bluuebunny/crossref_metadata_2025 huggingface dataset:
Tolerance of Facultative Metallophyte Carlina acaulis to Cadmium Relies on Chelating and Antioxidative Metabolites
Authors: Dresler Sławomir , Strzemski Maciej , Kováčik Jozef , Sawicki Jan , Staniak Michał , Wójciak Magdalena , Sowa Ireneusz , Hawrylak-Nowak Barbara
Published: April 2020

The impact of long-term chronic cadmium stress (ChS, 0.1 µM Cd, 85 days) or short-term acute cadmium stress (AS, 10 µM Cd, 4 days) on Carlina acaulis (Asteraceae) metabolites was compared to identify specific traits. The content of Cd was higher under AS in all organs in comparison with ChS (130 vs. 16 µg·g−1 DW, 7.9 vs. 3.2 µg·g−1 DW, and 11.5 vs. 2.4 µg·g−1 DW in roots, leaves, and trichomes, respectively) while shoot bioaccumulation factor under ChS (ca. 280) indicates efficient Cd accumulation. High content of Cd in the trichomes from the AS treatment may be an anatomical adaptation mechanism. ChS evoked an increase in root biomass (hormesis), while the impact on shoot biomass was not significant in any treatment. The amounts of ascorbic acid and sum of phytochelatins were higher in the shoots but organic (malic and citric) acids dominated in the roots of plants from the ChS treatment. Chlorogenic acid, but not ursolic and oleanolic acids, was elevated by ChS. These data indicate that both chelation and enhancement of antioxidative power contribute to protection of plants exposed to long-term (chronic) Cd presence with subsequent hormetic effect.
TNFAIP3 Deficiency Affects Monocytes, Monocytes-Derived Cells and Microglia in Mice
Authors: Montarolo Francesca , Perga Simona , Tessarolo Carlotta , Spadaro Michela , Martire Serena , Bertolotto Antonio
Published: April 2020

The intracellular-ubiquitin-ending-enzyme tumor necrosis factor alpha-induced protein 3 (TNFAIP3) is a potent inhibitor of the pro-inflammatory nuclear factor kappa-light-chain-enhancer of activated B cell (NF-kB) pathway. Single nucleotide polymorphisms in TNFAIP3 locus have been associated to autoimmune inflammatory disorders, including Multiple Sclerosis (MS). Previously, we reported a TNFAIP3 down-regulated gene expression level in blood and specifically in monocytes obtained from treatment-naïve MS patients compared to healthy controls (HC). Myeloid cells exert a key role in the pathogenesis of MS. Here we evaluated the effect of specific TNFAIP3 deficiency in myeloid cells including monocytes, monocyte-derived cells (M-MDC) and microglia analyzing lymphoid organs and microglia of mice. TNFAIP3 deletion is induced using conditional knock-out mice for myeloid lineage. Flow-cytometry and histological procedures were applied to assess the immune cell populations of spleen, lymph nodes and bone marrow and microglial cell density in the central nervous system (CNS), respectively. We found that TNFAIP3 deletion in myeloid cells induces a reduction in body weight, a decrease in the number of M-MDC and of common monocyte and granulocyte precursor cells (CMGPs). We also reported that the lack of TNFAIP3 in myeloid cells induces an increase in microglial cell density. The results suggest that TNFAIP3 in myeloid cells critically controls the development of M-MDC in lymphoid organ and of microglia in the CNS.
Pro-Arrhythmic Signaling of Thyroid Hormones and Its Relevance in Subclinical Hyperthyroidism
Authors: Tribulova Narcis , Kurahara Lin Hai , Hlivak Peter , Hirano Katsuya , Szeiffova Bacova Barbara
Published: April 2020

A perennial task is to prevent the occurrence and/or recurrence of most frequent or life-threatening cardiac arrhythmias such as atrial fibrillation (AF) and ventricular fibrillation (VF). VF may be lethal in cases without an implantable cardioverter defibrillator or with failure of this device. Incidences of AF, even the asymptomatic ones, jeopardize the patient’s life due to its complication, notably the high risk of embolic stroke. Therefore, there has been a growing interest in subclinical AF screening and searching for novel electrophysiological and molecular markers. Considering the worldwide increase in cases of thyroid dysfunction and diseases, including thyroid carcinoma, we aimed to explore the implication of thyroid hormones in pro-arrhythmic signaling in the pathophysiological setting. The present review provides updated information about the impact of altered thyroid status on both the occurrence and recurrence of cardiac arrhythmias, predominantly AF. Moreover, it emphasizes the importance of both thyroid status monitoring and AF screening in the general population, as well as in patients with thyroid dysfunction and malignancies. Real-world data on early AF identification in relation to thyroid function are scarce. Even though symptomatic AF is rare in patients with thyroid malignancies, who are under thyroid suppressive therapy, clinicians should be aware of potential interaction with asymptomatic AF. It may prevent adverse consequences and improve the quality of life. This issue may be challenging for an updated registry of AF in clinical practice. Thyroid hormones should be considered a biomarker for cardiac arrhythmias screening and their tailored management because of their multifaceted cellular actions.
Bone Marrow-Derived NCS-01 Cells Advance a Novel Cell-Based Therapy for Stroke
Authors: Brown John , Park You Jeong , Lee Jea-Young , Chase Thomas N. , Koga Minako , Borlongan Cesar V.
Published: April 2020

Human mesenchymal stem cells have been explored for their application in cell-based therapies targeting stroke. Identifying cell lines that stand as safe, accessible, and effective for transplantation, while optimizing dosage, timing, and method of delivery remain critical translational steps towards clinical trials. Preclinical studies using bone marrow-derived NCS-01 cells show the cells’ ability to confer functional recovery in ischemic stroke. Coculturing primary rat cortical cells or human neural progenitor cells with NCS-01 cells protects against oxygen-glucose deprivation. In the rodent middle cerebral artery occlusion model, intracarotid artery administration of NCS-01 cells demonstrate greater efficacy than other mesenchymal stem cells (MSCs) at improving motor and neurological function, as well as reducing infarct volume and peri-infarct cell loss. NCS-01 cells secrete therapeutic factors, including basic fibroblast growth factor and interleukin-6, while also demonstrating a potentially novel mechanism of extending filopodia towards the site of injury. In this review, we discuss recent preclinical advancements using in vitro and in vivo ischemia models that support the transplantation of NCS-01 in human stroke trials. These results, coupled with the recommendations put forth by the consortium of Stem cell Therapeutics as an Emerging Paradigm for Stroke (STEPS), highlight a framework for conducting preclinical research with the ultimate goal of initiating clinical trials.
Identification of EIL and ERF Genes Related to Fruit Ripening in Peach
Authors: Zhou Hui , Zhao Lei , Yang Qiurui , Amar Mohamed Hamdy , Ogutu Collins , Peng Qian , Liao Liao , Zhang Jinyun , Han Yuepeng
Published: April 2020

Peach (Prunus persica) is a climacteric fruit with a relatively short shelf life due to its fast ripening or softening process. Here, we report the association of gene families encoding ethylene insensitive-3 like (EIL) and ethylene response factor (ERF) with fruit ripening in peach. In total, 3 PpEILs and 12 PpERFs were highly expressed in fruit, with the majority showing a peak of expression at different stages. All three EILs could activate ethylene biosynthesis genes PpACS1 and PpACO1. One out of the 12 PpERFs, termed PpERF.E2, is a homolog of ripening-associated ERFs in tomato, with a consistently high expression throughout fruit development and an ability to activate PpACS1 and PpACO1. Additionally, four subgroup F PpERFs harboring the EAR repressive motif were able to repress the PpACO1 promoter but could also activate the PpACS1 promoter. Promoter deletion assay revealed that PpEILs and PpERFs could participate in transcriptional regulation of PpACS1 through either direct or indirect interaction with various cis-elements. Taken together, these results suggested that all three PpEILs and PpERF.E2 are candidates involved in ethylene biosynthesis, and EAR motif-containing PpERFs may function as activator or repressor of ethylene biosynthesis genes in peach. Our study provides an insight into the roles of EILs and ERFs in the fruit ripening process.
Changing ALK-TKI-Resistance Mechanisms in Rebiopsies of ALK-Rearranged NSCLC: ALK- and BRAF-Mutations Followed by Epithelial-Mesenchymal Transition
Authors: Urbanska Edyta M. , Sørensen Jens B. , Melchior Linea C. , Costa Junia C. , Santoni-Rugiu Eric
Published: April 2020

Anaplastic lymphoma-kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) is prone to developing heterogeneous, only partly known mechanisms of resistance to ALK-tyrosine-kinase-inhibitors (ALK-TKIs). We present a case of a 38-year old male, who never smoked with disseminated ALK-rearranged (EML4 (20) – ALK (20) fusion variant 2) lung adenocarcinoma, who received four sequentially different ALK-TKIs and two lines of chemotherapy in-between. We observed significant clinical benefit by the first three ALK-TKIs (Crizotinib, Ceritinib, Alectinib) and chemotherapy with Pemetrexed, resulting in overall survival over 3 years. Longitudinal assessment of progressions by rebiopsies from hepatic metastases showed different mechanisms of resistance to each ALK-TKI, including secondary ALK-mutations and the downstream p.V600E BRAF-mutation that had not been linked to second-generation ALK-TKIs before. Ultimately, in connection with terminal rapid progression and resistance to Alectinib and Lorlatinib, we identified phenotypical epithelial-mesenchymal transition (EMT) of newly occurred metastatic cells, a phenomenon not previously related to these two ALK-TKIs. This resistance heterogeneity suggests a continuously changing disease state. Sequential use of different generation’s ALK-TKIs and combination therapies may yield prolonged responses with satisfactory quality of life in patients with advanced ALK-positive NSCLC. However, the development of EMT is a major hurdle and may explain rapid disease progression and lack of response to continued ALK-inhibition.
Possible Role of Amyloidogenic Evolvability in Dementia with Lewy Bodies: Insights from Transgenic Mice Expressing P123H β-Synuclein
Authors: Fujita Masayo , Ho Gilbert , Takamatsu Yoshiki , Wada Ryoko , Ikeda Kazutaka , Hashimoto Makoto
Published: April 2020

Dementia with Lewy bodies (DLB) is the second most prevalent neurodegenerative dementia after Alzheimer’s disease, and is pathologically characterized by formation of intracellular inclusions called Lewy bodies, the major constituent of which is aggregated α-synuclein (αS). Currently, neither a mechanistic etiology nor an effective disease-modifying therapy for DLB has been established. Although two missense mutations of β-synuclein (βS), V70M and P123H, were identified in sporadic and familial DLB, respectively, the precise mechanisms through which βS mutations promote DLB pathogenesis remain elusive. To further clarify such mechanisms, we investigated transgenic (Tg) mice expressing P123H βS, which develop progressive neurodegeneration in the form of axonal swelling and non-motor behaviors, such as memory dysfunction and depression, which are more prominent than motor deficits. Furthermore, cross-breeding of P123H βS Tg mice with αS Tg mice worsened the neurodegenerative phenotype presumably through the pathological cross-seeding of P123H βS with αS. Collectively, we predict that βS misfolding due to gene mutations might be pathogenic. In this paper, we will discuss the possible involvement of amyloidogenic evolvability in the pathogenesis of DLB based on our previous papers regarding the P123H βS Tg mice. Given that stimulation of αS evolvability by P123H βS may underlie neuropathology in our mouse model, more radical disease-modifying therapy might be derived from the evolvability mechanism. Additionally, provided that altered βS were involved in the pathogenesis of sporadic DLB, the P123H βS Tg mice could be used for investigating the mechanism and therapy of DLB.
Endocannabinoid-Mediated Neuromodulation in the Olfactory Bulb: Functional and Therapeutic Significance
Authors: Bhatia-Dey Naina , Heinbockel Thomas
Published: April 2020

Endocannabinoid synthesis in the human body is naturally occurring and on-demand. It occurs in response to physiological and environmental stimuli, such as stress, anxiety, hunger, other factors negatively disrupting homeostasis, as well as the therapeutic use of the phytocannabinoid cannabidiol and recreational use of exogenous cannabis, which can lead to cannabis use disorder. Together with their specific receptors CB1R and CB2R, endocannabinoids are major components of endocannabinoid-mediated neuromodulation in a rapid and sustained manner. Extensive research on endocannabinoid function and expression includes studies in limbic system structures such as the hippocampus and amygdala. The wide distribution of endocannabinoids, their on-demand synthesis at widely different sites, their co-existence in specific regions of the body, their quantitative differences in tissue type, and different pathological conditions indicate their diverse biological functions that utilize specific and overlapping pathways in multiple organ systems. Here, we review emerging evidence of these pathways with a special emphasis on the role of endocannabinoids in decelerating neurodegenerative pathology through neural networks initiated by cells in the main olfactory bulb.
Akt3 Regulates the Tissue-Specific Response to Copaiba Essential Oil
Authors: Urasaki Yasuyo , Beaumont Cody , Talbot Jeffery N. , Hill David K. , Le Thuc T.
Published: April 2020

This study reports a relationship between Akt3 expression and tissue-specific regulation of the pI3K/Akt/mTOR signaling pathway by copaiba essential oil. Akt3, a protein kinase B isoform important for the regulation of neuronal development, exhibited differential expression levels in cells of various origins. In neuronal and microglial cells, where Akt3 is present, copaiba essential oil positively regulated the pI3K/Akt/mTOR signaling pathway. In contrast, in liver cells and T lymphocytes, where Akt3 is absent, copaiba essential oil negatively regulated the pI3K/Akt/mTOR signaling pathway. The expression of Akt3 via plasmid DNA in liver cells led to positive regulatory effects by copaiba essential oil on the pI3K/Akt/mTOR signaling pathway. In contrast, inhibition of Akt3 expression in neuronal cells via small interfering RNA molecules targeting Akt3 transcripts abrogated the regulatory effects of copaiba essential oil on the pI3K/Akt/mTOR signaling pathway. Interestingly, Akt3 expression did not impact the regulatory effects of copaiba essential oil on other signaling pathways. For example, copaiba essential oil consistently upregulated the MAPK and JAK/STAT signaling pathways in all evaluated cell types, independent of the Akt3 expression level. Collectively, the data indicated that Akt3 expression was required for the positive regulatory effects of copaiba essential oil, specifically on the pI3K/Akt/mTOR signaling pathway.
Can We Prevent Mitochondrial Dysfunction and Diabetic Cardiomyopathy in Type 1 Diabetes Mellitus? Pathophysiology and Treatment Options
Authors: Cieluch Aleksandra , Uruska Aleksandra , Zozulinska-Ziolkiewicz Dorota
Published: April 2020

Type 1 diabetes mellitus is a disease involving changes to energy metabolism. Chronic hyperglycemia is a major cause of diabetes complications. Hyperglycemia induces mechanisms that generate the excessive production of reactive oxygen species, leading to the development of oxidative stress. Studies with animal models have indicated the involvement of mitochondrial dysfunction in the pathogenesis of diabetic cardiomyopathy. In the current review, we aimed to collect scientific reports linking disorders in mitochondrial functioning with the development of diabetic cardiomyopathy in type 1 diabetes mellitus. We also aimed to present therapeutic approaches counteracting the development of mitochondrial dysfunction and diabetic cardiomyopathy in type 1 diabetes mellitus.
Mechanisms of Action of Autophagy Modulators Dissected by Quantitative Systems Pharmacology Analysis
Authors: Shi Qingya , Pei Fen , Silverman Gary A. , Pak Stephen C. , Perlmutter David H. , Liu Bing , Bahar Ivet
Published: April 2020

Autophagy plays an essential role in cell survival/death and functioning. Modulation of autophagy has been recognized as a promising therapeutic strategy against diseases/disorders associated with uncontrolled growth or accumulation of biomolecular aggregates, organelles, or cells including those caused by cancer, aging, neurodegeneration, and liver diseases such as α1-antitrypsin deficiency. Numerous pharmacological agents that enhance or suppress autophagy have been discovered. However, their molecular mechanisms of action are far from clear. Here, we collected a set of 225 autophagy modulators and carried out a comprehensive quantitative systems pharmacology (QSP) analysis of their targets using both existing databases and predictions made by our machine learning algorithm. Autophagy modulators include several highly promiscuous drugs (e.g., artenimol and olanzapine acting as activators, fostamatinib as an inhibitor, or melatonin as a dual-modulator) as well as selected drugs that uniquely target specific proteins (~30% of modulators). They are mediated by three layers of regulation: (i) pathways involving core autophagy-related (ATG) proteins such as mTOR, AKT, and AMPK; (ii) upstream signaling events that regulate the activity of ATG pathways such as calcium-, cAMP-, and MAPK-signaling pathways; and (iii) transcription factors regulating the expression of ATG proteins such as TFEB, TFE3, HIF-1, FoxO, and NF-κB. Our results suggest that PKA serves as a linker, bridging various signal transduction events and autophagy. These new insights contribute to a better assessment of the mechanism of action of autophagy modulators as well as their side effects, development of novel polypharmacological strategies, and identification of drug repurposing opportunities.
The Swing of Lipids at Peroxisomes and Endolysosomes in T Cell Activation
Authors: Dosil Sara G. , Rojas-Gomez Amelia , Sánchez-Madrid Francisco , Martín-Cófreces Noa B.
Published: April 2020

The immune synapse (IS) is a well-known intercellular communication platform, organized at the interphase between the antigen presenting cell (APC) and the T cell. After T cell receptor (TCR) stimulation, signaling from plasma membrane proteins and lipids is amplified by molecules and downstream pathways for full synapse formation and maintenance. This secondary signaling event relies on intracellular reorganization at the IS, involving the cytoskeleton and components of the secretory/recycling machinery, such as the Golgi apparatus and the endolysosomal system (ELS). T cell activation triggers a metabolic reprogramming that involves the synthesis of lipids, which act as signaling mediators, and an increase of mitochondrial activity. Then, this mitochondrial activity results in elevated reactive oxygen species (ROS) production that may lead to cytotoxicity. The regulation of ROS levels requires the concerted action of mitochondria and peroxisomes. In this review, we analyze this reprogramming and the signaling implications of endolysosomal, mitochondrial, peroxisomal, and lipidic systems in T cell activation.
Quantitative Phosphoproteomic Analysis Reveals the Regulatory Networks of Elovl6 on Lipid and Glucose Metabolism in Zebrafish
Authors: Wang Xueting , Sun Shouxiang , Cao Xiaojuan , Gao Jian
Published: April 2020

Elongation of very long-chain fatty acids protein 6 (Elovl6) has been reported to be associated with clinical treatments of a variety of metabolic diseases. However, there is no systematic and comprehensive study to reveal the regulatory role of Elovl6 in mRNA, protein and phosphorylation levels. We established the first knock-out (KO), elovl6−/−, in zebrafish. Compared with wild type (WT) zebrafish, KO presented significant higher whole-body lipid content and lower content of fasting blood glucose. We utilized RNA-Seq, tandem mass tag (TMT) labeling-based quantitative technology and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to perform the transcriptomic, proteomic and phosphoproteomic analyses of livers from WT and elovl6−/− zebrafish. There were 734 differentially expressed genes (DEG) and 559 differentially expressed proteins (DEP) between elovl6−/− and WT zebrafish, identified out of quantifiable 47251 transcripts and 5525 proteins. Meanwhile, 680 differentially expressed phosphoproteins (DEPP) with 1054 sites were found out of quantifiable 1230 proteins with 3604 sites. Gene ontology (GO) and kyoto encyclopedia of genes and genomes (KEGG) analysis of the transcriptomic and proteomic data further suggested that the abnormal lipid metabolism and glucose metabolism in KO were mainly related to fatty acid degradation and biosynthesis, glycolysis/gluconeogenesis and PPAR signaling pathway. Based on phosphoproteomic analyses, some kinases critical for lipid metabolism and glucose metabolism, including ribosomal protein S6 kinase (Rps6kb), mitogen-activated protein kinase14 (Mapk14) and V-akt murine thymoma viral oncogene homolog 2-like (Akt2l), were identified. These results allowed us to catch on the regulatory networks of elovl6 on lipid and glucose metabolism in zebrafish. To our knowledge, this is the first multi-omic study of zebrafish lacking elovl6, which provides strong datasets to better understand many lipid/glucose metabolic risks posed to human health.
The Role of Aryl Hydrocarbon Receptor (AhR) in Brain Tumors
Authors: Perepechaeva Maria L. , Grishanova Alevtina Y.
Published: April 2020

Primary brain tumors, both malignant and benign, are diagnosed in adults at an incidence rate of approximately 23 people per 100 thousand. The role of AhR in carcinogenesis has been a subject of debate, given that this protein may act as either an oncogenic protein or a tumor suppressor in different cell types and contexts. Lately, there is growing evidence that aryl hydrocarbon receptor (AhR) plays an important part in the development of brain tumors. The role of AhR in brain tumors is complicated, depending on the type of tumor, on ligands that activate AhR, and other features of the pathological process. In this review, we summarize current knowledge about AhR in relation to brain tumors and provide an overview of AhR’s potential as a therapeutic target.
The Effect of the Chorion on Size-Dependent Acute Toxicity and Underlying Mechanisms of Amine-Modified Silver Nanoparticles in Zebrafish Embryos
Authors: Chen Zi-Yu , Li Nian-Jhen , Cheng Fong-Yu , Hsueh Jian-Feng , Huang Chiao-Ching , Lu Fu-I , Fu Tzu-Fun , Yan Shian-Jang , Lee Yu-Hsuan , Wang Ying-Jan
Published: April 2020

As the worldwide application of nanomaterials in commercial products increases every year, various nanoparticles from industry might present possible risks to aquatic systems and human health. Presently, there are many unknowns about the toxic effects of nanomaterials, especially because the unique physicochemical properties of nanomaterials affect functional and toxic reactions. In our research, we sought to identify the targets and mechanisms for the deleterious effects of two different sizes (~10 and ~50 nm) of amine-modified silver nanoparticles (AgNPs) in a zebrafish embryo model. Fluorescently labeled AgNPs were taken up into embryos via the chorion. The larger-sized AgNPs (LAS) were distributed throughout developing zebrafish tissues to a greater extent than small-sized AgNPs (SAS), which led to an enlarged chorion pore size. Time-course survivorship revealed dose- and particle size-responsive effects, and consequently triggered abnormal phenotypes. LAS exposure led to lysosomal activity changes and higher number of apoptotic cells distributed among the developmental organs of the zebrafish embryo. Overall, AgNPs of ~50 nm in diameter exhibited different behavior from the ~10-nm-diameter AgNPs. The specific toxic effects caused by these differences in nanoscale particle size may result from the different mechanisms, which remain to be further investigated in a follow-up study.
Antagonistic Roles of GRK2 and GRK5 in Cardiac Aldosterone Signaling Reveal GRK5-Mediated Cardioprotection via Mineralocorticoid Receptor Inhibition
Authors: Maning Jennifer , McCrink Katie , Pollard Celina , Desimine Victoria , Ghandour Jennifer , Perez Arianna , Cora Natalie , Ferraino Krysten , Parker Barbara , Brill Ava , Aukszi Beatrix , Lymperopoulos Anastasios
Published: April 2020

Aldosterone (Aldo), when overproduced, is a cardiotoxic hormone underlying heart failure and hypertension. Aldo exerts damaging effects via the mineralocorticoid receptor (MR) but also activates the antiapoptotic G protein-coupled estrogen receptor (GPER) in the heart. G protein-coupled receptor (GPCR)-kinase (GRK)-2 and -5 are the most abundant cardiac GRKs and phosphorylate GPCRs as well as non-GPCR substrates. Herein, we investigated whether they phosphorylate and regulate cardiac MR and GPER. To this end, we used the cardiomyocyte cell line H9c2 and adult rat ventricular myocytes (ARVMs), in which we manipulated GRK5 protein levels via clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and GRK2 activity via pharmacological inhibition. We report that GRK5 phosphorylates and inhibits the cardiac MR whereas GRK2 phosphorylates and desensitizes GPER. In H9c2 cardiomyocytes, GRK5 interacts with and phosphorylates the MR upon β2-adrenergic receptor (AR) activation. In contrast, GRK2 opposes agonist-activated GPER signaling. Importantly, GRK5-dependent MR phosphorylation of the MR inhibits transcriptional activity, since aldosterone-induced gene transcription is markedly suppressed in GRK5-overexpressing cardiomyocytes. Conversely, GRK5 gene deletion augments cardiac MR transcriptional activity. β2AR-stimulated GRK5 phosphorylates and inhibits the MR also in ARVMs. Additionally, GRK5 is necessary for the protective effects of the MR antagonist drug eplerenone against Aldo-induced apoptosis and oxidative stress in ARVMs. In conclusion, GRK5 blocks the cardiotoxic MR-dependent effects of Aldo in the heart, whereas GRK2 may hinder beneficial effects of Aldo through GPER. Thus, cardiac GRK5 stimulation (e.g., via β2AR activation) might be of therapeutic value for heart disease treatment via boosting the efficacy of MR antagonists against Aldo-mediated cardiac injury.
Chemerin Treatment Inhibits the Growth and Bone Invasion of Breast Cancer Cells
Authors: Kim Hyungkeun , Lee Joo-Hee , Lee Sun Kyoung , Song Na-Young , Son Seung Hwa , Kim Ki Rim , Chung Won-Yoon
Published: April 2020

Chemerin is secreted as prochemerin from various cell types and then cleaved into the bioactive isoform by specific proteases. In various cancer types, chemerin exhibits pro- or antitumor effects. In the present study, chemerin treatment significantly inhibited the viability and invasion of breast cancer cells in the absence or presence of transforming growth factor (TGF)-β and insulin-like growth factor (IGF)-1. The expression levels of E-cadherin and vimentin were reduced in chemerin-treated breast cancer cells. However, chemerin treatment recovered the reduced E-cadherin expression level in breast cancer cells treated with TGF-β or IGF-1. Chemerin treatment inhibited nuclear β-catenin levels in breast cancer cells stimulated with or without TGF-β or IGF-1. In addition, chemerin treatment blocked the increase in the receptor activator of nuclear factor kappa-Β ligand (RANKL)/osteoprotegerin (OPG) ratio in osteoblastic cells exposed to metastatic breast cancer cell-derived conditioned medium. Chemerin treatment inhibited RANKL-induced osteoclast formation and bone resorption by reducing the secretion of matrix metalloproteinase (MMP)-2, MMP-9, and cathepsin K. Intraperitoneal administration of chemerin inhibited tumor growth in MCF-7 breast cancer cell-injected mice and reduced the development of osteolytic lesions resulting from intratibial inoculation of MDA-MB-231 cells. Taken together, chemerin inhibits the growth and invasion of breast cancer cells and prevents bone loss resulting from breast cancer cells by inhibiting finally osteoclast formation and activity.
Non-Coding RNAs as Key Regulators of Glutaminolysis in Cancer
Authors: Ortiz-Pedraza Yunuen , Muñoz-Bello J. Omar , Olmedo-Nieva Leslie , Contreras-Paredes Adriana , Martínez-Ramírez Imelda , Langley Elizabeth , Lizano Marcela
Published: April 2020

Cancer cells exhibit exacerbated metabolic activity to maintain their accelerated proliferation and microenvironmental adaptation in order to survive under nutrient-deficient conditions. Tumors display an increase in glycolysis, glutaminolysis and fatty acid biosynthesis, which provide their energy source. Glutamine is critical for fundamental cellular processes, where intermediate metabolites produced through glutaminolysis are necessary for the maintenance of mitochondrial metabolism. These include antioxidants to remove reactive oxygen species, and the generation of the nonessential amino acids, purines, pyrimidines and fatty acids required for cellular replication and the activation of cell signaling. Some cancer cells are highly dependent on glutamine consumption since its catabolism provides an anaplerotic pathway to feed the Krebs cycle. Intermediate members of the glutaminolysis pathway have been found to be deregulated in several types of cancers and have been proposed as therapeutic targets and prognostic biomarkers. This review summarizes the main players in the glutaminolysis pathway, how they have been found to be deregulated in cancer and their implications for cancer maintenance. Furthermore, non-coding RNAs are now recognized as new participants in the regulation of glutaminolysis; therefore, their involvement in glutamine metabolism in cancer is discussed in detail.
Skeletal Muscle Na,K-ATPase as a Target for Circulating Ouabain
Authors: Kravtsova Violetta V. , Bouzinova Elena V. , Matchkov Vladimir V. , Krivoi Igor I.
Published: April 2020

While the role of circulating ouabain-like compounds in the cardiovascular and central nervous systems, kidney and other tissues in health and disease is well documented, little is known about its effects in skeletal muscle. In this study, rats were intraperitoneally injected with ouabain (0.1–10 µg/kg for 4 days) alone or with subsequent injections of lipopolysaccharide (1 mg/kg). Some rats were also subjected to disuse for 6 h by hindlimb suspension. In the diaphragm muscle, chronic ouabain (1 µg/kg) hyperpolarized resting potential of extrajunctional membrane due to specific increase in electrogenic transport activity of the α2 Na,K-ATPase isozyme and without changes in α1 and α2 Na,K-ATPase protein content. Ouabain (10–20 nM), acutely applied to isolated intact diaphragm muscle from not injected rats, hyperpolarized the membrane to a similar extent. Chronic ouabain administration prevented lipopolysaccharide-induced (diaphragm muscle) or disuse-induced (soleus muscle) depolarization of the extrajunctional membrane. No stimulation of the α1 Na,K-ATPase activity in human red blood cells, purified lamb kidney and Torpedo membrane preparations by low ouabain concentrations was observed. Our results suggest that skeletal muscle electrogenesis is subjected to regulation by circulating ouabain via the α2 Na,K-ATPase isozyme that could be important for adaptation of this tissue to functional impairment.
Nanoparticle-Based Radiosensitization
Authors: Kempson Ivan
Published: April 2020

Radiotherapy is a highly multidisciplinary field with respect to its foundations of research and development, and in its clinical utility [...]
DDX3X is Epigenetically Repressed in Renal Cell Carcinoma and Serves as a Prognostic Indicator and Therapeutic Target in Cancer Progression
Authors: Lin Tsung-Chieh
Published: April 2020

DEAD (Asp-Glu-Ala-Asp) box polypeptide 3, X-linked (DDX3X) is a member of the DEAD-box family of RNA helicases whose function has been revealed to be involved in RNA metabolism. Recent studies further indicate the abnormal expression in pan-cancers and the relevant biological effects on modulating cancer progression. However, DDX3X’s role in renal cell carcinoma (RCC) progression remains largely unknown. In this study, a medical informatics-based analysis using The Cancer Genome Atlas (TCGA) dataset was performed to evaluate clinical prognoses related to DDX3X. The results suggest that DDX3X is epigenetically repressed in tumor tissue and that lower DDX3X is correlated with the poor overall survival of RCC patients and high tumor size, lymph node metastasis, and distant metastasis (TNM staging system). Furthermore, knowledge-based transcriptomic analysis by Ingenuity Pathway Analysis (IPA) revealed that the SPINK1-metallothionein pathway is a top 1-repressed canonical signaling pathway by DDX3X. Furthermore, SPINK1 and the metallothionein gene family all serve as poor prognostic indicators, and the expression levels of those genes are inversely correlated with DDX3X in RCC. Furthermore, digoxin was identified via Connectivity Map analysis (L1000) for its capability to reverse gene signatures in patients with low DDX3X. Importantly, cancer cell proliferation and migration were decreased upon digoxin treatment in RCC cells. The results of this study indicate the significance of the DDX3Xlow/SPINK1high/metallothioneinhigh axis for predicting poor survival outcome in RCC patients and suggest digoxin as a precise and personalized compound for curing those patients with low DDX3X expression levels.
Role of Genetic Variations in the Hepatic Handling of Drugs
Authors: Marin Jose J. G. , Serrano Maria A. , Monte Maria J. , Sanchez-Martin Anabel , Temprano Alvaro G. , Briz Oscar , Romero Marta R.
Published: April 2020

The liver plays a pivotal role in drug handling due to its contribution to the processes of detoxification (phases 0 to 3). In addition, the liver is also an essential organ for the mechanism of action of many families of drugs, such as cholesterol-lowering, antidiabetic, antiviral, anticoagulant, and anticancer agents. Accordingly, the presence of genetic variants affecting a high number of genes expressed in hepatocytes has a critical clinical impact. The present review is not an exhaustive list but a general overview of the most relevant variants of genes involved in detoxification phases. The available information highlights the importance of defining the genomic profile responsible for the hepatic handling of drugs in many ways, such as (i) impaired uptake, (ii) enhanced export, (iii) altered metabolism due to decreased activation of prodrugs or enhanced inactivation of active compounds, and (iv) altered molecular targets located in the liver due to genetic changes or activation/downregulation of alternative/compensatory pathways. In conclusion, the advance in this field of modern pharmacology, which allows one to predict the outcome of the treatments and to develop more effective and selective agents able to overcome the lack of effect associated with the existence of some genetic variants, is required to step forward toward a more personalized medicine.
Leveraging Nuclear Receptors as Targets for Pathological Ocular Vascular Diseases
Authors: Yao Pei-Li , Peavey Jeremy , Malek Goldis
Published: April 2020

Vasculogenesis and angiogenesis are physiological mechanisms occurring throughout the body. Any disruption to the precise balance of blood vessel growth necessary to support healthy tissue, and the inhibition of abnormal vessel sprouting has the potential to negatively impact stages of development and/or healing. Therefore, the identification of key regulators of these vascular processes is critical to identifying therapeutic means by which to target vascular-associated compromises and complications. Nuclear receptors are a family of transcription factors that have been shown to be involved in modulating different aspects of vascular biology in many tissues systems. Most recently, the role of nuclear receptors in ocular biology and vasculopathies has garnered interest. Herein, we review studies that have used in vitro assays and in vivo models to investigate nuclear receptor-driven pathways in two ocular vascular diseases associated with blindness, wet or exudative age-related macular degeneration, and proliferative diabetic retinopathy. The potential therapeutic targeting of nuclear receptors for ocular diseases is also discussed.
Impact of Leakage Inlet Swirl Angle in a Rotor–Stator Cavity on Flow Pattern, Radial Pressure Distribution and Frictional Torque in a Wide Circumferential Reynolds Number Range
Authors: Schröder Tilman Raphael , Dohmen Hans-Josef , Brillert Dieter , Benra Friedrich-Karl
Published: April 2020

In the side-chambers of radial turbomachinery, which are rotor–stator cavities, complex flow patterns develop that contribute substantially to axial thrust on the shaft and frictional torque on the rotor. Moreover, leakage flow through the side-chambers may occur in both centripetal and centrifugal directions which significantly influences rotor–stator cavity flow and has to be carefully taken into account in the design process: precise correlations quantifying the effects of rotor–stator cavity flow are needed to design reliable, highly efficient turbomachines. This paper presents an experimental investigation of centripetal leakage flow with and without pre-swirl in rotor–stator cavities through combining the experimental results of two test rigs: a hydraulic test rig covering the Reynolds number range of 4 × 10 5 ≤ R e ≤ 3 × 10 6 and a test rig for gaseous rotor–stator cavity flow operating at 2 × 10 7 ≤ R e ≤ 2 × 10 8 . This covers the operating ranges of hydraulic and thermal turbomachinery. In rotor–stator cavities, the Reynolds number R e is defined as R e = Ω b 2 ν with angular rotor velocity Ω , rotor outer radius b and kinematic viscosity ν . The influence of circumferential Reynolds number, axial gap width and centripetal through-flow on the radial pressure distribution, axial thrust and frictional torque is presented, with the through-flow being characterised by its mass flow rate and swirl angle at the inlet. The results present a comprehensive insight into the flow in rotor–stator cavities with superposed centripetal through-flow and provide an extended database to aid the turbomachinery design process.
Prevailing Approaches and Practices of Citizen Participation in Smart City Projects: Lessons from Trondheim, Norway
Authors: Gohari Savis , Baer Daniela , Nielsen Brita Fladvad , Gilcher Elena , Situmorang Welfry Zwestin
Published: April 2020

Citizen participation has become an important aspect in the design of smart cities. This paper investigates the frame and modality of citizen participation in a European Horizon2020 smart city project, +CityxChange, in Trondheim. +CityxChange aims at enabling citizen participation and co-creation in the transition to a positive energy city. The question is “what are the prevailing approaches and practices in relation to citizen participation amongst the key actors involved in +CityxChange? Which structures and processes have inhibited or fostered the participation mechanisms (e.g., for, by, and of people) and practices in Trondheim?” Through participatory observations and interviews with key local actors and citizens, we found that the focus of +CityxChange on efficiency and creating innovative solutions “for” people in partnership with the private sector has disturbed the “by” and “of” people mechanisms of participation. Citizens’ power and roles are not delegated to challenge or replace the project’s predetermined issue or plan. The anchorage of the project outside of the formal administrative structure has caused other functional barriers that inhibit citizen participation, rather than facilitate it. This paper discusses the causal relationships between these interconnected barriers and suggests how authorities can possibly overcome them.
Integration of BIM and Procedural Modeling Tools for Road Design
Authors: Biancardo Salvatore Antonio , Capano Alessandra , de Oliveira Sara Guerra , Tibaut Andrej
Published: April 2020

Building Information Modeling (BIM) is a design and management methodology strongly used in the Industry of Architecture, Engineering, and Construction (AEC). It allows the creation of a 3D model through parametric modelling in a workflow that updates data, geometry and semantics using the Industry Foundation Classes (IFC) standard. The purpose of this paper is to develop and apply a BIM method for road infrastructures. The creation of the BIM 3D models was carried out using different visual programming software and BIM tools, designing the spatial and parametric representation of the roadway. This way, it has been possible to discover the advantages of using procedural modelling to design road infrastructure through software that are usually used in the mechanical and architectural field. Finally, the interoperability of the software to extract and exchange information between these BIM tools was assessed.
Chemistry of Phosphorene: Synthesis, Functionalization and Biomedical Applications in an Update Review
Authors: Pica Monica , D’Amato Roberto
Published: April 2020

The present review aims to highlight the potential of an emerging 2D single element material: phosphorene. Attention is focused on the more recent studies on phosphorene, in terms of synthetic approaches, modification aimed at its stabilization, and potential applications in the biomedical field. Critical aspects for a practical use of phosphorene are discussed, in order to show a realistic scenario and challenges facing researchers.
Mis-Expression of a Cranial Neural Crest Cell-Specific Gene Program in Cardiac Neural Crest Cells Modulates HAND Factor Expression, Causing Cardiac Outflow Tract Phenotypes
Authors: Vincentz Joshua W. , Clouthier David E. , Firulli Anthony B.
Published: April 2020

Congenital heart defects (CHDs) occur with such a frequency that they constitute a significant cause of morbidity and mortality in both children and adults. A significant portion of CHDs can be attributed to aberrant development of the cardiac outflow tract (OFT), and of one of its cellular progenitors known as the cardiac neural crest cells (NCCs). The gene regulatory networks that identify cardiac NCCs as a distinct NCC population are not completely understood. Heart and neural crest derivatives (HAND) bHLH transcription factors play essential roles in NCC morphogenesis. The Hand1PA/OFT enhancer is dependent upon bone morphogenic protein (BMP) signaling in both cranial and cardiac NCCs. The Hand1PA/OFT enhancer is directly repressed by the endothelin-induced transcription factors DLX5 and DLX6 in cranial but not cardiac NCCs. This transcriptional distinction offers the unique opportunity to interrogate NCC specification, and to understand why, despite similarities, cranial NCC fate determination is so diverse. We generated a conditionally active transgene that can ectopically express DLX5 within the developing mouse embryo in a Cre-recombinase-dependent manner. Ectopic DLX5 expression represses cranial NCC Hand1PA/OFT-lacZ reporter expression more effectively than cardiac NCC reporter expression. Ectopic DLX5 expression induces broad domains of NCC cell death within the cranial pharyngeal arches, but minimal cell death in cardiac NCC populations. This study shows that transcription control of NCC gene regulatory programs is influenced by their initial specification at the dorsal neural tube.
Successful Treatment with Bedtime Basal Insulin Added to Metformin without Weight Gain or Hypoglycaemia over Three Years
Authors: Mertes Bernardo , Gödde Sybille , Piorkowski Michael , Kramer Guido , Müller Ulrich Alfons , Kuniss Nadine
Published: April 2020

The aim of this observational study was to follow-up patients with bedtime basal insulin (NPH insulin) added to metformin. In 285 patients with type 2 diabetes, a therapy with bedtime basal insulin added to metformin was started due to failure to achieve a glycaemic goal. Up until July 2019, 272 patients (95.4%) were followed-up (59.5 y, 92.6 kg, diabetes duration 6.6 y, HbA1c 8.4%/68.6 mmol/mol). HbA1c decreased by −1.2% and bodyweight by −1.7 kg after a duration of 31.7 ± 29.1 (range 2–133) months. Severe hypoglycaemia did not occur. In 144/272 patients (52.9%), the therapeutic goal for HbA1c was achieved over 32.7 months. In 69/272 patients (25.4%), the HbA1c target was achieved over 25.0 months (afterwards, therapy with basal insulin was discontinued because HbA1c was under target). In 36/272 patients (13.2%), the HbA1c goal was achieved until the submission of this manuscript (mean duration of treatment 57.4 ± 28.2 (range 13–121) months). Over 90% of patients with type 2 diabetes and failure of metformin reached their HbA1c goal with additional basal insulin at bedtime over several years in association with a reduction of bodyweight and without any event of severe hypoglycaemia.
Serum Follicle-Stimulating Hormone Levels are Associated with Cardiometabolic Risk Factors in Post-Menopausal Korean Women
Authors: Jung Eun-Soo , Choi Eun-Kyung , Park Byung-Hyun , Chae Soo-Wan
Published: April 2020

Menopause compounds many cardiometabolic risk factors through endogenous estrogen withdrawal. This study aimed to find the association between serum follicle-stimulating hormone (FSH) levels and cardiometabolic risk factors in post-menopausal Korean women. A total of 608 post-menopausal women from eight randomized double-blind, placebo-controlled clinical trials on menopause during the year 2012–2019 were analyzed. Cardiometabolic risk factors such as body mass index, waist circumference, systolic blood pressure, fasting glucose, triglycerides (TG), high density lipoprotein-cholesterol (HDL-C), and TG/HDL-C ratio were significantly improved as the FSH quartiles increased. Metabolic syndrome (MetS) and the number of components of MetS decreased as FSH quartiles increased. In regression analysis, FSH level was negatively associated with cardiometabolic risk factors including body mass index, body weight, waist circumference, fasting glucose and TG, while it was positively associated with HDL-C. The odds ratio of MetS in the first quartile of FSH was 2.682 compared with that in the fourth quartile of FSH in a logistic regression model. Serum FSH levels had a negative correlation with cardiometabolic risk factors in post-menopausal Korean women, suggesting that a low FSH can be a predictor for cardiovascular disease in post-menopausal women.
A New Customized Bioactive Glass Filler to Functionalize Resin Composites: Acid-Neutralizing Capability, Degree of Conversion, and Apatite Precipitation
Authors: Par Matej , Attin Thomas , Tarle Zrinka , Tauböck Tobias T.
Published: April 2020

This study introduced an experimental bioactive glass (BG) with a lower Na2O content than conventional BG 45S5 (10.5 wt% vs. 24.5 wt%), additionally containing CaF2 (12 wt%) and a network connectivity similar to that of BG 45S5. A series of experimental composites functionalized with 5–40 wt% of the novel BG was prepared and compared to a corresponding series of experimental composites functionalized with 5–40 wt% of BG 45S5. Commercial acid-neutralizing materials (alkasite, giomer, and glass ionomer) were used as references. The capabilities of the materials to neutralize hydrochloric acid (pH = 2.6) and lactic acid (pH = 4.5) were evaluated by real-time pH measurements over 1 h. The degree of conversion and precipitation of calcium phosphate were also investigated. Data were analyzed using one-way and Welch ANOVA at an overall level of significance of 0.05. The acid-neutralizing potential of the experimental BG incorporated into resin composites was generally comparable to that of BG 45S5, and better than that of a giomer and glass ionomer. Fluorine was identified in the precipitate that developed on the composites functionalized with the experimental BG, suggesting a capability of forming fluorapatite. Unlike the 45S5 composition, the experimental BG did not impair the degree of conversion of resin composites. The novel BG filler is therefore an interesting candidate for future investigations of caries-preventive resin composites, and their potential clinical applicability for restorative, preventive, and orthodontic purposes.