bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iron Absorption from Iron‐enriched Aspergillus oryzae is Similar to Ferrous Sulfate in Humans
Authors: Reddy Manju B. , Armah Seth M. , Stewart Jeanne , Bian Yilin , Bries Amanda , O'Brien Kimberly O. 
Published: November 2023

Iron deficiency anemia is the most common nutritional disorder in infants, children and young women – particularly in developing countries. Due to the problems associated with inorganic iron both as a supplement and fortificant, significant efforts have been made in finding effective alternatives. Though fortification is a sustainable strategy in reducing the incidence of anemia, challenges arise as highly absorbable iron compounds can cause undesirable sensory changes to the food matrix, whereas those iron compounds resulting in fewer sensory changes have low absorption. Our objective was to compare iron absorption from iron‐enriched Aspergillus oryzae, AspironTM, (ASP) with ferrous sulfate by using stable isotope methodology in humans. ASP is a natural free‐flowing powder of inactive fungal biomass containing 6–8% elemental iron produced by Cura Global Health, Inc. using a proprietary technology. ASP was intrinsically labelled by growing it in iron‐enriched media containing 58FeSO4 and the ferrous sulfate was labeled with 57Fe. Sixteen female subjects (18–35 y), non‐pregnant and non‐anemic with ferritin concentration of <40ug/L were recruited in this study. Subjects were randomized to consume test meals (semi‐purified meal that was used in several earlier studies) with stable iron isotopes on two consecutive days. Each meal contained 10 mg iron as 57FeSO4 form or 2 mg 58Fe plus 8 mg natural abundance iron in ASP form. At the beginning of the study, C‐reactive protein, hepcidin, and ferritin concentrations were measured. Iron absorption was assessed by measuring isotope enrichment in blood after 14 days of feeding. The 12% difference in absorption between 57Fe (17.18 ± 14.2%) and 58Fe (15.14 ± 12.3%) was not statistically significant. Iron absorption from both ferrous sulfate and ASP was inversely correlated with serum ferritin (R2 =0.53, p<0.002; R2=0.58, p<0.0005, respectively) as well as with hepcidin (R2=0.30, p<0.05; R2=0.31, p<0.05, respectively) suggesting that the absorption of ASP is regulated similarly to ferrous sulfate. In conclusion, ASP has the potential to be used as a fortificant, which can offer high bioavailability and may cause less organoleptic changes due to its limited solubility. Future studies are needed to assess its effectiveness in high phytate and high polyphenol containing meals.Support or Funding InformationCura Global Health, Inc. Ames, IA
Differential Regulation Of Transcriptional Factors Of Selenoprotein Genes By Moderately High Dietary Concentrations Of Se And Fat In Liver And Adipose Tissue Of Wildtype And Gpx1−/− Mice
Authors: Zhao Zeping , Zhou Jichang , Lei Xin Gen 
Published: November 2023

Our previous research demonstrated striking differences in regulations of selenoprotein gene mRNA between in the liver and adipose tissue of wild‐type (WT) and Gpx1−/− male mice (2–4 months of age) by moderately high dietary concentrations of Se (1.0 vs. 0.3 mg/kg as selenite) and/or high fat (25 vs. 5% as lard). This study was followed up to explore if there was an underlying transcriptional mechanism for those differential regulations. Initially, we submitted the promoter region sequences (−2000bp to 0bp) of all the affected selenoprotein genes by the high fat and Se diets to TRANSFAC database and identified 7 common transcription factors (TF): C/ebpβ, Yy1, Hoxa5, Gr, Hes1, Nf1 and Myod. Subsequently, we determined responses of mRNA abundances of these TF to the high fat and Se diets in the liver and adipose tissue samples collected from the previous experiment (total = 40 mice, n = 5/diet by age and genotype). In the adipose tissue of the WT mice, mRNA levels of all 7 TF were consistently down‐regulated (P < 0.05) by the high Se and fat diets. In contrast, the high fat diet enhanced (P < 0.05) Myod and Hes1 and suppressed (P < 0.05) only Hoxa5 and Nf1 mRNA, while the high Se diet enhanced (P < 0.05) only C/ebpβ and Gr mRNA in the liver of WT mice. Knockout of Gpx1 allowed both positive and negative effects (P < 0.05) of the high Se and fat diets on the mRNA levels of these TF in the liver and adipose tissue, but the overall regulation seemed to be intensified in the liver and attenuated in the adipose tissue compared with those in the WT mice. Correlation analysis revealed strong positive relationships (R2 > 0.8, P < 0.05) between mRNA of each of the 7 TF with 9 selenoproteins (Gpx4, Gpx6, Selh, Seli, Selk, Selm, Selo, SELP, Sels and Selv) in the adipose of WT mice. However, such correlations were shown between only 5 selenoprotein genes (Dio2, Dio3, GPX3, Gpx6 and Sep15) and 3 TF (Myod, Hes1 and Gr) in the liver of WT mice. Likewise, knockout of Gpx1 removed many of these correlations in the liver or adipose tissue and rendered 3 negative correlations (P < 0.05) between Gr and Dio1 and between Nf1/Yy1 and Gpx4 in the adipose tissue. In conclusion, the differential regulations of selenoprotein gene expression in the two tissues of two genotypes by the moderately high dietary intakes of Se and fat might be mediated by their impacts on the expression of the TF having binding domains in the promoters of these genes.Support or Funding InformationNIH DK 53018.
Chlorogenic Acid Ameliorates Alcoholic Liver Disease through MiRNA‐mediated Restoration of Mitochondrial Redox System
Authors: Kim Hyunjin , Pan Jeong Hoon , Kim Jae Kyeom , Kim Young Jun , Lee Jin Hyup , Park Jeen‐Woo 
Published: November 2023

MicroRNAs (miRNA) play essential roles in virtually all cellular and biological processes in liver development, differentiation and homeostasis. Altered expression levels of miRNA were observed in patients with alcoholic liver diseases (ALD) including liver steatosis, cirrhosis and hepatocellular carcinoma. Mitochondria, the main organelles involved in intracellular ROS production, play central roles in modulating redox‐dependent cellular processes, such as metabolism and apoptosis, and disruptions of the mitochondrial redox metabolism are closely associated with ALD. Dietary polyphenols are a versatile group of phytochemicals with many potentially beneficial activities in terms of disease prevention. It is recently reported that the dietary components can selectively activate or inactivate gene expression through epigenetic regulation including alteration in the miRNA expression to exhibit the physiological roles in the prevention of various diseases. In the present study therefore, we investigated if chlorogenic acid (CGA), a potent bioactive polyphenol present in vegetables, can selectively modulate gene expression through miRNA regulation to elicit their beneficial effects. Here we show that CGA protect alcohol‐induced liver injury in mice and these functions of CGA are closely associated with suppression of hepatic apoptosis and inflammation mediated by mitochondrial ROS. Of note, in the global miRNA profiling analysis, hepatic miRNAs were either elevated or suppressed in response to CGA supplementation. Predictions by Ingenuity Pathway Analysis indicated that some of miRNAs target genes are related with hepatic mitochondrial redox metabolism. Moreover, the epigenetic mechanisms are responsible for, at least in part, effects of CGA against the alcoholic liver injury through restoration of the mitochondrial redox system. Taken together, our results highlight the importance of miRNA in the regulation of mitochondrial redox systems and demonstrate that CGA plays a key role in modulating the alcohol‐induced liver injury through miRNA modulation. Further investigations are warranted regarding the net downstream effects of miRNA modulation as pertains to ALD.Support or Funding InformationThis work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIP) (Grant No. NRF‐2015R1A4A1042271).
Dietary Avicularin Alleviated Type 2 Diabetes in Mice
Authors: Zhu Xiaoai , Ouyang Wen , Miao Jianyin , Xiong Ping , Feng Konglong , Li Minxiong , Cao Yong , Xiao Hang 
Published: November 2023

Many dietary flavonoids exist as glycosides in fruits and vegetables, and they are considered as bioactive food components potentially responsible for various health benefits. Type 2 diabetes mellitus is a complex and polygenic disease with increasing global prevalence. In this study, the inhibitory effects of avicularin (quercetin‐3‐O‐α‐arabinofuranoside), a flavonoid glycoside commonly found in apple and mango, were determined in the mice with high fat diet/streptozotocin induced type 2 diabetes. Our results demonstrated that dietary avicularin treatment (100 mg/kg/d) reduced levels of fasting blood glucose, TG and LDL‐C, improved β‐cell function, and suppressed hepatic steatosis in diabetic mice. Gene expression analysis by RNA‐Seq revealed that arachidonic acid metabolism, drug metabolism‐cytochrome P450, drug metabolism‐other enzymes, MAPK signaling pathway, metabolic pathways, metabolism of xenobiotics by cytochrome P450, p53 signaling pathway and retinol metabolism were the major pathways altered in the liver of the diabetic mice in comparison with that of the negative control mice (healthy mice). Within the type 2 diabetes mellitus related pathways, ADIPO, P13K, SOCS, VDCC, SUR1, GK, PYK genes were upregulated in diabetic mice compared to the healthy mice, and avicularin treatment significantly downregulated these genes in the diabetic mice. Within the PPAR pathways, the mRNA levels of FABP1, SCD‐1, SCP‐X, ADIPO, PEPCK were increased in the diabetic mice, and avicularin treatment effectively decreased the levels of these gens in the diabetic mice. Avicularin treatment also upregulated the genes such as CYP7A1, CYP8B1, and CYP4A1 that was downregulated in the diabetic mice in comparison with the healthy mice. Taken together, our results demonstrated the protective effects of avicularin against diabetes and provided a global view of the effects of avicularin on the complexity transcriptome in diabetic mice.Support or Funding InformationThis study was supported by the University of International Cooperation in Science and Technology Innovation Platform Project of Guangdong (2013gjhz0003), the Education Department of Guang zhou Province (Grant No. 2013J4100075), the National Natural Science Foundation of China (Grant No. 31201321).
N‐3 Polyunsaturated Fatty Acids Increase Hepatic Fibroblast Growth Factor 21 Sensitivity Through PPARγ‐β‐klotho Pathway
Authors: Ling Wenhua , Yang Wenqi 
Published: November 2023

ObjectiveFibroblast growth factor 21 (FGF21) is an important physiological metabolic regulator with diverse functions in lipid and glucose metabolism. However, circulating FGF21 levels were elevated in obesity, nonalcoholic fatty liver disease (NAFLD) and atherosclerosis, which is also demonstrated in our previous study that elevated FGF21 levels were associated with dyslipidemia and insulin resistance. Paradoxically increased FGF21 levels in metabolic disorders indicate impaired FGF21 sensitivity or occurrence of FGF21 resistance. In the present study, we found that FGF21 was involved in fish oil‐mediated hepatic lipid‐regulating and anti‐inflammatory effects in mice fed with high fat diet. However, fish oil supplementation did not significantly increase hepatic and circulating FGF21 protein levels. Whether fish oil feeding‐induced benefits in liver are related to hepatic FGF21 sensitivity remains unclear and needs further investigation.MethodsTo determine the effects of n‐3 polyunsaturated fatty acids (PUFAs) on FGF21 sensitivity, we examined the response to acute FGF21 administration in vivo and in vitro.ResultsMale C57BL/6J mice were fed a low fat diet (LFD), a high fat diet (HFD) or a fish oil supplemented high fat diet (FOD) for 12 weeks. Fish oil improved HFD‐induced hepatic steatosis and inflammation while exerted no obvious effect on FGF21 protein expression. Nevertheless, FGF21 knockout studies demonstrated that FGF21 participated in fish oil‐induced metabolic benefits. Then the FGF21 signaling pathway of n‐3 PUFAs‐induced improvement in lipid metabolism were examined. In vivo and in vitro experiments showed that n‐3 PUFAs, DHA and EPA, promoted hepatic FGF21 signal transduction and enhanced FGF21‐induced changes in serum insulin and NEFA. N‐3 PUFAs‐mediated elevated hepatic FGF21 sensitivity was probably due to increased hepatic β‐klotho expression. Furthermore, PPARγ siRNA knockdown and PPARγ selective antagonist GW9662 treatment blocked the effects of DHA to enhance β‐klotho expression and FGF21 signaling, illustrating that PPARγ participated in DHA‐regulated β‐klotho expression and FGF21 sensitivity.ConclusionOur data indicate that n‐3 PUFAs increase hepatic FGF21 sensitivity and β‐klotho expression probably through a PPARγ dependent mechanism, and may thereby exert hepatic beneficial effects on lipid metabolism and inflammation.Support or Funding InformationThis work was supported by grants from the National Research Program of China (973 Program, 2012CB517506).
Novel Role of Lewis A Glycans in Regulating Neutrophil Trafficking
Authors: Brazil Jennifer C , Sumagin Ronen , Lee Goo , Louis Nancy A , Cummings Richard D , Parkos Charles A 
Published: November 2023

Pathogen‐triggered neutrophil (PMN) recruitment is critical for innate immunity, but aberrant PMN influx is also implicated in the pathogenesis of numerous inflammatory diseases of the gut and lungs. Fucosylated terminal glycans from the Lewis glycan family, such as Lewis‐x (Lex) and Sialyl Lewis‐x, have previously been implicated in the regulation of important PMN functions, including Selectin‐mediated PMN transendothelial trafficking. While such glycans based on the type 2 sequence (Galb1‐4GlcNAc‐R) are abundant on PMNs, the presence of type 1 Galb1‐3GlcNAc‐R glycans required for the expression of Lewis‐a (Lea) have not yet been reported. Here, we conclusively report that Lea is expressed in human PMNs as probed using mAbs whose specificity was confirmed using glycan array technology. Lea function was further probed using Lea‐selective mAbs and a Lea binding lectin resulting in increased PMN chemotaxis and migration across model intestinal epithelia. Analyses of glycan synthetic machinery in PMN revealed expression of a b1–3 Galactosyltransferase and an α1–4 Fucosyltransferase, glycosyltransferases that are required for Lea synthesis. Specificity of findings to Lea was confirmed by absence of antibody‐mediated effects using PMN from individuals deficient in α1–4 fucosylation. These results suggest that PMN expression of Lea has important functional consequences that may be relevant during PMN trafficking within inflamed mucosal tissues. We therefore propose that PMN Lea represents a new target for regulating intestinal innate immunity and modulating inflammation in diseases where dysregulated PMN influx is associated with bystander tissue damage. Furthermore, differential responses of human PMN to physiological ligands of Lea (based on an individuals Lewis phenotype) may provide insights into the mechanisms linking specific Lewis phenotypes with differential susceptibilities to bacterial infections, viral infections and coronary heart disease.Support or Funding InformationNIH ‐ RO1 DK072564‐21 (Parkos)CCFA ‐ Career Development Award (314660) (Brazil)
Gut Microbial Metabolites Establish a Gradient of Extracellular Protons, Which Mediate Microbiota‐Stimulated Intestinal Repair via Proton‐Sensing G‐Protein Coupled‐Receptors
Authors: Alam M. Ashfaqul , Wu Huixia , Matthews Jason , Saeedi Bejan , Jones Rheinallt , Neish Andrew S. 
Published: November 2023

The gut commensal microbiota interacts with intestinal epithelial cells to ensure intestinal homeostasis, development, and repair. Tissue regeneration is a complex but coordinated cellular process that involves both cellular proliferation and migration. We recently reported that the intestinal wound microenvironment specifically enriches a mucosa‐associated microbial consortium, which promoted repair of mucosal injuries. The mammalian gut microbiota generates a diverse array of metabolites that may influence host cellular reparative responses. We performed an unbiased screening analysis by mass spectrometry‐based metabolomic profiling of intact and wounded mucosa in germ‐free and conventional mice. Unlike the germ‐free animals, the colon of the conventional mice demonstrated increased amounts of acidic microbial metabolites, which established an extracellular pH gradient with more acidic pH at the apex of the colonic crypt. These findings led us to hypothesize that the intestinal microbiome‐produced metabolites generate a gradient of extracellular protons, which influence intestinal barrier function and mucosal homeostasis. We found that the colonic epithelial cells of conventional mice express elevated levels of the proton‐sensing G‐protein coupled‐receptors GPCR4 and GPCR68. Intriguingly, the murine colonic contents or a specific metabolite, 2‐hydroxy‐4‐methylpentanoic acid (HMP) decreases the extracellular pH to modulate claudin‐4 dependent paracellular permeability and to regulate the proliferation of colonic epithelial cells in a GPCR68 and GPCR4‐dependent manner. Importantly, our study revealed that GPCR68 and GPCR4 are activated by different levels of proton concentrations, show differential expression pattern along the murine colonic crypt, and also have an opposing functional role in colonic epithelial cell proliferation in mice. Collectively, our data highlight the importance of microbe derived metabolites in modulating the extracellular proton concentration in the gut mucosal microenvironment. Moreover, our findings show that the GPCR4 and GPCR68 function as the sensor of microbially modulated proton gradient that is potentially involved in the maintenance of gut mucosal homeostasis, repair, and barrier function.Support or Funding InformationCareer Development Award of Crohn's and Colitis Foundation of America (CCFA)
Selective intestinal epithelial loss of Junctional Adhesion Molecule‐A results in enhanced intestinal permeability and increased susceptibility to colitis
Authors: Flemming Sven , Luissint Anny‐Claude , Nusrat Asma , Parkos Charles A. 
Published: November 2023

Junctional Adhesion Molecule‐A (JAM‐A) is a transmembrane protein that is expressed in epithelial cells and leukocytes. JAM‐A has been proposed to regulate epithelial barrier function and leukocyte transendothelial migration. Since the tissue specific functions of JAM‐A in the intestinal epithelium have not been elucidated yet, we generated epithelial‐targeted JAM‐A deficient mice (Villin‐cre; JAM‐A fl/fl) and tamoxifen‐inducible epithelial‐targeted JAM‐A deficient mice (Villin‐creERT2; JAM‐A fl/fl) to gain insights into the relative contributions of JAM‐A in regulating intestinal barrier function under steady state and inflammatory conditions. Intestinal epithelial‐targeted loss of JAM‐A resulted in compromised intestinal epithelial barrier function with increased paracellular permeability to 4kDa FITC‐dextran under steady state conditions indicating epithelial JAM‐A as major contributor in epithelial barrier homeostasis. Interestingly, neither mice with constitutive loss of epithelial JAM‐A (Villin‐cre; JAM‐A fl/fl) nor mice with acute loss of JAM‐A (Villin‐creERT2; JAM‐A fl/fl) developed spontaneous colitis. Challenge of Villin‐cre; JAM‐A fl/fl mice with pro‐inflammatory cytokines (TNFa and IFNg) led to a further significant increase in epithelial paracellular permeability, supporting the role of epithelial JAM‐A in barrier compromise during mucosal inflammation. To further confirm the crucial role of epithelial JAM‐A in regulating epithelial barrier function under inflammatory conditions, we performed experiments using an acute DSS induced injury model of colitis and observed that Villin‐cre; JAM‐A fl/fl showed increased susceptibility to colitis as has been reported for JAM‐A −/− mice. Given the increase in sensitivity to development of colitis observed in the JAM‐A deficient mice, we established an intestinal loop model of acute inflammation to analyze the contribution of JAM‐A in regulating neutrophil transepithelial migration (TEpM). With this model, we quantified transmigrated PMNs in an isolated segment of the ileum or colon by flow cytometry and immunofluorescence staining. In JAM‐A −/− mice, we observed delayed neutrophil recruitment into the intestinal lumen with accumulation of neutrophils in the mucosal subepithelial space in response to the chemoattractant leukotriene B4 despite significantly increased paracellular permeability. Analogous studies using mice with epithelial and leukocyte targeted loss of JAM‐A are underway. These findings provide novel insight on the pivotal role of epithelial‐specific loss of JAM‐A in regulation of mucosal barrier function under steady state and inflammatory conditions and highlight a novel contribution of JAM‐A in the process of PMN transepithelial migration.Support or Funding InformationRO1 DK072564‐21DFG FL870/1‐1
Neuregulin‐1β Induces ErbB3‐dependent Proliferation and Survival of Normal Human Cardiac Ventricular Fibroblasts
Authors: Galindo Cristi Lara , Kirabo Annet , Gupte Manisha , Ryzhov Sergey , Sawyer Douglas B 
Published: November 2023

Neuregulin‐1β (NRG‐1β) is critical for cardiac development and repair and is currently being assessed as a possible therapeutic for systolic heart failure. Our laboratory and others have shown that NRG‐1β improves heart function in several animal models of heart disease, and several human trials indicate that it is a promising treatment for human heart disease. We previously demonstrated that NRG‐1β reduces cardiac fibrosis in an animal model of myocardial infarction, suggesting that it might influence cardiac fibroblast signaling. Here we show that NRG‐1β receptors (ErbB2, ErbB3, and ErbB4) are indeed expressed in normal human cardiac ventricular (NHCV) fibroblasts. Treatment of NHCV fibroblasts with exogenous recombinant NRG‐1β induced activation of the AKT pathway, which was phosphoinositide 3‐kinase (PI3K)‐dependent. Moreover, the NRG‐1β‐induced PI3K/AKT signaling in these cells required phosphorylation of both ErbB2 and ErbB3 receptors at tyrosine (TY)1248 and TY1289 respectively. RNASeq analysis of NRG‐1β‐treated cardiac fibroblasts obtained from three different donor hearts revealed a global gene expression signature consistent with cell growth and survival. We confirmed enhanced cellular proliferation and viability in NHCV fibroblasts in response to NRG‐1β, which was abrogated by PI3K, ErbB2, and ErbB3 inhibitors. These novel findings suggest a role for NRG‐1β in the regulation of cardiac ventricular fibroblast growth and survival via ErbB2/ErbB3 receptor phosphorylation with subsequent activation of the PI3K‐AKT signaling pathway.Support or Funding InformationThis work was supported in part by National Institutes of Health grants 1K01HL13049701(Kirabo) and K01HL121045 (Galindo). VANTAGE is supported in part by CTSA Grant (5UL1 RR024975‐03), the Vanderbilt Ingram Cancer Center (P30 CA68485), the Vanderbilt Vision Center (P30 EY08126), and NIH/NCRR (G20 RR030956).
Regulation of translational fidelity and neurodegeneration
Authors: Ackerman Susan L. 
Published: November 2023

The faithful execution of protein production from mRNAs is largely controlled by accurate charging of tRNAs by the aminoacyl tRNA tRNA synthetases. Many of these enzymes have editing domains that can recognize and correct mischarging of cognate tRNAs. We previously identified a spontaneous mutation in the editing domain of the mouse alanyl tRNA‐synthetase gene which leads to aggregates of misfolded proteins and degeneration of cerebellar Purkinje cells. By forward genetics we have identified a modifier gene of this mutation that prevents aggregate formation and neurodegeneration. Our data demonstrates that this novel vertebrate‐specific protein plays an important, previously unappreciated role in translational fidelity.Support or Funding InformationThis work was supported by NIH and Howard Hughes Medical Institute.