scholarly journals Antiplatelet Effects of Qishen Yiqi Dropping Pill in Platelets Aggregation in Hyperlipidemic Rabbits

2012 ◽  
Vol 2012 ◽  
pp. 1-5 ◽  
Author(s):  
Yi Wang ◽  
Jie Wang ◽  
Liping Guo ◽  
Xiumei Gao
Keyword(s):  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Camp Level ◽  
High Fat ◽  
Platelet Factor ◽  
Aggregation Effect ◽  
Antiplatelet Aggregation ◽  
Prostaglandin F ◽  
Camp Metabolism

We investigated the effects of Qishen Yiqi Dropping Pill (QSYQ) on platelets aggregation and its possible mechanisms. Hyperlipidemic model in rabbits was produced by a high fat/cholesterol diet for 6 weeks, the therapeutic effect of QSYQ with 2.0 g/kg, 1.0 g/kg, and 0.5 g/kg was observed. Fourteen days after drug treatment, platelet aggregation induced by adenosine diphosphate (ADP), arachidonic acid (AA), and collagen (COLL) was significantly reduced in rabbits of model group. Moreover,β-thromboglobulin (β-TG) level decreased obviously but no significant change in P-selectin and platelet factor 4 (PF4) level, while QSYQ significantly decreased the ratio of thromboxane B2 (TXB2) to 6-keto-prostaglandin F1α(6-Keto-PGF1α) and increased cyclic adenosine monophosphate (cAMP) level in rabbits. In summary, QSYQ can improve platelets aggregation and inhibit the over-release ofβ-TG in hyperlipidemic rabbits; and the increased cAMP level may be involved in this process. These results suggest that the antiplatelet aggregation effect of QSYQ may be due to its ability to increase cAMP level for improving cAMP metabolism.

scholarly journals Mutants in the ADP-ribosyltransferase Cleft of Cholera Toxin Lack Diarrheagenicity but Retain Adjuvanticity

1997 ◽  
Vol 185 (7) ◽  
pp. 1203-1210 ◽  
Author(s):  
Shingo Yamamoto ◽  
Yoshifumi Takeda ◽  
Masafumi Yamamoto ◽  
Hisao Kurazono ◽  
Koichi Imaoka ◽  
...  
Keyword(s):  
Cholera Toxin ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Site Directed Mutagenesis ◽  
T Helper ◽  
Th2 Cell ◽  
A Subunit ◽  
Adp Ribosyltransferase ◽  
Type Response

Cholera toxin (CT), the most commonly used mucosal adjuvant in experimental animals, is unsuitable for humans because of potent diarrhea-inducing properties. We have constructed two CT-A subunit mutants, e.g., serine→ phenylalanine at position 61 (S61F), and glutamic acid→ lysine at 112 (E112K) by site-directed mutagenesis. Neither mutant CT (mCT), in contrast to native CT (nCT), induced adenosine diphosphate-ribosylation, cyclic adenosine monophosphate formation, or fluid accumulation in ligated mouse ileal loops. Both mCTs retained adjuvant properties, since mice given ovalbumin (OVA) subcutaneously with mCTs or nCT, but not OVA alone developed high-titered serum anti-OVA immunoglobulin G (IgG) antibodies (Abs) which were largely of IgG1 and IgG2b subclasses. Although nCT induced brisk IgE Ab responses, both mCTs elicited lower anti-OVA IgE Abs. OVA-specific CD4+ T cells were induced by nCT and by mCTs, and quantitative analysis of secreted cytokines and mRNA revealed a T helper cell 2 (Th2)-type response. These results now show that the toxic properties of CT can be separated from adjuvanticity, and the mCTs induce Ab responses via a Th2 cell pathway.

scholarly journals Inhibitory effect of Fruitflow on platelet function: a randomized placebo-controlled trial in elderly subjects

2020 ◽  
Author(s):  
Huilian Chen ◽  
Shenghao Zhang ◽  
Hui Wang ◽  
Yun Jiang ◽  
Li Bao ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Controlled Trial ◽  
Adenosine Diphosphate ◽  
The Elderly ◽  
Inhibitory Effect ◽  
Water Soluble ◽  
Elderly Subjects ◽  
Platelet Factor ◽  
Prostaglandin F

Abstract Background: The elderly have a high risk of cardiovascular disease, which is often accompanied by platelet hyperactivity. Tomato extracts can inhibit platelet activation and have beneficial health effects. We aimed to investigate the effect of Fruitflow (FF), a water-soluble tomato extract, on platelet function in elderly subjects.Methods: This randomized group study was conducted with people over 50 years old. The participants were randomly divided into four groups: placebo (150 mg/day), FF (150 mg/day), acetylsalicylic acid (ASA; 100 mg/day), and FF (150 mg/day) + ASA (100 mg/day). These groups received the respective supplements after dinner daily for 7 days. Fasting blood was collected from the participants on days 0 and 8 to analyze platelet aggregation and the content of thromboxane B2 (TXB2), 6-keto-prostaglandin F1α, and platelet factor 4 (PF4). Results: One hundred ninety elderly subjects were recruited and completed this clinical trial. The results showed that the FF intervention for 7 days decreased platelet aggregation by 7.7% in adenosine diphosphate-stimulated platelets, which was similar to the effect of ASA, which decreased platelet aggregation by 9.4%. Fruitflow reduced platelet aggregation by 10.2% in collagen-stimulated platelets, and ASA reduced platelet aggregation by 38.3% in collagen-activated platelets. This suggests that ASA exerts a stronger inhibitory effect than FF on collagen-stimulated platelet aggregation. The combination of FF + ASA did not exert a synergistic inhibitory effect on platelet aggregation. Treatment with FF significantly decreased plasma TXB2, 6-keto-PGF1α, and PF4 levels, and its effects were similar to ASA. Conclusion: Fruitflow suppressed platelet aggregation and decreased TXB2, 6-keto-PGF1α, and PF4 levels in elderly subjects. These findings indicate that FF might reduce the risk of thrombosis in cardiovascular diseases.Trial registration code: ChiCTR2000034647 at www.clinicaltrials.gov.

scholarly journals The effect of pharmacologic inhibition of phospholipid methylation on human platelet function

Blood ◽  
1982 ◽  
Vol 59 (5) ◽  
pp. 906-912
Author(s):  
SJ Shattil ◽  
JA Montgomery ◽  
PK Chiang
Keyword(s):  
Platelet Activation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Serotonin Release ◽  
Platelet Phospholipid ◽  
Biochemical Effect ◽  
Methylation Pathway ◽  
Pharmacologic Inhibition

Human platelets are capable of synthesizing their major membrane phospholipid, phosphatidylcholine, by a methylation pathway. This involves the sequential transfer of methyl groups from S-adenosyl-L- methionine (AdoMet) to phosphatidylethanolamine, and in the process, AdoMet is converted to S-adenosylhomocysteine (AdoHcy). The activity of this methylation pathway is decreased upon stimulation of platelets by various agonists. We inhibited methylation reactions pharmacologically to see whether this inhibition plays any role in the process of platelet activation. Two inhibitors of AdoHcy hydrolase, 3-deaza- adenosine and 3-deaza-(+/-)aristeromycin (500 microM each), were effective in increasing platelets levels of AdoHcy and preventing turnover of AdoMet. Also, these compounds were equipotent in inhibiting platelet phospholipid methylation. However, while 3-deaza-adenosine potentiated platelet aggregation and 14C-serotonin release induced by epinephrine or adenosine diphosphate (ADP) (p less than 0.01), 3-deaza- aristeromycin had no such effect. Neither compound affected platelet responses to thrombin or collagen. Inhibition of methylation reactions was not the only biochemical effect of 3-deaza-adenosine since it also blunted significantly the elevation of platelet cyclic adenosine monophosphate (AMP) levels induced by prostaglandin E1 (p less than 0.02). Therefore, these studies demonstrate that inhibition of platelet phospholipid methylation, per se, has no discernable effect on the function of human platelets. The methylation pathway, though active in platelets, does not appear to be primarily involved in membrane events responsible for platelet activation.

scholarly journals Differential requirements for platelet aggregation and inhibition of adenylate cyclase by epinephrine. Studies of a familial platelet alpha 2-adrenergic receptor defect

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 494-501 ◽  
Author(s):  
AK Rao ◽  
J Willis ◽  
MA Kowalska ◽  
YT Wachtfogel ◽  
RW Colman
Keyword(s):  
Platelet Aggregation ◽  
Adenylate Cyclase ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Normal Subjects ◽  
Camp Levels ◽  
Epinephrine Concentration

Abstract We describe a family whose members have impaired platelet aggregation and secretion responses to epinephrine with normal responses to adenosine diphosphate and collagen. Platelet alpha 2-adrenergic receptors (measured using 3H methyl-yohimbine) were diminished in the propositus (78 sites per platelet), his two sisters (70 and 27 sites per platelet), and parents (37 and 63 sites per platelet), but not in two maternal aunts (12 normal subjects, 214 +/- 18 sites per platelet; mean +/- SE). However, the inhibition of cyclic adenosine monophosphate (cAMP) levels by epinephrine in platelets exposed to 400 nmol/L PGI2 was similar in the patients and five normal subjects (epinephrine concentration for 50% inhibition, 0.04 +/- 0.01 mumol/L v 0.03 +/- 0.01 mumol/L; P greater than .05). In normal platelets, the concentration of yohimbine (0.18 mumol/L) required for half maximal inhibition of aggregation induced by 2 mumol/L epinephrine was lower than that for inhibition of its effect on adenylate cyclase (1.6 mumol/L). In quin2 loaded platelets, thrombin (0.1 U/mL) stimulated rise in cytoplasmic Ca2+ concentration, [Ca2+]i, was normal in the two patients studied. The PGI2 analog ZK 36,374 completely inhibited thrombin-induced rise in [Ca2+]i; the reversal of this inhibition by epinephrine was normal in the two patients. Thus, despite the impaired aggregation response to epinephrine, platelets from these patients have normal ability to inhibit PGI2-stimulated cAMP levels. These patients with an inherited receptor defect provide evidence that fewer platelet alpha 2-adrenergic receptors are required for epinephrine-induced inhibition of adenylate cyclase than for aggregation.

scholarly journals Adenosine and Forskolin Inhibit Platelet Aggregation by Collagen but not the Proximal Signalling Events

2019 ◽  
Vol 119 (07) ◽  
pp. 1124-1137 ◽  
Author(s):  
Joanne C. Clark ◽  
Deirdre M. Kavanagh ◽  
Stephanie Watson ◽  
Jeremy A. Pike ◽  
Robert K. Andrews ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
G Protein ◽  
Platelet Activation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Receptor Activation ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Adenosine Receptor Agonist

Background The G protein-coupled receptor, adenosine A2A, signals through the stimulatory G protein, Gs, in platelets leading to activation of adenylyl cyclase and elevation of cyclic adenosine monophosphate (cAMP) and inhibition of platelet activation. Objective This article investigates the effect of A2A receptor activation on signalling by the collagen receptor glycoprotein (GP) VI in platelets. Methods Washed human platelets were stimulated by collagen or the GPVI-specific agonist collagen-related peptide (CRP) in the presence of the adenosine receptor agonist, 5′-N-ethylcarboxamidoadenosine (NECA) or the adenylyl cyclase activator, forskolin and analysed for aggregation, adenosine triphosphate secretion, protein phosphorylation, spreading, Ca2+ mobilisation, GPVI receptor clustering, cAMP, thromboxane B2 (TxB2) and P-selectin exposure. Results NECA, a bioactive adenosine analogue, partially inhibits aggregation and secretion to collagen or CRP in the absence or presence of the P2Y12 receptor antagonist, cangrelor and the cyclooxygenase inhibitor, indomethacin. The inhibitory effect in the presence of the three inhibitors is largely overcome at higher concentrations of collagen but not CRP. Neither NECA nor forskolin altered clustering of GPVI, elevation of Ca2+ or spreading of platelets on a collagen surface. Further, neither NECA nor forskolin, altered collagen-induced tyrosine phosphorylation of Syk, LAT nor PLCγ2. However, NECA and forskolin inhibited platelet activation by the TxA2 mimetic, U46619, but not the combination of adenosine diphosphate and collagen. Conclusion NECA and forskolin have no effect on the proximal signalling events by collagen. They inhibit platelet activation in a response-specific manner in part through inhibition of the feedback action of TxA2.

Role of phosphodiesterases in the development of takotsubo syndrome

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
D Huebscher ◽  
T Borchert ◽  
G Hasenfuss ◽  
V.O Nikolaev ◽  
K Streckfuss-Boemeke
Keyword(s):  
Resonance Energy ◽  
Induced Pluripotent Stem Cell ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Left Ventricular ◽  
Camp Level ◽  
Camp Signaling ◽  
Patient Specific ◽  
Funding Source ◽  
Takotsubo Syndrome

Abstract Background/Purpose Takotsubo syndrome (TTS) is characterized by acute transient left ventricular dysfunction in the absence of obstructive coronary lesions. We identified a higher sensitivity to catecholamine-induced stress toxicity as mechanism associated with the TTS phenotype in our former study, but the pathogenesis of TTS is still not completely understood. In this study our aim was to prove the hypothesis of an altered phosphodiesterase (PDE)-dependent 3',5'-cyclic adenosine monophosphate (cAMP)-signaling in TTS in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs). Methods and results We generated functional TTS-iPSC-CMs and treated them with catecholamines to mimic a TTS-phenotype. To directly address the hypothesis that local cAMP dynamics might be altered in TTS, we used Förster resonance energy transfer (FRET) based cAMP sensors, which are specifically located in the cytosol or at the sarcoplasmic/endoplasmic reticulum calcium ATPase 2a (SERCA) micro domain. We demonstrated that β-adrenergic receptor (β-AR) stimulations resulted in stronger cytosolic FRET responses in TTS-CMs compared to controls. In contrast, no differences of cAMP level were observed in the SERCA-PLN micro domain between TTS- and control-iPSC-CMs. To analyze the interplay of β-AR signaling and specific PDE contribution to the cAMP signaling in TTS, specific PDE-inhibitors were used. We were able to show in the cytosol that after β-AR stimulation, the strong effects of the PDE4 family of control cells were significantly decreased in diseased TTS CMs, which is in line with previously described reduced PDE4 activity in failing mouse hearts. In contrast, the contribution of PDE3 to cytoplasmic cAMP degradation was increased in TTS (Figure 1 A). This is in line with increased PDE3A and down-regulated PDE4D protein expression in TTS-iPSC-CMs compared to control cells. Analysis of PDE-dependent cAMP level in the SERCA micro domain show also a significantly reduced PDE4 activity. But the dynamic cytosolic PDE contribution of PDE2 and PDE3 after catecholamine treatment in TTS is lost in SERCA micro domain (Figure1B). Conclusion Our data showed for the first time alterations of local cAMP signaling in healthy and diseased TTS-iPSC-CMs. We demonstrated an isozym shift from PDE4 in control to PDE3 and PDE2 in TTS and identified PDE4 as an important player in the β-adrenergic cAMP signaling in TTS. Therefore, PDE4 activators may be a possible new therapeutic target option in the treatment of TTS. Figure 1 Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): DZHK

Concentration of 3′,5′ cyclic adenosine monophosphate in ventricular CSF of patients following severe head trauma

1977 ◽  
Vol 47 (4) ◽  
pp. 517-524 ◽  
Author(s):  
Alan S. Fleischer ◽  
Daniel R. Rudman ◽  
C. Babson Fresh ◽  
George T. Tindall
Keyword(s):  
Head Trauma ◽  
Lateral Ventricle ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Content Type ◽  
Therapeutic Implications ◽  
Level Of Consciousness ◽  
The Central Nervous System ◽  
Camp Metabolism ◽  
Coma Grade

✓ Previous studies have demonstrated that cerebrospinal fluid (CSF) from the lateral ventricle of patients without disturbance of sensorium or intracranial pressure, contains 15 to 30 nM 3′,5′ cyclic adenosine monophosphate (cAMP). The concentration of this cyclic nucleotide was measured by radioimmunoassay in 133 samples of CSF from the lateral ventricle of 26 patients who were comatose following acute head trauma for periods up to 40 days. Concentration of CSF cAMP in diminishing coma Grades V, IV, III, II, and I was 1.5 ± 0.1 nM; 1.24 ± 0.34 nM; 3.14 ± 0.7 nM; 10.06 ± 3.47 nM; and 13.36 ± 1.38 nM, respectively. After the sensorium cleared (coma Grade 0), cAMP was 22.0 ± 1.7 nM. The correlation between the grade of coma and cAMP concentration was −0.80 (p > 0.01). These results imply that alteration in the level of consciousness following head trauma is associated with a disturbance of cAMP metabolism within the central nervous system. Possible mechanisms explaining this observation as well as therapeutic implications are discussed.

scholarly journals The effect of pharmacologic inhibition of phospholipid methylation on human platelet function

Blood ◽  
1982 ◽  
Vol 59 (5) ◽  
pp. 906-912 ◽  
Author(s):  
SJ Shattil ◽  
JA Montgomery ◽  
PK Chiang
Keyword(s):  
Platelet Activation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Serotonin Release ◽  
Platelet Phospholipid ◽  
Biochemical Effect ◽  
Methylation Pathway ◽  
Pharmacologic Inhibition

Abstract Human platelets are capable of synthesizing their major membrane phospholipid, phosphatidylcholine, by a methylation pathway. This involves the sequential transfer of methyl groups from S-adenosyl-L- methionine (AdoMet) to phosphatidylethanolamine, and in the process, AdoMet is converted to S-adenosylhomocysteine (AdoHcy). The activity of this methylation pathway is decreased upon stimulation of platelets by various agonists. We inhibited methylation reactions pharmacologically to see whether this inhibition plays any role in the process of platelet activation. Two inhibitors of AdoHcy hydrolase, 3-deaza- adenosine and 3-deaza-(+/-)aristeromycin (500 microM each), were effective in increasing platelets levels of AdoHcy and preventing turnover of AdoMet. Also, these compounds were equipotent in inhibiting platelet phospholipid methylation. However, while 3-deaza-adenosine potentiated platelet aggregation and 14C-serotonin release induced by epinephrine or adenosine diphosphate (ADP) (p less than 0.01), 3-deaza- aristeromycin had no such effect. Neither compound affected platelet responses to thrombin or collagen. Inhibition of methylation reactions was not the only biochemical effect of 3-deaza-adenosine since it also blunted significantly the elevation of platelet cyclic adenosine monophosphate (AMP) levels induced by prostaglandin E1 (p less than 0.02). Therefore, these studies demonstrate that inhibition of platelet phospholipid methylation, per se, has no discernable effect on the function of human platelets. The methylation pathway, though active in platelets, does not appear to be primarily involved in membrane events responsible for platelet activation.

scholarly journals Comparative In Vitro Study of Various α2-Adrenoreceptor Agonist Drugs for Ticagrelor Reversal

2020 ◽  
Vol 9 (3) ◽  
pp. 809
Author(s):  
Guillaume Porta Bonete ◽  
Anne Godier ◽  
Pascale Gaussem ◽  
Tiphaine Belleville-Rolland ◽  
Alexandre Leuci ◽  
...  
Keyword(s):  
In Vitro Study ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Camp Pathway ◽  
P2y12 Receptor Antagonist ◽  
Induced Aggregation ◽  
Camp Levels ◽  
Platelet Functions

Ticagrelor, an antiplatelet adenosine diphosphate (ADP)-P2Y12 receptor antagonist, increases the risk of bleeding. Its management is challenging because platelet transfusion is ineffective and no specific antidote is currently available. Epinephrine, a vasopressor catecholamine prescribed during shock, restores platelet functions inhibited by ticagrelor through stimulation of α2A-adrenoreceptors. It subsequently inhibits cyclic adenosine monophosphate (cAMP) pathway and PI3K signaling. However, since epinephrine may expose a patient to deleterious hemodynamic effects, we hypothesized that other α2-adrenoreceptor agonist drugs used in clinical practice with fewer side effects could reverse the antiplatelet effects of ticagrelor. We compared in vitro the efficacy of clonidine, dexmedetomidine, brimonidine, and norepinephrine with epinephrine to restore ADP- and PAR-1-AP-induced washed platelet aggregation inhibited by ticagrelor, as well as resulting platelet cAMP levels. In ticagrelor-free samples, none of the α2-adrenoreceptor agonists induced aggregation by itself but all of them potentiated ADP-induced aggregation. Compared with epinephrine, norepinephrine, and brimonidine partially restored ADP- and fully restored PAR-1-AP-induced aggregation inhibited by ticagrelor while clonidine and dexmedetomidine were ineffective. Indeed, this lack of effect resulted from a lower decrease in cAMP concentration elicited by these partial α2-adrenoreceptor agonists, clonidine, and dexmedetomidine, compared with full α2-agonists. Our results support the development of specific full and systemic α2-adrenoreceptor agonists for ticagrelor reversal.

scholarly journals Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate

Blood ◽  
1992 ◽  
Vol 80 (11) ◽  
pp. 2787-2796 ◽  
Author(s):  
M Cattaneo ◽  
A Lecchi ◽  
AM Randi ◽  
JL McGregor ◽  
PM Mannucci
Keyword(s):  
Monoclonal Antibody ◽  
Platelet Function ◽  
Signal Transduction Pathway ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Fibrin Clot ◽  
Clot Retraction ◽  
Release Reaction ◽  
Function Defect

Abstract This study characterizes a congenital hemorrhagic disorder caused by a platelet function defect with the following features: (1) severely impaired platelet aggregation and fibrinogen or von Willebrand factor (vWF) binding induced by adenosine diphosphate (ADP); (2) defective aggregation, release reaction, and fibrinogen or vWF binding induced by other agonists; (3) normal aggregation and release reaction induced by high concentrations of thrombin or collagen; (4) no further inhibition by ADP scavengers of aggregation, release reaction, and fibrinogen or vWF binding, comparable with those observed for normal platelets in the presence of ADP scavengers; (5) normal membrane glycoprotein (GP) composition and normal binding of the anti-GP IIb/IIIa monoclonal antibody 10E5; (6) no acceleration by ADP of binding of the anti-GP IIb/IIIa monoclonal antibody 7E3; (7) normal platelet-fibrin clot retraction if induced by thrombin or reptilase plus epinephrine, absent if induced by reptilase plus ADP; (8) no inhibition by ADP of the prostaglandin E1-induced increase in platelet cyclic adenosine monophosphate, but normal inhibition by epinephrine; (9) defective mobilization of cytoplasmic Ca2+ by ADP; (10) normal binding of 14C-ADP to fresh platelets, but defective binding of [2–3H]-ADP to formalin- fixed platelets. This congenital platelet function defect is characterized by selective impairment of platelet responses to ADP, caused by either decreased number of platelet ADP receptors or abnormalities of the signal-transduction pathway of platelet activation by ADP.

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