bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vitamin D regulates cross talk between epithelial cells and immune cells through the secretion of CD14
Authors: Simmons Katrina , Welsh JoEllen 
Published: June 2021

Inflammatory signaling between epithelial cells and immune cells contributes to a variety of diseases including cancer, autoimmune disorders, and obesity. Vitamin D, a potent immunomodulator, has been shown to regulate immune responses and reduce the risk of infections by acting on immune cells, yet its effects on the immune functions of epithelial cells and their impact on the immune microenvironment in epithelial tissues are less clear. We have demonstrated that 1α,25‐dihydroxyvitamin D (1,25D) dramatically increases the expression of the pattern recognition receptor CD14, which binds microbial lipopolysaccahride (LPS), in human mammary epithelial (HME) cells. We found through ELISA and microscopy that 1,25D enhances the accumulation of soluble not membrane‐localized CD14 and that conditioned media from 1,25D‐treated HME cells, which contains soluble CD14, promotes anti‐inflammatory responses from macrophages when exposed to LPS. Studies with the vitamin D receptor (VDR) analog JN, a non‐genomic VDR agonist, found JN induces CD14 expression and secretion comparable to 1,25D suggesting the membrane‐localized VDR contributes to 1,25D's induction of CD14. Overall this study supports the concept that 1,25D stimulates the secretion of CD14 from epithelial cells through the VDR to promote an anti‐inflammatory environment.Grant Funding Source: National Center for Complementary and Alternative Medicine Predoctoral F31 NRSA Fellowship
Dynamic Model Predicting Overweight, Obesity, and Extreme Obesity Prevalence Trends
Authors: Thomas Diana Maria , Weederman Marion , Fuemmeler Bernard , Martin Corby , Dhurandhar Nikhil , Bredlau Carl , Heymsfield Steven B. , Ravussin Eric , Bouchard Claude 
Published: June 2021

ObjectiveTo model known multiple population parameters associated with changes in the prevalence of body mass index (BMI) classes (overweight, obese, and extremely obese) and to establish the necessary conditions under which the prevalence of obesity will eventually plateau.MethodsA six differential equation system was developed that predicts population‐wide obesity prevalence trends. The model considers both social and non‐social influences on weight gain, incorporates other known parameters affecting obesity trends, and allows for country specific population growth. Long‐term obesity trends were calculated after input of parameters specific to the US.ResultsThe dynamic model predicts that the prevalence at which obesity plateaus in a population is primarily a function of birth rate and the probability of being born in an obesogenic environment; that obesity prevalence will eventually plateau independent of current prevention strategies if key population‐specific parameters such as birth rate remain constant; and that the US prevalence of obesity, overweight, and extreme obesity will plateau by about 2030 at 28%, 32%, and 9%, respectively.ConclusionsThe US prevalence of obesity is tapering off and will plateau in less than two decades, independent of current preventative strategies. This trend has important implications in accurately evaluating the impact of various anti‐obesity strategies aimed at reducing the national obesity prevalence.
Gender‐specific associations of socioeconomic factors and obesity among urban adults in Turkey
Authors: Fitzgerald Nurgul , Turnagol Husrev , Basoglu Sevil , Kosar Nazan 
Published: June 2021

This study examined the associations between socioeconomic factors and obesity in a nationally representative sample of adults (≥19) in 13 urban centers in Turkey. Data were collected through face‐to‐face household interviews; anthropometric measurements were conducted by study assistants. The analytical sample included 4,813 adults with measured weight, height, and weight circumference (WC) values. Logistic regression analyses were used to analyze the determinants of obesity (BMI≥30.0) and high WC (≥102 cm for men, ≥88cm for women).The average age in the sample was 41.7yr, 61.5% were females, and 58.3% reported eighth grade or less education. Obesity and high WC were more common among women than men (34.3 vs 14.9% and 51.0 vs 15.8%, respectively, p<0.001). After adjusting for age, migration, home ownership and health insurance status, obesity was linked to being married, having a car and less than college education among women; education, migration, and being married were also positively related to having a high WC. Among men, not having health insurance was linked to less likelihood of obesity and high WC (p<0.05).Relatively high rates of overall and central obesity among adults in urban Turkey seem to have gender‐specific associations with individual and household level socioeconomic characteristics.
Serum and Dietary Advanced Glycation End Products in Patients with Diabetic Foot Ulcers
Authors: Maier Haiyan Min , Spicer Maria T. , Arjmandi Bahram H. 
Published: June 2021

Diabetic foot ulcers (DFU) occur in patients with a history of poorly controlled blood glucose. Advanced glycation end products (AGEs) may influence the occurrence of DFU due to elevated oxidative stress (OS) and inflammation. This study examined the association between AGEs and serum markers of OS and inflammation in diabetic patients with (DFU) and without diabetic foot ulcer (DM).Eighty adult participants were recruited and categorized into one of three groups: non‐diabetic control (C), DM, and DFU. Twenty‐four hour food recalls, foot ulcer history and blood samples were collected from each participant for analyses. Dietary and serum AGEs, tumor necrosis factor‐α (TNF‐α), and thiobarbituric acid reactive substances (TBARS) were determined. Using SPSS 21, one way ANOVA and Pearson correlation were used for statistical analyses.The diabetic groups had significantly higher levels of dietary AGEs and TNF‐α than C (P < 0.05). Serum AGEs and TBARS were elevated in DFU, compared with C (P < 0.05). TBARS were significantly higher in DFU than DM and C (P < 0.5). Serum AGEs and TBARS were significantly correlated with dietary AGEs (P < 0.01).Both dietary and serum AGEs were the highest in DFU. Dietary AGEs modulates serum AGEs concentration. Reducing dietary AGEs intake may benefit patients with DFU by decreasing OS.Grant Funding Source: Florida State University
Effects of folylpolyglutamate synthase modulation on CpG promoter DNA methylation and gene expression in human colon cancer cells
Authors: Kim Sung‐Eun , Hinoue Toshinori , Kim Michael , Sohn Kyoung‐Jin , Weisenberger Daniel , Laird Peter W. , Kim Young‐In 
Published: June 2021

Folylpolyglutamate synthase (FPGS) facilitates intracellular retention of folate by polyglutamylation, thereby playing a critical role in folate homeostasis. We investigated whether FPGS modulation would affect CpG promoter methylation and gene expression profiles in human HCT116 colon cancer cells. Illumina HT‐12 and Infinium Methylation assay were used, and functional analysis was performed by Ingenuity Pathway Analysis. We validated mRNA expression of selected genes by qRT‐PCR. 2897 genes (most involved pathways: cell cycle and DNA replication, recombination, and repair) were differentially expressed in the FPGS‐overexpressed cells, while 359 genes (most involved pathways: cell death and cell cycle) were differentially expressed in the FPGS‐inhibited cells. 864 and 626 genes showed altered CpG promoter methylation associated with FPGS overexpression and inhibition, respectively. An integrated analysis revealed 65 and 6 differentially expressed genes involved in cell cycle, cell death, and cell‐to‐cell signaling and interaction, expression of which was regulated by CpG promoter methylation changes associated with FPGS overexpression and inhibition, respectively. FPGS modulation can affect differential gene expression and CpG promoter methylation involved in important biological pathways, and some of the observed differential gene expression appear to be epigenetically regulated.Grant Funding Source: CIHR Fund 14126
Bile acid depletion increases susceptibility to acetaminophen‐induced hepatotoxicity in mice
Authors: Bhushan Bharat , Borude Prachi , Edwards Genea , Walesky Chad , Cleveland Joshua , Li Feng , Ma Xiaochao , Apte Udayan 
Published: June 2021

Bile acids are known to play significant role in liver homeostasis. However, the role of bile acids in pathogenesis of acetaminophen (APAP)‐induced acute liver failure (ALF) is not known. Here we report that depletion of bile acids using cholestyramine (CSA), a bile acid sequestering resin, increases susceptibility of C57BL6 mice to APAP‐induced hepatotoxicity. C57BL6 mice were fed either normal diet or 2% CSA containing diet for 1 week, treated with 400 mg/kg APAP (ip) and analyzed over a time course of 0 to 24 hr. The CSA‐fed mice developed rapid and higher liver injury after APAP treatment. Depletion of bile acids by CSA did not alter metabolism of APAP. However, CSA‐fed mice exhibited rapid and significantly higher activation of c‐Jun N‐terminal protein Kinase (JNK) following APAP treatment. Furthermore, a significant decrease in intestinal fibroblast growth factor 15 (FGF15) mRNA was observed in CSA fed mice before and after APAP treatment. Compensatory liver regeneration following APAP overdose was delayed in the CSA‐fed mice up to 12 hr but was not different than the normal diet fed mice at 24 hr after APAP treatment. Taken together, these data indicate that depletion of intestinal bile acid increases susceptibility to APAP by rapid and higher hepatic JNK activation. These data indicate that bile acids and FGF15‐mediated gut‐liver signaling axis play an important role in cytoprotection following APAP‐induced ALF.These studies were supported by NIH ‐ P20 RR021940 (Udayan Apte), and AASLD/ALF Liver Scholar Award (Udayan Apte)
Coping with Unexpected Environments – Implications for Epigenesis
Authors: Soen Yoav 
Published: June 2021

Developing organisms have evolved a wide range of mechanisms for coping with recurrent environmental conditions. How they cope with rare or unforeseen challenges is, however, unclear as are the implications to subsequent generations of non‐exposed offspring.We investigate these questions using a synthetic drug/anti‐drug system which allows us to confront the development of the fly, D. melanogaster, with artificial distributions of toxic stress that are not expected to occur during fly development. Survival of the flies in this system depends of their ability to modify their development. We found that under a wide range of toxic scenarios, the challenge modifies the otherwise robust patterns of development, resulting in changes in gene expression as well as in the rate of larval development and adult morphology (in some of the cases). We show that part of this response is enabled by suppression of Polycomb group genes (PcG), which leads to de‐repression of developmental regulators and their expression in new domains, hence the change in developmental patterns. Remarkably, some of the developmental alterations were non‐genetically inherited by subsequent generations of unchallenged offspring suggesting that the challenge also modifies the germline of the flies.This was indeed confirmed by analysis of maternal RNA in eggs of challenged versus unchallenged flies. These results reveal a process of epigenesis by which stressful, non‐familiar environment suppresses the Polycomb system and induces developmental modifications that persist across generations through non‐Mendelian mechanisms.
Fluid Shear Stress induces the Clustering of Heparan Sulfate via Mobility of Glypican‐1 in Lipid Rafts
Authors: Zeng Ye , Ebong Eno , Rizzo Victor , Tarbell John 
Published: June 2021

The endothelial glycocalyx plays important roles in mechanotransduction. We recently investigated the distribution and interaction of glycocalyx components on statically cultured endothelial cells. In the present study, we further explored the unknown organization of the glycocalyx during early exposure (first 30 min) to shear stress using confocal microscopy and tested the hypothesis that proteoglycans with glycosaminoglycans, which are localized in different lipid microdomains, respond distinctly to shear stress. During the initial 30 minutes, we observed that heparan sulfate (HS) and glypican‐1 clustered in the cell junctions. In contrast, chondroitin sulfate, bound albumin and syndecan‐1 did not move. The caveolae marker, caveolin‐1, did not move indicating that caveolae are anchored sufficiently to resist shear stress. Shear stress induced significant changes in the distribution of ganglioside GM1 (a marker for membrane rafts labeled with cholera toxin B subunit – CTx‐B). Thus, fluid shear stress induced the cell junctional clustering of lipid rafts with their anchored glypican‐1 and associated HS. In contrast, the mobility of chondroitin sulfate, transmembrane bound syndecan‐1, and caveolae were constrained during exposure to shear stress. This study illuminates the role of changes in glycocalyx organization that underlie mechanisms of mechanotransduction.Grants: Supported by NIH Grant HL 094889.
A novel interplay between AR and DAX‐1 controls aromatase expression in estrogen‐dependent cancers
Authors: Lanzino Marilena , Maris Pamela , Sirianni Rosa , Barone Ines , Chimento Adele , Giordano Cinzia , Morelli Catia , Trombino Giovanna Elvi , Bonofiglio Daniela , Catalano Stefania , Andò Sebastiano 
Published: June 2021

In situ estrogen production by aromatase is a critical determinant for breast cancer growth and progression while androgens have a protective role in mammary carcinogenesis. Here we demonstrate in breast cancer cells, a novel androgen receptor (AR) mediated mechanism that negatively affects aromatase expression, reducing local estrogen production and cell proliferation. Ligand‐activated AR induces the expression of the orphan nuclear receptor DAX‐1 by binding to a newly identified ARE within the DAX‐1 promoter. In turn, increased DAX‐1 is recruited with the corepressor N‐CoR onto the SF‐1/LRH‐1 site of the aromatase promoter, thereby repressing aromatase expression and activity. Moreover DAX‐1 overexpression induces an apoptotic cell phenotype lying on an enhanced bad/bcl‐2 ratio. This molecular mechanism is reproduced in highly expressing aromatase R2C cells, a model for Leydig tumor, another estrogen‐dependent type of cancer. Interestingly, in vivo studies conducted in testes tissues from Fisher rats, spontaneously developing Leydig cell tumor, confirm the inverse relationship between AR/DAX‐1 and aromatase levels.In elucidating a novel mechanism by which androgens, through DAX‐1, inhibit aromatase expression in E2‐dependent tumors, these findings sustain the theory of androgen opposing estrogen action, opening new avenues for therapeutic intervention in endocrine‐related cancers.
Dietary Linoleic Acid Elevates Endogenous Endocannabinoids (2‐AG and Anandamide) and Induces Obesity
Authors: Hibbeln Joseph R. , Malde Marian , Osei‐Hyiaman Douglas , Lin Yu Hong , Pawlosky Robert , Madsen Lise , Kristiansen Karsten , Frøyland Livar , Avelheim Anita 
Published: June 2021

Suppressing hyperactive endocannabinoid tone is a critical target for reducing obesity. The endocannabinoids 2‐arachidonoylglycerol (2‐AG) and anandamide (AEA) derive from arachidonic acid (AA). Here we posited that excessive dietary intake of linoleic acid (LA), the precursor of AA, would induce endocannabinoid hyperactivity and promote obesity. LA was isolated to reflect dietary increases in LA from 1 percent of energy (en%) to 8 en% occurring in the United States during the 20th century. Mice were fed diets containing 1 en% LA, 8 en% LA, and 8 en% LA + 1 en% eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) in medium‐fat diets (35 en% fat) and high‐fat diets (60 en%) for 14 weeks from weaning.ResultsIncreasing LA from 1 en% to 8 en% elevated AA‐phospholipids (PL) in liver and erythrocytes, tripled 2‐AG + 1‐AG and AEA associated with increased food intake, feed efficiency, and adiposity. Selectively reducing LA to 1 en% reversed the obesogenic properties of a 60 en% fat diet. In summary, increasing prevalence rates of obesity 20th century were successfully modeled; elevating dietary LA increased tissue AA and induced hyperactive endocannabinoid status, subsequently resulting in obesity.
Dietary macronutrients modulate the fatty acyl composition of rat liver mitochondrial cardiolipins
Authors: Stavrovskaya Irina G , Bird Susan S. , Marur Vasant R. , Sniatynski Matthew J. , Baranov Sergei V. , Greenberg Heather K. , Porter Caryn L. , Kristal Bruce S. 
Published: June 2021

Cardiolipins (CLs) are a family of phospholipids essential for mitochondrial structure and function. The defective remodeling of the CL molecules (i.e., the changing of the fatty acyl [FA] composition) has been linked to human pathology. We examined diet‐mediated CL changes in liver mitochondria from healthy male FBNF1 rats fed 24 different low‐fat, isocaloric diets. Growth rates and mitochondrial respiratory parameters were essentially unaffected, but mass spectrometry‐based, mitochondrial lipidomics profiling revealed up‐regulation of CLs in rats fed saturated or trans fat‐based diets with a high glycemic index. These mitochondria showed elevated monolysocardiolipins and decreased ubiquinone Q9, implying a low‐grade mitochondrial redox abnormality and compensatory CL elevation. Extended analysis of the rat liver mitochondrial CL pools has revealed previously unobserved regulation of CL, suggesting that (i) dietary fats and, to a lesser extent, carbohydrates induce changes in the relative abundance of CL species; (ii) FA incorporation into mature CLs undergoes both positive (~400‐fold) and negative (≥2.4‐fold) regulation; (iii) dietary lipid abundance and incorporation of FAs into both the CL pool and specific mature tetra‐acyl CLs are inversely related, suggesting compensatory regulation.This study was funded by U01‐ES16048 (BSK, PI) and P30‐DK040561 (W. A. Walker, PI).
S100A4 signaling in thyroid cancer
Authors: Medapati Manoj Reddy , Dahlmann Mathias , Ulrike Stein , Ghavami Saied , Hombach‐Klonisch Sabine 
Published: June 2021

Thyroid cancer (TC) is one of the most frequently occurring cancers of endocrine glands in Canada and the United States. Most differentiated TC are curable, but some TCs develop a more aggressive phenotype with resulting metastasis and treatment failures. Our group has shown that relaxin‐like peptides promote TC cell tumor growth and migration, in part mediated via S100A4 which is known to promote metastasis and to confer poor prognosis in patients with TC. Several S100 proteins signal via receptor for advanced glycation end products (RAGE). This study investigates S100A4 signaling in promoting TC cell survival, growth and metastasis. TC cells were stimulated with S100A4 to determine cell motility, proliferation and apoptosis and to identify S100A4‐induced signaling pathways. Using PCR and immunohistochemistry expression of RAGE was detected in TC cells and in TC tissues, but not in normal thyroid tissues. RAGE pull‐down experiments demonstrated S100A4 to bind to RAGE in TC. ERK and JNK/SAPK signaling pathways were activated in TC cells upon S100A4 stimulation. We used RAGE blocking antibodies and diaphanous‐1 knock‐down to prevent RAGE‐mediated S100A4‐signaling in TC. S100A4‐induced ERK‐signaling appeared to be independent of RAGE in TC. We identified TLR4 expression in TC cells and demonstrate here that the effects of S100A4 are, in part, mediated via TLR4 in TC. This research is funded by NSERC of Canada and Dept of surgery research fund.Grant Funding Source: n/a
N‐sulfation of Cell Surface Heparan Sulfate Glycosaminoglycans is Critical for Podocyte‐Matrix Interactions
Authors: Sugar Terrel , McCarthy Deborah J. , Green Jonette , Orr A. Wayne , Esko Jeffrey D. , McCarthy Kevin J. 
Published: June 2021

Podocytes adhere to the glomerular basement membrane via cell surface receptors which include heparan sulfate (HS) proteoglycans (PG). Podocytes unable to assemble HS glycosaminoglycan chains have defective cell attachment and spreading, and cytoskeletal disruption in vitro and in vivo. The current report explores the importance of heparan sulfation in regulating podocyte cell‐matrix interactions, using an immortalized podocyte cell line having the genomic deletion of N‐deacetylase/ N‐sulfotransferase 1 (NDST1), the enzyme responsible for N‐sulfation of HS. Compared to wild type podocytes, mutant podocytes attached, spread and migrated less efficiently in assays than control cells. In the process of cell‐matrix interaction, the mutant cells showed decreased clustering of syndecan 4, the cell surface HSPG involved in focal adhesion formation, and decreased recruitment of PKCα, α‐actinin 4, vinculin, and pFAK to focal adhesions. Cell surface integrin expression and integrin activation/signaling was significantly diminished in the mutant cells. These results serve to highlight the critical role of HS N‐sulfation in regulating the ability of podocytes to interact with the extracellular matrix.Grant Funding Source: NIDDK RO1‐DK07786
Vesicular glutamate transporter 1‐immunoreactive sensory neurons in the rat intrinsic cardiac ganglia
Authors: Wang Ting , Zhang Zijia , Miller Kenneth E. 
Published: June 2021

Sensory neurons that reside in intrinsic cardiac ganglia (ICG) have an important role in monitoring the cardiac milieu for regional cardiac dynamic control. We recently described sensory neurons in ICG that project to the cardiac ventricular wall and currently are evaluating their neurochemical phenotype. Since many primary sensory neurons are glutamatergic, we hypothesized that ICG sensory neurons are glutamatergic, utilizing vesicular glutamate transporter 1 (VGLUT1) to package glutamate into synaptic vesicles. In the present study, the rat ventricle wall was injected (retro‐diaphragmatic, 8μl) with the retrograde tracer wheat germ agglutinin‐horseradish peroxidase (WGA‐HRP). After 72h, rats were euthanized and transcardially perfused with fixative. ICG were processed for immunohistochemistry studies. Our results demonstrated that: (1) VGLUT1‐immunoreactive (ir) neurons were present in ICG; (2) Some VGLUT1‐ir neurons were labeled from the ventricles with WGA‐HRP. Our previous studies indicated that sensory ICG neurons contain glutaminase, the synthetic enzyme for glutamate. These and the current results indicate that ICG sensory neurons are glutamatergic in neurochemical phenotype. Further investigation of VGLUTs during cardiac physiological and pathological conditions will help in deciphering the function of glutamate as a neurotransmitter in the ICG. Supported by NIH AR47410 (KEM).Grant Funding Source: NIH AR47410