scholarly journals Self-regulated hirudin delivery for anticoagulant therapy

2020 ◽  
Vol 6 (41) ◽  
pp. eabc0382
Author(s):  
Xiao Xu ◽  
Xuechao Huang ◽  
Ying Zhang ◽  
Shiyang Shen ◽  
Zhizi Feng ◽  
...  
Keyword(s):  
Anticoagulant Therapy ◽  
Anticoagulant Activity ◽  
Feedback Mechanism ◽  
Recombinant Hirudin ◽  
Efficient System ◽  
Negative Feedback Mechanism ◽  
Embolism And Thrombosis ◽  
The Stability ◽  
Release Strategy

Pathological coagulation, a disorder of blood clotting regulation, induces a number of cardiovascular diseases. A safe and efficient system for the delivery of anticoagulants to mimic the physiological negative feedback mechanism by responding to the coagulation signal changes holds the promise and potential for anticoagulant therapy. Here, we exploit a “closed-loop” controlled release strategy for the delivery of recombinant hirudin, an anticoagulant agent that uses a self-regulated nanoscale polymeric gel. The cross-linked nanogel network increases the stability and bioavailability of hirudin and reduces its clearance in vivo. Equipped with the clot-targeted ligand, the engineered nanogels promote the accumulation of hirudin in the fibrous clots and adaptively release the encapsulated hirudin upon the thrombin variation during the pathological proceeding of thrombus for potentiating anticoagulant activity and alleviating adverse effects. We show that this formulation efficiently prevents and inhibits the clot formation on the mouse models of pulmonary embolism and thrombosis.

Expression and self-regulatory function of cardiac interleukin-6 during endotoxemia

2000 ◽  
Vol 279 (5) ◽  
pp. H2241-H2248 ◽  
Author(s):  
Hiroshi Saito ◽  
Cam Patterson ◽  
Zhaoyong Hu ◽  
Marschall S. Runge ◽  
Ulka Tipnis ◽  
...  
Keyword(s):  
Feedback Mechanism ◽  
Intercellular Adhesion Molecule ◽  
Regulatory Function ◽  
Heart Cells ◽  
Intercellular Adhesion Molecule 1 ◽  
Negative Feedback Mechanism ◽  
Proinflammatory Mediators ◽  
Tnf Α

Interleukin (IL)-6 reportedly has negative inotropic and hypertrophic effects on the heart. Here, we describe endotoxin-induced IL-6 in the heart that has not previously been well characterized. An intraperitoneal injection of a bacterial lipopolysaccharide into C57BL/6 mice induced IL-6 mRNA in the heart more strongly than in any other tissue examined. Induction of mRNA for two proinflammatory cytokines, IL-1β and tumor necrosis factor (TNF)-α, occurred rapidly before the induction of IL-6 mRNA and protein. Although stimulation of isolated rat neonatal myocardial cells with IL-1β or TNF-α induced IL-6 mRNA in vitro, nonmyocardial heart cells produced higher levels of IL-6 mRNA upon stimulation with IL-1β. In situ hybridization and immunohistochemical analyses localized the IL-6 expression primarily in nonmyocardial cells in vivo. Endotoxin-induced expression of cardiac IL-1β, TNF-α, and intercellular adhesion molecule 1 was augmented in IL-6-deficient mice compared with control mice. Thus cardiac IL-6, expressed mainly by nonmyocardial cells via IL-1β action during endotoxemia, is likely to suppress expression of proinflammatory mediators and to regulate itself via a negative feedback mechanism.

IN VITRO DEMONSTRATION OF "HEPARIN REBOUND"

1987 ◽  
Author(s):  
C Taylor ◽  
R F Baugh
Keyword(s):  
Whole Blood ◽  
Cardiovascular Surgery ◽  
Anticoagulant Activity ◽  
Blood Levels ◽  
In Vitro Test ◽  
Neutralizing Activity ◽  
Vitro Test ◽  
The Stability

"Heparin rebound", the in vivo appearance of measurable heparin anticoagulant activity following theapparent neutralization of heparin by protamine, hasbeen a problem sporadically associated with the use of heparin in cardiovascular surgery. A number of mechanisms have been proposed to explain rebound, and to some extent each may contribute to the phenomena. As yet no reliable, predictable method has been demonstrated for measuring, reproducing or quantifying "heparin rebound".We have demonstrated and measured the appearance of heparin anticoagulant activity following neutralization with protamine in citrated whole blood. The reappearance of heparin anticoagulant activity was associated with a rapid loss of protamine. The loss of protamine followed 1st order enzyme kinetics, and was indicative of the action of an enzyme. The anticoagulant activity which eappeared could be titrated againwith protamine. The loss of protamine neutralizing activity, in whole blood, could be followed by titration with heparin using a recalcified activated clotting time. The rate of loss varied with both individual blood donors and with the type and source of protamine. The rate of loss of protamine was great enough to influence in. vivo heparin/protamine neutralization ratios, i.e. at 4 units of heparin/ml, 1 unit/ml anticoagulant activity was routinely recovered within 30 minutes following initial neutralization. The indications for cardiovascular surgery are:1)the in vivo neutralization ratio should be adjusted to account for loss of protamine activity, 2) the higherthe blood levels of heparin used during surgery, themore significant the potential for heparin rebound, and 3) protamines may be evaluated in an in vitro test which measures the stability of protamine neutralizing activity in whole blood.

3,5-Di-iodo-l-thyronine suppresses TSH in rats in vivo and in rat pituitary fragments in vitro

1995 ◽  
Vol 145 (2) ◽  
pp. 291-297 ◽  
Author(s):  
C Horst ◽  
A Harneit ◽  
H J Seitz ◽  
H Rokos
Keyword(s):  
Body Weight ◽  
Significant Influence ◽  
Suppressive Effect ◽  
Feedback Mechanism ◽  
Organ Weights ◽  
Negative Feedback Mechanism ◽  
Rat Pituitary ◽  
Tsh Secretion

Abstract 3,5-Di-iodo-l-thyronine (T2) is a naturally occurring metabolite of thyroxine (T4). Contrary to earlier findings, T2 has recently been shown to have rapid effects in rat liver and in mononuclear blood cells. In the experiments described here, T2 was tested to determine whether it has a TSH suppressive effect in rats in vivo and in rat pituitary fragments in vitro. In experiments over 2 weeks in rats in vivo, low doses of T2 (20–200 μg/100 g body weight per day) had no significant influence on body and organ weights, but significantly decreased TSH and T4 serum concentrations. At 200 μg/100 g per day, T2 suppressed TSH to 43% and T4 to 29% of control levels. At 1–15 μg/100 g per day, 3,5,3′-tri-iodo-l-thyronine (T3), used as a comparison to T2, had significant effects on TSH and T4 levels, and also on body weight. Fifteen μg T3/100 g per day decreased TSH to 44%, T4 to 25%, and body weight to 59% of control levels. In experiments over 3 months in rats in vivo, a low dose (25 μg/100 g per day) of T2 suppressed TSH to 60% and T4 to 57% of control levels and had no significant influence on other parameters. Conversely, 0·1 μg/100 g per day T3 had significant effects on body and organ weights as well as pellet intake, but a less pronounced TSH suppressive effect: TSH concentrations were unchanged and T4 concentrations were down to 80% of control values. In rat pituitary fragments in vitro, a clear suppression of TSH secretion after a TRH pulse was demonstrated. To summarise, T2 is a specific agonist in the negative feedback mechanism on TSH secretion at the pituitary level without other apparent thyromimetic effects. Journal of Endocrinology (1995) 145, 291–297

scholarly journals The Yeast Telomere Length Counting Machinery Is Sensitive to Sequences at the Telomere-Nontelomere Junction

1999 ◽  
Vol 19 (1) ◽  
pp. 31-45 ◽  
Author(s):  
Alo Ray ◽  
Kurt W. Runge
Keyword(s):  
Telomere Length ◽  
Feedback Mechanism ◽  
Yeast Cells ◽  
Telomere Elongation ◽  
Negative Feedback Mechanism ◽  
Folded Structure ◽  
Length Regulation ◽  
Threshold Length

ABSTRACT Saccharomyces cerevisiae telomeres consist of a continuous 325 ± 75-bp tract of the heterogeneous repeat TG1-3 which contains irregularly spaced, high-affinity sites for the protein Rap1p. Yeast cells monitor or count the number of telomeric Rap1p molecules in a negative feedback mechanism which modulates telomere length. To investigate the mechanism by which Rap1p molecules are counted, the continuous telomeric TG1-3 sequences were divided into internal TG1-3 sequences and a terminal tract separated by nontelomeric spacers of different lengths. While all of the internal sequences were counted as part of the terminal tract across a 38-bp spacer, a 138-bp disruption completely prevented the internal TG1-3 sequences from being considered part of the telomere and defined the terminal tract as a discrete entity separate from the subtelomeric sequences. We also used regularly spaced arrays of six Rap1p sites internal to the terminal TG1-3 repeats to show that each Rap1p molecule was counted as about 19 bp of TG1-3 in vivo and that cells could count Rap1p molecules with different spacings between tandem sites. As previous in vitro experiments had shown that telomeric Rap1p sites occur about once every 18 bp, all Rap1p molecules at the junction of telomeric and nontelomeric chromatin (the telomere-nontelomere junction) must participate in telomere length measurement. The conserved arrangement of these six Rap1p molecules at the telomere-nontelomere junction in independent transformants also caused the elongated TG1-3 tracts to be maintained at nearly identical lengths, showing that sequences at the telomere-nontelomere junction had an effect on length regulation. These results can be explained by a model in which telomeres beyond a threshold length form a folded structure that links the chromosome terminus to the telomere-nontelomere junction and prevents telomere elongation.

scholarly journals General, negative feedback mechanism for regulation of Trithorax-like gene expression in vivo: new roles for GAGA factor in flies

2007 ◽  
Vol 35 (21) ◽  
pp. 7150-7159 ◽  
Author(s):  
J. Bernues ◽  
D. Pineyro ◽  
A. Kosoy
Keyword(s):  
Gene Expression ◽  
Negative Feedback ◽  
Feedback Mechanism ◽  
Gaga Factor ◽  
Negative Feedback Mechanism

scholarly journals A feedback loop of conditionally stable circuits drives the cell cycle from checkpoint to checkpoint

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Dávid Deritei ◽  
Jordan Rozum ◽  
Erzsébet Ravasz Regan ◽  
Réka Albert
Keyword(s):  
Cell Cycle ◽  
Feedback Loop ◽  
Free Cell ◽  
Feedback Mechanism ◽  
Cell Cycle Checkpoints ◽  
Negative Feedback Mechanism ◽  
Mammalian Cell Cycle ◽  
External Conditions ◽  
The Stability ◽  
Stable Motif

Abstract We perform logic-based network analysis on a model of the mammalian cell cycle. This model is composed of a Restriction Switch driving cell cycle commitment and a Phase Switch driving mitotic entry and exit. By generalizing the concept of stable motif, i.e., a self-sustaining positive feedback loop that maintains an associated state, we introduce the concept of a conditionally stable motif, the stability of which is contingent on external conditions. We show that the stable motifs of the Phase Switch are contingent on the state of three nodes through which it receives input from the rest of the network. Biologically, these conditions correspond to cell cycle checkpoints. Holding these nodes locked (akin to a checkpoint-free cell) transforms the Phase Switch into an autonomous oscillator that robustly toggles through the cell cycle phases G1, G2 and mitosis. The conditionally stable motifs of the Phase Switch Oscillator are organized into an ordered sequence, such that they serially stabilize each other but also cause their own destabilization. Along the way they channel the dynamics of the module onto a narrow path in state space, lending robustness to the oscillation. Self-destabilizing conditionally stable motifs suggest a general negative feedback mechanism leading to sustained oscillations.

scholarly journals A feedback loop of conditionally stable circuits drives the cell cycle from checkpoint to checkpoint

2019 ◽  
Author(s):  
Dávid Deritei ◽  
Jordan Rozum ◽  
Erzsébet Ravasz Regan ◽  
Réka Albert
Keyword(s):  
Cell Cycle ◽  
Feedback Loop ◽  
Free Cell ◽  
Feedback Mechanism ◽  
Cell Cycle Checkpoints ◽  
Negative Feedback Mechanism ◽  
Mammalian Cell Cycle ◽  
External Conditions ◽  
The Stability ◽  
Stable Motif

AbstractWe perform logic-based network analysis on a model of the mammalian cell cycle. This model is composed of a Restriction Switch driving cell cycle commitment and a Phase Switch driving mitotic entry and exit. By generalizing the concept of stable motif, i.e., a self-sustaining positive feedback loop that maintains an associated state, we introduce the concept of conditionally stable motif, the stability of which is contingent on external conditions. We show that the stable motifs of the Phase Switch are contingent on the state of three nodes through which it receives input from the rest of the network. Biologically, these conditions correspond to cell cycle checkpoints. Holding these nodes locked (akin to a checkpoint-free cell) transforms the Phase Switch into an autonomous oscillator that robustly toggles through the cell cycle phases G1, G2 and mitosis. The conditionally stable motifs of the Phase Switch Oscillator are organized into an ordered sequence, such that they serially stabilize each other but also cause their own destabilization. Along the way they channel the dynamics of the module onto a narrow path in state space, lending robustness to the oscillation. Self-destabilizing conditionally stable motifs suggest a general negative feedback mechanism leading to sustained oscillations.

scholarly journals In vitro membrane remodelling by ESCRT-II/ESCRT-III is regulated by negative feedback from membrane tension

2018 ◽  
Author(s):  
Andrew Booth ◽  
Christopher J. Marklew ◽  
Barbara Ciani ◽  
Paul A. Beales
Keyword(s):  
Negative Feedback ◽  
Feedback Mechanism ◽  
Membrane Mechanics ◽  
Artificial Cells ◽  
Membrane Area ◽  
Endosomal Sorting ◽  
Negative Feedback Mechanism ◽  
Membrane Compartments

AbstractArtificial cells can shed new light on the molecular basis for life and hold potential for new chemical technologies. Inspired by how nature dynamically regulates its membrane compartments, we aim to repurpose the endosomal sorting complex required for transport (ESCRT) to generate complex membrane architectures as suitable scaffolds for artificial cells. Purified ESCRT-III components perform topological transformations on giant unilamellar vesicles (GUVs) to create complex “vesicles-within-a-vesicle” architectures resembling the compartmentalisation in eukaryotic cells. Thus far, the proposed mechanisms for this activity are based on how assembly and disassembly of ESCRT-III on the membrane drives deformation. Here we demonstrate the existence of a negative feedback mechanism from membrane mechanics that regulates ESCRT-III activity. ILV formation removes excess membrane area, increasing tension, which in turn suppresses downstream ILV formation. This mechanism for in vitro regulation of ESCRT-III activity may also have important implications for its in vivo functions.

scholarly journals A20 protects cells from TNF-induced apoptosis through linear ubiquitin-dependent and -independent mechanisms

2019 ◽  
Vol 10 (10) ◽  
Author(s):  
Dario Priem ◽  
Michael Devos ◽  
Sarah Druwé ◽  
Arne Martens ◽  
Karolina Slowicka ◽  
...  
Keyword(s):  
Cell Death ◽  
Complex I ◽  
Molecular Mechanisms ◽  
Feedback Mechanism ◽  
Dependent Manner ◽  
Negative Feedback Mechanism ◽  
Signaling Complex ◽  
Induced Apoptosis

Abstract The cytokine TNF promotes inflammation either directly by activating the MAPK and NF-κB signaling pathways, or indirectly by triggering cell death. A20 is a potent anti-inflammatory molecule, and mutations in the gene encoding A20 are associated with a wide panel of inflammatory pathologies, both in human and in the mouse. Binding of TNF to TNFR1 triggers the NF-κB-dependent expression of A20 as part of a negative feedback mechanism preventing sustained NF-κB activation. Apart from acting as an NF-κB inhibitor, A20 is also well-known for its ability to counteract the cytotoxic potential of TNF. However, the mechanism by which A20 mediates this function and the exact cell death modality that it represses have remained incompletely understood. In the present study, we provide in vitro and in vivo evidences that deletion of A20 induces RIPK1 kinase-dependent and -independent apoptosis upon single TNF stimulation. We show that constitutively expressed A20 is recruited to TNFR1 signaling complex (Complex I) via its seventh zinc finger (ZF7) domain, in a cIAP1/2-dependent manner, within minutes after TNF sensing. We demonstrate that Complex I-recruited A20 protects cells from apoptosis by stabilizing the linear (M1) ubiquitin network associated to Complex I, a process independent of its E3 ubiquitin ligase and deubiquitylase (DUB) activities and which is counteracted by the DUB CYLD, both in vitro and in vivo. In absence of linear ubiquitylation, A20 is still recruited to Complex I via its ZF4 and ZF7 domains, but this time protects the cells from death by deploying its DUB activity. Together, our results therefore demonstrate two distinct molecular mechanisms by which constitutively expressed A20 protect cells from TNF-induced apoptosis.

Understanding the in-vivo relevance of S-nitrosothiols in insulin action

2012 ◽  
Vol 90 (7) ◽  
pp. 887-894 ◽  
Author(s):  
Ana B. Fernandes ◽  
Maria P. Guarino ◽  
M. Paula Macedo
Keyword(s):  
Insulin Sensitivity ◽  
Feedback Mechanism ◽  
Glucose Disposal ◽  
No Production ◽  
Fasting Period ◽  
Negative Feedback Mechanism ◽  
Parasympathetic Nerves ◽  
Before And After ◽  
Male Wistar Rats

Insulin sensitivity is maximal in the postprandial state, decreasing with a fasting period through a mechanism that is dependent on the integrity of the hepatic parasympathetic nerves/nitric oxide (NO) production and increased hepatic glutathione (GSH) levels. GSH and NO react to form S-nitrosoglutathione (GSNO), an S-nitrosothiol (RSNO) for which the in-vivo effects are still being determined. The goal of this study was to test the hypothesis that in-vivo administration of RSNOs, GSNO, or S-nitroso-N-acetylpenicillamine (SNAP) increases insulin sensitivity in fasted or fed-denervated animals, but not in fed animals, where full postprandial insulin sensitivity is achieved. Fasted, fed, or fed-denervated male Wistar rats were used as models for different insulin sensitivity conditions. The rapid insulin sensitivity test (RIST) was used to measure insulin-stimulated glucose disposal before and after drug administration (GSNO, SNAP, or 3-morpholinosydnonimine (SIN-1), intravenous (i.v.) or to the portal vein (i.p.v.)). Fast insulin sensitivity was not altered by administration of SIN-1 (neither i.v. nor i.p.v.). Intravenous infusion of RSNOs in fasted and fed hepatic denervated rats increased insulin sensitivity by 126.35% ± 35.43% and 82.7% ± 12.8%, respectively. In fed animals, RSNOs decreased insulin sensitivity indicating a negative feedback mechanism. These results suggest that RSNOs incremental effect on insulin sensitivity represent a promising therapeutical tool in insulin resistance states.

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