bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mitochondrial dynamics regulate brown adiopcyte energy expenditure
Authors: Mahdaviani Kiana , Wikstrom Jakob D , Sereda Samuel B , Si Yaguang , Liesa Marc , Las Guy , Twig Gilad , Corkey Barbara , Cannon Barbara , Nedergaard Jan , Shirihai Orian S. 
Published: June 2021

Brown adipose tissue has gained much attention as a potential therapeutic approach for obesity and insulin resistance. This tissue is unique in its ability to go through hormonal mediated fast transition from efficient, ATP‐generating metabolism to inefficient, heat producing metabolism. As such, the brown adipocyte is a unique system in which the relationship between mitochondrial architecture and bioenergetics can be studied.Brown pre‐adipocyes were harvested from C57BL6/J mice and differentiated in culture. Oxygen consumption (using Seahorse XF24) and mitochondrial membrane potential (using TMRE and Zeiss LSM 710 confocal microscope) were measured before and after activation with NE (1 uM) and FFA (Plamitate or Oleate 0.4 mM).Immediately upon stimulation, mitochondrial networks underwent complete fragmentation and arrest of fusion. Fragmentation could only be achieved by beta3‐adrenergic stimulation and could not be mimicked by treatment with free fatty acids. Examination of the mitochondrial fusion proteins revealed that the long form of Opa1 was cleaved during the activation. Remarkably, within each cell, mitochondrial membrane depolarization and mitochondrial fragmentation propagated in a wave‐like fashion. To evaluate the role of mitochondrial fragmentation in energy expenditure, brown adipocytes were infected with a DRP1 dominant negative adenovirus. Inhibition of mitochondrial fission resulted in reduced levels of hormone stimulated oxygen consumption and membrane potential depolarization by 50%.Together, these data reveals that mitochondrial fission is essential for the activation of uncoupled respiration in brown adipocytes and its transition from bioenergetic efficient to inefficient metabolism.
Identification of Divergent Regulatory Mechanisms across the RGK Family of Small GTPases
Authors: Kaminski Catherine , Manning Janet R. , Magyar Janos , Shi Geng‐Xian , Sievert Gail , Satin Jonathan , Andres Doug 
Published: June 2021

The small GTPases Rem, Rem2, Rad, and Gem/Kir (RGK) potently block L‐type calcium current (ICa,L) when overexpressed. Multiple RGK proteins are expressed in excitable tissues such as the heart. This study aims to understand how RGK proteins are regulated and how they function physiologically. Analysis of cardiac hypertrophy and ICa,L in Rem and Rad knockout mice suggests separable functions for these closely related G‐proteins. As a potential regulatory mechanism, Rem phosphorylation by protein kinase D (PKD) after α‐adrenergic stimulation was reported to relieve Rem‐mediated ICa,L inhibition (Jhun BS et al. Circulation Research 2012; 110:59–70). Using phospho‐Rem and phospho‐Gem specific antibodies, we also observed PKD‐dependent phosphorylation of Rem downstream of α‐adrenergic stimuli. Interestingly, while α‐adrenergic stimulation had no effect on the phosphorylation state of Gem, robust phosphorylation of Gem was achieved downstream of β‐adrenergic stimuli and was dependent on protein kinase A. Together, these studies suggest that individual RGK proteins have divergent roles in ICa,L modulation and that distinct kinase cascades may allow differential regulation of RGK proteins for fine tuning of ICa,L control.This work was supported by the National Institutes of Health R01 HL072936 (to DAA and JS) and T32 HL072743 (to CNK).
Effect of omega‐3 fatty acid intake on homocysteine in African and Haitian Americans with type 2 diabetes
Authors: Vaccaro Joan A , Exebio Joel C , Ajabshir Sahar , Zarini Gustavo G , Huffman Fatma G 
Published: June 2021

ObjectiveHomocysteine (HCY) has been considered an independent risk factor for cardiovascular disease. The aim of the study was to assess the relationships among ethnicity, diabetes, omega‐3 fatty acid (n‐3) intake and HCY.MethodsThis was a cross‐sectional study of N=410 African (AA) (n=172) and Haitian (HA) (n=238) Americans with and without type 2 diabetes recruited from the area of Miami‐Dade and Broward counties in Florida, USA using mailing lists and community methods. Sociodemographics, anthropometrics and blood samples were collected after participants signed informed consent. All dietary variables were collected using a semi‐quantitative food frequency questionnaire.ResultsEthnicity by n‐3 intake was associated with HCY (p=.004) in an adjusted model [χ2 (10) = 30.9 (N=406) p = 0.001]. The odds of having high HCY for AA with low n‐3 intake (≥ 1.0 g/day) was [OR = 4.36 (1.59, 12.0) p = .004]. Ethnicity (p = .155), diabetes (p = .770) and diabetes by n‐3 intake (p = .965) were not significantly associated with HCY.ConclusionOmega‐3 fatty acid intake and HCY should be investigated within ethnicities to determine beneficial levels. Funding was by an NIH/NIDDK grant.
Elevated plasma C‐Reactive Protein (CRP) and low carotenoid levels are associated with increased mortality in colorectal cancer patients
Authors: Cooney Robert Vincent , Chai Weiwen , Franke Adrian A. , Caberto Christian , Wilkens Lynne R. , Kolonel Laurence N. , Custer Laurie , Morrison Cynthia , Le Marchand Loic 
Published: June 2021

ObjectiveTo determine the associations of plasma CRP and carotenoids with survival in colorectal cancer patients.MethodsUsing stored patient plasma samples from a multiethnic population‐based case‐control study of colorectal cancer, we determined associations of post‐treatment blood levels of CRP and carotenoids with survival. Patients (n = 455) were followed (mean of 8 years) after phlebotomy, during which time 20% died of colorectal cancer and 24% from other causes. Hazard ratios were estimated by Cox proportional hazards regression with adjustment for stage and age at diagnosis, ethnicity, sex, and smoking status.ResultsA strong positive association with all‐cause mortality was observed for plasma CRP (Ptrend < 0.0001). Inverse associations were seen for α‐carotene (Ptrend = 0.02), α‐cryptoxanthin (Ptrend = 0.002), lycopene (Ptrend = 0.006), and lutein/zeaxanthin (Ptrend = 0.07), whereas no significant associations were observed for the pro‐vitamin A carotenoids, β‐carotene and β‐cryptoxanthin.ConclusionsResults are consistent with a direct relationship for increased inflammation with poor survival among colorectal cancer patients. Future studies of nutritional approaches to reduce inflammation and CRP levels and increase specific carotenoids in deficient patients may be warranted as a complementary treatment strategy for colorectal cancer.
Food group consumption and its association with BMI z‐score and socioeconomic characteristics in rural school‐aged children
Authors: Choumenkovitch Silvina Furlong , McKeown Nicola M , Hyatt Raymond R , Kraak Vivica I , Cohen Juliana F W , Economos Christina D 
Published: June 2021

U.S. children's compliance with dietary recommendations varies by age, gender, and socioeconomic and weight status. We analyzed data from 1273 children (grades 1–6) participating in the Creating Healthy, Active and Nourishing Growing‐up Environments (CHANGE) study, an obesity‐prevention intervention in eight rural US communities. Children's intakes of fruits, vegetables, whole grains, protein foods and dairy were assessed using the Block Food Screener for ages 2–17 y. General linear models were used to calculate adjusted prevalence of meeting 50% of recommended whole‐grain servings and 100% of recommended servings for the other groups and to study the association between covering recommendations and weight. Prevalence of meeting dietary recommendations decreased across age groups for all food groups except fruits. Prevalence of meeting the fruit recommendations was lower in boys than girls. Hispanic children were more likely to consume recommended fruit and dairy servings, compared to black and white children, and whole grains compared to white children. BMI z‐score and prevalence of overweight and obesity was lower in children meeting recommendations for all food groups compared to children who met no recommendations (1.13 vs.0.77, P=0.02 and 39 vs. 61%, P < 0.001, respectively). Adhering to dietary recommendations varied by age, gender, race and weight status in this population of rural children.Support was provided by Save the Children's U.S. Programs.
Low retinol levels virtually undetected in coastal Guatemala: Findings from a convenience sample of women and schoolchildren
Authors: Soto‐Méndez María José , Campos Raquel , Martínez Ana Carolina , Detlefsen Michelle , Solomons Noel W 
Published: June 2021

BackgroundGuatemala was the first nation ever to mandate fortification of granulated table sugar with vitamin A. Norms specify a concentration of from 10 to 20 mg of retinol as retinyl palmitate per kg of sugar. The program has been in continuous operation since 1987.ObjectiveTo assess vitamin A status with circulating retinol concentration in a convenience sample of women and children from coastal plain of Guatemala.MethodsPlasma samples were collected from 157 adult women and 134 schoolchildren from among 12 rural communities in the sugarcane‐growing Pacific lowlands of Guatemala. Retinol concentration was determined by high precision liquid chomatography at INCAP, and values were expressed in μg/dL.ResultsThe global median retinol concentration was 52 μg/dL. The mean retinol concentration of 63±23 μg/dL for women was significantly higher than the 46±14 μg/dL in children (p<0.001). The overall distribution of retinol concentration values was: <20 μg/dL, 0%; 20–29 μg/dL, 3%; 30–49 μg/dL, 44%; 50–69 μg/dL, 37%; 70–89 μg/dL, 11%; >;90 μg/dL, 5%.ConclusionRetinol concentration in the deficient (<20 μg/dL) and low (20–29 μg/dL) ranges were virtually undetected in coastal Guatemala, related, in part, we propose to the national sugar fortification program.Funded by Cabcorp, Guatemala and the Hildegard Grunow Foundation, Munich
Breastfeeding improves biochemical control in children with phenylketonuria
Authors: O'sullivan Elizabeth , Boyle Fiona , Mehta Saurabh , Kearney John 
Published: June 2021

ObjectiveThis research sought to analyze blood levels of phenylalanine (Phe) in children with phenylketonuria (PKU) by breastfeeding status and duration.Methods173 patients with severe and moderately severe PKU born between January 1st 1994 and December 31st 2008 were retrospectively identified from the patient database of the NCIMD, Ireland. Data on duration of breastfeeding were collected from medical charts and all recorded Phe blood levels from 3 weeks to 5 years of age were accessed from patients’ digital and paper records. Data was analyzed using SAS 9.3; repeated measures modeling was used to examine the impact of breastfeeding on blood Phe levels.ResultsAll models were fitted controlling for severity of disease (moderate/severe). A significant main effect of breastfeeding was found, suggesting that infants ever breastfed had lower Phe levels than those never breastfed. Breastfeeding for a longer duration reduced Phe levels significantly more than breastfeeding for shorter durations.ConclusionsPreliminary analysis of this data indicates that breastfeeding may lower blood Phe levels in children with PKU. Additionally, there may be a dose‐response effect with longer durations of breastfeeding leading to better biochemical control.
Breastmilk and the lactating breast as a tool to elucidate breast cancer
Authors: Hassiotou Foteini , Hartmann Peter E. , Blancafort Pilar 
Published: June 2021

Mammary stem cells (MaSCs) are responsible for the normal expansion of the breast during pregnancy/lactation. MaSCs are also primary targets of malignant transformation, giving rise to invasive breast carcinomas, a subset of which display lactating features. We have recently reported expression of OCT4 and associated embryonic stem cell (ESC) genes in the normal lactating breast and breastmilk stem cells (hBSCs). This prompted us to examine OCT4 expression in breast cancers with lactating features and to compare it with that observed during normal lactation. Minimal OCT4 expression was found in the normal resting breast, whereas this significantly increased in the normal lactating breast. Further increase was found in breast tumours with lactating features. Comparison of normal hBSCs with OCT4‐overexpressing tumorigenic breast cell lines (OTBCs) showed that OTBCs had unbalanced expression of ESC genes. Similar to hBSCs, OTBCs differentiated into functional lactocytes synthesising milk proteins both in vitro and in vivo. These findings highlight ESC genes as potential regulators of the normal remodelling of the breast towards a milk‐secretory organ and of aberrant breast cell proliferation upon deregulation of their expression, suggesting a role in both normal lactation and breast oncogenesis.Grant Funding Source: Women and Infants Research Foundation; and Medela AG (Switzerland)
Plasma glutathione resettlement by oral glutamine supplementation is associated with glycine normalization in HIV+ treated patients
Authors: Burini Roberto Carlos , Borges‐Santos Maria Doroteia , Moreto Fernando , Ming‐Yu Yong 
Published: June 2021

HIV+ patients present low concentrations of reduced GSH and its precursors. To investigate the responses of the GSH pathway to Gln dietary supplements in 12 HIV+ treated patients (6 men and 6 women, 22 – 45 years old) and 20 healthy controls (Co, 10 men and 10 women, 20 – 59 years old) were studied at their usual diet (Do) and after 7‐day dietary‐supplements containing glutamine (Gln, 20g/d). Blood samples were drawn after overnight fast and HPLC plasma analysis of amino acids, total (GSH) and oxidized glutathione (GSSG) were carried out at moments before (M0) and after the intervention period (M1). Statistical comparisons were made between groups (Co X HIV+) with p<0.05. Under Do the HIV+ group showed higher GSSG along with lower concentrations of GSH and all amino acids except Hcy. Met, Gly and GSH were normalized by the dietary Gln. The 71.4% increase of GSH in Gln group at M1 was followed by the increase of its precursors markedly Gly (27.2%) and slightly by Glu (13.7%) and Cys (10.8%), nevertheless without detectable reduction in the GSSG/GSH ratio. Moreover the intervention led to an increased Tau/Cys (18.9%) and decrease of Glu/Gln (6.6%) ratios relatively to Co. In conclusion, the restoration of GSH normal levels by Gln was markedly supported by Gly replenishment. The restricted contribution of Cys and Glu to GSH generation could be due to either their limited formation (Gln→Glu) and/or higher utilization (Cys→Tau).Supported by FAPESP, CAPES, CNPq
Estimation of Dietary Vitamin K Intakes and Food Sources: Using the Korean National Health and Nutrition Examination Survey
Authors: Sohn Cheongmin , Kim Eunsu , Kim Misung , Na Woori 
Published: June 2021

It is well known that vitamin K works for blood clotting reaction and helps forming bones by boosting formation of osteoblast. Recently it has been reported that it also prevents various illnesses like type 2 diabetes, obesity and cardiovascular disorders. However, there has been insufficient development of nutrition intake tools for estimating vitamin K intakes and analyzing the amount of vitamin K intakes for Korean people. Therefore, this study aims to provide the basic data for developing tools to analyze vitamin K intakes by analyzing Koreans’ vitamin K intakes and its food sources. This study used the primitive data of the 5th the Korean National Health and Nutrition Examination Survey, and analyzed data from 8,027 subjects who participated in the survey among total 9,691 subjects of the nutrition examination survey.The vitamin K intakes were shown as 248.03±4.34 μg/day for men and 199.25±3.54 μg/day for women(p<0.001). In case of intakes for each age group, this study found 127.64±3.09 μg/day for teens, 208.10±8.67 μg/day for 20s, 264.88±7.08 μg/day for 30s, 271.63±7.68 μg/day for 40s, 294.17 ± 10.49 μg/day for 50s, 256.20±11.28 μg/day for 60s and 220.05±6.55 μg/day for 70s(p<0.001). For the contribution of vitamin K to each food group, vegetable was the highest(84.3%) and then respectively seaweed(5.5%), fruits(2.9%), seasoning(2.8%), fat and oil(2.2%), beans(1.2%). As dish sources for vitamin K, we found respectively cabbage kimchi(14.9%), seasoned spinach(9.5%), soybean past soup with dried radish greens(4.8%), rich soybean paste stew(3.9%) and gimbap(2.9%) in the order.This study found that Koreans’ average vitamin K intakes is 233 μg/day, which means that Koreans’ vitamin K intakes is relatively higher than Westerners. It is considered that such results reflect Koreans’ dietary composition which helps to frequently intake food that contains a lot of vitamin K like cabbage, spinach and radish greens as side dishes.
Metabolism of ginger component [6]‐shogaol in liver microsomes from mouse, rat, dog, monkey, and human
Authors: Soroka Dominique Nicole , Chen Huadong , Zhu Yingdong , Sang Shengmin 
Published: June 2021

[6]‐Shogaol, a major bioactive component of ginger, has been reported to have potent anti‐cancer activity. The in vitro metabolism of [6]‐shogaol was compared among five species with respect to metabolic profiles using liver microsomes from mouse (MLM), rat (RLM), dog (DLM), monkey (CyLM), and human (HLM). Following incubations with [6]‐shogaol, major reductive metabolites 1‐(4′‐hydroxy‐3′‐methoxyphenyl)‐4‐decen‐3‐ol (M6), 1‐(4′‐hydroxy‐3′‐methoxyphenyl)‐decan‐3‐ol (M9), and 1‐(4′‐ hydroxy‐3′‐methoxyphenyl)‐decan‐3‐one (M11) were found in all species. Two new oxidized metabolites of 6‐shogaol, M14 and M15, were identified as (1E,4E)‐1‐(4‐Hydroxy‐3‐ methoxyphenyl)deca‐1,4‐dien‐3‐one and (E)‐1‐(4‐Hydroxy‐3‐ methoxyphenyl)dec‐1‐en‐3‐one, respectively. The kinetic parameters of M6 in liver microsomes from each respective species were quantified using Michaelis‐Menton theory. A broad CYP450 inhibitor, 1‐aminobenzotriazole (ABT), precluded formation of oxidative metabolites M14 and M15 in HLM, and diminished oxidative metabolism in MLM, RLM, DLM, and CyLM. Additionally, 18β‐glycyrrhetinic acid, an aldo‐keto reductase (AKR) inhibitor, eradicated the formation of the reductive metabolites M6, M9, and M11 in all species. Metabolites M14 and M15 were tested for cancer cell growth inhibition and induction of apoptosis and both showed substantial activity, with M14 displaying greater potency than [6]‐shogaol.We conclude that [6]‐shogaol is metabolized extensively in mammalian species mouse, rat, dog, monkey, and human, and that there are significant interspecies differences to consider when planning pre‐clinical trials towards [6]‐shogaol chemoprevention.This work was supported by NIH grants CA138277 and CA138277S1 to S. Sang.
Agonist‐induced conformational change of the Formyl Peptide Receptors
Authors: Cooray Sadani Nandima , Clark Adrian , Flower Roderick , Perretti Mauro 
Published: June 2021

The human Formyl Peptide Receptor family (FPR1, FPR2/ALX and FPR3) belongs to the superfamily of class A GPCRs and is responsive to a variety of agonists. ALX is the first GPCR known to be able to bind to both peptides and lipids and transduce both pro and anti‐inflammatory cellular responses. To investigate the versatility and potential ligand biased agonism of ALX, we explored the possibility that FPRs may exist as dimeric structures and tested whether these interactions may be modulated by different ligands. We used a combination of the co‐immunoprecipitation (co‐IP) technique and Bioluminescence Resonance Energy Transfer (BRET) in HEK293 cells transfected with epitope tagged receptors. We show that FPRs are constitutively dimerised and reveal opposing effects on the BRET signal between the ALX homodimers in response to the anti‐inflammatory (AnxA1 and LXA4) and proinflammatory (SAA) agonists. The pan agonist Ac2–26 enhanced the BRET signal only when ALX was expressed, alone or together with FPR1. We conclude that ALX can adopt a ligand‐directed conformation upon application of pro‐resolving agonists leading to specific intracellular signalling. Our findings indicate that agonist binding, activation of signalling molecules as well as the dimerisation state of the receptors may contribute to the conformational landscape of the FPRs.Support: Wellcome Trust (Programme 08667/Z/08/Z)
Heparanase upregulation in the inflammatory airway facilitates syndecan shedding and sustained inflammation
Authors: Wu Lap Kei Kenneth , Chan Stanley CH , Ip Mary SM , Shum Daisy KY 
Published: June 2021

Shed syndecan‐1 and neutrophil elastase forms anti‐elastase resistant complexes in the airway fluids. This is thought to be the cause of airway damage and deteriorating lung function in COPD and bronchiectasis. We aim to develop strategies to decrease syndecan‐1 shedding for the treatment of COPD and bronchiectasis.Elevated levels of heparanse but not matrix metalloproteinase‐7 (MMP‐7) in sputum samples of such patients suggested that the action of the GAG digesting enzyme heparanase modifies syndecan‐1 to become more susceptible to shedding by MMP‐7 cleavage.We show in vitro that heparanase induced syndecan‐1 shedding in cultured human epithelial cells, and that heparanase‐treated recombinant syndecan‐1 was more readily cleaved by MMP‐7 than control treatment of the recombinant syndecan‐1. Surface plasmon resonance analysis demonstrated an increase in affinity of syndecan‐1 for MMP‐7 upon heparanse treatment. Co‐immunoprecipitation study targeting syndecan‐1 found associated MMP‐7, significantly higher in the sputum samples of bronchiectasis and COPD patients than in induced sputum of healthy individuals. The results support that heparanase activity in the inflammatory airway environment enhances shedding of syndecan‐1 and thus a target for the treatment of bronchiectasis and COPD. This work is supported by the HKRGC.
Increased plasma ammonia concentration contributes to methamphetamine‐induced blood‐brain barrier damage
Authors: Northrop Nicole Alia , Halpin Laura E , Yamamoto Bryan K 
Published: June 2021

Recently our lab has shown that the psychostimulant, methamphetamine (Meth), produces liver damage. In models of acute liver failure, increases in plasma ammonia mediate brain edema and disruption of tight junction proteins of the blood‐brain barrier (BBB). Neurotoxic doses of Meth that produce liver damage also disrupt the structure and function of tight junction proteins, occludin and claudin‐5. Therefore, we hypothesized that Meth‐induced increases in plasma ammonia will disrupt BBB structure and function. A neurotoxic Meth regimen (10 mg/kg, ip, q 2hr, ×4) produced an 86±12% increase in plasma ammonia 2 hr after the last Meth injection, compared to saline treated controls. Pretreatment with lactulose (5.3 g/kg, po, q 12hr), a drug that increases the excretion of ammonia, prevented these increases. Meth significantly decreased expression of occludin by 51±8% and claudin‐5 by 51±7%, and increased BBB permeability as measured by FITC‐dextran extravasation, compared to saline treated controls 24 hr after treatment. Meth‐induced BBB disruption was prevented by lactulose pretreatment. These data indicate that Meth‐induced increases in plasma ammonia contribute to the disruption of BBB structure and function. These findings identify a novel mechanism through which Meth disrupts the BBB and a novel consequence of Meth‐induced liver damage.Supported by NIH DA07606.