bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elevated Irisin Expression in NASH Livers
Authors: Nugent Colleen , Baker Susan , Liu Wensheng , Mastrandrea Lucy , Baker Robert , Zhu Lixin 
Published: June 2021

BackgroundData mining with our microarray database suggested that irisin is one of the most highly elevated genes in livers of non‐alcoholic steatohepatitis (NASH). NASH is the severe form of non‐alcoholic fatty liver disease (NAFLD) and is characterized by hepatic steatosis, inflammation and fibrosis. Irisin, an adipomyokine implicated in the initiation of a browning effect of adipose that may profoundly affect the metabolic status of NASH patients. Our microarray analysis suggested elevated liver irisin and chemokine ligand 14 (CXCL14). CXCL14 is a chemokine that participates in glucose metabolism and inflammation. We therefore tested the hypothesis that inflammation is a trigger for hepatic irisin expression.MethodsBiopsy‐proven adolescent NASH patients were compared to controls from healthy livers from donors of similar age and gender. Irisin gene expression was evaluated by microarray and quantitative real‐time PCR.ResultsHepatic irisin gene expression was increased in NASH compared to controls. Microarray data showed NASH/Normal = 30.49(p = 0.0008) and CXCL14/Normal = 108.34 (p = 0.0005). qRT‐PCR showed elevated irisin (p =0.0001) and CXCL14 (p=0.0009) expression. Significant correlations were noted between irisin message and hepatic inflammation grade (r = ‐ 0.65, p = 0.0008) but not the pathologic scores for fibrosis or steatosis.ConclusionsThis study indicates that irisin gene expression is induced in NASH. Irisin expression correlates with CXCL14, a representative inflammatory chemokine. These observations suggest that irisin may be playing a role in the mechanism of inflammation.
Tissue Bioavailability of Tart Cherry Anthocyanins
Authors: Kirakosyan Ara , Seymour E Mitchell , Kaufman Peter , Bolling Steven 
Published: June 2021

The therapeutic effects of tart cherry anthocyanins cannot be understood without analysis of their tissue distribution,metabolism, and excretion. The definition of bioavailability simply refers to the proportion of known compound that is absorbed and metabolised in an organism. Tissue uptake of anthocyanins may depend on their chemical structure, as influenced by the nature of the attached sugar moiety, and also, by the structure of the aglycone. The parent phytochemicals contain functional groups (e.g., a hydroxyl group) that often undergo conjugation reactions with endogenous compounds to yield more polar and water‐soluble compounds. The latter are usually ideal substrates for active transport out of cells, tissues, and organs with eventual excretion from the body. The sugar conjugates of anthocyanins may also have an effect on the bioavailability of bioactive phytochemicals. Consequently, it is not only important to know how much of a bioactive metabolite is present in tart cherry; but it is even more important to know how much of that present is bioavailable. In the present study, we show that intake of tart cherry is associated with anthocyanin appearance in several tissues of healthy rats. This information affects hypotheses of the molecular mechanisms of bioactive compounds at target sites and how they vary among tissues. While the current work focuses on anthocyanin tissue bioavailability, results may be impacted by the complex polypharmacy of bioavailable tart cherry phytochemicals and their varied sugar moieties that affect absorption, distribution, metabolism, and excretion.Acknowledgements: This study was supported by an unrestricted grant provided by The Cherry Marketing Institute, MI, USA.
QUERCETIN IMPACTS ETC/OXPHOS ACTIVITIES IN ISOLATED HEPATIC MITOCHONDRIA OF MICE
Authors: Guo Xin , Wu Lei , Clarke Stephen , Lin Dingbo 
Published: June 2021

ObjectiveIn general, quercetin attenuates oxidative stress and enhances mitochondrial biogenesis in the development of obesity and/or diabetes. In this study we wished to determine how quercetin impacted the mitochondrial function by examining mitochondrial electron transport chain/oxidative phosphorylation (ETC/OXPHOS) in isolated mouse hepatic mitochondria.MethodsMale wild type 129 S6 (WT) mice, at 6 weeks of age, were used. Isolated hepatic mitochondria were treated with quercetin (0, 2.5, 5, 10, and/or 20 μM) for 15 min. Then the individual ETC complex activity, basal oxygen consumption, maximum ATP utilization, maximum respiratory capacity, and proton leak were measured via assays of electron flow and coupling.ResultsQuercetin decreased the basal respiratory rate and the maximum respiratory capacity. No change was observed in maximum ATP utilization, proton leak, and activities of ETC complex I, II and III. However, quercetin at a low dose (e.g., 2.5 μM) significantly increased the ETC complex IV activity. The effect was then diminished dose dependently.ConclusionsQuercetin may lower the mitochondrial respiratory activity through mediating the ETC complex IV.
Coronary Arteries Injury in a Model of Pulmonary Fat Embolism Syndrome (PES)
Authors: Patel Chirag , Alqalyoobi Shehabaldin , Naji Darwish , Herndon Betty , Poisner Alan , Molteni Agostino 
Published: June 2021

Lung inflammation, vasculitis, and fibrosis occur in FES following bone fractures, surgical procedures, and liposuction. We reported the onset of myocardial damage in a rat model of FES with pulmonary fibrosis. This study continues our earlier work with attention to the evolution of the inflammatory process of the coronaries.Of 28 male SD rats, 14 received 0.2 mL IV triolein (FES model) and 14 received IV saline. Six weeks later, Losartan (0.3 mg/kg) was given IP to half of each group up to ten weeks. At necropsy, the tissues were stained for H&E, SMA‐1, and Trichrome for collagen. Six photos at 400x were made of each heart. The coronary vasculitis was assessed by measurement of the medial thickening and lumen patency.In addition to the lung fibrosis, the heart of the triolein treated rats showed intense SMA‐1 staining of the coronary media, intima, and adventitia. Lumen patency was reduced versus saline controls (p < 0.05). Losartan and saline treated rats did not differ from controls. Losartan protected the triolein treated rats from the heart damage with mild medial staining and wider lumen patency (p = 0.05). A small rim of collagen (trichrome) was seen in the adventitia of all the rats with more intensity in the triolein treated groups. Losartan reduced its presence.SMA‐1 staining by evidencing the transformation of fibroblasts and myofibroblasts shows the beginnings of collagen‐induced fibrosis. Would a longer treatment result in a more severe coronaropathy? The protective effect of Losartan was again confirmed underlining the role of the Renin‐Angiotensin system in this disease. Information from this model may help treating patients with FES.
Atypical Antipsychotic Off Label Use: Should We Worry About Cardiovascular Complications?
Authors: Packer Jonathan , Houseknecht Karen , Davidoff Amy 
Published: June 2021

Despite label warnings for severe metabolic side effects causing insulin resistance and increased mortality, prescribing of atypical antipsychotic drugs (AADs) has increased significantly in recent years, particularly in children and elderly for non‐psychotic behaviors. Adverse cardiovascular (CV) events have been reported, including arrhythmias in elderly; however the underlying pharmacology is unknown. The goal of this study was to evaluate acute CV effects of several AADs. Anesthetized male adult rats were cannulated (femoral vein for drug delivery, right carotid artery for blood pressures), and sc electrodes for EKGs. Drugs selected for diverse receptor pharmacology and metabolic side effect profiles were chosen, and cumulative dose/response measurements were recorded (0.1 – 1.0 mg/kg, ~5 min intervals between doses). All drugs acutely reduced mean arterial pressure (MAP) with no compensatory increase in heart rate. Aripiprazole had the least effect on MAP (<10% reduction), while the other drugs reduced MAP by 50‐60%. Increased pulse pressure accompanied reduced MAP only with Risperidone. MAP effects were transient, recovering ~1‐2 min. No effects on EKG were detected.ConclusionsPotency of drugs on MAP were positively correlated with Ki values for both α1‐adrenergic and D2 receptors: Risperidone<Clozapine<Olanzapine<Aripiprazole, whereas efficacy was similar for all, except reduced for Aripiprazole. Our results support the view that Aripiprazole is least likely to induce orthostatic hypotension, and its more selective D2 effects may contribute to reduced side effects.Funded by grant DK095143 (KLH), Peter Morgane Research Fellowship (JDP)
DNA‐Dependent Protein Kinase Inhibition Blocks Asthma in Mice and Modulates Human Endothelial and CD4+T Cell Function Without Causing SCID
Authors: Pyakurel Kusma , Ghonim Mohamed , Ju Jihang , Rodriguez Paulo , Lammi Matthew , Davis Christian , Abughazleh Mohammad , Naura Amarjit , Boulares Hamid 
Published: June 2021

We reported that DNA‐dependent Protein Kinase (DNA‐PK) is critical for the expression of NF‐κB‐dependent genes in TNF‐α‐treated glioblastoma cells, suggesting an involvement in inflammation. Cell culture and ovalbumin (OVA) or house dust mite (HDM)‐based murine asthma models were used in this study.ResultsDNA‐PK was essential for monocyte adhesion to TNF‐α–treated‐endothelial cells. Administration of the DNA‐PK inhibitor, NU7441, reduced airway eosinophilia, mucus hypersecretion, airway hyperresponsiveness (AHR), and OVA‐specific IgE production in mice. Such effects correlated with a marked reduction in lung VCAM‐1 expression and production of several inflammatory cytokines and chemokines. DNA‐PK heterozygosity also prevented manifestation of asthma‐like traits. Remarkably, such protection occurred without causing SCID. These results were confirmed in a chronic model of asthma using HDM. Adoptive transfer of Th2‐skewed OT‐II‐WT CD4+ T cells reversed IgE and Th2 cytokine production but not AHR in ova‐challenged DNA‐PKcs+/‐ mice. DNA‐PK inhibition reduced IL‐4/IL‐5/IL‐13/eotaxin/IL‐8/MCP‐1 production without affecting IL‐2/IL‐12/IFN‐γ/IP‐10 production in CD3/CD28‐stimulated human T cells potentially by blocking expression of gata‐3. These effects occurred without significant reductions in T‐cell proliferation. In mouse T cells, DNA‐PK inhibition, in vitro, severely blocked CD3/CD28‐induced gata‐3 and t‐bet expression in T cells and prevented differentiation of Th1 and Th2 cells. Our results suggest DNA‐PK as a novel determinant of asthma and a potential target for the treatment of the disease. Support: NIH; AHA; LCRC
The Zinc Finger Transcription Factor Mds1‐Evi1 Forms a Novel Protein Complex in MLL leukemia
Authors: McGlynn Kelly , Zhang Yi , Perkins Archibald 
Published: June 2021

The dual transcription factor‐methyltransferase Mds1‐Evi1 is frequently overexpressed in high‐risk leukemias. Mds1‐Evi1 contributes to leukemias induced by the mixed lineage leukemia (MLL) fusion protein MLL‐AF9, although the mechanism is unknown. MLL contains chromatin‐targeting and histone lysine methyltransferase domains, and fusion to AF9 can cause aberrant protein recruitment to target genes. Although Mds1‐Evi1 contains a methyltransferase domain, it does not appear to act on histones. Therefore, we are interested in how protein‐protein interactions involving Mds1‐Evi1 contribute to leukemogenesis. Many known interactors of MLL and Mds1‐Evi1 include chromatin modifying enzymes, suggesting that coordination between epigenetic modulators is key in leukemia pathogenesis.Here, we report the biochemical purification of a novel Mds1‐Evi1‐containing protein complex using a unique murine model of leukemia. To isolate the complex, we induced acute MLL‐AF9 leukemia in mice containing a tandem affinity purification (TAP) tag knocked into the endogenous Mds1‐Evi1 gene. Leukemic spleen tissue from these mice was used to purify the TAP‐tagged protein complex. Proteomic analysis revealed several members of the SWI/SNF chromatin remodeling complex, which is involved in epigenetic control of a variety of gene programs. Association between Mds1‐Evi1 and SWI/SNF may allow the activation of cell‐cycle and differentiation programs, contributing to transformation. SWI/SNF also coordinates with MLL fusion proteins to activate the Hox family of leukemia oncogenes. Our results provide a link between Mds1‐Evi1 and the chromatin remodeling machinery, where abnormal coordination of Mds1‐Evi1, MLL‐AF9 and SWI/SNF may lead to gene activation and the development of leukemia.
Longitudinal Effects of Menopausal Hormone Treatments (MHT) on Platelet Characteristics and Cell‐Derived Microvesicles
Authors: Miller Virginia , Lahr Brian , Bailey Kent , Heit John , Harman S , Jayachandran Muthuvel 
Published: June 2021

ObjectiveActivated platelets serve as a catalyst for thrombin generation. Furthermore, oral MHT may carry greater thrombotic risk than transdermal products. This study compared effects of oral and transdermal MHT on platelet characteristics including platelet‐derived microvesicles (MV) in recently menopausal women.MethodsPlatelets and MV were prepared from blood of a subset of women (n=117) enrolled in the Kronos Early Estrogen Prevention Study prior to and after 4 years of treatment with either oral conjugated equine estrogen (0.45 mg, oCEE), transdermal 17β estradiol (50 µg/day, tE2), each with intermittent progesterone (200 mg/day for 12 days a month), or placebo pills and patch.ResultsPlatelet count, and activated platelet P‐selectin and fibrinogen‐binding receptor expression were similar across groups. Numbers of tissue factor positive and platelet‐derived MV increased significantly in the tE2 compared to placebo.ConclusionsFour years of MHT did not increase thrombogenic characteristics of platelets. Thrombotic risk associated with oral MHT most likely involves liver‐derived proteins than platelets per se. Differential effects of oCEE and tE2 on circulating MV may reflect the hormonal composition of the two formulations on non‐genomic pathways in circulating platelets.FundingThis work was supported by grants from the Aurora Foundation to the Kronos Longevity Research Institute, NIH HL90639, UL1TR000131, American Heart Association‐ Scientist Development Grant, AHA 08‐30503Z, American Heart Association, Grant‐in‐Aid, 12GRNT12050147, and the Mayo Foundation.
Vascular Collateralization Investigated in the Chorio‐Allantoic Membrane (CAM)
Authors: Pries Axel , Reglin Bettina , Rong Wenwei , Nitzsche Bianca , Maibier Martin , Secomb Tim , Xiang Weiwei 
Published: June 2021

IntroductionCollateralization upon obstruction of an arterial vessel is crucial to maintain tissue perfusion. The aim of this study is to quantify the dynamics of structural adaptation on the microvascular level in a model where vascular reactions can be observed continuously.MethodWhite leghorn chicken eggs were transferred on incubation day E3 into petri dishes. On E12, a selected arteriole of the CAM was occluded by laser irradiation. At several time points before and after occlusion, the area perfused by the arteriole was scanned using video microscopy. Blood flow velocity in selected vessels in the recorded area was measured (spatial correlation) and hemoglobin oxygen saturation was determined (hyperspectral analysis).Results and ConclusionBefore occlusion, the occluded arterioles were 64.86 ± 6.33 µm in diameter and microvasculature displayed an interdigitated pattern of arterioles and venules. Flow velocities exhibited a strong linear decline with decreasing vessel diameter. After the occlusion, functional collaterals were typically observed either between one daughter arteriole and an adjacent arteriole not fed by the obstructed vessel or between one daughter and the upstream sister arteriole. They developed from pre‐existing terminal arterioles (3 of 20) and/or by remodeling of capillary meshes (17 of 20). Collateralization resulted in reversal of flow in arterioles downstream of the occlusion. It is concluded that in the CAM model, collateralization maintains local microcirculatory function via pre‐existing arterial anastomoses vessels or via capillary meshes.Supported by EU / ITN “REVAMMAD” # 316990
The Spatial Distribution of Nitric Oxide‐evoked cGMP Can Produce Biphasic Effects on Na+/H+ Exchanger‐1 Activity in the Rat Ventricular Myocyte
Authors: Richards M , Paterson D , Vaughan‐Jones R , Swietach P 
Published: June 2021

We investigated the effects of nitric oxide (NO)‐signalling on Na+/H+ Exchanger (NHE1), the principal H+‐extruding protein in ventricular cardiac myocytes.H+‐extrusion by NHE1 was activated by ammonium pre‐pulse (HEPES‐buffered Tyrode) and measured by pH‐sensitive fluorescence (cSNARF1).NHE1 was inhibited by high [NO] (20nM; released from NOC‐12), but activated by low [NO] (2nM; NOC‐12 plus NO‐scavenger CPTIO). These biphasic effects were blocked by the guanylate cyclase (GC) inhibitor ODQ, implicating the NO‐GC‐cGMP pathway. The stimulatory effect of low [NO] was mimicked by the phosphodiesterase (PDE)‐resistant cGMP analogue, 8pCPTcGMP. In contrast, the inhibitory effect of high [NO] may be attributed to a cGMP‐evoked rise in cAMP (NHE1 inhibitor) involving PDE3 (high cGMP inhibits cAMP degradation by PDE3). Indeed, the inhibitory effect of high [NO] was mimicked by the PDE3 inhibitor cilostamide. To explore the spatial aspects of NO signalling, dual microperfusion was used to restrict [NO] to the proximal region of the cell (confirmed with DAR4 fluorescence). High [NO] applied locally to one end of the cell stimulated NHE1 distally, beyond the compartmentalized [NO] zone, in an ODQ‐sensitive manner, arguing against direct S‐nitros(yl)ation. Results suggest that cGMP is a mobile messenger, reaching low concentrations distally, sufficient to stimulate NHE1 but below the threshold for evoking a local rise in cAMP.The net effect of NO on NHE1 activity is set by the balance between activation by cGMP and inhibition via cGMP‐cAMP coupling. This balance depends on the spatial concentration profile of cGMP evoked by NO. NO can modulate intracellular pH with an unprecedented degree of plasticity.Funded by BHF
In Vivo Effects of Platelet Apheresis on Oxygen Metabolism in Pigs
Authors: Martini Wenjun , Rodriguez Cassandra , Richardson Jonathan , Cap Andrew , Dubick Michael 
Published: June 2021

IntroductionPlatelet apheresis is a routine clinical practice. Although the efficacy of collected platelets has been studied, the impact of apheresis on the physiology of the donor is less clear. This study investigated oxygen metabolism in pigs during a 4 hour platelet apheresis as a prelude to initiating studies of hemorrhage and resuscitation in swine with reduced platelets.MethodsForty pigs (39.8±0.6 kg) were catheterized with a femoral vein catheter for platelet apheresis, using a Haemonetics MCS9000. Hemodynamics was recorded during the apheresis process. Arterial and venous samples were collected before and after apheresis for blood gases and CBC.ResultsDuring apheresis, blood‐withdrawing decreased MAP from 74<a name=”OLE_LINK2”></a><a name=”OLE_LINK1”>±</a>2 to 45±1 mmHg and increased heart rate from 104±3 to 129±4 bpm (both p<0.05); blood‐returning recovered MAP and HR to baseline values, with no changes observed in cardiac output. Platelet counts in pigs decreased to 40±3% of baseline values after 4 hours of apheresis (p<0.05). Pig blood glucose was increased by apheresis from 4.1±0.3mM to 5.2±0.2mM, Ca++ decreased from 1.34±0.01mM to 1.13±0.02mM, and lactate decreased from 2.2±0.1mM to 1.3±0.1mM (all p<0.05), with no changes in Hct, Hgb and RBCs. Oxygen delivery was not affected by apheresis, but oxygen extraction was decreased from 27±2% to 20±1%, and oxygen consumption was decreased from 4.0±0.2 O2/dL blood to 3.1±0.2 ml O2/dL blood (both p<0.05).ConclusionIn addition to reducing platelet counts, platelet apheresis caused large fluctuations in MAP and compromised oxygen metabolism, which can impact the physiologic response to hemorrhage in these animals.
Distinct Mechanisms Underlie Cardiomyocyte Contractile Dysfunction in Male and Female Endotoxemic Mice
Authors: Hobai Ion , Aziz Kanwal , Siwik Deborah , Colucci Wilson 
Published: June 2021

Sepsis induced cardiomyopathy results (at least partially) from the dysregulation of myocardial calcium (Ca2+) handling. In male (M) mice, this involves redox‐mediated dysfunction of cellular Ca2+ tranporters. No data is available about Ca2+ signaling in septic female (F) hearts.We studied M and F C57Bl6 mice (WT), as well as mice deficient in soluble guanylyl cyclase (sGC) activity (sGCα1‐/‐). Lipopolysaccharide (LPS) administration (ip) induced an inflammatory shock syndrome and cardiomyopathy. A dose of 7 μg/g LPS induced 59% mortality in M WT mice, 44% in M sGCα1‐/‐, and no mortality in F WT or F sGCα1‐/‐ mice. 20 μg/g LPS induced 100% mortality in WT F and 50% mortality in F sGCα1‐/‐ mice.We measured sarcomere shortening (SS) and Ca2+ transients (ΔCai) in isolated, externally paced cardiomyocytes. 12h after LPS (25 μg/g) challenge, WT M mice had decreased SS and ΔCai, to 60 ± 7 and 78 ± 4% of baseline (bl), respectively (n > 60 cells from 8 mice for all groups, 60/8; p<0.05 for this and following). In sGCα1‐/‐ M, the decrease in SS and ΔCai was more pronounced than in WT (to 26 ± 3 and 53 ± 3% of bl, respectively, n>60/8). In F WT, LPS induced a decrease in SS (to 39 ± 6% of bl, n>40/4), but not in ΔCai, consistent with myofilament dysfunction. SS decrease was less in sGCα1‐/‐ F mice (70 ± 8%, n>35/4) than in WT F.In conclusion, in M mice, LPS induces a parallel, sGC‐independent decrease in SS and ΔCai. In contrast, in F, LPS does not decrease ΔCai, but induces a (partially) sGC‐dependent myofilament dysfunction. Different therapeutic approaches may thus be required in septic M and F patients.
Hydrogen Sulfide Is An Endogenous Cytoprotective Gaseous Mediator in Cerebral Circulation
Authors: Liu Jianxiong , Leffler Charles , Parfenova Helena 
Published: June 2021

Hydrogen sulfide (H2S) is a gaseous mediator with vasodilator and antioxidant properties produced by cystathionine γ‐lyase (CSE) and cystathionine β‐synthase (CBS). In the brain, CSE and CBS are predominant H2S‐producing enzymes in vessels and astrocytes, respectively. We investigated cytoprotective properties of H2S in a model of cerebrovascular disease caused by neonatal seizures. In newborn piglets, bicuculline‐induced epileptic seizures produce long‐term cerebral vascular dysfunction. During seizures, brain CBS activity is increased as indicated by H2S elevation in periarachnoid cerebrospinal fluid (CSF) that was selectively inhibited by aminooxyacetate. We addressed the hypothesis that H2S improves the cerebral vascular outcome of seizures. An H2S donor NaHS (3 mg/kg) administered enterally or parenterally rapidly increased H2S in CSF. At this dose, NaHS had no effects on core body temperature, mean arterial blood pressure, or heart rate. To test the cytoprotective effects of NaHS, the drug was administered before or during seizures. Cerebral vascular reactivity to physiologically relevant vasodilators was tested by the cranial window technique 48 h after seizures. In the control group, we observed a great reduction in postictal dilator responses to endothelium‐ and/or astrocyte‐dependent stimuli bradykinin, glutamate, and hemin. NaHS administered enterally or parenterally before or during seizures improved all postictal vascular responses. We conclude that H2S, endogenously produced in the brain via CBS activation during seizures, or pharmacologically delivered to the brain during a therapeutic window, reduces the adverse cerebral vascular outcome of neonatal seizures thus leading to vascular neuroprotection.The study was supported by NIH/NLBI.