bluuebunny/crossref_metadata_2025_split huggingface dataset:
The brominated flame retardant tetrabromobisphenol‐A increases DNA methylation at the THY1 (CD90) locus to promote adipogenesis
Authors: Flores E'Lissa 
Published: June 2021

Obesity has been classically linked to poor diet/excessive calorie intake and insufficient physical activity. However, an emerging concept is that environmental pollutants may be driving the global obesity epidemic. The rapid increase in the prevalence of obesity in industrialized, developed and even undeveloped countries cannot be strictly accounted for by poor diet and physical inactivity. Environmental chemicals, termed “obesogens” can promote adipogenesis (fat cell formation). Tetrabromobisphenol‐A (TBBPA), a brominated flame retardant found in infant mattresses and electronics such as cell phones, is an obesogens. However, its mechanism of action remains unknown. We hypothesize that TBBPA promotes adipogenesis by decreasing levels of THY1 (CD90), a cell surface protein present on pre‐adipocytes, certain fibroblasts, and stem cells. We previously determined that fibroblasts are heterogeneous for THY1 expression, where only THY1‐/low fibroblasts differentiate into adipocytes, pointing to THY1's crucial role during adipogenesis and cell fate. Using the well‐established mouse pre‐adipocyte cell line (3T3‐L1), we determined that TBBPA reduces THY1 mRNA and protein levels, promoting adipogenesis. Epigenetic changes, such as increases in global DNA methylation are known to occur during adipogenesis and obesity. DNA hypermethylation typically silences gene expression. Therefore, we hypothesized that obesogens, such as TBBPA, alter epigenetic regulation of THY1 to decrease its expression, thereby priming precursor cells to become adipocytes. Using pyrosequencing, we found that CG rich regions on THY1 are hypermethylated during adipogenesis, resulting in decreased THY1 expression and cell differentiation to adipocytes. Using the methylation inhibitor, 5‐aza‐dC, we determined that the adipogenic effects of TBBPA are blunted when methylation is impeded, which results in increased THY1 levels. Our results confirm THY1 plays a critical role in adipogenesis and that its expression is regulated by increases in DNA methylation. Furthermore, TBBPA, a widely‐used flame retardant, increases DNA methylation at the Thy1 locus to promote adipogenesis. Environmental obesogens contribute to the worldwide obesity epidemic and their further study is critical to combating this epidemic.Support or Funding InformationP30 ES 001247, F31 ES027767‐02This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Effects of Resveratrol in Cell Migration and Invasion by Studying the CXCR4‐CXCL12 axis in Breast Cancer Cell Lines
Authors: Arroyo‐Martinez Gerardo Antonio , Figueroa Maria , Muñoz‐Forti Kevin , Trossi Geralin , Robles Jose , Maldonado Alexandra Arroyo , Suarez Edu , Ruiz Abigail 
Published: June 2021

Every year, approximately half a million people die due to breast cancer (BC), comprising 16% of the incidence of all cancer occurrences in females. It is the most prevalent invasive cancer among women around the world. In several studies, researchers have suggested the presence of certain chemokines associated with cancer. The chemokine receptor CXCR4, a G‐protein coupled receptor, has a role in trafficking, cell activation, and differentiation in non‐malignant. It has been shown that CXCR4 is overexpressed in cancerous tissues compared to non‐malignant cells. This overexpression has led to an increase in proliferation, migration, and angiogenesis of malignant cells. Tissues with higher expression of the CXCR4 specific ligand CXCL12, are more likely to metastasis to tissue expressing CXCR4. These target tissues include lungs, bone marrow, and lymph nodes. Due to the impact of this disease, there is a need of developing new therapies or adjuvants to target BC. For example, resveratrol is a natural product and a polyphenol derived from grapes, wine, and nuts, among others. Recent studies found that it plays a role in apoptosis, inflammation, and neovascularization. We hypothesized that resveratrol will decrease the expression of CXCR4 in a dose and time‐dependent manner, leading to a decrease in the migration and invasion cellular processes. Using western blot analysis of HS578T (Human Breast Carcinoma) compared with CCD1074Sk (Non‐malignant Human Breast Tissue) cell lines we studied the effects of resveratrol at the CXCR4 protein level and invasion markers involved in metastatic processes. Migration and invasion were assessed using a wound healing assay and matrigel invasion assay, respectively. The preliminary data shows that as the concentration (25, 50, 100, 200μM) increases the cell migration and invasion decreases compared to our control vehicle (EtOH). In addition, we observed a decrease in the expression of pro‐migration and invasion proteins such as N‐cadherin and Cathepsin‐b. This study suggests an effect of resveratrol in cell migration and invasion leading to a decrease of the in‐vitro cell metastatic potential. Currently we are evaluating CXCR4 at the protein expression level to complete our data.Support or Funding InformationThis work was supported by UPR PRISE Program NIH‐NIGMS #2R25GM096955This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
HCT116 Colorectal Cancer Cells Secrete Chemokines Which Induce The Chemotaxis and Intracellular Calcium Mobilization of NK92 Cells. Influence of Dimethyl Fumarate and Monomethyl Fumarate
Authors: Maghazachi Azzam , Elemam Noha , Al‐Jaderi Zaidoon 
Published: June 2021

Our group recently reported that pre‐treatment of IL‐2 activated human natural killer (NK) cells with the drugs dimethyl fumarate (DMF) and monomethyl fumarate (MMF) up‐regulated the expression of chemokine receptor CCR10 on the surface of these cells. Ligands for CCR10, namely CCL27 and CCL28 induced the chemotaxis of these cells. Here, we performed bioinformatics analysis to see what chemokines might be secreted from human HCT116 colorectal cancer cells. We observed that in addition to CCL27 and CCL28, HCT116 cells highly express CXCL16 which binds CXCR6. Consequently, we examined whether CXCL16, CCL27 and CCL28 might induce the in vitro chemotaxis of NK92 cells after pre‐treatment with DMF and MMF for 24 h. Incubation of NK92 cells with 100 μM MMF enhanced their chemotaxis towards the 10 ng/ml concentration of CCL27 and towards 10 and 100 ng/ml concentrations of CCL28, whereas pretreatment with 100 μM DMF enhanced their chemotaxis towards the 100 ng/ml concentration of CCL28. Similar to their effects on human IL‐2‐activated NK cells, MMF and DMF up‐regulated the expression of CCR10 on the surface of NK92 cells. Supernatants collected from HCT116 cells after 24 or 48 h incubation also induced the chemotaxis of NK92 cells. CXCL16, CCL27 and CCL28 as well as supernatants collected from HCT116 cells induced the mobilization of intracellular (Ca)+2 in NK92 cells. Cross‐desensitization experiments revealed that supernatants collected after 24 h from HCT116 colorectal cancer cells desensitized the activity of CXCL16 and CCL28 but not CCL27, whereas the 48 h supernatant desensitized the activity of all three chemokines examined. In summary, these results might have important implication in directing the anti‐tumor effectors NK cells towards the sites of tumor growth, particularly colorectal cancers.Support or Funding InformationThis work is supported by grants from the university of SharjahThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Cloning the P53 DNA Binding Domain
Authors: Jones Janae , Faustino Vroniqa , Nogaj Luiza A. 
Published: June 2021

P53 is a tumor suppressor protein that binds to the DNA and is responsible for regulating cell growth. Mutations of p53 are associated with numerous types of cancers in patients worldwide. Mutants of p53 affect not only its structure, but its original function, causing p53 to gain oncogenic functions. The focus of this research is to clone the DNA binding domain (DBD) from the wild type p53 as well as its most common mutants and to characterize their p53 DBD. It is proposed that when missense mutations are present within the p53 DBD, p53 will destabilize, leading to its aggregation within the cell. We used molecular cloning techniques such as PCR to isolate the DBD from p53. We also utilized mammalian cell viability assays such as MTT and cytotoxicity to determine the effects of p53 on human cells. PCR results showed that DBD was amplified from full length p53 and cloned into expression vectors pET28 and pcDNA3.1. In our preliminary results both the MTT and cytotoxicity assays showed that WT p53 decreases the viability of mammalian cells. Therefore, we successfully cloned the DBD from p53 and are in the process of characterizing the effects of mutant p53 on cell viability and aggregation propensity.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Sirtuin 4 controls leucine metabolism and insulin secretion by reversing effects of reactive metabolites
Authors: Huynh Frank K. , Anderson Kristin A. , Stuart J. Darren , Lin Zhihong , Hirschey Matthew D. 
Published: June 2021

Sirtuins are a family of conserved NAD+‐dependent enzymes that remove a variety of post‐translational acyl lysine modifications. By performing this deacylation function, sirtuins can regulate several aspects of metabolism and aging. Recently, we discovered new post‐translational modifications (PTMs) that can be removed by sirtuin 4 (SIRT4). Interestingly, these PTMs can be generated by reactive metabolites produced during leucine oxidation and in the absence of SIRT4, these PTMs accumulate on and inhibit enzymes in the leucine oxidation pathway. These observations suggest that SIRT4 is a key regulator of leucine metabolism through a novel mechanism that responds to levels of reactive metabolites. Accordingly, we found that SIRT4KO mice have dysregulated leucine metabolism. As a consequence of this, SIRT4KO mice have elevated leucine‐stimulated insulin secretion. Long‐term stimulation of insulin secretion by leucine over time in SIRT4KO mice led to elevated plasma insulin levels even in the basal state. This chronic elevation of insulin was associated with an acceleration of aging‐induced insulin resistance in SIRT4KO mice. Interestingly, when leucine was administered as a bolus with glucose, insulin secretion was synergistically increased more than 3‐fold over glucose or leucine alone in aged SIRT4KO mice. Importantly, this elevated insulin secretion resulted in total normalization of glucose tolerance to resemble that of a young mouse and despite extremely high insulin levels, there was no sign of dangerous hypoglycemia. Thus, our data reveal that short‐term inhibition of SIRT4 potentially has therapeutically relevant effects on leucine metabolism and insulin secretion, but a long‐term loss of SIRT4 can drive inappropriate hyperinsulinemia and lead to insulin resistance. Taken together, our data reveal a novel mechanism of metabolic control involving reactive metabolites and position SIRT4 as a key regulator of leucine metabolism and insulin secretion.Support or Funding InformationWe would like to acknowledge funding support from the American Heart Association grants 12SDG8840004 and 12IRG9010008, The Ellison Medical Foundation, the National Institutes of Health and the NIA grant R01AG045351, and the Duke Pepper Older Americans Independence Center (OAIC) Program in Aging Research supported by the National Institute of Aging (P30AG028716‐01). FKH was supported by an American Diabetes Association/Canadian Diabetes Association Post‐doctoral Fellowship (PF‐3‐13‐4342‐FH).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
How Do You Measure Up? BMI versus Waist to Height Ratio
Authors: Smolinski Kasia , Ward Taketa , Hall Brandon , Hurst Sarah Elizabeth 
Published: June 2021

For many years, clinical screening rationale for issues such as obesity or type 2 diabetes (T2D) has been the body mass index (BMI) calculation. Our research as well as many others show that a more useful measurement of an individual's health and risk for disease is the waist to height ratio (WtHR). In this study, we measured height, weight, and waist circumference of 65 participants, calculated both BMI and WtHR, and analyzed the data. Using the BMI calculations, our results showed that most males were overweight [F (7, 14) = 3.147, p = 0.03], while most females were classified as normal [F (7, 14) = 3.474, p = 0.02]. However, using WtHR measurements, distributions changed for both men and women. Males were more normal [F (7, 28) = 2.263, p = 0.06], while females were more evenly distributed with some being slender/underweight and others were highly obese [F (7, 28) = 11.77, p < 0.0001]. Evaluating co‐morbidities using both BMI and WtHR, obese males report more medical issues then their normal and overweight peers. For the females, both the obese and highly obese report more co‐morbidities; both sexes had more people who reported no medical issues. Taken together, using more accurate measurements as health indicators will aid physicians and health care professionals in making better, cost‐effective decisions regarding patient treatment. Furthermore, many institutions including NIH have already transitioned into using the WtHR.Support or Funding InformationFunding provided by donations to The ATP10A Project.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Anti‐photoaging activity of sinapic acid in UVB‐irradiated human skin fibroblasts through increasing the expression of PPARδ
Authors: Yeon Dasom , Kim Younghwa , Lee Junsoo 
Published: June 2021

Sinapic acid is a phenylpropanoid compound extensively found in spices, citrus and berry fruits, vegetables, cereals, and oilseed crops. Sinapic acid is known to exhibit antioxidant, anti‐inflammatory, anticancer, antimutagenic, antiglycemic, neuroprotective, and antibacterial activities. However, the inhibitory effect of sinapic acid on photoaging has not been fully investigated. The aim of this study was to investigate the protective effect of sinapic acid on UVB‐induced photoaging through PPARδ mediated mechanism in Hs68 cells. Sinapic acid attenuated UVB‐induced expression of MMP‐1 and increased the production of collagen in Hs68 cells. Furthermore, UVB‐induced ROS generation was markedly attenuated by pretreatment with sinapic acid, demonstrating that sinapic acid is to be a potent ROS scavenger. These effects were abolished by treatment with GSK0660, a specific inhibitor of PPARδ. These results suggest that PPARδ is a key regulator of UVB‐induced photoaging and sinapic acid may ameliorate the UVB‐induced photoaging in human skin fibroblasts through modulatiing PPARδ expression.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
Betulinic acid alleviates body fat accumulation and dyslipidemia by inhibiting de novo lipogenesis and stimulating lipolysis in vivo
Authors: Kim Hyunkyung , Ryu Yungsun , Go Gwang‐woong 
Published: June 2021

Betulinic acid (BA), derived from natural substances especially birch wood bark, is a pentacyclic triterpenic acid. BA has beneficial bioactive effects as an antagonist for tumors, HIV and oxidants. Studies on BA effects against obesity and dyslipidemia have not clearly clarified the lipogenic pathway. This research hypothesized that betulinic acid would improve body fat and dyslipidemia in vivo. Male C57BL/6 mice were randomly assigned to five groups as follows: 1) high cholesterol diet (HCLD, 45% kcal from fat, 1.25% cholesterol) as control, 2) fenofibrate (150 mg/kg b.w + HCLD) as positive control 3) BA5 (BA 5 mg/kg b.w + HCLD), 4) BA15 (BA 15 mg/kg b.w + HCLD) and 5) BA25 (BA 25 mg/kg b.w + HCLD). BA was orally administered for 12 weeks. Body weight of BA25 was decreased compared to the control from 2 weeks to 12 weeks (p < 0.05 and p < 0.01). Fat mass was reduced by approximately 32% in all BA treatment groups (p < 0.05 and p < 0.001). Serum triglyceride was improved by all BA treatments (p < 0.001). Free fatty acid was reduced by all BA treatment groups (p < 0.01 for BA 25). Total cholesterol was diminished by all BA treatments (p < 0.001). LDL‐cholesterol was reduced by BA5 and BA15 (p < 0.05, p < 0.01 respectively). Acetyl‐CoA carboxylase1, a lipogenic enzyme in the liver, was inactivated by BA treatments (p < 0.001 for BA25). Stearoyl CoA desaturase was decreased by BA15 and BA25 (p < 0.01 and p < 0.05 respectively). Fatty acid synthase and sterol regulatory element‐binding protein 1 were reduced by BA although not significantly. Lipase, an enzyme related to lipolysis in white adipose tissue, was increased by BA15 and BA25 (p < 0.01 and p < 0.05 respectively). Phosphorylation hormone sensitive lipase was increased by BA5 (p < 0.01). Inactivating low‐density lipoprotein receptor‐related protein 6 in liver, which plays a major role in lipid homeostasis, was increased by BA25 (p < 0.001). Major factors of dyslipidemia in serum were alleviated by inhibiting lipogenesis in liver and increasing lipolysis in white adipose tissue. It was confirmed that BA is a potential compound for prevention and treatment of metabolic diseases caused by obesity.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Effects of Renin‐Angiotensin System on Endoplasmic Reticulum Stress in Pancreatic Beta Cells
Authors: Sopontammarak Boontharick , Menikdiwela Kalhara , Ramalingam Latha , Moustaid‐Moussa Naima 
Published: June 2021

Type 2 diabetes is an emerging epidemic and affects more than 25 million people in the United States. The Renin Angiotensin System (RAS) is classically known to regulate blood pressure and fluid balance. Interestingly, components of RAS, including the product angiotensin II (Ang II), which is the active hormone of this system, are expressed in both adipose tissues and pancreas. Studies conducted in our laboratory have shown that mice overexpressing RAS specifically in adipose tissue had insulin resistance, higher levels of inflammation, and endoplasmic reticulum (ER) stress. However, no studies have investigated the relationship between RAS and ER stress in beta cells. Hence, we hypothesized that activation of RAS in beta cells leads to increased ER stress and reduced insulin secretion. To test this hypothesis, we treated clonal beta cells with Ang II, and found that Ang II significantly increased the expression of ER stress genes such as CHOP and ATF4. In addition, Ang II treatments also reduced insulin secretion. Furthermore, inhibition of Ang II production in beta cells using an angiotensin converting enzyme inhibitor (ACEi) significantly reduced ER stress. Additionally, pharmacological inhibition of angiotensin type I and II receptors significantly reduced ER stress. These results indicate involvement of the RAS pathway in ER stress in pancreatic beta cells. We are currently determining effects of these RAS inhibitors on insulin secretion. In conclusion, this research will help better understand the role of RAS activation via ER stress on diabetes progression and may help develop new anti‐diabetes therapeutic targets.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
The Protein Phosphatase PHLPP1 Suppresses Insulin Signaling and Inflammation in Mouse Model
Authors: Lorden Gema , Skovsø Søs , Riopel Matthew , Cohen‐Katsenelson Ksenya , Johnson James D. , Newton Alexandra C. 
Published: June 2021

The PH domain Leucine Rich Repeat Protein Phosphatase 1 (PHLPP1) directly dephosphorylates and inactivates Akt2, the Akt isozyme that is a key transducer of insulin signaling. Elevated levels of PHLPP1 protein have been associated with obesity and insulin resistance in humans, suggesting PHLPP1 may be a novel therapeutic target to combat insulin resistance in diabetes and metabolic syndrome. Here we examine how loss of PHLPP1 affects insulin signaling using the Phlpp1−/− mice. Insulin tolerance tests of mice on a normal chow diet reveal a modest but statistically‐significant increase in the insulin sensitivity of mice lacking PHLPP1 compared to littermate Phlpp1+/+ controls. Analyses of liver from these mice reveal elevated Akt signaling in the mice lacking PHLPP1, as assessed by increased phosphorylation of Akt itself and downstream substrates such as GSK‐3 and MDM2. In addition, consistent with previous studies, the steady state levels of EGF receptor are elevated. We also note that there was an approximately 15% increase in the steady state levels of PHLPP2. Consistent with in vivo results, deletion of PHLPP1 in HepG2 liver cells also increases insulin‐dependent signaling, assessed by increased phosphorylation of the insulin receptor and Akt. Thus, both in vivo and in vitro studies are consistent with PHLPP1 suppressing insulin signaling. In contrast to results from normal chow diet, Phlpp1−/− and Phlpp1+/+ mice subjected to a high fat diet had the same insulin sensitivity. Furthermore, biochemical analysis of liver from these mice revealed a striking decrease in phosphorylation of Akt and downstream substrates such as S6kinase, and a decrease in PKCα. PHLPP2 levels remained elevated. Additionally, we also found that in livers, high fat diet promotes an up‐regulation of pro‐inflammatory genes such as Il6 and Tnfa, which is significantly enhanced in PHLPP1 deficient mice. Our data are consistent with a model in which loss of PHLPP1 enhances both insulin sensitivity and inflammation. The pro‐inflammatory effects of high fat diet may be exacerbated in the Phlpp1−/− cells, masking an insulin sensitivity phenotype.Support or Funding InformationThis work was funded by NIH P01DK054441This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.