scholarly journals Targeted inhibition of gut microbiota proteins involved in TMAO production to reduce platelet aggregation and arterial thrombosis: a blueprint for drugging the microbiota in the treatment of cardiometabolic disease?

2018 ◽  
Vol 17 (1) ◽  
pp. 3-5 ◽  
Author(s):  
T. E. Mens ◽  
H. R. Büller ◽  
M. Nieuwdorp
Keyword(s):  
Platelet Aggregation ◽  
Gut Microbiota ◽  
Arterial Thrombosis ◽  
Cardiometabolic Disease ◽  
Reduce Platelet Aggregation ◽  
Targeted Inhibition

The Effects of Acute Smoking on Platelet Behaviour, Fibrinolysis and Haemorheology in Habitual Smokers

1984 ◽  
Vol 51 (01) ◽  
pp. 006-008 ◽  
Author(s):  
J J F Belch ◽  
B M McArdle ◽  
P Burns ◽  
G D O Lowe ◽  
C D Forbes
Keyword(s):  
Platelet Aggregation ◽  
Factor Viii ◽  
Plasminogen Activator ◽  
Arterial Thrombosis ◽  
Plasma Viscosity ◽  
Red Cell ◽  
Cell Deformability ◽  
Red Cell Deformability ◽  
Cigarette Smokers ◽  
Smoking Group

SummaryThere is an increased frequency of arterial thrombosis in cigarette smokers. The changes in blood coagulation seen in these subjects have been studied by many workers but results have not always been in agreement. We wished to study the effects of acute .smoking on platelet behaviour, fibrinolysis and haemorheology in ten habitual smokers, and to compare these results with nonsmoking controls. Results show that the smoking group had higher plasma fibrinogen (p <0.04), lower plasminogen (p <0.02) and plasminogen activator (p <0.05), and higher plasma viscosity (p <0.003). The changes seen in cigarette smokers after smoking three cigarettes were an increase in the rate of platelet aggregation to ADP (p <0.02), an increase in α2M, (p <0.02), and factor VIII RAG (p <0.05). Plasma viscosity was decreased (p <0.02) as was red cell deformability (p >0.02).We confirm an increased tendency to hypercoagulability in smokers compared to controls which becomes more pronounced immediately after smoking three cigarettes.

A Crucial Role for Diet in the Relationship Between Gut Microbiota and Cardiometabolic Disease

2020 ◽  
Vol 71 (1) ◽  
pp. 149-161 ◽  
Author(s):  
Ilias Attaye ◽  
Sara-Joan Pinto-Sietsma ◽  
Hilde Herrema ◽  
Max Nieuwdorp
Keyword(s):  
Gut Microbiota ◽  
Global Scale ◽  
Cardiometabolic Disease ◽  
Microbiota Composition ◽  
Dietary Interventions ◽  
Fermentable Carbohydrates ◽  
Cost Efficient ◽  
And Function ◽  
Gut Microbiota Composition

Cardiometabolic disease (CMD), such as type 2 diabetes mellitus and cardiovascular disease, contributes significantly to morbidity and mortality on a global scale. The gut microbiota has emerged as a potential target to beneficially modulate CMD risk, possibly via dietary interventions. Dietary interventions have been shown to considerably alter gut microbiota composition and function. Moreover, several diet-derived microbial metabolites are able to modulate human metabolism and thereby alter CMD risk. Dietary interventions that affect gut microbiota composition and function are therefore a promising, novel, and cost-efficient method to reduce CMD risk. Studies suggest that fermentable carbohydrates can beneficially alter gut microbiota composition and function, whereas high animal protein and high fat intake negatively impact gut microbiota function and composition. This review focuses on the role of macronutrients (i.e., carbohydrate, protein, and fat) and dietary patterns (e.g., vegetarian/vegan and Mediterranean diet) in gut microbiota composition and function in the context of CMD.

Dextran and postoperative thromboembolism

1975 ◽  
Vol 13 (11) ◽  
pp. 41-43
Keyword(s):  
Platelet Aggregation ◽  
Coagulation Factors ◽  
Venous Thromboembolic Disease ◽  
Vein Thrombosis ◽  
Dextran 70 ◽  
Lower Blood ◽  
Venous Thromboembolic ◽  
Reduce Platelet Aggregation ◽  
Increase Platelet Aggregation ◽  
Deep Vein

Two preparations of dextran have been tried for prevention of venous thromboembolic disease, dextran-40 (average m. w. 40,000) and dextran-70 (average m.w. 70,000). Dextrans reduce platelet aggregation and lower blood viscosity.1 Dextran may also reduce the peri-operative rise in the coagulation factors V and VIII.2 However, in some tests dextrans increase platelet aggregation3 and accelerate fibrin formation,4 so that only clinical trial can show whether dextran reduces the incidence of either deep-vein thrombosis or of pulmonary embolism.

scholarly journals ROLE OF NITRIC OXIDE (NO) IN CAPSAICIN MEDIATED ANTI-PLATELET ACTIVITY IN IN VITRO, IN VIVO, EX-VIVO MODEL OF PLATELET AGGREGATION ASSAY AND ARTERIAL THROMBOSIS IN RAT: POTENTIAL THERAPEUTIC TARGET?

2018 ◽  
Vol 10 (4) ◽  
pp. 44
Author(s):  
Mihir K Patel ◽  
Kiranj K. Chaudagar ◽  
Anita A. Mehta
Keyword(s):  
Platelet Aggregation ◽  
Arterial Thrombosis ◽  
Ex Vivo ◽  
Platelet Activity ◽  
Aggregation Assay ◽  
Thrombosis Model ◽  
Platelet Aggregation Assay

Objective: Although recent advances in the treatment of congestive heart disease, mortality among patients’ remains a questionable remark. Therefore, we evaluated the role of capsaicin on in vitro and ex vivo platelet aggregation induced by Adenosine Di-Phosphate (ADP) as well as in in vivo thrombosis models and role of NO, KATP was also identified in the capsaicin-induced anti-platelet animal model as well as in vivo model of arterial thrombosis.Methods: According to body weight wistar rats were divided into five groups. Group I and Group II was treated with saline and capsaicin (3 mg/kg, i. v), while animals from Group III were treated with N(ω)-nitro-L-arginine methyl ester (L-NAME) (30 mg/kg, i. v) 30 min before administration of capsaicin (3 mg/kg, i. v). Group IV animals were treated with glibenclamide (10 mg/kg,i. v) 30 min before administration of capsaicin (3 mg/kg, i. v). Group V was considered as a positive control and administered clopidogrel (30 mg/kg, p. o). Animals were subjected for in vitro, ex-vivo platelet aggregation assay. ADP (30µM) was utilized as an aggregating agent in these experiments. After these assays; animals of each group were subjected for subaqueous tail bleeding time in a rat model and FeCl3-induced arterial thrombosis model in rats.Results: In ADP-induced in vitro platelet aggregation, a significant reduction in % platelet aggregation was observed at 50µM (64.35±4.641) and 100µM (52.72±4.192) concentration of capsaicin as compared to vehicle control (85.82±3.716). Capsaicin (3 mg/kg, i. v) also showed a significant reduction (49.53±4.075) in ex-vivo ADP-induced platelet aggregation as compared to vehicle control (89.38±2.057). In FeCl3 induced arterial thrombosis model, Capsaicin (3 mg/kg, i. v) exhibited an increase in time to occlusion in this rodent model and presence of the L-NAME and glibenclamide had inhibited the activity of capsaicin.Conclusion: In our study, capsaicin (50 µM, 100µM) exhibited potent anti-platelet activity in ADP-induced platelet aggregation, similarly capsaicin exhibited significant anti-platelet action in the ex-vivo study. Moreover, the presence of L-NAME and glibenclamide inhibited the anti-thrombotic and anti-platelet action of capsaicin. Therefore, it was concluded that NO and KATP may be involved in the anti-thrombotic action of capsaicin.

scholarly journals Lipid Receptor GPR31 (G-Protein–Coupled Receptor 31) Regulates Platelet Reactivity and Thrombosis Without Affecting Hemostasis

2020 ◽  
Author(s):  
Layla Van Doren ◽  
Nga Nguyen ◽  
Christopher Garzia ◽  
Elizabeth Fletcher ◽  
Ryan Stevenson ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Carotid Artery ◽  
G Protein ◽  
Arterial Thrombosis ◽  
Platelet Reactivity ◽  
Human Platelets ◽  
Calcium Flux ◽  
G Protein Coupled Receptor ◽  
Carotid Artery Injury ◽  
G Protein Coupled

Objective: 12-LOX (12-lipoxygenase) produces a number of bioactive lipids including 12(S)-HETE that are involved in inflammation and platelet reactivity. The GPR31 (G-protein–coupled receptor 31) is the proposed receptor of 12(S)-HETE; however, it is not known whether the 12(S)-HETE-GPR31 signaling axis serves to enhance or inhibit platelet activity. Approach and Results: Using pepducin technology and biochemical approaches, we provide evidence that 12(S)-HETE-GPR31 signals through Gi to enhance PAR (protease-activated receptor)-4–mediated platelet activation and arterial thrombosis using both human platelets and mouse carotid artery injury models. 12(S)-HETE suppressed AC (adenylyl cyclase) activity through GPR31 and resulted in Rap1 and p38 activation and low but detectable calcium flux but did not induce platelet aggregation. A GPR31 third intracellular (i3) loop–derived pepducin, GPR310 (G-protein–coupled receptor 310), significantly inhibited platelet aggregation in response to thrombin, collagen, and PAR4 agonist, AYPGKF, in human and mouse platelets but relative sparing of PAR1 agonist SFLLRN in human platelets. GPR310 treatment gave a highly significant 80% protection ( P =0.0018) against ferric chloride–induced carotid artery injury in mice by extending occlusion time, without any effect on tail bleeding. PAR4-mediated dense granule secretion and calcium flux were both attenuated by GPR310. Consistent with these results, GPR310 inhibited 12(S)-HETE–mediated and PAR4-mediated Rap1-GTP and RASA3 translocation to the plasma membrane and attenuated PAR4-Akt and ERK activation. GPR310 caused a right shift in thrombin-mediated human platelet aggregation, comparable to the effects of inhibition of the Gi-coupled P2Y 12 receptor. Co-immunoprecipitation studies revealed that GPR31 and PAR4 form a heterodimeric complex in recombinant systems. Conclusions: The 12-LOX product 12(S)-HETE stimulates GPR31-Gi–signaling pathways, which enhance thrombin-PAR4 platelet activation and arterial thrombosis in human platelets and mouse models. Suppression of this bioactive lipid pathway, as exemplified by a GPR31 pepducin antagonist, may provide beneficial protective effects against platelet aggregation and arterial thrombosis with minimal effect on hemostasis.

scholarly journals Pharmacology and therapeutic uses of antiplatelet drugs

2020 ◽  
pp. 101-104
Author(s):  
E Osuch ◽  
TL Rasakanya
Keyword(s):  
Platelet Aggregation ◽  
Arterial Thrombosis ◽  
Antiplatelet Agents ◽  
Clot Formation ◽  
Antiplatelet Drugs ◽  
Appropriate Use ◽  
Pharmacological Management ◽  
Risks And Benefits ◽  
Therapeutic Uses

Antiplatelet agents prevent clot formation and growth through prevention of platelet aggregation. Antiplatelet agents are essential for the prophylaxis and pharmacological management of arterial thrombosis. Appropriate use of these agents requires knowledge of their pharmacology and therapeutic uses with appropriate assessment of risks and benefits.

scholarly journals Microbial enzymes induce colitis by reactivating triclosan in the mouse gastrointestinal tract

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Jianan Zhang ◽  
Morgan E. Walker ◽  
Katherine Z. Sanidad ◽  
Hongna Zhang ◽  
Yanshan Liang ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Metabolic Activation ◽  
Consumer Products ◽  
Environmental Chemicals ◽  
Intestinal Microbes ◽  
Targeted Inhibition

AbstractEmerging research supports that triclosan (TCS), an antimicrobial agent found in thousands of consumer products, exacerbates colitis and colitis-associated colorectal tumorigenesis in animal models. While the intestinal toxicities of TCS require the presence of gut microbiota, the molecular mechanisms involved have not been defined. Here we show that intestinal commensal microbes mediate metabolic activation of TCS in the colon and drive its gut toxicology. Using a range of in vitro, ex vivo, and in vivo approaches, we identify specific microbial β-glucuronidase (GUS) enzymes involved and pinpoint molecular motifs required to metabolically activate TCS in the gut. Finally, we show that targeted inhibition of bacterial GUS enzymes abolishes the colitis-promoting effects of TCS, supporting an essential role of specific microbial proteins in TCS toxicity. Together, our results define a mechanism by which intestinal microbes contribute to the metabolic activation and gut toxicity of TCS, and highlight the importance of considering the contributions of the gut microbiota in evaluating the toxic potential of environmental chemicals.

scholarly journals Cysteine sulfenylation by CD36 signaling promotes arterial thrombosis in dyslipidemia

2020 ◽  
Vol 4 (18) ◽  
pp. 4494-4507 ◽  
Author(s):  
Moua Yang ◽  
Wei Li ◽  
Calvin Harberg ◽  
Wenjing Chen ◽  
Hong Yue ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Hydrogen Peroxide ◽  
Platelet Aggregation ◽  
Platelet Activation ◽  
Arterial Thrombosis ◽  
Reactive Oxygen ◽  
Src Family Kinases ◽  
Oxygen Species ◽  
Carbon Nucleophiles ◽  
Platelet Proteins

Abstract Arterial thrombosis in the setting of dyslipidemia promotes clinically significant events, including myocardial infarction and stroke. Oxidized lipids in low-density lipoproteins (oxLDL) are a risk factor for athero-thrombosis and are recognized by platelet scavenger receptor CD36. oxLDL binding to CD36 promotes platelet activation and thrombosis by promoting generation of reactive oxygen species. The downstream signaling events initiated by reactive oxygen species in this setting are poorly understood. In this study, we report that CD36 signaling promotes hydrogen peroxide flux in platelets. Using carbon nucleophiles that selectively and covalently modify cysteine sulfenic acids, we found that hydrogen peroxide generated through CD36 signaling promotes cysteine sulfenylation of platelet proteins. Specifically, cysteines were sulfenylated on Src family kinases, which are signaling transducers that are recruited to CD36 upon recognition of its ligands. Cysteine sulfenylation promoted activation of Src family kinases and was prevented by using a blocking antibody to CD36 or by enzymatic degradation of hydrogen peroxide. CD36-mediated platelet aggregation and procoagulant phosphatidylserine externalization were inhibited in a concentration-dependent manner by a panel of sulfenic acid–selective carbon nucleophiles. At the same concentrations, these probes did not inhibit platelet aggregation induced by the purinergic receptor agonist adenosine diphosphate or the collagen receptor glycoprotein VI agonist collagen-related peptide. Selective modification of cysteine sulfenylation in vivo with a benzothiazine-based nucleophile rescued the enhanced arterial thrombosis seen in dyslipidemic mice back to control levels. These findings suggest that CD36 signaling generates hydrogen peroxide to oxidize cysteines within platelet proteins, including Src family kinases, and lowers the threshold for platelet activation in dyslipidemia.

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