scholarly journals A helminth chitinase structurally similar to mammalian chitinase displays immunomodulatory properties

2019 ◽  
Author(s):  
Friederike Ebner ◽  
Katja Balster ◽  
Katharina Janek ◽  
Agathe Niewienda ◽  
Piotr H. Malecki ◽  
...  
Keyword(s):  
Inflammatory Marker ◽  
Disease Model ◽  
Three Dimensional ◽  
Gastrointestinal Nematode ◽  
Airway Hyperreactivity ◽  
Allergic Airway Disease ◽  
Biologically Active ◽  
Dimensional Structure ◽  
Trichuris Suis ◽  
Immunomodulatory Properties

AbstractPreviously, we reported significant immunomodulatory effects of the entire excretory-secretory (ES) proteins of the first larval stage (L1) of the gastrointestinal nematodeTrichuris suisin a rodent model of allergic hyperreactivity. In the present study, we aimed to identify the proteins accounting for the modulatory effects of theT. suisL1 ES proteins and thus studied selected components for their immunomodulatory efficacy in an OVA-induced allergic airway disease model. In particular, an enzymatically activeT. suischitinase mediated amelioration of airway hyperreactivity, primarily associated with suppression of eosinophil recruitment into the lung. The three-dimensional structure of theT. suischitinase as determined by high-resolution X-ray crystallography revealed significant similarities to mouse acidic mammalian chitinase (AMCase). In addition, the unique ability ofT. suischitinase to form dimers, as well as acidic surface patches within the dimerization region may contribute to the formation of cross-reactive antibodies to the mouse homologs. This hypothesis is supported by the observation thatT. suischitinase treatment induced cross-reactive antibodies to mouse AMCase and chitinase-like protein BRP-39 in the AHR model. In conclusion, a biologically activeT. suischitinase exhibits immunomodulatory properties despite its structural similarity to the mammalian counterpart.Author summaryExperimental immunotherapy via reintroduction of intestinal worms to treat and prevent autoimmune, chronic inflammatory or allergic diseases is being discussed but the underlying mechanisms are still not fully understood. Here, we investigated the immunomodulatory potential of specific proteins of the whipwormTrichuris suisthat are secreted very early during larval development. Using a murine model of allergic lung disease, we show that in particular oneT. suisprotein, functionally characterized as an active chitinase, is reducing the lung inflammation. TheT. suischitinases three-dimensional protein structure revealed remarkable similarities to the hosts’ chitinase, an enzyme known to play a pivotal role in lung allergy. We also show that treatment with the helminth chitinase induced cross-reactive antibody responses against murine chitinase and chitinase-like proteins, both being inflammatory marker and regulators of type 2 immunity. Thus, our study provides a novel mechanism of immunomodulation by helminth components and may contribute to a better understanding of clinical responses of patients receiving helminthic therapy.

scholarly journals A Helminth-Derived Chitinase Structurally Similar to Mammalian Chitinase Displays Immunomodulatory Properties in Inflammatory Lung Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-24
Author(s):  
Friederike Ebner ◽  
Katja Lindner ◽  
Katharina Janek ◽  
Agathe Niewienda ◽  
Piotr H. Malecki ◽  
...  
Keyword(s):  
Cell Activation ◽  
Disease Model ◽  
Three Dimensional ◽  
Clinical Signs ◽  
Gastrointestinal Nematode ◽  
Chitinase Activity ◽  
Airway Hyperreactivity ◽  
Allergic Airway Disease ◽  
Dimensional Structure ◽  
Dendritic Cell Activation

Immunomodulation of airway hyperreactivity by excretory-secretory (ES) products of the first larval stage (L1) of the gastrointestinal nematode Trichuris suis is reported by us and others. Here, we aimed to identify the proteins accounting for the modulatory effects of the T. suis L1 ES proteins and studied six selected T. suis L1 proteins for their immunomodulatory efficacy in a murine OVA-induced allergic airway disease model. In particular, an enzymatically active T. suis chitinase mediated amelioration of clinical signs of airway hyperreactivity, primarily associated with suppression of eosinophil recruitment into the lung, the associated chemokines, and increased numbers of RELMα+ interstitial lung macrophages. While there is no indication of T. suis chitinase directly interfering with dendritic cell activation or antigen presentation to CD4 T cells, treatment of allergic mice with the worm chitinase influenced the hosts’ own chitinase activity in the inflamed lung. The three-dimensional structure of the T. suis chitinase as determined by high-resolution X-ray crystallography revealed high similarities to mouse acidic mammalian chitinase (AMCase) but a unique ability of T. suis chitinase to form dimers. Our data indicate that the structural similarities between the parasite and host chitinase contribute to the disease-ameliorating effect of the helminth-derived chitinase on allergic lung inflammation.

scholarly journals Three-Dimensional In Vitro Lymphangiogenesis Model in Tumor Microenvironment

2021 ◽  
Vol 9 ◽  
Author(s):  
Youngkyu Cho ◽  
Kyuhwan Na ◽  
Yesl Jun ◽  
Jihee Won ◽  
Ji Hun Yang ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Metastasis ◽  
Lymphatic Vessel ◽  
Disease Model ◽  
Three Dimensional ◽  
Lymphatic Vessels ◽  
Dimensional Structure ◽  
Biomechanical Stress

Lymphangiogenesis is a stage of new lymphatic vessel formation in development and pathology, such as inflammation and tumor metastasis. Physiologically relevant models of lymphatic vessels have been in demand because studies on lymphatic vessels are required for understanding the mechanism of tumor metastasis. In this study, a new three-dimensional lymphangiogenesis model in a tumor microenvironment is proposed, using a newly designed macrofluidic platform. It is verified that controllable biochemical and biomechanical cues, which contribute to lymphangiogenesis, can be applied in this platform. In particular, this model demonstrates that a reconstituted lymphatic vessel has an in vivo–like lymphatic vessel in both physical and biochemical aspects. Since biomechanical stress with a biochemical factor influences robust directional lymphatic sprouting, whether our model closely approximates in vivo, the initial lymphatics in terms of the morphological and genetic signatures is investigated. Furthermore, attempting an incorporation with a tumor spheroid, this study successfully develops a complex tumor microenvironment model for use in lymphangiogenesis and reveals the microenvironment factors that contribute to tumor metastasis. As a first attempt at a coculture model, this reconstituted model is a novel system with a fully three-dimensional structure and can be a powerful tool for pathological drug screening or disease model.

scholarly journals Dendrimers: A New Race of Pharmaceutical Nanocarriers

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Pooja Mittal ◽  
Anjali Saharan ◽  
Ravinder Verma ◽  
Farag M. A. Altalbawy ◽  
Mohammed A. Alfaidi ◽  
...  
Keyword(s):  
Three Dimensional ◽  
Chemical Properties ◽  
Biologically Active ◽  
Dimensional Structure ◽  
Synthesis Mechanism ◽  
Drug Conjugates ◽  
Wide Range ◽  
New Race ◽  
Physical And Chemical ◽  
And Chemical Properties

Dendrimers are nanosized, symmetrical molecules in which a small atom or group of atoms is surrounded by the symmetric branches known as dendrons. The structure of dendrimers possesses the greatest impact on their physical and chemical properties. They grow outwards from the core-shell which further reacts with monomers having one reactive or two dormant molecules. Dendrimers’ unique characteristics such as hyperbranching, well-defined spherical structure, and high compatibility with the biological systems are responsible for their wide range of applications including medical and biomedical areas. Particularly, the dendrimers’ three-dimensional structure can incorporate a wide variety of drugs to form biologically active drug conjugates. In this review, we focus on the synthesis, mechanism of drug encapsulations in dendrimers, and their wide applications in drug delivery.

scholarly journals Mutagenesis of Glu403 to Cys in rabbit neutral endopeptidase-24.11 (neprilysin) creates a disulphide-linked homodimer: analogy with endothelin-converting enzyme

1997 ◽  
Vol 327 (3) ◽  
pp. 925-929 ◽  
Author(s):  
V. Mien HOANG ◽  
E. Clare SANSOM ◽  
J. Anthony TURNER
Keyword(s):  
Three Dimensional ◽  
Neutral Endopeptidase ◽  
Biologically Active ◽  
Dimensional Structure ◽  
Mutant Form ◽  
Converting Enzyme ◽  
Wild Type ◽  
Endopeptidase 24.11 ◽  
Reducing Conditions ◽  
Endothelin Converting Enzyme

Neutral endopeptidase-24.11 (NEP; neprilysin; EC 3.4.24.11) and endothelin-converting enzyme (ECE) are related zinc metallopeptidases involved in the processing of biologically active peptides. Only ECE, however, exists as a disulphide-linked homodimer. The covalent linkage in rat ECE is between Cys412 in each subunit, which is equivalent to Glu403 in rabbit NEP. Here we report that directed mutagenesis of Glu403 to cysteine in rabbit NEP creates a disulphide-linked homodimer, as revealed by transient transfection in COS-1 cells and SDS/PAGE of a membrane fraction. Under reducing conditions, both the mutant (E403C) and the wild-type NEP migrate as a polypeptide of 92 kDa. However, under non-reducing conditions, the Mr of the wild type remains unchanged, whereas that of the mutant is doubled. Co-transfection of wild-type ECE and E403C NEP cDNA did not result in the production of a NEP-ECE heterodimer. Comparison of the kinetic constants for wild-type and E403C mutant NEP with either [D-Ala2,Leu5]enkephalin or 3-carboxypropanoyl-alanyl-alanyl-leucine-4-nitroanilide (Suc-Ala-Ala-Leu-NH-Np) as substrate show a decrease of approx. 50% in Vmax/Km for the mutant form. The IC50 value for inhibition of the mutant by phosphoramidon or thiorphan is increased 3-fold and 5-fold respectively. Although NEP and ECE exhibit only about 40% identity and differ substantially in substrate specificity and some other characteristics, these data indicate that they have considerable similarity in three-dimensional structure, allowing dimer formation in the mutant NEP with the disulphide link probably occurring in a hydrophilic surface loop.

scholarly journals AutoGPA: An Automated 3D-QSAR Method Based on Pharmacophore Alignment and Grid Potential Analysis

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Naoyuki Asakawa ◽  
Seiichi Kobayashi ◽  
Junichi Goto ◽  
Noriaki Hirayama
Keyword(s):  
Prior Information ◽  
Three Dimensional ◽  
3D Qsar ◽  
Biologically Active ◽  
Dimensional Structure ◽  
Active Molecule ◽  
Main Requirement ◽  
Qsar Models ◽  
Grid Potential ◽  
Real World Problems

3D-QSAR approach has been widely applied and proven to be useful in the case where no reliable crystal structure of the complex between a biologically active molecule and the receptor is available. At the same time, however, it also has highlighted the sensitivity of this approach. The main requirement of the traditional 3D-QSAR method is that molecules should be correctly overlaid in what is assumed to be the bioactive conformation. Identifying an active conformation of a flexible molecule is technically difficult. It has been a bottleneck in the application of the 3D-QSAR method. We have developed a 3D-QSAR software named AutoGPA especially based on an automatic pharmacophore alignment method in order to overcome this problem which has discouraged general medicinal chemists from applying the 3D-QSAR methods to their “real-world” problems. Applications of AutoGPA to three inhibitor-receptor systems have demonstrated that without any prior information about the three-dimensional structure of the bioactive conformations AutoGPA can automatically generate reliable 3D-QSAR models. In this paper, the concept of AutoGPA and the application results will be described.

Structure and conformation of 3′-azido-3′-deoxythymidine (AZT), an inhibitor of the HIV (AIDS) virus

1987 ◽  
Vol 65 (9) ◽  
pp. 2135-2139 ◽  
Author(s):  
George I. Birnbaum ◽  
Jerzy Giziewicz ◽  
Eric J. Gabe ◽  
Tai-Shun Lin ◽  
William H. Prusoff
Keyword(s):  
Active Form ◽  
Three Dimensional ◽  
Direct Methods ◽  
High Energy ◽  
Biologically Active ◽  
Dimensional Structure ◽  
Human Immunodeficiency Virus Replication ◽  
Monoclinic Space Group ◽  
Sugar Ring ◽  
Immunodeficiency Syndrome

3′-Azido-3′-deoxythymidine (AZT), an inhibitor of HIV (human immunodeficiency virus) replication, was recently found to improve the condition of patients suffering from AIDS (acquired immunodeficiency syndrome) or ARC (AIDS-related complex). An X-ray analysis of AZT was undertaken in order to determine the three-dimensional structure of this thymidine analogue. The crystals belong to the monoclinic space group P21 and the cell dimensions are a = 5.6282(4), b = 12.0130(7), c = 17.5072(10) Å, β = 95.946(5)°. The structure was determined by direct methods and refined to R = 0.028 for 2029 observed reflections. Two crystallographically independent molecules were found in the asymmetric unit. One of them, molecule A, adopts a conformation which is fairly common in nucleosides, viz. a C2′ endo/C3′ exo pucker of the furanose ring and a glycosidic torsion angle χCN = 53.4°. However, the conformation of molecule B is highly unusual. The sugar ring pucker is C3′ exo/C4′ endo and χCN = 2.3°. This high-energy conformation may represent the biologically active form of AZT. Its determination may therefore assist in the design of other inhibitors of HIV.

scholarly journals Crystal structure of 3-{[4-(2-methoxyphenyl)piperazin-1-yl]methyl}-5-(thiophen-2-yl)-1,3,4-oxadiazole-2(3H)-thione

2016 ◽  
Vol 72 (2) ◽  
pp. 269-272 ◽  
Author(s):  
Monirah A. Al-Alshaikh ◽  
Hatem A. Abuelizz ◽  
Ali A. El-Emam ◽  
Mohammed S. M. Abdelbaky ◽  
Santiago Garcia-Granda
Keyword(s):  
Hydrogen Bonds ◽  
Dihedral Angle ◽  
Thiophene Ring ◽  
Three Dimensional ◽  
Chair Conformation ◽  
Biologically Active ◽  
Dimensional Structure ◽  
Piperazine Ring ◽  
Π Interactions ◽  
Compound C

The title compound, C18H20N4O2S2, is a new 1,3,4-oxadiazole and a key pharmacophore of several biologically active agents. It is composed of a methyl(thiophen-2-yl)-1,3,4-oxadiazole-2(3H)-thione moiety linked to a 2-methoxyphenyl unitviaa piperazine ring that has a chair conformation. The thiophene ring mean plane lies almost in the plane of the oxadiazole ring, with a dihedral angle of 4.35 (9)°. The 2-methoxyphenyl ring is almost normal to the oxadiazole ring, with a dihedral angle of 84.17 (10)°. In the crystal, molecules are linked by weak C—H...S hydrogen bonds and C—H...π interactions, forming layers parallel to thebcplane. The layers are linkedviaweak C—H...O hydrogen bonds and slipped parallel π–π interactions [intercentroid distance = 3.6729 (10) Å], forming a three-dimensional structure. The thiophene ring has an approximate 180° rotational disorder about the bridging C—C bond.

Conformation of Ribosomes from Escherichia Coli

1974 ◽  
Vol 32 ◽  
pp. 210-211
Author(s):  
M. Boublik ◽  
W. Hellmann ◽  
F. Jenkins
Keyword(s):  
Binding Sites ◽  
Ribosomal Proteins ◽  
Fluorescent Dyes ◽  
Protein Biosynthesis ◽  
Three Dimensional ◽  
Spatial Arrangement ◽  
Dimensional Structure ◽  
Complete Understanding ◽  
And Function

The present knowledge of the three-dimensional structure of ribosomes is far too limited to enable a complete understanding of the various roles which ribosomes play in protein biosynthesis. The spatial arrangement of proteins and ribonuclec acids in ribosomes can be analysed in many ways. Determination of binding sites for individual proteins on ribonuclec acid and locations of the mutual positions of proteins on the ribosome using labeling with fluorescent dyes, cross-linking reagents, neutron-diffraction or antibodies against ribosomal proteins seem to be most successful approaches. Structure and function of ribosomes can be correlated be depleting the complete ribosomes of some proteins to the functionally inactive core and by subsequent partial reconstitution in order to regain active ribosomal particles.

Three-Dimensional Reconstruction Using Stereo Pairs from Serial Thick Sections

1977 ◽  
Vol 35 ◽  
pp. 562-563
Author(s):  
Robert Glaeser ◽  
Thomas Bauer ◽  
David Grano
Keyword(s):  
Three Dimensional ◽  
Dimensional Structure ◽  
Serial Sections ◽  
Thin Sections ◽  
3 Dimensional ◽  
Transmission Electron ◽  
Freeze Dried ◽  
Dimensional Reconstruction ◽  
Stereo Imagery ◽  
Whole Mounts

In transmission electron microscopy, the 3-dimensional structure of an object is usually obtained in one of two ways. For objects which can be included in one specimen, as for example with elements included in freeze- dried whole mounts and examined with a high voltage microscope, stereo pairs can be obtained which exhibit the 3-D structure of the element. For objects which can not be included in one specimen, the 3-D shape is obtained by reconstruction from serial sections. However, without stereo imagery, only detail which remains constant within the thickness of the section can be used in the reconstruction; consequently, the choice is between a low resolution reconstruction using a few thick sections and a better resolution reconstruction using many thin sections, generally a tedious chore. This paper describes an approach to 3-D reconstruction which uses stereo images of serial thick sections to reconstruct an object including detail which changes within the depth of an individual thick section.

Electron Microscopy of Cytoplasmic Contractile Proteins

1978 ◽  
Vol 36 (3) ◽  
pp. 606-614 ◽  
Author(s):  
T.D. Pollard ◽  
P. Maupin
Keyword(s):  
Electron Microscopy ◽  
Actin Filaments ◽  
Three Dimensional ◽  
Uranyl Acetate ◽  
Contractile Proteins ◽  
Dimensional Structure ◽  
X Ray Diffraction ◽  
Cytoplasmic Matrix ◽  
Computer Image Processing ◽  
Nonmuscle Cells

In this paper we review some of the contributions that electron microscopy has made to the analysis of actin and myosin from nonmuscle cells. We place particular emphasis upon the limitations of the ultrastructural techniques used to study these cytoplasmic contractile proteins, because it is not widely recognized how difficult it is to preserve these elements of the cytoplasmic matrix for electron microscopy. The structure of actin filaments is well preserved for electron microscope observation by negative staining with uranyl acetate (Figure 1). In fact, to a resolution of about 3nm the three-dimensional structure of actin filaments determined by computer image processing of electron micrographs of negatively stained specimens (Moore et al., 1970) is indistinguishable from the structure revealed by X-ray diffraction of living muscle.

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