bluuebunny/crossref_metadata_2025_split huggingface dataset:
Copper Oxide Nanoparticles Activate Nrf2, KEAP 1, and Downstream Target Genes in JB6 Cells possibly through ROS Generation and Antioxidant Response Element (ARE) Mechanisms
Authors: Barber Tabatha L. , Aldinger Joni , Arnold Joshua , Leonard Stephen , Ding Min 
Published: April 2020

Occupational exposures to Copper Oxide (CuO) nanoparticles havebeen reported to be harmful to human health, with possible risk of cancer amongworkers from many sectors. CuOnanoparticles have not, to our knowledge, been extensively examined forpotential carcinogenic toxicological effects. To investigate the mechanisms ofCuO‐induced pathogenesis, the effect of metal oxide fine and nanoparticles on antioxidantresponse mechanisms and ROS generation were investigated. The results indicated that CuO caused a2‐fold increase in AP‐1 activity in JB6 cells. The induction of AP‐1 activityin cultured cell lines was time and dose‐dependent. The signal transductionpathways for AP‐1 activation were also investigated. Western Blot analysisdemonstrate that CuO nanoparticles stimulate phosphorylation of p38 MAPK andERKs. CuO also generated ROS whenincubated with the cells as measured by electron spin resonance (ESR). Nano‐sized CuO generated more ROS than thefine sized particles when incubated with the cells. COMET assay suggests thatexposure of the cells to CuO resulted in DNA damage. Cells pre‐treated with ROSinhibitors sodium formate and Polyvinylpyridine‐N‐Oxide (PVPNO) before exposureto CuO nanoparticles demonstrate a significant reduction in p‐38 and ERKactivity, suggesting the H2O2 may have a role in the ROSmechanism. CuO Nanoparticles induced Nrf2 translocation and activation in adose and time‐dependent manner. Glutathione S‐transferase and NAD(P)H:quinoneoxidoreductase 1(NQO1) were increased in a time‐dependent manner following JB6exposure to CuO nanoparticles. Unraveling the complex mechanisms associatedwith these events suggests that activation of Nrf2 and subsequent activation ofthe ARE by ROS generation may contribute to adverse health effects followingexposure to CuO nanoparticles.Support or Funding InformationThis project was supported by a grant from the Nanotechnology Research Center.
Implementing Pathology Peer Teaching Program in a Medical School
Authors: Lomiguen Christine M. , Gross Hannah , Terrell Mark A. , Ogunsakin Olalekan , Junsanto-Bahri Tipsuda 
Published: April 2020

PurposePathology intimidates many first‐year medical students because it requires interdisciplinary critical thinking required to diagnose and to treat disease, and often, students are uninterested in the subject. These two factors cause students to disengage in the educational setting. To combat this problem, a mutually‐beneficial pilot teaching assistant (TA) program was developed in a General Pathology course to facilitate first‐year medical students’ abilities to apply General Pathology to integrative, interdisciplinary questions early in undergraduate medical education. TAs were second‐year medical students who cognitively benefited from the experience of teaching first years through the educational principle “To teach is to learn something twice,” thus aiding in their preparations for licensure examinations.MethodsThirteen (13) medical students from the second‐year Systemic Pathology class at an urban osteophathic medical school volunteered to serve as TA’s for the first‐year General Pathology class. The first‐year General Pathology class consisted of 135 medical students, divided into 23 small groups composed of between two to eight students per group. The 23 groups were then divided into two lecture halls. At least one pathology faculty member was also present in each lecture hall. First‐year students were presented with an integrative pathology case, provided to second‐year students in advance, and given guiding questions with the support of their assigned second‐year TA to develop critical thinking.ResultsResults consisted of positive preliminary feedback in the program’s initial implementation in the Spring 2019 semester from both first‐year students interested in exposure to board‐relevant questions early in their education and second‐year medical students actively preparing for their board examinations and interested in reviewing first‐year material.ConclusionPathology requires the integration of foundational concepts from anatomy, biochemistry, physiology, and immunology to understand the various aspects of the disease process. Training developed in digesting complex material is of utmost importance for success on national licensure examinations, such as the United States Medical Licensing Examinations (USMLE) and Comprehensive Osteopathic Medical Licensing Examinations of the United States of America (COMLEX‐USA), for board certification. The pilot teaching assisting program in the General Pathology course exposed first‐year medical students to challenging, integrative questions early in undergraduate medical education and re‐exposed second‐year medical students who were actively preparing for licensure examinations, benefiting both sets of students. Further studies will evaluate the effectiveness of the pathology teaching assistant program on academic performance and on licensure examinations.
Cerebral erythropoietin increases the hippocampal mitochondrial respiration during the postnatal development
Authors: Soliz Jorge , Arias-Reyes Christian , Laouafs Sofien , Jacobs Robert A. , Schneider Gasser Edith M. 
Published: April 2020

Mitochondrial respiration is the metabolic process in which ATP is formed as a result of electron transfer and substrate oxidation. However, in addition to this classic role, mitochondrial respiration, and the concomitant production of ROS, are also required to maintain ionic cell membrane gradients, develop synaptic pruning (axonal and dendritic growth), provide effective neurotransmission, modulate signaling pathways and regulate neurogenesis and differentiation. While all these processes occur during brain development, little is known about the regulation of mitochondrial respiration in the postnatal development of hippocampal tissue. In parallel, studies conducted over the past two decades demonstrated that cerebral erythropoietin (Epo) plays a crucial role in the development of the nervous system. Remarkably, Epo‐mediated neurodevelopment requires the activation of molecular mechanisms that are tightly associated with mitochondrial functions. Inline, recent published literature demonstrated that Epo modulates mitochondrial bioenergetics and control of oxidative stress in several tissues, including the brain. In this work, we evaluated the impact of Epo in the regulation of hippocampal mitochondrial respiration of mice during postnatal development. To do so, the hippocampus of wild type (WT) and transgenic mice constitutively overexpressing Epo in the brain only (Tg21) at postnatal ages 3 (P3), 7 (P7), 14 (P14), and 21 (P21) was collected. Mitochondrial oxygen consumption was measured by using our oxygraph‐2K system (O2k‐OROBOROS). Recording of the mitochondrial oxygen consumption was evaluated in 2 mg of tissue permeabilized with saponin, after the activation of complexes I (CI), I+II (C I+II), and IV (CIV). Our results showed that at P14 and P21, Epo in hippocampal tissue: 1) increases the mitochondrial respiratory activity; 2) increases the mitochondrial respiratory capacity; 3) maximizes the respiratory efficiency; and 4) augments the number mitochondria per tissue. Additional analysis, performed by using colorimetric assay kits, revealed that Epo at P14 increases the activity of superoxide dismutase (SOD). Altogether, our results suggest that Epo promotes an increased oxidative metabolism in the hippocampus at an age when this structure undergoes a full process of development and maturation.Support or Funding InformationJorge Soliz is supported by the “Fonds de recherche du Quebec‐Santé” (FRQ‐S; FQ121919)
Modulating the immune response and the pericardial environment with LPS or prednisolone in the axolotl does not change the regenerative capacity of cryoinjured hearts
Authors: Pedersen Kathrine , Rasmussen Rikke Kongsgaard , Dittrich Anita , Pedersen Michael , Lauridsen Henrik 
Published: April 2020

IntroHumans are incapable of regenerating after suffering from a myocardial infarction. Instead a fibrotic scar without contractile or electrically conducting properties is formed. This results in cardiac remodeling, which steers the heart towards heart failure. It is hypothesized that the time frame and composition of infiltrating immune cells play a role in the fibrotic outcome.A popular model organism capable of cardiac regeneration is the axolotl (Ambystoma mexicanum). It is believed that the immune response to cardiac injury in the axolotl progresses with a timing and distribution of infiltrated immune cells that supports regeneration rather than extensive inflammation and scar formation. Patients suffering from cardiovascular disease display a systemic pro‐inflammatory state, which includes an upregulation of inflammatory factors, and will likely influence the immune response mounted in the incidence of a myocardial infarction. Though fully healthy mammals are not able to functionally regenerate from cardiac injury such as a myocardial infarction, it is interesting to evaluate how a strong modulation of the immune response will affect an animal model capable of regeneration. Therefore, we have chosen to modulate the immune response in a pro‐ and anti‐inflammatory direction by injecting LPS or prednisolone respectively.MethodsIn this study 24 axolotls were given a cryoinfarction injury on the ventricle, thereby mimicking a myocardial infarction. The regenerative potential was observed in three different environments; a pro‐inflammatory (10 μg LPS), an anti‐inflammatory (20 μg prednisolone) and a saline control (amphibian Ringer’s solution) by injecting 20 μL of one of the three chosen substances into the pericardium of the axolotl every five days. LPS and prednisolone were hypothesized to alter the timing and distribution of infiltrating immune cells and inhibit regeneration. Echocardiography and quantitative histology were applied to measure function (ventricular stroke volume) and anatomical regeneration (healed volumetric fraction) of injured hearts.ResultsAll treatment groups showed extensive heart regeneration and no statistically significant differences in stroke volume or healed fraction between groups were observed.ConclusionSince neither echocardiographic nor histological data, showed any statistically significant differences in the functional or anatomical regeneration, this brings into question the importance of the immune system during regeneration in the axolotl.
Looking for LARP6 function in the Brain
Authors: Rogers Beth , Warner Lisa 
Published: April 2020

LARP6, or La‐related protein 6, is known to play a role in post‐transcriptional regulation of collagen mRNA. The La Module of LARP6 is an RNA recognition module that is comprised of a La Motif and an RRM domain. The La Module binds to a conserved stem loop structure on the 5′ UTR of collagen type 1a1 and 1a2 mRNA. Interaction between LARP6 and the 5′ UTR has been shown to increase the expression of collagen type 1. Interestingly, LARP6 mRNA is highly expressed within the brain while collagen mRNA is expressed at very low levels. The purpose of this project is to investigate the functions of LARP6 within a brain system, where the cognate function of LARP6 may differ from collagen rich tissues. Here we report on characterization of several potential model cell lines, SH‐SY5Y, PC12, bEnd.3 and LX‐2 cells, using western blot analysis, confocal microscopy, and qPCR for studying LARP6 in the brain. Once an ideal system is identified we will conduct CLIP‐seq, which will allow us to identify new RNA ligands of LARP6.Support or Funding InformationThe project described was supported by Institutional Development Awards (IDeA) from the National Institute of General Medical Sciences of the National Institutes of Health under Grants #P20GM103408 and P20GM109095. We also acknowledge the support from The Biomolecular Research Center at Boise State with funding from the National Science Foundation, Grants # 0619793 and #0923535; the MJ Murdock Charitable Trust; and the Idaho State Board of Education.
Spinal delivery of ampakine CX717 impacts phrenic motor output in adult rats
Authors: Thakre Prajwal P. , Perim Raphael R. , Sunshine Michael D. , Tadjalli Arash , Mitchell Gordon S. , Fuller David D. 
Published: April 2020

Throughout the brainstem and spinal cord, α‐amino‐3‐hydroxy‐5‐methy‐4‐isoxazole propionate receptors (AMPARs) play an essential role in respiratory motor control. Ampakines are positive allosteric modulators of AMPARs which can enhance glutamatergic currents. Our laboratory recently reported that intravenous delivery of low‐dose ampakine CX717 can evoke increases in phrenic nerve inspiratory burst amplitude. However, this increased phrenic bursting could reflect an impact of the ampakine on pre‐motor brainstem circuits or a direct action on spinal neurons. In ongoing experiments, we are testing the hypothesis that delivery of ampakines to the cervical spinal cord is sufficient to evoke a sustained increase in phrenic nerve inspiratory burst amplitude. Phrenic motor output was measured in urethane‐anesthetized, mechanically ventilated, vagotomized adult male Sprague‐Dawley rats. Along with amplitude of inspiratory phrenic motor output, arterial blood pressure and end‐tidal CO2 were recorded. For intrathecal delivery of ampakine CX717 (15μl, 500μM, dissolved in 10% HPCD), the spinal cord was exposed via a dorsal approach followed by laminectomy and durotomy to enable drug administration over the mid‐cervical spinal cord. At least 15 min of stable phrenic burst amplitude was recorded as baseline after which intrathecal CX717 was applied. The initial results (n=3 sham, n=3 CX717) indicate that spinally directed CX717 causes a gradual and sustained increase in phrenic inspiratory burst amplitude lasting up to 60 min. Conversely, intrathecal delivery of 10% HPCD (sham) had no consistent impact on phrenic burst amplitude. These preliminary results are consistent with the hypothesis that allosteric modulation of spinal AMPA receptors can increase phrenic motor output. Phrenic motor neurons express AMPA receptors and are a likely candidate for the site of CX717 action.Support or Funding Information5 R01 HL139708 02 (DDF)
Macrophage Class A Scavenger Receptors Bind Tumor‐Associated Carbohydrate Antigens and Promote Breast Cancer Growth and Metastases in Mice
Authors: Post Steven R. , Monzavi-Karbassi Behjatolah , Simecka Christy M. , Kumarapeli Asangi , Jousheghany Fariba , Webber Jessica , He Beixiang , Wadley Taylor , Meece Trevor , Siegel Eric R. , Kelly Thomas 
Published: April 2020

Tumor‐associated macrophages (TAMs) play a key role in determining the immune response in cancer. Macrophages express pattern‐recognition receptors, such as Class A Scavenger Receptors (SR‐A), that bind a variety of different ligands and regulate macrophage immune phenotype. SR‐A expression by TAMs is thought to reflect a tumor‐promoting M2 macrophage phenotype, and the accumulation of SR‐A expressing macrophages is associated with increased tumor aggressiveness and poor patient prognosis in a variety of cancers, including breast cancer. Previous studies indicate that SR‐A ligands are present in the medium of cultured tumor cells. To test the possibility that SR‐A may directly bind to tumor cells, we developed a flow cytometry based binding assay using a soluble SR‐A (sSR‐A) protein and showed that SR‐A binds directly to breast cancer cells. This binding depended on glycosylation indicating SR‐A binds to cell‐surface glycans on tumor cells, which is important because tumor‐associated carbohydrate antigens (TACAs) are associated with immune suppression, tumor progression, and poor prognosis for breast cancer patients. The ability of SR‐A to bind TACAs was tested using carbohydrate mimetic peptides (CMPs) that are structurally similar to TACAs. sSR‐A bound to CMPs, and a CMP designed to react with mannose‐rich structures blocked sSR‐A binding to tumor cells. Because SR‐A induces an immune‐suppressive macrophage phenotype, we hypothesized that SR‐A would enhance the progression of breast cancer. Using mouse models of spontaneous breast cancer, our results show that development of palpable tumors was significantly delayed and the number of lung metastases significantly decreased in mice that do not express SR‐A (SR‐A−/−). These findings demonstrate that SR‐A binds to TACAs on breast cancer cells, and that SR‐A enhances breast cancer growth and metastases. Together with previous findings, our results indicate a model in which SR‐A binds to TACAs to induce an immune‐suppressive macrophage phenotype, which contributes to immune suppression, tumor growth, and metastases.Support or Funding InformationThis research was supported by grants from the NIH (R21CA185691), the Arkansas Breast Cancer Research Program, and a DEAP award from UAMS.
Improved Vascular Function Following 7 days of L‐Citrulline Administration in Heart Failure with Preserved Ejection Fraction
Authors: Ratchford Stephen , Bunsawat Kanokwan , Alpenglow Jeremy , Richardson Russell , Wright Josephine , Ryan John , Wray D. Walter 
Published: April 2020

BackgroundThere is increasing evidence to support the presence of peripheral vascular dysfunction in patients with heart failure with preserved ejection fraction (HFpEF), which may be due, at least in part, to disease‐related changes in nitric oxide (NO) signaling. L‐Arginine (L‐Arg) is the sole substrate for NO synthesis, but is susceptible to intestinal and hepatic degradation via arginase when administered orally. L‐Citrulline (L‐Cit) is catabolized to L‐Arg at the tissue level and is not a substrate for arginase, and therefore enteral L‐Cit administration has emerged as an effective approach for increasing NO substrate bioavailability.PurposeThe present investigation sought to determine whether oral L‐Cit administration (6g/day for 7 days) would improve vascular function in patients with HFpEF.MethodsIn 13 patients NYHA Class II (n=9) and III (n=4) with HFpEF (2M/11F, 69±10y, EF: 66±7%), flow mediated dilation (FMD) and reactive hyperemia (RH) were evaluated to assess conduit artery and microvascular function, respectively. FMD was expressed as % change in brachial artery diameter (%FMD) and % change corrected for shear rate (%FMD/shear), and RH was calculated as area‐under‐the‐curve for brachial artery blood flow. Plasma L‐Cit and L‐Arg concentrations were assessed to confirm absorption and evaluate circulating NO substrate, and the ratio of L‐Arg to plasma asymmetric dimethylarginine (ADMA) was calculated as a biomarker of NO bioavailability.ResultsCompared to baseline, L‐Cit administration improved FMD (0d: 2.5 ± 0.5%, 7d: 4.7 ± 0.9%), FMD/shear (0d: 0.07 ± 0.02, 7d: 0.12 ± 0.01AU) and RH (0d: 450 ± 46ml, 7d: 574 ± 62ml). L‐Cit (0d: 42 ± 3μM/L, 7d: 370 ± 60 μM/L), L‐Arg (0d: 65 ± 8μM/L, 7d: 257 ± 25μM/L), and L‐Arg:ADMA (0d: 136 ± 14AU, 7d: 481 ± 50AU) all increased following L‐Cit administration.ConclusionsThis study has identified the efficacy of a 7d administration of L‐Cit to improve NO substrate bioavailability, the L‐Arg/ADMA ratio, and both conduit artery and microvascular function in patients with HFpEF. These results provide new insight into the mechanisms that govern peripheral vascular dysfunction in this patient group, and demonstrate a promising plasticity in the peripheral vasculature among patients with this chronic disease.Support or Funding InformationSupport or Funding Information: This project is funded in part by the National Institutes of Health (HL118313; D.W.W., R56AG057584; R.S.R., T32HL139451 R.S.R) and the U.S. Department of Veterans Affairs (I01RX001311; D.W.W., I01RX001697; R.S.R., I01RX002323; R.S.R., I21RX001433; R.S.R., I01RX000182; R.S.R.) and the American Heart Association (18POST33960192; K.B.).
TIFA‐NF‐κB axis modulates inflammatory microenvironment to offset sorafenib cytotoxicity in hepatocellular carcinoma
Authors: Wei Tong-You Wade , Tsai Ming-Daw 
Published: April 2020

Sorafenib is the promising first‐line drug to treat advanced hepatocellular carcinoma (HCC), with the acquired resistance within 6 months in most treated patients. The resistance to sorafenib treatment has been correlated to inflammation or viral hepatitis, but the underlying molecular mechanism remains elusive. We previously reported that the TRAF‐interacting protein TIFA sustains an inflammatory feedback loop of TNFα and NF‐κB to drive a survival pathway. Here we investigated how the inflammatory microenvironment is modulated by TIFA‐NF‐κB axis to confer a sorafenib‐resistant niche for HCC recurrence. The prognostic analysis showed that severe hepatitis was highly associated with poorer clinical responses to sorafenib treatment, suggesting that the sorafenib‐resistant HCC involves chronic inflammation. In support, inflammatory cytokines TNF‐α protected HCC lines form sorafenib cytotoxicity, while inhibition of TIFA‐NF‐κB axis reversed the effect. In addition, we showed that TIFA‐NF‐κB axis offset sorafenib cytotoxicity by supporting BCL‐2‐dependent survival signaling. To further explore the therapeutic relevance, we targeted TIFA‐NF‐κB axis using a liver‐tropic adeno‐associated virus to deliver shRNAs in an orthotopic xenograft HCC model, and result showed significant repression of tumor growth and prolonged animal survival in addition to sorafenib treatment. More intriguingly, such inhibition also abrogated the liver‐infiltration of tumor‐associated macrophages, a mechanistic event proven to be triggered by the TIFA‐NF‐κB‐regulated secretion of damage‐associated molecular pattern molecules S100A8/A9 in response to sorafenib, thereby recruiting precursor monocytes. As consequences of monocyte/macrophage infiltration, the TIFA‐NF‐κB axis in HCC cells compromised sorafenib cytotoxicity in alliance with pro‐tumor M2 macrophages, and harnessed their release of IL‐7 to enhance proliferation, sorafenib resistance, and directional migration of HCC cells. Our results collectively demonstrated that TIFA‐NF‐κB axis supports inflammatory responses to offset sorafenib cytotoxicity, and that its targeting provides therapeutically intervention concomitant with sorafenib treatment in HCC.Support or Funding InformationThis study was supported by Academia Sinica and the Taiwan Protein Project funded by Ministry of Science and Technology (MOST; Grant No. AS‐KPQ‐105‐TPP), and in part by grants MOST 104‐2314‐B‐182A‐060 and Chang Gung Memorial Hospital CMRPG3G0561.