bluuebunny/crossref_metadata_2025_split huggingface dataset:
The nuclear receptor cochaperone FKBP51 is required for diet‐induced visceral adiposity
Authors: Stechschulte Lance Alan , Warrier Manya , Hinds Terry D. , Sanchez Edwin R. 
Published: June 2021

Nuclear receptors are hormone‐regulated transcription factors that form heterocomplexes with Hsp90 and several cochaperones, including FK506‐binding protein‐51 (FKBP51), FKBP52, PP5, and Cyp40. We have evidence that loss of FKBP51 increases glucocorticoid receptor (GR) and decreases peroxisome proliferator‐activated receptor‐γ (PPARγ) transcriptional activity. In this study, we investigate the hypothesis that loss of FKBP51 leads to reciprocal dysregulation of GR and PPARγ, thereby increasing the expression of genes regulating lipid oxidation and/or energy expenditure. FKBP51‐KO mice were subjected to a high fat diet, compared to wild‐type mice, FKBP51‐KO animals were resistant to diet‐induced obesity, with reduced visceral adiposity, serum triglyceride, and free fatty acids. Food consumption, insulin secretion and clearance, and hepatic lipid accumulation were unchanged. Gene profiling of adipose showed elevated expression of thermogenic genes in the KO mice. In vitro adipogenesis studies showed FKBP51‐KO cells to be highly resistant to differentiation and lipid accumulation. The phosphorylation states of GR were tested using phospho‐specific antibodies for serines 212, 220 and 234 – the major sites of hormone‐induced phosphorylation. Results show FKBP51 controls GR phosphorylation at serines 220 and 234. These investigations have uncovered FKBP51 as a key regulator of adipogenesis and thermogenesis and may serve as a new drug target in the treatment of obesity and related disorders.Supported by NIH grant DK70127 to E.R.S.
Modulation of Gastrointestinal Function by MuDelta, a mixed Mu Opioid Receptor Agonist/Delta Opioid Receptor Antagonist
Authors: Hornby Pamela J 
Published: June 2021

Background & PurposeLoperamide is a selective mu (μ) opioid receptor (OR) agonist acting locally in the gastrointestinal (GI) tract as an effective anti‐diarrheal, but can result in ‘rebound’ constipation. We tested whether modulating μOR agonism with δOR antagonism, by combining reference compounds or using a novel compound (“MuDelta”), could normalize GI motility without constipation.Experimental approachMuDelta was characterized in vitro as a potent μOR agonist and high affinity δOR antagonist. Compounds were assessed in guinea pig intestinal smooth muscle contractility and mouse intestinal epithelial ion transport. Colonic δOR immunoreactivity was quantified. MuDelta and loperamide were evaluated for upper GI transit, entire GI transit or fecal output in novel environment stressed mice, or four weeks after intracolonic mustard oil.Key ResultsδOR antagonism opposed μOR agonism in isolated intestinal and in vivo motility assays. Stress up‐regulated δOR expression in colonic epithelial cells. MuDelta reduced contractility in intestinal tissue similar to combined μOR agonists and δOR antagonists, and inhibited neurogenically‐mediated secretion. Very low plasma levels of MuDelta were detected after oral administration. In stressed mice, MuDelta normalized GI transit and fecal output to control levels over a wide dose range up to 100 mg/kg p.o, whereas loperamide completely prevented these at 10 mg/kg. MuDelta also reduced upper GI transit in the post‐inflammatory model.Conclusions and ImplicationsMixed μOR agonism/δOR antagonism normalizes, but does not prevent, perturbed GI transit over a wide dose‐range in mice. These data support the assessment of MuDelta in clinical trials in patients with diarrhea‐predominant irritable bowel syndrome.
Tissue concentrations of Doxorubicin and Doxorubicinol 24 and 96 hours following injection in the rat
Authors: Chenard Pam , Fabris Sergio , MacLean David 
Published: June 2021

Doxorubicin (DOX) is an anti‐cancer chemotherapeutic and although widely used, its accumulation over time in different tissues has not been thoroughly investigated. The purpose of this study was to examine the concentration of both DOX and its metabolite, doxrubicinol (DOXol) in liver and heart tissue of rats. Two doses (1.5 mg/kg and 4.5 mg/kg) were injected intraperitoneally and tissue samples were collected either 24 or 96 hrs post‐injection. In all tissues DOX and DOXol were elevated (P<0.05) as compared to control at all time points. In both heart and liver the concentration of DOX was higher (P<0.05) following the 4.5 mg/kg as compared to the 1.5 mg/kg dose at 24 and 96 hrs. Heart tissue DOX concentrations decreased (P<0.05) from 0.8±0.1 and 1.8±0.3nmol/g at 24 hrs to 0.4±0.01 and 1.0±0.1 nmol/g at 96 hrs, for the 1.5 and 4.5 mg/kg dose, respectively. Similarly, liver DOX levels decreased (P<0.05) from 3.9±1.1 and 5.3±0.9nmol/g at 24 hrs to 0.6±0.1 and 3.2±0.4 nmol/g at 96 hrs, for the 1.5 and 4.5 mg/kg dose, respectively. DOXol was detectable in all tissues at all time points, however its concentration was lower (P<0.05) than that of DOX. Overall, both heart and liver responded in a dose dependant fashion to the injections of DOX. Furthermore, the accumulation of the drug and its cardiotoxic metabolite decreased over time suggesting that either the drug is rapidly metabolized and/or eliminated or stored in tissues other than the heart and liver.Supported by NSERC.
A potential acute renal failure marker of MicroRNA494 modulates expression of the inducible transcription factor ATF3 and affects kidney function in a mice model of ischemia reperfusion
Authors: Lan Yi-Fan , Lai Pei Fang , Lin Heng 
Published: June 2021

BackgroundPrevious reports have shown ATF3 plays a protective role in acute renal failure, ischemia/reperfusion (I/R) injury. The aim of this study was to analyze the potential regulation of ATF3 expression by microRNAs.Methods and ResultsIn this study, we demonstrated that miR‐494 target 3′ untranslated region of ATF3 reporter and decreased ATF3 mRNA expression by reporter assay and molecular analysis. Overexpression lenti‐miR‐494 in mice kidney was significantly attenuate ATF3 mRNA and protein, accompany with I/R induced inflammatory related factor include IL‐6, MCP‐1, P‐selectin resulting cells apoptosis and renal function decreased. Importantly, the mice urinary miR‐494 was increased significantly earlier than serum creatinine after renal I/R. In clinical, the urinary miR‐494 expression was higher in acute kidney injury (AKI) patients than patients with no AKI and normal. Besides, we also find the increasing level of miR‐494 in urine of AKI is consistent with two of comparator AKI biomarker gelatinase‐associated lipocalin (NGAL) and cystatin C.ConclusionThese data suggest that up‐regulation of miR‐494 contributes to inflammatory factor or adhesion molecule induced kidney injury after I/R via inhibition ATF3 expression and miR‐494 may act as an early specific and non‐invasive biomarker in AKI. The source of research supported from National Science Council (Taiwan).
Effects of Electroacupuncture and Moxabusrion in the Progression of Renal Disease in Rats
Authors: Paterno Josne Carla , Bergamaschi Cassia toledo , Campos Ruy Ribeiro , Oliveira-Sales Elisabeth B , Teixeira Vicente Paulo Castro 
Published: June 2021

Traditional Chinese Medicine (TCM) has been increasingly recognized as an effective therapeutic approach in several fields of medicine. Among its therapeutic strategies are electroacunpucture (EA) and moxibustion (MO). The aim of this study was to investigate the renal and hemodynamic effects of EA‐MO in an experimental model of PDR in rats. Male wistar rats were submitted to 5/6 nephrectomy (5/6 nx) for eight weeks and divided in three groups. Control (NX); Sham‐EA‐MO (NX‐AS): 5/6 nx and EA‐MO session in sham‐points; and EA‐MO (NX‐AM): 5/6 nx and EA‐MO session in real points. Biochemical studies, blood pressure (MAP) and renal sympathetic nerve activity (RSNA) measurement and Nitric Oxide Levels (NO) were assessed.

Groups
24hproteinuria (mg/24h)
MAP (mmHg)
Serum NO (μM)
RSNA (Hz)

NX
153,86±22,93
181,23±20,01
65,02±13,75
207,11±41,82

NXAS
159,37±43,98
174,25±12,17
59,93±14,93
176,52±19,32

NXAM
75,30±8,30*
121,67±15,52*
162,92±42,19*
129,66±10,31*

(p<0,05: * vs NX, NX‐AS)

Our results suggest that EA‐MO had a benefic effects by the modulation of RSNA and increase NO levels, which contribute to the hypotensive effects and attenuated the PDR in the experimental model of 5/6 nephrectomy.Supported by CNPq
Biochemical analysis of the human mismatch repair proteins hMutSalpha MSH2G674A‐MSH6 and MSH2‐MSH6T1219D
Authors: Geng Hui , Sakato Miho , DeRocco Vanessa , Yamane Kazuhiko , Du Chunwei , Erie Dorothy A. , Hingorani Manju , Hsieh Peggy 
Published: June 2021

The human MutSalpha protein, a heterodimer between MSH2 and MSH6, initiates DNA mismatch repair (MMR) by recognizing mismatched bases that result from replication errors. Msh2G674A or Msh6T1217D mice that have mutations in or near the ATP binding site of MSH2 or ATP hydrolysis catalytic site of MSH6, respectively, develop cancer and have reduced lifespan due to loss of the MMR pathway. Mouse embryonic fibroblasts from these mice retain an apoptotic response to DNA damage.Mutant human MutSa proteins, MSH2G674A‐MSH6wt and MSH2wt‐MSH6T1219D, are profiled in a variety of functional assays and, as expected, fail to support MMR in vitro, although they retain mismatch recognition activity. Kinetic analyses of DNA binding and ATPase activities and examination of the excision step of MMR reveal that the two mutants differ in their underlying molecular defects. MSH2wt‐MSH6T1219D fails to couple nucleotide binding and mismatch recognition; whereas, MSH2G674A‐MSH6wt has a partial defect in nucleotide binding. Nevertheless, both mutant proteins remain bound to the mismatch and fail to promote efficient excision thereby inhibiting MMR in vitro in a dominant manner. Our findings highlight differences in the molecular defects of the G674A and T1219D mutant MutSalpha proteins and provide a basis for thinking about how they might mediate the apoptotic response to certain DNA damaging agents.
Down‐Regulation of Replication Factor C‐40 (RFC40) causes chromosomal missegregation in neonatal and hypertrophic adult rat cardiac myocytes
Authors: Ata Hirotaka , Shrestha Deepa , Oka Masahiko , Ochi Rikuo , Jong Chian Ju , Gebb Sarah , Benjamin John , Schaffer Stephen , Hobart Holly , Downey James , McMurtry Ivan , Gupte Rakhee 
Published: June 2021

BackgroundAdult mammalian cardiac myocytes (CMs) are generally assumed to be terminally differentiated, nonetheless, a small fraction of CMs have been shown to replicate during ventricular remodeling. However, the expression of Replication Factor C (RFC; RFC140/40/38/37/36) protein that is required for DNA synthesis, in the adult normal and hypertrophied hearts has rarely been studied.MethodsWe performed qRT‐PCR, Western blot analysis and immunohistochemical analysis to determine the levels of RFC message and protein in adult normal and pulmonary arterial hypertension induced right ventricular hypertrophied hearts. We determined chromosomal missegregation using Fluorescent in situ hybridization (FISH) for rat chromosome 12.ResultsRFC40 message and protein increased marginally in the hypertrophied hearts as compared to the fetal hearts. Immunohistochemical analyses revealed RFC40, cyclin A, phospho‐Aurora A/B/C kinase and phosphohistone 3 positive right ventricular CMs. FISH analyses demonstrated chromosomal missegregation in these hearts. Knock‐down of RFC40 caused chromosomal missegregation and decrease in the rat neonatal CM numbers.ConclusionOur novel findings suggest that insufficient re‐expression of RFC40 may be responsible for causing chromosomal missegregation in CMs during right ventricular hypertrophy.
CDK1 differentially regulates G‐overhang generation at leading and lagging telomeres
Authors: Dai Xueyu , Huang Chenhui , Chai Weihang 
Published: June 2021

Mammalian telomeres contain a single‐stranded 3′ overhang (G‐overhang) that functions in telomere end protection and telomerase action. Previously we have demonstrated that G‐overhang length undergoes cell cycle‐regulated dynamics that is controlled by multiple steps involving C‐strand end resection, telomerase elongation, and C‐strand fill‐in. The objective of this study is to understand the mechanism regulating these steps. Here we report that in both telomerase positive and negative cells, C‐strand fill‐in takes place at lagging daughter telomeres but not at leading daughter telomeres. We also identified a second end resection step in the G2 phase at leading daughter telomeres. Using inhibitors and RNAi, we show that Cdk1 functions in G‐overhang generation. Further study reveals that CDK1 controls both C‐strand fill‐in and end resection. In addition, we find that DNA polymerase alpha (Polα) association with telomeres is elevated upon CDK1 inhibition, suggesting that CDK1 may modulate the synthesis activity of Polα rather than control the loading of Polα to telomeres. Stn1, a subunit of the Ctc1/Stn1/Ten1 complex that plays a role in telomere protection, functions in the same pathway with CDK1 during fill‐in. In summary, we propose that there are different steps for G‐overhang generation at leading and lagging telomeres, and CDK1 regulates these steps.Supported by “NIH R15GM099008”
Palm Fruit Juice phenolics reduce the number of mutations caused by 3′‐Azido‐3′‐deoxythymidine treatment in a cultured human cell line
Authors: Osborne Adam , Stopa Arielle , Solomon Martha , Wangh Lawrence , Hayes Kenneth C 
Published: June 2021

3′‐Azido‐3′‐deoxythymidine (AZT), used to treat HIV/AIDS, has been shown to cause mitochondrial dysfunction over time. How this dysfunction develops and its relation to long‐term adverse side effects of treatment, that include diabetes and Alzheimer's disease, is not known. One hypothesis is that AZT causes mutations in mitochondrial DNA (mtDNA) that build up over time, and that these mutations lead to mitochondrial dysfunction and disease. A broadly applicable approach to detect mutations without sequencing was developed using a LATE‐PCR Lights‐On/Lights‐ Off multiplex assay. The study objective tested whether AZT increases mitochondrial DNA mutations over time and whether palm fruit juice (PFJ) would reduce this damage. PFJ contains phenolics that might act to reduce the amount of reactive oxygen species, which are mutagenic to mtDNA. Three gene targets, HV2, CO2, and ND1, from the mitochondria of HepG2 cells were studied to assess AZT‐induced mutations in cell culture. Initial results revealed that AZT treatment for 30 days induced up to a 9‐ fold increase in mutations in all three target genes compared to normal culture media. When palm fruit juice was added with AZT, mutations decreased by 35% versus AZT alone. These results provide insight into how AZT damages mtDNA and suggest a possible way to ameliorate AZT effects in patients.This work was supported by a grant from the Malaysian Palm Oil Board.
Synergistic Effects of Digitoxin Analogues in Combination with Chemotherapeutic Drugs
Authors: Hinds John William , McKenna Sean 
Published: June 2021

Digitoxin is a cardiotonic agent that has traditionally been used as a treatment of congestive heart failure. Recently, it has been acknowledged for its potential in cancer treatment.[1–3] We have characterized a digitoxin‐glycoside, which is believed to express its cytotoxic effect through inhibition of the Na+/K+‐ATPase pump. This inhibition of Na+/K+ exchange by digitoxin is believed to induce apoptosis or programmed cell death selectively in cancer cells via Src‐tyrosine kinase.[4]In previous studies we have synthesized various digitoxin analogues focusing on the stereochemical effects of the C3′/C4′ stereocenters. From this research we identified our lead analogue, α‐L‐rhamno 1.[5] In this study we aim to further the scientific understanding of α‐L‐rhamno 1 and its synergistic effects with other chemotherapeutic agents. The study was conducted on several cancer cell lines using MTT assays to measure cytotoxic effect and to generate dose‐response curves. The drugs chosen to be tested for synergistic or antagonistic effects were selected based on their widely varying mechanisms of action, and conventional use in chemotherapy. These drugs include camptothecin, doxorubicin, oxaliplatin, and 5‐fluorouracil.
Associations between nutritional status of micronutrients and the growth, body composition and biomarkers of metabolic risk in Chilean children
Authors: de Romana Daniel Lopez , Corvalan Camila , Uauy Ricardo , Cediel Gustavo , Duran Gabriela , Palomino Ana Maria 
Published: June 2021

IntroductionThe associations between micronutrients and obesity and/or chronic diseases are not consistent.MethodsCross‐sectional study of 300, 8–11 y children. The following measurements were obtained: 1) Anthropometry: weight (wt), height (ht), zBMI; 2) Body composition: % body fat; 3) Biomarkers metabolic risk: insulin, glucose, serum lipids, adiponectin, leptin; 4) Micronutrient indicators: hemoglobin (hb), serum ferritin (SF), serum transferrin receptors (TfR), hepcidin, plasma zinc (ZnPl) and serum VD concentrations (25OHD).Results26% of children were overweight and 29% obese. None of the children were anemic or Zn deficient. 4% were Fe deficient and 28% VD deficient. No associations were found between FS or 25OHD and either wt, ht, % fat or metabolic risk indicators. A significant direct association was observed between TfR and Wt (r 0.24), ht (r 0.14), zBMI (r 0.25), % body fat (r 0.22). Significant correlations were found between hepcidin and both wt (r −0.12) and zBMI (r −0.12). ZnPl correlated with % body fat (r 0.12) and insulin (r −0.20). No significant differences in Hb, SF, hepcidin or 25OHD were found between obese (Ob) and non‐obese children. Both TfR and ZnPl were significantly higher in Ob children.ConclusionsVitamin D status is not associated to Ht, % body fat or biomarkers of metabolic risk. Ob children had higher ZnPl and TfR concentrations than N children.Source of funding: FONDECYT research grants 1090252, 1100206 and 1110085.
Effectiveness of ¡Pilas!, a community‐based pilot intervention for chronic disease prevention in Guatemalan school‐age children
Authors: Chacon Ana Violeta , Letona Paola , Ramirez‐Zea Manuel , Gittelsohn Joel , Caballero Benjamin 
Published: June 2021

BackgroundChildhood obesity is increasing in Guatemala. Culturally appropriate interventions to promote healthy lifestyles in school‐age children are needed to prevent future chronic disease.ObjectiveTo assess short‐term effectiveness of a school and community‐based intervention ¡Pilas! that promotes healthy eating, physical activity (PA), and discourages alcohol and tobacco use in Guatemalan children.MethodsThis was a pre/post‐test, single sample study involving 119 children (aged 10–12 yrs) in two public schools in a poor urban area. The 17 week intervention had three components: school, food kiosk, and community. We measured knowledge, attitudes, self‐efficacy, dietary intake (24‐h food list measuring average times/day) and PA (steps/day and min/d at of moderate‐vigorous PA).ResultsChildren increased their knowledge and self‐efficacy for healthy eating (p<0.01). PA knowledge, attitudes and self‐efficacy (p<0.01) also increased. Sweet‐beverage (from 0.74 to 0.64, p<0.01) and processed food intake (from 2.71 to 2.64, p=0.04) decreased. Self‐efficacy for avoiding alcohol and tobacco use increased (p<0.01). The intervention did not increase PA.ConclusionsThe intervention may improve psychosocial factors related to healthy eating, PA, alcohol and tobacco use in children. A randomized controlled trial is needed to assess a longer intervention with stronger PA strategies.Grant Funding Source: NHLBI‐HHSN 268200900028C
A case study: Nutrition and Physical Activity Environments of Public Childcare Centers in Korea, Sweden, and US
Authors: Kim Juhee , Jackson Natalie , Elinder Liselotte Schäfer , Singhru Deepa , Olsson Linnea , Bremberg Sven , Kim Keunsei 
Published: June 2021

ObjectivesTo compare nutrition and physical activity environments in public childcare centers across nations; we conducted a case study in Korea, Sweden, and US.MethodsThe Nutrition and Physical Activity Self‐Assessment for Child Care questionnaire was filled out by a childcare director from conveniently sampled public childcare centers from high‐ and low‐income areas in each nation (2 sites per nation).ResultsA greater variability was seen in physical activity than in nutrition in all three nations. All nations need to improve the “Education for Staff’ in nutrition and physical activity. Overall, Sweden's low‐income site received the lowest total score at 43.0; whilst the US's high‐income site scored the highest at 53.1. The US showed the largest disparity between the low‐and high income (43.7 and 53.1); whereas Korean sites showed similar scores (47.5 and 47.6).ConclusionThe findings have limited interpretations because of a convenient sampling; however, there are areas to improve nutrition and physical activity‐related practices and policies, regardless of nations. Further, this study demonstrated feasibility to conduct an international comparison study. (Funding: National Research Foundation of Korea Grant (NRF‐2011–330‐B00190), European Union Center Grant & INSPIRE Grant at University of Illinois.)
Increased Gut Microbiome Diversity Following a High Fiber Mediterranean Style Diet
Authors: Steinle Nanette , Cirimotch Shana , Ryan Kathy , Fraser Claire , Shuldiner Alan , Mongodin Emmanuel 
Published: June 2021

We investigated the effects of a Mediterranean style diet on the composition of the gut microbiome, and on fasting lipids. Nine men and women age 50–65 years with BMIs 25–35 kg/m2 and with impaired fasting glucose collected fecal samples during a 2‐week run‐in period, and after the 2‐week calorically‐neutral diet intervention, and provided blood for the analysis of fasting lipids. Bacterial RNA was extracted from pre and post intervention fecal samples, and 454 pyrosequencing of 16S rRNA transcripts (as cDNA) was performed. We sequenced 391,870 high‐quality 16S reads. There was a mean 14% decrease in triglyceride levels (180.8 mg/dl vs 156.8 mg/dl; SD = ± 57.5, p= 0.25), and a mean 12% decrease in LDL cholesterol levels (157.8 mg/dl vs 139.2 mg/dl; SD = ± 16.4, p= 0.009). We observed clustering of individuals’ microbial profiles; (e.g. each microbiome appears to be unique, and within each individual cluster, pre‐diet datapoints cluster separately from post diet datapoints). The number of species‐level operational taxonomic units increased following the diet intervention (+9.64% on average); richness as calculated by the Chao1 (+8.22%) and Ace estimates (+6.37%) increased, as well as the Simpson diversity index (+34%). Ongoing studies focus on identifying which specific group of microbes is responsible for this increase in diversity and their associations with metabolic and inflammatory markers.Grant Funding Source: P30 DK072488 and the Dry Bean Health Research Program