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Ji-Young Kim, Ji-Hae Han, Geon Park, Young-Woo Seo, Cheol-Won Yun, Byung-Chul Lee, Jeehyeon Bae, Ae Ran Moon, Tae-Hyoung Kim
[This corrects the article DOI: 10.18632/oncotarget.8719.].
June 1, 2018: Oncotarget
Jian Li, Lingkai Zhang, Wanqiu Liu
Natural products with significant biological activities continuously act as rich sources for drug discovery and development. To harness the potential of these valuable compounds, robust methods need to be developed for their rapid and sustainable production. Cell-free biosynthesis of pharmaceutical natural products by in vitro reconstruction of the entire biosynthetic pathways represents one such solution. In this review, we focus on in vitro biosynthesis of two important classes of natural products, polyketides (PKs) and nonribosomal peptides (NRPs)...
June 2018: Synthetic and Systems Biotechnology
Joseph R Podojil, Ming-Yi Chiang, Igal Ifergan, Ronald Copeland, Linda N Liu, Sebastien Maloveste, Solomon Langermann, David Liebenson, Roumen Balabanov, Hongbo Chi, Lieping Chen, Dario A A Vignali, Stephen D Miller
The potent immune regulatory function of an agonistic B7-H4-Ig fusion protein (B7-H4Ig) has been demonstrated in multiple experimental autoimmune models; however, the identity of a functional B7-H4 receptor remained unknown. The biological activity of B7-H4 is associated with decreased inflammatory CD4+ T cell responses as supported by a correlation between B7-H4-expressing tumor-associated macrophages and Foxp3+ T cells within the tumor microenvironment. Recent data indicate that members of the semaphorin (Sema)/plexin/neuropilin (Nrp) family of proteins both positively and negatively modulate immune cell function...
June 13, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
Farzaneh Rezazadeh, Nourollah Sadeghzadeh, Seyed Mohammad Abedi, Saeid Abediankenari
INTRODUCTION: The aim of this study was to evaluate the ability of D (LPR), a novel retro-inverso peptidomimetic derivative for imaging colon cancer. METHODS: Two different D (LPR) analogs were designed and compared based on conjugation of HYNIC at peptide's C or N terminal and then labeled with technetium-99m using tricine/EDDA as an exchange coligands. The radiolabeled conjugates were assessed for in vitro stability in saline and serum. The VEGFR-1 and NRP-1 receptors affinity, in vitro internalization and also dissociation Constance was evaluated...
May 31, 2018: Nuclear Medicine and Biology
Huan Wang, Xiaoyi Wang, Cao Xie, Mingfei Zhang, Huitong Ruan, Songli Wang, Kuan Jiang, Fei Wang, Changyou Zhan, Weiyue Lu, Hao Wang
Heptapeptide ATWLPPR (A7R) binds specifically to vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1) overexpressed in glioma cells, exhibiting high potential to achieve glioma targeted drug delivery. However, in vivo application of A7R peptide remains challenging due to the poor proteolytic stability and inaccessibility of A7R to the brain. To tackle these problems, we identified a glycosylated A7R derivative to enhance in vivo stability and brain transport efficacy. Our results showed that glycosylation of peptide could efficiently improve stability in serum, traverse the blood-brain barrier (BBB) and be uptaken by glioma cells...
June 6, 2018: Journal of Controlled Release: Official Journal of the Controlled Release Society
Mingfei Zhang, Weiyue Lu
Malignant glioma is usually accompanied by vigorous angiogenesis to provide essential nutrients. An effective glioma targeting moiety should include excellent tumor-cell homing ability as well as good neovasculature-targeting efficiency, and should be highly resistant to enzyme degradation in the bloodstream. The phage display-selected heptapeptide, the glioma-initiating cell peptide (GICP), was previously reported as a ligand for the VAV3 protein (a Rho-GTPase guanine nucleotide exchange factor), which is mainly expressed on glioma cells; the stabilized heptapeptide D A7R has been shown to be the ligand of both vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1), and has demonstrated good neovasculature-targeting ability...
January 2018: Acta Pharmaceutica Sinica. B
Carolina de Miranda Silva, Amirhossein Hajihosseini, Jenny Myrick, Jocelyn Nole, Arnold Louie, Stephan Schmidt, George L Drusano
Tuberculosis is the ninth-leading cause of death worldwide. Treatment success is approximately 80% for susceptible strains and decreases to 30% for extensively resistant strains. Shortening therapy duration for Mycobacterium tuberculosis ( Mtb ) is a major goal, which can be attained with the use of combination therapy. However, the identification of the most promising combination is a challenge given the quantity of older and newer agents available. Our objective was to identify promising 2-drug combinations using an in vitro strategy to ultimately be tested in an in vitro Hollow Fiber Infection Model (HFIM) and in animal models...
June 4, 2018: Antimicrobial Agents and Chemotherapy
G L Drusano, Jenny Myrick, Michael Maynard, Jocelyn Nole, Brandon Duncanson, David Brown, Stephan Schmidt, Michael Neely, C A Scanga, Charles Peloquin, Arnold Louie
The therapy of Mycobacterium tuberculosis (MTB) infection is long and arduous. It has been hypothesized that the therapy duration is driven primarily by populations of organisms in different metabolic states that replicate slowly or not at all (Acid-phase and NRP-phase organisms). Linezolid is an oxazolidinone antimicrobial with substantial activity against Log-phase MTB. Here, we examined organisms in Acid-phase growth and Non-Replicative Persister phenotype growth and determined the effect of differing clinically-relevant exposures to linezolid in a Hollow Fiber Infection Model (HFIM)...
June 4, 2018: Antimicrobial Agents and Chemotherapy
Anbu Mozhi, Israr Ahmad, Qari Muhammad Kaleem, Ruslan G Tuguntaev, Ahmed Shaker Eltahan, Chen Wang, Rong Yang, Chan Li, Xing-Jie Liang
Mitochondria are considered the power house of cells where ATP is generated for cellular metabolism, and they also act as a crucial regulator of the intrinsic apoptosis pathway. During ATP synthesis, reactive oxygen species (ROS) are produced as secondary products. Overproduction of ROS can promote mitochondrial DNA mutation, dysfunction and depolarization of the mitochondrial membrane, ultimately resulting in cell death. Therefore, the destruction of mitochondria would be an effective therapeutic approach to kill malignant tumors...
May 31, 2018: International Journal of Pharmaceutics
Peeyush K Lala, Pinki Nandi, Mousumi Majumder
Lymphangiogenesis (formation of new lymphatic vessels), unlike angiogenesis, has been a lesser-focused field in cancer biology, because of earlier controversy regarding whether lymphatic metastasis occurs via pre-existing or newly formed lymphatics. Recent evidence reveals that peri-tumoral or intra-tumoral lymphangiogenesis is a precursor for lymphatic metastasis in most carcinomas and melanomas. Two major lymphangiogenic factors, vascular endothelial growth factor (VEGF)-C and VEGF-D, are produced by cancer cells or immune cells such as macrophages in the tumor-stroma to promote sprouting of lymphatics from lymphatic endothelial cells (LEC) or LEC precursors (LECP) by binding to their primary (high affinity) receptor VEGF-R3 or secondary receptors VEGF-R2, neuropilin (NRP)2 and α9/β1 integrin...
June 1, 2018: Cancer Metastasis Reviews
Chikako Sumi, Naoto Hirose, Makoto Yanoshita, Mami Takano, Sayuri Nishiyama, Yuki Okamoto, Yuki Asakawa, Kotaro Tanimoto
Background: Excessive mechanical stress causes inflammation and destruction of cartilage and is considered one of the cause of osteoarthritis (OA). Expression of semaphorin 3A (Sema3A), which is an axon guidance molecule, has been confirmed in chondrocytes. However, there are few reports about Sema3A in chondrocytes, and the effects of Sema3A on inflammation in the cartilage are poorly understood. The aim of this study was to examine the role of Sema3A in inflammation caused by high magnitude cyclic tensile strain (CTS)...
2018: Mediators of Inflammation
Noemi Gioelli, Federica Maione, Chiara Camillo, Michela Ghitti, Donatella Valdembri, Noemi Morello, Marie Darche, Lorena Zentilin, Gabriella Cagnoni, Yaqi Qiu, Mauro Giacca, Maurizio Giustetto, Michel Paques, Ilaria Cascone, Giovanna Musco, Luca Tamagnone, Enrico Giraudo, Guido Serini
Vascular normalizing strategies, aimed at ameliorating blood vessel perfusion and lessening tissue hypoxia, are treatments that may improve the outcome of cancer patients. Secreted class 3 semaphorins (SEMA3), which are thought to directly bind neuropilin (NRP) co-receptors that, in turn, associate with and elicit plexin (PLXN) receptor signaling, are effective normalizing agents of the cancer vasculature. Yet, SEMA3A was also reported to trigger adverse side effects via NRP1. We rationally designed and generated a safe, parenterally deliverable, and NRP1-independent SEMA3A point mutant isoform that, unlike its wild-type counterpart, binds PLXNA4 with nanomolar affinity and has much greater biochemical and biological activities in cultured endothelial cells...
May 23, 2018: Science Translational Medicine
Xiaocong Wang, Huihua Hu, Hebo Liu
This work aims to explore the roles and related mechanisms of RNA binding protein Lin28B in gastric cancer cells stemness. We found that Lin28B expression was negatively correlated with the overall survival (OS) of gastric cancer patients, and significantly increased in gastric cancer cells compared with that in gastric epithelial cells. Lin28B overexpression increased spheroid formation, expression of gastric cancer stemness-related markers, and decreased cisplatin sensitivity in gastric cancer cells. Mechanistically, Lin28B could directly bind to NRP-1 3'UTR, thus increasing NRP-1 mRNA stability and expression, and activate the downstream Wnt/β-catenin signaling...
May 19, 2018: Biomedicine & Pharmacotherapy, Biomédecine & Pharmacothérapie
Maria Liza Espinoza, Po-Yin Cheung, Tze-Fun Lee, Megan O'Reilly, Georg M Schmölzer
BACKGROUND: The Neonatal Resuscitation Program (NRP) states that if adequate positive pressure ventilation (PPV) was given for a low heart rate (HR), the infant's HR should increase within the first 15 s of PPV. OBJECTIVE: To assess changes in HR in piglets with asphyxia-induced bradycardia. METHODS: Term newborn piglets (n=30) were anaesthetised, intubated, instrumented and exposed to 50 min normocapnic hypoxia followed by asphyxia. Asphyxia was achieved by clamping the tube until severe bradycardia (defined as HR at <u><</u>25% of baseline)...
May 19, 2018: Archives of Disease in Childhood. Fetal and Neonatal Edition
Chenxi Hu, Panrong Zhu, Youyou Xia, Kaiyuan Hui, Mei Wang, Xiaodong Jiang
PURPOSE: To determine if inhibiting neuropilin-1 (NRP-1) affects the radiosensitivity of NSCLC cells through a vascular endothelial growth factor receptor 2 (VEGFR2)-independent pathway, and to assess the underlying mechanisms. METHODS: The expression of VEGFR2, NRP-1, related signaling molecules, abelson murine leukemia viral oncogene homolog 1 (ABL-1), and RAD51 were determined by RT-PCR and Western blotting, respectively. Radiosensitivity was assessed using the colony-forming assay, and the cell apoptosis were analyzed by flow cytometry...
May 17, 2018: Journal of Cancer Research and Clinical Oncology
Roy Maimon, Ariel Ionescu, Avichai Bonnie, Sahar Sweetat, Shane Wald-Altman, Shani Inbar, Tal Gradus, Davide Trotti, Miguel Weil, Oded Behar, Eran Perlson
Axon degeneration and disruption of neuromuscular junctions (NMJs) are key events in Amyotrophic Lateral Sclerosis (ALS) pathology. Although the disease's etiology is not fully understood, it is thought to involve a non-cell-autonomous mechanism and alterations in RNA metabolism. Here, we identified reduced levels of miR-126-5p in pre-symptomatic ALS male mice models, and an increase in its targets: axon destabilizing type-3 Semaphorins and their co-receptor Neuropilins. Utilizing compartmentalized in vitro co-cultures, we demonstrated that myocytes expressing diverse ALS-causing mutations promote axon degeneration and NMJ dysfunction, which were inhibited by applying Neuropilin1 (NRP1) blocking antibody...
May 17, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Tahereh Khamechian, Behnaz Irandoust, Hanieh Mohammadi, Hassan Nikoueinejad, Hossein Akbari
In recent years, it has been recognized that regulatory T cells (Tregs) play a critical role in maintaining immune tolerance. Moreover, the expression of two markers named Helios and neurophilin-1 (NRP-1) has been highlighted in such cells. Helios, an intracellular transcription marker, largely differentiates twomost operative sub group of Tregs, namely naturally occurring (nTreg) and induced (iTreg) Tregs, and NRP-1 is reckoned as a membranous activity marker of Tregs. We aimed to count peripheral mononuclear cells expressing such markers in a group of type 1 diabetes patients to elucidate the possible role of Tregs in the pathogenesis of such disease and its complications...
April 2018: Iranian Journal of Allergy, Asthma, and Immunology
Daniel Grun, Gautam Adhikary, Richard L Eckert
We have identified an epidermal cancer stem (ECS) cell population that drives formation of rapidly growing and highly invasive and vascularized tumors. VEGF-A and neuropilin-1 (NRP-1) are highly expressed in ECS cell tumors and VEGF-A/NRP-1 interaction is required for ECS cell survival and tumor vascularization. We now identify a novel signaling cascade that is triggered by VEGF-A/NRP-1. We show that NRP-1 forms a complex with GIPC1 and α6/β4-integrin to activate FAK/Src signaling, which leads to stabilization of a YAP1/∆Np63α to enhance ECS cell survival, invasion, and angiogenesis...
May 14, 2018: Oncogene
Sabrina Copsel, Dietlinde Wolf, Brandon Kale, Henry Barreras, Casey O Lightbourn, Cameron S Bader, W Alperstein, Norman H Altman, Krishna V Komanduri, Robert B Levy
Regulatory T cells (Tregs) are essential for the maintenance of tolerance and immune homeostasis. In allogeneic hematopoietic stem cell transplantation (aHSCT), transfer of appropriate Treg numbers is a promising therapy for the prevention of graft-versus-host disease (GVHD). We have recently reported a novel approach which induces the marked expansion and selective activation of Tregs in vivo by targeting TNF receptor superfamily 25 (TNFRSF25) and CD25. A potential advance to promote clinical application of Treg cells to ameliorate GVHD and other disorders would be the generation of more potent Treg populations...
May 8, 2018: Biology of Blood and Marrow Transplantation
Mingfei Zhang, Linwei Lu, Man Ying, Huitong Ruan, Xiaoyi Wang, Huan Wang, Zhilan Chai, Songli Wang, Changyou Zhan, Jun Pan, Weiyue Lu
The robust proliferation of tumors relies on rich neovasculature for nutrients supply. Therefore, a basic strategy of tumor targeting therapy should include not only killing regular cancer cells but also blocking tumor neovasculature. D-peptide DA7R, which was previously reported to specifically bind vascular endothelial growth factor receptor 2 (VEGFR2) and neuropilin-1 (NRP-1), could achieve the goal of multi-targets recognition. Accordingly, the main purposes of this work were to establish a carfilzomib loaded lipid nanodisk modified with multifunctional peptide DA7R (DA7R-ND/CFZ) and to evaluate its anti-glioblastoma efficacy in vitro and in vivo...
May 7, 2018: Molecular Pharmaceutics
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