bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ginkgo biloba extract potentiates human vitamin D receptor‐mediated increase in CYP2B6 reporter activity by 1α,25‐dihydroxyvitamin D3 (1141.8)
Authors: Lau Aik Jiang , Chang Thomas 
Published: June 2021

Vitamin D receptor (VDR) regulates the expression of a broad array of genes, including those involved in drug biotransformation (e.g. CYP2B6). Ginkgo biloba extract induces CYP2B6, but it is not known whether it activates VDR. Therefore, we characterized the effect of G. biloba extract on human VDR (hVDR) activity. As assessed in a cell‐based dual‐luciferase reporter gene assay, G. biloba extract did not activate hVDR in cells transfected with a hVDR expression plasmid and a CYP2B6‐PBREM/XREM reporter plasmid. In contrast, 1α,25‐dihydroxyvitamin D3, which is a hVDR agonist, increased it by 16‐fold compared to the vehicle‐treated group. The combination of G. biloba extract and 1α,25‐dihydroxyvitamin D3 further increased hVDR activity by another 14‐fold (i.e. 225‐fold increase compared to the vehicle‐treated group). This potentiation effect was evident in multiple lots of G. biloba extract and with other VDR agonists (i.e. lithocholic acid and 9‐cis retinoic acid), and it increased as the concentration of the extract or 1α,25‐dihydroxyvitamin D3 increased. In contrast, the potentiation did not occur when cells were transfected with a plasmid expressing human constitutive androstane receptor, human pregnane X receptor, or mouse VDR. Overall, the findings indicate that G. biloba extract potentiates hVDR‐mediated CYP2B6 reporter activity.Grant Funding Source: Supported by the Canadian Institutes of Health Research and Michael Smith Fdn. for Health Res.
Mobilization of bone marrow stem/progenitor cells by AMD3100 or G‐CSF is impaired in diabetes (1142.4)
Authors: Vasam Goutham , Bartelmez Stephen , Jarajapu Yagna 
Published: June 2021

The success of autologous cell therapies for the treatment of cardiovascular disease in patients with diabetes is dependent on mobilization of bone marrow derived stem/progenitor cells (BMSPCs). We tested the efficacy of bone marrow (BM) mobilizing agents in experimental diabetes. Mice with Streptozotocin‐induced type 1 diabetes were used either at 14 (short‐term, D‐ST) or 22 (long‐term, D‐LT) weeks of diabetes with respective age‐matched controls. BM‐derived stem/progenitor cells (BMSPCs), Sca‐1+ or c‐Kit+ subsets of lineage‐negative cells (LS, LK and LSK), in peripheral blood were enumerated by flow cytometry before and after administration of AMD3100 (5 mg/Kg, s.c.) or G‐CSF (125 mcg/Kg, s.c., twice a day for four days). Basal levels of LK and LSK cells in PB were decreased in both D‐ST and D‐LT compared to age‐matched controls (Ctrl, P<0.005). LS, LK and LSK were increased by AMD3100 or G‐CSF in D‐ST. In D‐ST group, mobilization of BMSPCs by AMD3100 or G‐CSF was similar to that in controls. In D‐LT group mobilization of all three subsets of BMSPCs by AMD3100 or G‐CSF was attenuated compared to the control group (P<0.005 or P<0.001, respectively). The number of SPCs in BM and the in vitro proliferation of BM‐LS cells were decreased in D‐LT (P<0.001 vs control). These results suggest that long‐term diabetes is associated with impaired mobilization of BMSPCs to clinically used mobilizers, decreased proliferative potential and reduced number of resident BMSPCs.Grant Funding Source: Supported by NIH (P30 GM103332‐01) and AACP‐NIA
Identification of a urinary cyclized metformin‐methylglyoxal metabolite in metformin‐treated diabetes patients (1142.9)
Authors: Kinsky Owen , Anumol Tarun , Hargraves Tiffanie , Snyder Shane , Monks Terrence , Lau Serrine 
Published: June 2021

Reactive dicarbonyls such as methylglyoxal (MG) are elevated in type‐2 diabetes mellitus (T2DM) patients and their ability to covalently modify proteins contributes to diabetic complications. The T2DM first‐line drug metformin (MF) significantly reduces diabetes‐related endpoints and mortality more effectively than other glucose‐lowering medications. We have examined whether, in addition to its ability to reduce hepatic gluconeogenesis, MF directly scavenges dicarbonyls as an additional mechanism to reduce T2DM complications. We synthesized a MF/MG cyclized product (183 mw) according to a published method, and characterized the product by ESI‐MS/MS mass spectrometry (MH+, 184 m/z; Agilent 6490) and 13C and 1H NMR (Bruker AVIII‐400). Using an LC‐MS‐based multiple reaction monitoring analysis we measured MF and cyclized metabolite (CM) in human urine with nM sensitivity of detection. The CM was detected in all 30+ MF‐treated T2DM subjects analyzed to date. Quantitation of CM in MF subjects is ongoing, using creatinine or specific gravity normalization. Correlations between CM levels and diabetic complications will be determined. The data reveal that urine from every T2DM patient treated with MF contains this MG scavenging product. The role of the CM in the reduction of diabetic complications warrants further study.Grant Funding Source: Supported by DK090958, ABRC, ES016652, T32ES007091, P30ES006694.
Andrographolide downregulates pro‐inflammatory cytokines and free radical productions to prevent dopaminergic neuro‐degeneration induced by lipopolysaccharide (1143.16)
Authors: Sani Dahiru , Ramli Noorlela , Kirby Brian , Sumon Shariful , Basri Hamidon , Stanslas Johnson 
Published: June 2021

Oxidative stress and inflammation triggers the production of free radicals and toxic pro‐inflammatory cytokines leading to neurodegeneration. Down‐regulation of oxidative stress and inflammatory mediators offers defence against development and progression of the disease. Andrographolide is the most abundant diterpene lactone isolated from the leaves of Andrographis paniculata. Despite the increasing literature studies on the anti‐inflammatory effect of andrographolide, there is still paucity regarding its neuroprotective role as can be ascertained from the search of literature. The present study investigated the potential therapeutic role of andrographolide as a neuroprotective agent via in vitro model of lipopolysaccharide (LPS)‐induced brain injury using microglial (BV2) and dopaminergic (N27) cells. Pre‐treatment of andrographolide at non‐cytotoxic concentration range (0.25‐2.0 µM) of BV2 cells followed by LPS dose‐dependently suppressed nitric oxide production, pro‐inflammatory cytokines (TNF‐α, IL‐6) as well as attenuating intracellular reactive oxygen species (ROS) and thiobarbituric acid reactive substance (TBARS) compared to cells without andrographolide pretreatment. Further, conditioned media (CM) of the pretreatment had diminished toxicity towards dopaminergic neurons as compared to CM without pretreatment.Grant Funding Source: The Malaysian Ministry of Agriculture through NRGS grant allocation (NH0612D009)
Ultrasonic bone stimulation increases orthostatic tolerance after 24 hours of bed rest (1171.6)
Authors: Ray Chester , Sauder Charity , Dyckman Damian 
Published: June 2021

Our studies indicate that stimulation of the otolith organs by gravitational (head‐down rotation) and non‐gravitational (ultrasonic bone stimulation of mastoid; UBS) activation increases muscle sympathetic activity in humans. These findings suggest that otolith stimulation might assist in maintaining vascular resistance and arterial blood pressure during orthostatic challenges. To test this hypothesis, 16 subjects were placed in head‐down bed rest for 24 hours and then tested twice with an 80° head‐up tilt test once with and without UBS. The order of the two tilt tests was randomized with a maximum test duration of 30 min. Eight subjects were able to complete both tests after bed rest. In the remaining 8 subjects (2 M, 6 F, 26 ± 2 yr, 172.4 ± 3.0 cm, 74.6 ± 5.8 kg) who could not complete the tilt tests, tilt time was significantly greater in 7 of the 8 subjects with UBS compared to without (743 ± 180 vs. 574 ± 158 s, P = 0.002). Mean arterial pressure was 60±6 mmHg at the stoppage of the control tilt test and 90±5 mmHg at the same time point during UBS trial (P = 0.006). However, heart rate was unaffected by UBS during head‐up tilt (95 ± 5 and 93 ± 11 bpm for UBS and control, respectively). These findings indicate that UBS can improve orthostatic tolerance in subjects following bed rest. Similar results might be expected in subjects that experience orthostatic intolerance due to other reasons.Grant Funding Source: Supported by NIH (HL109952), NSBRI (CA00404)
Transitioning to eupnea during the first hour after birth in term and preterm mice (1177.6)
Authors: Koschnitzky Jenna , Youngquist Tiffany , Smith Charles , Ramirez Jan‐Marino 
Published: June 2021

We used lipopolysaccharide (LPS) to induce cytokine‐mediated inflammation and preterm labor. Dams injected with LPS gave birth on G18.5, one day early. Saline injected dams either gave birth at term (G19.5) or had a c‐section (C‐S) on G18.5. Breathing and cardiac function were then assessed <10 and >60 min. after birth. C‐S preterm and term animals had high survival rates (~94%). LPS preterm animals had low survival rates (43%). Survival corresponded with a fast transition from a low frequency, high tidal volume, long duration ('large') breath pattern to a eupneic pattern. Non‐survivors failed to make the transition. Heart rate was directly related to breathing rate and correlated with survival. However, cardiac activity continued after non‐survivors took their last breath indicating that respiratory, not cardiac, failure was the primary cause of death. A subset of animals that did not transition to a eupneic pattern were administered caffeine. Caffeine improved survival outcomes, however, after an anoxic bout these animals had delayed heart and breathing rate recovery times. In conclusion, LPS‐mediated preterm birth increases mortality rates. This is due to a failure to transition from an initial 'large' respiratory pattern to a eupneic pattern and may correspond with an inability to alter network dynamics when transitioning from a low to high oxygen environment.Grant Funding Source: Supported by Seattle Children's Hospital Inter‐Center Funds
Recovery of respiratory motor function after repeated exposure to intermittent hypoxia in mice genetically depleted of brain serotonin (1178.8)
Authors: Mateika Jason , Richardson Chelsea , Solarewicz Julia , Angoa‐Perez Mariana , Nantwi Kwaku , Kuhn Donald 
Published: June 2021

Purpose: Our study was designed to determine if daily exposure to intermittent hypoxia (IH) promotes recovery of respiratory motor function in mice following spinal cord hemisection and to determine if serotonin in the central nervous system is required to induce this process.Methods: Telemetry transmitters were surgically implanted in 9 wild type mice (Tph2+/+) and 6 tryptophan hydroxylase 2 knockout mice (Tph2‐/‐) to measure electroencephalography, core body temperature and activity. Thereafter, a C2 hemisection was completed. Following recovery mice were exposed to 12 ‐ 4 minute episodes of hypoxia (10% oxygen) for 10 consecutive days while measures of ventilation were monitored via whole body plethysmography.Results: Following 10 days of exposure to IH, tidal volume (VT) and ventilatory drive (VD) were enhanced compared to baseline measures on the initial day in the Tph2‐/‐ but not the Tph2+/+ mice (VT ‐ 1.25 ± 0.08 vs. 0.97 ± 0.03, p = 0.001; VD ‐ 1.28 ± 0.11 vs. 0.97 ± 0.04, p = 0.001; standardized to baseline on initial day), while breathing frequency was reduced in both groups (0.92 ± 0.04 vs. 0.92 ± 0.04, p = 0.02; standardized to baseline on initial day).Conclusion: Recovery of respiratory motor function in spinal cord hemisected mice following repeated daily exposure to IH does not require central nervous system serotonin.Grant Funding Source: Supported by VA award 1IO1 RX000458 (DMK) & 1I21RX001412 (JHM)
Obesity‐induced pancreatic tumor growth is accompanied by the accumulation of myeloid‐derived suppressor cells and altered metabolic mediators (123.6)
Authors: Collins Shawntawnee , Turbitt William , Rogers Connie 
Published: June 2021

Obesity increases the risk of several solid tumors, including pancreatic cancer. One mechanism underlying the obesity‐induced increase in tumor incidence may be an obesity‐induced increase in tumor‐derived immunosuppressive factors. Thus, the goal of the current study was to evaluate the emergence and functionality of obesity induced myeloid derived suppressor cells (MDSCs) in our subcutaneous pancreatic tumor model (Panc.02). MDSCs inhibit anti‐tumor immunity, and expand significantly as a result of numerous tumor‐derived inflammatory signals. C57BL/6 mice (n=8/group) were fed either a 30% calorie restricted diet; a 10% kcal from fat diet fed ad libitum; or a 60% kcal from fat diet fed ad libitum to generate lean, control and obese mice, respectively. Mice were injected with 1 X106 Panc.02 cells after 16 weeks on each diet. In this study we observed a progressive accumulation of MDSCs between days 30‐60 post tumor implantation. The accumulation of MDSCs was significantly correlated with body weight (r=0.789, p<0.001); and changes in body weight were positively correlated with insulin (ρ=0.6328; p=0.0027), leptin (ρ =0.699; p<0.001), and monocytes chemoattractant protein‐1 (MCP‐1 (ρ=0.384; p=0.094). Obesity‐induced accumulation of MDSCs may be mediated by obesity‐induced inflammatory and metabolic mediators.Grant Funding Source: Supported by National Institutes of Health (NIH), National Cancer Institute (NCI)
Mono‐2‐ethylhexyl phthalate exposure impairs embryonic growth and nutrition and alters epigenetic programming during early organogenesis (137.8)
Authors: Sant Karilyn , Jilek Joseph , Dolinoy Dana , Harris Craig 
Published: June 2021

The early organogenesis stage of development provides a window of susceptibility during which the nutrient environment guides processes such as epigenetic programming, cellular differentiation, and overall growth. The placenta is not yet functional, leaving receptor mediated endocytosis (RME) of proteins and their cargoes through the visceral yolk sac as the primary source of embryonic (EMB) nutrition. Supplementation of maternal diets with methyl donors and cofactors required for one‐carbon metabolism (C1) has been shown to modify epigenetic programming and prevent neural tube defects. Environmental agents, such as the plasticizer MEHP, are associated with abnormal growth and neurodevelopment, yet the mechanistic relationship between chemical and nutritional agents remains unknown. Our objective was to assess whether MEHP impairs growth, attenuates embryonic nutrient uptake, and alters epigenetic programming during organogenesis.Mouse conceptuses were explanted into whole embryo culture (WEC) on GD 8 and exposed directly to 100 or 250 μg/ml MEHP. After 24 h, exposed embryos showed a dose‐dependent increase of incomplete closure of the neural tube, increased cellular oxidation, and produced a significant reduction in overall growth. Assessment of RME activity, based on FITC‐albumin uptake, showed dose‐dependent decreases in histiotrophic nutrition. Conceptal C1 substrates were measured after 24 hr using mass spectrometry with vitamin B12, choline, and homocysteine being decreased only at the low dose. Betaine and folate were decreased in both the low‐ and high‐dose samples while methionine, cysteine, and S‐adenosylmethionine increased with dose. Histone hypermethylation due to treatment occurred at H3K27 loci, while hypermethylation of H3K4 occurred only in EMB with open neural tubes. This work demonstrates the ability of environmental chemicals to modify EMB nutrition and epigenetic programming, and shows that these changes may lead to growth dysregulation.Grant Funding Source: Supported by NIEHS (P30 ES017885, T32 ES07062) and the Bill & Melinda Gates Foundation (Round 7).
Leukocyte specific protein‐1: a novel regulator of hepatoma proliferation and migration (144.10)
Authors: Koral Kelly , Paranjpe Shirish , Mars Wendy , Michalopoulos George 
Published: June 2021

Copy number variation analysis of human hepatocellular carcinoma samples revealed leukocyte specific protein‐1 (LSP1) gene had the greatest number of deletions. The role of LSP1 in the development or progression of hepatocellular carcinoma remains unknown therefore our objective was to determine the functional significance of LSP1 in liver cancer. Using shRNA against LSP1, we were able to create a stable cell line using the LSP1 expressing JM1 rat hepatoma cells. Analysis of proliferation and migration utilizing the MTT and scratch assay, respectively revealed that loss of LSP1 expression leads to increased proliferation and migration in the JM1 stable cell line as compared to scrambled shRNA control. The stably expressing LSP1 shRNA JM1 cells expressed higher levels of the proliferation markers, cyclin D1 and PCNA providing further evidence of a role for LSP1 in regulating the proliferation of hepatoma cells. Future studies will aim to examine if expression of LSP1 in a LSP1 deficient cell line will result in decreased proliferation and migration. Understanding the function of LSP1 in liver cancer may lead to novel therapeutic targets to combat this deadly disease.Grant Funding Source: Supported by NIH
Therapeutic induction of arteriogenesis in humans (19.4)
Authors: Seiler Christian 
Published: June 2021

Coronary collaterals are an alternative source of blood supply to myocardium jeopardized by ischemia. In comparison to other species, the human coronary collateral circulation is very well developed. Collateral arteries preventing myocardial ischemia during a brief vascular occlusion are present in 1/3 of patients with coronary artery disease (CAD). Among individuals without coronary stenoses, there are preformed collateral arteries preventing myocardial ischemia in 20‐25%. Determinants of preformed coronary collaterals are low heart rate and the absence of systemic arterial hypertension. Collateral flow sufficient to prevent myocardial ischemia during coronary occlusion amounts to 1/5th to 1/4th the normal flow through the open vessel. Myocardial infarct size, the most important prognostic determinant after such an event, is the product of coronary artery occlusion time, area at risk for infarction and the inverse of collateral supply. Well developed coronary collateral arteries in patients with CAD mitigate myocardial infarcts and improve survival.Approximately 1 out of 5 patients with CAD cannot be revascularized by percutaneous coronary intervention or coronary artery bypass grafting. Therapeutic promotion of collateral growth is a valuable treatment strategy in those patients. Promotion of collateral growth should aim at inducing the development of large conductive collateral arteries (i.e. arteriogenesis). They appear to be effectively induced by activation of monocytes / macrophages or by physical augmentation of coronary blood flow velocity.
Comparison of dietary supplement intake reporting between the Automated Self‐Administered 24‐Hour Recall (ASA24) and Automated Multiple Pass Method (AMPM) recalls (245.2)
Authors: Schap TusaRebecca , Thompson Frances , Dodd Kevin , Potischman Nancy , George Stephanie , Coleman Laura , Gahche Jaime , Alexander Gwen , Groesbeck Michelle , Kahle Lisa , Kushi Lawrence , Clancy Heather , Sundaram Maria , Kirkpatrick Sharon , Dixit‐Joshi Sujata , Zimmerman Thea , Douglass Deirdre , Mittl Beth , Bailey Regan , Subar Amy 
Published: June 2021

Objective: To compare dietary supplement use reported on self‐administered (ASA24) versus interviewer‐administered (AMPM) 24‐hour recalls.Methods: About 1200 women and men were recruited from three integrated health systems using quota sampling to capture a range of ages and racial/ethnic backgrounds. Participants were randomized into four groups and asked to complete two recalls: 1) two ASA24s; 2) two AMPMs; 3) ASA24 first, AMPM second; 4) AMPM first, ASA24 second. Dietary supplements were coded using the 2007‐2008 NHANES Dietary Supplement Database. Difference in prevalence of reported supplement use was tested using a Chi‐square test.Results: Food and supplement data were complete for 1089 participants. Prevalence of use of any dietary supplement on either day was not significantly different by recall mode overall (47.8% for AMPM (n=1022) vs.48.5% for ASA24 (n=1012); p=0.82) or within sex, age, or race/ethnicity groups. Among supplement users, the prevalence of reported multivitamin use was significantly higher on AMPM compared to ASA24 (65.9% vs. 57.2%; p <0.01). In ASA24, 50 participants reported 114 supplements as “unknown”, meaning they were unable to find their supplement in the ASA24 database.Discussion: The ASA24 performs similarly to AMPM for estimating overall prevalence of dietary supplement use. Significant differences found in the reporting of multivitamins specifically could be related to the number of unknown supplements reported in ASA24. Coding of text entered for supplements not found in ASA24 may be necessary to obtain accurate prevalence of supplement type and nutrient estimates. Based on these findings, future versions of ASA24 will include questions when unknown supplements are reported for the purpose of assigning reasonable default supplement codes.
Blood glucose lowering effect of Tridax procumbens in type 2 diabetes may be attributed to AMPK activation and suppression of hepatic gluconeogenesis (259.8)
Authors: Desai Gauri , Desai Shirish , Gavaskar Rajendra , Mathews Suresh 
Published: June 2021

Traditional knowledge and anecdotal evidence suggest that Tridax procumbens Linn may have anti‐inflammatory and blood glucose lowering properties. Recent studies have shown that T.procumbens extract was effective in lowering blood glucose (42‐71% blood glucose reduction at 250‐500 mg/kg body weight) in alloxan‐induced diabetic rats. The goals of this study were to evaluate blood glucose lowering potential of T.procumbens extract in subjects with type 2 diabetes and characterize underlying molecular mechanisms. Twenty individuals with established type 2 diabetes were orally administered (15 ml, twice daily) T.procumbens extract, prepared according to Ayurveda guidelines, for a period of 4 weeks. Fasting blood glucose concentrations were reduced by 11% in men and 20% in women, and post‐prandial blood glucose concentrations were decreased by 26% in men and 29% in women. No adverse effects were reported by the participants. Chemical and microbial analyses of T. procumbens extract demonstrated the presence of phenolics, carotenoids, and flavonoids, and absence of microbial contaminants, aflatoxins, and heavy metals. T.procumbens extract demonstrated strong antioxidant potential and anti‐inflammatory activity as evidenced through Trolox equivalent antioxidant capacity, ferric‐ion reducing potential, hydrogen peroxide scavenging activity, and metal ion chelating effect in vitro, and inhibition of NFκB and IkBα in LPS‐stimulated RAW 264.7 murine macrophages. T.procumbens extract significantly increased AMPK activation and suppressed dexamethasone‐induced PEPCK and G6Pase gene expression with subsequent decrease in hepatic glucose production in H4IIE cells. Our studies indicate that T.procumbens extract exhibits strong antioxidant and anti‐inflammatory properties. Activation of AMPK and suppression of hepatic glucose production may be one mechanism that contributes to the glucose‐lowering property of T. procumbens.Grant Funding Source: Diabetes Action Research and Education Foundation