73,375 results match your criteria Blood cells molecules & diseases[Journal]


Integrative analysis of transcriptome-wide association study data and messenger RNA expression profiles identified candidate genes and pathways for inflammatory bowel disease.

J Cell Biochem 2019 Apr 22. Epub 2019 Apr 22.

Key Laboratory of Trace Elements and Endemic Diseases of National Health and Family Planning Commission, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Collaborative Innovation Center of Endemic Diseases and Health Promotion in Silk Road Region, School of Public Health, Health Science Center, Xi'an Jiaotong University, Xi'an, Shaanxi, P.R. China.

Inflammatory bowel disease (IBD) is a complex disease, resulting from abnormal immune response to intestinal tract microbiota in genetically susceptible individuals. Crohn's disease and ulcerative colitis (UC) are the two major types of IBD. Transcriptome-wide association study (TWAS) of IBD was first performed using a large-scale genome-wide association study summary data sets of IBD. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/jcb.28744DOI Listing

The immune checkpoint molecules PD-1, PD-L1, TIM-3 and LAG-3 in diffuse large B-cell lymphoma.

Oncotarget 2019 Mar 12;10(21):2030-2040. Epub 2019 Mar 12.

Division of Blood Disorders, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ, USA.

Signaling through immune checkpoint receptors may lead to T-cell exhaustion and function as immune escape mechanisms in cancer. For diffuse large B-cell lymphoma (DLBCL), the mechanistic and prognostic importance of these markers on tumor cells and the tumor microenvironment remains unclear. We determined the immunohistochemical expression of PD-1, PD-L1, TIM-3, and LAG-3 on tumor cells and on tumor infiltrating lymphocytes (TILs) among 123 DLBCL patients. Read More

View Article

Download full-text PDF

Source
http://www.oncotarget.com/fulltext/26771
Publisher Site
http://dx.doi.org/10.18632/oncotarget.26771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459346PMC
March 2019
1 Read

Dysregulated T Cell Activation and Aberrant Cytokine Expression Profile in Systemic Lupus Erythematosus.

Mediators Inflamm 2019 17;2019:8450947. Epub 2019 Mar 17.

Clinical Research Center, The Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China.

Accumulating evidence indicates a critical role for T cells and relevant cytokines in the pathogenesis of systemic lupus erythematosus (SLE). However, the specific contribution of T cells together with the related circulating cytokines in disease pathogenesis and organ involvement is still not clear. In the current study, we investigated relevant molecule expressions and cytokine levels in blood samples from 49 SLE patients and 22 healthy control subjects. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/8450947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441516PMC

Establishment of three-dimensional canine osteosarcoma cell lines showing vasculogenic mimicry and evaluation of biological properties after treatment with 17-AAG.

Vet Comp Oncol 2019 Apr 21. Epub 2019 Apr 21.

Faculty of Veterinary Medicine, University of Teramo, Teramo (TE), Italy.

Vasculogenic mimicry (VM) is an alternative type of blood perfusion characterized by formation of non-endothelial cell-lined microcirculatory channels and is responsible for aggressive tumor biology and increased tumor-related mortality. VM-correlated genes are associated with vascular endothelial grown factor receptor 1 (VEGFR1), and hypoxia-related (hypoxia inducible factor 1 α - HIF1α) signaling pathways, whose molecules are client proteins of Hsp90 (Heat shock protein 90) and are potential therapeutic targets. This pilot study was aimed to investigate vasculogenic mimicry in a three-dimensional (3D) cell culture system of two aggressive canine osteosarcoma (OSA) cell lines (D22 and D17), and to evaluate the response of these cells to 17-AAG treatment in relation to tubular-like structure formation in vitro. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1111/vco.12482DOI Listing

Spinal Cord Injury: Animal Models, Imaging Tools and the Treatment Strategies.

Neurochem Res 2019 Apr 20. Epub 2019 Apr 20.

Inserm, U-1192-Laboratoire Protéomique, Réponse Inflammatoire et Spectrométrie de Masse-PRISM, Université de Lille, 59000, Lille, France.

Spinal cord injury (SCI) often leads to irreversible neuro-degenerative changes with life-long consequences. While there is still no effective therapy available, the results of past research have led to improved quality of life for patients suffering from partial or permanent paralysis. In this review we focus on the need, importance and the scientific value of experimental animal models simulating SCI in humans. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11064-019-02800-wDOI Listing

Matrix metalloproteinase inhibitors prevent the release and proteolytic activity of monocyte/macrophage-derived microparticles.

Pharmacol Rep 2019 Jan 31;71(3):485-490. Epub 2019 Jan 31.

Department of Pharmacy, University of Pisa, Pisa, Italy.

Background: The role of monocyte/macrophage-derived microparticles (MPs) in the pathophysiology of cancer and chronic inflammatory diseases has been reported; nevertheless, the mechanism underlying microparticles release is currently unclear. The aim of the current study was to investigate whether matrix metalloproteinase (MMP) inhibitors could prevent MP shedding from stimulated human monocyte/macrophage.

Methods: Microparticles were obtained by isolated peripheral blood mononuclear cells after stimulation with the calcium ionophore, A23187. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pharep.2019.01.013DOI Listing
January 2019

Permselective glucose sensing with GLUT1-rich cancer cell membranes.

Biosens Bioelectron 2019 Apr 12;135:82-87. Epub 2019 Apr 12.

School of Biomedical Engineering, Korea University, Seoul, 02841, Republic of Korea. Electronic address:

Enzymatic blood glucose detection with selectivity is one of the most important conundrums, because human blood contains many components that can hinder enzyme-substrate reactions. Meanwhile, cancer cells express much higher levels of glucose transporter-1 on their cell membrane to selectively and excessively uptake more α-D-glucose than do normal cells. Inspired by such cellular permselectivity for glucose, herein we significantly improved the selectivity of a glucose sensor by using a breast cancer cell membrane (BCCM). Read More

View Article

Download full-text PDF

Source
https://linkinghub.elsevier.com/retrieve/pii/S09565663193028
Publisher Site
http://dx.doi.org/10.1016/j.bios.2019.04.007DOI Listing
April 2019
1 Read
6.409 Impact Factor

Triple co-culture of human alveolar epithelium, endothelium and macrophages for studying the interaction of nanocarriers with the air-blood barrier.

Acta Biomater 2019 Apr 17. Epub 2019 Apr 17.

HIPS - Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research (HZI), Saarland University, Universitätscampus E8.1, 66123 Saarbrücken, Germany; Department of Pharmacy, Saarland University, 66123, Saarbrücken, Germany. Electronic address:

Predictive in vitro models are valuable alternatives to animal experiments for evaluating the transport of molecules and (nano)particles across biological barriers. In this work, an improved triple co-culture of air-blood barrier was set-up, being exclusively constituted by human cell lines that allowed to perform experiments at air-liquid interface. Epithelial NCI-H441 cells and endothelial HPMEC-ST1. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.actbio.2019.04.037DOI Listing

Shedding New Light on The Role of ανβ3 and α5β1 Integrins in Rheumatoid Arthritis.

Molecules 2019 Apr 18;24(8). Epub 2019 Apr 18.

The Engineering Research Center of Synthetic Polypeptide Drug Discovery and Evaluation of Jiangsu Province, China Pharmaceutical University, Nanjing 210009, China.

ανβ3 and α5β1 are essential glycoproteins involved in the pathogenesis of rheumatoid arthritis (RA). Understanding of the role these integrins play in disease have been analyzed via description of cells-expressing ανβ3 and α5β1 and their mediators to trigger inflammation. ανβ3 and α5β1 facilitate cells-ECM and cell-cell communication, producing pro-inflammatory factors. Read More

View Article

Download full-text PDF

Source
https://www.mdpi.com/1420-3049/24/8/1537
Publisher Site
http://dx.doi.org/10.3390/molecules24081537DOI Listing
April 2019
2 Reads

MicroRNA-Based Diagnosis and Treatment of Metastatic Human Osteosarcoma.

Cancers (Basel) 2019 Apr 18;11(4). Epub 2019 Apr 18.

Division of Pathological Biochemistry, Tottori University Faculty of Medicine, Yonago, Tottori 683-8503, Japan.

Osteosarcoma is a malignant tumor of the bones that commonly occurs in young individuals. The 5-year survival rate of osteosarcoma patients is 60-70%. Metastasis to the lungs leads to death in 30-40% of osteosarcoma patients. Read More

View Article

Download full-text PDF

Source
https://www.mdpi.com/2072-6694/11/4/553
Publisher Site
http://dx.doi.org/10.3390/cancers11040553DOI Listing
April 2019
2 Reads

Pediatric Patients With Steroid-Sensitive Nephrotic Syndrome Have Higher Expression of T Regulatory Lymphocytes in Comparison to Steroid-Resistant Disease.

Front Pediatr 2019 2;7:114. Epub 2019 Apr 2.

Unidade de Nefrologia Pediátrica, Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.

Idiopathic nephrotic syndrome (INS) is classified according to the response to drug therapy in steroid-sensitive (SS), steroid-dependent (SD), and steroid-resistant (SR) categories. Previous studies showed changes in inflammatory activity of subpopulations of lymphocytes in INS. This study aimed to compare SS and SR patients in regard to subpopulations of leukocytes, profile of regulatory lymphocytes, and migratory activity of lymphocyte subpopulations. Read More

View Article

Download full-text PDF

Source
https://www.frontiersin.org/article/10.3389/fped.2019.00114/
Publisher Site
http://dx.doi.org/10.3389/fped.2019.00114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6455073PMC
April 2019
1 Read

Activated Mesenchymal Stromal Cells Process and Present Antigens Regulating Adaptive Immunity.

Front Immunol 2019 3;10:694. Epub 2019 Apr 3.

Department of Diabetes Immunology, Diabetes and Metabolism Research Institute at the Beckman Research Institute of City of Hope, Duarte, CA, United States.

Mesenchymal stromal cells (MSCs) are inherently immunomodulatory through production of inhibiting soluble factors and expression of immunosuppressive cell surface markers. We tested whether activated MSCs qualify for the induction of antigen-specific immune regulation. Bone marrow derived human MSCs were activated by interferon-γ and analyzed for antigen uptake and processing and immune regulatory features including phenotype, immunosuppressive capacity, and metabolic activity. Read More

View Article

Download full-text PDF

Source
https://www.frontiersin.org/article/10.3389/fimmu.2019.00694
Publisher Site
http://dx.doi.org/10.3389/fimmu.2019.00694DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6457321PMC
April 2019
1 Read

The Roles of Cholesterol and Its Metabolites in Normal and Malignant Hematopoiesis.

Authors:
Hideyuki Oguro

Front Endocrinol (Lausanne) 2019 2;10:204. Epub 2019 Apr 2.

Cellular Engineering, The Jackson Laboratory for Genomic Medicine, Farmington, CT, United States.

Hematopoiesis is sustained throughout life by hematopoietic stem cells (HSCs) that are capable of self-renewal and differentiation into hematopoietic progenitor cells (HPCs). There is accumulating evidence that cholesterol homeostasis is an important factor in the regulation of hematopoiesis. Increased cholesterol levels are known to promote proliferation and mobilization of HSCs, while hypercholesterolemia is associated with expansion of myeloid cells in the peripheral blood and links hematopoiesis with cardiovascular disease. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.3389/fendo.2019.00204DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454151PMC

Real-Time Measurement of Melanoma Cell-Mediated Human Brain Endothelial Barrier Disruption Using Electric Cell-Substrate Impedance Sensing Technology.

Biosensors (Basel) 2019 Apr 15;9(2). Epub 2019 Apr 15.

Department of Molecular Medicine and Pathology, School of Medical Sciences, Faculty of Medical and Health Sciences, University of Auckland, Auckland 1023, New Zealand.

Electric cell-substrate impedance sensing (ECIS) is an impedance-based method for monitoring changes in cell behaviour in real-time. In this paper, we highlight the importance of ECIS in measuring the kinetics of human melanoma cell invasion across human brain endothelium. ECIS data can be mathematically modelled to assess which component of the endothelial paracellular and basolateral barriers is being affected and when. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.3390/bios9020056DOI Listing

Comparison of six commercial serum exosome isolation methods suitable for clinical laboratories. Effect in cytokine analysis.

Clin Chem Lab Med 2019 Apr 16. Epub 2019 Apr 16.

Department of Biochemistry, Clínica Universidad de Navarra, Pamplona, Spain.

Background Exosomes are nanovesicles released by cells that can be detected in blood. Exosomes contain several molecules, such as cytokines that have potential utility as disease biomarkers. The aim of the present work is to compare six different commercial kits suitable for the clinical laboratory in relation to the efficiency and purity of exosome isolation, and their effect in subsequent cytokines analysis. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1515/cclm-2018-1297DOI Listing

A Ratiometric Fluorescent Probe for Monitoring Endogenous Methylglyoxal in Living Cells and Diabetic Blood Samples.

Anal Chem 2019 Apr 16. Epub 2019 Apr 16.

Optical imaging provides noninvasive powerful tools not only for better understanding the physiological and pathological roles of Methylglyoxal (MGO) in living systems but also for potential clinical diagnosis of MGO-related diseases such as diabetic complications. However, so far only very few "turn-on" MGO fluorescent sensors have been developed, and they are all based on the reaction between MGO and benzenediamines. Due to the possible reactions of benzenediamines with other cellular molecules such as NO and FA, these sensors suffer from limited selectivity and potential deactivation in cells. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.analchem.8b05426DOI Listing
April 2019
1 Read

The hallmarks of CMV-specific CD8 T-cell differentiation.

Med Microbiol Immunol 2019 Apr 13. Epub 2019 Apr 13.

Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands.

Upon cytomegalovirus (CMV) infection, large T-cell responses are elicited that remain high or even increase over time, a phenomenon named memory T-cell inflation. Besides, the maintained robust T-cell response, CMV-specific T cells seem to have a distinctive phenotype, characterized by an advanced differentiation state. Here, we will review this "special" differentiation status by discussing the cellular phenotype based on the expression of CD45 isoforms, costimulatory, inhibitory and natural killer receptors, adhesion and lymphocyte homing molecules, transcription factors, cytokines and cytotoxic molecules. Read More

View Article

Download full-text PDF

Source
http://link.springer.com/10.1007/s00430-019-00608-7
Publisher Site
http://dx.doi.org/10.1007/s00430-019-00608-7DOI Listing
April 2019
1 Read

Endothelial barrier reinforcement relies on flow-regulated glycocalyx, a potential therapeutic target.

Biorheology 2019 Mar 29. Epub 2019 Mar 29.

Department of Bioengineering, Northeastern University, Boston, MA, USA.

Background: The onset of many disease processes depends on the function of the endothelial cell (EC) glycocalyx (GCX) which acts as a flow-dependent barrier to cellular infiltration and molecular transport across the blood vessel wall.

Objective: This review aims to examine these processes with the potential end goal of implementing GCX repair to restore EC barrier function and slow the progression of disease.

Methods: Cell and mouse studies were employed to examine the state of EC GCX in healthy versus disruptive flow conditions. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.3233/BIR-180205DOI Listing

Mechanism for IL-15-Driven B Cell Chronic Lymphocytic Leukemia Cycling: Roles for AKT and STAT5 in Modulating Cyclin D2 and DNA Damage Response Proteins.

J Immunol 2019 Apr 15. Epub 2019 Apr 15.

The Feinstein Institute for Medical Research, Northwell Health, Manhasset, NY 11030;

Clonal expansion of B cell chronic lymphocytic leukemia (B-CLL) occurs within lymphoid tissue pseudofollicles. IL-15, a stromal cell-associated cytokine found within spleens and lymph nodes of B-CLL patients, significantly boosts in vitro cycling of blood-derived B-CLL cells following CpG DNA priming. Both IL-15 and CpG DNA are elevated in microbe-draining lymphatic tissues, and unraveling the basis for IL-15-driven B-CLL growth could illuminate new therapeutic targets. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1801142DOI Listing
April 2019
1 Read

Tumor-derived α-fetoprotein suppresses fatty acid metabolism and oxidative phosphorylation in dendritic cells.

Cancer Immunol Res 2019 Apr 15. Epub 2019 Apr 15.

Research, Parker Institute for Cancer Immunotherapy

Cellular metabolism supports immune cell function. Here, we identify a reduction in fatty acid synthesis and mitochondrial metabolism in dendritic cells (DCs) due to α-fetoprotein (AFP), a protein secreted by hepatocellular cancer (HCC). DCs cultured in the presence of AFP show reduced expression of the metabolic regulatory molecules SREBP-1 and PGC1-α. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1158/2326-6066.CIR-18-0513DOI Listing

Immunosuppressive effects of tick protein RHcyst-1 on murine bone marrow-derived dendritic cells.

Parasit Vectors 2019 Apr 15;12(1):169. Epub 2019 Apr 15.

Key Laboratory of Animal Parasitology of Ministry of Agriculture, Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, China.

Background: Ticks, as blood-feeding arthropod vectors, have evolved their own unique mechanism to suppress host immune responses and evade immune defenses in order to complete blood-feeding. The immunoregulatory effect of tick bioactive molecules on hosts has been widely reported, and the cystatin family has been identified as one of the major immunomodulators. In previous studies, we obtained a novel tick salivary bioactive protein named RHcyst-1, which belongs to the type 1 cystatin family. Read More

View Article

Download full-text PDF

Source
https://parasitesandvectors.biomedcentral.com/articles/10.11
Publisher Site
http://dx.doi.org/10.1186/s13071-019-3411-1DOI Listing
April 2019
1 Read

Investigation of Circulating Serum MicroRNA-328-3p and MicroRNA-3135a Expression as Promising Novel Biomarkers for Autism Spectrum Disorder.

Balkan J Med Genet 2018 Dec 31;21(2):5-12. Epub 2018 Dec 31.

Department of Plant Physiology and Molecular Biology, University of Plovdiv "Paisii Hilendarski," Plovdiv, Plovdiv, Bulgaria.

Circulating microRNAs (miRNAs) are emerging as promising diagnostic biomarkers for autism spectrum disorder (ASD), but their usefulness for detecting ASD remains unclear. Nowadays, development of promising biomarkers for ASD remains a challenge. Recently, dysregulation of the miRNAs expression in postmortem brain tissue, serum and peripheral blood, have been associated with ASD. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.2478/bjmg-2018-0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6454235PMC
December 2018
1 Read

Immunophenotype and Immune-Modulatory Activities of Human Fetal Cartilage-Derived Progenitor Cells.

Cell Transplant 2019 Apr 14:963689719842166. Epub 2019 Apr 14.

1 Department of Molecular Science and Technology, Ajou University, Suwon, Korea.

We have previously reported human fetal cartilage progenitor cells (hFCPCs) as a novel source of therapeutic cells showing high proliferation and stem cell properties superior to those of adult mesenchymal stem cells (MSCs). In this study, we investigated the immunophenotype and immune-modulatory activities of hFCPCs. With institutional review board approval, hFCPCs were isolated from fetuses at 11-13 weeks of gestation. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1177/0963689719842166DOI Listing

AdipoRon Protects Against Secondary Brain Injury After Intracerebral Hemorrhage via Alleviating Mitochondrial Dysfunction: Possible Involvement of AdipoR1-AMPK-PGC1α Pathway.

Neurochem Res 2019 Apr 13. Epub 2019 Apr 13.

Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, 88 Jiefang Road, Hangzhou, 310009, Zhejiang, China.

Intracerebral hemorrhage (ICH) is a stroke subtype that is associated with high mortality and disability rate. Mitochondria plays a crucial role in neuronal survival after ICH. This study first showed that activation of adiponectin receptor 1 (AdipoR1) by AdipoRon could attenuate mitochondrial dysfunction after ICH. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11064-019-02794-5DOI Listing

Characterization of fat body cells at different developmental stages of Culex pipiens.

Acta Histochem 2019 Apr 9. Epub 2019 Apr 9.

Section of Zoology, Department of Biology, Faculty of Science, Ege University, İzmir, Turkey.

The fat body, originates from mesoderm, has many metabolic functions which changes as the embryonic development of the insect progresses. It plays an important role in the intermediate metabolism and in the metabolism of proteins, lipids and carbohydrates. It has roles in synthesis, absorption and storage of nutrients from hemolymph. Read More

View Article

Download full-text PDF

Source
https://linkinghub.elsevier.com/retrieve/pii/S00651281193000
Publisher Site
http://dx.doi.org/10.1016/j.acthis.2019.04.002DOI Listing
April 2019
1 Read

Plasmodium infection inhibits the expansion and activation of MDSCs and Tregs in the tumor microenvironment in a murine Lewis lung cancer model.

Cell Commun Signal 2019 Apr 12;17(1):32. Epub 2019 Apr 12.

State Key Laboratory of Respiratory Disease, Center of Infection and Immunity, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, 510530, People's Republic of China.

Background: A major challenge in the development of effective cancer immunotherapy is the ability of tumors and their microenvironment to suppress immune cells through immunosuppressive cells such as myeloid -derived suppressor cells and regulatory T cells. We previously demonstrated that Plasmodium infection promotes innate and adaptive immunity against cancer in a murine Lewis lung cancer model but its effects on immunosuppressive cells in the tumor microenvironment are unknown.

Methods: Whole Tumors and tumor-derived sorted cells from tumor-bearing mice treated with or without plasmodium infected red blood cells were harvested 17 days post tumor implantation and analyzed using QPCR, western blotting, flow cytometry, and functional assays. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12964-019-0342-6DOI Listing

Biological Activities of Leaves Ethanolic Extract and the Extract Fabricated Gold Nanoparticles (AuNPs).

Molecules 2019 Apr 11;24(7). Epub 2019 Apr 11.

Unit of Bee Research and Honey Production, Faculty of Science, King Khalid University, P.O. Box 9004, Abha 61413, Saudi Arabia.

leaves extract (EpExt) and gold nanoparticles (AuNPs) phytofabricated with extract (EpExt-AuNPs) were investigated for biological activities. EpExt and EpExt-AuNPs were screened for: (i) anticancer activity against Hela and HepG2 cell lines; (ii) antimicrobial activity; (iii) hemolytic activity; (iv) cytotoxic or stimulatory effects; and (v) insecticidal activity. AuNPs (size 50 nm) were synthesized. Read More

View Article

Download full-text PDF

Source
https://www.mdpi.com/1420-3049/24/7/1431
Publisher Site
http://dx.doi.org/10.3390/molecules24071431DOI Listing
April 2019
1 Read

Cell Internalization in Fluidic Culture Conditions Is Improved When Microparticles Are Specifically Targeted to the Human Epidermal Growth Factor Receptor 2 (HER2).

Pharmaceutics 2019 Apr 11;11(4). Epub 2019 Apr 11.

Unitat de Biologia Cel·lular, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Biociències, Universitat Autònoma de Barcelona, Bellaterra, 08193 Barcelona, Spain.

Purpose: To determine if the specific targeting of microparticles improves their internalization by cells under fluidic conditions.

Methods: Two isogenic breast epithelial cell lines, one overexpressing the Human Epidermal Growth Factor Receptor 2 (HER2) oncogene (D492HER2) and highly tumorigenic and the other expressing HER2 at much lower levels and non-tumorigenic (D492), were cultured in the presence of polystyrene microparticles of 1 µm in diameter, biofunctionalized with either a specific anti-HER2 antibody or a non-specific secondary antibody. Mono- and cocultures of both cell lines in static and fluidic conditions were performed, and the cells with internalized microparticles were scored. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.3390/pharmaceutics11040177DOI Listing

Pharmacological and transcriptome profiling analyses of Fufang E'jiao Jiang during chemotherapy-induced myelosuppression in mice.

J Ethnopharmacol 2019 Apr 9;238:111869. Epub 2019 Apr 9.

Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China. Electronic address:

Ethnopharmacological Relevance: Fufang E'jiao Jiang (FEJ), a famous traditional Chinese medicine formula from "Liangyi Ointment", consists of five crude drugs, Colla corii asini, Radix Ginseng Rubra, Radix Rehmanniae Preparata, Codonopsis pilosula, and Crataegus pinnatifida Bge. It has pronounced functions of qi-nourishing and blood-activating. Recently, it has been widely used in China as a medication against myelosuppression in cancer treatment. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jep.2019.111869DOI Listing
April 2019
1 Read

C1q/TNF-related protein-9 attenuates retinal inflammation and protects blood-retinal barrier in db/db mice.

Eur J Pharmacol 2019 Apr 10;853:289-298. Epub 2019 Apr 10.

Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, 430060, PR China; Cardiovascular Research Institute, Wuhan University, Wuhan, 430060, PR China; Hubei Key Laboratory of Cardiology, Wuhan, 430060, PR China. Electronic address:

C1q/TNF-related protein-9(CTRP9) is an adipose cytokine, a closest adiponectin paralog, which has anti-inflammatory, antioxidant, vasodilation and anti-atherosclerosis effects. In addition, it can increase insulin sensitivity, decrease blood glucose level and inhibit the apoptosis of endothelial cells. However, it remains unclear whether CTRP9 has beneficial effects on diabetic retinopathy (DR). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejphar.2019.04.012DOI Listing
April 2019
1 Read
2.532 Impact Factor

The LRP6 functional mutation rs2302685 contributes to individual susceptibility to alcoholic liver injury related to the Wnt/β-catenin-TCF1-CYP2E1 signaling pathway.

Arch Toxicol 2019 Apr 11. Epub 2019 Apr 11.

Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, China.

Low-density lipoprotein receptor-related protein 6 (LRP6) is an important coreceptor in the Wnt/β-catenin upstream signaling pathway. Rs2302685 is a common functional mutation of LRP6 that has been previously associated with reduced alcoholic liver injury among alcoholic liver disease (ALD) patients, and the present research was designed to study the underlying mechanisms of that finding. A total of 107 ALD patients and 138 non-ALD patients were recruited from hospitalized alcoholics in China. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00204-019-02447-0DOI Listing
April 2019
5.980 Impact Factor

Multi-region sequencing unveils novel actionable targets and spatial heterogeneity in esophageal squamous cell carcinoma.

Nat Commun 2019 04 11;10(1):1670. Epub 2019 Apr 11.

Shenzhen Peking University-The Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Peking University Shenzhen Hospital, 518035, Shenzhen, PR China.

Esophageal squamous cell carcinoma (ESCC) ranks fourth among cancer-related deaths in China due to the lack of actionable molecules. We performed whole-exome and T-cell receptor (TCR) repertoire sequencing on multi-regional tumors, normal tissues and blood samples from 39 ESCC patients. The data revealed 12. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-09255-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6459928PMC
April 2019
2 Reads
10.742 Impact Factor

Chemical modifications of imidazole-containing alkoxyamines increase C-ON bond homolysis rate: Effects on their cytotoxic properties in glioblastoma cells.

Bioorg Med Chem 2019 May 18;27(10):1942-1951. Epub 2019 Mar 18.

Aix Marseille Univ, CNRS, ICR, Marseille, France; Aix Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, CRCM, Marseille, France. Electronic address:

Previously, we described alkoxyamines bearing a pyridine ring as new pro-drugs with low molecular weights and theranostic activity. Upon chemical stimulus, alkoxyamines undergo homolysis and release free radicals, which can, reportedly, enhance magnetic resonance imaging and trigger cancer cell death. In the present study, we describe the synthesis and the anti-cancer activity of sixteen novel alkoxyamines that contain an imidazole ring. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bmc.2019.03.029DOI Listing

Evidence for three populations of the glucose transporter in the human erythrocyte membrane.

Blood Cells Mol Dis 2019 Mar 29;77:61-66. Epub 2019 Mar 29.

Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA; Institute for Drug Discovery, Purdue University, West Lafayette, IN 47907, USA. Electronic address:

Glucose transporter 1 (GLUT1) is one of 13 members of the human equilibrative glucose transport protein family and the only glucose transporter thought to be expressed in human erythrocyte membranes. Although GLUT1 has been shown to be anchored to adducin at the junctional spectrin-actin complex of the membrane through interactions with multiple proteins, whether other populations of GLUT1 also exist in the human erythrocyte membrane has not been examined. Because GLUT1 plays such a critical role in erythrocyte biology and since it comprises 10% of the total membrane protein, we undertook to evaluate the subpopulations of erythrocyte GLUT1 using single particle tracking. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bcmd.2019.03.005DOI Listing

Effects of different levels of soluble PD-L1 protein on the growth of Lewis lung cancer transplanted tumor.

J Biol Regul Homeost Agents 2019 Mar-Apr;33(2):537-542

Respiratory and Critical Care Medicine, Weifang Respiratory Disease Hospital (Weifang No.2 people's Hospital), Weifang, Shandong, China.

To investigate the effects of different doses of soluble PD-L1 (soluble form of Programmed death ligand 1, sPD-L1) protein on Lewis lung cancer cells, flow cytometry was used to detect the expression of PD-L1 (Programmed death ligand 1) on the surface of Lewis lung cancer cell lines and the expression of PD-1 on the surface of T lymphocytes in peripheral blood and spleen cells of C57BL/6 mice. A Lewis lung cancer animal model of C57BL/6 mice was established by transplanting Lewis lung cancer cells subcutaneously. The sPD-L1 protein was injected into the abdominal cavity of the mouse (sPD-L1 Ig) (working dose: 2. Read More

View Article

Download full-text PDF

Source

CpG Oligodeoxynucleotides Modulate Innate and Adaptive Functions of IgM B Cells in Rainbow Trout.

Front Immunol 2019 26;10:584. Epub 2019 Mar 26.

Fish Immunology and Pathology Laboratory, Animal Health Research Center (CISA-INIA), Madrid, Spain.

Oligodeoxynucleotides (ODN) containing unmethylated CpG motifs have been widely postulated as vaccine adjuvants both in mammals and teleost fish. However, to date, the effects that CpGs provoke on cells of the adaptive immune system remain mostly unexplored in fish. Given that rainbow trout () IgM B cells from spleen and blood transcribe high levels of toll like receptor 9 (TLR9), the receptor responsible for CpG detection in mammals, in the current work, we have investigated the effects of CpGs on both spleen and blood IgM B cells from this species. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2019.00584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443966PMC

Targeted antibody and cytokine cancer immunotherapies through collagen affinity.

Sci Transl Med 2019 Apr;11(487)

Institute for Molecular Engineering, University of Chicago, Chicago, IL 60637, USA.

Cancer immunotherapy with immune checkpoint inhibitors (CPIs) and interleukin-2 (IL-2) has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune system activation. Here, we addressed this need by targeting both the CPI antibodies anti-cytotoxic T lymphocyte antigen 4 antibody (αCTLA4) + anti-programmed death ligand 1 antibody (αPD-L1) and the cytokine IL-2 to tumors via conjugation (for the antibodies) or recombinant fusion (for the cytokine) to a collagen-binding domain (CBD) derived from the blood protein von Willebrand factor (VWF) A3 domain, harnessing the exposure of tumor stroma collagen to blood components due to the leakiness of the tumor vasculature. We show that intravenously administered CBD protein accumulated mainly in tumors. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1126/scitranslmed.aau3259DOI Listing
April 2019
1 Read

Arf6, JIP3 and Dynein shape and mediate Macropinocytosis.

Mol Biol Cell 2019 Apr 10:mbcE19010022. Epub 2019 Apr 10.

Cell and Developmental Biology Center, National Heart, Lung and Blood Institute, NIH, Bethesda, MD 20892.

Macropinocytosis is an actin-driven form of clathrin-independent endocytosis that generates an enlarged structure, the macropinosome. Although many studies focus on signaling molecules and phosphoinositides involved in initiating macropinocytosis, the commitment to forming a macropinosome and the handling of that membrane has not been studied in detail. Here we show in HT1080 cells, a human fibrosarcoma cell line, a requirement for microtubules, dynein, the JIP3 microtubule motor scaffold protein, and Arf6, a JIP3 interacting protein, for the formation and inward movement of the macropinosome. Read More

View Article

Download full-text PDF

Source
https://www.molbiolcell.org/doi/10.1091/mbc.E19-01-0022
Publisher Site
http://dx.doi.org/10.1091/mbc.E19-01-0022DOI Listing
April 2019
7 Reads

Non-coding RNAs in kidney injury and repair.

Am J Physiol Cell Physiol 2019 Apr 10. Epub 2019 Apr 10.

Department of Nephrology, The Key Laboratory of Kidney Disease and Blood Purification of Hunan Province, Second Xiangya Hospital at Central South University, Changsha, Hunan, China; Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, GA, USA.

Acute kidney injury (AKI) is major kidney disease featured by a rapid decline of renal function. Pathologically, AKI is characterized by tubular epithelial cell injury and death. Besides its acute consequence, AKI contributes critically to the development and progress of chronic kidney disease (CKD). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpcell.00048.2019DOI Listing
April 2019
1 Read

Acid-Responsive H -Releasing 2D MgB Nanosheet for Therapeutic Synergy and Side Effect Attenuation of Gastric Cancer Chemotherapy.

Adv Healthc Mater 2019 Apr 10:e1900157. Epub 2019 Apr 10.

Guangdong Provincial Key Laboratory of Biomedical Measurements and Ultrasound Imaging, National-Regional Key Technology Engineering Laboratory for Medical Ultrasound, School of Biomedical Engineering, Health Science Center, Shenzhen University, No. 1066 Xueyuan Road, Nanshan District, Shenzhen, 518060, Guangdong, China.

The hydrogen molecule is recognized as a high potential to attenuate toxic side effects of chemotherapy and also enhance chemotherapeutic efficacy, and the development of a novel hydrogen-generating prodrug for facile, safe, and efficient hydrogen delivery is vitally important for combined hydrogenochemotherapy but is still challenging. Here, targeting gastric cancer, a 2D magnesium boride nanosheet (MBN) is synthesized as a new type of acid-responsive hydrogen-releasing prodrug by an ultrasound-assisted chemical etching route, which is used to realize hydrogenochemotherapy by combination of facile oral administration of polyvinylpyrrolidone (PVP)-encapsulating MBN (MBN@PVP) pills with routine intravenous injection of doxorubicin (DOX). The MBN@PVP pill has high stability in normal tissues/blood environments as well as high gastric acid-responsiveness with sustained release behavior, which matches well with its metabolism rate in the stomach in great favor of continuous and long-term hydrogen administration. Read More

View Article

Download full-text PDF

Source
https://onlinelibrary.wiley.com/doi/abs/10.1002/adhm.2019001
Publisher Site
http://dx.doi.org/10.1002/adhm.201900157DOI Listing
April 2019
2 Reads

TNF-α Drives the CCL4 Expression in Human Monocytic Cells: Involvement of the SAPK/JNK and NF-κB Signaling Pathways.

Cell Physiol Biochem 2019 ;52(4):908-921

Animal and Zebrafish Core Facility, Dasman Diabetes Institute, Kuwait City, Kuwait.

Background/aims: Increased circulatory levels of both TNF-α and CCL4/MIP-1β are found in metabolic diseases. However, it is unclear whether TNF-α which is a signature proinflammatory cytokine involved in metabolic inflammation, can induce/promote the expression of CCL4.

Methods: THP-1 human monocytic cells and THP-1-derived macrophages were stimulated with TNF-α and LPS-treatment as a positive control. Read More

View Article

Download full-text PDF

Source
https://www.cellphysiolbiochem.com/Articles/000063/
Publisher Site
http://dx.doi.org/10.33594/000000063DOI Listing
April 2019
4 Reads
2.875 Impact Factor

Discrimination of low- and high-grade appendiceal mucinous neoplasms by targeted sequencing of cancer-related variants.

Mod Pathol 2019 Apr 8. Epub 2019 Apr 8.

Division of Surgical Oncology, University of Pittsburgh, Pittsburgh, PA, 15232, USA.

DNA was obtained from matching micro-dissected, primary tumor cells, paired metastases, and peripheral blood mononuclear cells (germline) from patients with appendiceal mucinous neoplasms. We compared specimens from patient cohorts comprising low-grade adenomucinous neoplasm versus high-grade mucinous adenocarcinoma using a targeted, amplicon sequencing panel of 409 cancer related genes (Ion Torrent Comprehensive Cancer Panel, Thermo-Fisher, Waltham, MA). Copy number variants, single nucleotide variants and small insertions/deletions were identified using a multiplex algorithm pipeline (GATK, VarScan2, MuTect2, SIFT, SIFT-INDEL, PolyPhen-2, Provean). Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41379-019-0256-2DOI Listing

ZnO Quantum Dots Modified by pH-Activated Charge-Reversal Polymer for Tumor Targeted Drug Delivery.

Polymers (Basel) 2018 Nov 15;10(11). Epub 2018 Nov 15.

Institute of Biomedical Materials and Engineering, College of Materials Science and Engineering, College of Chemistry and Chemical Engineering, Qingdao University, Qingdao 266071, China.

In this paper, we reported a pH responsive nano drug delivery system (NDDS) based on ZnO quantum dots (QDs) for controlled release of drugs. Zwitterionic poly(carboxybetaine methacrylate) (PCBMA) and poly(2-(dimethylamino) ethyl methacrylate) (PDMAEMA) were introduced to modify ZnO QDs, which can help enhance water stability, increase blood circulation time, and promote endocytosis. After tuning of PCBMA/PDMAEMA ratios, the ZnO@P(CBMADMAEMA) nanoplatform shows a sensitive switch from strong protein adsorption resistance (with negatively charged surface) at physiological pH to strong adhesion to tumor cell membranes (with positively charged surface) at the slightly acidic extracellular pH of tumors. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.3390/polym10111272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6401959PMC
November 2018
2.505 Impact Factor

Extracellular vesicles in autoimmune vasculitis - Little dirts light the fire in blood vessels.

Autoimmun Rev 2019 Apr 5. Epub 2019 Apr 5.

Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Corporal Michael J. Crescenz VA Medical Center (Philadelphia), Philadelphia, PA 19104, USA. Electronic address:

Systemic vasculitis is diverse group of autoimmune disorders which are characterized by inflammation of blood vessel walls with deep aching and burning pain. Their underlying etiology and pathophysiology still remain poorly understood. Extracellular vesicles (EVs), including exosomes, microvesicles (MVs), and apoptotic bodies, are membrane vesicular structures that are released either during cell activation, or when cells undergo programmed cell death, including apoptosis, necroptosis, and pyroptosis. Read More

View Article

Download full-text PDF

Source
https://linkinghub.elsevier.com/retrieve/pii/S15689972193008
Publisher Site
http://dx.doi.org/10.1016/j.autrev.2018.12.007DOI Listing
April 2019
9 Reads

Hydrogen sulfide stabilizes atherosclerotic plaques in apolipoprotein E knockout mice.

Pharmacol Res 2019 Apr 5;144:90-98. Epub 2019 Apr 5.

Shanghai Key Laboratory of Bioactive Small Molecules, Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, 201203, China; School of Pharmacy, Macau University of Science and Technology, Avenida Wai Long, Taipa, Macau, China. Electronic address:

Hydrogen sulfide gas (HS) has protective effects in the cardiovascular system that includes preventing the development of atherosclerosis when tested in several in vivo models. Plaque instability is a major risk factor for thromboembolism, myocardial infarction, and stroke, so we examined if HS can promote plaque stability and the potential underlying mechanisms. Apolipoprotein E knockout mice fed an atherogenic diet were administered the exogenous HS donor sodium hydrosulfide (NaHS) or pravastatin as a positive control daily for 14 weeks. Read More

View Article

Download full-text PDF

Source
https://linkinghub.elsevier.com/retrieve/pii/S10436618183186
Publisher Site
http://dx.doi.org/10.1016/j.phrs.2019.04.006DOI Listing
April 2019
1 Read

The Caveolin-3 P104L mutation in LGMD-1C patients inhibits non-insulin-stimulated glucose metabolism and growth but promotes myocyte proliferation.

Cell Biol Int 2019 Apr 8. Epub 2019 Apr 8.

Department of Physiology, School of Basic Medical Sciences, Guangxi Medical University, Nanning, Guangxi, China, 2 Department of Endocrinology, Guangxi Medical University First Affiliated Hospital, Nanning, Guangxi, China.

The caveolin-3 (CAV3) protein is known to be specifically expressed in various myocytes, and skeletal muscle consumes most of the blood glucose as an energy source to maintain normal cell metabolism and function. The P104L mutation in the coding sequence of the human CAV3 gene leads to the autosomal dominant disease limb-girdle muscular dystrophy type 1C (LGMD-1C). We previously reported that C2C12 cells transiently transfected with the P104L CAV3 mutant exhibited decreased glucose uptake and glycogen synthesis after insulin stimulation. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1002/cbin.11144DOI Listing
April 2019
3 Reads

Transient blood-brain barrier disruption is induced by low pulsed electrical fields in vitro: an analysis of permeability and trans-endothelial electric resistivity.

Drug Deliv 2019 Dec;26(1):459-469

b The Joseph Sagol Neuroscience Center, Sheba Medical Center , Ramat Gan , Israel.

The blood-brain barrier (BBB) is limiting transcellular and paracellular movement of molecules and cells, controls molecular traffic, and keeps out toxins. However, this protective function is the major hurdle for treating brain diseases such as brain tumors, Parkinson's disease, Alzheimer's disease, etc. It was previously demonstrated that high pulsed electrical fields (PEFs) can disrupt the BBB by inducing electroporation (EP) which increases the permeability of the transcellular route. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1080/10717544.2019.1571123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461088PMC
December 2019
1 Read

Mesenchymal stromal cells for bone sarcoma treatment: Roadmap to clinical practice.

J Bone Oncol 2019 Jun 19;16:100231. Epub 2019 Mar 19.

Academic Orthopaedic Unit, Papageorgiou General Hospital, Aristotle University Medical School, West Ring Road of Thessaloniki, Pavlos Melas Area, N. Efkarpia, 56403 Thessaloniki, Greece.

Over the past few decades, there has been growing interest in understanding the molecular mechanisms of cancer pathogenesis and progression, as it is still associated with high morbidity and mortality. Current management of large bone sarcomas typically includes the complex therapeutic approach of limb salvage or sacrifice combined with pre- and postoperative multidrug chemotherapy and/or radiotherapy, and is still associated with high recurrence rates. The development of cellular strategies against specific characteristics of tumour cells appears to be promising, as they can target cancer cells selectively. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbo.2019.100231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6434099PMC
June 2019
1 Read

The role of extracellular vesicles from different origin in the microenvironment of head and neck cancers.

Mol Cancer 2019 Apr 6;18(1):83. Epub 2019 Apr 6.

State Key Laboratory of Oral Diseases & National Clinical Research Center for Oral Diseases & Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management & West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, Sichuan, China.

The proliferation and metastasis ability of tumors are mediate by the "mutual dialogue" between cells in the tumor microenvironment (TME). Extracellular vesicles (EVs), mainly exosomes and microvesicles, play an important role in achieving intercellular substance transport and information transfer in the TME. Initially considered "garbage dumpsters" and later referred to as "signal boxes", EVs carry "cargo" (proteins, lipids, or nucleic acids) that can redirect the function of a recipient cell. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12943-019-0985-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451295PMC

Gelatin-chlorin e6 conjugate for in vivo photodynamic therapy.

J Nanobiotechnology 2019 Apr 5;17(1):50. Epub 2019 Apr 5.

Department of Medical Life Sciences, College of Medicine, The Catholic University of Korea, 222 Banpo-daero, Seocho-gu, Seoul, 06591, Republic of Korea.

Background: Improving the water solubility of hydrophobic photosensitizer and increasing its accumulation in tumor tissue are essential for in vivo photodynamic therapy (PDT). Considering commercialization or clinical application in future, it will be promising to achieve these purposes by developing new agents with simple and non-toxic structure.

Results: We conjugated multiple chlorin e6 (Ce6) molecules to gelatin polymer, synthesizing two types of gelatin-Ce6 conjugates with different amounts of Ce6: gelatin-Ce6-2 and gelatin-Ce6-8. Read More

View Article

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12951-019-0475-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6449946PMC