming bone. Osteoclasts, the cells associated with breakdown of bone, are stimulated by a cytokine known as RANKL (receptor activator of nuclear factor κB ligand), a member of the tumor necrosis factor (TNF) superfamily. Polyphenols such as flavonoids found in plant‐derived foods have demonstrated anti‐inflammatory effects in various tissues. Red raspberries are a rich source of such polyphenolic compounds. Using mouse macrophage cells (RAW 264.7), we examined whether red raspberry polyphenols (RRP) could inhibit the proliferation and activity of RANKL‐induced osteoclastic cells in a dose‐dependent manner. Tartrate resistant acid phosphatase (TRAP) activity and staining of TRAP positive multinucleated osteoclasts, used as indicators of osteoclast differentiation and activity, decreased in a dose dependent manner with RRP treatment. Although, nitrite concentrations were not influenced by RRP treatment, there was a reduction in interleukin (IL)‐1β and IL‐6 with RPP demonstrating its anti‐inflammatory role in bone cells. Western blot analyses showed a dose‐dependent reduction in expression of inducible nitric oxide synthase (iNOS) protein and bone morphogenetic protein‐2 (BMP‐2) by RRP indicating that the polyphenols act to retrain the RANKL mediated osteoclastogenesis. Overall, these findings suggest that the polyphenols associated with red raspberry would inhibit the negative effects of osteoclasts on bone health. Further investigation is warranted to elucidate the molecular mechanisms by which RRP affect osteoclastogenesis.

Support or Funding Information

Supported by funds from the Undergraduate Research Microgrant Program at Texas Woman's University. Lyophilized red raspberry was generously provided by Van Drunen Farms.
Phyllodulcin as a sugar complement exerts anti‐diabetic effects in db/db mouse
Authors: Kim Eunju , Yoo Sang‐Ho , Kim Yuri
Published: November 2023

Type 2 diabetes mellitus is a chronic metabolic disease and characterized by insulin resistance, and is frequently accompanied by obesity or overweight. Phyllodulcin, a dihydroisocoumarin, is a well‐known sweetener in Hydrangea macrophylla var. The aim of study was to evaluate the anti‐diabetic potential of phyllodulcin in C57BL/KsJ‐db/db mice. In the present study, male mice were randomized into five groups; (1) a control group of C57BL/6 mice that received AIN93G (Ctrl), (2) a diabetic control group of C57BL/KsJ‐db/db mice that received AIN93G (DB), (3) a 20 mg/kg body weight (b.w.) of stevioside supplemented DB mice (SVS 20), (4) a 10 mg/kg b.w. of phyllodulcin supplemented DB mice (P 10), and (5) a 20 mg/kg b.w. of phyllodulcin (P 20) supplemented DB mice (P 20). The water and food intake was significantly lower in the SVS 20, P10 and P20 group compared to that of DB group. Phyllodulcin supplementation suppressed the levels of fasting blood glucose and HbA1c. In addition, the plasma TG levels in the SVS 20, P 10 and P 20 groups were significantly lower than that of DB group. Furthermore, the expression phosphoenolpyruvate carboxylase (PEPCK) was significantly lower in stevioside and phyllodulcin supplementation group and the expression of glucose transporter 4 (GUT4) was significantly higher in phyllodulcin supplemented group. In conclusion, phyllodulcin may be useful for improving blood glucose intolerance and abnormalities of diabetic conditions.

Support or Funding Information

This research was supported by High Value‐added Food Technology Development Program (Project number: 313024‐03‐2‐HD040), Ministry for Food, Agriculture, Forestry and Fisheries, Republic of Korea), and Brain Korea 21 Plus (Project No. 22A20130012143).
Hypolipidemic and antioxidant effects of Hawthorn extract in pre‐ and postmenopausal rats
Authors: Liu Yanan , Yoo Jeong‐Hyun , Ko Eun‐Jeong , Jeong Heesoo , Kim Hyun‐Sook
Published: November 2023

Even though many previous studies have reported the antioxidative, hypolipidemic and cardiovascular protective effects of hawthorn, none of them were tested using ovariectomized model. The aim of the present study was to investigate lipid profiles and antioxidant properties of hawthorn extract in pre‐ and postmenopausal models of rat. Forty‐two female Sprague‐Dawley rats were randomly divided into six groups; non‐OVX control(Sham), Sham+100mg/kg b.w of hawthorn extract(SL) and Sham+200mg/kg b.w of hawthorn extract(SH), OVX‐control(OVX), OVX+100mg/kg b.w of hawthorn extract(OL) and OVX+200mg/kg b.w of hawthorn extract(OH). Treatment groups were administered with hawthorn extract every day for 8 weeks. Final body weight of OVX group were significantly higher than Sham group(p<0.05), however the increment was significantly lower in both OL and OH group when compared with OVX group(p<0.05). Compared to Sham group, uterine weight and 17β‐estradiol level were significantly decreased in all OVX groups(p>0.05). These results show that ovariectomy is induced properly as intended. Serum total cholesterol(TC) level was significantly elevated in OVX group compared with Sham group(p<0.05), whereas OL and OH groups showed significant decrease(p<0.05). Hepatic triglyceride(TG) level was significantly reduced in both SL and SH group compared with Sham group(p<0.05). In addition, OH group showed the lowest hepatic TG level and highest HDL‐cholesterol level compared with OVX group(p<0.05). The OL and OH groups had significantly lower non‐HDL cholesterol level than OVX group(p<0.05). Serum glutathione peroxidase(GPx) activity of OH group was significantly higher than OVX group(p<0.05). The mRNA expression of GPx was highest in OL group(p<0.05) and the mRNA expression of catalase(CAT) was higher in both SL and SH group than Sham group(p<0.05). These results suggest that hawthorn extract could have protective effects on pre‐ and postmenopausal rats by improving lipid profiles and increasing antioxidant enzyme activity.
Effects of Naringin on hepatic paraoxonase activity and lipid metabolism in type 2 diabetic rats
Authors: Rotimi Solomon Oladapo , Adelani Isaacson B , Bankole Goodness Esther , Rotimi Oluwakemi A
Published: November 2023

Naringin is one of the citrus‐derived flavonoids that have been reported for its antihyperglycemic, antihyperlipidemic and antioxidant properties. Although its usefulness as nutraceutical in the management of diabetes has been reported, there is a dearth of information on involvement of lipid‐associated protein antioxidant like paraoxonase in its antidiabetic activity. In order to investigate this, high fat‐low streptozocin model of type 2 diabetic rats were treated daily with 50mg/kg, 100mg/kg and 200mg/kg naringin orally for 21days. The levels of plasma insulin and dipeptidyl peptidase‐4 (DPP IV) were determined using enzyme‐linked immunosorbent assay while other biomarkers of T2DM, activity of paraoxonase and lipid profile were assayed spectrophotometrically. The levels of expression of hepatic 3‐hydroxy‐3‐methyl‐glutaryl‐CoA reductase (HMGCR), scavenger receptor class B member 1 (SCARB1), Aryl Hydrocarbon Receptor (AhR), Lipoprotein Lipase (LIPL), and Lecithin—cholesterol acyltransferase (LCAT) were assessed using reverse transcriptase polymerase chain reaction technique. Naringin treatment resulted in a significant (p<0.05) decrease in levels of plasma glucose, insulin, free fatty acid, amylase and DPP IV. Naringin treatment was also associated with a significant (p<0.05) decrease in the levels of cholesterol and triglyceride in the plasma and liver in the dose‐dependent pattern. In the liver, the activity of carnitine palmitoyltransferase was significantly increased (p<0.05) while the expression of HMGCR was only significantly (p<0.05) reduced by 200mg/Kg naringin treatment. Meanwhile, SCARB1, AhR, LIPL and LCAT were significantly (p<0.05) upregulated by naringin treatment. Although T2DM resulted in increased activities of PON in the plasma, HDL and VLDL, a decrease in activity was observed in the liver. These alterations in PON activities were however significantly (p<0.05) reversed by naringin treatment. These results showed that PON is involved in the antidiabetic action of naringin.
Dietary tocotrienols improve glucose homeostasis and bone turnover biomarkers in high‐fat‐diet‐ induced obese male mice
Authors: Shen Chwan‐Li (Leslie) , Kaur Gurvinder , Ramalingam Latha , Tomison Michael D , Chung Eunhee , Moustaid‐Moussa Naima , Guo Chun , Web Cynthia Reinoso , Mo Huanbiao , Dufour Jannette D
Published: November 2023

Diabetes is a risk factor for osteoporosis. It is critical to emphasize the importance of glycemic control during osteoporosis treatment in patients with type 2 diabetes (T2D). However, diabetic therapies have potentially adverse effects on bone metabolism. In this study, we evaluated the effects of dietary tocotrienols (TT) on glucose homeostasis and bone turnover biomarkers in high‐fat‐diet‐induced obese male mice. Fifty‐eight male C57BL/6J mice were divided into 5 groups: low‐fat diet (LFD), high‐fat diet (HFD), HFD+400 mg TT/kg (lowTT), HFD+1600 mg TT/kg (highTT), and HFD+200 mg metformin/kg (Met, used as a T2D positive control treatment) for 14 weeks. Compared to the LFD group, the HFD group had greater body weight, hyperglycemia, insulin resistance, lower serum procollagen I intact N‐terminal propeptide (P1NP, bone formation marker), and higher serum collagen type 1 cross‐linked C‐telopeptide (CTX, bone resorption marker). Relative to the HFD group, TT supplementation (1) improved glucose homeostasis by lowering 2‐hour fasting blood glucose levels from both glucose tolerance test (369.3±22.6, 285.1±20.5, 228.8±18.9 mg/dL for HFD, low TT, and high TT, respectively) and insulin tolerance test (relative to time zero: HFD: 53.1%, low TT: 47.6%, high TT: 42.9%) in a dose‐dependent manner, (2) increased P1NP concentrations, and (3) decreased CTX levels. There were no significant differences in glucose homeostasis and bone markers between the HFD and the Met groups. This study demonstrates that the protective effect of tocotrienols on bone turnover biomarkers that may be mediated in part through improved glucose homeostasis in T2D animals.

Support or Funding Information

Funded by American River Nutrition, Inc.
Acute Effects on Satiety from White Button and Shiitake Mushroom Powder Supplementation in a High Fat Meal
Authors: Robak Theodore J , Talal Lillian A , Morris Matthew J , Williams Brian T , Browne Richard W , Horvath Peter J
Published: November 2023

Background

The current trend of rising obesity leads to an increase in cardiovascular disease and dyslipidemia. One of the factors involved with this trend are diets high in fat. Supplementing high‐fat meals with bioactive compounds may be an effective way to limit the negative consequences of such a diet. Mushrooms contain high levels of fungosterols and β‐glucans which are thought to be involved in the primary mechanism for improved postprandial lipemia. Mushroom supplementation may have effects on acute satiety which could dictate eating habits.

Purpose

To examine the acute effects on satiety by adding shiitake and white button mushroom powder to a high‐fat meal.

Methods

Three high‐fat meals were administered to 13 healthy subjects (6 males and 7 females, 24 ± 2yr, 20±6 % body fat, 57.1±11.5 kg fat free mass) in a double blinded, randomized design. Each meal (Control, White Button (WB), Shiitake (SH)) consisted of an 8oz cooked beef patty and a bun (819 kcal, 47g fat) with no mushroom powder or 14g of WB or 14 g of SH dried mushroom powder. Dietary intake on the day before testing was similar among subjects (2079 ± 791 kcal). Subjects were fasted and avoided vigorous exercise on the day prior to testing. Satiety was measured using a Likert visual analog scale every 2 hours for 6 hours following each meal. Blood from an indwelling catheter was also taken every 2 hours to measure plasma glucose and lipids. The effects of each meal were determined by measuring differences between meals.

Results

A more gradual decline in satiation from hour 2 to 6 was observed for treatments with mushrooms as compared to the control treatment. With the control burger there was a significant decline in satiety between hour 4 and 6 (P = 0.01) that was not seen with either mushroom powder. Plasma glucose was positively correlated with satiety values in all groups (P = 0.02). However, there was no relationship between plasma triglycerides and satiety.

Conclusion

Adding mushroom supplements to a high‐fat meal does not appear to change subjective satiety from 0 to 4 hours after consumption. However, between hours 4 and 6 after consumption, subjects were likely to have a longer feeling of fullness with mushrooms than without mushrooms. Plasma triglycerides levels did not predict satiety levels while plasma glucose was shown to be a better predictor of satiety. Using mushroom supplementation may limit the rise in felt hunger following a meal and could lead to less food consumption overall.

Support or Funding Information

Supported by a grant from the University at Buffalo Honors College.
Effects of Raspberry Dietary Supplementation on Risk Biomarkers of Diabetes Related Complications and Heart Disease in Diabetic Mice
Authors: Noratto Giuliana , Chew Boon , Mencia Alejandra
Published: November 2023

We investigated the effects of raspberry consumption on diabetes‐related complications and heart disease in obese diabetic mice. Mice (4–5 wk old) were fed either AIN‐93G (control) or AIN‐93G supplemented with freeze‐dried raspberries (9.75%) (isocaloric) for 8 wk. At the end of the study, blood and heart tissues were collected and analyzed using standard analytical protocols.

Raspberry intake, at dose equivalent to 208 g freeze dried raspberry/day for a 60‐kg human adult; protected against appetite loss, weight loss and cachexia observed in the control group. However, levels of lipid peroxidation, pro‐atherogenic molecules, and endotoxins in plasma were similar between groups. Plasma adipokine resistin, a hormone signaling molecule correlated with hyperinsulinemia/hyperglycemia, was higher in raspberry group (1777 vs 1165 ρg/mL, p < 0.05). Controversially, no differences were found in plasma insulin concentrations; whereas fasting glucose tended (p = 0.08) to be lower in the raspberry group (688 vs 759 mg/dL). This suggests that higher concentrations of plasma resistin in the raspberry group is correlated with higher body weight and is consistent with its delayed cachexia. Heart tissue disease biomarkers leptin, resistin, total cholesterol, triglycerides, and oxidized lipids were similar between experimental groups. However; plasminogen activator inhibitor‐1 (PAI‐1) tended to be lower in the raspberry compared to the control group (1124 vs 1234 ρg/mg protein) (p > 0.05). PAI‐1 has been linked to decreased oxidative stress and interleukin‐6 in blood.

These findings demonstrate that raspberry consumption helps to decrease cachexia and may decrease cardiac fibrosis in diabetes at an advanced age. Future studies are needed to prove the clinical relevance of raspberry consumption.

Support or Funding Information

National Processed Raspberry Council, Grant # 3057‐6667
Blueberry supplementation impacts gut microbiota, inflammatory profiles, and insulin sensitivity in high‐fat fed rats
Authors: Lee Sunhye , Kirkland Rebecca , Fischer Joan G. , de La Serre Claire
Published: November 2023

Obesity and insulin resistance are associated with chronic inflammation, which is believed to originate from the gastrointestinal (GI) tract. Changes in microbiota composition and an increase in circulating pro‐inflammatory endotoxin are notably associated with impaired glucose tolerance. Our objective was to determine whether blueberry supplementation could impact microbiota composition and systemic inflammation as well as glucose tolerance in high‐fat fed rats.

Wistar rats (n=8/group) were fed low‐fat (LF, 10% fat), high‐fat (HF, 45% fat) or high‐fat with 10% blueberry (HF_BB) diets for 8 weeks. HF and HF_BB diets were isocolaric and animals were pair‐fed. All diets were matched for sugar and fiber contents.

Compared to the LF diet, HF feeding resulted in increased adiposity and liver fat deposition in both HF and HF_BB rats. Blueberry supplementation altered the microbiota composition, with decreases in Firmicutes and Bacteroidetes and increases in Proteobacteria and Fusobacteria. Gammaproteobacteria were the most noticeable change in the HF_BB group. Along with these changes, GI barrier integrity was improved in HF_BB animals, characterized by a decrease in circulating lipopolysaccharide‐binding protein and increases in protective gene expression levels in the ileum (defensin β2 and mucin 2). Moreover, blueberry treatment significantly decreased systemic inflammation, characterized by a decrease in tumor necrosis factor α (TNFα) and interleukin‐6 protein levels in the liver and reduced TNFα and cluster of differentiation 11d (a macrophage infiltration marker) gene expression in visceral fat. Inflammation has been shown to affect insulin signaling and HF_BB rats showed improvements in glucose tolerance and insulin sensitivity. Glucose and insulin levels during an oral glucose tolerance test were significantly decreased in HF_BB rats. Additionally, blueberry treatment increased ileal glucagon‐like‐peptide‐1 expression and significantly down‐regulated the level of hepatic pSer307 IRS‐1/IRS‐1 ratio (insulin receptor substrate 1), which are associated with improved glucose tolerance and impaired insulin signaling, respectively.

Taken together, these data showed a potential anti‐inflammatory effect of blueberry supplementation associated with improved glucose tolerance. These effects may result from the alleviation of metabolic endotoxemia and intestinal inflammation and the modulation of gut microbiota.

Support or Funding Information

This material is based upon work that is supported by the National Institute of Food and Agriculture, USDA, under award number 2014‐67017‐21757.
F93D Mutation in HDAC4 N‐Terminal Glutamine‐Rich Domain and its Effect on Photoreceptor Survival
Authors: Juarez Michelle C. , Sample Vedangi , Cepko Constance
Published: November 2023

Over 60 genes have been associated with Retinitis Pigmentosa (RP), making it the most common form of retinal disease. There is currently no cure for RP but gene therapy approaches appear to be promising. HDAC4 has been shown to regulate the survival of photoreceptors in normal and RP diseased mouse models. HDAC4 has multiple binding domains, and truncations within these different domains suggest that residues 1–118 of HDAC4 are sufficient to promote rod survival. The two characterized domains within this 1–118 region are the C‐terminal binding protein (CTBP) domain and part of the glutamine rich region. Crystal structure of the N‐terminal glutamine rich domain reveals 4 monomers assembled into a tetramer, with a central hydrophobic core that function in stability of the tetramer complex. A point mutation in the 93rd residue from Phenylalanine to Aspartic Acid disrupts this hydrophobic core and the tetramer stability. We report expression of our F93D mutant construct through electroporations of mice models in attempts to identify whether this key residue of HDAC4 is important in rescuing diseased rod photoreceptors.

Support or Funding Information

Howard Hughes Medical Institute, EXROP program
Validation of a Quantitative Polymerase Chain Reaction (qPCR)‐based Method for Detecting Lymph Node Metastasis by Melanoma Cells
Authors: Goodloe Travis Bedsole , Hargadon Kristian M
Published: November 2023

Melanoma, a cancer of pigment‐producing melanocytes in the skin, is a highly lethal type of cancer because of its propensity to metastasize to several vital organs, including the lungs, brain, bone, and kidneys. Melanoma has also been shown to metastasize to tumor‐draining lymph nodes, and such lymph node metastasis correlates with dysfunctional anti‐tumor immunity and poor patient prognosis. In order to better understand 1) how melanomas spread to regional lymph nodes and 2) how lymph node involvement by melanomas contributes to immune suppression and disease progression, a model system for detecting melanoma cell invasion of local lymph nodes is sorely needed. Therefore, the goal of this study was to develop a quantitative Reverse Transcription‐Polymerase Chain Reaction (qRT‐PCR)‐based approach to assess melanoma metastasis to tumor‐draining lymph nodes by measuring in lymph node cell populations expression of the tyrosinase‐related protein‐2 (Trp2) gene that is involved in the melanin biosynthesis pathway. We demonstrate in both a primary tumor and lung metastasis model of murine melanoma that this approach is a highly sensitive system for the detection of melanoma cells in tumor‐draining lymph nodes.

Support or Funding Information

Commonwealth Health Research Board

Virginia Academy of Science Jeffress Memorial Fellowship

Virginia Foundation for Independent Colleges Mednick Memorial Fellowship

Hampden‐Sydney College Student‐Faculty Research Fund

Sigma Xi Grants‐In‐Aid of Research

Hampden‐Sydney College Faculty‐Student Research

Fund Hampden‐Sydney College Department of Biology
Vasculogenic mimicry in non‐functioning pituitary adenomas: fact or fallacy?
Authors: Rotondo Fabio , Di Michele Joseph , Kovacs Kalman , Syro Luis V , Yousef George M , Cusimano Michael D , Di Ieva Antonio
Published: November 2023

Introduction

Vasculogenic mimicry (VM) refers to the formation of vascular channels within genetically dysregulated tumor cells. It occurs de novo without the presence of an endothelial cell lining. Since its introduction in 1999, it has been observed in several tumor types and is proposed to be an alternative means of providing blood perfusion to tumors. Pituitary tumors are generally slow growing, benign adenomas. To date, VM in pituitary adenomas has not been described. Herein, we studied whether these channels occur in clinically non‐functioning pituitary adenomas (NFPA).

Materials and Methods

We studied the presence of VM in 49 randomly selected cases of surgically‐removed clinically NFPA using CD34 and Periodic Acid‐Schiff (PAS). Tumors were divided into 2 groups (19 recurring and 30 non‐recurring). 10 surgically removed and 5 autopsy‐obtained non‐tumorous pituitaries from patients with no endocrine diseases and no hormone treatment were also included.

To demonstrate vascular change, CD34‐PAS double immunostaining on paraffin‐embedded sections was used. Slides were assessed for the presence of CD34‐negative and PAS‐positive channels indicating that they were not lined by endothelial cells. Immunohistochemical findings were evaluated under low and high magnification.

Results

Immunopositivity for CD34 demonstrated endothelial cells lined blood vessels, which were localized in all 49 cases of clinically NFPA. The PAS‐ positive pattern, which stained sub‐endothelial matrix, was also visible in all cases. Slides were assessed for the presence of CD34‐negative and PAS‐positive channels indicating that they were not lined by endothelial cells. This staining pattern suggestive of VM was observed in 22/49 (45%) of the clinically NFPA. The amount of staining pattern varied both from case to case and within groups. No statistically significant correlation was found between the presence of this staining pattern within each group and the gender of the patients. An intriguing finding was the correlation between staining pattern and age. In 22 cases studied where the staining was identified, 14 cases (64%) were in the age range between 52–59 yrs while the remainder of the cases were equally distributed between the age range 25–75 yrs. In 27 cases where the staining pattern was not identified, 12 cases (44%) were in the age range between 51–57 yrs and 22/27 (81%) of the negative cases in the age range between 31–57 yrs. This was an intriguing finding since cases studied were randomly selected.

Conclusion

This finding carries potential clinical implications with respect to patient response to therapy as well as clinical course. More work is needed to prove that the presence of sub‐endothelial matrix without endothelial lining represents VM.

Support or Funding Information

Acknowledgement Authors are grateful to the Jarislowsky and Lloyd Carr‐Harris Foundations for their generous support.
CD44, CD133 and Lgr5 as biomarkers for early detection of H. pylori‐associated gastric cancer
Authors: Walker Rachel , Mejia Jaime , Enderling Heiko , Pimiento Jose M , Malafa Mokenge , Coppola Domenico
Published: November 2023

Background

Gastric cancer remains the second most common cause of cancer deaths worldwide, yet specific biomarkers for early detection remain elusive. The present work proposes an increase in stem cell prevalence during the progression through the Correa pathway from normal gastric mucosa (NM) to inflammation and intestinal metaplasia (IM), dysplasia (DS) and gastric cancer (GC), and identifies several stem cell biomarkers which demonstrate increased expression throughout this pathway.

Methods

Retrospective gastric tissue samples were obtained from a cohort of 63 patients from Colombia, a region where virulent CagA+ H. pylori infection and associated gastric cancer is highly prevalent. We measured variations in expression of stem cell markers CD44 (antibody #HPA005785, Sigma Aldrich, St. Louis, MO), CD133 (antibody MAB4399, Millipore, Billerica, MA) and Lgr5 (antibody ab75850, Abcam, Cambridge, MA) during disease progression. Samples were divided as follows: 10 NM; 17 IM; 10 DS and 26 GC. All cases were stained using the Ventana automated immunostainer Discovery XT (Ventana, Tucson, AZ). Scoring was conducted using the Allred scoring system featuring a proportion score and an intensity score to give a total score between 0 and 8.

Results

A significant increase in expression of all three stem cell markers (CD44, CD133 and Lgr5) was observed during each progression stage (NM to IM, IM to DS, and DS to GC). Statistical analysis of overall correlation between respective biomarker expression and disease stage is provided in Table 1. Expression increase between each individual stage of progression is demonstrated in Figure 1 for all 3 markers: CD44 (green), CD133 (blue) and Lgr5 (red). Statistical significance of increase at each stage is indicated by asterisks: p < 0.05 (*), p < 0.01 (**), p < 0.001 (***).

Conclusion

Stem cell dynamics as represented by common epithelial stem cell markers may allow early detection of the transition from to GC in patients at increased risk for gastric cancer.

Statistical analysis of correlation between respective markers and disease stage.

Marker
Spearman correlation
T value
P value

CD44
0.771
8.9828
9.148e‐13

CD133
0.818
9.3961
1.827e‐13

Lgr5
0.834
9.3466
2.216e‐13
Control of Breast Cancer through the Resolution of Inflammation
Authors: Vatnick Donna Rachel , Lehner Kristen , Gilligan Molly , Panigrahy Dipak , Gus‐Brautbar Yael , Ramon Sesquile , Huang Sui , Serhan Charles
Published: November 2023

Background

Current breast cancer therapies, including chemotherapy and targeted therapy, reduce tumor burden by killing tumor cells. However, they result in apoptotic and necrotic cell bodies, or “tumor cell debris,” which may act as a source of tumor stimulation by promoting inflammation. Thus, chemotherapy and targeted therapy may be a double‐edged sword. Enhancing clearance of tumor debris by specialized pro‐resolving mediators (SPMs) may target the endogenous mechanisms driving tumor growth, resistance, and dormancy escape. Maresin 1 (MaR1), a key mediator of resolution, is biosynthesized by human macrophages from endogenous docosahexaenoic acid. We hypothesize that maresins represent a novel modality in breast cancer treatment by resolving inflammation and enhancing endogenous clearance of tumor cell debris by macrophage phagocytosis.

Methods

Trypan blue assay and flow cytometry confirmed generation of breast tumor estrogen receptor positive (ER+) and estrogen receptor negative (ER−) tumor cells with chemotherapy or anti‐hormone therapy (cisplatin, tamoxifen or fulvestrant). Macrophage phagocytosis of tumor cell debris following resolvin or maresin treatment was quantified. Cytokine/chemokine levels were measured via cytokine array and ELISA.

Results

Chemotherapy and anti‐hormone therapy generated tumor cell debris. We demonstrate that tamoxifen‐induced debris stimulates primary breast tumor growth in vivo, and that systemic administration of MaR1 inhibits debris‐stimulated breast cancer tumors. MaR1 promotes the clearance of tumor debris by stimulating macrophage phagocytosis of apoptotic tumor cells, and by counter‐regulating critical pro‐inflammatory cytokines, as well as stimulating endogenous anti‐inflammatory cytokines (i.e. IL‐1ra).

Conclusions

Maresins suppress primary breast tumor growth via stimulating the uptake of apoptotic tumor cells by macrophages and endogenous anti‐inflammatory cytokines. Thus, the maresin pathway or the enhancement of endogenous resolution processes offers an entirely novel approach for controlling chronic inflammation as a modality of cancer treatment, complementing current approaches that focus on pro‐inflammatory mediators.
Breast Cancer Emergence from Dormancy can be Activated by Hepatic Stellate Cells
Authors: Khazali Ahmad Suhail , Clark Amanda , Wheeler Sarah , Wells Alan
Published: November 2023

Tumor dormancy is a well‐known clinical phenomenon. Studies have shown that in breast cancer survivors, the cancer recurs within 5–10 years (up to 20%) and more than 10 years (up to 11%) post initial treatment. Liver is one of the main metastatic sites for breast cancer recurrence as 60% of breast cancer patients had liver metastases at autopsy and 5–14% of the patients had liver metastases 4–10 years after radical mastectomy suggesting tumor dormancy. The factors and mechanisms for tumor outgrowth in the liver still remain unclear. Inflammation may increase the risk of breast cancer recurrence as increased levels of inflammation markers have been correlated with poor disease‐free and overall survival. We hypothesized that inflammatory signals from activated liver non‐parenchymal cells (NPC) can stimulate dormant micrometastatic cancer cells to grow and form macrometastases. In this study, we performed co‐culture experiments of breast cancer cell lines with hepatic stellate cell lines. Transwell assay was performed to determine whether soluble factors contribute to tumor growth. Protein array and luminex assays were conducted to determine the soluble factors secreted by the stellate cells. Finally, induction of breast cancer growth by these chemokines was validated in both in‐vitro and ex‐vivo. Human and rat hepatic stellate cell lines promoted significant breast cancer cells (MCF‐7) growth in‐vitro. Transwell assay indicated that MCF‐7 growth was due to soluble factors. IL‐8 and MCP‐1 were highly secreted by the stellate cells in‐vitro as well as by primary human NPC in a 3D ex‐vivo microphysiologic system, Liverchip. In‐vitro and ex‐vivo assays verified that IL‐8, but not MCP‐1, could directly stimulate breast cancer cell proliferation. These data suggest that activated NPC may mediate breast cancer escape from dormancy in the liver by secreting inflammatory signals. Disrupting inflammation might be an ideal therapeutic alternative to prevent tumor escape from dormancy in the liver.

Support or Funding Information

Joint support by the NIH (UH3TR000496), NCATS and NCI
A Very Short Story: the 6 minute TED talk
Authors: Reidenberg Joy S.
Published: November 2023

We've all heard of TED talks, but did you know that there are different types? I will describe the essential elements of one of the shortest types, the TEDed talk. This is a 6 minute talk, often focused on a particular audience (e.g., youth). It is harder to give a short talk than a long one, because every word counts – literally! What's the secret to making a successful short talk, and enjoying giving it? If you triage out 2/3 of a regular scientific talk, will it be reduced to a mere list of bullet points? When faced with cutting down on time, some speakers make the mistake of taking out the “color commentary” in an attempt to get all the facts in. That makes a talk dry and boring. It's better to forego some data in favor of presenting more energy. The most important thing to do is to engage your audience. You can do that with your tone of voice, but it also helps to have a “hook” ‐ something that sparks interest. Just the beginning of the end of a story is sometimes enough. No one likes a mystery unsolved – they want it resolved! Set up the dilemma, and then take them back to the beginning of the story. Give only enough background information to build the case. Keep them hungry to know the answer. Ask the “w” questions (what, when, where, why, which), and then show them “how.” The “w's” are your hypotheses, and the “how” is your methods section. Did you use the scientific method to tackle the question? Don't get bogged down in too many details, but do give brief examples. TED style talks focus on bringing the audience on that journey of discovery from ignorance to truth. Build to that “Eureka!” moment, when all the pieces fall into place and the results make sense. That's where you present the “twist” in your story (the part that makes it interesting). You can emphasize the moment by doing or saying something unexpected to make it memorable. An unpredictable ending or an unusual path to discovery (e.g., a “good” accident, or learning from mistakes) makes a good story. It shows that anyone can succeed, and heroes can come from unlikely places. It can be a happy ending, or a scary ending (e.g., consequences of global climate change, extinction, toxic exposures, etc.), so long as the story is told in a way that “touches” people. Pull at their emotions! Capture the audience with humor or stark sad revelations (depending on your message), and strive to use really good graphic visuals and action (e.g., audio‐video, volunteers, interactive stunts, demos). Don't worry if you didn't get to tell the whole story. If you have sparked their interest, they will pursue you and ask questions to get the rest of the details later. Above all, allow yourself to be immersed in the moment. If you are passionate about the subject, then the audience will be too.
ATP‐BINDING CASSETTE TRANSPORTER ABCA1 IS DECREASED IN SKELETAL MUSCLE FROM INSULIN RESISTANT MICE
Authors: Llanos Paola , Sanchéz Pablo , Cerda‐Kohler Hugo , Arias‐Calderón Manuel , Diaz‐Vegas Alexis , Campos Cristián , Contreras‐Ferrat Ariel , Hidalgo Cecilia , Jaimovich Enrique
Published: November 2023

INTRODUCTION

Insulin resistance (IR) is associated with obesity, metabolic syndrome and type 2 diabetes. Skeletal muscle is the main source of GLUT4‐mediated glucose transport in animals. Most GLUT4‐mediated glucose transport occurs in the transverse tubules (TT), a specialized cholesterol‐enriched plasma membrane system of skeletal muscle. In IR, GLUT4 translocation to the TT membrane is defective. Interestingly, we found that cholesterol levels in TT from skeletal muscle are higher in IR mice. We have centered our efforts in understanding the role of cholesterol accumulation in TT in muscle and its relation to IR. We have shown that the cholesterol‐lowering agent methyl‐β‐cyclodextrin promotes glucose uptake in adult muscle fibers and reduces insulin resistance in obese mice. Recent reports indicate that ATP‐binding cassette transporter ABCA1 (ABCA1), a transporter that mediates cellular cholesterol efflux, has a role in regulating lipid content, glucose tolerance and insulin sensitivity in adipose tissue. In skeletal muscle, however, a direct demonstration of the expression for ABCA1 during IR is lacking.

MATERIAL AND METHODS

Male C57BL/6J mice were fed with normal (NCD) or high fat diet (HFD) for 8‐weeks. qPCR, immunohistochemistry and immunocitochemistry were performed.

RESULTS

Both, relative mRNA level and protein content of ABCA1 were decreased in muscle homogenates and isolated triads from HFD‐fed mice compared to NCD‐fed mice. In addition, ABCA1 decreased in transversal cross section of whole muscle and isolated fibers from HFD‐fed mice.

DISCUSSION

The results obtained will help us to define if changes in ABCA1 expression/function contribute to the anomalous cholesterol accumulation displayed by skeletal muscle TT membranes in IR condition. (pllanos@odontologia.uchile.cl)

Support or Funding Information

FIOUCH‐ENLACE 001/2015 and FONDECYT 1151293 & 11150243
ACTIVITY OF SPHINGOMYELINASE IN PLASMA, URINE, AND TISSUES OF DIABETIC RATS
Authors: Bautista‐Pérez Rocio , Pérez‐Villavicencio Roxana , del Valle‐Mondragón Leonardo , Pérez‐Méndez Oscar , Franco Martha
Published: November 2023

Background

Sphingomyelinase (SMase) hydrolyse sphingomielin, releasing ceramide, and a cascade of bioactive lipids (sphingosine, and sphingosine‐1‐phosphate). SMase activation occurs in different cardiovascular system cell types. In the present study we investigated the changes in activity of SMase in kidney, aorta, heart, plasma and urine from diabetic rats.

Methods

Experiments were performed in male Wistar rats weighing 300–350 g. The rats were divided into two groups: control (C) and streptozotocin‐induced diabetic (D)(n=10 each). The activity of SMase was determined using a method described by Bautista et al, 2015.

Results

At day 30, diabetic animals exhibited hyperglycemia, lower body weight, glycosuria, diuresis. SMase activity decreased in the medulla and cortex renal as well as in plasma, but no changes were observed in aorta, heart and urine from rats diabetic.

Conclusions

SMase activity may contribute to the accumulation of ceramide/sphingosine in the kidney and plasma from rats diabetic.