PEGylation Extends Circulation Half-Life While Preserving In Vitro and In Vivo Activity of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1)

The brain’s endogenous capacity to restore damaged myelin deteriorates during the course of demyelinating disorders. Currently, no treatment options are available to establish remyelination. Chronic demyelination leads to damaged axons and irreversible destruction of the central nervous system (CNS). We identified two promising therapeutic candidates which enhance remyelination: oncostatin M (OSM), a member of the interleukin-6 family, and downstream mediator tissue inhibitor of metalloproteinases-1 (TIMP-1). While remyelination was completely abrogated in OSMRβ knockout (KO) mice, OSM overexpression in the chronically demyelinated CNS established remyelination. Astrocytic TIMP-1 was demonstrated to play a pivotal role in OSM-mediated remyelination. Astrocyte-derived TIMP-1 drove differentiation of oligodendrocyte precursor cells into mature oligodendrocytes in vitro. In vivo, TIMP-1 deficiency completely abolished spontaneous remyelination, phenocopying OSMRβ KO mice. Finally, TIMP-1 was expressed by human astrocytes in demyelinated multiple sclerosis lesions, confirming the human value of our findings. Taken together, OSM and its downstream mediator TIMP-1 have the therapeutic potential to boost remyelination in demyelinating disorders.

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Influence of Different Strategies of Volume Replacement on the Activity of Matrix Metalloproteinases

Anesthesiology ◽

10.1097/00000542-200701000-00016 ◽

2007 ◽

Vol 106 (1) ◽

pp. 85-91 ◽

Cited By ~ 27

Author(s):

Carlo A. Volta ◽

Valentina Alvisi ◽

Matilde Campi ◽

Elisabetta Marangoni ◽

Raffaele Alvisi ◽

...

Keyword(s):

Hydroxyethyl Starch ◽

Plasma Levels ◽

Tissue Inhibitor Of Metalloproteinases ◽

Tissue Inhibitor ◽

Vitro Experiment ◽

In Vitro Experiment ◽

Ringer’S Solution ◽

Lactated Ringer's Solution

Background Excessive production of matrix metalloproteinase 9 (MMP-9) is linked to tissue damage and anastomotic leakage after large bowel surgery. Hence, the aim of this study was to verify whether different strategies of fluids administration can reduce MMP-9 expression. Methods In the in vitro experiment, the authors tested the hypothesis of a direct inhibition of MMP-9 by the fluids used perioperatively, i.e., lactated Ringer's solution, 3.4% poligeline, and hydroxyethyl starch 130/0.4. In the in vivo experiment, 36 patients undergoing surgery for colon cancer were randomly assigned to three groups to receive lactated Ringer's solution, poligeline, or hydroxyethyl starch. MMP-9 and tissue inhibitor of metalloproteinases were measured from venous blood samples; the MMP-9/tissue inhibitor of metalloproteinases ratio was calculated as an index of equilibrium between the action of MMP-9 and its inhibition. Results In the in vitro experiment, the presence of hydroxyethyl starch 130/0.4 in the MMP-9 assay system showed a strong inhibition of the enzymatic activity compared with lactated Ringer's solution. In the in vivo experiment, MMP-9 and tissue inhibitor of metalloproteinases plasma levels did not differ among the three groups at baseline, whereas those levels increased significantly at the end of surgery. At that time, the MMP-9 plasma levels and the MMP-9/tissue inhibitor of metalloproteinases ratio were significantly higher in the lactated Ringer's solution and poligeline groups than in the hydroxyethyl starch group. These results were confirmed 72 h after surgery. Conclusions This study demonstrates that hydroxyethyl starch 130/04 decreases the circulating levels of MMP-9 in patients undergoing abdominal surgery.

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Induced secretion of tissue inhibitor of metalloproteinases-1 (TIMP-1) in vivo and in vitro by hepatotoxin rubratoxin B

Food and Chemical Toxicology ◽

10.1016/j.fct.2006.01.012 ◽

2006 ◽

Vol 44 (7) ◽

pp. 1138-1143 ◽

Cited By ~ 7

Author(s):

H. Nagashima ◽

K. Maeda-Nakamura ◽

K. Iwashita ◽

T. Goto

Keyword(s):

Tissue Inhibitor Of Metalloproteinases ◽

Tissue Inhibitor

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Kinetics of Various 99mTc-Sn-Pyrophosphate Compounds in the Rat

Nuklearmedizin ◽

10.1055/s-0037-1620623 ◽

1977 ◽

Vol 16 (04) ◽

pp. 157-162 ◽

Cited By ~ 1

Author(s):

C. Schümichen ◽

B. Mackenbrock ◽

G. Hoffmann

Keyword(s):

Normal Saline ◽

Half Life ◽

Compound A ◽

Short Half Life ◽

Low Concentrations ◽

The Stability ◽

Kinetics Of ◽

In Vitro Stability

SummaryThe bone-seeking 99mTc-Sn-pyrophosphate compound (compound A) was diluted both in vitro and in vivo and proved to be unstable both in vitro and in vivo. However, stability was much better in vivo than in vitro and thus the in vitro stability of compound A after dilution in various mediums could be followed up by a consecutive evaluation of the in vivo distribution in the rat. After dilution in neutral normal saline compound A is metastable and after a short half-life it is transformed into the other 99mTc-Sn-pyrophosphate compound A is metastable and after a short half-life in bone but in the kidneys. After dilution in normal saline of low pH and in buffering solutions the stability of compound A is increased. In human plasma compound A is relatively stable but not in plasma water. When compound B is formed in a buffering solution, uptake in the kidneys and excretion in urine is lowered and blood concentration increased.It is assumed that the association of protons to compound A will increase its stability at low concentrations while that to compound B will lead to a strong protein bond in plasma. It is concluded that compound A will not be stable in vivo because of a lack of stability in the extravascular space, and that the protein bond in plasma will be a measure of its in vivo stability.

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Half-Life of Platelet Factor 4 (PF-4) in Plasma and Platelets from Macaca Mulatta

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649203 ◽

1977 ◽

Vol 37 (01) ◽

pp. 073-080 ◽

Cited By ~ 5

Author(s):

Knut Gjesdal ◽

Duncan S. Pepper

Keyword(s):

Macaca Mulatta ◽

Half Life ◽

Human Platelet ◽

Gel Filtration ◽

Platelet Factor 4 ◽

Active Protein ◽

Platelet Factor ◽

Membrane Bound

SummaryHuman platelet factor 4 (PF-4) showed a reaction of complete identity with PF-4 from Macaca mulatta when tested against rabbit anti-human-PF-4. Such immunoglobulin was used for quantitative precipitation of in vivo labelled PF-4 in monkey serum. The results suggest that the active protein had an intra-platelet half-life of about 21 hours. In vitro 125I-labelled human PF-4 was injected intravenously into two monkeys and isolated by immuno-precipita-tion from platelet-poor plasma and from platelets disrupted after gel-filtration. Plasma PF-4 was found to have a half-life of 7 to 11 hours. Some of the labelled PF-4 was associated with platelets and this fraction had a rapid initial disappearance rate and a subsequent half-life close to that of plasma PF-4. The results are compatible with the hypothesis that granular PF-4 belongs to a separate compartment, whereas membrane-bound PF-4 and plasma PF-4 may interchange.

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Development of Stable Chimeric IL-15 for Trans-Presentation by the Antigen Presenting Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.646159 ◽

2021 ◽

Vol 12 ◽

Author(s):

Manoj Patidar ◽

Naveen Yadav ◽

Sarat K. Dalai

Keyword(s):

T Cells ◽

T Cell ◽

Half Life ◽

Therapeutic Potential ◽

Chimeric Protein ◽

Antigen Presenting Cells ◽

T Cell Response ◽

Antigen Presenting

IL-15 is one of the important biologics considered for vaccine adjuvant and treatment of cancer. However, a short half-life and poor bioavailability limit its therapeutic potential. Herein, we have structured IL-15 into a chimeric protein to improve its half-life enabling greater bioavailability for longer periods. We have covalently linked IL-15 with IgG2 base to make the IL-15 a stable chimeric protein, which also increased its serum half-life by 40 fold. The dimeric structure of this kind of IgG based biologics has greater stability, resistance to proteolytic cleavage, and less frequent dosing schedule with minimum dosage for achieving the desired response compared to that of their monomeric forms. The structured chimeric IL-15 naturally forms a dimer, and retains its affinity for binding to its receptor, IL-15Rβ. Moreover, with the focused action of the structured chimeric IL-15, antigen-presenting cells (APC) would transpresent chimeric IL-15 along with antigen to the T cell, that will help the generation of quantitatively and qualitatively better antigen-specific memory T cells. In vitro and in vivo studies demonstrate the biological activity of chimeric IL-15 with respect to its ability to induce IL-15 signaling and modulating CD8+ T cell response in favor of memory generation. Thus, a longer half-life, dimeric nature, and anticipated focused transpresentation by APCs to the T cells will make chimeric IL-15 a super-agonist for memory CD8+ T cell responses.

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Shortened platelet half-life in multiple myeloma

Blood ◽

10.1182/blood.v68.2.514.bloodjournal682514 ◽

1986 ◽

Vol 68 (2) ◽

pp. 514-520

Author(s):

E Fritz ◽

H Ludwig ◽

W Scheithauer ◽

H Sinzinger

Keyword(s):

Multiple Myeloma ◽

Half Life ◽

Serum Levels ◽

Statistical Correlation ◽

Control Group ◽

Healthy Controls ◽

Platelet Factor ◽

Healthy Control

Various defects in platelet function have been reported as being associated with multiple myeloma. In 30 myeloma patients and 15 healthy controls, we investigated platelet survival using in vitro labeling of autologous platelets with 111indium-oxine and measuring the in vivo kinetics of the radioisotope. Significantly shortened platelet half- life in patients averaged 73 hours, while platelet half-life in the healthy controls averaged 107 hours. In myeloma patients, serum levels of thromboxane B2, beta-thromboglobulin, and platelet factor 4 were significantly elevated; aggregation indices were within the pathological range; platelet counts and spleen-liver indices, however, were comparable to those of the healthy control group. No statistical correlation was found between platelet half-life and paraprotein concentrations. Our findings suggest an initial--so far unexplained-- intravascular process of platelet activation and consumption that finally manifests in shortened platelet half-life. It seems that overt thrombocytopenia develops only when the compensatory capacity of the bone marrow finally becomes exhausted. Further studies should be able to elucidate the pathophysiologic processes involved.

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In vitro suppression of programmed cell death of B cells by tissue inhibitor of metalloproteinases-1.

Journal of Clinical Investigation ◽

10.1172/jci2881 ◽

1998 ◽

Vol 102 (11) ◽

pp. 2002-2010 ◽

Cited By ~ 283

Author(s):

L Guedez ◽

W G Stetler-Stevenson ◽

L Wolff ◽

J Wang ◽

P Fukushima ◽

...

Keyword(s):

Cell Death ◽

B Cells ◽

Programmed Cell Death ◽

Tissue Inhibitor Of Metalloproteinases ◽

Tissue Inhibitor

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Smart delivery of lethal poly-peptide composite for effective cancer therapy

Biomedical Materials ◽

10.1088/1748-605x/ac494c ◽

2022 ◽

Author(s):

Xin Yuan ◽

Yingzhou Qin ◽

Qingmei Tian ◽

Cuijuan Liu ◽

Xiangzhou Meng ◽

...

Keyword(s):

Half Life ◽

Low Cost ◽

Drug Loading ◽

Nsclc Cell Line ◽

Peptide Drug ◽

Loading System ◽

Penetration Ability ◽

Cleavable Peptide

Abstract In the past decade, multifunctional peptides have attracted increasing attention in the biomedical field. Peptides possess many impressive advantages, such as high penetration ability, low cost, and etc. However, the short half-life and instability of peptides limit their application. In this study, a poly-peptide drug loading system (called HKMA composite) was designed based on the different functionalities of four peptides. The peptide compositions of HKMA composite from N-terminal to C-terminal were HCBP1, KLA, MMP-2-cleavable peptide and ABD. The targeting and lethality of HKMA to NSCLC cell line H460 sphere cells and the half-life of the system were measured in vivo. The results showed that the HKMA composite had a long half-life and specific killing effect on H460 sphere cells in vitro and in vivo. Our result proposed smart peptide drug loading system and provided a potential methodology for effective cancer treatment.

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In Vitro Characterization of Rabbit Thrombin, Antithrombin III, and Thrombin-Antithrombin III Complex, and Determination of Their Survival Times in Vivo

10.1055/s-0039-1682652 ◽

1977 ◽

Author(s):

Christine N. Vogel ◽

Kingdon S. Henry ◽

Roger L. Lundblad

Keyword(s):

Gel Electrophoresis ◽

Half Life ◽

Antithrombin Iii ◽

Specific Activity ◽

Sodium Dodecyl ◽

In Vivo Studies ◽

Survival Times ◽

At Iii

Our intention is to study the interaction of rabbit thrombin with antithrombin III (AT-III) in vitro and in vivo. After activation of crude prothrombin with tissue thromboplastin and CaCl2, thrombin was purified and showed two species of thrombin with molecular weights of 36,000 and 39,000 daltons as determined by sodium dodecyl sulfate discontinuous gel electrophoresis. Rabbit AT-III was purified using a heparin agarose column and had a molecular weight of 55,000 daltons. The inhibition of thrombin by AT-III was followed by fibrinogen clotting assays and an AT-III-thrombin complex was observed on gel electrophoresis. For the in vivo studies both thrombin and AT-III were radiolabelled with Na125i using the solid state lactoperoxidase method and retained 99% of the pre-iodinated specific activity. Radiolabelled thrombin and a radiolabelled AT-III-thrombin complex were injected into different rabbits. The rate of removal of both was very similar with a half-life of approximately 9 hours. When radiolabelled AT-III was injected, the half-life was approximately 60 hours. Since the disappearance rate of thrombin more closely approximates that of the preformed AT-III-thrombin complex and is clearly shorter than the turnover rate of AT-III, the possibility is raised that thrombin combines in vivo with a native inhibitor such as AT-III and may in fact be removed from the circulation as a complex rather than as a native molecule.

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