bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of hypercaloric diet on RAGE mRNA expression, oxidative stress and kidney function in rats
Authors: Pierine Damiana Tortolero , Luvizoto Renata Azevedo Melo , Francisqueti Fabiane Valentini , Ferreira Ana Lucia Anjos , Yeum Kyung‐Jin , Correa Camila Renata 
Published: June 2021

Advanced glycation end products (AGEs) produced under oxidative stress can trigger porinflammatory responses by interacting with receptors for AGEs (RAGE). RAGE may link to the pathogenesis of chronic kidney diseases.ObjectiveTo evaluate the influence of hypercaloric diet on RAGE mRNA expression and oxidative stress in the kidney and its physiologic function.MethodsMale Wistar rats were fed a control diet (C, n=14) or a hypercaloric diet (HD, n=14) for 12 weeks. The adiposity index (AI) was used as an obesity indicator. Kidney function was evaluated by glumerular filtration rate, kidney RAGE mRNA expression by real time PCR, and kidney oxidative stress by total antioxidant performance (TAP).ResultsRAGE mRNA expression was significantly (p<0,001) higher in HD (1.89±0.77) than C rats (0.76±0.37). A positive correlation between RAGE and AI (r=0.64, p <0.001) was found. There were no differences in glomerular filtration rate and TAP between groups.ConclusionThe hypercaloric diet for 12 weeks resulted in an increase of RAGE mRNA expression, which may lead to inflammation in the kidneys from HD group.Support: CAPES, FAPESP (2010/06100–9)
Effects of iron deficiency on the expression of insulin‐like growth factor II and its receptor (IGF‐IIR) in murine glial cells
Authors: Morales‐González Esmeralda , Contreras Irazú , Estrada José Antonio 
Published: June 2021

ObjectiveTo determine the expression of IGF‐II and IGF‐IIR on iron‐deficient murine glial cells.MethodsPrimary glial cultures were established from purified cells obtained from the brain of newborn BALB/c mice. Mixed glial cultures were plated at a density of 120,000 cells/cm2 in complete DMEM (10% FBS) and cultured for 14 days. Subsequently, half of the cells were treated with deferoxamine (100 μM/mL) for 24 hours, to simulate iron‐deficient conditions. After treatment, cells were lysed and their protein contents extracted. Protein concentrations were assessed by the Bradford method and adjusted at 1 μg/μL. 70 μg of protein per sample were used to detect expression of IGF‐II and IGF‐IIR by western‐blot.ResultsWe detected decreased expression of IGF‐IIR in cells treated with deferoxamine, compared with controls. No difference was observed in the expression of IGF‐II under the same conditions.ConclusionIron deficiency decreases the expression of IGF‐IIR, but not IGF‐II, in murine mixed glial cultures. Decreased expression of this receptor may have important consequences for the development and function of the central nervous system during iron deficiency.
Pharmacokinetics of a novel eicosapentaenoic acid derived anti‐leukemic prostaglandin, Δ12‐ prostaglandin J3 in a murine model
Authors: Kudva Avinash Kundadka , Kaushal Naveen , Paulson Robert F , Prabhu Sandeep K 
Published: June 2021

Cyclopentenone prostaglandins are downstream metabolites of prostaglandin D series that exhibit anti‐inflammatory and anti‐carcinogenic activities. Recently, our laboratory has shown that Δ12‐prostaglandin J3 (Δ12‐PGJ3), produced from dietary omega‐3 polyunsaturated fatty acid (n‐3 PUFA), eicosapentaenoic acid (EPA), alleviates the progression of leukemia in three murine models with a remarkable selectivity towards leukemia stem cells (LSC), but not the normal hematopoietic stem cells (HSC). In the present study, we have evaluated the stability and pharmacokinetic properties of Δ12‐PGJ3in vivo models to establish efficacy and toxicology profile enabling better therapeutic strategies in the future. These studies should have a bearing on the nutritional intervention strategies using EPA‐rich diets in the above models of the disease.Grant Funding Source: NIH
Influence of Diabetes on Plasma Pharmacokinetics and Brain Bioavailability of Grape Polyphenols in the Zucker Rat Model
Authors: Chen Tzu‐Ying , Janle Elsa M , Ferruzzi Mario G , Simon James E , Wu Qing‐Li , Talcott Stephen T , Weaver Connie , Wang Jun , Ho Lap , Pasinetti Giulio M 
Published: June 2021

Grape polyphenols (GP) have been demonstrated to prevent Alzheimer's disease (AD) in a mouse model. Patients with diabetes mellitus are at greater risk of developing AD than non‐diabetic patients. To investigate the effect of the diabetic condition on bioavailability and brain distribution of flavan‐3‐ols, flavonols, and anthocyanins, Zucker diabetic fatty (ZDF) rats and their lean control (LN) were dosed orally with a combination of GP from grape seed extract, Concord grape juice and resveratrol (RES). Eight hour plasma pharmacokinetics was conducted after oral gavage of GP or water for 10 days. LC‐MS/MS analysis identified 3‐glucuronide (3‐glucur) and 3′‐methylglucuronide (3′‐OMe‐glucur) as the main metabolites for catechin (C), epicatechin (EC), quercetin (Q), and RES present in plasma and brains. ZDF rats exhibited significantly diminished maximum plasma concentrations for all above metabolites. ZDF rats showed significantly lower bioavailability by 77%, 79% and 45% in 3′‐OMeC‐glucur, 3′‐OMeEC‐glucur and RES‐3‐glucur relative to the LN. ZDF rats exhibited significantly lower levels than LN in all above metabolites except for Q‐3‐glucur in brain tissues. This study showed that the diabetic condition may impact absorption and distribution of polyphenols, suggesting that dosages required to reach therapeutic efficacy may need to be adjusted for disease condition.Grant Funding Source: NIH Grant P01AT004511
Beta cell dysfunction during hyperglycemia: protective role of erythritol?
Authors: Boesten Danielle , den Hartog Gertjan , de Cock Peter , Bosscher Douwina , Bast Aalt 
Published: June 2021

Diabetes is characterized by an alteration of insulin secretory function. The main cell type affected is the beta cell, the only insulin producing cell in the body. Hyperglycemia, as occurring during diabetes, has a harmful effect on the function and development of beta cells. Consequently, chronic hyperglycemia will result in beta cell dysfunction and ultimately cell death. In previous studies erythritol, a polyol bulk sweetener, has been shown to prevent loss of ex vivo endothelium dependent vasorelaxation in streptozotocin diabetic rats and protect endothelial cells during exposure to high concentrations of glucose in vitro1. Extending these studies, we investigated the potential of erythritol to protect beta cells against glucose induced cell death in two cell lines, the hamster beta cell line HIT‐T15 and the human beta cell line 1.1E7. Additionally, we investigated the insulin secretory function of the beta cells and determined the expression of genes involved in apoptosis and insulin secretion.Research financially supported by Cargill Inc.
Quercetin induces growth arrest through transcription factor FOXO1 in EGFR‐overexpressing oral cancer
Authors: Huang Chun‐Yin , Chan Chien‐Yi , Chou I‐Tai , Lien Chia‐Hsien , Lee Ming‐Fen 
Published: June 2021

The squamous cell carcinomas of the head and neck (SCCHN) with aberrant epidermal growth factor receptor (EGFR) signaling are often associated with poor prognosis and low survival. Therefore, efficient inhibition of the EGFR signaling could intervene with the development of malignancy. Quercetin appears anti‐tumorigenesis, but the underlying mechanism is unclear in oral cancer. Fork‐head box O (FOXO) transcription factors, Akt downstream effectors, are important regulators of cell growth. Here, we hypothesized that FOXO1 might be crucial in quercetin‐induced growth inhibition in EGFR‐overexpressing oral cancer. Quercetin treatment suppressed cell growth by inducing G2/M arrest and apoptosis in EGFR‐overexpressing HSC‐3 and TW206 oral cancer cells. Quercetin inhibited EGFR/Akt activation with a concomitant induction of FOXO1 activation. FOXO1‐knockdown attenuated quercetin‐induced p21 and FasL expression and subsequent G2 arrest and apoptosis, respectively. Likewise, quercetin suppressed tumor growth in HSC‐3 xenograft mice. Taken together, our data indicate that quercetin is an effective anti‐cancer agent, and that FOXO1 is crucial in quercetin‐induced growth suppression in EGFR‐overexpressing oral cancer.This work was supported by the grants from China Medical University CMU97–303 and National Science Council NSC98–2320‐B‐039–021‐MY3
Community mobilization activities for the Zambia 2012 Orange Maize Efficacy Trial
Authors: Kaliwile Chisela , Arscott Sara A. , Masi Cassim , Tanumihardjo Sherry A. 
Published: June 2021

In some societies, blood drawing, vaccinations, and supplementation, are surrounded by myths and beliefs. If not clarified, they may affect study implementation and negatively impact well‐intended studies. Against this background, the implementation team of the “2012 Zambian Orange Maize Study” undertook community mobilization activities to dispel myths, including meetings, drama performances, critical collaborations with local government, and continuous monitoring. The primary aim, assessment of vitamin A status of Zambian children in response to feeding orange maize, was communicated to all stakeholders. This study followed a similar study conducted in the same communities in 2010 and the differences and current study design were discussed. Other activities included renovation of intervention sites, sharing of previous results, staff recruitment, equipment inventory, and phase‐out strategy development. Signing a memorandum of understanding between the stakeholders was critical. Blood drawing, remuneration, and menu items were a source of complaints by parents and slight adjustments were made to the menu based on parental feedback. In conclusion, with all the challenges encountered, the study was successfully implemented according to schedule. Subject participation was good, with few losses to follow‐up. Analysis of the quantitative data is on‐going.Funded by HarvestPlus.
13′‐Carboxychromanol, a long‐chain metabolite of delta‐tocopherol, has potent anti‐cancer effects by interrupting de novo sphingolipid synthesis in human cancer cells
Authors: Jang Yumi , Kuah Soo Yee , Jiang Qing 
Published: June 2021

Natural forms of vitamin E are metabolized to long‐chain carboxychromanols and their sulfated counterparts and the carboxychromanols have been shown to have anti‐inflammatory activities. Although long‐chain carboxychromanols were recently reported to induce apoptosis in hepatocarcinoma HepG2 cells, whether these vitamin E metabolites are effective anticancer agents against other types of cancer remains to be determined. Here we showed that 13′‐carboxychromanol (13′‐COOH), a long‐chain metabolite of delta‐tocopherol (δT), inhibited the growth and induced death of human pancreatic (PANC‐1), breast (MCF‐7) and colon (HCT‐116, HT‐29) cancer cells with IC50 of 6–8 μM, which was much more potent than tocopherols and even gamma‐tocotrienol. Using liquid chromatography tandem mass spectrometry (LC‐MS‐MS), we found that 13′‐COOH induced accumulation of intracellular dihydroceramides and dihydrosphingosin, which are sphingoid bases in the de novo synthesis of sphingolipid pathway. Importantly, this alteration of sphingolipids occurred as early as after 2‐h incubation with 13′‐COOH and therefore preceded its induction of cell death. Meanwhile, an increase of ceramides was observed after 8‐h treatment when cell death became obvious. Our studies demonstrate that 13′‐COOH has more potent anti‐cancer effect than unmetabolized vitamin E forms by modulating sphingolipid metabolism in cancer cells.Grant Funding Source: R21CA152588 and R01AT006882 from National Institutes of Health
Adult‐onset obesity induced by early life overnutrition could be reversed by caloric restriction
Authors: Liu Hung‐Wen , Mahmood Saleh , Srinivasan Malathi , Smiraglia Dominic J , Patel Mulchand 
Published: June 2021

Overnutrition during the suckling period (small litter, SL) results in the development of adult‐onset obesity. The aim of the study was to investigate if caloric restriction (CR) in the postweaning period can reverse this phenomenon. The control litter (CL) had 12 pups/dam and SL had 3 male pups/dam from the postnatal day 3 until 21. In the postweaning period rats consumed lab chow as indicated: (i) CL and SL groups were on ad libitum regimen up to day 140, (ii) SL/CR group received 24% reduction in daily food intake compared to SL, and (iii) SL/CR/AL group was on 24% CR up to day 94 and then switched over to ad libitum feeding. CR caused reduction in body weight gains and normalized serum glucose, insulin, and leptin levels in SL/CR and SL/CR/AL rats compared to CL. The expression of neuropeptide Y (Npy) and leptin receptor (Lepr) returned to control levels in the hypothalami from SL/CR and SL/CR/AL rats compared to CL. No differences in the expression of pro‐opiomelanocortin and insulin receptor (Insr) were observed among these groups. Altered methylation of specific CpG dinucleotides in the proximal promoter region was observed for the Npy and Insr among these groups. CR resulted in normalized metabolic phenotype and gene expression involved in controlling food intake. The results show that the CR can be a successful intervention for reversing obese phenotype induced by lactational overfeeding.Grant Funding Source: NIH DK61518
Cav1.3 does not contribute to active 1,25D‐regulated intestinal Ca absorption
Authors: Fernandez Perla Citlali Reyes , Replogle Rebecca , Li Qiang , Fleet James C 
Published: June 2021

Intestinal Ca absorption occurs through a 1,25(OH)2D3 (1,25D)‐regulated transcellular pathway when habitual dietary Ca intake is low. Recently the L‐type Ca channel, Cav1.3, has been proposed to mediate active Ca absorption. We examined the role of Cav1.3 in Ca absorption using mouse models. Study 1 examined the relationship between Cav1.3 mRNA level and Ca absorption in a genetically diverse population of mice fed a normal (0.5%) or low (0.25%) Ca diet from 3–12 wks of age. Ca absorption was measured by oral gavage of a buffer containing 10 mM fructose and Ca45. Low Ca diets induced an increase in 1,25D and Ca absorption. Cav1.3 mRNA was detected in the duodenum, however, it was not associated with Ca absorption (r=−0.09, p=0.3) nor was it increased by low Ca intake (p=0.4). Study 2 examined whether glucose‐induced depolarization of the apical membrane of enterocytes enhances Ca absorption through Cav1.3. 10 wk‐old mice were fed high (1%) or low (0.125%) Ca diets for 1 wk. Ca absorption was examined using transport buffers containing Ca45 and either 25 mM glucose or fructose. While low Ca intake doubled Ca absorption, the sugar in the transport buffer did not increase Ca absorption efficiency (p=0.6) regardless of diet (p=0.19). Our data provide no support for the hypothesis that Cav1.3 and glucose‐induced depolarization are critical components of Ca absorption physiology.Grant Funding Source: NIH awards DK54111 and ES019103 (JCF)
Early growth response‐1 in the pathogenesis of cysteamineinduced duodenal ulcer
Authors: Khomenko Tetyana , Deng Xiaoming , Patel Khushin N , Sandor Zsuzsanna , Szabo Sandor 
Published: June 2021

We showed earlier that the immediate‐early gene & its zinc finger transcription factor early growth response (Egr) product were enhanced, including the expression of target genes (e.g., bFGF, PDGF, VEGF) in early stage of cysteamine (C)‐induced DU. Our recent studies demonstrated that deletion of egr‐1 gene led to 4.4‐fold increase in C‐induced DU in egr‐1 knockout (KO) vs. wild‐type (WT) mice. mRNA expression of bFGF, VEGF & PDGF was still increased but protein expression of bFGF, VEGF & PDGF was diminished in egr‐1 KO mice. We hypothesized that specific miRNAs in egr‐1 KO mice might be activated & inhibit protein synthesis of egr‐1 target genes. Using miRXplore Microarray study we found that 11 miRNAs (e.g., mir‐696, mir‐467E, mir‐152 & mir‐301B) were elevated by 1.8‐ to 1.9‐fold in egr‐1 KO mice vs. WT mice. Mir‐1892 decreased by 1.7‐fold in egr‐1 KO vs. WT mice. These miRNAs partially share validated targets relating to growth factor responses, e.g., FGFR3 & VEGF. We also demonstrated that DU was significantly reduced in rats treated with adenovirus encoding egr‐1 on days 7 & 14 (p < 0.05) respectively. The mRNA & protein expressions of egr‐1, bFGF, VEGF & PDGF markedly increased in rats after egr‐1 gene therapy. We conclude that Egr‐1 plays a preventive role in the pathogenesis of DU & further studies are needed to identify miRNA expression in egr‐1 KO & WT mice with DU.(This work was supported by the Veterans Health Administration Merit Review Grant to S. Szabo).
Combined Foxp3 and IgG4 staining reveal distinct subsets of inflammatory bowel disease
Authors: Seidman Michael A , Bellizzi Andrew M 
Published: June 2021

The two disease model in idiopathic inflammatory bowel disease (IBD), i.e. ulcerative colitis (UC) vs. Crohn's disease (CD), insufficiently captures the diseases' genetic and phenotypic diversity. We have utilized immunohistochemical staining for two markers of “regulatory” immune cells, IgG4 and FoxP3, to better characterize IBD, hoping to improve diagnosis, prognostication, and therapy. These stains were examined in cases of CD (n=11), UC (n=11), and demographically equivalent disease‐free patients (n=22). Biopsies taken from sites throughout the colon at all levels of disease activity were evaluated. The maximal number of cells staining per high power field (hpf) was scored. Neither IgG4 nor FoxP3 counts correlated with diagnosis (p>;0.05). Both correlated with disease activity (both p≈0.01). Neither showed correlation with age, gender, or anatomic site. Generalized linear models did not determine IgG4 or FoxP3 counts to be good predictors of diagnosis, even when corrected for disease activity. However, supervised hierarchical clustering revealed that the combination of the two stains identified clinically meaningful subsets of disease (Figure 1).These data provide insight into IBD that will help guide future understanding and therapies, going beyond the currently prevailing two disease paradigm.Research was supported entirely by internal (i.e. departmental) funds.
Identification and assessment of regulatory T cells (Treg*) associated with inflammation and tumorigenesis in Inflammatory Bowel Disease (IBD) patients
Authors: Downey Katherine J , Wang Yanhua , Sun Katherine , Lin Elain , Wu Yuanyuan , Liu Qiang 
Published: June 2021

The pathogenesis of Inflammatory Bowel Disease is multifactorial. A widely accepted theory for the pathogenesis of IBD lays blame on the host's exaggerated immune response to commensal bacteria, implying a loss of self tolerance. Chronic inflammation is a well known risk factor for the development of dysplasia and cancer. Regulatory T cells (Treg*) therefore play a critical role in the regulation of immunity and a pivotal role in tumorigenesis of several cancer types by suppressing anti‐tumor immune responses, thereby promoting tumor progression. We set out to identify and assess Treg* expression in IBD and Cancer patients vs. disease‐free individuals which may help explain tumor progression.Retrospective sequential in‐house cases (n=53): 34 IBD, 9 Colon cancer, and 10 normal. Immunohistochemistry used to delineate Treg* cells. Blinded counts performed using the average of 3 HPF's (40X) in areas of highest concentration. Data analysis by unpaired t‐test and ANOVA reveal significant differences in Treg* expression: IBD >; normal (p<0.001); Cancer >; normal (p<0.001 ); Cancer >; IBD (p<0.003); no significant difference between UC and Crohn's (p=0.371). ANOVA analysis showed statistically significant difference amongst all groups (p<0.001: Cancer >; IBD >; normal).Our results show increased Treg* cells in the cancer arm (cancer >; IBD >;>; normal), thereby supporting an important role of Treg* cells in inflammation and tumorigenesis in IBD. Therapeutic manipulation of Treg* cells (i.e. selective depletion) holds great potential in treating IBD and preventing subsequent tumor progression.Funding provided by Montefiore Medical Center Clinical Research Committee
Kinin B1 receptor regulates inflammatory cell recruitment during low laminar shear stress
Authors: Martin Katherine , Perretti Mauro , Ahluwalia Amrita 
Published: June 2021

The kinin B1 receptor (B1R) is an inducible receptor that is only weakly expressed, if at all, under normal physiological conditions but is induced under situations of stress. We have previously shown that when endothelial cells are exposed to inflammatory stimuli or low laminar shear stress (LSS), two factors commonly associated with atherosclerosis, B1R expression is induced. In vivo, B1R agonists stimulate inflammatory cell recruitment including neutrophils and macrophages. We now show in vitro that subjecting human aortic endothelial cells to low LSS enhances leukocyte adherence compared to physiological LSS. Moreover, this effect is enhanced in the presence of the cytokine interleukin‐1β, both conditions associated with increased endothelial B1R expression. Importantly treatment of endothelial cells with a B1R antagonist reduced cell adherence in cells exposed to low LSS but had no significant effect on the response under physiological LSS conditions. These results suggest that B1R may play an important role in inflammatory cell recruitment at sites of low LSS and targeting this protein might prove beneficial in the treatment of atherosclerosis.This work and KRM are funded by The British Heart Foundation
Role of Toll‐Like Receptor 4 in Legionella pneumophila infection with C3H/HeJ Mouse Model
Authors: Wu Wei‐wei , Wang Su‐ping , Zhang Fan , Gao Xiang‐dong , Dong Jieming 
Published: June 2021

ObjectiveTo explore the relationship between TLR4 and Legionella infection in a mouse model.MethodsC3H/HeJ and C3H/HeN mice were used as experimentl animal. Infection group and contol group were tracheal injection of bacterial suspension or sterile saline nasal respectively. All mice were sacrificed at 12h, 24h, 48h, 72h respectively. Left lung upper lobe was taken to do fixed biopsy. TLR4 protein expression level of each group on PBMC were detected by flow cytometry.ResultsPathological examination showed that the C3H/HeJ and C3H/HeN infection group in lung tissue were showed infiltration of inflammatory cells and alveolar vascular bleeding, the control group was not found inflammatory reaction. Legionella pneumonia model established successfully. There was significantly difference of TLR4 protein expression in three groups, each timing and the interaction of groups and timing(P<0.001). Comparison between groups found that C3H/HeJ infection group and C3H/HeN infection group, C3H/HeJ infection group and C3H/HeN control group shows statistical significance(P<0.001). But C3H/HeN infection group and C3H/HeN control group had no statistical significance(P>;0.05).ConclusionThe TLR4 gene mutations make it low reaction to Legionella. However, the anti‐inflammatory effects of TLR4 to Legionella needs further study.This study was supported by the National Natural Science Funds of China (grant no. 30872154)