bluuebunny/crossref_metadata_2025_split huggingface dataset:
Redox state as a master regulator of liver function
Authors: Nocito Laura , Yoo Elsia J , Corkey Barbara E 
Published: June 2021

ObjectiveTo determine if redox, as a regulator of metabolic and mitochondrial responses, controls the fate of fuels and liver function by generating reactive oxygen species (ROS).MethodsPrimary hepatocytes were treated with extracellular redox couples: cysteine/cystine (Cys/CySS), reduced/oxidized glutathione (GSH/GSSG), βhydroxybutyrate/acetoacetate (βOHB/Acoc) and lactate/pyruvate (L/P). ROS generation was measured using H2DCFDA. Endogenous glucose production and circulating redox metabolites were measured from cell incubation media using fluorescent methods. Oxygen consumption was measured using the XF24 extracellular analyzer.ResultsRedox couple induced oxidized conditions increased intracellular ROS generation. Endogenous glucose production, mitochondrial respiration, and ketone bodies and L/P secretions were also analyzed. Both endogenous glucose production and mitochondrial respiration decreased under oxidized conditions, whereas the ratios of ketone bodies (βOHB/Acoc) and L/P secretions increased.ConclusionsWe show that oxidized extracellular conditions induce ROS in primary hepatocytes. The extracellular oxidized milieu determined by βOHB/Acoc causes a decrease in the maximal respiratory capacity induced by the uncoupler FCCP. These effects are associated with a decrease in hepatocyte gluconeogenic capacity.
Shed syndecan‐1 drives tumor progression by binding to the cell surface and translocating to the nucleus
Authors: Stewart Mark , Ramani Vishnu , Sanderson Ralph 
Published: June 2021

Multiple myeloma is a hematological malignancy that disseminates throughout the body. The serum of some myeloma patients contains high levels of shed syndecan‐1 (sSDC1), an independent indicator of poor prognosis. Shed SDC1 drives myeloma tumor progression in vivo, but the mechanism(s) mediating this remain unknown. Based on preliminary findings, we hypothesized that sSDC1 regulates gene expression by binding to the tumor cell surface and translocating to the nucleus. We utilized ARH‐77 cells, a human lymphoblastoid cell line lacking SDC1 expression. When grown in the presence of medium containing murine or human sSDC1, sSDC1 was taken up by these cells and translocated to the nucleus. Additionally, exogenous sSDC1 added to myeloma cells also translocated to the nucleus. Tumor cells engineered to express high levels of sSDC1 exhibited a 50% reduction in histone acetyltransferase activity and increased phosphorylated extracellular signal‐regulated kinase (p‐ERK) as compared to cells not expressing sSDC1. Shed SDC1 translocation to the nucleus and increase in p‐ERK are dependent on the presence of intact heparan sulfate chains on its core protein. These data demonstrate for the first time that sSDC1 binds to the cell surface and translocates to the nucleus of cells. Therapeutic regulation of SDC1 shedding, its binding to the cell surface or translocation to the nucleus represent novel strategies to control the progression of myeloma and other cancers.Work supported by NIH grants CA135075 and CA138340 (to R.D.S.).
Persistent EGF Signaling Serves to Promote Lactotrope Differentiation in GH4 Pituitary Somatolactotrope Tumor Cells, whereas Activation of the PI3K/mTOR/S6K Pathway Promotes Cell Proliferation and the Transformed Phenotype
Authors: Gomez Crystal Lynna , Trudeau Tammy , Gutierrez‐Hartmann Arthur 
Published: June 2021

BackgroundPituitary somatotropes and lactotropes, expressing GH and PRL, respectively, retain plasticity, allowing rapid cell expansions in response to increased physiological demands. Unfortunately, very little is known about the signaling events that instruct somato‐lactotrope cells to proliferate and then terminally differentiate or that contribute to the transformed phenotype. A number of in vivo transgenic mouse studies revealed that uncontrolled activation of growth factor Ras/MAPK signaling pathways in lactotropes results in lactotrope hyperplasia. Moreover, in vitro studies using GH4 rat pituitary somato‐lactotrope tumor cell lines have shown that activated pMAPK is necessary for both short‐term proliferation and differentiation, with possibly the duration of pMAPK activation dictating differential responses. However, these proliferation studies all relied on short‐term (6–24 hrs) assays. Thus, the specific role of MAPK in durable lactotrope proliferation and differentiation responses remain unknown.MethodsIn order to directly interrogate the role of EGF and mTOR in lactotrope differentiation, proliferation and transformation, we used persistent EGF addition or pharmacological inhibitors of mTOR, to investigate the role of these pathways in GH4 cell proliferation, clonogenicity, and soft agar growth.ResultsUsing long‐term proliferation, clonogenicity and soft agar growth assays, we find that treating cycling GH4 cells with 5nM EGF and mTOR inhibitors, rapamycin and Torin 1, reduced cell proliferation, clonogenicity, and soft agar growth.ConclusionCollectively, these data reveal that the EGF signaling pathway Ras/Raf/MAPK, promotes lactotrope differentiation, whereas activation of the PI3K/mTOR/S6K pathway regulates lactotrope proliferation and transformed phenotype.
Novel protease mediated mechanisms promote the spread of cancer cells via the blood circulation
Authors: Hooper John , Yaowu He , Casar Berta , Ying Dong , Wortmann Andreas , Adams Mark , Clements Judith , Quigley James 
Published: June 2021

Although the dysfunctional activities of proteases in cancer metastasis have been recognised for some time, the particular mechanisms mediating the roles of these enzymes in the spread of cancer remain poorly defined. Recently we have demonstrated that signals initiated by proteolytic cleavage of cell surface receptors can initiate metastasis promoting responses. One of these receptors is the cell surface glycoprotein CUB domain containing protein 1 (CDCP1). Our data indicate that CDCP1 is cleaved at the cell surface in vitro and in vivo by serine proteases thereby initiating intracellular signalling cascades involving activation and docking to CDCP1 of the kinases Src and PKCδ and downstream activation of Akt. Interestingly, we have shown that this cascade protects cancer cells as they disseminate via blood vessels in vivo and we have identified proteases initiating this protection in model systems. Our findings further demonstrate roles for CDCP1 in cell migration in vitro including its competition as a Src substrate with a critical mediator of cell adhesion, FAK, and its role in migration induced by EGFR signalling. Targeting CDCP1 and its signalling effectors may be a rational approach to treat cancer patients at risk of recurrent disease.Support: Wesley Research Institute, Australian Research Council, Cancer Council Queensland, National Health and Medical Research Council of Australia
Aspirin prevents growth and differentiation of breast cancer cells: lessons from in vitro and in vivo studies
Authors: Maity Gargi , De Archana , Banerjee Snigdha , Das Amlan , Banerjee Sushanta 
Published: June 2021

Aspirin, a classical non‐steroidal anti‐inflammatory drug (NSAID) is widely used to reduce pains and fever. Epidemiological and experimental studies suggested that Aspirin use reduces the risk of different cancers including breast cancer and may be used as a chemopreventive agent against breast cancer and other carcinogenesis. These studies have raised the tempting possibility that Aspirin could serve as a preventive medicine for breast cancer. However lack of in‐depth knowledge of the mechanism of action of Aspirin reshapes the debate of risk and benefit of Aspirin in prevention of breast cancer. Our aim is to investigate effects of Aspirin on pathophysiological events like epithelial to mesenchymal transition (EMT), migration, stemness of cell in breast cancer cells. Our studies using in vitro and in vivo tumor xenograft model show a strong beneficial effects of Aspirin in prevention of breast carcinogenesis. We find Aspirin not only prevents breast tumor cell proliferation in vitro and tumor growth in xenograft mouse model, it also significantly inhibits other pathophysiological events in breast cancer such as EMT, cell migration as well as reprogramming of stemness in breast cancer cells. Collectively our studies suggest that intake of an ASPIRIN a day might offer additional avenues for breast cancer prevention and treatment.(Support: VA Merit Grants ;S. Banerjee and S.K. Banerjee)
A Novel Mechanism of Bortezomib Function in Prostate Cancer Cells
Authors: Manna Subrata , Phyo Sai Aung , Vancura Michelle 
Published: June 2021

Proteasome inhibition is a promising therapeutic strategy in a number of human cancers, including the metastatic prostate cancer, one of the most common malignancies in men.Bortezomib (BZ) is the first approved proteasome inhibitor that has a remarkable anti‐tumor activity in many hematological malignancies. In solid tumors, BZ has been less effective; however, the underlying mechanisms are not fully understood. The rationale behind the BZ development and use was the inhibition of NFκB activity and suppression of NFκB‐dependent proinflammatory and anti‐apoptotic genes. Unexpectedly however, we found that while BZ decreases expression of most NFκB‐regulated genes, it actually increases expression of the pro‐inflammatory and pro‐angiogenic cytokines IL‐6 and IL‐8 in the metastatic prostate cancer PC‐3 cells. The goal of this study was to investigate the mechanisms underlying the BZ‐increased IL‐6 and IL‐8 expression in PC‐3 cells. Our results show that the BZ‐increased IL‐6 and IL‐ 8 expression in PC‐3 cells is mediated by the IKK kinase. In addition, our data indicate that BZ has a previously unrecognized function that consists of increasing the nuclear accumulation and activity of IKKα and IKKβ. Together, our data suggest that a new combination therapy targeting both IKK and proteasome might enhance the BZ effectiveness in the treatment of solid tumors, including the metastatic prostate cancer.
Thoracic Cavity Fluid Accumulation: A Possible Novel Biomarker in Hemodialysis Patients
Authors: Sussman Elizabeth J , Johnston Carol S. , Boren Kenneth , Singh Bhupinder 
Published: June 2021

Research shows chronic hemodialysis (HD) patient's hydration state, measured by whole body bioimpedence spectroscopy, is an independent predictor of mortality. Hyperphosphatemia is also independently associated with mortality in HD patients. It has yet to be determined if fluid accumulation, specifically in the thoracic cavity, is correlated to other predictors of mortality, including phosphorus. In this cross‐sectional study, stable HD patient's (n=25, 61.5±3.2y) thoracic cavity fluid accumulation (TCFA) was measured using the ZOE fluid status monitor (normal range: 19–30 ohms, lower values indicate greater fluid accumulation) and correlated to other traditional nutrition markers, including phosphorus, interdialytic weight gain (IDWG), and HD vintage (months). Results showed TCFA and phosphorus negatively correlated (r=−.479, r2=0.23, p=0.021), while TCFA and IDWG, and TCFA and HD vintage trended toward significance (r=−.386, p=0.063 and r= .371, p=0.074, respectively). These results suggest as two independent predictors of mortality (phosphorus and IDWG) increase, a greater TCFA is seen. Alternatively, as HD vintage increases, TCFA decreases. Funding: Academy of Nutrition and Dietetics FoundationGrant Funding Source: Academy of Nutrition and Dietetics Foundation
Dietary potassium and sodium impact blood pressure in adolescence
Authors: Buendia Justin Rene Goce , Hasnain Syed Ridda , Bradlee M. Loring , Moore Lynn L 
Published: June 2021

Adolescent blood pressure is a strong predictor of adult BP but the role of dietary sodium and potassium on adolescent BP is unclear. Our goal was to estimate effects of dietary sodium, potassium and the ratio of the two on adolescent BP. Data from 2379 girls, initially ages 9–10, and followed 10 years in the National Growth and Health Study, was used. Mean sodium and potassium intakes were 3.1 and 2.0 g respectively from an average of 6.6 sets of 3‐ day diet records. While sodium and potassium intakes were highly correlated (r=0.59), they had opposite BP effects. ANCOVA & repeated measures mixed models were used to estimate mean BP change over 10 yrs and at 18–20 yrs of age, controlling for height, race, TV/video time, activity, total energy, low‐fat dairy, BMI. Adjusted mean BP levels (mean age=18.3 yrs) declined linearly with increasing tertiles of potassium intake (SBP:109.5, 109.1, 108.4 mmHg; DBP:66.2, 65.2, 64.9 mmHg; p‐trend<0.05 for both). BP also declined with increasing tertiles of K:Na ratio (SBP:109.6, 109.5, 108.0 mmHg; DBP:65.9, 65.6, 64.9 mmHg; ns). In longitudinal models, girls with the highest K:Na ratio (>;0.75) & potassium intakes (>;2275 mg) had statistically significantly lower systolic (but not diastolic) BP levels throughout adolescence. Sodium intake had no effect on adolescent BP. This study suggests that dietary potassium may play a more important role than sodium in determining adolescent BP levels.Grant Funding Source: NIDDK and National Dairy Council
Breastfeeding knowledge, attitudes, and intent in a sample of Chinese undergraduate students
Authors: Lou Zixin , Zeng Guo , Huang Lujiao , Liu Fang , Pang Xuehong , Kavanagh Katherine 
Published: June 2021

The principle objective of the study was to explore, among Chinese undergraduates, any relationships between breastfeeding (BF) knowledge, attitudes, previous exposures, and intent to breastfeed a future child. A questionnaire relevant to this population was developed and carried out in several undergraduate classes in a major public university located in southwest China. Three hundred and ninety‐four undergraduates completed the questionnaire, with the sample consisting primarily of freshmen and sophomores. Knowledge scores ranged from 1 to 13 (with 13 being the highest possible score), with a mean of 8.3±1.5 (64.0% of the total score). Responses showed that one‐third of the sample disapproved BF in public (32.7%), and another one‐third was neutral to this behavior (32.5%). In addition, 34.3% believed BF to be painful, and 52.2% believed BF would restrict the freedom of mothers. Most students expressed intent to breastfeed a future child (75.0%), though males were significantly more likely to do so than females (81.6% vs. 71.7%, p=0.03). Future BF intent was associated with positive BF attitudes and with having been breastfed as an infant. Results indicate that BF knowledge is at a moderate level in this population, though intent to BF future children is high. Future research is warranted to explore and address the negative views of BF.Grant Funding Source: The University of Tennessee, Department of Nutrition, the Office of the Dean, and the Office of Research (SARIF Award).
Testing the internal validity of a questionnaire measuring dietary satisfaction through factor analysis
Authors: Wheeler Brooke E. , Hsiao Pao Ying , Durward Carrie M. , Rolls Barbara J. , Nickols‐Richardson Sharon M. 
Published: June 2021

Although dietary satisfaction is thought to play an important role in compliance with weight loss interventions, few tools exist to measure this construct. The objective was to test the validity of a previously developed 45‐item dietary satisfaction questionnaire (DSAT) in a sample of premenopausal women with overweight/obesity (n =180; Mean age 34.5 y SD ± 6.9; BMI 30.3, SD ± 3.6) participating in a weight loss intervention. Factor analysis with a Varimax rotation was used to test the validity of the original DSAT. Examination of eigenvalues and a scree plot were used to determine the number of factors to retain. The analysis resulted in 36 items that loaded onto six factors ranging from .316 to .933. Factors were labeled: “Preoccupation with diet”, “Benefits of diet”, “Eating away from home”, “Diet planning”, “Family impact”, and “Financial cost.” A valid dietary satisfaction questionnaire may be a valuable measure of compliance to a prescribed weight loss intervention. This tool also may be useful for tailoring advice to increase dietary satisfaction to maximize weight loss and weight loss maintenance.Grant Funding Source: N/A
Manganese Neurotoxicity is Enhanced by Iron Depletion.
Authors: Seo Young Ah , Li Yuan , Wessling‐Resnick Marianne 
Published: June 2021

Chronic exposure to manganese (Mn) results in neurobehavioral problems, particularly in children, but the molecular mechanisms are unknown. Accumulating evidence suggests that endoplasmic reticulum (ER) stress plays a significant role in neurodegenerative diseases. ER stress and the unfolded protein response (UPR) lead to cell apoptosis. Using dopaminergic SH‐SY5Y cells, we have characterized Mn cytotoxicity. Mn‐induced apoptosis was potentiated by iron depletion upon cell treatment with desferoxamine (DFO), a potent iron chelator. Mn exposure induced ER stress genes, including ER chaperone GRP94 and the pro‐apoptotic CHOP protein, with activation of ER resident caspase‐12. The important effector caspase‐3 was also activated. All of the Mn‐induced responses were enhanced by DFO treatment. To study Mn intoxication in vivo, iron‐deficient and control rats were intranasally instilled with 60 mg MnCl2/kg across 3 weeks. TUNEL staining of olfactory tissue confirmed that Mn induced apoptosis through a pathway potentiated by iron depletion. Taken together, our data reveal that Mn induces neuronal cell death through ER stress and the UPR response pathway and that this apoptotic effect is potentiated by iron deficiency. These studies provide insight into mechanisms of Mn neurotoxicity and raise awareness of the potential susceptibility of iron‐deficient children exposed to high Mn.Grant Funding Source: National Institute of Health
Formation of thiol conjugates of shogaols in mice and in humans and modulation of glutathione levels in cancer cells by [6]‐shogaol
Authors: Chen Huadong , Soroka Dominique N. , Sang Shengmin 
Published: June 2021

Extensive research has characterized ginger's anti‐inflammatory, antioxidant, and antitumor activities. Shogaols, a series of major constituents in dried ginger with the most abundant being [6]‐, [8]‐, and [10]‐shogaols, show much higher anti‐cancer potencies than gingerols. Previously, we reported the mercapturic acid pathway as a major metabolic route for [6]‐shogaol in mice. However, it is still unclear how the side chain length affects the metabolism of shogaols. In the present study, we first investigate the metabolism of [10]‐shogaol in mouse urine, with special focus on the mercapturic acid pathway, and then investigate the biotransformation of shogaols ([6]‐, [8]‐, and [10]‐shogaols ) in human urine. Our results show that eight major thiol‐conjugated metabolites of [10]‐shogaol were detected in mouse urine, while six major thiol‐conjugated metabolites of [6]‐shogaol, two thiol‐conjugated metabolites of [8]‐shogaol, and two thiol‐conjugated metabolites of [10]‐shogaol were detected in urine collected from human after drinking ginger tea, using liquid chromatography/electrospray ionization tandem mass spectrometry. Our results clearly indicate the mercapturic acid pathway is a major metabolic route for shogaols in mice and in humans. Furthermore, we also investigated the regulation of glutathione (GSH) by [6]‐shogaol in human colon cancer cells HCT‐116. Our results show [6]‐shogaol, after initially depleting glutathione levels, can subsequently restore and increase GSH levels over time. This activation mechanism will also be discussed.Grant Funding Source: NIH
Accumulation of dietary naringenin and metabolites in mice
Authors: Ke Jia‐Yu , Schwartz Steven J , Riedl Ken M , Yee Lisa D , Kliewer Kara L , Belury Martha A 
Published: June 2021

Naringenin is a grapefruit flavonoid that may ameliorate metabolic disturbances and exert anti‐carcinogenic actions in mice. The bioavailability of naringenin and its metabolites in tissues is still unknown. In a pilot study, we used LC‐MS/MS to analyze naringenin metabolites in plasma, inguinal adipose tissue, and liver. Male mice fed a diet with 3wt% naringenin did not show differences in food intake or tissue weights after 12 days of feeding. Plasma contained the highest concentration of naringenin (13.38 ± 4.00 μM). Naringenin monoglucuronides were the major derivatives identified in inguinal adipose tissue, while free naringenin was the dominant form of accumulated naringenin in liver. Currently, we are analyzing tissue samples from ovariectomized female mice fed with high fat diets containing 1% or 3% naringenin to compare the concentration of metabolites in tissues. Evaluation of naringenin metabolites and their concentration in metabolically relevant tissues will improve our understanding of the cellular and molecular mechanism by which diets/foods enriched in naringenin may exert beneficial effects on metabolic disturbances and carcinogenesis.Grant Funding Source: 1R03CA162551–01A1
The Effect of Whole‐Grape Powder on Body Composition, and Serum Biomarkers of Adipose Tissue and Bone Metabolism in Postmenopausal Women
Authors: Zemenu Elleni , Kelly Owen , DiMarco Nancy 
Published: June 2021

The effects of consuming freeze‐dried, whole‐grape powder (GP) or a placebo powder (P) for 12 weeks on body composition, biomarkers of inflammation, adipose tissue, and bone metabolism were determined. A randomized, double‐blind, placebo‐controlled study was performed with 40 post‐menopausal women (mean age 52.4±7.4) from 16 cities in Texas. Body composition and bone mineral densities (BMD) were determined using dual‐energy X‐ray absorptiometry (DXA). Serum concentrations of cross‐linked N‐telopeptide of type I collagen (NTX), alkaline phosphatase (ALP), osteocalcin (OC), insulin‐like growth factor‐1 (IGF‐1), adiponectin, leptin, prostaglandin E2 (PGE2), and leukotriene E4 (LTE4) were assayed using ELISA. Participants BMD were within normal ranges at baseline and at the end of study. NTX (p=0.04) and ALP (p=0.04) were significantly different between groups at baseline. In the placebo group (n=14), OC (p<0.01), adiponectin (p=0.01), and LTE4 (p=0.02) significantly decreased by 60.6%, 45.8%, and 61.9%, respectively. OC (p=0.02) and adiponectin (p=0.02) significantly decreased in GP group (n=11) by 50.9% and 59.7%, respectively. There were no significant differences between groups at 12 weeks. In the short term, freeze‐dried whole‐grape powder may exert no favorable effects on bone or adipose tissue biomarkers in post‐menopausal women.Grant Funding Source: California Table Grape Commission.
Ursolic Acid Protects Monocytes Against Priming and Dysfunction Induced by Metabolic Stress by Preventing Induction of Nox4
Authors: Ullevig Sarah Lynn , Kim Hong Seok , Hambright William Sealy , Tavakoli Sina , Asmis Reto 
Published: June 2021

We showed that mice fed at high‐fat diet (HFD) supplemented with ursolic acid (UA), an anti‐inflammatory phytochemical, were protected against atherosclerosis and monocyte dysfunction. Here we determine the molecular mechanism by which UA prevents metabolic stress‐induced monocyte priming and dysfunction. UA (0.3. 1, 3, 10 μM) protected THP‐1 monocytes against the sensitizing effect of metabolic stress on MCP‐1‐induced chemotaxis. Metabolically stressed monocytes treated with UA showed a decrease in total protein‐ and actin‐S‐glutathionylation, measures of thiol oxidative stress. MAPK phosphatase‐1 protein expression and phosphatase activity, reduced by metabolic stress, were rescued if UA was present during metabolic priming. UA treatment did not change protein and mRNA expression of glutaredoxin‐1, an enzyme that reduces glutathionylated proteins. However, UA blocked metabolic stress induction of Nox4. We therefore propose that UA prevents monocyte priming and dysfunction by suppressing Nox‐4 induction, thereby, preventing Nox4‐dependent dysregulation of redox‐sensitive processes, including actin turnover and MAPK‐signaling. These studies provide a novel mechanism of action for the anti‐inflammatory properties of UA. Funded by NIH RO1 HL070963 & HL115858 (RA).Grant Funding Source: NIH RO1 HL070963 & HL115858